CA2167179C - Examination of breast tissue using time-resolved spectroscopy - Google Patents
Examination of breast tissue using time-resolved spectroscopy Download PDFInfo
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- CA2167179C CA2167179C CA2167179A CA2167179A CA2167179C CA 2167179 C CA2167179 C CA 2167179C CA 2167179 A CA2167179 A CA 2167179A CA 2167179 A CA2167179 A CA 2167179A CA 2167179 C CA2167179 C CA 2167179C
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
- A61B5/0082—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes
- A61B5/0091—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes for mammography
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
- A61B5/14551—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters for measuring blood gases
- A61B5/14552—Details of sensors specially adapted therefor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/43—Detecting, measuring or recording for evaluating the reproductive systems
- A61B5/4306—Detecting, measuring or recording for evaluating the reproductive systems for evaluating the female reproductive systems, e.g. gynaecological evaluations
- A61B5/4312—Breast evaluation or disorder diagnosis
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
- G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
- G01J3/28—Investigating the spectrum
- G01J3/2889—Rapid scan spectrometers; Time resolved spectrometry
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/47—Scattering, i.e. diffuse reflection
- G01N21/49—Scattering, i.e. diffuse reflection within a body or fluid
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/59—Transmissivity
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N2021/1789—Time resolved
- G01N2021/1791—Time resolved stroboscopic; pulse gated; time range gated
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/47—Scattering, i.e. diffuse reflection
- G01N21/4795—Scattering, i.e. diffuse reflection spatially resolved investigating of object in scattering medium
- G01N2021/4797—Scattering, i.e. diffuse reflection spatially resolved investigating of object in scattering medium time resolved, e.g. analysis of ballistic photons
Abstract
A method and a system (4) for breast tissue examination includes a time-resolved spectroscopy apparatus (20; 20A; 20B), a support (8; 9;
11; 12; 13) with an input port (14) and an output port (16) separated by a selected distance is positioned relative to the examined breast. A light source (32; 34; 60) generates pulses of electromagnetic radiation of a selected wavelength in the visible or infrared range. The pules are introduced into the breast tissue at the input port (14) and detected over time at the output port (16). Signals corresponding to photons of detected modified pulses are accumulated over time. Values of the scattering coefficient or the absorption coefficient of the examined breast tissue are calculated based on the shape of the modified pulses.
The examined breast tissue is characterized based on the values of the scattering coefficient or the absorption coefficient.
11; 12; 13) with an input port (14) and an output port (16) separated by a selected distance is positioned relative to the examined breast. A light source (32; 34; 60) generates pulses of electromagnetic radiation of a selected wavelength in the visible or infrared range. The pules are introduced into the breast tissue at the input port (14) and detected over time at the output port (16). Signals corresponding to photons of detected modified pulses are accumulated over time. Values of the scattering coefficient or the absorption coefficient of the examined breast tissue are calculated based on the shape of the modified pulses.
The examined breast tissue is characterized based on the values of the scattering coefficient or the absorption coefficient.
Description
WO 95/02987 11,'1'/US94/07984 -z-FAM 1.N_AT_19N Q_f' _$R.F.AST_'.i',1 S S f~F
~$.~.~ ",~~~.F?~$Q~VEU SPEC:'I'RQSCOPY
~~c~cgroyDd o~tiie v_entJpn The inventioti featur.es a time-resolved spectroscopic method and apparatus for breast tissue examinatiori .
Breast cancer is among the most common and the most feared malignancies in women. It has an unpredictable course, the treatment is frequently physically and emotionally drainitig and the risk of metastatic spread persists for mariy years. Due to its high occurrence rate, routine breast cancer screening, which includes physical examination and x-ray mammography, plays an important role in current health care. X-ray mammography can detect over 90% of all masses and increases ttie 10-year survival rate to about 95% for patients with cancers solely detected by mammography. Although the modern mammography uses a low-dose of x-rays, it still involves some small risk of inducing cancers by the radiation. other tests, such as magnetic resonance 3..maging (MRI) and gadolinium enhanced MRI, have been used successfully for detection of breast tumors atid may be used routinely for screening in ttie future.
After a small suspicious mass is detected in the breast non-itivasively, an e1rrisionaJ b:Lopsy is usually performed to exclude or diagnose malignancy. The biopsy specimen is removed under local anesthesia and is used for histopathological diagnosis. Ttie statistics show that in about 75% of the excisional biopsies; the biopsied tissue is diagnosed to be ben.i.gn. Thus, a majority of patients undergoes this unpleasant and costly procedure unnecessar-il.y. Fur.-ttierinorP, it has beeti ~
~$.~.~ ",~~~.F?~$Q~VEU SPEC:'I'RQSCOPY
~~c~cgroyDd o~tiie v_entJpn The inventioti featur.es a time-resolved spectroscopic method and apparatus for breast tissue examinatiori .
Breast cancer is among the most common and the most feared malignancies in women. It has an unpredictable course, the treatment is frequently physically and emotionally drainitig and the risk of metastatic spread persists for mariy years. Due to its high occurrence rate, routine breast cancer screening, which includes physical examination and x-ray mammography, plays an important role in current health care. X-ray mammography can detect over 90% of all masses and increases ttie 10-year survival rate to about 95% for patients with cancers solely detected by mammography. Although the modern mammography uses a low-dose of x-rays, it still involves some small risk of inducing cancers by the radiation. other tests, such as magnetic resonance 3..maging (MRI) and gadolinium enhanced MRI, have been used successfully for detection of breast tumors atid may be used routinely for screening in ttie future.
After a small suspicious mass is detected in the breast non-itivasively, an e1rrisionaJ b:Lopsy is usually performed to exclude or diagnose malignancy. The biopsy specimen is removed under local anesthesia and is used for histopathological diagnosis. Ttie statistics show that in about 75% of the excisional biopsies; the biopsied tissue is diagnosed to be ben.i.gn. Thus, a majority of patients undergoes this unpleasant and costly procedure unnecessar-il.y. Fur.-ttierinorP, it has beeti ~
- 2 -suggested that the excisional biopsy may cause spreading of the malignant tumor cells.
Therefore, a non-invasive, relatively inexpensive technique that can detect and characterize breast tumors may find its place in today's health care, alone or in conjunction with the above-mentioned techniques.
Summary of the Invention The invention features a system and a method for breast tissue examination using time-resolved spectroscopy.
In general, in one aspect, the method includes the following steps. A support that includes an input port and an output port separated by a selected distance is positioned relative to the examined breast. Locations of the input and output ports are selected to examine a tissue region of the breast. Light pulses of a selected wavelength and duration less than a nanosecond are introduced into the breast tissue at the input port and detected over time at the detection port. Signals corresponding to photons of detected modified pulses are accumulated over the arrival time of detected photons.
Values of a scattering coefficient or an absorption coefficient of the examined breast tissue are calculated based on the shape of the modified pulses. The examined breast tissue is characterized based on the values of the scattering coefficient or the absorption coefficient.
In general, in another aspect, the method includes the following steps. A support that includes an input port and an output port separated by a selected distance is positioned relative to the examined breast.
Locations of the input and output ports are selected to examine a tissue region of the breast. Light pulses of a selected wavelength and duration less than a nanosecond are introduced into the breast tissue at the input port and detected over time at the detection port. Signals
Therefore, a non-invasive, relatively inexpensive technique that can detect and characterize breast tumors may find its place in today's health care, alone or in conjunction with the above-mentioned techniques.
Summary of the Invention The invention features a system and a method for breast tissue examination using time-resolved spectroscopy.
In general, in one aspect, the method includes the following steps. A support that includes an input port and an output port separated by a selected distance is positioned relative to the examined breast. Locations of the input and output ports are selected to examine a tissue region of the breast. Light pulses of a selected wavelength and duration less than a nanosecond are introduced into the breast tissue at the input port and detected over time at the detection port. Signals corresponding to photons of detected modified pulses are accumulated over the arrival time of detected photons.
Values of a scattering coefficient or an absorption coefficient of the examined breast tissue are calculated based on the shape of the modified pulses. The examined breast tissue is characterized based on the values of the scattering coefficient or the absorption coefficient.
In general, in another aspect, the method includes the following steps. A support that includes an input port and an output port separated by a selected distance is positioned relative to the examined breast.
Locations of the input and output ports are selected to examine a tissue region of the breast. Light pulses of a selected wavelength and duration less than a nanosecond are introduced into the breast tissue at the input port and detected over time at the detection port. Signals
- 3 -corresponding to photons of detected modified pulses are integrated over at least two selected time intervals separately spaced over the arrival time of the modified pulses. A value of an absorption coefficient of the examined breast tissue is calculated based on the shape of the modified pulses. The examined breast tissue is characterized based on the value of the absorption coef f icient .
In this aspect, the method may include further steps. The detected photons are integrated over other selected time intervals separately spaced over the arrival time of the modified pulses. Time dependence of the light intensity is determined based on the number of photons integrated over each time interval, and a value of a scattering coefficient of the examined breast tissue is determined. The examined breast tissue is characterized based on the value of the scattering coefficient.
Preferred methods use the above-described steps and additional steps as follows.
The input port and the output port are moved to a different location to examine another tissue region of the breast. Values of the scattering coefficient or absorption coefficient are again determined by repeating the above-described steps for the newly selected tissue region. The tissue region is characterized using the additional values of the scattering coefficient or the absorption coefficient.
The above-described steps are performed over several tissue regions to examine the entire breast.
The characterizing step includes comparing the calculated values of the scattering or absorption coefficient with selected values of scattering or absorption coefficient, respectively.
In this aspect, the method may include further steps. The detected photons are integrated over other selected time intervals separately spaced over the arrival time of the modified pulses. Time dependence of the light intensity is determined based on the number of photons integrated over each time interval, and a value of a scattering coefficient of the examined breast tissue is determined. The examined breast tissue is characterized based on the value of the scattering coefficient.
Preferred methods use the above-described steps and additional steps as follows.
The input port and the output port are moved to a different location to examine another tissue region of the breast. Values of the scattering coefficient or absorption coefficient are again determined by repeating the above-described steps for the newly selected tissue region. The tissue region is characterized using the additional values of the scattering coefficient or the absorption coefficient.
The above-described steps are performed over several tissue regions to examine the entire breast.
The characterizing step includes comparing the calculated values of the scattering or absorption coefficient with selected values of scattering or absorption coefficient, respectively.
- 4 -The selected values of the scattering and absorption coefficient correspond to normal breast tissue, normal contralateral breast tissue or series of homogenous breast tumors.
The characterizing step includes comparing the calculated values of the scattering coefficient or the absorption coefficient with selected values of` the scattering coefficient or the absorption coefficient, respectively.
If the recited characterizing step reveals that the examined tissue includes abnormal tissue, the following steps are performed. Other locations of the input port and the output port are selected to define a new tissue region proximate to the region having abnormal tissue. The values of the scattering coefficient or the absorption coefficient of the newly selected tissue region are determined by applying the corresponding above recited steps. Abnormal breast tissue is localized by comparing values of the scattering coefficient or the absorption coeff'icient of different selected tissue regions. The type of the abnormal tissue may be determined by comparing values of the scattering coefficient or the absorption coeff`icient of the localized tissue to values of the scattering coefficient or the absorption coefficient corresponding to selected tissue masses.
The tissue masses include one of the following:
carcinoma, fibroadenoma or fibrocystic tissue.
The size and location of the abnormal tissue region is determined.
If the above recited characterizing step reveals that the examined tissue includes abnormal tissue, the following steps are performed. A contrast agent exhibiting known optical properties at the selected wavelength is injected into the blood stream of the subject. Other locations of the input port and the output port are selected tc>
.~
WO 95/02987 t'C't'/US94/07984
The characterizing step includes comparing the calculated values of the scattering coefficient or the absorption coefficient with selected values of` the scattering coefficient or the absorption coefficient, respectively.
If the recited characterizing step reveals that the examined tissue includes abnormal tissue, the following steps are performed. Other locations of the input port and the output port are selected to define a new tissue region proximate to the region having abnormal tissue. The values of the scattering coefficient or the absorption coefficient of the newly selected tissue region are determined by applying the corresponding above recited steps. Abnormal breast tissue is localized by comparing values of the scattering coefficient or the absorption coeff'icient of different selected tissue regions. The type of the abnormal tissue may be determined by comparing values of the scattering coefficient or the absorption coeff`icient of the localized tissue to values of the scattering coefficient or the absorption coefficient corresponding to selected tissue masses.
The tissue masses include one of the following:
carcinoma, fibroadenoma or fibrocystic tissue.
The size and location of the abnormal tissue region is determined.
If the above recited characterizing step reveals that the examined tissue includes abnormal tissue, the following steps are performed. A contrast agent exhibiting known optical properties at the selected wavelength is injected into the blood stream of the subject. Other locations of the input port and the output port are selected tc>
.~
WO 95/02987 t'C't'/US94/07984
- 5 _ define a new tissue region proximate to ttie region having abnormal tisstie. The values of ttie scattering coefficient or the absorption coefficient of tlie newly selected tissue reqion are determi.ned. Ttie abnormal.
breast tissue is localized by comparing values of the scattering coefficient or the absorption coefficient of different selected tissue regions.
The type of the abtiormal tissue inay be determined by comparing values of ttie scattering coefficient or the absorption coefficient of ttie 1_ocali.zed tissue to values of the scattering coefficietit or the absorption coefficient corresponding to selPcted tissue masses comprising the cotitrast agettt.
If the above-recited characterizing step reveals that the examined tissue includes abnormal tissue, the following steps are performed. A contrast agent exhibiting known optical properties at the selected wavelength is injected into the abnormal tissue. Other locations of the input port and the output port is selected. Ttie values of ttie scattering coefficient or the absorption coefficient of the newly selected tissue region are determined. 'I'he abnormal breast tissue is localized by comparing values of the scattering coefficient or the absorption coefficient of different selected tissue regions.
The type of the abtiormal tisstte may be determitied by comparing values of the scattering coefficient or the absorption coefficient of the localized tissue to values of the scattering coefficient or ttie absorption coefficient corresponding to se:l.ected tissue masses comprising ttie contrast agent.
Ttie contrast agent is a fluorescing material or absorbing material. The contrast agent is prefer.entially absorbed by the tissue mass.
~ ,,. . . _.
breast tissue is localized by comparing values of the scattering coefficient or the absorption coefficient of different selected tissue regions.
The type of the abtiormal tissue inay be determined by comparing values of ttie scattering coefficient or the absorption coefficient of ttie 1_ocali.zed tissue to values of the scattering coefficietit or the absorption coefficient corresponding to selPcted tissue masses comprising the cotitrast agettt.
If the above-recited characterizing step reveals that the examined tissue includes abnormal tissue, the following steps are performed. A contrast agent exhibiting known optical properties at the selected wavelength is injected into the abnormal tissue. Other locations of the input port and the output port is selected. Ttie values of ttie scattering coefficient or the absorption coefficient of the newly selected tissue region are determined. 'I'he abnormal breast tissue is localized by comparing values of the scattering coefficient or the absorption coefficient of different selected tissue regions.
The type of the abtiormal tisstte may be determitied by comparing values of the scattering coefficient or the absorption coefficient of the localized tissue to values of the scattering coefficient or ttie absorption coefficient corresponding to se:l.ected tissue masses comprising ttie contrast agent.
Ttie contrast agent is a fluorescing material or absorbing material. The contrast agent is prefer.entially absorbed by the tissue mass.
~ ,,. . . _.
-6-The above described steps are performed in conjuciton with x-ray mammography, MRI mammography or a needle localization procedure.
In another aspect, the invention features a system for performing the above-described method.
In still another aspect, the invention seeks to provide an apparatus for in vivo examination of biological tissue of a subject, comprising:
a light source constructed and arranged to generate pulses of light of a wavelength in the visible or infra-red range, said pulses having duration of less than a nanosecond, said wavelength being sensitive to a contrast agent of known optical properties, a support, positionable relative to said tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, one of said input ports optically connected to said source and constructed and arranged to introduce into the tissue said generated pulses of light of said selected wavelength, each output port constructed and arranged to define a detection location of said tissue, said support being constructed and arranged for use inside an magnetic resonance imaging (MRI) magnet and is associated with MRI pick-up coil, a light detector optically connected to one of said output ports, constructed and arranged to detect over time photons of modified pulses that have migrated over scatter paths in said tissue to said output port and produce corresponding electrical signals, said distance specifying -6a-a volume of the examined tissue in which said pulses have migrated, a photon counter, connected to said detector, constructed and arranged to accumulate over time said electrical signals corresponding to a shape of said modified pulses, wherein said shape depends on absorptive and scattering properties of the tissue in which said photons migrate, and a processor, connected to said photon counter, constructed and arranged to calculate values of a scattering coefficient (uS) or an absorption coefficient (Pa) of the examined tissue depending on said pulse shape, and determine a physiological property of the examined tissue based on said coefficient.
In still another aspect, the invention seeks to provide an apparatus for in vivo examination of biological tissue of a subject, comprising:
a light source constructed and arranged to generate pulses of light of a wavelength in the visible or infra-red range, said pulses having duration of less than a nanosecond, said wavelength being sensitive to a contrast agent having known optical properties and being absorbed in an abnormal tissue, a support, positionable relative to said tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, one of said input ports optically connected to said source and constructed and arranged to introduce into the tissue said generated pulses of light of said selected wavelength, -6b-each output port constructed and arranged to define a detection location of said tissue, a light detector optically connected to one of said output ports, constructed and arranged to detect over time photons of modified pulses that have migrated over scatter paths in said tissue to said output port and produce corresponding electrical signals, said distance specifying a volume of the examined tissue in which said pulses have migrated, a photon counter, connected to said detector, constructed and arranged to accumulate over time said electrical signals corresponding to a shape of said modified pulses, wherein said shape depends on absorptive and scattering properties of the tissue in which said photons migrate, and a processor, connected to said photon counter, constructed and arranged to calculate values of a scattering coefficient (us) or an absorption coefficient (ua) of the examined tissue depending on said pulse shape, and determine a physiological property of the examined tissue based on said coefficient.
In still another aspect, the invention seeks to provide an apparatus for in vivo examination of biological tissue of a subject, comprising:
a light source constructed and arranged to generate pulses of light of a wavelength in the visible or infra-red range, said pulses having duration of less than a nanosecond, said wavelength being an excitation wavelength of a fluorescing material included in a contrast agent of known optical properties, -6c-a support, positionable relative to said tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, one of said input ports optically connected to said source and constructed and arranged to introduce into the tissue said generated pulses of light of said selected wavelength, each output port constructed and arranged to define a detection location of said tissue, a light detector, optically connected to one of said output ports, including a filter constructed and arranged to pass only said fluorescent light emitted from said fluorescing material, said detector being constructed and arranged to detect over time fluorescent light of modified pulses that have migrated over scatter paths in said tissue after excitation to said output port and produce corresponding electrical signals, said distance specifying a volume of the examined tissue in which said pulses have migrated, a photon counter, connected to said detector, constructed and arranged to accumulate over time said electrical signals corresponding to a shape of said modified pulses, wherein said shape depends on absorptive and scattering properties of the tissue in which said photons migrate, and a processor, connected to said photon counter, constructed and arranged to calculate values of a scattering coefficient (us) or an absorption coefficient (ua) of the examined tissue depending on said pulse shape, and determine a physiological property of the examined tissue based on said coefficient.
-6d-In still another aspect, the invention seeks to provide an apparatus for in vivo examination of biological tissue of a subject, comprising:
a light source constructed and arranged to generate pulses of light of a wavelength in the visible or infra-red range, said pulses having duration of less than a nanosecond, a support, positionable relative to said tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, one of said input ports optically connected to said source and constructed and arranged to introduce into the tissue said generated pulses of light of said selected wavelength, each output port constructed and arranged to define a detection location of said tissue, said support including an optical material, at least partially surrounding the examined tissue for limiting escape of photons through the skin outside of said tissue or providing additional photon migration paths to said detector, a light detector optically connected to one of said output ports, constructed and arranged to detect over time photons of modified pulses that have migrated over scatter paths in said tissue to said output port and produce corresponding electrical signals, said distance specifying a volume of the examined tissue in which said pulses have migrated, a photon counter, connected to said detector, constructed and arranged to accumulate over time said electrical signals corresponding to a shape of said -6e-modified pulses, wherein said shape depends on absorptive and scattering properties of the tissue in which said photons migrate, and a processor, connected to said photon counter, constructed and arranged to calculate values of a scattering coefficient (ps) or an absorption coefficient (pa) of the examined tissue depending on said pulse shape, and determine a physiological property of the examined tissue based on said coefficient.
In still another aspect, the invention seeks to provide a method for examination of biological tissue of a subject using pulses of light of a selected wavelength, said method comprising the steps of:
providing a support, positionable relative to the examined tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, each output port constructed and arranged to define a detection location of said tissue, selecting locations of said input and output ports to examine a tissue region, introducing into the tissue, at said input port, pulses of light wavelength in the visible or infra-red range, said pulse having duration of less than a nanosecond, said wavelength being sensitive to a contrast agent of known optical properties present in the blood stream of said subject, said contrast agent modifying photons of said pulses while migrating in said tissue, detecting over time, at said detection port, photons of modified pulses that have migrated over scatter paths in the examined tissue, = -6f-accumulating, over arrival time of said detected photons, electrical signals corresponding to said detected photons of said modified pulses, a shape of said modified pulses depends on absorptive and scattering properties of the tissue in which said photons migrate, calculating values of a scattering coefficient (us) or an absorption coefficient (ua) of the examined tissue depending on said pulse shape, and characterizing the examined tissue based on said values of the scattering coefficient or the absorption coefficient.
Brief Description of the Drawings Fig. 1 depicts diagrammatically a time-resolved spectroscopic system for breast tissue examination.
Figs. 1A, 1B, 1C and 1D depict different embodiments of an optical fiber support for breast tissue examination.
Fig. 2 depicts diagrammatically a single photon apparatus arranged for breast tissue examination.
Fig. 3 diagrammatically a TRS boxcar apparatus arranged for breast tissue examination.
Fig. 3A shows a timing diagram of the apparatus of Fig. 3.
Fig. 3B shows a typical time resolved spectrum collected by the apparatus of Fig. 3.
Fig. 4 depicts diagrammatically examination of breast tissue using a fluorescing contrast agent.
Figs. 4A and 4B depict diagrammatically examination of breast tissue suing MRI and time-resolved spectroscopy.
Figs. 4A, 5B, 5C, 5D, 5E and 5F display values of the absorption coefficient and the scattering coefficient of normal breast tissue measured at different locations of the right breast and the left breast.
-6g-Figs. 6A and 6B display values of the absorption coefficient and the scattering coefficient, respectively, of normal breast tissue for women of different ethnic background.
In another aspect, the invention features a system for performing the above-described method.
In still another aspect, the invention seeks to provide an apparatus for in vivo examination of biological tissue of a subject, comprising:
a light source constructed and arranged to generate pulses of light of a wavelength in the visible or infra-red range, said pulses having duration of less than a nanosecond, said wavelength being sensitive to a contrast agent of known optical properties, a support, positionable relative to said tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, one of said input ports optically connected to said source and constructed and arranged to introduce into the tissue said generated pulses of light of said selected wavelength, each output port constructed and arranged to define a detection location of said tissue, said support being constructed and arranged for use inside an magnetic resonance imaging (MRI) magnet and is associated with MRI pick-up coil, a light detector optically connected to one of said output ports, constructed and arranged to detect over time photons of modified pulses that have migrated over scatter paths in said tissue to said output port and produce corresponding electrical signals, said distance specifying -6a-a volume of the examined tissue in which said pulses have migrated, a photon counter, connected to said detector, constructed and arranged to accumulate over time said electrical signals corresponding to a shape of said modified pulses, wherein said shape depends on absorptive and scattering properties of the tissue in which said photons migrate, and a processor, connected to said photon counter, constructed and arranged to calculate values of a scattering coefficient (uS) or an absorption coefficient (Pa) of the examined tissue depending on said pulse shape, and determine a physiological property of the examined tissue based on said coefficient.
In still another aspect, the invention seeks to provide an apparatus for in vivo examination of biological tissue of a subject, comprising:
a light source constructed and arranged to generate pulses of light of a wavelength in the visible or infra-red range, said pulses having duration of less than a nanosecond, said wavelength being sensitive to a contrast agent having known optical properties and being absorbed in an abnormal tissue, a support, positionable relative to said tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, one of said input ports optically connected to said source and constructed and arranged to introduce into the tissue said generated pulses of light of said selected wavelength, -6b-each output port constructed and arranged to define a detection location of said tissue, a light detector optically connected to one of said output ports, constructed and arranged to detect over time photons of modified pulses that have migrated over scatter paths in said tissue to said output port and produce corresponding electrical signals, said distance specifying a volume of the examined tissue in which said pulses have migrated, a photon counter, connected to said detector, constructed and arranged to accumulate over time said electrical signals corresponding to a shape of said modified pulses, wherein said shape depends on absorptive and scattering properties of the tissue in which said photons migrate, and a processor, connected to said photon counter, constructed and arranged to calculate values of a scattering coefficient (us) or an absorption coefficient (ua) of the examined tissue depending on said pulse shape, and determine a physiological property of the examined tissue based on said coefficient.
In still another aspect, the invention seeks to provide an apparatus for in vivo examination of biological tissue of a subject, comprising:
a light source constructed and arranged to generate pulses of light of a wavelength in the visible or infra-red range, said pulses having duration of less than a nanosecond, said wavelength being an excitation wavelength of a fluorescing material included in a contrast agent of known optical properties, -6c-a support, positionable relative to said tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, one of said input ports optically connected to said source and constructed and arranged to introduce into the tissue said generated pulses of light of said selected wavelength, each output port constructed and arranged to define a detection location of said tissue, a light detector, optically connected to one of said output ports, including a filter constructed and arranged to pass only said fluorescent light emitted from said fluorescing material, said detector being constructed and arranged to detect over time fluorescent light of modified pulses that have migrated over scatter paths in said tissue after excitation to said output port and produce corresponding electrical signals, said distance specifying a volume of the examined tissue in which said pulses have migrated, a photon counter, connected to said detector, constructed and arranged to accumulate over time said electrical signals corresponding to a shape of said modified pulses, wherein said shape depends on absorptive and scattering properties of the tissue in which said photons migrate, and a processor, connected to said photon counter, constructed and arranged to calculate values of a scattering coefficient (us) or an absorption coefficient (ua) of the examined tissue depending on said pulse shape, and determine a physiological property of the examined tissue based on said coefficient.
-6d-In still another aspect, the invention seeks to provide an apparatus for in vivo examination of biological tissue of a subject, comprising:
a light source constructed and arranged to generate pulses of light of a wavelength in the visible or infra-red range, said pulses having duration of less than a nanosecond, a support, positionable relative to said tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, one of said input ports optically connected to said source and constructed and arranged to introduce into the tissue said generated pulses of light of said selected wavelength, each output port constructed and arranged to define a detection location of said tissue, said support including an optical material, at least partially surrounding the examined tissue for limiting escape of photons through the skin outside of said tissue or providing additional photon migration paths to said detector, a light detector optically connected to one of said output ports, constructed and arranged to detect over time photons of modified pulses that have migrated over scatter paths in said tissue to said output port and produce corresponding electrical signals, said distance specifying a volume of the examined tissue in which said pulses have migrated, a photon counter, connected to said detector, constructed and arranged to accumulate over time said electrical signals corresponding to a shape of said -6e-modified pulses, wherein said shape depends on absorptive and scattering properties of the tissue in which said photons migrate, and a processor, connected to said photon counter, constructed and arranged to calculate values of a scattering coefficient (ps) or an absorption coefficient (pa) of the examined tissue depending on said pulse shape, and determine a physiological property of the examined tissue based on said coefficient.
In still another aspect, the invention seeks to provide a method for examination of biological tissue of a subject using pulses of light of a selected wavelength, said method comprising the steps of:
providing a support, positionable relative to the examined tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, each output port constructed and arranged to define a detection location of said tissue, selecting locations of said input and output ports to examine a tissue region, introducing into the tissue, at said input port, pulses of light wavelength in the visible or infra-red range, said pulse having duration of less than a nanosecond, said wavelength being sensitive to a contrast agent of known optical properties present in the blood stream of said subject, said contrast agent modifying photons of said pulses while migrating in said tissue, detecting over time, at said detection port, photons of modified pulses that have migrated over scatter paths in the examined tissue, = -6f-accumulating, over arrival time of said detected photons, electrical signals corresponding to said detected photons of said modified pulses, a shape of said modified pulses depends on absorptive and scattering properties of the tissue in which said photons migrate, calculating values of a scattering coefficient (us) or an absorption coefficient (ua) of the examined tissue depending on said pulse shape, and characterizing the examined tissue based on said values of the scattering coefficient or the absorption coefficient.
Brief Description of the Drawings Fig. 1 depicts diagrammatically a time-resolved spectroscopic system for breast tissue examination.
Figs. 1A, 1B, 1C and 1D depict different embodiments of an optical fiber support for breast tissue examination.
Fig. 2 depicts diagrammatically a single photon apparatus arranged for breast tissue examination.
Fig. 3 diagrammatically a TRS boxcar apparatus arranged for breast tissue examination.
Fig. 3A shows a timing diagram of the apparatus of Fig. 3.
Fig. 3B shows a typical time resolved spectrum collected by the apparatus of Fig. 3.
Fig. 4 depicts diagrammatically examination of breast tissue using a fluorescing contrast agent.
Figs. 4A and 4B depict diagrammatically examination of breast tissue suing MRI and time-resolved spectroscopy.
Figs. 4A, 5B, 5C, 5D, 5E and 5F display values of the absorption coefficient and the scattering coefficient of normal breast tissue measured at different locations of the right breast and the left breast.
-6g-Figs. 6A and 6B display values of the absorption coefficient and the scattering coefficient, respectively, of normal breast tissue for women of different ethnic background.
7 PC'[=/US94/0798<1 Oescriation_Qf_ t ie P~ef~r~ec~~m~o~l~m~~s Fig. 1 depicts a breast tissue examination system 4 placed on a human breast 5 for breast tissue examination. The system includes an optical. fiber support 8 witti mtrltiple input ports 14 and multiple output ports 16. Support 8 is placed around breast 5 so that input ports 14 and output ports 16 define irradiation locations and detection locations on the skin of breast 5, respectively. Connected to selected input and output ports are optical fibers 15 and 17, respectively. System 4 uses a TRS device 20 that is either a single photon tissue resolved apparatus 20A or a time resolved apparatus 20B using boxcar type integration, shown in Figs. 2 and 3, respectively.
Referring also to Figs. 1.n, 1B, 1C and 1D, system 4 uses different types of the optical fiber supports designed to introduce and detect photons at selected locations and thus shape the optical field. The optical fiber supports are made of flexible or rigid materials and are shaped to accommodate breasts of different volumes. Furthermore, ttie inside surface of the supports may include material of kriown scattering and absorptive properties. The material is selected to either return back to ttte breast tissue phatons escaping through the skin (i.e., a low absorber and high scatterer) or provide additional pattis for the escaping photons to the detector (i.e., ttie material has substantially the same optical properties as riormal breast tissue). The supports are designed for use with a time-resolved spectrophotometer (TRS) alone or in conjunction with x-ray mammography, MRI or a needle localization procedur.e. Specifically, fiberoptic support 9 shown in Fig. 1A includes tltree sets of the input and detection ports labeled 1.0a, 1.0b, and 10c. Sets 10a and lOc are used to measure control data and set lOb is used to examine a suspected mass 7. Ftar_t.hermor.e, support 9 ~
.
Referring also to Figs. 1.n, 1B, 1C and 1D, system 4 uses different types of the optical fiber supports designed to introduce and detect photons at selected locations and thus shape the optical field. The optical fiber supports are made of flexible or rigid materials and are shaped to accommodate breasts of different volumes. Furthermore, ttie inside surface of the supports may include material of kriown scattering and absorptive properties. The material is selected to either return back to ttte breast tissue phatons escaping through the skin (i.e., a low absorber and high scatterer) or provide additional pattis for the escaping photons to the detector (i.e., ttie material has substantially the same optical properties as riormal breast tissue). The supports are designed for use with a time-resolved spectrophotometer (TRS) alone or in conjunction with x-ray mammography, MRI or a needle localization procedur.e. Specifically, fiberoptic support 9 shown in Fig. 1A includes tltree sets of the input and detection ports labeled 1.0a, 1.0b, and 10c. Sets 10a and lOc are used to measure control data and set lOb is used to examine a suspected mass 7. Ftar_t.hermor.e, support 9 ~
.
- 8 -enables precise characterization of the distances between the three sets, between input ports 14 and detection ports 16 (p) and from the chest wall 6 to each set (dn).
Supports 11 and 12, shown in Figs. 1B, 1C and 1D, are used with x-ray mammography and needle localization procedure, respectively, and their functions are described below.
Referring to Fig. 2, a dual wavelength, time correlated single photon counting TRS apparatus 20A is connected to support 13 positioned on breast 5. Pulsed laser diodes 32 and 34 (model PLP-10 made by Hamamatsu, Japan), are driven by a 5 mW pulser 36 connected to a 100 MHz pulse generator 37, and generate light pulses on the order of 500 psec or less. The light from laser diodes 32 and 34 is electro-mechanically time shared using a 60 Hz vibrating mirror 33 and is coupled to one end of optical fiber 15. Optical fiber 15, which has about 200 m diameter, alternatively conducts pulses of 754 nm and 810 nm light to input port 14. The introduced photons migrate in the examined breast tissue and some of them arrive at output port 16. Optical fiber 17 collects photons of the modified pulses from an area of about 10 mm2 and transmits them to a PMT detector 40.
The output of PMT 40 is connected to a wide band amplifier 42 with appropriate roll-off to give good pulse shape and optimal signal to noise ratio. output signals from amplifier 42.are sent to a high/low level discriminator 44, which is a pulse amplitude discriminator with the threshold for pulse acceptance set to a constant fraction of the peak amplitude of the pulse. Next, the discriminator pulses are sent to a time-to-amplitude convertor (TAC) 46. TAC 46 produces an output pulse with an amplitude proportional to the time difference between the start and stop pulses received from pulser 36. The TAC pulses (47) are routed by a
Supports 11 and 12, shown in Figs. 1B, 1C and 1D, are used with x-ray mammography and needle localization procedure, respectively, and their functions are described below.
Referring to Fig. 2, a dual wavelength, time correlated single photon counting TRS apparatus 20A is connected to support 13 positioned on breast 5. Pulsed laser diodes 32 and 34 (model PLP-10 made by Hamamatsu, Japan), are driven by a 5 mW pulser 36 connected to a 100 MHz pulse generator 37, and generate light pulses on the order of 500 psec or less. The light from laser diodes 32 and 34 is electro-mechanically time shared using a 60 Hz vibrating mirror 33 and is coupled to one end of optical fiber 15. Optical fiber 15, which has about 200 m diameter, alternatively conducts pulses of 754 nm and 810 nm light to input port 14. The introduced photons migrate in the examined breast tissue and some of them arrive at output port 16. Optical fiber 17 collects photons of the modified pulses from an area of about 10 mm2 and transmits them to a PMT detector 40.
The output of PMT 40 is connected to a wide band amplifier 42 with appropriate roll-off to give good pulse shape and optimal signal to noise ratio. output signals from amplifier 42.are sent to a high/low level discriminator 44, which is a pulse amplitude discriminator with the threshold for pulse acceptance set to a constant fraction of the peak amplitude of the pulse. Next, the discriminator pulses are sent to a time-to-amplitude convertor (TAC) 46. TAC 46 produces an output pulse with an amplitude proportional to the time difference between the start and stop pulses received from pulser 36. The TAC pulses (47) are routed by a
- 9 -switch 48 to either a multichannel analyzer (MCA) 50 or an MCA 52. Switch 48 operates at 60 Hz and is synchronized with mirror 33. The photon emission, detection cycle is repeated at a frequency on the order of 10 MHz.
Each MCA collects only a single photon for each light pulse introduced to the tissue. Each MCA acquires and sums photons of only one designated wavelength and stores the corresponding pulse of a shape that depends on properties of the examined tissue. The pulses are preferably accumulated over about 2 to 3 minutes so that at least 105 counts are collected at the maximum of the pulse shape. The detected pulse shape is analyzed by a computer 56. Computer 56 is connected to pulse generator 37 and MCAs 50 and 52 via an interface module 54 and is adapted to control the entire operation of the system.
Alternatively, TRS apparatus 20 represents a boxcar TRS apparatus 20B, as shown in Fig. 3. A pulsed laser diode 60 is driven by a 5 mW pulser 62 connected to a 100 MHz pulse generator 64. Laser diode 60 generates a train of 100 ps light pulses of 754 nm wavelength coupled to optical input fiber 15. The light pulses are introduced to breast tissue at input port 14. The introduced photons migrate in the examined tissue and a portion of them arrives at an output port 16. In the migration process, the input pulse has been mbdified by the scattering and absorptive properties of the examined tissue. Photons arriving at detection port 16 are transmitted by optical fiber 17 to a detector 66, (for example, Hamamatsu photomultipliers R928, R1517, MCP
R1712, R1892).
The output of detector 66 is amplified in a wide band preamplifier/impedance changer 67 and coupled to a boxcar integrator 68. Integrator 68 activated by a pulse gate 73 collects all arriving photons over a Ni'O 95/02987 t'(I'/US94/07984
Each MCA collects only a single photon for each light pulse introduced to the tissue. Each MCA acquires and sums photons of only one designated wavelength and stores the corresponding pulse of a shape that depends on properties of the examined tissue. The pulses are preferably accumulated over about 2 to 3 minutes so that at least 105 counts are collected at the maximum of the pulse shape. The detected pulse shape is analyzed by a computer 56. Computer 56 is connected to pulse generator 37 and MCAs 50 and 52 via an interface module 54 and is adapted to control the entire operation of the system.
Alternatively, TRS apparatus 20 represents a boxcar TRS apparatus 20B, as shown in Fig. 3. A pulsed laser diode 60 is driven by a 5 mW pulser 62 connected to a 100 MHz pulse generator 64. Laser diode 60 generates a train of 100 ps light pulses of 754 nm wavelength coupled to optical input fiber 15. The light pulses are introduced to breast tissue at input port 14. The introduced photons migrate in the examined tissue and a portion of them arrives at an output port 16. In the migration process, the input pulse has been mbdified by the scattering and absorptive properties of the examined tissue. Photons arriving at detection port 16 are transmitted by optical fiber 17 to a detector 66, (for example, Hamamatsu photomultipliers R928, R1517, MCP
R1712, R1892).
The output of detector 66 is amplified in a wide band preamplifier/impedance changer 67 and coupled to a boxcar integrator 68. Integrator 68 activated by a pulse gate 73 collects all arriving photons over a Ni'O 95/02987 t'(I'/US94/07984
- 10 -predetermined time interval 75, as sliowrl i..n Fig. 3A. The integrator output (78) is sent to computer interf.ace module 80 and computer 82. Computer 82 stores the total number of counts detected duri.ng the collPCtion interval of integrator 68.
Integrator 68 includes a trigger 70, which Is triggered by a signal 63 from p+_tlser 62. Trigger 70 activates a delay gate 72 which, in turn, starts counting of all detected photons during the time interval specified by a gate width ci_rcu.i.t 74. Output from a gate width normalizer 76 is an analog siqna:l or a digital signal representing all photons that ar.rived at detection port 16 during the preselected gate width interval. (75). A
suitable integrator is a boxcar. SR 250 manufactured by Stanford Research Systems.
Depending on the application, computer 82 sets the delay time (71) of delay gate 72 and the gate width time (75) of gate width circuit 74. Gate width normalizer 76 adjusts the width of ttie integration time depending on the detected signal level. The gate width may be increased logarithmically for signals at t tm,,, wherein the detected number of photoris decreases exponentially;
this increases ttie signal-to-noise ratio. Furthermore, computer 82 can scan ttie integration gate widths over the whole time profile of the detected pulse. By scanriing the delay times (71) and appropriately adjustitig ttie gate widths (75), the computer collects data corresponding to the entire detected pulse. Subsequently, computer 82 calculates the shape (85) of ttie detected pulse and stores the time depetidetit light intensity profile T(t).
The pulse shape, I(t), detected either by apparatus 20A or apparatus 208 possesses information about the scattering and absorptive properties of the examined breast tissue and is used to determine the scattering and absorption coef:ficients. Referring to ~
v-v 73tOZY57 = CA 02167179 2004-08-16 PCTlUS94107984
Integrator 68 includes a trigger 70, which Is triggered by a signal 63 from p+_tlser 62. Trigger 70 activates a delay gate 72 which, in turn, starts counting of all detected photons during the time interval specified by a gate width ci_rcu.i.t 74. Output from a gate width normalizer 76 is an analog siqna:l or a digital signal representing all photons that ar.rived at detection port 16 during the preselected gate width interval. (75). A
suitable integrator is a boxcar. SR 250 manufactured by Stanford Research Systems.
Depending on the application, computer 82 sets the delay time (71) of delay gate 72 and the gate width time (75) of gate width circuit 74. Gate width normalizer 76 adjusts the width of ttie integration time depending on the detected signal level. The gate width may be increased logarithmically for signals at t tm,,, wherein the detected number of photoris decreases exponentially;
this increases ttie signal-to-noise ratio. Furthermore, computer 82 can scan ttie integration gate widths over the whole time profile of the detected pulse. By scanriing the delay times (71) and appropriately adjustitig ttie gate widths (75), the computer collects data corresponding to the entire detected pulse. Subsequently, computer 82 calculates the shape (85) of ttie detected pulse and stores the time depetidetit light intensity profile T(t).
The pulse shape, I(t), detected either by apparatus 20A or apparatus 208 possesses information about the scattering and absorptive properties of the examined breast tissue and is used to determine the scattering and absorption coef:ficients. Referring to ~
v-v 73tOZY57 = CA 02167179 2004-08-16 PCTlUS94107984
- 11 -Fig. 3B, a test measurement was performed on apparatus 20A and found that due to a somewhat slow response time, the detector broadens the reflectance profile, as seen on spectrum 86. Thus the experimental spectra (87) are deconvoluted to separate the instrumental response from the profile dispersion due to the diffusion. The deconvolution yields about 6% increase in the value of /Aa and about 23% decrease in the value of ,.
The examined tissue region is defined by the distribution of photon pathlengths forming an optical field in the tissue. The size and shape of the optical field is a function of the input-output port separation (p) as well as the optical properties of the tissue (i.e., absorption coefficient, =, scattering coefficient, ,, and the mean cosine of anisotropic scattering, g). The general diffusion equation is used to describe the photon migration in tissue, as analyzed by B.M. Sevick, B. Chance, J. Leigh, S. Nioka, and M.
Maris in Analytical Biochemistry =, 330 (1991).
7.0 The diffusion equation is solved for the intensity of detected light in the reflectance qeoaetry, R(p,t), or the transmittance geometry T(p,d,t). In the reflectance geometry, in a semi-infinite media with the separation of the input and output ports on the order of centimeters, the absorption coefficient is a function of the reflectance spectrum as follows:
d loq0R(P, t) - --5 - ,c + P 2.- (1) dt 2 t 4Dct For t-+ w the absorption coefficient p is determined as follows:
WO 95/02987 I'C'I'/US94/O798'1
The examined tissue region is defined by the distribution of photon pathlengths forming an optical field in the tissue. The size and shape of the optical field is a function of the input-output port separation (p) as well as the optical properties of the tissue (i.e., absorption coefficient, =, scattering coefficient, ,, and the mean cosine of anisotropic scattering, g). The general diffusion equation is used to describe the photon migration in tissue, as analyzed by B.M. Sevick, B. Chance, J. Leigh, S. Nioka, and M.
Maris in Analytical Biochemistry =, 330 (1991).
7.0 The diffusion equation is solved for the intensity of detected light in the reflectance qeoaetry, R(p,t), or the transmittance geometry T(p,d,t). In the reflectance geometry, in a semi-infinite media with the separation of the input and output ports on the order of centimeters, the absorption coefficient is a function of the reflectance spectrum as follows:
d loq0R(P, t) - --5 - ,c + P 2.- (1) dt 2 t 4Dct For t-+ w the absorption coefficient p is determined as follows:
WO 95/02987 I'C'I'/US94/O798'1
12 -litn d a.o9 R(P, t) c dt 4iõ (2) wherein p Is the separation betweeti input and detection ports and c is speed of light in ttae medium. llowever, it Is difficult to measure the at t. tmAx because itt this region the data stiow substantial noise. Thus, to measure Jta at t tmnx1 requires determination of the pulse st-ape at a tiigh number of counts.
If the approximation of infini.te time is not valid, Eq. 1 can be rewritten tto obtain jiA as follows:
__d 5 ~~ _Log~R(p, t) + _4Dct ^ 2t (3) The value for D can either be the average value obtained from numerical simulations or a value specific to ttie type of tissue being measurecl.
The effective scattering coefficierit (1-g)= A Is determined as follows:
(1-g) s (44teC2LmAx;lOCG,mrx) Ile (4) p wherein tmax is ttie delay time at which the detected reflectance time profile (R(p,t) m I(t)) reacties maximum.
After detecting ttte pulse shape corresponding to the examined tissue the compute.r calculates the absorption coefficient (tc$) , and the scatterinq coefficient (/.tA) .
The absorption coefficient Is quantified by evaluatinq the decaying slope of the detected pulse, using Eqs. 2 or 3. The effective scattering coefficietit, (:l.-q) = A, is determined from Eq. 4.
The breast screan3.ng procAdure starts by selecting a support with appropriate arrangements of i.nput ports 14 and output ports 16. 'I'he absorptive and scatter_ing properties of the tissue are measurecl for orie set of ~.
WO 95/029$7 t'C'I'/US94/079R4
If the approximation of infini.te time is not valid, Eq. 1 can be rewritten tto obtain jiA as follows:
__d 5 ~~ _Log~R(p, t) + _4Dct ^ 2t (3) The value for D can either be the average value obtained from numerical simulations or a value specific to ttie type of tissue being measurecl.
The effective scattering coefficierit (1-g)= A Is determined as follows:
(1-g) s (44teC2LmAx;lOCG,mrx) Ile (4) p wherein tmax is ttie delay time at which the detected reflectance time profile (R(p,t) m I(t)) reacties maximum.
After detecting ttte pulse shape corresponding to the examined tissue the compute.r calculates the absorption coefficient (tc$) , and the scatterinq coefficient (/.tA) .
The absorption coefficient Is quantified by evaluatinq the decaying slope of the detected pulse, using Eqs. 2 or 3. The effective scattering coefficietit, (:l.-q) = A, is determined from Eq. 4.
The breast screan3.ng procAdure starts by selecting a support with appropriate arrangements of i.nput ports 14 and output ports 16. 'I'he absorptive and scatter_ing properties of the tissue are measurecl for orie set of ~.
WO 95/029$7 t'C'I'/US94/079R4
13 _ ports and theri the optical field is transferred by using another set of ports. 'I'he eriti.r.e breast is examined by selecting sequentially different ports. In the reflection geometry, the optical field can be represented by a three dimensional, "bana.ia-shaped" distiribution pattern or, in the transmission geometry, a"cigar-shaped" distribution pattern. In the "banana-shaped"
pattern, the shallow boundary is due to the escape of photons ttiat reach the ai..r-RCatterer interface while ttie deeper boundary is due to attenuation of long path photons by the absorbers. The penetration depth of the photons is about one half of ttie port separation (p).
During the screening procedure, the computer calculates A. and e for ttie entire breast and compares the measured values with ttirestiold values of m atid l.cA of normal tissue or series of . and It. values of different homogeneous tumor types. As is shown in Figs. 5A throuqh 5F, from one person to another there is some variation in a and p for normal tissue, but only a very smal.l. variation between the left breast and the right breast: of the same person. Cancerous tissue, whicti is usuall.y highly perfused, exhibits higher values of IL A and Itp than fibrous tissue. Normal tissue, whicii has a relatively hiqh amount of fat, exhibits ttie lowest values of g and B.
Alternatively, instead of calculating A and ;Lq, the system can calcu:late an average pattilenqth of the migrating photons. From the detected and deconvoluted photon intensity profile, R(t), a mean pattilength of the distribution of pathlengths <L> is determined as follows:
c fo-_t (t) t at.
< L > (5) .z-(r)at ~
V 95/02987 I'CT1US94/07984 _ 14 -wtierein c is the speed of light in vacuum and nft 1.36 is the average refractive index of tissue.
If a breast tumor is outside of the optical field, it does not alter the banana-shaped distribution of pathlengths. As the optical field is moved closer to the breast tumor, which is a strongly absorbing mass, the photons that have migrated ttie farthest distance from the input and detection ports are elimiriated by the absorption process. Since photons with ttie longest pathlengths are absorbed by the mass, the system detects reduction in the average pathlength. When the optical field is moved even closer to the mass, some of the detected photons now migrate around the mass without being absorbed;
this is detected as lengthening of the distribution of pathlengths. Thus, the average pathlength measurement can reveal location of the breast mass.
In the screening process, the breast tissue is characterized by several tissue variables which may be used alone or in combination. TRS device 20 measures the absorption coefficient, the scattering coefficient, the blood volume or tissue oxygenation using one or more selected wavelengths of the laser. The wavelengths are sensitive to naturally occurring pigments or contrast agents that may be preferentially absorbed by ttie diseased tissue. Suitable naturally occurring pigments are, for example, hemoglobin (Hb) or oxytiemoglob:i.n (11b02) sensitive to 754 nm and 816 nm, respectively.
Alternatively, suitable color dyes, such as cardio-green or indocyiniri-green, may be injected to the blood system alone or bound to a vetaicle sucti as a gadolinium contrast agent, which is preferentially absorbed by tumors in ttie first five to ten minutes. An appropriate wavelength is selected for ttie color dye, for example, cardio-green exhibits maximuin absorption at 805 rim.
~
WO 95/02987 I'( T/US94/07989 21 fi7 179 The computer can create "maps" of the breast by mapping the spacial variatian of the measured values for at F blood volume or hemoglobin saturation. 'I'he resolutiori is enhanced when several tissue variabl.es are mapped. The blood volume is measured using a, pair of contrabestic wavelertgths (e.g., 754 nm and 816 nm) or the isobestic wavelength (i.e., 805 nm). 'Che hemoglobiti saturation (Y) is measured at two wavelengths (e.g., 754 nm and 816 nm) and is calculated by taking ttie ratio of absorptiott coef f icients at these wavelengths atid then using the following equatioti:
ra Y(X100$) -_ 1as~ (6) eiF
wherein the coefficients are determined from the extinction values of hemoglobin at 754 nm and 816 nm that are sHb - 0.38 cm-i mM-1, strb - 0.18 cm-1mM-1 , respectively, and the difference in extinction coefficierits between oxyhemogl.ob.in and hemoglobin that are AEHbO-Hb - 0.025 cm-1 mM-1 and AFttbO-Hb ' 0.03 cm-1 mM-1, respectively.
In another preferred embodiment, TRS apparatus 20 is used in combinatiori with x-ray mammography. The combined procedure is performed if a suspected mass is detected by the above-described optical method, x-ray mammography or anotlier screening method.
Referring to Fi.g. 1H, breast 5 i.s compressed in either a horizontal or vertical position between an x-ray film case 90 with the x-ray film and a support 11 with input ports and output ports located on a grid. An x-ray mammogram is taken to determine location of suspected mass 7 relative to ttie grid. Stiitable input port 14 and output port 16 are selected so ttrat the introducPd ~
95/029$7 YC'I'/US94/07981 -.16 optical field 92 ericompasses mass 7. Ttien, TRS apparatus 20A or 20B is used to meastire iig, E..rH, ttho blood volume or oxygen concentration of the examitied tissue using the above-described techniques. The measured values are again compared to the values corresporiding to normal tissue or different types of di.seased tissue to characterize the mass. If an unequivocal result is obtained, an exploratory excisiona]. biopsy is not iieeded.
In another preferred einbadimerit, TRS apparatus 20 is used in combination with the needie localization procedure. The needl.e localization procedure locates ttie mass that is then examined by system 4. Furthermore, a needle used in the rieedle localization procedure may introduce an optical fiber directly to mass 7.
Referring to Figs. 1C and 1D, breast 5 is compressed between x-ray film case 90 and a support 12 with input ports and output ports located on a grid and a centrally located opening for a needle 94 or a needle 98. One or more x-ray mammograms are takeri to determine the location of suspected mass 7 relative to the grid and to the needle opening. The needle is inserted into ttie breast and the needle tip is positioned in the center of mass 7.
Additional x-ray mammograms may be takeri to verify or adjust the position of the needle.
As shown in Fig. 1C, if the needle is used only to localize mass 7, i.nput port 14 and output port 16 are selected so that their separation is equal or larger than two times the deptki of mass 7. This separation assures that the introduced optical field 96 encompasses mass 7.
After needle 94 is positioned, a tiriy wire is inserted into the mass and left there far marking purposes. TRS
apparatus 20 measures a, blood volume or oxygen concentration of the examined tissue using the above-described techniques. The measured values are again compared to the values of normal tissue and ~
_ . ..,., .. . .. .,. , _ . .,. .. ..,,. ~. . ...:.., _. ..,,. .. .. .
different types of diseased tissue, and to characterize the tissue of mass 7.
As shown in Fig 1D, needle 98 positions an end 99 of optical input fiber 15 directly inside mass 7. Here, the optical fiber with a diameter of about 100 pm or less is threaded inside needle 98 and end 99 is slightly extended from the needle so that the introduced photons are directly coupled to mass 7. The location of detection port 16 defines optical field 100. In this arrangement, all detected photons migrate in the targeted tissue; this increases the relative amount of the targeted tissue being examined and thus increases the resolution of the system. To compare tissue of mass 7 with normal tissue, the same geometry of the input port and the detection port is used to measure the optical properties of the coritralateral breast. Alternatively, in the same breast, rieedle 98 is moved outside of: mass 7 so that the positions of the optical fiber end 99 and detection port 16 define an optical field completely removed from mass 7.
To characterize the mass, the values of p,, and u9 measured for mass 7 are compared either to the values of normal tissue measured in the same arrangement or to values of different types of diseased tissue.
In another embodiment, the detection contrast is enhanced using fluorescing contrast agents. A tumor is permeated with a fluorescing coritrast agent that has a decay time of less than 1 risec, and the labeled tumor is then again examined using TRS device 20. Suitable agents emit fluorescing radiatiori in the range of 800 nm t:o 1000 nm, for example, carbocyanene dyes or porphoriri compotinds.
Referririg to Fig. 4, the fluorescirig contrast agent is injected to the blood systein alone or bound to a vehicle, such as a gadolinium coritrast agent, which is initially preferentially absorbed by a breast tumor_.
~
V 95/02987 I'C1'/US94/07984 ' - 18 -Alternatively, the fluorescitig ageiit is injected directly into the tumor. TRS device 20 getierates 150 psec light pulses introduced into breast 5 at input port 14. The introduced photons of selected excitation wavelength reach tumor 7 and excite a fluorescing radiation 110, which propagates in all directions from tumor.7. Ttie photons of fluorescing radiation 110 migrate in ttie examined breast tissue and some of them arrive at output port 16. output port 16 has an interference filter that passes only photons at the wavelength of fluorescing ' radiation 110. Optical fiber 17 collects the transmitted photons,'which are delivered to the PM'I' detector. System 4 may detect fluorescing radiation 110 at several output ports at the same time or move the ports to different positions on the fiber optic support.
TRS device 20 detects the ptilses of fluorescing radiation 110; the shape of these pulses depends on the decay time of the fluorescing agent and optical.
properties of both the tumor tissue and the normal breast tissue.
In another embodiment, referring to Figs. 4A and 4B, TRS apparatus 20 is used in combination with MRI.
MRI examines the breast with or without using a rare earth contrast agent. A network of surface coils 112 is cooperatively arranged with a fiberoptic support 114, which is constructed for use with MRI. The network of coils 112 and support 114 are appropriately located around the examined breast. At ttie same time as ttie MRI
data are collected, TRS apparatus 20 collects the optical data. If an abnormal mass is detected, MRI
.identifies the size atid location of ttie mass. The optical data are theri used to characterize the mass.
optical contrast agents may be used alone or in combination with the rare earth contrast agents, as described above.
~
_ ... . ..... .,...
BBPERIMENTB:
Preliminary experiments were conducted under a pre-approved protocol and after receiving informed consent of women with normal breast tissue and of women having a mass detected in their breast.
The examination of normal breast tissue was performed at several different locations of the right and left breast of the same woman. Referring to Figs. 2 and 3, letters RR, LR, LR and LL denote the right and left breast and the right and left breast side where the input and detection ports were located, respectively. Figs. 5A
and 5B summarize the absorption coefficient ( a) and the scattering coefficient ( e'= (1-g)= B), respectively, measured on the right and left breast at a separation p 6 cm. The values of a and e' for the right breast are identical to the values for the left breast within the measurement error. Figs. 5C and 5D summarize a, s', respectively, for the tissue on the left side and the right side of each breast,.and Figs. 5E and 5F summarize a, s', respectively, for the tissue located at different distances from the chest wall. The data shown in Figs.
5A through 5F confirm that there is no significant difference in the optical properties measured over the entire breast.
The examination of normal breast tissue also measured differences in the optical properties corresponding to the volume of the breast, type of the breast tissue, the age of the woman and ethnic background. Based on the decreasing X-ray background absorption, the breast tissue was categorized as "dense", "fatty", or a "mixture" of the two tissue types. The values of a and B' of "fatty" tissue are lower than for "dense" tissue, which has a higher fibrous content.
Since the shape of the breast varies, it was difficult to ._....~..aw,.~~..w~.M....~.~.~.~.. ., .....,. ..... ,...um....u........ ....
.. ........
WO 95/02987 2~ ~~ 17Q PCT/US94/07984 categorize precisely the breast volume. For the volume measurement, the breast was stabilized on a plate and the length was measured from the chest to the end of the breast. The width and the thickness were measured at approximately 1 cm from the chest. Tissue of a large volume breast exhibits lower values of a and s' than that of a small volume breast. The same trend is observed for women above the age 50 when compared to women below 50. Figs. 6A and 6B display values of a and B', respectively, for Caucasians and African-Americans.
Normal breast tissue of Caucasians and African-Americans exhibits substantially the same optical properties except for the values of s' measured at the 4 cm separation.
Since the skin forms a higher relative percentage of the examined tissue at a smaller separation of the input and output ports, the lower values of e' may be due to a lower scattering coefficient of the skin with more pigment.
In all measurements, a smaller separation of the input and output ports yielded larger values of A. and 8' than a larger separation of the ports. This differences can be explained by violation of the semi-infinite boundary conditions at the smaller separations, i.e., a larger escape of photons through the tissue surface before they are collected by optical fiber 17.
Furthermore, this dependence exists since the slope of the photon decay was measured not sufficiently far from the peak of the reflectance data as expressed in Eqs. 1, 2 and 3. This problem arises due to a low photon count of approximately 10,000 counts at the peak. Thus the measured data have a low signal to noise ratio and a reliable reflectance data can not be taken at t tmax.
The corresponding error in the absorption coefficient, E(p,t)I ab8, is determined using Eq. 7.
WO 95/02987 216 ?' 17 9 PCT/US94/07984 E(p, t) = C[ 2t + 4DCI' (7) The error of scattering coefficient, E(p,t, a)I sct, arises due to the error in the absorption coefficient.
The corresponding error is determined using Eq. S.
E(p, t, a) /sct = 31P 2 [4E(p, t) /~SC2tm2ax] -E(p, t) /,b6 (8) The preliminary values of a and g' corrected for the error using Eqs. 7. and 8 are shown in Table 1.
Separation Mean a Mean Mean g (cm) a Error 6 tmax (ns) Error Adjusted Adjus'ted 4 0.029 0.020 16.2 1.55 14.1 1 5 0.023 0.021 11.4 1.9 10.9 6 0.019 0.022 9.5 2.3 10.1 7 0.017 0.021 7.9 2.7 8.7 The corrected values of mean a for different separations, p, are substantially the same, but the corrected values of mean A. still are p dependent although their spread is reduced considerably.
The examination of a breast with abnormal tissue was performed substantially the same way as the above-described examination of normal breast tissue. The breast tissue was first characterized by x-ray mammography and the size and location of a mass was determined. The examined breast was compressed between x-ray film case 90 and a support 12, as shown in Fig. 1C.
Input port 14 and output port 16 were selected so that mass 7 was located in optical field 96. .
The values of a and 8' measured around tumor 7 (using input output port set lOb of Fig. 1A) were compared to control data measured on the same breast (using input output port sets l0a and lOc of Fig. 1A).
The measured data were also correlated with pathology information on abnormalities in the examined breasts.
The abnormalities were divided into the following three categories: fibrocystic, Fibroadenoma, and Carcinoma.
Furthermore, these three categories are subdivided according to the size of the tumors as follows: smaller in diameter than 1 cm, and equal or larger in the diameter than 1 cm. Preliminary data measured on over fifty patients show an increase in the values of both a and 8' when compared with normal tissue but statistical significance has not been demonstrated.
Other embodiments are within the following claims:
pattern, the shallow boundary is due to the escape of photons ttiat reach the ai..r-RCatterer interface while ttie deeper boundary is due to attenuation of long path photons by the absorbers. The penetration depth of the photons is about one half of ttie port separation (p).
During the screening procedure, the computer calculates A. and e for ttie entire breast and compares the measured values with ttirestiold values of m atid l.cA of normal tissue or series of . and It. values of different homogeneous tumor types. As is shown in Figs. 5A throuqh 5F, from one person to another there is some variation in a and p for normal tissue, but only a very smal.l. variation between the left breast and the right breast: of the same person. Cancerous tissue, whicti is usuall.y highly perfused, exhibits higher values of IL A and Itp than fibrous tissue. Normal tissue, whicii has a relatively hiqh amount of fat, exhibits ttie lowest values of g and B.
Alternatively, instead of calculating A and ;Lq, the system can calcu:late an average pattilenqth of the migrating photons. From the detected and deconvoluted photon intensity profile, R(t), a mean pattilength of the distribution of pathlengths <L> is determined as follows:
c fo-_t (t) t at.
< L > (5) .z-(r)at ~
V 95/02987 I'CT1US94/07984 _ 14 -wtierein c is the speed of light in vacuum and nft 1.36 is the average refractive index of tissue.
If a breast tumor is outside of the optical field, it does not alter the banana-shaped distribution of pathlengths. As the optical field is moved closer to the breast tumor, which is a strongly absorbing mass, the photons that have migrated ttie farthest distance from the input and detection ports are elimiriated by the absorption process. Since photons with ttie longest pathlengths are absorbed by the mass, the system detects reduction in the average pathlength. When the optical field is moved even closer to the mass, some of the detected photons now migrate around the mass without being absorbed;
this is detected as lengthening of the distribution of pathlengths. Thus, the average pathlength measurement can reveal location of the breast mass.
In the screening process, the breast tissue is characterized by several tissue variables which may be used alone or in combination. TRS device 20 measures the absorption coefficient, the scattering coefficient, the blood volume or tissue oxygenation using one or more selected wavelengths of the laser. The wavelengths are sensitive to naturally occurring pigments or contrast agents that may be preferentially absorbed by ttie diseased tissue. Suitable naturally occurring pigments are, for example, hemoglobin (Hb) or oxytiemoglob:i.n (11b02) sensitive to 754 nm and 816 nm, respectively.
Alternatively, suitable color dyes, such as cardio-green or indocyiniri-green, may be injected to the blood system alone or bound to a vetaicle sucti as a gadolinium contrast agent, which is preferentially absorbed by tumors in ttie first five to ten minutes. An appropriate wavelength is selected for ttie color dye, for example, cardio-green exhibits maximuin absorption at 805 rim.
~
WO 95/02987 I'( T/US94/07989 21 fi7 179 The computer can create "maps" of the breast by mapping the spacial variatian of the measured values for at F blood volume or hemoglobin saturation. 'I'he resolutiori is enhanced when several tissue variabl.es are mapped. The blood volume is measured using a, pair of contrabestic wavelertgths (e.g., 754 nm and 816 nm) or the isobestic wavelength (i.e., 805 nm). 'Che hemoglobiti saturation (Y) is measured at two wavelengths (e.g., 754 nm and 816 nm) and is calculated by taking ttie ratio of absorptiott coef f icients at these wavelengths atid then using the following equatioti:
ra Y(X100$) -_ 1as~ (6) eiF
wherein the coefficients are determined from the extinction values of hemoglobin at 754 nm and 816 nm that are sHb - 0.38 cm-i mM-1, strb - 0.18 cm-1mM-1 , respectively, and the difference in extinction coefficierits between oxyhemogl.ob.in and hemoglobin that are AEHbO-Hb - 0.025 cm-1 mM-1 and AFttbO-Hb ' 0.03 cm-1 mM-1, respectively.
In another preferred embodiment, TRS apparatus 20 is used in combinatiori with x-ray mammography. The combined procedure is performed if a suspected mass is detected by the above-described optical method, x-ray mammography or anotlier screening method.
Referring to Fi.g. 1H, breast 5 i.s compressed in either a horizontal or vertical position between an x-ray film case 90 with the x-ray film and a support 11 with input ports and output ports located on a grid. An x-ray mammogram is taken to determine location of suspected mass 7 relative to ttie grid. Stiitable input port 14 and output port 16 are selected so ttrat the introducPd ~
95/029$7 YC'I'/US94/07981 -.16 optical field 92 ericompasses mass 7. Ttien, TRS apparatus 20A or 20B is used to meastire iig, E..rH, ttho blood volume or oxygen concentration of the examitied tissue using the above-described techniques. The measured values are again compared to the values corresporiding to normal tissue or different types of di.seased tissue to characterize the mass. If an unequivocal result is obtained, an exploratory excisiona]. biopsy is not iieeded.
In another preferred einbadimerit, TRS apparatus 20 is used in combination with the needie localization procedure. The needl.e localization procedure locates ttie mass that is then examined by system 4. Furthermore, a needle used in the rieedle localization procedure may introduce an optical fiber directly to mass 7.
Referring to Figs. 1C and 1D, breast 5 is compressed between x-ray film case 90 and a support 12 with input ports and output ports located on a grid and a centrally located opening for a needle 94 or a needle 98. One or more x-ray mammograms are takeri to determine the location of suspected mass 7 relative to the grid and to the needle opening. The needle is inserted into ttie breast and the needle tip is positioned in the center of mass 7.
Additional x-ray mammograms may be takeri to verify or adjust the position of the needle.
As shown in Fig. 1C, if the needle is used only to localize mass 7, i.nput port 14 and output port 16 are selected so that their separation is equal or larger than two times the deptki of mass 7. This separation assures that the introduced optical field 96 encompasses mass 7.
After needle 94 is positioned, a tiriy wire is inserted into the mass and left there far marking purposes. TRS
apparatus 20 measures a, blood volume or oxygen concentration of the examined tissue using the above-described techniques. The measured values are again compared to the values of normal tissue and ~
_ . ..,., .. . .. .,. , _ . .,. .. ..,,. ~. . ...:.., _. ..,,. .. .. .
different types of diseased tissue, and to characterize the tissue of mass 7.
As shown in Fig 1D, needle 98 positions an end 99 of optical input fiber 15 directly inside mass 7. Here, the optical fiber with a diameter of about 100 pm or less is threaded inside needle 98 and end 99 is slightly extended from the needle so that the introduced photons are directly coupled to mass 7. The location of detection port 16 defines optical field 100. In this arrangement, all detected photons migrate in the targeted tissue; this increases the relative amount of the targeted tissue being examined and thus increases the resolution of the system. To compare tissue of mass 7 with normal tissue, the same geometry of the input port and the detection port is used to measure the optical properties of the coritralateral breast. Alternatively, in the same breast, rieedle 98 is moved outside of: mass 7 so that the positions of the optical fiber end 99 and detection port 16 define an optical field completely removed from mass 7.
To characterize the mass, the values of p,, and u9 measured for mass 7 are compared either to the values of normal tissue measured in the same arrangement or to values of different types of diseased tissue.
In another embodiment, the detection contrast is enhanced using fluorescing contrast agents. A tumor is permeated with a fluorescing coritrast agent that has a decay time of less than 1 risec, and the labeled tumor is then again examined using TRS device 20. Suitable agents emit fluorescing radiatiori in the range of 800 nm t:o 1000 nm, for example, carbocyanene dyes or porphoriri compotinds.
Referririg to Fig. 4, the fluorescirig contrast agent is injected to the blood systein alone or bound to a vehicle, such as a gadolinium coritrast agent, which is initially preferentially absorbed by a breast tumor_.
~
V 95/02987 I'C1'/US94/07984 ' - 18 -Alternatively, the fluorescitig ageiit is injected directly into the tumor. TRS device 20 getierates 150 psec light pulses introduced into breast 5 at input port 14. The introduced photons of selected excitation wavelength reach tumor 7 and excite a fluorescing radiation 110, which propagates in all directions from tumor.7. Ttie photons of fluorescing radiation 110 migrate in ttie examined breast tissue and some of them arrive at output port 16. output port 16 has an interference filter that passes only photons at the wavelength of fluorescing ' radiation 110. Optical fiber 17 collects the transmitted photons,'which are delivered to the PM'I' detector. System 4 may detect fluorescing radiation 110 at several output ports at the same time or move the ports to different positions on the fiber optic support.
TRS device 20 detects the ptilses of fluorescing radiation 110; the shape of these pulses depends on the decay time of the fluorescing agent and optical.
properties of both the tumor tissue and the normal breast tissue.
In another embodiment, referring to Figs. 4A and 4B, TRS apparatus 20 is used in combination with MRI.
MRI examines the breast with or without using a rare earth contrast agent. A network of surface coils 112 is cooperatively arranged with a fiberoptic support 114, which is constructed for use with MRI. The network of coils 112 and support 114 are appropriately located around the examined breast. At ttie same time as ttie MRI
data are collected, TRS apparatus 20 collects the optical data. If an abnormal mass is detected, MRI
.identifies the size atid location of ttie mass. The optical data are theri used to characterize the mass.
optical contrast agents may be used alone or in combination with the rare earth contrast agents, as described above.
~
_ ... . ..... .,...
BBPERIMENTB:
Preliminary experiments were conducted under a pre-approved protocol and after receiving informed consent of women with normal breast tissue and of women having a mass detected in their breast.
The examination of normal breast tissue was performed at several different locations of the right and left breast of the same woman. Referring to Figs. 2 and 3, letters RR, LR, LR and LL denote the right and left breast and the right and left breast side where the input and detection ports were located, respectively. Figs. 5A
and 5B summarize the absorption coefficient ( a) and the scattering coefficient ( e'= (1-g)= B), respectively, measured on the right and left breast at a separation p 6 cm. The values of a and e' for the right breast are identical to the values for the left breast within the measurement error. Figs. 5C and 5D summarize a, s', respectively, for the tissue on the left side and the right side of each breast,.and Figs. 5E and 5F summarize a, s', respectively, for the tissue located at different distances from the chest wall. The data shown in Figs.
5A through 5F confirm that there is no significant difference in the optical properties measured over the entire breast.
The examination of normal breast tissue also measured differences in the optical properties corresponding to the volume of the breast, type of the breast tissue, the age of the woman and ethnic background. Based on the decreasing X-ray background absorption, the breast tissue was categorized as "dense", "fatty", or a "mixture" of the two tissue types. The values of a and B' of "fatty" tissue are lower than for "dense" tissue, which has a higher fibrous content.
Since the shape of the breast varies, it was difficult to ._....~..aw,.~~..w~.M....~.~.~.~.. ., .....,. ..... ,...um....u........ ....
.. ........
WO 95/02987 2~ ~~ 17Q PCT/US94/07984 categorize precisely the breast volume. For the volume measurement, the breast was stabilized on a plate and the length was measured from the chest to the end of the breast. The width and the thickness were measured at approximately 1 cm from the chest. Tissue of a large volume breast exhibits lower values of a and s' than that of a small volume breast. The same trend is observed for women above the age 50 when compared to women below 50. Figs. 6A and 6B display values of a and B', respectively, for Caucasians and African-Americans.
Normal breast tissue of Caucasians and African-Americans exhibits substantially the same optical properties except for the values of s' measured at the 4 cm separation.
Since the skin forms a higher relative percentage of the examined tissue at a smaller separation of the input and output ports, the lower values of e' may be due to a lower scattering coefficient of the skin with more pigment.
In all measurements, a smaller separation of the input and output ports yielded larger values of A. and 8' than a larger separation of the ports. This differences can be explained by violation of the semi-infinite boundary conditions at the smaller separations, i.e., a larger escape of photons through the tissue surface before they are collected by optical fiber 17.
Furthermore, this dependence exists since the slope of the photon decay was measured not sufficiently far from the peak of the reflectance data as expressed in Eqs. 1, 2 and 3. This problem arises due to a low photon count of approximately 10,000 counts at the peak. Thus the measured data have a low signal to noise ratio and a reliable reflectance data can not be taken at t tmax.
The corresponding error in the absorption coefficient, E(p,t)I ab8, is determined using Eq. 7.
WO 95/02987 216 ?' 17 9 PCT/US94/07984 E(p, t) = C[ 2t + 4DCI' (7) The error of scattering coefficient, E(p,t, a)I sct, arises due to the error in the absorption coefficient.
The corresponding error is determined using Eq. S.
E(p, t, a) /sct = 31P 2 [4E(p, t) /~SC2tm2ax] -E(p, t) /,b6 (8) The preliminary values of a and g' corrected for the error using Eqs. 7. and 8 are shown in Table 1.
Separation Mean a Mean Mean g (cm) a Error 6 tmax (ns) Error Adjusted Adjus'ted 4 0.029 0.020 16.2 1.55 14.1 1 5 0.023 0.021 11.4 1.9 10.9 6 0.019 0.022 9.5 2.3 10.1 7 0.017 0.021 7.9 2.7 8.7 The corrected values of mean a for different separations, p, are substantially the same, but the corrected values of mean A. still are p dependent although their spread is reduced considerably.
The examination of a breast with abnormal tissue was performed substantially the same way as the above-described examination of normal breast tissue. The breast tissue was first characterized by x-ray mammography and the size and location of a mass was determined. The examined breast was compressed between x-ray film case 90 and a support 12, as shown in Fig. 1C.
Input port 14 and output port 16 were selected so that mass 7 was located in optical field 96. .
The values of a and 8' measured around tumor 7 (using input output port set lOb of Fig. 1A) were compared to control data measured on the same breast (using input output port sets l0a and lOc of Fig. 1A).
The measured data were also correlated with pathology information on abnormalities in the examined breasts.
The abnormalities were divided into the following three categories: fibrocystic, Fibroadenoma, and Carcinoma.
Furthermore, these three categories are subdivided according to the size of the tumors as follows: smaller in diameter than 1 cm, and equal or larger in the diameter than 1 cm. Preliminary data measured on over fifty patients show an increase in the values of both a and 8' when compared with normal tissue but statistical significance has not been demonstrated.
Other embodiments are within the following claims:
Claims (31)
1. An apparatus for in vivo examination of biological tissue of a subject, comprising:
a light source constructed and arranged to generate pulses of light of a wavelength in the visible or infra-red range, said pulses having duration of less than a nanosecond, said wavelength being sensitive to a contrast agent of known optical properties, a support, positionable relative to said tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, one of said input ports optically connected to said source and constructed and arranged to introduce into the tissue said generated pulses of light of said selected wavelength, each output port constructed and arranged to define a detection location of said tissue, said support being constructed and arranged for use inside an magnetic resonance imaging (MRI) magnet and is associated with MRI pick-up coil, a light detector optically connected to one of said output ports, constructed and arranged to detect over time photons of modified pulses that have migrated over scatter paths in said tissue to said output port and produce corresponding electrical signals, said distance specifying a volume of the examined tissue in which said pulses have migrated, a photon counter, connected to said detector, constructed and arranged to accumulate over time said electrical signals corresponding to a shape of said modified pulses, wherein said shape depends on absorptive and scattering properties of the tissue in which said photons migrate, and a processor, connected to said photon counter, constructed and arranged to calculate values of a scattering coefficient (µs) or an absorption coefficient (µa) of the examined tissue depending on said pulse shape, and determine a physiological property of the examined tissue based on said coefficient.
a light source constructed and arranged to generate pulses of light of a wavelength in the visible or infra-red range, said pulses having duration of less than a nanosecond, said wavelength being sensitive to a contrast agent of known optical properties, a support, positionable relative to said tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, one of said input ports optically connected to said source and constructed and arranged to introduce into the tissue said generated pulses of light of said selected wavelength, each output port constructed and arranged to define a detection location of said tissue, said support being constructed and arranged for use inside an magnetic resonance imaging (MRI) magnet and is associated with MRI pick-up coil, a light detector optically connected to one of said output ports, constructed and arranged to detect over time photons of modified pulses that have migrated over scatter paths in said tissue to said output port and produce corresponding electrical signals, said distance specifying a volume of the examined tissue in which said pulses have migrated, a photon counter, connected to said detector, constructed and arranged to accumulate over time said electrical signals corresponding to a shape of said modified pulses, wherein said shape depends on absorptive and scattering properties of the tissue in which said photons migrate, and a processor, connected to said photon counter, constructed and arranged to calculate values of a scattering coefficient (µs) or an absorption coefficient (µa) of the examined tissue depending on said pulse shape, and determine a physiological property of the examined tissue based on said coefficient.
2. An apparatus according to claim 1, wherein said support includes a network of coils cooperatively arranged and constructed for use with MRI.
3. An apparatus for in vivo examination of biological tissue of a subject, comprising:
a light source constructed and arranged to generate pulses of light of a wavelength in the visible or infra-red range, said pulses having duration of less than a nanosecond, said wavelength being sensitive to a contrast agent having known optical properties and being absorbed in an abnormal tissue, a support, positionable relative to said tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, one of said input ports optically connected to said source and constructed and arranged to introduce into the tissue said generated pulses of light of said selected wavelength, each output port constructed and arranged to define a detection location of said tissue, a light detector optically connected to one of said output ports, constructed and arranged to detect over time photons of modified pulses that have migrated over scatter paths in said tissue to said output port and produce corresponding electrical signals, said distance specifying a volume of the examined tissue in which said pulses have migrated, a photon counter, connected to said detector, constructed and arranged to accumulate over time said electrical signals corresponding to a shape of said modified pulses, wherein said shape depends on absorptive and scattering properties of the tissue in which said photons migrate, and a processor, connected to said photon counter, constructed and arranged to calculate values of a scattering coefficient (µs) or an absorption coefficient (µa) of the examined tissue depending on said pulse shape, and determine a physiological property of the examined tissue based on said coefficient.
a light source constructed and arranged to generate pulses of light of a wavelength in the visible or infra-red range, said pulses having duration of less than a nanosecond, said wavelength being sensitive to a contrast agent having known optical properties and being absorbed in an abnormal tissue, a support, positionable relative to said tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, one of said input ports optically connected to said source and constructed and arranged to introduce into the tissue said generated pulses of light of said selected wavelength, each output port constructed and arranged to define a detection location of said tissue, a light detector optically connected to one of said output ports, constructed and arranged to detect over time photons of modified pulses that have migrated over scatter paths in said tissue to said output port and produce corresponding electrical signals, said distance specifying a volume of the examined tissue in which said pulses have migrated, a photon counter, connected to said detector, constructed and arranged to accumulate over time said electrical signals corresponding to a shape of said modified pulses, wherein said shape depends on absorptive and scattering properties of the tissue in which said photons migrate, and a processor, connected to said photon counter, constructed and arranged to calculate values of a scattering coefficient (µs) or an absorption coefficient (µa) of the examined tissue depending on said pulse shape, and determine a physiological property of the examined tissue based on said coefficient.
4. An apparatus for in vivo examination of biological tissue of a subject, comprising:
a light source constructed and arranged to generate pulses of light of a wavelength in the visible or infra-red range, said pulses having duration of less than a nanosecond, said wavelength being an excitation wavelength of a fluorescing material included in a contrast agent of known optical properties, a support, positionable relative to said tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, one of said input ports optically connected to said source and constructed and arranged to introduce into the tissue said generated pulses of light of said selected wavelength, each output port constructed and arranged to define a detection location of said tissue, a light detector, optically connected to one of said output ports, including a filter constructed and arranged to pass only said fluorescent light emitted from said fluorescing material, said detector being constructed and arranged to detect over time fluorescent light of modified pulses that have migrated over scatter paths in said tissue after excitation to said output port and produce corresponding electrical signals, said distance specifying a volume of the examined tissue in which said pulses have migrated, a photon counter, connected to said detector, constructed and arranged to accumulate over time said electrical signals corresponding to a shape of said modified pulses, wherein said shape depends on absorptive and scattering properties of the tissue in which said photons migrate, and a processor, connected to said photon counter, constructed and arranged to calculate values of a scattering coefficient (µs) or an absorption coefficient (µa) of the examined tissue depending on said pulse shape, and determine a physiological property of the examined tissue based on said coefficient.
a light source constructed and arranged to generate pulses of light of a wavelength in the visible or infra-red range, said pulses having duration of less than a nanosecond, said wavelength being an excitation wavelength of a fluorescing material included in a contrast agent of known optical properties, a support, positionable relative to said tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, one of said input ports optically connected to said source and constructed and arranged to introduce into the tissue said generated pulses of light of said selected wavelength, each output port constructed and arranged to define a detection location of said tissue, a light detector, optically connected to one of said output ports, including a filter constructed and arranged to pass only said fluorescent light emitted from said fluorescing material, said detector being constructed and arranged to detect over time fluorescent light of modified pulses that have migrated over scatter paths in said tissue after excitation to said output port and produce corresponding electrical signals, said distance specifying a volume of the examined tissue in which said pulses have migrated, a photon counter, connected to said detector, constructed and arranged to accumulate over time said electrical signals corresponding to a shape of said modified pulses, wherein said shape depends on absorptive and scattering properties of the tissue in which said photons migrate, and a processor, connected to said photon counter, constructed and arranged to calculate values of a scattering coefficient (µs) or an absorption coefficient (µa) of the examined tissue depending on said pulse shape, and determine a physiological property of the examined tissue based on said coefficient.
5. An apparatus for in vivo examination of biological tissue of a subject, comprising:
a light source constructed and arranged to generate pulses of light of a wavelength in the visible or infra-red range, said pulses having duration of less than a nanosecond, a support, positionable relative to said tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, one of said input ports optically connected to said source and constructed and arranged to introduce into the tissue said generated pulses of light of said selected wavelength, each output port constructed and arranged to define a detection location of said tissue, said support including an optical material, at least partially surrounding the examined tissue for limiting escape of photons through the skin outside of said tissue or providing additional photon migration paths to said detector, a light detector optically connected to one of said output ports, constructed and arranged to detect over time photons of modified pulses that have migrated over scatter paths in said tissue to said output port and produce corresponding electrical signals, said distance specifying a volume of the examined tissue in which said pulses have migrated, a photon counter, connected to said detector, constructed and arranged to accumulate over time said electrical signals corresponding to a shape of said modified pulses, wherein said shape depends on absorptive and scattering properties of the tissue in which said photons migrate, and a processor, connected to said photon counter, constructed and arranged to calculate values of a scattering coefficient (µs) or an absorption coefficient (µa) of the examined tissue depending on said pulse shape, and determine a physiological property of the examined tissue based on said coefficient.
a light source constructed and arranged to generate pulses of light of a wavelength in the visible or infra-red range, said pulses having duration of less than a nanosecond, a support, positionable relative to said tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, one of said input ports optically connected to said source and constructed and arranged to introduce into the tissue said generated pulses of light of said selected wavelength, each output port constructed and arranged to define a detection location of said tissue, said support including an optical material, at least partially surrounding the examined tissue for limiting escape of photons through the skin outside of said tissue or providing additional photon migration paths to said detector, a light detector optically connected to one of said output ports, constructed and arranged to detect over time photons of modified pulses that have migrated over scatter paths in said tissue to said output port and produce corresponding electrical signals, said distance specifying a volume of the examined tissue in which said pulses have migrated, a photon counter, connected to said detector, constructed and arranged to accumulate over time said electrical signals corresponding to a shape of said modified pulses, wherein said shape depends on absorptive and scattering properties of the tissue in which said photons migrate, and a processor, connected to said photon counter, constructed and arranged to calculate values of a scattering coefficient (µs) or an absorption coefficient (µa) of the examined tissue depending on said pulse shape, and determine a physiological property of the examined tissue based on said coefficient.
6. An apparatus according to any one of claims 1 to 5, wherein said photon counter is constructed to accumulate over time said electrical signals of the detected photons including a corresponding photon migration time and determine therefrom a shape of said modified pulses, and said processor determining said scattering coefficient (µs) or said absorption coefficient (µa) based on said shape of said modified pulses.
7. An apparatus according to any one of claims 1 to 5, wherein said photon counter includes a gated integrator and an integrator timing control constructed and arranged to receive said signals and to integrate said detected photons over at least two selected time intervals separately spaced over the arrival time of said modified pulses, and said processor calculating said absorption coefficient (µa) based on the number of photons integrated over each time interval.
8. An apparatus according to claim 7, wherein said gated integrator, said integrator timing control, and said processor are further constructed and arranged to determine the delay time (t max) between a time when a pulse is introduced and a time at which the corresponding modified pulse has the maximum value, and said processor being further programmed to determine the effective scattering coefficient (1-g)µs of the examined tissue.
9. An apparatus according to any one of claims 6 to 8, wherein said processor is further constructed and arranged to compare said calculated values of the scattering coefficient or the absorption coefficient to selected values of the scattering coefficient or the absorption coefficient, respectively.
10. An apparatus according to any one of claims 1 to 9, wherein said support is constructed and arranged to be positioned on the breast of a female subject.
11. An apparatus according to claim 10, wherein said input port and said output port of said support are touching the skin of the breast.
12. An apparatus according to claim 10, wherein said support is further constructed and arranged to enable movement of at least one of said input port and said output port.
13. An apparatus according to claim 10, wherein said support further comprises an opening constructed and arranged to accommodate a needle used in said needle localization procedure.
14. An apparatus according to claim 10, wherein said support includes a pliable material.
15. An apparatus according to claim 10, wherein said support includes a rigid material shaped for said examination.
16. A method for examination of biological tissue of a subject using pulses of light of a selected wavelength, said method comprising the steps of:
providing a support, positionable relative to the examined tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, each output port constructed and arranged to define a detection location of said tissue, selecting locations of said input and output ports to examine a tissue region, introducing into the tissue, at said input port, pulses of light wavelength in the visible or infra-red range, said pulse having duration of less than a nanosecond, said wavelength being sensitive to a contrast agent of known optical properties present in the blood stream of said subject, said contrast agent modifying photons of said pulses while migrating in said tissue, detecting over time, at said detection port, photons of modified pulses that have migrated over scatter paths in the examined tissue, accumulating, over arrival time of said detected photons, electrical signals corresponding to said detected photons of said modified pulses, a shape of said modified pulses depends on absorptive and scattering properties of the tissue in which said photons migrate, calculating values of a scattering coefficient (µs) or an absorption coefficient (µa) of the examined tissue depending on said pulse shape, and characterizing the examined tissue based on said values of the scattering coefficient or the absorption coefficient.
providing a support, positionable relative to the examined tissue, comprising a set of input ports and a set of output ports separated by a selected distance, each input port constructed and arranged to define an irradiation location of said tissue, each output port constructed and arranged to define a detection location of said tissue, selecting locations of said input and output ports to examine a tissue region, introducing into the tissue, at said input port, pulses of light wavelength in the visible or infra-red range, said pulse having duration of less than a nanosecond, said wavelength being sensitive to a contrast agent of known optical properties present in the blood stream of said subject, said contrast agent modifying photons of said pulses while migrating in said tissue, detecting over time, at said detection port, photons of modified pulses that have migrated over scatter paths in the examined tissue, accumulating, over arrival time of said detected photons, electrical signals corresponding to said detected photons of said modified pulses, a shape of said modified pulses depends on absorptive and scattering properties of the tissue in which said photons migrate, calculating values of a scattering coefficient (µs) or an absorption coefficient (µa) of the examined tissue depending on said pulse shape, and characterizing the examined tissue based on said values of the scattering coefficient or the absorption coefficient.
17. A method of claim 16, wherein said accumulating step includes registering said electrical signals individually with a corresponding photon migration time to determine a shape of said modified pulses and said calculating of said scattering coefficient (µs) or said absorption coefficient (µa) is based on said shape.
18. A method of claim 16, wherein said accumulating step includes integrating said photons over at least two selected time intervals separately spaced over the arrival time of said modified pulses, and said calculating of said absorption coefficient (µa) is based on the number of photons integrated over each time interval.
19. A method of claim 18, wherein said integrating and calculating steps further comprise:
integrating said photons over other selected time intervals separately spaced over the arrival time of said modified pulses, determining the time delay (t max) between a time when a pulse is introduced and a time at which the corresponding modified pulse has the maximum value, based on the number of photons integrated over said time intervals, and calculating a value of a scattering coefficient (µs) of the examined breast tissue by employing said absorption coefficient and said time delay.
integrating said photons over other selected time intervals separately spaced over the arrival time of said modified pulses, determining the time delay (t max) between a time when a pulse is introduced and a time at which the corresponding modified pulse has the maximum value, based on the number of photons integrated over said time intervals, and calculating a value of a scattering coefficient (µs) of the examined breast tissue by employing said absorption coefficient and said time delay.
20. A method of claim 16 or claim 19 wherein, upon determining that said calculated values match selected values of abnormal tissue, said method further comprising the steps of:
selecting another location of said input port and said output port to define a new tissue region proximate to said region having said calculated values matching said selected values of abnormal tissue, repeating said steps of introducing light, detecting, accumulating and calculating to determine values of the scattering coefficient (µs) or the absorption coefficient (µa)of the newly selected tissue region, and localizing said region of said selected values of abnormal tissue by comparing calculated values of the scattering coefficient (µs) or the absorption coefficient (µa) of different selected tissue regions.
selecting another location of said input port and said output port to define a new tissue region proximate to said region having said calculated values matching said selected values of abnormal tissue, repeating said steps of introducing light, detecting, accumulating and calculating to determine values of the scattering coefficient (µs) or the absorption coefficient (µa)of the newly selected tissue region, and localizing said region of said selected values of abnormal tissue by comparing calculated values of the scattering coefficient (µs) or the absorption coefficient (µa) of different selected tissue regions.
21. A method of claim 20, wherein said localization step includes determining the size of abnormal tissue region.
22. A method according to any one of claims 16 to 21, wherein said support is positioned on the breast of a female subject and said characterizing step further includes comparing said calculated values of the scattering coefficient or the absorption coefficient to selected values of the scattering coefficient or the absorption coefficient, respectively.
23. A method of claim 22, wherein said selected values correspond to values of the scattering coefficient (µs) or the absorption coefficient (µa) corresponding to selected tissue masses, respectively.
24. A method of claim 23, wherein said tissue masses comprise one of member selected from the group consisting of carcinoma tissue, fibroadenoma tissue and fibrocystic tissue.
25. A method of claim 23, wherein said selected values correspond to one member selected from the group consisting of normal breast tissue of the examined breast, normal breast tissue of the contralateral breast and a homogenous breast tumor.
26. A method of claim 20 wherein, upon determining that said calculated values match selected values of abnormal tissue, said method further comprising the steps of:
selecting another location of said input port and said output port to define a new tissue region proximate to said region having said calculated values matching said selected values of abnormal tissue;
repeating said steps of introducing light, detecting, accumulating and calculating to determine values of the scattering coefficient (µs) or the absorption coefficient (µa) of the newly selected tissue region; and localizing said region of said selected values of abnormal tissue by comparing calculated values of the scattering coefficient (µs) or the absorption coefficient (µa) of different selected tissue regions.
selecting another location of said input port and said output port to define a new tissue region proximate to said region having said calculated values matching said selected values of abnormal tissue;
repeating said steps of introducing light, detecting, accumulating and calculating to determine values of the scattering coefficient (µs) or the absorption coefficient (µa) of the newly selected tissue region; and localizing said region of said selected values of abnormal tissue by comparing calculated values of the scattering coefficient (µs) or the absorption coefficient (µa) of different selected tissue regions.
27. A method of claim 26, wherein said localization step includes determining the size of abnormal tissue region.
28. A method of claim 16, wherein said contrast agent that is absorbed by abnormal tissue.
29. A method of claim 16, wherein said contrast agent that is fluorescing when irradiated, and said detecting step includes detecting the fluorescent radiation.
30. A method of claim 16, wherein said contrast agent that is also magnetically active and said method further including performing magnetic resonance imaging (MRI) examination.
31. A method according to any one of claims 16 to 30, further including performing x-ray mammography.
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|---|---|---|---|
| US08/093,208 | 1993-07-16 | ||
| US08/093,208 US5555885A (en) | 1988-12-21 | 1993-07-16 | Examination of breast tissue using time-resolved spectroscopy |
| PCT/US1994/007984 WO1995002987A2 (en) | 1993-07-16 | 1994-07-15 | Examination of breast tissue using time-resolved spectroscopy |
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| CA2167179A1 CA2167179A1 (en) | 1995-02-02 |
| CA2167179C true CA2167179C (en) | 2010-04-20 |
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| CA2167179A Expired - Lifetime CA2167179C (en) | 1993-07-16 | 1994-07-15 | Examination of breast tissue using time-resolved spectroscopy |
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| US (2) | US5555885A (en) |
| EP (1) | EP0708616A4 (en) |
| JP (1) | JP3718224B2 (en) |
| CN (1) | CN1253127C (en) |
| CA (1) | CA2167179C (en) |
| WO (1) | WO1995002987A2 (en) |
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- 1994-07-15 CA CA2167179A patent/CA2167179C/en not_active Expired - Lifetime
- 1994-07-15 WO PCT/US1994/007984 patent/WO1995002987A2/en not_active Application Discontinuation
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1995
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| JPH09500304A (en) | 1997-01-14 |
| EP0708616A1 (en) | 1996-05-01 |
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| CN1253127C (en) | 2006-04-26 |
| US5555885A (en) | 1996-09-17 |
| CA2167179A1 (en) | 1995-02-02 |
| JP3718224B2 (en) | 2005-11-24 |
| WO1995002987A3 (en) | 1995-04-06 |
| US5899865A (en) | 1999-05-04 |
| CN1126945A (en) | 1996-07-17 |
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