Surgery – Diagnostic testing – Liquid collection
Reexamination Certificate
2001-07-30
2004-01-06
Marmor, Charles (Department: 3736)
Surgery
Diagnostic testing
Liquid collection
C600S584000, C604S028000
Reexamination Certificate
active
06673024
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The field of this invention is evaluating human breast duct epithelial cells by cytology to identify breast cancer and breast precancer.
2. Description of the Background Art
Breast cancer is believed to originate in the lining of a single breast milk duct in the breast; and additionally human breasts are believed to contain from 6 to 9 of these ducts. See Sartorius,
JAMA
224 (6): 823-827 (1973). For several decades significant members of the medical community dedicated to studying breast cancer have believed and shown that the cytological analysis of cells retrieved from nipple discharge from the breast milk ducts can provide valuable information leading to identifying patients at risk for breast cancer. Indeed, Papanicolaou contributed to the genesis of such a possibility of a “Pap” smear for breast cancer by analyzing the cells contained in nipple discharge. See Papanicolaou et al, “Exfoliative Cytology of the Human Mammary Gland and Its Value in the Diagnosis of Cancer and Other Diseases of the Breast” Cancer (1958) March/April 377-409. See also Petrakis, “Physiological, biochemical, and cytological aspects of nipple aspirate fluid”,
Breast Cancer Research and Treatment
1986; 8:7-19; Petrakis, “Studies on the epidemiology and natural history of benign breast disease and breast cancer using nipple aspirate fluid”
Cancer Epidemiology, Biomarkers and Prevention
(January/February 1993) 2:3-10; Petrakis, “Nipple Aspirate Fluid in epidemiological studies of breast disease”,
Epidemiologic Reviews
(1993) 15:188-195. More recently, markers have also been detected in nipple fluid. See Sauter et al, “Nipple aspirate fluid: a promising non-invasive method to identify cellular markers of breast cancer risk”,
British Journal of Cancer
76(4):494-501 (1997). The detection of CEA in fluids obtained by a nipple blot is described in Imayama et al. (1996)
Cancer
78: 1229-1234.
Despite a long history of nipple aspirate fluid and corresponding cytology, questions have remained about the validity and use of nipple aspirate cytology either for making a diagnosis of breast cancer or breast precancer, or for the correlative value of nipple aspirate fluid cytology to histological and pathological readings from a tissue sample or fine needle aspirate (FNA) cytological readings of the same breast.
Random fine needle aspiration (FNA) of breast tissue has been used to detect lesions in the breast, Fabian et al,
J Cell Biochem Suppl
1997; 28-29: 101-10, using cytological analysis of material retrieved from breast by fine needle aspiration. Sample from FNA can be evaluated by a uniform scheme as detailed in
Amer. J. Surg,
1997; 174:371-385. FNA as preformed on the breast has several drawbacks. Usually several punctures with an aspiration needle are needed to locate a target lesion; tracks are created with the withdrawal of cancerous cells through the breast with a coordinate risk of spreading the cancer cells to the blood stream along the tracks; scarring can occur at the sites of entry; the punctures can be painful; multiple punctures can result in a sore breast for a time after the procedure; often multiple entries are needed to locate a lesion that provides a positive sample.
Otto Sartorius starting about the mid-1970s obtained some amount of ductal fluid. He accomplished this using a hair thin catheter to infuse saline in the duct, removing the catheter and squeezing the breast or aspirating the nipple surface to get small fluid amounts from the surface. Ductal “washings” have also been reporter by Susan Love in Love & Barsky, (1996)
Lancet
348: 997-999. Susan Love used a catheter to infuse fluid into a breast duct, then removed the catheter after infusing about 1.5 ml of saline, and collected resulting expressed fluid by squeezing the breast and collecting the “washings” from the nipple surface with a capillary tube.
So described previous attempts at obtaining ductal fluid including nipple aspiration at the nipple surface, either with or without first infusing fluid into the duct, and early attempts at obtaining fluid oozing from the nipple surface after removing the fluid infusion catheter from the duct post fluid infusion have been found inadequate to obtain sufficient cellular yields for a cytological analysis. These samples were not found to be a consistent, uniform, and respected diagnostic tool of breast cancer. Such cytological results, so obtained, have remained ancillary and supportive of other diagnosis (e.g. such as FNA, histology by biopsy, lumpectomy or mastectomy, mammography) and have not been respected as diagnostic information that can stand alone.
The deficiencies of previous nipple aspirate fluid cytology can be mainly attributed to the fact that cellular yields of nipple aspirate fluid are much lower than ductal lavage cell yields when ductal lavage is performed and fluid is retrieved with an indwelling catheter. Petrakis reports that in his studies of some thousands of women over a 20 year study that his average cell yield is about 100 cells per breast, and often less than that using one of the above-mentioned techniques. In a recent clinical trial of about 500 women on whom nipple aspirate fluid was collected prior to ductal lavage with an indwelling catheter, the median number of ductal epithelial cells collected by nipple aspiration was about 120 cells per breast. In addition, samples collected by nipple aspiration tend to yield individual cells, and aggregates or groups of cells of less than 10 cells per aggregate, often less than 5 cells per aggregate, where such groups are collected. Likewise cell yields from these methods using a catheter for fluid infusion of about 1.5 ml of wash fluid, and where the catheter is withdrawn prior to collection of any expressed fluid on the nipple surface, have not yielded cell counts much improved from traditional nipple aspiration.
In contrast, cell yields from ductal lavage samples from infusion of total fluid amounts greater than 2 ml of wash fluid per duct, often greater than 5 ml of wash fluid, commonly as much as in the range from about 10 ml to about 50 ml of wash fluid, and in some cases greater than 50 ml of wash fluid during a lavage procedure on one breast duct where the cells and wash fluid collected are collected while the catheter remains in place in the duct during the procedure have been often greater than 500 cells, commonly from 1000 to 10,000 cells per breast duct, or more per breast duct. In the first trial conducted of its kind with 500 women using a ductal access tool for ductal lavage that permitted infusion of fluid into the breast duct and collection of the fluid mixed with cells while the tool remained in the duct, the mean number of ductal epithelial cells retrieved by ductal lavage was about 40,000 cells/duct and the median number of cells retrieved was about 13,500 cells/duct.
In addition, the cells retrieved by ductal lavage using the methodology of infusion of fluid volumes greater than about 2 ml of saline (e.g. up to about 50 ml or more of fluid during the entire lavage procedure on single duct) and retrieval of the ductal fluid through the lumen of an indwelling catheter, resulted in not only more and larger clumps or clusters of cells, but larger numbers of cells per clump or cluster. Typically, and previously, nipple aspiration yielded clusters or clumps of less than 5 cells per cluster (when clusters are retrieved) and ductal lavage yields clusters or clumps of 10 or more cells per cluster or clump, and substantial numbers of these clumps or clusters. The advantage to cytological readings of clumps or clusters is that they give a cytologist yet another desirable context for relationships between the cells. This context can provide advantages similar to the context derived from a histological analysis where the cells remain in the architecture of the original tissue. The potential for frequent retrieval of cell clumps greater than about 5 cells per clump, especially greater than 10 cells per clump, is a phenomenon not seen in ductal e
Chew Karen
Ljung Britt-Marie
Soito Angela
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