Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Diagnostic or test agent produces visible change on skin
Reexamination Certificate
1998-09-15
2002-09-24
Devi, S. (Department: 1645)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Diagnostic or test agent produces visible change on skin
C424S009600, C424S009100, C435S007100, C435S007230, C436S543000, C604S028000, C604S058000, C604S104000
Reexamination Certificate
active
06455027
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to medical methods and devices for accessing body lumens and in particular to methods and apparatus for identifying ductal orifices in human breasts and accessing the ducts through the identified orifices.
Breast cancer is the most common cancer in women, with well over 100,000 new cases being diagnosed each year. Even greater numbers of women, however, have symptoms associated with breast diseases, both benign and malignant, and must undergo further diagnosis and evaluation in order to determine whether breast cancer exists. To that end, a variety of diagnostic techniques have been developed, the most common of which are surgical techniques including core biopsy and excisional biopsy. Recently, fine needle aspiration (FNA) cytology has been developed which is less invasive than the surgical techniques, but which is not always a substitute for surgical biopsy.
A variety of other diagnostic techniques have been proposed for research purposes. Of particular interest to the present invention, fluids from the breast ducts have been externally collected, analyzed, and correlated to some extent with the risk of breast cancer. Such fluid collection, however, is generally taken from the surface of the nipple and represents fluid from the entire ductal structure or from a single duct which is spontaneously discharging. In either case, information on the condition of a preselected individual duct is generally not provided. Information on individual ducts can be obtained through cannulation and endoscopic examination, but such examinations have been primarily in women with nipple discharge or for research purposes and have generally not provided for examination of each individual duct in the breast.
Since breast cancer usually arises from a single ductal system and exists in a precancerous state for a number A of years, endoscopy in and fluid collection from individual breast ducts holds great diagnostic and therapeutic promise. Much of the promise, however, cannot be realized until identification of and access to each and every duct in a patient's breast can be assured. Presently, ductal access may be obtained by a magnification of the nipple and identification of ductal orifice(s) using conventional medical magnifiers, such as magnification loupes. While such magnified examination is relatively simple, it cannot be relied on to identify all orifices. Moreover, the ductal orifices can be confused with other tissue structures, such as sebaceous glands and simple keratin-filled caruncles of the nipple. Thus, before ductal techniques can be further developed for diagnosis, therapy, research, or other purposes, it will be useful to provide methods and apparatus which facilitate identification of ductal orifices to distinguish them from other nipple surface features, and allow subsequent ductal access in selected and/or all ducts in each breast.
2. Description of the Background Art
Publications by the inventors herein relating to breast duct access include Love and Barsky (1996) Lancet 348: 997-999; Love (1992) “Breast duct endoscopy: a pilot study of a potential technique for evaluating intraductal disease,” presented at 15th Annual San Antonio Breast Cancer Symposium, San Antonio, Tex., Abstract 197; Barsky and Love (1996) “Pathological analysis of breast duct endoscoped mastectomies,” Laboratory Investigation, Modern Pathology, Abstract 67. A description of the inventors' breast duct access work was presented in Lewis (1997) Biophotonics International, pages 27-28, May/June 1997.
Nipple aspiration and/or the introduction of contrast medium into breast ducts prior to imaging are described in Sartorius (1995) Breast Cancer Res. Treat. 35: 255-266; Satorious et al. (1977) “Contrast ductography for the recognition and localization of benign and malignant breast lesions: An improved technique,” in: Logan (ed.), Breast Carcinoma, New York, Wiley, pp. 281-300; Petrakis (1993) Cancer Epidem. Biomarker Prev. 2: 3-10; Petrakis (1993) Epidem. Rev. 15: 188-195; Petrakis (1986) Breast Cancer Res. Treat. 8: 7-19; Wrensch et al. (1992) Am. J. Epidem. 135: 130-141; Wrensch et al. (1990) Breast Cancer Res. Treat. 15: 39-51; and Wrensch et al. (1989) Cancer Res. 49: 2168-2174. The presence of abnormal biomarkers in fine needle breast aspirates is described in Fabian et al. (1993) Proc. Ann. Meet. Am. Assoc. Cancer Res. 34: A1556. The use of a rigid 1.2 mm ductoscope to identify intraductal papillomas in women with nipple discharge is described in Makita et al. (1991) Breast Cancer Res. Treat. 18: 179-188. The use of a 0.4 mm flexible scope to investigate nipple discharge is described in Okazaki et al. (1991) Jpn. J. Clin. Oncol. 21: 188-193. The detection of CEA in fluids obtained by a nipple blot is described in Imayama et al. (1996) Cancer 78: 1229-1234. Delivery of epithelium-destroying agents to breasts by ductal cannulation is described in WO 97/05898.
SUMMARY OF THE INVENTION
The present invention provides improved methods, kits, and other apparatus for locating breast ducts in the breasts of human patients. In particular, the methods of the present invention permit reliable identification of the orifices within the nipple of a breast, where individual orifices lead to each of the multiple ductal networks within the breast. By reliably identifying each orifice, all of the ductal networks can be located and subsequently accessed for diagnostic, risk assessment, therapeutic, research, or other purposes.
Broadly, the present includes a wide variety of techniques for transiently marking and locating individual orifices in a nipple of a breast, usually a human breast. By “marking,” it is meant that a substance, label, energy, or stimulus is applied to the nipple to cause labelling, a reaction, or other response which permits or enhances distinguishing an orifice from surrounding tissue in the nipple. Usually, but not necessarily, the methods will result in the marking of all orifices in a nipple to permit subsequent access to all or selected one(s) of the ductal networks associated with the orifices. The marking will be “transient,” e.g. will not be permanent but instead will remain visible or otherwise detectable for a time sufficient to permit subsequent access to the associated ductal lumens, usually for a period of at least 15 minutes, preferably for about 1 to 2 hours. For the most part, the present invention will rely on introducing a detectable substance, such as a labelling reagent, dye, or the like, to the nipple so that the substance localizes and/or accumulates at or near the orifice to permit visual, automated, or other detection. Alternatively, the present invention can utilize other stimuli for inducing a response, change, or reaction at or near a location of the orifice in the nipple. For example, it may be possible to illuminate the nipple with certain light or other energies which help distinguish between the orifice and other tissue surfaces. It may also be possible to introduce chemical reagents which react with ductal secretions at the orifice to enhance visibility e.g. to produce a visible or otherwise detectable reaction product.
In a first aspect of the present invention, a method for locating an orifice of a breast duct comprises labelling ductal cells disposed at the ductal orifice with a visible or otherwise detectable label. The orifice may then be located based on the presence of the label at the orifice. Specific and preferred methods for labeling the orifices are described below in connection with a second aspect of the present invention. After the orifices have been located, an access device, such as a guidewire, catheter or fiberoptic viewing scope, can be introduced through at least one of the orifices and into the associated breast duct. The method may further comprise introducing the same or a different access device through other orifices, often into each of the orifices to permit diagnosis, treatment, or other evaluation of all of the ductal networks of a breast.
An
Alpaugh Mary L.
Barsky Sanford H.
Love Susan M.
Devi S.
Gates & Cooper LLP
The Regents of the University of California
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