Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
1998-05-05
2001-11-13
Smith, Ruth S. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C600S477000, C436S063000
Reexamination Certificate
active
06317624
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the detection of the margins of tumors.
BACKGROUND OF THE INVENTION
Approximately one million new skin tumors, e.g., non-melanoma and melanoma tumors, are diagnosed each year in the United States. The treatment for most such tumors involves excising the tumor and a region of the skin surrounding the tumor. This so-called peritumoral region may contain tumor cells which have spread locally beyond the observable tumor. In addition to tumor cells, the peritumoral region may also include stroma that has been altered by the cells of the tumor, e.g., by tumor-mediated breakdown of components of the extracellular matrix. To determine the optimal amount of skin to remove, the treating physician typically makes a crude estimate, based upon a visual inspection of the tumor, and removes a corresponding section of the skin.
If the peritumoral region is underestimated, there is the possibility of tumor recurrence from tumor cells lying outside the excised area. Conversely, if the tumor region is overestimated, an unnecessarily large area of skin can be removed, and there is the possibility of unnecessary discomfort and disfigurement to the patient.
For a more precise measurement of the peritumoral region, the treating physician may perform Mohs micrographic surgery (MMS), in which horizontal sections of the region surrounding the excised tumor are examined microscopically for the presence of tumor cells. If tumor cells are detected, then additional skin is removed. MMS can be technically complex and also time consuming because of the time required to process and analyze the samples.
SUMMARY OF THE INVENTION
The invention is based on the discovery that endogenous fluorescence at excitation wavelengths of about 340 to 400 nm is almost entirely suppressed within, and in the immediate vicinity of, basal and squamous cell carcinomas. Accordingly, the invention provides a method of non-invasively detecting the margins of skin tumors by monitoring suppression of dermal fluorescence.
In general, the invention features a method for detecting the margin of a tumor in a target tissue, e.g., skin containing a skin tumor, by (a) exposing the target tissue to incident radiation at a wavelength of about 340 to about 400 nm, e.g., 330 to 410 nm, 350 nm to 400 nm, 360 to 380 nm, or 365 to 375 nm, that induces normal tissue but not tumorous tissue to emit fluorescence; and (b) detecting fluorescence emitted upon irradiation with the incident ultraviolet radiation, wherein a decrease in fluorescence compared to fluorescence emitted from normal tissue indicates the margin of a tumor within the target tissue.
The method can be used on tissues such to as skin, where it can be used to diagnose skin tumors such as basal cell and squamous cell carcinomas.
The method can be carried out by measuring the target tissue in a patient, e.g., any mammal, e.g., a human, dog, cat, or horse, in vivo, or by excising the target tissue from a patient and measuring the tissue in vitro.
The invention also features a method for detecting the breakdown of cross-linked collagen fibers in a target tissue, e.g., skin, by (a) exposing the target tissue to incident radiation at a wavelength that induces normal tissue but not tissue containing non-crosslinked collagen to emit fluorescence; and (b) detecting fluorescence emitted upon irradiation with the incident radiation, wherein a decrease in fluorescence compared to fluorescence emitted from normal tissue indicates the breakdown of collagen fibers within the target tissue, e.g., as associated with a skin tumor, skin atrophy, or with the formation of scar tissue.
In another aspect, the invention features an apparatus for detecting the margin of a tumor in a target tissue. The apparatus includes (a) an ultraviolet light source that irradiates the target tissue at a wavelength, e.g., 340 to 410 nm, that induces normal tissue but not tumorous tissue to emit fluorescence; (b) a detector to detect fluorescence emitted from the irradiated target tissue, e.g., at a wavelength of 420 to 480 nm, wherein a decrease in fluorescence compared to fluorescence emitted from normal tissue indicates the margin of a tumor within the target tissue; and (c) an element for suppressing blood flow in an irradiated area. The element can be an optical element e.g., a concave optical element.
By “tumor margin” is meant the region surrounding a tumor in which the stroma has been altered by the tumor. The tumor margin thus includes tumor cells that have grown beyond the edge of the tumor visible to the naked eye and also stromal regions that have been altered due to the presence of the tumor.
The invention has many advantages. In particular, the new methods provide a non-invasive, rapid, and accurate way to determine tumor margins. In addition, the methods provide a way for rapidly identifying the margin of a tumor in unstained histological sections of fresh tissue specimens in vitro, such as those obtained in MMS.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
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Fallon Jerome D.
Fewkes Jessica L.
Flotte Thomas J.
Kollias Nikiforos
Fish & Richardson P.C.
Smith Ruth S.
The General Hospital Corporation
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