U.S. patent application number 12/755261 was filed with the patent office on 2010-08-05 for remotely activated marker.
This patent application is currently assigned to SenoRx, Inc.. Invention is credited to Fred H. Burbank, Nancy Forcier, Michael L. Jones, Paul Lubock.
Application Number | 20100198059 12/755261 |
Document ID | / |
Family ID | 22912794 |
Filed Date | 2010-08-05 |
United States Patent
Application |
20100198059 |
Kind Code |
A1 |
Burbank; Fred H. ; et
al. |
August 5, 2010 |
REMOTELY ACTIVATED MARKER
Abstract
A biopsy site marker having at least one small marker body or
pellet of bioresorbable material such as gelatin, collagen,
polylactic acid, polyglycolic acid which has a radiopaque object,
preferably with a non-biological configuration. The at least one
bioresorbable body or pellet with a radiopaque object is deposited
into the biopsy site, by a delivery device that includes an
elongated tubular body with a piston slidable within the tubular
body. One end of the tube is placed into the biopsy site. At least
one but preferably several marker bodies or pellets are deposited
sequentially into the biopsy site through the tube. At least the
bioresorbable materials of the detectable markers remain present in
sufficient quantity to permit detection and location of the biopsy
site at a first time point (e.g., 2 weeks) after introduction but
clear from the biopsy site or otherwise do not interfere with
imaging of tissues adjacent the biopsy site at a second time point
(e.g., 5-7 months) after introduction.
Inventors: |
Burbank; Fred H.; (San Juan
Capistrano, CA) ; Lubock; Paul; (Laguna Niguel,
CA) ; Jones; Michael L.; (Capistrano Beach, CA)
; Forcier; Nancy; (Laguna Niguel, CA) |
Correspondence
Address: |
EDWARD J. LYNCH, PATENT ATTORNEY
FOUR EMBARCADERO CENTER, SUITE 1700
SAN FRANCISCO
CA
94111
US
|
Assignee: |
SenoRx, Inc.
|
Family ID: |
22912794 |
Appl. No.: |
12/755261 |
Filed: |
April 6, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12317100 |
Dec 18, 2008 |
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12755261 |
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11258324 |
Oct 25, 2005 |
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12317100 |
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10719448 |
Nov 21, 2003 |
6996433 |
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11258324 |
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10684124 |
Oct 10, 2003 |
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10719448 |
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10001043 |
Oct 31, 2001 |
6662041 |
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10684124 |
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09343975 |
Jun 30, 1999 |
6347241 |
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10001043 |
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09241936 |
Feb 2, 1999 |
6161034 |
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09343975 |
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Current U.S.
Class: |
600/431 ;
600/567 |
Current CPC
Class: |
A61M 37/0069 20130101;
A61B 2090/395 20160201; A61B 2090/3925 20160201; A61B 2090/3987
20160201; A61B 2090/3975 20160201; A61B 2090/3788 20160201; A61B
2090/3995 20160201; A61B 2090/3908 20160201; A61B 90/39 20160201;
A61B 2090/3933 20160201; A61B 2090/3929 20160201; A61K 49/006
20130101; A61B 10/02 20130101; A61B 2017/00004 20130101 |
Class at
Publication: |
600/431 ;
600/567 |
International
Class: |
A61B 6/00 20060101
A61B006/00; A61B 10/02 20060101 A61B010/02 |
Claims
1. A target tissue localization device for marking a biopsy cavity
site comprising: an elongate tubular member having a proximal end,
a distal end, and an inner lumen therebetween and at least one
bioabsorbable solid body having a radiographically detectable
component contained within the inner lumen of the elongate tubular
member and bioabsorbable powder within the inner lumen which are
collectively configured to at least partially fill the biopsy
cavity site when disposed therein.
2-17. (canceled)
18. A method for marking a biopsy cavity for subsequent remote
imaging, comprising: a. providing a target tissue localization
device for marking a biopsy cavity site comprising: an elongate
tubular member having a proximal end, a distal end, a discharge
opening at or near the distal end and an inner lumen extending to
and in fluid communication with the discharge opening and at least
one marker body having a transmitter or transponder that will emit
a detectable signal when interrogated; b. removing a biopsy
specimen from a breast of a patient, thereby creating a biopsy
site; c. inserting the at least one signal emitting body into the
biopsy site; and d. interrogating the signal emitting body to emit
a detectable signal which allows the operator to locate the biopsy
site.
19. The method of claim 18 wherein the marker body is interrogated
by an interrogating energy.
20. The method of claim 19 wherein the interrogating energy is
ultrasound.
21. The method of claim 18 wherein the marker body emits a
detectable radiofrequency or ultrasound signal when interrogated.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
11/258,324, filed Oct. 25, 2005, which is a continuation of
application Ser. No. 10/719,448, filed on Nov. 21, 2003, now U.S.
Pat. No. 6,996,433, which is a continuation of application Ser. No.
10/684,124, filed on Oct. 10, 2003, which is a continuation of
application Ser. No. 10/001,043, filed on Oct. 31, 2001, now U.S.
Pat. No. 6,347,241, which is a continuation of application Ser. No.
09/343,975, now U.S. Pat. No. 6,662,041, filed on Jun. 30, 1999,
and is a continuation-in-part application to application Ser. No.
09/241,936, filed on Feb. 2, 1999, now U.S. Pat. No. 6,161,034,
from which all priority is claimed and which all are incorporated
herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention is in the field of markers to be
employed at biopsy sites to permanently mark the site, and to
methods and apparatus for applying the permanent marker. More
particularly, the present invention relates to a marker that is
optimally adapted for marking biopsy sites in human breast tissue
with permanently placed markers that are detectable by X-ray.
BACKGROUND OF THE INVENTION
[0003] In modern medical practice small tissue samples, known as
biopsy specimens, are often removed from tumors, lesions, organs,
muscles and other tissues of the body. The removal of tissue
samples may be accomplished by open surgical technique, or through
the use of a specialized biopsy instruments such as a biopsy
needle. A well known state-of-the-art instrument that is often used
in connection with the practice of the present invention is known
as the "vacuum assisted large core biopsy device".
[0004] After a tissue sample has been removed, it is typically
subjected to diagnostic tests or examinations to determine
cytology, histology, presence or absence of chemical substances
that act as indicators for disease states, or the presence of
bacteria or other microbes. The above mentioned and other
diagnostic tests and examinations per se are well known in the art
and need not be described here. It is sufficient to note that the
information obtained from these diagnostic tests and/or
examinations is often of vital importance for the well-being of the
patient and is used to make or confirm diagnoses and often to
formulate treatment plans for the patient. As is known, obtaining a
tissue sample by biopsy and the subsequent examination are
frequently, almost invariably, employed in the diagnosis of cancers
and other malignant tumors, or to confirm that a suspected lesion
or tumor is not malignant, and are frequently used to devise a plan
for the appropriate surgical procedure or other course of
treatment.
[0005] Examination of tissue samples taken by biopsy, often by the
above-mentioned "vacuum assisted large core biopsy sampler" is of
particular significance in the diagnosis and treatment of breast
cancer which is the most common cancer suffered by women in the
U.S.A and elsewhere in the industrially developed world. Proper
diagnostic procedures, frequent examination by well known
techniques such as "mammography" and prompt subsequent surgical
treatment have, however, significantly reduced the mortality rate
caused by this form of cancer. For this reason, in the ensuing
discussion of the pertinent background art and in the ensuing
description the invention will be described as used for marking
biopsy sites in human and other mammalian breast, although the
invention is suitable for marking biopsy sites in other parts of
the human and other mammalian body as well.
[0006] Thus, as is known, when an abnormal mass in the breast is
found by physical examination or mammography a biopsy procedure
follows almost invariably. The nature of the biopsy procedure
depends on several factors. Generally speaking, if a solid mass or
lesion in the breast is large enough to be palpable (i.e., felt by
probing with the fingertips) then a tissue specimen can be removed
from the mass by a variety of techniques, including but not limited
to open surgical biopsy or a technique known as Fine Needle
Aspiration Biopsy (FNAB). In open surgical biopsy, an incision is
made and a quantity of tissue is removed from the mass for
subsequent histopathological examination. In the FNAB procedure, a
small sample of cells is aspirated from the mass through a needle
and the aspirated cells are then subjected to cytological
examination.
[0007] If a solid mass of the breast is small and non-palpable
(e.g., the type typically discovered through mammography), a
relatively new biopsy procedure known as "stereotactic needle
biopsy" may be used. In performing a stereotactic needle biopsy of
a breast, the patient lies on a special biopsy table with her
breast compressed between the plates of a mammography apparatus and
two separate digital x-rays are taken from two slightly different
points of view. A computer calculates the exact position of the
lesion with X and Y coordinates as well as depth of the lesion
within the breast. Thereafter, a mechanical stereotactic apparatus
is programmed with the coordinates and depth information calculated
by the computer, and such apparatus is used to precisely advance
the biopsy needle into the small lesion. Usually at least five
separate biopsy specimens are obtained from locations around the
small lesion as well as one from the center of the lesion.
[0008] After the biopsy sample is taken, it may take several days
or even a week before the results of the examination of the sample
are obtained, and still longer before an appropriate treatment
decision is reached. If the decision involves surgery it is clearly
important for the surgeon to find the location in the breast from
where the tumor tissue has been taken in the biopsy procedure, so
that the entire tumor and possibly surrounding healthy tissue can
be removed. For example, the particular treatment plan for a given
patient may require the surgeon to remove the tumor tissue and 1
centimeter of the tissue surrounding the tumor. A co-pending
application for United States Letters Patent by the same inventors
discloses markers which are particularly well adapted for marking
biopsy sites in the human breast, and which markers remain
detectable by X-ray, ultrasound or some other detection technique
only for a given time period (i.e. for 6 months) and slowly
disappear thereafter, for example by absorption into the body. The
purpose of such markers is to facilitate the surgical procedure
that is performed while the marker is still detectable. The
disappearance of the marker after a longer period of time may be
advantageous to avoid obscuring or interfering with follow-up
studies or further mammography or other imaging studies.
[0009] In connection with the background art the following specific
printed art is mentioned. U.S. Pat. Nos. 2,192,270 and 5,147,307
describe visually discernible markers that are applied externally
to the patient's skin. Radiographically (X-ray) detectable tissue
markers (e.g., clips or staples) that are attached to tissue
adjacent to the site from which the biopsy specimen has been
removed, are described in International Patent Publication No. WO
98/06346. Radiographically visible markers (e.g. marker wires) that
may be introduced into the biopsy site and are inserted through the
biopsy needle after a tissue sample is removed and which are
thereafter allowed to remain protruding from the patient's body,
are also described in WO 98/06346. However, due to the consistency
of breast tissue and the fact that these biopsy site markers are
typically introduced while the breast is still compressed between
the mammography plates, these biopsy markers of the prior art may
become attached to adjacent bands of connective tissue that do not
remain at the specific location of the biopsy after the breast has
been decompressed and removed from the mammography apparatus, and
may suffer from additional disadvantages as well.
[0010] Thus, there is still a need in the art for of biopsy site
markers that are deliverable into the cavity created by removal of
the biopsy specimen and not into tissue that is located outside of
that biopsy cavity, and which will not migrate from the biopsy
cavity even when the breast tissue is moved, manipulated or
decompressed. Moreover, such desired markers should remain
detectable at the biopsy site i.e. within the biopsy cavity for an
indefinite time period, and still should not interfere with imaging
of the biopsy site and adjacent tissues at a later point of time,
and most importantly should be readily distinguishable in the
various imaging procedures from lines of calcifications which
frequently are signs for a developing malignancy. The present
invention provides such permanent biopsy site markers as well as
apparatus and method for delivering such markers into the biopsy
cavity.
SUMMARY OF THE INVENTION
[0011] It is an object of the present invention to provide a biopsy
site marker that is deliverable into the cavity created by removal
of the biopsy specimen.
[0012] It is another object of the present invention to provide a
biopsy site marker that does not migrate from the biopsy cavity
even when the surrounding tissue is moved, manipulated or
decompressed.
[0013] It is still another object of the present invention to
provide a biopsy site marker that meets the foregoing requirements
and that remains detectable at the biopsy site for an indefinite
period of time.
[0014] It is yet another object of the present invention to provide
a biopsy site marker that meets the foregoing requirements and that
is readily distinguishable by X-ray from granules or lines of
calcifications which frequently are signs for a developing
malignancy.
[0015] It is a further object of the present invention to provide
an apparatus and method for placing into the biopsy cavity a biopsy
site marker that meets the foregoing requirements.
[0016] These and other objects and advantages are attained by a
biopsy site marker that comprises small bodies or pellets of
gelatin which enclose substantially in their interior a radio
(X-ray) opaque object. The gelatin pellets are deposited into the
biopsy site, typically a cylindrical opening in the tissue created
by the recent use of a vacuum assisted large core biopsy device, by
injection from an applicator through a tube that is placed into the
biopsy site. Typically, several gelatin pellets, only some of which
typically do, but all of which may contain the radio opaque object,
are deposited sequentially from the applicator into the site
through the tube. The radio opaque objects contained in the gelatin
bodies have a non-biological shape or configuration to be
identifiable as a man-made object such that in observation by
typical mammography equipment, that is when viewed from at least
two different viewing angles, they do not assume the shape of a
line, whereby they are readily distinguishable from granules or
lines of calcification.
[0017] The present invention also provides chemical preparations
and methods for marking biopsy sites, whereby a detectable marker
(i.e., a substance or article that is detectable by imaging and/or
palpation and/or visualization) is introduced into the cavity
created by removal of a biopsy specimen (e.g., the "biopsy cavity")
such that (i) the marker will remain present and detectable at the
biopsy at a first time point (e.g. 2 weeks after introduction), and
(ii) the marker will clear sufficiently from the biopsy site, or
will otherwise be undetectable by imaging so as not to interfere
with follow-up imaging of the biopsy site and adjacent tissues at a
second time point (e.g. typically 5-8 months and preferably at
about 6 months after introduction).
[0018] A. Types of Markers
[0019] (i) Imageable Embodiments of the Marker
[0020] In embodiments of the invention wherein the marker is
detectable by imaging, it will typically be imageable by a suitable
imaging means or apparatus. For example, the marker may be
radiographically visible (e.g., more radiopaque or more radiolucent
than the surrounding tissue so as to be imageable by x-ray, CT
scan, mammography, fluoroscopy, or other roentgenological means. In
other imageable embodiments, the marker may be imageable by other
means such as magnetic resonance imaging (MRI), ultrasound,
Doppler, or other presently known or hereafter invented imaging
techniques.
[0021] (ii) Palpable Embodiments of the Marker
[0022] In embodiments of the invention wherein the marker is
detectable by palpation, the marker will comprise a space occupying
substance or object(s) that, when introduced into the cavity
created by the removal of the biopsy specimen, will form a palpable
mass that can be located by closed palpation of the breast and/or
by local palpation by a surgeon during dissection of the
surrounding breast tissue. Space occupying markers that are
palpable include balloon(s), beads, microspheres, of flowable
bulking materials such as collagen.
[0023] (iii) Visually Discernible Embodiments of the Marker
[0024] In embodiments of the invention wherein the marker is
visually detectable, the marker will comprise a substance or
object(s) that is of a color that is different from the color of
breast tissue and blood such that, when introduced into the cavity
created by the removal of the biopsy specimen, the marker will be
visually detectable by a surgeon during dissection of the
surrounding breast tissue.
[0025] (iv) Energy-Emitting Embodiments of the Marker
[0026] In some embodiments of the invention, the marker may emit
energy that is detectable by a suitable detection apparatus. For
example, the marker may comprise a radioactive substance that is
detectable by way of a gamma detector, scintillation counter or
other apparatus for detecting radiation. Similarly, the marker may
comprise a signal emitting apparatus (e.g. a transmitter or
transponder) that will continuously, or occasionally when
interrogated by ultrasound or other type of interrogating energy,
emit a signal (e.g., radiofrequency, ultrasound, etc.) that can be
detected by an apparatus that is useable to detect that particular
type of signal.
[0027] (v) Marker Embodiments that are Detectable by More than One
Detection Means
[0028] In some embodiments of the invention, the detectable marker
may be detectable by a combination of any two or more of the
above-summarized imaging, visual, palpation and/or
emission/detection techniques. For example, an imageable marker of
the present invention may additionally comprise a palpable
component as described above (e.g., a space occupying material or
article) so as to render the marker both imageable and palpable
after implantation at the biopsy site. Alternatively, an imageable
marker of the present invention may additionally be provided with a
visible component as described above (e.g., a colored substance or
article) so as to render the marker both imageable and visually
discernible after implantation at the biopsy site. Similarly, by
way of illustrative example, an imageable marker of the present
invention may additionally comprise a palpable component as
described above (e.g., a space occupying material or article) and a
visible component as described above (e.g., a colored substance or
article) so as to render the marker imageable, palpable and visible
during surgery.
[0029] B. Consistency and Properties of the Marker
[0030] (i) Substantially Insoluble Marker Substances
[0031] In accordance with the invention, the detectable marker may
comprise a substance (e.g., a gas, lipid, oil, powder, suspension
or slurry) that may be delivered into the cavity formed by removal
of a biopsy sample (i.e., the "biopsy cavity"), and which has
solubility and/or biodistributive properties that allow it to
remain present and detectable (e.g., imageable, palpable,
energy-emitting and/or visible) at the biopsy site until at least
the first predetermined time point (e.g., at least 2 weeks after
introduction), but which will allow the substance to be
substantially cleared (e.g., dissolved, distributed from or locally
metabolized) from the biopsy site at the second predetermined time
point (e.g., 6 weeks after introduction).
[0032] (ii) Soluble Marker Substances with Clearance Delaying
Element(s)
[0033] Further in accordance with the invention, the detectable
marker may comprise a) a detectable (e.g., imageable, palpable,
energy-emitting and/or visible) substance that, if delivered alone
into the cavity formed by removal of the biopsy specimen, would
clear from such biopsy cavity so as to be no longer detectable at
the first predetermined time point (e.g., two (2) weeks after
introduction) in combination with b) a clearance limiting element
(e.g., a diffusion-limiting polymer matrix, a membrane or liposomal
encapsulation, a biodegradable matrix or encapsulant, etc. . . . )
that will limit the dissolution, biodistribution and/or local
metabolism of the detectable substance to remain present and
detectable at the biopsy site for at least 2 weeks after
introduction, but which will allow the detectable substance to be
substantially cleared (e.g., dissolved, distributed from or locally
metabolized) from the biopsy site at the second predetermined time
point (e.g., 5-8 months and preferably at about 6 months after
introduction).
[0034] (iii) Markers that do not Interfere with Subsequent Imaging
Studies
[0035] Still further in accordance with the invention, the
detectable marker may comprise a substance or article that is
detectable by a detection method that is different from the imaging
method that is intended to be used for follow-up imaging of the
biopsy site and adjacent tissues, thus allowing the marker to
reside at the biopsy site beyond the second time point (i.e., that
time point at which follow-up imaging studies are to be conducted)
or even indefinitely, without interfering with such follow-up
imaging studies. For example, the marker may be detectable by
palpation, visualization and/or ultrasound but not visible on
x-ray, thereby allowing for follow-up x-ray studies without
interference by the marker while remaining locatable by palpation,
visualization, specialized detection and/or ultrasound in the event
that a surgeon, radiologist or other practitioner may wish to
subsequently locate the biopsy site.
[0036] (iv) Markers that Adhere to the Wall(s) of the Biopsy
Cavity
[0037] Still further in accordance with the invention, the
detectable marker of the present invention may comprise, or may be
combined with, an adhesive which will cause the detectable marker
to adhere to tissue immediately adjacent the void created by
removal of the biopsy sample.
[0038] C. Methods for Using Biopsy Site Markers of the Present
Invention
[0039] Still further in accordance with the invention, there are
provided methods for surgical excision of tissue that is located
adjacent to or surrounding a biopsy cavity in which a visually
detectable marker of the present invention has been delivered. The
method generally comprises the steps of a) visualizing the
perimeter of the visually discernible marker and b) excising tissue
that lies adjacent to the perimeter of said visually discernible
marker. This method of surgical excision may be used to accurately
excise and remove a quantity of tissue of a specific width (e.g., a
region or band that is 2 centimeters wide) that surrounds or lies
adjacent to the original biopsy cavity. Because the biopsy site
markers of the present invention actually occupy the original
biopsy cavity, they serve to accurately mark the perimeter of that
biopsy cavity. As such, the surgeon is able to accurately visualize
the boundary of the biopsy cavity and to then excise and remove
tissue that lies within a certain distance (e.g., 2 centimeters) of
that cavity boundary. Such visualization of the biopsy cavity
boundary may be made easier or enhanced when the biopsy site marker
comprises, in addition to a visually discernible component such as
a dye or carbon particles, a space-occupying bulking agent as
described above in reference to palpable embodiments of the
invention as the presence of such space occupying or bulking agent
may serve to dilate or distend the biopsy cavity, thereby making it
easier for the surgeon to visualize the boundaries of that biopsy
cavity. This surgical excision method may be particularly suitable
in cases where the histopathological evaluation of the biopsy
specimen suggests that additional cancerous cells may continue to
reside in tissue located within a certain distance of the original
biopsy cavity boundary.
[0040] The features of the present invention can be best understood
together with further objects and advantages by reference to the
following description, taken in connection with the accompanying
drawings, wherein like numerals indicate like parts.
[0041] Additional objects, embodiments and advantages of the
present invention will become apparent to those of skill in the
relevant art upon reading and understanding of the following
detailed description of preferred embodiments and the accompanying
drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0042] FIG. 1 is a perspective view of a preferred embodiment of
the biopsy site marker of the present invention.
[0043] FIG. 2 is a perspective view of a plurality of biopsy site
markers in accordance with the first embodiment of the present
invention.
[0044] FIG. 3 is a perspective view of an applicator apparatus in
accordance with the present invention, for depositing the biopsy
site marker at a biopsy site.
[0045] FIG. 4 is a perspective view of the applicator apparatus of
FIG. 3, showing the applicator with an extended piston indicating
that the applicator is loaded with biopsy site markers.
[0046] FIG. 5 is a cross-sectional view of the site marker shown in
FIG. 4, the cross section taken on lines 5-5 of FIG. 4.
[0047] FIG. 6 is an enlarged cross sectional view showing the
applicator of FIG. 4 loaded with biopsy site markers in accordance
with the present invention.
[0048] FIG. 7 is a schematic view of a human breast, showing a
biopsy cavity of the type obtained by a vacuum assisted large core
biopsy sampler, into which a plurality of biopsy markers are
deposited in accordance with the present invention.
[0049] FIG. 8 is a perspective view of a human breast having a
lesion from which a biopsy specimen has been removed, and showing a
syringe and introduction cannula operatively positioned for
introduction of a detectable marker of the present invention into
the cavity created by removal of the biopsy specimen.
[0050] FIG. 8a is an enlarged perspective view of a portion of the
breast of FIG. 8 after the detectable marker has been introduced
and after the syringe and introduction cannulas have been
removed.
[0051] FIGS. 9a-9g are schematic, step-by-step showings of a
preferred method for using a detectable marker of the present
invention to mark the site of a lesion that has been biopsied while
the breast is compressed within a mammography apparatus.
[0052] FIG. 10a is a schematic showing of a first embodiment of a
detectable marker of the present invention after introduction into
a biopsy site.
[0053] FIG. 10b is a schematic showing of a second embodiment of a
detectable marker of the present invention after introduction into
a biopsy site.
[0054] FIG. 10c is a schematic showing of a third embodiment of a
detectable marker of the present invention after introduction into
a biopsy site.
[0055] FIG. 11 is a longitudinal sectional view of an injector
device that is useable to introduce a solid (e.g., powdered,
particulate or granular) marker substance of the present invention
into a biopsy site.
[0056] FIGS. 12a-12c are showings of a preferred method of excising
and removing tissue that lies within a predetermined zone located
on all sides or only one side of the boundary of a
previously-created biopsy cavity.
DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
[0057] The following specification taken in conjunction with the
drawings sets forth the preferred embodiments of the present
invention. The embodiments of the invention disclosed herein are
the best modes contemplated by the inventors for carrying out their
invention in a commercial environment, although it should be
understood that various modifications can be accomplished within
the parameters of the present invention.
[0058] Referring now to the drawing figures and particularly to
FIGS. 1 and 2, a body 20 of gelatin or reconstituted collagen in
the shape of a pellet that includes or incorporates a radio-opaque
marker 22 of a definite shape is disclosed. The gelatin or
reconstituted collagen body 20 can be of virtually any shape or
configuration, however the herein shown shape of a cylinder or
pellet is preferred. The gelatin body of pellet 20 is of such size
that several of the pellets can be deposited in a biopsy site, such
as a typical biopsy site obtained by using the vacuum assisted
large core biopsy device that is frequently used in current medical
practice. The gelatin body or pellet 20 is stored and is applied,
that is deposited in the biopsy site, in a dehydrated form through
an applicator device that forms another aspect of this invention.
However, when the gelatin body or pellet 20 of the invention is not
deposited through the applicator device, it does not necessarily
need to be stored and applied in a dehydrated form. Nevertheless,
storing the gelatin pellets 20 in dehydrated form increases their
useful shelf-life and renders it easier to keep them sterile.
[0059] After having been deposited at the biopsy site the gelatin
marker 20 slowly absorbs moisture from the surrounding tissue and
becomes hydrated. In the dehydrated form, shown in the appended
drawing figures, the gelatin body or pellet 20 is approximately 1
to 3 mm in diameter and is approximately 5 to 10 mm long. The
presently preferred embodiment of the gelatin pellet 20 is
approximately 2 mm in diameter and is approximately 8 mm long.
After the pellet 20 has reached hydration equilibrium with the
surrounding tissue it becomes approximately 3 to 5 mm in diameter
and approximately 10 to 15 mm long. After hydration the presently
preferred embodiment of the pellet 20 is approximately 4 mm in
diameter and approximately 10 mm long.
[0060] The gelatin or reconstituted collagen material itself is
observed under ultrasound examination as a white spot because of
the air pockets usually entrapped in its matrix. In mammography the
gelatin is observed as dark spots in normal breast, because of the
presence of the air pockets. In a fatty breast viewed by
mammography the gelatin marker is observed as a lighter area
containing dark spots, due to the water in the hydrated gelatin
absorbing more energy than the surrounding matrix and the air
pockets within the matrix. A pellet 20 or plurality of pellets 20
due to their bulk may also be palpable and locatable by tactile
means within the breast tissue or other tissue. The gelatin or
reconstituted collagen marker itself can be made even more
radio-opaque by ion-impregnation and chelation techniques which are
described in detail in the aforesaid co-pending application Ser.
No. 09/241,936 filed on Feb. 2, 1999 by the same inventors in
connection with the description of biopsy markers of that
application, and the description of this method of rendering the
gelatin markers radio-opaque is also provided here below. The
disclosure of co-pending application Ser. No. 09/241,936 is
incorporated herein by reference in its entirety. The gelatin or
reconstituted collagen material can also be made more
radio-translucent by entrapping (mixing) a substantial amount of
air in the gelatin. Moreover, a visually detectable substance, such
as carbon particles, or a suitable dye (e.g. methylene blue or
indigo) may also be added to the gelatin to make the marker visible
by a surgeon during dissection of the surrounding breast
tissue.
[0061] The gelatin or reconstituted collagen per se does not serve
as a permanent marker of the biopsy site because it is eventually
reabsorbed by the body, although the dye or even ionic material
that made the gelatin visible or radio-opaque, respectively, may
remain at the site for longer time period than the palpable gelatin
pellet, and may remain there indefinitely. Factors which influence
how long the gelatin or reconstituted collagen pellet remains at
the site, and various means to adjust this time period are
described in the aforementioned co-pending application Ser. No.
09/241,936.
[0062] It is a novel and important aspect of the present invention
to incorporate into the gelatin or reconstituted collagen body or
pellet 20 the radio-opaque marker 22. The radio-opaque or X-ray
detectable marker 22 that is incorporated or enclosed in the
gelatin pellet 20 must have the following properties. First, by its
very nature it must be detectable by X-ray, including the type of
radiography used in the practice of mammography. It must be
comprised of a material or composition that is not absorbed by the
body and stays for indefinite time at the biopsy site, retains its
shape and remains X-ray detectable at the biopsy site also for an
indefinite time. The material or composition of the radio-opaque
marker 22 must, of course, be biocompatible at the site where it is
deposited. Another important requirement is that the biocompatible
marker must have an identifiable specific non-biological shape or
form. The purpose of specific form for the marker is to render the
marker distinguishable under X-ray or in a mammographic examination
from naturally formed calcification granules or a line of such
granules, which are also X-ray opaque. As is known, a line of
calcification which normally forms along ducts is considered a sign
of developing malignancy. Thus, the marker 22 should be of such
specific configuration that when it is viewed sterically, as during
a mammography examination, it should be distinguishable from an
X-ray opaque line. Numerous specific shapes or configurations
satisfy the foregoing requirements, however amorphous X-ray opaque
material that would be uniformly (or substantially uniformly)
distributed in the gelatin pellet 20 is unlikely to satisfy these
requirements.
[0063] Materials or compositions which are suitable for the marker
22 include metal, such as stainless steel, tantalum, titanium,
gold, platinum, palladium, various alloys that are normally used in
bioprosthesis and ceramics and metal oxides that can be compressed
into specific shapes or configurations. Among these the use of
biocompatible metals is presently preferred, and the herein
described preferred embodiment of the marker 22 is made of
stainless steel. Generally speaking the marker 22 is approximately
0.01 to 0.06 inches wide, approximately 0.03 to 0.2 inch long and
approximately 0.002 to 0.02 inch thick. The presently preferred
permanent marker 22 shown in the drawing figures has the
configuration or shape approximating an upside down turned Greek
letter gamma, is approximately 0.10 inch long and approximately
0.04 inch wide. The upside-down Greek letter gamma shape is
believed to be unique, has some resemblance to the popular breast
cancer awareness ribbon and is readily distinguishable under X-ray
and mammography as a "man-made" marker object from any naturally
formed X-ray opaque body. Various manufacturing techniques which
per se are well known in the art, can be utilized to manufacture
the X-ray opaque permanent marker 22. Thus, the marker 22 can be
formed from wire, or can be electrochemically etched or laser cut
from metal plates. The presently preferred embodiment of the gamma
shaped marker 22 is formed by electrochemical etching from
stainless steel plates.
[0064] FIGS. 1, 2 and the other drawing figures, as applicable,
show only one marker in the gelatin pellet 20, although more than
marker may be incorporated in the pellet 20. FIG. 1 discloses a
cylindrically shaped gelatin pellet 20 that in accordance with the
present invention includes the gamma shaped stainless marker 22,
and as an optional feature also includes a dye or other coloring
material (e.g. indigo) that also stays substantially permanently at
the biopsy site and is visible by a surgeon when the breast tissue
is dissected, as in an operation where tumor tissue is removed
(lumpectomy). Gelatin bodies or pellets 20 all of which include one
or more permanent radio opaque markers 22 in accordance with the
present invention may be deposited at a biopsy site. Alternatively,
a series of gelatin bodies or pellets 20 where only some but not
all include a permanent X-ray opaque marker 22 of unique
non-biological shape, may be deposited at the biopsy site.
Preferably, a series of pellets 20 are deposited where each second,
each third, or each fourth etc., pellet includes the marker 22.
FIG. 2 discloses an example of a series or sequence of pellets 20
where each second pellet 20 includes the metal marker 22 and where
each pellet 20 that does not include the metal marker 22 includes
carbon black or dye that is visible to the surgeon during
operation. In this connection it should be understood and
appreciated that as noted above the gelatin bodies or pellets 20
themselves serve a purpose of marking the biopsy site for a
predetermined length of time, that is until they become absorbed by
the body.
[0065] The drawing figures, particularly FIGS. 1 and 2 show the
metal marker 22 disposed substantially in the center of the
cylindrical gelatin pellet 20. This is preferred but is not
necessary for the present invention. The metal marker 22 can be
embodied in or included in the gelatin body 20 virtually anywhere.
The gelatin body or pellet 20 however has to have sufficient
integrity or firmness to retain the metal marker 22 and air bubbles
which are usually deliberately entrapped in the gelatin. As is
known, the firmness or bodily integrity of gelatin is measured in
units of Bloom. Generally speaking it was found in accordance with
the present invention that the higher the Bloom strength of the
gelatin used in the marker 20 the better the marker performs. The
higher Bloom strength gelatin holds gas bubbles within its matrix
better than lower Bloom strength gelatin. Gelatin with a Bloom
strength of approximately 150 especially 175 is adequate for the
practice of the present invention, but a more preferred range is
200 to 300 Bloom, the most preferred range being between 250 and
300. (For comparison, typical food gelatin is approximately 75
Bloom, and gelatin of 300 Bloom feels like a soft rubber
eraser.)
[0066] A description how to obtain gelatin or reconstituted
collagen bodies suitable for use as markers 20 with various
properties, before the permanent radio-opaque metal or like marker
22 of specific form is incorporated therein, is provided below in
connection with following examples.
[0067] Example of Radiograpically Visible/Palpable Marker Material
Formed of Metal Ions in Combination with a Collagenous or
Gelatinous Matrix
[0068] U.S. Pat. No. 4,847,049 (Yamamoto incorporated herein by
reference) describes an ion-impregnation or chelation technique
whereby an ion may be impregnated or chelated to collagen for the
purpose of imparting antimicrobial properties to the collagen
preparation. Thus, using this technique, imageable ions such as
radiographically visible metal ions, may be bound to a bulky
collagenous material to form a marker 10 that may be a) imaged by
radiographic means and b) located by palpation of tissue
surrounding the biopsy site. For example, a silver ion-renatured
collagen composition may be prepared by the following process:
[0069] Step 1--Renaturation of Collagen (or Gelatin)
[0070] Collagen may be renatured to an insoluble form by processing
of denatured collagen that has been obtained from a natural source
such as bovine corium (hide), bovine tendon, and porcine skin.
Alternatively, pre-processed, insoluble collagen may be purchased
in the form of a commercially available hemostatic material such as
Collastat.TM. and Avitene.TM. nonwoven web. Methods for renaturing
collagen are known in the literature, including, for example, those
methods described in U.S. Pat. Nos. 4,294,241 and 3,823,212. The
specifications of U.S. Pat. Nos. 4,294,241 and 3,823,212 are
incorporated herein by reference.
[0071] A particularly preferred form of renatured collagen for
utilization in accordance with the present invention is one that
has been renatured and covalently cross-linked. This collagen may
be prepared by utilizing readily available polyfunctional cross
linking agents or fixatives, such as dialdehydes, dicarboxylic
acids, diamines, and the like. Typically, tropocollagen is
dissolved in a buffer of pH 3.0 to 5.0 to provide a solution
containing approximately 1 to 2% by weight of the collagen. Then 1%
of a dialdehyde cross-linking agent such as glutaraldehyde or
formaldehyde is then added. The mixture is then frozen and stored
for approximately 24 hours. After thawing and washing to remove
unreacted cross linking agent, the renatured cross-linked collagen
is then ready for contact with a silver ion-containing
solution.
[0072] Step 2--Binding of Metal Ions to the Renatured Collagen
[0073] The source of silver ion may be a water soluble silver salt,
preferably silver nitrate. While the concentration of the silver
ion in the solution is not particularly critical, it will be
usually convenient to utilize solutions in the concentration range
of about 10 to 10 millimolar.
[0074] The renatured collagen is preferably contacted with a silver
ion-containing solution in the pH range of about 4 to 9. The pH of
the silver ion-containing solution can be controlled by the
addition of an appropriate titrating agent, such as nitric acid, or
potassium hydroxide, as required, to maintain the pH at less than
about 9.0 to avoid the degradation of the silver. There is not
believed to be any lower limit for the pH, however, normally a pH
above 4.0 will be convenient. A particularly preferred range for
the pH is from 7.0 to 7.5. The binding capacity of silver by
collagen is particularly effective within this preferred pH range,
although the amount of binding by silver by the collagen is further
controllable by the concentration of the silver ion-containing
solution and/or exposure time of the collagen to the silver
ion-containing solution. Simultaneous with or subsequent to
exposure of the collagen to the silver ion-containing solution, the
collagen is then exposed to ultraviolet radiation of energy and
duration sufficient to strengthen the binding of the silver ions to
the collagen without substantial formation of metallic silver
formed as a result of oxidation of various functional groups in the
collagen by the silver ion. While the exact limits of the ranges of
the conditions which will be sufficient to strengthen the binding
of the silver ions without substantial formation of metallic silver
are not precisely determinable, it will generally suffice to
maintain the pH of the silver-collagen environment at less than 8.0
while exposing the collagen to ultraviolet radiation in the range
of about 210 to 310 nm wavelength for about from 5 to 15 minutes.
The time of UV exposure for complete reaction is inversely
proportional to the light intensity which is preferably in the
range of 100 to 1,000 microwatts/cm.sup.2. A slight coloration of
the collagen due to the exposure to ultraviolet radiation is
acceptable, i.e., a turning from white to a light brown to yellow
color, indicating a slight oxidation reaction occurring in the
collagen, however, the radiation should not be to the extent that
dark brown or black areas in the collagen occur due to
over-oxidation and/or substantial formation of metallic silver.
Normally the exposure will be performed at ambient temperatures,
i.e., in the range of about 20.degree. to 25.degree. C., however,
there is not believed to be any reason why the exposure could not
occur at higher or lower temperatures providing that the
temperature is not high enough to cause degradation of the collagen
and/or silver ion. There is not believed to be any lower limit to
the temperature at which the exposure may take place, provided it
is above the freezing point of the ion-containing solution.
Ultraviolet radiation may be provided by any conventional
ultraviolet radiation source of appropriate wavelength, such as
germicidal lamps and mercury/xenon lamps.
[0075] Step 3 (Optional)--Addition of Visible Component to
Marker
[0076] If it is desired for the marker to be detectable visually,
as well as by imaging and palpation, a quantity of a visible
substance having a color dissimilar blood or tissue may be added.
For example, carbon particles or a dye (e.g., methylene blue,
indigo) may be added to the above-prepared silver ion/collagen
preparation to provide a colored silver ion/collagen marker 10 that
is imageable (by radiographic means), palpable (by hand) and
visible (under white light in the operating room).
[0077] The above-described collagen-metal ion marker 10 (with or
without visible marker component) is introduced into the cavity
created by removal of the biopsy specimen. The quantity of this
marker 10 introduced may be sufficient to distend or stretch the
biopsy cavity somewhat, thereby creating a more palpable and
obvious mass of marker material at the biopsy site.
[0078] Renatured gelatin or a cross-linked gelatin preparation such
as Gelfoam.TM. may be impregnated or combined with a metal ion to
provide a gelatin-metal ion marker material. The gelatin may be
prepared and ion-bound by the same method as set forth hereabove
for collagen.
[0079] Example of Radiographically or Ultrasonically
Visible/Palpable Marker Material
[0080] Step 1--Renaturation of Collagen (or Gelatin)
[0081] Collagen or gelatin is renatured, as by the method described
in Step 1 of the immediately preceding example and described in the
literature, including, for example, those methods described in U.S.
Pat. Nos. 4,294,241 and 3,823,212.
[0082] Step 2--Dispersing of Air or Other Gas in the Renatured
Collagen or Gelatin Matrix
[0083] Air or another biologically inert gas (e.g., carbon dioxide)
is then dispersed throughout the renatured collagen or gelatin
matrix by a suitable means such as mixing, mechanical blending,
nucleation, bubbling, etc. This results in the formation of many
small gas bubbles throughout the collagenous or gelatinous matrix
and provides a marker substance that can be introduced into the
biopsy cavity through a cannula or tube and is substantially more
radio-lucent than the tissue surrounding the biopsy cavity. In this
regard, this marker can be imaged by x-ray or ultrasound but will
not block or obscure imaging of tissue that lies immediately
adjacent the biopsy cavity. Also, because of the bulk of the
collagen or gelatin matrix, the marker is readily palpable and
locatable by tactile means within the surrounding breast tissue or
other tissue.
[0084] Step 3 (Optional)--Addition of Visible Marker Component
[0085] If it is desired for the marker to be detectable visually,
as well as by imaging and palpation, a quantity of a visible
substance having a color dissimilar to blood or tissue may be
added. For example, carbon particles or a dye (e.g., methylene
blue, indigo) may be added to the above-prepared silver
ion/collagen preparation to provide a colored silver ion/collagen
marker 10 that is imageable (by radiographic means), palpable (by
hand) and visible (under white light in the operating room).
[0086] In routine use, the above-described collagen/gas or
gelatin/gas marker 10 (with or without visible marker component) is
introduced into the cavity created by removal of the biopsy
specimen. The quantity of this marker 10 introduced may be
sufficient to distend or stretch the biopsy cavity somewhat,
thereby creating a more palpable and obvious mass of marker
material at the biopsy site.
Preferred Example of Preparing Cylindrically Shaped Gelatin Pellets
20 Having a Colorant and Including the Permanent Marker
[0087] 80 grams of dry gelatin obtained from porcine skin is mixed
into 1000 ml of hot water (180.degree. F.). Variations in gelatin
to water ratio will change the consistency but are nevertheless
permissible within the scope of the invention. The 80 grams of
gelatin is about the maximum amount which will dissolve in water
without modifications to pH. The gelatin is then fully dissolved in
the water with slight mixing. In a separate container, 1.6 grams of
indigo colorant is mixed into 20 ml of ethyl alcohol. Then the
ethanol solution of the colorant is added by mixing to gelatin
dissolved in water. Air is then whipped into gelatin mixture to
froth the mixture.
[0088] The gelatin dissolved in water is then poured into molds
(not shown) which have the shape of the desired gelatin body. In
the preferred embodiment the mold is shaped to provide the
cylindrical pellet shown in the drawing figures. One gamma
(.gamma.) shaped permanent marker 22, made by chemical etching from
stainless steel plates, is deposited into the gelatin in each mold.
(In alternative embodiments more than one marker 22 may be
deposited into each mold.) Due to the viscosity of the gelatin
solution the marker 22 does not usually sink to the bottom of the
mold. The top of the plate (not shown) holding a plurality of molds
is squeegeed to level the mixture.
[0089] After cooling to approximately 40.degree. F. or cooler
temperature the gelatin sets and provides the gelatin body 20 that
incorporates the permanent marker 22 However, in order to dehydrate
the marker it is first frozen and thereafter lyophilized in
commercial lyophilization apparatus. Gelatin pellets containing the
permanent marker 22 but not having a colorant can be prepared in
the same manner, but without adding indigo dye or other colorant.
Gelatin bodies or markers 20 that do not include or incorporate a
permanent marker 22 can also be made in this manner, but without
depositing the marker 22 into the gelatin after it has been placed
into the mold. The gelatin body 20 prepared in this manner is
reabsorbed from the biopsy site by the human body in approximately
three weeks, whereas the permanent marker 22 remains
indefinitely.
Description of the Applicator Apparatus and its Use in Conjunction
with the Biopsy Marker of the Invention
[0090] Referring now to FIGS. 3-7 the applicator device or
apparatus 24 with which the biopsy markers of the invention are
preferably applied or deposited, is disclosed. In this connection
it should be understood that the biopsy markers of the invention
can be used without the applicator, and can be deposited in
accordance with the various methods and techniques utilized in the
state-of-the-art. However, a preferred technique of applying the
biopsy markers of the invention is to place or deposit them in a
biopsy cavity that is obtained with a vacuum assisted large core
biopsy device of the type presently used in the state-of-the-art.
Such a device, distributed for example by Johnson and Johnson Endo
Surgery is well known in the art, and is schematically shown in
FIG. 7.
[0091] The applicator 24 of the invention comprises an elongated
cylindrical body 26 having an interior cavity and a piston 28 that
fits and slides back and forth in the elongated cylindrical body
26. The cylindrical body 26 has an enlarged disk 30 at one end 32.
The disk 30 serves to render it convenient for a user (not shown)
to operate the applicator 24, as is described below. The
cylindrical body 26 that can also be described as an elongated
flexible tube has an opening 34 that commences a relatively short
distance, that is approximately 0.3 inch before its other, closed
end 36. The opening 34 is configured to form a ramp in the side of
the tube 26. The outer diameter of the tube 26 is such that it fits
through the vacuum assisted large core biopsy device 38 shown in
FIG. 7. In this connection it should of course be understood that
the precise dimensions of the tube 26 are coordinated with the
dimensions of the piston 28 and with the vacuum assisted large core
biopsy device 38. Moreover, the diameters of the gelatin pellets 20
in their dehydrated form are also coordinated with the inner
diameter of the cylinder or tube 26. The cylinder or tube 26 and
the piston 28 can be made from any appropriate medical grade
plastic material, and is preferably made of high density
polyethylene. The outer diameter of the presently preferred
embodiment of the cylinder or tube 26 is approximately 0.093 inch
and its inner diameter is approximately 0.07 inch.
[0092] In the preferred manner of using the biopsy markers of the
present invention having the permanent markers 22 incorporated in a
gelatin body 20, as well as using biopsy markers that have only the
gelatin body 20 without a permanent marker 22, the applicator
device 24, more precisely the tube 26 is loaded with a desired
number of pellets 20, as is shown in FIGS. 4-6. Any number of
pellets 20 within the range of 1 to approximately 30 may be loaded
within the tube 26, however presently it appears that approximately
8 pellets 20 are optimal for being loaded into the tube 26 and to
be deposited in a biopsy cavity where approximately 1 gram of
tissue had been removed. Such a biopsy cavity 40 in a human breast
42 is schematically illustrated in FIG. 7. The pellets 20 which are
loaded into the applicator tube 26 may all include the permanent
marker 22, but it is presently preferred that only every other
pellet 20 loaded into the applicator tube 26 have the permanent
marker 22. Such an array of 8 pellets 20, alternating between
pellets with and without permanent markers 22 is shown in FIG.
2.
[0093] When the pellets 20 are in the tube 26 the piston 28 is
extended, as is shown in FIGS. 4 and 5. The pellets 20 are expelled
one-by-one from the tube 26 through the ramp-shaped opening 34 as
the piston 28 is pushed into the cylinder or tube 26. During this
process the closed end 36 of the tube 26 is disposed in the cavity
40 formed by biopsy sampling. It is contemplated that the dispersed
radio-opaque permanent markers 22 provide a good definition of the
entire biopsy cavity 40 for subsequent observation or surgical
procedure. FIG. 3 illustrates the applicator device 24 after the
pellets 20 have been expelled from the applicator tube 26.
[0094] FIGS. 8 and 8a shows a human breast B which contains a
lesion L, such as a mass suspected to be cancerous. An outer
cannula 52 has been inserted percutaneously into the lesion L and a
biopsy needle (not shown) has been passed through the outer cannula
52 and used to remove a biopsy specimen from the center of the
lesion, thereby forming a biopsy cavity BC within the lesion L.
After removal of the biopsy needle (not shown), a marker
introduction cannula 55 has been passed through the outer cannula
such that its distal end 52d is located within the biopsy cavity
BC. A device 54 for delivering a flowable, detectable marker 50 of
the present invention is attached to the proximal end 52p of the
introduction cannula 55 and is being used to inject a quantity of
the detectable marker 50 into the biopsy cavity BC, as shown. FIGS.
9a-9g are schematic, step by step showings of a preferred method
for using a detectable marker 50 to mark the site of a lesion L
that has been biopsied while the breast B is compressed within a
mammography apparatus 56a and 56b.
[0095] Properties and Functional Requirements of the Detectable
Marker
[0096] Preferred Imageable and Instrument-Detectable
Embodiments
[0097] The detectable markers 50 of the present invention may be
visible on an image created by the particular type or imaging
device(s) available during the procedure. In many cases, a form of
roentgenographic imaging (e.g., mammography, x-ray, fluoroscopy,
CT, etc.) will be used, and the imageable marker 50 will thus
comprise a material that is more or less radio-lucent or more or
less radiopaque than the tissue surrounding the biopsy cavity
(e.g., air, other gas, lipid, oil, a metal salt, barium powder,
etc.) such that the marker 50 can be imaged by such x-ray means. In
other instances, ultrasound imaging may be used and the imageable
marker will comprise a material or substance that has different
ultrasound reflective properties (and possible different
radiographic density) than the body tissue surrounding the biopsy
cavity BC (e.g., air, carbon dioxide, other gasses, saline
solution, other liquids, etc.) In other instances, a magnetic
imaging technique such as magnetic resonance imaging (MRI) may be
used and the imageable marker 50 will comprise a ferromagnetic
material or material (e.g., iron powder) having different magnetic
density than the body tissue surrounding the biopsy cavity BC.
[0098] Similarly, the marker 50 may be a substance or article that
emits energy (e.g., radiation) that is detectable by an instrument
(e.g., a gamma detector).
[0099] Preferred Palpable Embodiments
[0100] The preferred palpable embodiments of the invention
preferable comprise a substance (e.g., a collagen material as
described in U.S. Pat. No. 4,066,083) or an article (e.g.,
balloon(s), bead(s), etc.) that are sufficient mass to be palpated
and located by tactile means while disposed within the biopsy
site.
[0101] Preferred Visible Embodiments
[0102] The preferred visible embodiments of the invention may
comprise a colored substance such as a dye or colorant (e.g.,
methylene blue, gentian violet, indigo, dyes used in tattooing,
etc.) or colorant particles (e.g., india, indigo, carbon particles
or carbon preparations described in Langlois, S. L. P. and Carter,
M. L., Carbon Localization of Impalpable Mammographic
Abnormalities, Australas Radiol. 35: 237-241 (1991) and/or Svane,
G. A Stereotaxis Technique for Preoperative Marking of Non-Palpable
Breast Lesions, Acta Radiol. 24(2): 145-151 (1983).
[0103] Preferred Combination Embodiments
[0104] The markers 50 of this invention may combine the attributes
of any of the imageable, palpable and/or visible embodiments to
provide for detection of the marker 50 by multiple means, such as
a) imaging and palpation, b) imaging and visualization, c) imaging,
palpation and visualization, or d) visualization and palpation.
[0105] Preferred Residence Time of the Marker at the Biopsy
Site
[0106] The detectable markers 10 of the present invention are
formulated and/or constructed so as not to move or migrate from the
biopsy site when the surrounding tissue is flexed or reconfigured
(e.g., as occurs when a breast is decompressed and removed from a
mammography machine). Additionally, the detectable markers 10 are
formulated and/or constructed to (i) remain present at the site in
sufficient quantity to permit imaging and location of the site for
at least two (2) weeks after introduction and (ii) clear
sufficiently from the site to permit imaging of tissue adjacent to
the site, without interference from said detectable marker, at six
(6) months after introduction.
[0107] Because the marker 50 is located at, and does not move or
migrate from, the biopsy site it serves as a landmark that the
surgeon may use to locate and treat or remove the remaining portion
of the lesion without having to dissect and explore the surrounding
tissue in attempting to locate the lesion. This aspect of the
invention is particularly beneficial in cases (such as breast
lumpectomy procedures) where it is desired to surgically remove the
lesion L with minimal disfigurement, scarring or change in
architecture of the surrounding tissue.
[0108] Because the marker 50 remains detectable at the biopsy site
for at least two (2) weeks, the commencement of medical or surgical
treatment of the lesion L may be delayed for up to two (2) weeks
following the removal of the biopsy specimen and the marker 50 will
still be present and useable to assist the treating surgeon or
other physician in locating and directing treatment to the
remaining portion of the lesion. This two (2) week minimum period
of residence is especially beneficial in cases where immediate
frozen sections can not be read by a pathologist, such as cases of
suspected breast cancer wherein a small, non-palpable lesion of the
breast has been biopsied by stereotactic biopsy, and the biopsy
specimen is sent for routine histopathological evaluation (e.g.,
fixing, staining and microscopic examination) which takes several
days to complete.
[0109] Also, because the marker substantially clears from the
biopsy site within six (6) months after its introduction, it will
not interfere with or obscure subsequent diagnostic imaging of any
remaining portion of the lesion L or the surrounding tissue. This
six (6) month maximum residence time of the marker is especially
beneficial in cases where the lesion is determined not to be
cancerous at present, but presents a risk for future tumorigenesis
that warrants periodic imaging of the site of the lesion L and
surrounding tissue.
[0110] Embodiments where the Properties of the Marker's Detectable
Component Alone Result in Desired Residence Time
[0111] In some embodiments, the detectable marker 10 may comprise a
detectable material that has pharmacokinetic properties (e.g.,
solubility, dissolution, potential for distribution from the biopsy
site, potential for local metabolism or break down at the biopsy
site) that cause it to remain present at the biopsy site in
sufficient quantity to permit imaging of and location of the site
for at least 2 weeks after its introduction, while clearing
sufficiently from the site to permit imaging of tissue adjacent to
the site without interference from said detectable marker, at 6
months after introduction.
[0112] In many applications of the invention, the particular
pharmacokinetic or biodistributive property(ies) that determine the
rate at which the marker 10 clears from the biopsy site may include
its solubility in the interstitial fluids that are present at the
biopsy site. In this regard, it has been determined that when the
marker 50 is formed of detectable material having a solubility
coefficient of less than 1.times.10.sup.-3 grams per 100 cubic
centimeters of water, such detectable material will typically have
the desired detectable residence time within the biopsy site of at
least two (2) weeks but not more than 5 to 7 months, and preferably
not more than about 6 months. However, it will be appreciated that
the detectable residence time of the marker 50 at the biopsy site
will additionally vary with the amount of marker 50 material that
has been introduced in the biopsy cavity. In this regard, a large
volume of a material having a relatively high solubility
coefficient can be introduced into the biopsy cavity to ensure
that, even though the material has a relatively fast clearance
rate, an imageable amount of the material will remain present at
the biopsy site at the first time point (e.g., two (2) weeks). On
the other hand, a relatively small volume of material having a low
solubility coefficient may be introduced into the biopsy cavity
and, due to its slow clearance rate, will remain imageable at the
biopsy site at the first time period (e.g., two (2) weeks).
[0113] Specific examples of radiographically visible materials
that, if introduced into the biopsy site alone, would exhibit the
desired detectable residence time (i.e., at least 2 weeks but not
more than 6 weeks) include but are not necessarily limited to;
AgCl; AgI; BaCO.sub.3; BaSO.sub.4; K; CaCO.sub.4; ZnO;
Al.sub.2O.sub.3; and the possible combinations thereof.
[0114] Embodiments with a Clearance Delaying Element to Provide the
Desired Residence Time
[0115] In other embodiments, the detectable marker 50 may comprise
a detectable material that, if introduced into biopsy site alone,
would clear substantially from the biopsy site in less than two (2)
weeks after its introduction, thereby failing to provide the
desired minimum detectable residence time at the biopsy site of at
least two (2) weeks. In such embodiments, the detectable material
will be combined (e.g., mixed with, encapsulated by, suspended in,
etc.) a clearance delaying element that will cause the detectable
material to remain present at the biopsy site in sufficient
quantity to permit imaging of and location of the site for at least
2 weeks after its introduction, while still allowing the detectable
material to clear sufficiently from the biopsy site to permit
imaging of tissue adjacent to the site without interference from
said detectable marker, at 6 weeks after introduction.
[0116] Examples of radiographically visible materials that would
clear from most biopsy sites in less than two (2) weeks include but
are not necessarily limited to; air, gas, lipid, oil, AgNO.sub.3;
ammonium salts; sodium salts; potassium salts; ethiodized oil
(Ethiodol available commercially from Savage Laboratories,
Mellville, N.Y., and certain radiographic contrast agents such as
iohexyl (Omnipaque, available from Nyegaard-Schering AG, available
from Squibb/Bristol Myers.
[0117] Examples of clearance delaying elements that may be combined
with the detectable material to form a detectable marker of the
present invention include but are not necessarily limited to;
polylactic acid; polyglycolic acid; polycapriolactone; an
encapsulating membrane surrounding the detectable material.
The following examples are presently preferred formulations for
detectable markers 50 of this embodiment:
TABLE-US-00001 Formulation 1 Component Amount AgNO.sub.3 20-70
parts by weight Polylactic Acid 30-80 parts by weight
TABLE-US-00002 Formulation 2 Component Amount Ethiodol 10-50 parts
by weight Polyglycolic Acid 50-90 parts by weight
TABLE-US-00003 Formulation 3 Component Amount Ethiodol 10-70 parts
by weight Topical Thrombin 30-90 parts by weight
TABLE-US-00004 Formulation 4 Component Amount Polylactic Acid 50-70
parts by weight Air 30-50 parts by weight
[0118] Form and Consistency of the Detectable Marker
[0119] FIGS. 10a-10c illustrate examples of the different possible
forms or consistencies of detectable markers 50 of the present
invention.
[0120] Flowable Markers
[0121] FIG. 10a shows an example of a detectable marker 50a of a
flowable consistency that is injectable through the lumen of the
introduction cannula 55 into the biopsy cavity BC formed within the
lesion L. Typically, such flowable markers 50a will comprise a dry
powder, suspension, or solution. For example, a quantity of dry
AgCl powder of 10-1000 micron particle size may be passed through
the introduction cannula 55.
[0122] FIG. 11 shows an example of an injector device 60 that is
useable in place of the introduction cannula 55, to introduce a
solid (e.g., powdered, particulate or granular) marker 50 of the
present invention into a biopsy site. As shown, this device 60
comprises a non-tapered tubular barrel 61 having a substantially
cylindrical inner wall 62 and a plunger 63 that is advanceable
within the barrel 61. A quantity of a solid marker material of this
invention is loaded into the barrel 61 of the device 60, the barrel
61 is inserted into the biopsy site, and the plunger 63 is advanced
so as to expel the marker material out of the distal end of the
barrel 61 and into the biopsy site.
[0123] Plurality of Beads or Pellets
[0124] FIG. 10b shows an example of a detectable marker 50b that
comprises a plurality of beads or pellets of approximately 10-1000
microns in diameter. Each bead or pellet may itself be formed of
detectable material that is biodegradeable or otherwise clearable
from the biopsy site so as to exhibit the desired detectable
residence time as described hereabove such as silver chloride or
silver nitrate.
[0125] Alternatively, each bead or pellet may contain a detectable
material in its interior and the outer surface of the bead or
pellet may be a skin or encapsulating material that is
biodegradable such as polylactic acid, so as to provide for the
desired detectable residence time within the biopsy site.
[0126] Beads or pellets filled with air, carbon dioxide, or other
suitable gas may be used as markers 50b of the present invention
that are detectable by either ultrasound or x-ray. However, even
though such gas-filled markers 50b of the present invention are
visible on x-ray, they will not obscure or block x-ray imaging of
tissue adjacent to the biopsy cavity and, thus, need not biodegrade
or clear from the biopsy site by the second time point (e.g., 5-7
months).
[0127] Inflatable Balloon
[0128] FIG. 10c shows an example of a detectable marker 50c that
comprises an inflatable balloon. Such inflatable balloon is passed
through the introduction cannula and inflated within the biopsy
cavity BC formed within the lesion L. The material of the balloon
itself may be detectable and biodegradable or otherwise clearable
from the biopsy site so as to exhibit the desired detectable
residence time as described hereabove. One example of such a
material is polyurethane that has been subjected to hydrolysis in
situ. Alternatively, the balloon may contain a detectable material
and the balloon itself may form a skin or encapsulating material
(e.g., polyurethane) that is biodegradable so as to provide for the
desired detectable residence time within the biopsy site.
[0129] Balloons filled with air, carbon dioxide, or other suitable
gas may be used as markers 50c of the present invention that are
detectable by either ultrasound or x-ray. However, even though such
gas-filled markers 50c of the present invention are visible on
x-ray, they will not obscure or block x-ray imaging of tissue
adjacent to the biopsy cavity and, thus, need not biodegrade or
clear from the biopsy site by the second time point (e.g., 5-7
months).
[0130] Optional Adhesive For Attaching the Marker to Tissue
Adjacent the Site
[0131] In any of the above-described embodiments of the invention,
the marker 10 may have inherent adhesive properties, or the marker
may further comprise an adhesive such as a polyurethane,
polyacrylic compound, polyhydroxymethacrylate, fibrin glue (e.g.,
Tisseal.TM.), collagen adhesive, or other biological or
biocompatable adhesive that will cause the marker to adhere to
tissue adjacent the biopsy cavity BC. Such optional adhesive will
further ensure that the marker 10 does not migrate or move from the
biopsy site as tissue surrounding the site is moved, flexed,
compressed or decompressed.
[0132] Method for Surgical Excision of Tissue Located Adjacent a
Biopsy Site
[0133] FIGS. 12a-12c show a preferred method for using a visually
discernible marker 50 of the present invention to guide the
excision and removal of tissues located within a specific band,
region or location adjacent the boundaries of the biopsy cavity. As
shown in FIG. 12a, a visible marker 50 has been introduced into the
biopsy cavity BC so as to permit visualization of the boundary BOU
of the biopsy cavity BC by the surgeon. Such visualization of the
boundary BOU of this biopsy cavity BC can enable the surgeon to
selectively remove tissue that is located within a general zone
Z.sub.1 of potentially cancerous tissue surrounding the entire
biopsy cavity BC (FIG. 12b) or within a specific zone Z.sub.2
located on only one side of the biopsy cavity BC (FIG. 12c).
[0134] With specific reference to the showing of FIG. 12b, the
removal of all tissue within a general zone Z.sub.1 surrounding the
entire biopsy cavity BC may be desirable in cases where the
pathology report has indicated that the previously removed biopsy
specimen had no clear margin and, thus, it is desirable to remove
all tissue within the zone Z.sub.i of width X surrounding the
biopsy cavity BC on all sides.
[0135] With specific reference to the showing of FIG. 12c, the
removal of certain tissue within a specific zone Z.sub.2 located to
one side of an axis that has been projected throughout the biopsy
cavity BC may be desirable in cases where the pathology report has
indicated that the previously removed biopsy specimen had clear
margins on all but one side and, thus, it is desirable to remove
only tissue that is located within the specific zone Z.sub.2 of
width X on one side of the biopsy cavity BC.
[0136] The invention has been described hereabove with reference to
certain presently preferred embodiments, and no attempt has been
made to describe all possible embodiments in which the invention
may take physical form. Indeed, numerous modifications, additions,
deletions and alterations may be made to the above-described
embodiments without departing from the intended spirit and scope of
the invention. Accordingly, it is intended that all such additions,
deletions, modifications and alterations be included within the
scope of the following claims.
* * * * *