CA2173154A1 - Methods and apparatus for performing sonomammography and enhanced x-ray imaging - Google Patents

Methods and apparatus for performing sonomammography and enhanced x-ray imaging

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Publication number
CA2173154A1
CA2173154A1 CA002173154A CA2173154A CA2173154A1 CA 2173154 A1 CA2173154 A1 CA 2173154A1 CA 002173154 A CA002173154 A CA 002173154A CA 2173154 A CA2173154 A CA 2173154A CA 2173154 A1 CA2173154 A1 CA 2173154A1
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CA
Canada
Prior art keywords
biological tissue
ultrasound images
ultrasonic transducer
ray
gel pad
Prior art date
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Granted
Application number
CA002173154A
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French (fr)
Other versions
CA2173154C (en
Inventor
Ascher Shmulewitz
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United States Surgical Corp
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Individual
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Filing date
Publication date
Priority claimed from US08/145,958 external-priority patent/US5474072A/en
Application filed by Individual filed Critical Individual
Priority to CA2694783A priority Critical patent/CA2694783C/en
Publication of CA2173154A1 publication Critical patent/CA2173154A1/en
Application granted granted Critical
Publication of CA2173154C publication Critical patent/CA2173154C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/44Constructional features of the ultrasonic, sonic or infrasonic diagnostic device
    • A61B8/4483Constructional features of the ultrasonic, sonic or infrasonic diagnostic device characterised by features of the ultrasound transducer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
    • A61B6/42Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment with arrangements for detecting radiation specially adapted for radiation diagnosis
    • A61B6/4291Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment with arrangements for detecting radiation specially adapted for radiation diagnosis the detector being combined with a grid or grating
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
    • A61B6/44Constructional features of apparatus for radiation diagnosis
    • A61B6/4417Constructional features of apparatus for radiation diagnosis related to combined acquisition of different diagnostic modalities
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
    • A61B6/50Clinical applications
    • A61B6/502Clinical applications involving diagnosis of breast, i.e. mammography
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
    • A61B6/52Devices using data or image processing specially adapted for radiation diagnosis
    • A61B6/5211Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data
    • A61B6/5229Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data combining image data of a patient, e.g. combining a functional image with an anatomical image
    • A61B6/5247Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data combining image data of a patient, e.g. combining a functional image with an anatomical image combining images from an ionising-radiation diagnostic technique and a non-ionising radiation diagnostic technique, e.g. X-ray and ultrasound
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/08Detecting organic movements or changes, e.g. tumours, cysts, swellings
    • A61B8/0825Detecting organic movements or changes, e.g. tumours, cysts, swellings for diagnosis of the breast, e.g. mammography
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/42Details of probe positioning or probe attachment to the patient
    • A61B8/4209Details of probe positioning or probe attachment to the patient by using holders, e.g. positioning frames
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/42Details of probe positioning or probe attachment to the patient
    • A61B8/4272Details of probe positioning or probe attachment to the patient involving the acoustic interface between the transducer and the tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/10Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges for stereotaxic surgery, e.g. frame-based stereotaxis
    • A61B90/14Fixators for body parts, e.g. skull clamps; Constructional details of fixators, e.g. pins
    • A61B90/17Fixators for body parts, e.g. skull clamps; Constructional details of fixators, e.g. pins for soft tissue, e.g. breast-holding devices
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
    • A61B10/02Instruments for taking cell samples or for biopsy
    • A61B10/0233Pointed or sharp biopsy instruments
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/34Trocars; Puncturing needles
    • A61B17/3403Needle locating or guiding means
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00831Material properties
    • A61B2017/00902Material properties transparent or translucent
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00831Material properties
    • A61B2017/00902Material properties transparent or translucent
    • A61B2017/00924Material properties transparent or translucent for ultrasonic waves
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/16Details of sensor housings or probes; Details of structural supports for sensors
    • A61B2562/168Fluid filled sensor housings
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S128/00Surgery
    • Y10S128/915Ultrasound mammography

Abstract

Apparatus (10) is provided that combines mammography equipment with an ultrasonic transducer (16) to generate ultrasonic images of the internal structure of breast tissue that are in geometric registration with a mammogram. The apparatus includes a includes and sonolucent compression plate (15), and in alternative embodiments, a gantry driven ultrasound transducer (16) or a phased array ultrasonic transducer. Methods are provided for generating a mammogram and a plurality of corresponding ultrasound images without moving the breast between the mammogram exposure and the ultrasound imaging. Methods are also provided for viewing and analyzing the ultra sound images. Apparatus and methods are also provided for enhancing X-ray images obtained from conventional mammographic systems, and with reduced overall X-ray dosage to the patient.

Claims (48)

1. Apparatus (10, 50, 70) for generating a plurality of ultrasound images of a biological tissue, the apparatus for use with an X-ray system (13, 14, 20, 53, 54, 58) that forms an image of the biological tissue in a receptor (22, 59, 75), the apparatus comprising an ultrasonic transducer (16, 57, 76) and a compression surface (15, 56, 72) against which the biological tissue is immobilized, the apparatus (10, 50, 70) characterized in that the ultrasonic transducer (16, 57, 76) generates a plurality of ultrasound images of the biological tissue while the biological tissue remains immobilized against the compression surface (15, 56, 72), so that the plurality of ultrasound images may be geometrically registered with the image formed in the receptor (22, 59, 75).
2. The apparatus (10) as defined in claim 1, wherein the compression surface is the lower surface of a compression plate (15) that is sonolucent and radiolucent, the compression plate (15) has an upper surface and the ultrasonic transducer (16) is disposed adjacent the upper surface, the apparatus further comprising drive means (25) for moving the ultrasonic transducer (16) across the upper surface.
3. The apparatus (10) as defined in claim 2 wherein the compression plate (15) comprises a material selected for a group consisting of a polyimide, a sodium-based ionomer, and a polymethyl pentene.
4. The apparatus (10) as defined in claim 2 wherein the compression plate (15) comprises a polymethyl pentene.
5. The apparatus (10) as defined in claim 3 or 4 wherein the material (95) hasa periphery and the material (95) is coupled around the periphery to a rigid frame (96).
6. The apparatus (10) as defined in any of claims 2 to 5 further comprising a gel pad (23) for acoustically coupling a portion of the biological tissue to the ultrasonic transducer (16).
7. The apparatus (10) as defined in claim 6 wherein the gel pad (23) is disposed against the compression surface and in contact with the biological tissue, and comprises a material that conforms to the shape of the biological tissue and has an X-ray attenuation characteristic near the X-ray attenuation characteristic of the biological tissue.
8. The apparatus (10) as defined in claim 7 wherein the X-ray system (13,14,20) emits X-ray radiation and the gel pad (23) reduces scattering of the X-ray radiation relative to scattering of the X-ray radiation in air.
9. The apparatus (10) as defined in any of claims 6 to 8 wherein the compression plate (15) imposes a force on the biological tissue to compress the biological tissue to a uniform thickness, and the gel pad (23) conforms to the non-uniform shape of the biological tissue to distribute the force and reduce discomfort in the patient.
10. The apparatus (10) as defined in any of claims 6 to 9 wherein the gel pad (23) comprises an adherent surface that assists in positioning the biological tissue relative to the compression surface.
11. The apparatus (10) as defined in any of claims 2 to 1 further comprising lubricating means (112) for providing a film of fluid between the ultrasonic transducer (16) and the compression plate (15) to lubricate and acoustically couple the ultrasonic transducer (16) and the compression plate (15).
12. The apparatus (10) as defined in any of claims 2 to 11 wherein the drive means (25) further comprises:
a gantry support (18);
a gantry (17) movably engaged with the gantry support (18) for movement in the distal and proximal directions;
a carriage (26) movably engaged with the gantry (17) for lateral movement.
13. The apparatus (10) as defined in claim 12 wherein the drive means (25) further comprises:
a first motorized cable arrangement (30) for driving the gantry (17) along the gantry support (18);
a second motorized cable arrangement (27) for driving the carriage (26) along the gantry (17); and circuitry (82) for controlling operation of the first and second motorized cablearrangements (30,27).
14. The apparatus (10) as defined in any of claims 2 to 13 further comprising:
a biopsy instrument support (40);
means (21) for aligning the biopsy instrument support with the ultrasonic transducer (16) so that a medical practitioner may perform a biopsy guided by the plurality of ultrasonic images.
15. The apparatus (50) defined in claim 1, wherein the compression surface (56)is radiolucent and the ultrasonic transducer (57) is disposed beneath the compression surface (56) and acoustically coupled thereto for transmitting acoustic energy to the biological tissue, the apparatus further comprising control circuitry (83) for activating the ultrasonic transducer (57).
16. The apparatus (50) as defined in claim 15 further comprising a gel pad (23)for acoustically coupling a portion of the biological tissue to the ultrasonic transducer (57).
17. The apparatus (50) as defined in claim 16, wherein the gel pad (23) is disposed against the compression surface (56) and in contact with the biological tissue, and the gel pad (23) comprises a material that conforms to the shape of the biological tissue and has an X-ray attenuation characteristic near the X-ray attenuation characteristic of the biological tissue.
18. The apparatus (50) as defined in claim 16 or 17 wherein the X-ray system (53,54,58) emits X-ray radiation and the gel pad (23) reduces scattering of the X-ray radiation relative to scattering of the X-ray radiation in air.
19. The apparatus (50) as defined in any of claims 16 to 18 wherein the compression surface (56) imposes a force on the biological tissue to compress the biological tissue to a uniform thickness, and the gel pad (23) conforms to the non-uniform shape of the biological tissue to distribute the force and reduce discomfort in the patient.
20. The apparatus (50) as defined in any of claims 16 to 19 wherein the gel pad(23) comprises an adherent surface that assists in positioning the biological tissue relative to the compression surface (56).
21. The apparatus (50) as defined in any of claims 15 to 20 wherein the ultrasonic transducer (16) comprises a multiplicity of piezoelectric transducer elements (63').
22. The apparatus (50) as defined in claim 21 wherein the control circuitry (83) further comprises circuitry for activating predetermined ones of the multiplicity of piezoelectric transducer elements to provide beam forming and elevational focussing of the acoustic energy.
23. The apparatus (50) as defined in claim 21 wherein the control circuitry (83) comprises circuitry for activating a predetermined plurality of the multiplicity of piezoelectric elements (63') to generate an ultrasonic image at a predetermined location, the apparatus further comprising:
a biopsy instrument support (40);
means (21) for aligning the biopsy instrument support with the predetermined plurality of piezoelectric elements so that a medical practitioner may perform a biopsy guided by the ultrasonic image at the predetermined location.
24. The apparatus (70) as defined in claim 1, wherein said compression surface (72) is a first compression surface, the ultrasonic transducer (76) is disposed between the first (72) and a second compression surface (73) and theapparatus further includes drive means (78) for moving the ultrasonic transducer (76) through a predetermined path between the first and second compression surfaces (72,73).
25. The apparatus (70) as defined in claim 24 further comprising a gel pad (77)for acoustically coupling a portion of the biological tissue to the ultrasonic transducer (76).
26. The apparatus (70) as defined in claim 25 wherein the gel pad (77) is disposed between the first and second compression surfaces (72,73) and in contact with the biological tissue, and the gel pad (77) comprises a material that conforms to the shape of the biological tissue and has an X-ray attenuation characteristic near the X-ray attenuation characteristic of the biological tissue.
27. The apparatus (70) as defined in claim 25 or 26 wherein the X-ray system emits X-ray radiation and the gel pad (77) reduces scattering of the X-ray radiation relative to scattering of the X-ray radiation in air.
28. The apparatus (70) as defined in any of claims 25 to 27 wherein the first and second compression surfaces (72,73) impose a force on the biological tissue, and the gel pad (77) conforms to the non-uniform shape of the biological tissue to distribute the force and reduce discomfort in the patient.
29. The apparatus (70) as defined in any of claims 25 to 28 wherein the gel pad (77) comprises an adherent surface that assists in positioning the biological tissue between the first and second compression surfaces (72,73).
30. A method of obtaining an X-ray image of a biological tissue and an ultrasound image of the biological tissue that may be geometrically registered with the X-ray image, comprising a series of steps of:
(a) immobilizing a biological tissue with respect to a reference point;
(b) exposing the biological tissue to X-ray radiation to generate an X-ray image of the biological tissue in a receptor;
(c) generating a plurality of ultrasound images of the biological tissue by acoustically coupling an ultrasonic transducer (16) to the biological tissue, without intervening movement of the biological tissue with respect to the reference point; and (d) displaying any one of the plurality of ultrasound images corresponding to a predetermined location on the X-ray image.
31. The method as defined in claim 30 wherein step (b) is performed after step (c).
32. The method as defined in claim 30 further comprising the steps of:
(e) repeatedly generating and displaying a plurality of ultrasound images on a timewise basis;
(f) inserting a biopsy instrument into the biological tissue so that a portion of the biopsy instrument is visible in the plurality of ultrasound images; and (g) maneuvering the biopsy instrument to a desired location within the biological tissue based on the X-ray image and the plurality of ultrasound images.
33. The method as defined in claim 30 further comprising steps of:
(e) storing the plurality of ultrasound images in a storage medium; and (f) retrieving any one of the plurality of ultrasound images from the storage medium corresponding to a predetermined location on the X-ray image.
34. The method as defined in any of claims 30 to 33 further comprising a step of processing the plurality of ultrasound images to enhance the diagnostic capabilities of those images.
35. The method as defined in claim 30 further comprising steps of:
(e) repeatedly generating and displaying a plurality of ultrasound images on a timewise basis at a location within the biological tissue;
(f) processing the plurality of ultrasound images at the location to provide an indicator corresponding to blood flow at that location.
36. The method as defined in claim 30 further comprising steps of:
(e) generating a plurality of Doppler signals for the biological tissue by acoustically coupling an ultrasonic transducer (16) to the biological tissue, without intervening movement of the biological tissue with respect to the reference point; and (f) displaying an indicator corresponding to the plurality of Doppler signals for a predetermined location on the X-ray image.
37. The method as defined in claim 30 further comprising a series of steps of:
(e) storing the plurality of ultrasound images in a storage medium; and (f) displaying selected ones of the plurality of ultrasound images to provide a holographic view of the interior features of the biological tissue.
38. The method as defined in claim 30 wherein the ultrasonic transducer (16) has a surface in an X-Y plane and each one of the ultrasound images comprises a multiplicity of digitally encoded data values obtained at a multiplicity of planes along a Z
axis orthogonal to the X-Y plane, the method further comprising the steps of:
(e) summing the multiplicity of digitally encoded data values along the Z axis to generate a projection of the plurality of ultrasound images into the X-Y plane; and (f) displaying the projection.
39. The method as defined in claim 38 further comprising a step of comparing the X-ray image to the projection to isolate selected ones of the interior features of the biological tissue.
40. The method as defined in claim 39 further comprising a step of colour codingthe X-ray image and the projection.
41. The method as defined in claim 39 wherein step (b) is performed after step (c).
42. The method as defined in claim 37 further comprising the steps of:
repeatedly generating and displaying a plurality of ultrasound images on a timewise basis;
inserting a biopsy instrument into the biological tissue so that a portion of the biopsy instrument is visible in the plurality of ultrasound images; and maneuvering the biopsy instrument to a desired location within the biological tissue based on the display of selected ones of the plurality of ultrasound images.
43. The method as defined in claim 37 further comprising the steps of:
repeatedly generating and displaying a plurality of ultrasound images on a timewise basis at a location within the biological tissue;
processing the plurality of ultrasound images at the location to provide an indicator corresponding to blood flow at that location.
44. The method as defined in claim 37 further comprising the steps of:
generating a plurality of Doppler signals for the biological tissue by acoustically coupling an ultrasonic transducer (16) to the biological tissue, without intervening movement of the biological tissue with respect to the reference point; and displaying an indicator corresponding to the plurality of Doppler signals.
45. A method as defined in claim 30 for use in screening the biological tissue for abnormalities wherein steps (a) through (c) are performed while a first compressive load is applied to the biological tissue, step (c) generating a first plurality of digitally encoded ultrasound images, the method further comprising the steps of:

(e) storing the first plurality of digitally encoded ultrasound images;
(f) applying a second compressive load to the biological tissue, the second compressive load different than the first compressive load;
(g) operating the ultrasound transducer (16) to generate a second plurality of digitally encoded ultrasound images of the biological tissue with respect to the reference point;
(h) digitally subtracting each one of the second plurality of digitally encoded ultrasound images from a corresponding one of the first plurality of digitally encoded ultrasound images with respect to the reference point;
(i) displaying the difference of first and second digitally encoded ultrasound images; and (j) comparing the difference of the first and second digitally encoded ultrasound images at a predetermined location to a corresponding location on the X-ray image.
46. The method as defined in claim 45 further comprising a step of color coding the first and second pluralities of digitally encoded ultrasound images.
47. Apparatus (10) for performing an image-guided biopsy comprising a compression plate (15) that is sonolucent, the compression plate having first and second surfaces, the first surface forming a compression surface against which the biological tissue is immobilized, an ultrasonic transducer (16) disposed adjacent the second surface, drive means (25) for moving the ultrasonic transducer (16) across the second surface while the biological tissue remains immobilized against the compression surface ( 15), the ultrasonic transducer (16) generating a plurality of ultrasound images of the biological tissue, and means (46) for displaying selected ones of the plurality of ultrasound images, the apparatus characterized by:
a biopsy instrument support (40); and means (21) for aligning the biopsy instrument support with the ultrasonic transducer (16), so that a medical practitioner may perform a biopsy guided by the plurality of ultrasonic images.
48. A method of obtaining an ultrasound image of interior features of a biological tissue, comprising a series of steps of:
immobilizing a biological tissue with respect to a reference point;
generating a plurality of ultrasound images of the biological tissue with respect to the reference point by acoustically coupling an ultrasonic transducer (16) to the biological tissue;
displaying selected ones of the plurality of ultrasound images;
repeatedly generating and displaying a plurality of ultrasound images on a timewise basis;
inserting a biopsy instrument into the biological tissue so that a portion of the biopsy instrument is visible in the selected ones of the plurality of ultrasound images;
and maneuvering the biopsy instrument to a desired location within the biological tissue based on the display of the selected ones of the plurality of ultrasound images.
CA2173154A 1993-10-29 1994-10-21 Methods and apparatus for performing sonomammography and enhanced x-ray imaging Expired - Fee Related CA2173154C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA2694783A CA2694783C (en) 1993-10-29 1994-10-21 Methods and apparatus for performing sonomammography and enhanced x-ray imaging

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US08/145,958 US5474072A (en) 1993-10-29 1993-10-29 Methods and apparatus for performing sonomammography
US08/145,958 1994-07-20
US08/277,894 1994-07-20
US08/277,894 US5479927A (en) 1993-10-29 1994-07-20 Methods and apparatus for performing sonomammography and enhanced x-ray imaging
PCT/US1994/012118 WO1995011627A1 (en) 1993-10-29 1994-10-21 Methods and apparatus for performing sonomammography and enhanced x-ray imaging

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CA2694783A Division CA2694783C (en) 1993-10-29 1994-10-21 Methods and apparatus for performing sonomammography and enhanced x-ray imaging

Publications (2)

Publication Number Publication Date
CA2173154A1 true CA2173154A1 (en) 1995-05-04
CA2173154C CA2173154C (en) 2010-03-23

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US (2) US5664573A (en)
EP (1) EP0730431B1 (en)
JP (3) JP3461509B2 (en)
AT (1) ATE191136T1 (en)
AU (1) AU8123494A (en)
CA (1) CA2173154C (en)
DE (1) DE69423778T2 (en)
WO (1) WO1995011627A1 (en)

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EP0730431A1 (en) 1996-09-11
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US5664573A (en) 1997-09-09
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ATE191136T1 (en) 2000-04-15
JP3461509B2 (en) 2003-10-27
US5938613A (en) 1999-08-17
EP0730431B1 (en) 2000-03-29
CA2173154C (en) 2010-03-23
JP2003325523A (en) 2003-11-18
JPH09504211A (en) 1997-04-28

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