Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-15
2004-04-20
Padmanabhan, Sreeni (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C424S009400, C424S009430, C424S009440
Reexamination Certificate
active
06723746
ABSTRACT:
BACKGROUND OF THE INVENTION
A. Field of the Invention
This invention relates to medical imaging and specifically to methods for functional radiographic imaging, and imaging agents.
B. Description of the Related Art
Radiography involves examination of internal organs of the body by transillumination with X-rays. The image receptor may be radiographic film, a film/intensifying screen combination, a stimulable phosphor storage plate, a fluoroscopic image intensifier, an amorphous silicon sensor array, a CCD/scintillator combination, or another type of X-ray sensitive receptor. In digital radiography, a computer digitizes the acquired image and may enhance it using image processing algorithms. The most commonly performed radiographic procedures include mammography, in which images of the breast are generated to detect breast cancer, and thoracic radiography, in which images of the lungs and heart are generated to detect a variety of diseases, including lung cancer.
A major goal of radiography is the reliable detection of malignant tissue and its accurate differentiation from non-malignant tissue. In current practice, the radiologist decides whether tissue is malignant, benign or normal solely by visual inspection of the radiograph. The appearance of tissue on a radiograph mainly depends on the degree to which the transilluminating X-ray beam is attenuated during its traversal of the different areas of the tissue being examined. However, it has been repeatedly demonstrated that the visual appearance of tissue on the radiograph is not a reliable criterion for definitive diagnosis of malignancy.
Studies confirm a high error rate in the radiological diagnosis of cancer. These errors fall into two categories: false positives and false negatives. A false positive, also called an error in specificity, occurs when a radiograph is judged to display malignant tissue that ultimately proves benign. A false negative, also called an error in sensitivity, occurs when malignant tissue actually present is not detected on the radiograph.
One of the most commonly performed radiographic procedures is mammography, in which the breasts are examined for evidence of cancer. Approximately 25 million primary screening mammograms are performed annually in the United States. However, the high incidence of false positives and false negatives reduces the reliability of mammography as a diagnostic tool.
The major sources of false positives on mammograms are cysts and fibroadenomas. Cysts are benign fluid-filled tissue structures that may often be present in an otherwise normal breast. Fibroadenomas are benign growths of tissue that may also be present in a normal breast. Both types of structures may feel lumpy during palpation by the patient or a physician, and may thus resemble malignant tumors in a physical examination. In addition, both cysts and fibroadenomas appear as areas of decreased radiographic density on mammograms. Their radiographic appearance can closely resemble that of malignant tumors, which also appear as areas of decreased density.
According to various published studies, between 6% and 13% of primary screening mammograms manifest radiographic evidence of possible malignancy, but of these positive or suspicious results, approximately 80% are ultimately diagnosed as benign [Elmore J G et al.: N. Eng. J. Med. 338: 1089-1096 (1998)]. However, as previously noted, it is currently impossible to reliably differentiate malignant from benign tissue solely by visual inspection of the mammogram. Consequently, the majority of patients with positive primary results require further diagnostic procedures, including additional mammograms and excisional (surgical) or needle biopsies. Secondary diagnostic workups that include biopsies usually cost between $1500-3000. In addition to increased cost, biopsies carry the risk of infection, scarring, pain, and anxiety.
Thus, a method for more accurate differentiation of malignant tissue from benign and normal tissue on mammograms would eliminate the need for many of the biopsies now performed, decreasing procedure cost and patient morbidity.
A more serious problem in diagnostic mammography is the high incidence of false negatives, in which malignant tumors that are actually present are not detected on the mammogram. Missed tumors may be detected months or years later on a subsequent mammogram or by palpation. During this interval the tumor may grow larger and, in the worst case, metastasize. Various published studies on diagnostic accuracy in mammography report a false negative rate of between 8% and 24% [van Dijck J A et al.: Cancer 72: 1933-1938 (1993); Bird R E et al.: Radiol. 184: 613-617 (1992); Wallis M G et al.: Clin. Radiol. 44: 13-15 (1991)]. Particularly in their early stages of development, malignant tumors may not be noticed even upon careful inspection of the mammogram by an experienced radiologist. Tumors may be too small to be detected, or their appearance may be obscured by benign tumors or cysts. The visibility of malignant tumors may be further obscured in younger women, whose breast tissue is often dense. As a consequence, the rate of false negatives in these women is even higher than in the general population.
It has reliably been demonstrated that the stage at which malignant breast tumors are detected is an important determinant of the effectiveness of therapy and of the patient's survival time. [Ries L A G et al. (eds): SEER Cancer Statistics Review, 1973-1995, National Cancer Institute (1998)].
The high incidence of missed cancers on mammograms suggests that there is a minimum size threshold for detection of malignant tumors using current radiographic methods, and that these tumors may be present in the body long before they are detected.
Thus, an improved method for visualization of small malignant tumors on mammograms would enable their earlier detection, enhance the effectiveness of therapy, and prolong patient survival time.
Similar diagnostic problems are common in thoracic radiography, in which radiographic imaging of the lungs and heart is performed to detect abnormal tissue, particularly malignant tumors. Over 16 million thoracic radiographs are performed annually in the United States. Approximately 3 of every 100 thoracic radiographs show evidence of small isolated masses in the lung. Approximately 50% of these masses, known as solitary pulmonary nodules, are benign. However, it is impossible to reliably differentiate malignant nodules from benign nodules solely by inspection of the radiograph. Definitive diagnosis of these nodules currently requires surgical resection or invasive biopsy. As in the case of breast biopsies, these procedures are expensive and add patient morbidity risk.
Thus, an improved method for differentiation of malignant tissue from benign and normal tissue on thoracic radiographs would reduce the large number of unnecessary follow-up procedures currently performed, decreasing cost and morbidity.
As in the case of mammography, false negatives in thoracic radiography lead to less effective therapy and shorter patient survival time. Particularly in their early stages of development, malignant lung tumors may not be detected even upon careful inspection of the radiograph. The early detection of lung cancer is of particular importance because the overall survival rate from the disease is very low. It has been repeatedly shown that the survival time of patients whose lung tumors are detected at an early stage in their development is much longer than that of patients whose tumors are detected in later stages [Ries L A G et al. (eds): SEER Cancer Statistics Review, 1973-1995, National Cancer Institute (1998)].
Thus, an improved method for visualization of small malignant lung tumors on thoracic radiographs would enable earlier detection of these tumors and prolong patient survival time.
Recognition of the current inadequacies of the radiographic art has led to attempts to develop more accurate methods for diagnostic imaging of cancer.
One commonly pursued approach to the imp
Cairns Nicholas
Salb Jesse
Padmanabhan Sreeni
Veritas Pharmaceuticals, Inc.
Wells Lauren Q.
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