Cryosurgical instrument and related techniques

A cryosurgical instrument includes a cryoprobe operative to form an ice ball in tissue of a patient targeted for cryosurgery upon activation, a sheath disposed over the cryoprobe and at least one measuring device supported by the sheath for measuring a parameter of the tissue of the patient. The instrument includes a processor for predicting formation of the ice ball by the cryoprobe over time and a display for displaying the prediction of ice ball formation. The processor is responsive to an output signal provided by the measuring device and a model of the effective thermal conductivity of the tissue of the patient targeted for surgery. In one embodiment, the measuring device is embedded in the sheath and measures temperature, thermal conductivity, blood perfusion rate and/or thermal diffusivity. The processor may be further responsive to an impedance measurement circuit for verifying the prediction.

BACKGROUND OF THE INVENTION
 Cryosurgery, a surgical procedure in which a target area of a patient is
 frozen, is known for treating various medical conditions. Most often,
 cryosurgery is used in the treatment of cancer, in which a cancerous mass
 or tumor is destroyed during the freezing process. Over time, the frozen
 mass deteriorates and is consumed by the body. One application for
 cryosurgery is in the treatment of prostate cancer.
 Prostate cancer is one of the most frequently diagnosed malignancies in
 American males and is the second leading cause of cancer related deaths.
 Successful treatment requires confining the cancer to the prostate gland
 and surrounding tissue, referred to as the prostatic capsule, in order to
 prevent the spread and metastasizing of the cancer.
 In addition to cryosurgery, other conventional treatment therapies for
 prostate cancer include radical prostatectomy, radiation therapy and
 medical or surgical castration. In radical prostatectomy, the prostate
 gland and a margin of the surrounding tissue are surgically removed.
 However, a relatively high rate of recurrent, or residual tumors have been
 reported following radical prostatectomy. Further, this form of treatment
 suffers from a relatively high rate of impotence and/or incontinence.
 In radiation therapy, radiation is applied to the prostate gland either by
 an external source or by radioactive implants. However, in many reported
 cases, the ability of radiation therapy to control cancer has been found
 to last only a few years.
 Medical castration involves the administering of drugs that shut down a
 bodily process, such as the production of testosterone or the effect of
 testosterone on the prostate gland. This form of therapy does not cure the
 cancer and, over time, the cancer usually progresses. Surgical castration
 does not appear to be any more effective than medical castration and both
 types of castration can cause hot flashes, loss of sex drive, enlargement
 of the breasts and impotence.
 Prostate cryosurgery involves the use of multiple liquid nitrogen or gas
 cooled probes (i.e., cryoprobes) inserted into the prostate through the
 perineum to freeze the prostate gland, thereby killing the cancer.
 Typically, five cryoprobes are used and the frozen area around each
 cryoprobe is sometimes referred to as an "ice ball." An ultrasound probe
 is used to guide the cryoprobes into position in the prostate and to
 permit the physician to visualize the edge of the ice balls or the overall
 ice ball formed by the cryoprobes. Temperature sensing thermocouples are
 positioned external to the prostatic capsule to measure the surrounding
 temperatures.
 By visualizing the edge of the ice balls and monitoring the temperature
 adjacent to the prostate gland, the physician controls activation of the
 cryoprobes in an effort to ensure that the entire cancerous area is frozen
 and further, to ensure that adjacent areas are not frozen in order to
 prevent certain side effects. In particular, freezing nerves adjacent to
 prostate or the seminal vesicle can cause impotence and freezing the
 urethra, bladder or the rectal sphincter muscle can cause incontinence
 problems. During the cryosurgical procedure, generally, a warm fluid is
 directed through the urethra which passes through the prostate gland in
 order to help prevent freezing of the urethra.
 Since ultrasound provides a two-dimensional image, only the edge of the ice
 balls can be visualized and thus, the physician is not provided with any
 information regarding temperatures behind the ice ball edge. Further, the
 edge of the ice ball is at approximately 0.degree. C. and, in order to
 effectively destroy cancer, the tissue must be frozen to temperatures
 between approximately -20.degree. C. and -40.degree. C. Thus, the
 physician must estimate what portion of the ice ball has effectively
 destroyed the cancer. This task is complicated by the fact that ice ball
 formation is dependent on certain physiological parameters of the patient,
 such as blood flow and tissue properties.
 Although prostate cryosurgery has not been in use as long as the other
 prostate cancer treatment therapies, it has displayed nearly an
 eighty-percent success rate in destroying prostate cancer. Further,
 prostate cryosurgery has the advantage that patients usually do not suffer
 serious urinary control problems. However, the success of prostate
 cryosurgery in destroying cancer without causing impotence and other side
 effects is dependent on the precision with which the entire cancerous area
 and no additional area is frozen.
 BRIEF SUMMARY OF THE INVENTION
 The invention relates to a cryosurgical instrument including at least one,
 and preferably a plurality of cryoprobes adapted for being positioned in
 tissue of a patient targeted for cryosurgery, such as the prostate gland,
 and operative to form an ice ball in the tissue upon activation. Each of
 the cryoprobes has a sheath disposed over at least a portion thereof which
 supports at least one measuring device for measuring a parameter of the
 tissue of the patient. Preferably, the measuring device is embedded in the
 sheath and measures tissue temperature, thermal conductivity, blood
 perfusion rate and/or thermal diffusivity. In one embodiment, the sheath
 includes a plurality of measuring devices embedded therein and spaced
 along a portion of the sheath both axially and longitudinally.
 The instrument further includes a processor for predicting formation of an
 ice ball by each of the cryoprobes in the tissue over time and a display
 for displaying the ice ball formation prediction. More particularly, the
 processor is responsive to an output signal of the measuring device
 indicative of a measurement performed prior to cryosurgery for providing
 the ice ball formation prediction. The processor is further responsive to
 a model of the thermal properties of the tissue of the patient and to the
 effect of urethral warming. The display provides a representation of the
 temperature contours within the prostate gland that would result from
 activation of the cryoprobes. With this arrangement, a physician is able
 to perform "trial" cryosurgical procedures without activating the
 cryoprobes in order to determine an optimum treatment procedure.
 In one embodiment, the measuring device is further operative to measure a
 parameter of the tissue following activation of the cryoprobes (i.e.,
 during cryosurgery). The processor is responsive to this "surgery"
 measurement for verifying the ice ball formation prediction. The
 cryosurgical instrument may further include an impedance measurement
 circuit coupled to selected ones of the cryoprobes for providing an output
 signal indicative of the tissue impedance with which the ice ball
 formation prediction is verified.
 Also provided is a method of predicting ice ball formation by one or more
 cryoprobes in tissue of a patient targeted for cryosurgery including the
 steps of forming a model of the thermal properties of the tissue of the
 patient and measuring at least one parameter associated with the tissue of
 the patient prior to activation of the cryoprobes. The method further
 includes predicting the formation of the ice balls by the cryoprobes in
 the tissue of the patient in response to the model and the measured
 parameter. The method may further include the step of measuring a tissue
 parameter following activation of the cryoprobes and verifying the ice
 ball formation prediction based on this "surgery" measurement. Further
 optional steps include measuring the impedance of the tissue and verifying
 the ice ball formation prediction based on the measured impedance.

DETAILED DESCRIPTION OF THE INVENTION
 Referring to FIG. 1, a cryosurgical instrument, or system 10 according to
 the invention includes a control unit 14, a display 20 and a cryoprobe
 machine 24 including a plurality of cryoprobes 18a, 18b, . . . 18n. The
 cryoprobes 18a-18n are adapted for insertion into tissue of a patient
 targeted for cryosurgery. Upon activation, each cryoprobe 18a-18n freezes
 surrounding tissue so as to form an "ice ball". Generally, the cryoprobes
 18a-18n are positioned such that individual ice balls formed by the
 cryoprobes 18a-18n overlap to form a cumulative ice ball. Over time, the
 ice balls deteriorate and are consumed by the body.
 The illustrative cryosurgical system 10 is particularly well-suited for
 prostate cryosurgery and will be described with specific reference to that
 application. It will be appreciated by those of ordinary skill in the art
 however, that the apparatus and techniques described herein are suitable
 for use in other cryosurgical applications.
 The cryoprobes 18a-18n are elongated, partially hollow tubular devices,
 each having a sheath 22a, 22b, . . . 22n covering at least a portion
 thereof in use. The probes 18a-18n are cooled by a cooling agent, such as
 liquid nitrogen, nitrogen oxide gas or carbon dioxide gas, which is
 circulated through the cryoprobe. Typically, the cryoprobe machine 24
 includes five cryoprobes. In accordance with one feature of the invention,
 each of the sheaths 22a-22n includes at least one measuring device 80a-80h
 (FIG. 3), such as a thermistor, for measuring a parameter of the tissue of
 the patient and for providing a parameter output signal to the control
 unit 14 via measurement connections 30, as will be described.
 In the illustrative embodiment, the control unit 14 includes cryoprobe
 controls 28 coupled to the cryoprobe machine 24 via control connections 34
 for controlling the operation of the cryoprobes 18a-18n. As examples, the
 controls 28 govern activation, de-activation, and the amount of cooling
 agent delivered to the cryoprobes 18a-18n (i.e., the operating temperature
 of the cryoprobes). The controls 28 may replicate controls 26 on the
 cryoprobe machine 24, in which case the cryoprobe machine 24 includes a
 remote control pad 32 abutting the controls 26. With this arrangement,
 when a control 28 on the control unit 14 is actuated, a signal is
 transmitted to the remote control pad 32 which energizes an
 electromechanical plunger, causing the plunger to press down against and
 actuate the corresponding one of the cryoprobe controls 26 on the
 cryoprobe machine 24. Alternatively, the controls 26 on the cryoprobe
 machine 24 may be connected directly to the controls 28 on the control
 unit 14, thereby eliminating the need for the remote control pad 32. As a
 further alternative, the cryoprobe controls 28 on the control unit 14 may
 be eliminated and cryoprobe control effected by actuation of the controls
 26 on the cryoprobe machine 24. This arrangement would require the time of
 activation and de-activation of each cryoprobe 18a-18n as well as the
 operating temperature of the cryoprobes to be manually entered into the
 control unit 14 via a user interface 15, such as a keyboard, for use as
 described below.
 The cooling agent may be housed in a unit 29 disposed in, or proximal to
 the cryoprobe machine 24, as shown. In this case, a valve 27 coupled
 between the controls 26 and the cryoprobes 18a-18n controls the flow of
 cooling agent to and from the probes in response to actuation of the
 controls 28 of the control unit 14. Various types of valves, including
 proportional valves and on/off pulsed valves, are suitable for this
 purpose. Alternatively, the cooling agent unit 29 and valve 27 may be
 located in, or proximal to, the control unit 14, in which case the control
 connections 34 between the cryoprobe controls 28 on the control unit 14
 and the cryoprobe controls 26 on the cryoprobe machine 24 include tubing
 for carrying the cooling agent to and from the probes 18a-18n.
 As will become apparent, it is contemplated that the cryosurgical system 10
 be used in conjunction with ultrasound equipment, including an ultrasound
 probe 60 (FIG. 2) and associated controls, to facilitate placement of the
 probes 18a-18n in the targeted tissue. Ultrasound controls 46 may be
 incorporated into the control unit 14 as shown in FIG. 1 or,
 alternatively, may be provided as part of a separate unit (not shown).
 A prediction processor 36 predicts the formation of ice balls in the tissue
 of a patient targeted for cryosurgery by each of the cryoprobes 18a-18n
 prior to the cryosurgical procedure. The processor 36 is responsive to the
 tissue parameter, or parameters measured by the measuring devices 80a-80h
 associated with the probe sheaths 22a-22n (FIG. 3) and to a model of
 thermal characteristics of the treated tissue, such as thermal
 conductivity (i.e., a "global tissue model"). To this end, a tissue model
 processor 40 generates the global tissue model in response to measured
 tissue parameters and to certain treatment parameters entered by the
 operator of the apparatus and provides the global tissue model to the
 prediction processor 36 via connection 44.
 It will be appreciated by those of ordinary skill in the art, that the
 prediction processor 36 and tissue model processor 40 may be implemented
 using various software executable on various hardware, such as an
 INTEL-compatible microprocessor of a standard personal computer. In the
 illustrative embodiment, the prediction processor 36 is implemented with a
 commercially available heat transfer computer program entitled Systems
 Improved Numerical Differencing Analyzer (SINDA) sold by Network Analysis,
 Inc. of Tempe, Ariz. and the tissue model processor 40 is implemented with
 software compatible with SINDA, since the global tissue model provides an
 input to the SINDA program.
 The control unit 14 further includes a thermistor circuit 51 for permitting
 measurements to be made by thermistor measuring devices 80a-80h (FIG. 3)
 associated with the sheaths 22a-22n, including temperature, thermal
 conductivity, blood perfusion rate and thermal diffusivity, as will be
 described further below. A product including such a thermistor circuit 51
 is commercially available from Thermal Technologies of Cambridge, Mass. In
 general, the thermistor circuit 51 applies electrical energy to the
 thermistors to elevate their temperature relative to the surrounding
 tissue by a predetermined amount. The amount of applied electrical energy
 is measured and used to compute effective tissue thermal conductivity and,
 optionally, also blood perfusion rate and thermal diffusivity. Temperature
 is measured with the thermistors 80a-80h by passing a known current
 through the thermistors and measuring the resulting voltage drop.
 Also provided in the control unit 14 is an optional impedance circuit 48
 for measuring the impedance of the treated tissue. When measuring
 impedance, the impedance circuit 48 introduces an alternating current (AC)
 voltage to two of the cryoprobes 18a-18n, one of which is located at a
 measurement site and the other of which serves as a reference probe
 located at a reference site (both probes being referred to collectively as
 the measurement probes). Alternatively, a separate reference probe, not
 operative to freeze tissue, may be provided for insertion into the
 patient. Suitable reference probes include gold-plated or stainless steel
 rod-type electrodes. While it is contemplated that the impedance circuit
 48 permits both the frequency and magnitude of the applied AC voltage to
 be varied, preferably, the AC voltage has a nominal frequency on the order
 of 1 KHz. It is further contemplated that the spacing between the
 impedance measurement probes be on the order of between 0.25 and 1.5
 inches.
 Since the voltage applied to the measurement probe by the impedance circuit
 48 is known, a readout of the current passing between the probes provides
 an indication of the tissue impedance therebetween. The impedance circuit
 48 may be a "self-contained" unit which permits readout of the impedance
 measurements in addition to applying the AC voltage to the measurement
 probes, such as the type sold by Hewlett-Packard as the 4263B LCR meter or
 the 4192A LF impedance analyzer. Alternatively, the impedance circuit 48
 may serve only to apply the AC voltage to the measurement probes and the
 impedance measurement readout may be performed by a readout subsystem 42
 of the control unit 14.
 The prediction processor 36 is coupled to the display 20 via connection 38,
 as shown. The ice ball formation prediction provided by the processor 36
 is displayed on the display 20, as described further in conjunction with
 FIG. 8. With this arrangement, a physician can perform "trial"
 cryosurgical procedures, prior to surgery, during which the physician is
 able to observe predicted ice ball formation prior to activation of the
 cryoprobes. This information is useful to determine and implement an
 optimum cryosurgical treatment procedure. Further, during cryosurgery, the
 physician is able to visualize ice ball formation and, in particular,
 temperature contours within and around the treated tissue in real time, as
 the ice ball is being formed.
 It will be appreciated that the particular arrangement and grouping of
 system components in FIG. 1 is illustrative only and can be varied in many
 instances. For example, components of the control unit 14 may be housed
 together, or in one or more separate units. As one example, the components
 of the control unit 14, including the cryoprobe controls 28, ultrasound
 controls 46, impedance circuit 48, readout subsystem 42 and a computer on
 which the prediction processor 36 and tissue model processor 40 are
 implemented, are housed in a single hardware rack or enclosed housing.
 Alternatively, many or all of the components of the control unit 14 may be
 implemented in the chassis of a standard personal computer modified to
 receive the control unit components such as the cryoprobe controls 28,
 ultrasound controls 46, impedance circuit 48, thermistor circuit 51 and
 readout subsystem 42, which may be implemented on printed circuit boards
 adapted to plug into input/output slots of the computer chassis.
 Referring to FIG. 2, an illustrative prostate treatment region is shown to
 have three cryoprobes 18a, 18b and 18c inserted therein, for simplicity of
 illustration. The prostate gland 50 is a muscular, walnut size gland
 positioned directly behind the bladder 52. The urethra 56 passes through
 the prostate gland 50. Also shown in FIG. 2 is an ultrasound probe 60
 disposed in the rectum. The ultrasound probe 60 is used to guide the
 cryoprobes 18a-18c through the perineum 64 and into the prostate gland 50.
 The importance of precision in freezing the prostate gland 50 so as to
 avoid deleterious side effects is evident from consideration of the
 anatomy of the prostate region. While a warm fluid is, generally directed
 through the urethra 56 during cryosurgery in order to help prevent
 freezing the urethra, it is likewise desirable to avoid freezing the mouth
 of the bladder 52, the rectal sphincter muscle 68 and the seminal vesicle
 53, all of which are located in close proximity to the prostate gland 50.
 Referring also to FIG. 3, an enlarged view of an illustrative cryoprobe 18a
 and sheath 22a is shown. As noted above, the cryoprobe 18a is an
 elongated, partially hollow tubular element through which a cooling agent,
 such as liquid nitrogen, is circulated. The cryoprobe 18a may take various
 forms. As one example, the cryoprobe 18a includes a relatively short,
 actively cooled tip portion 17 coupled to a longer metal tube 21 and then
 to a plastic tube which has a threaded fitting 19 adapted for attachment
 to the cryoprobe machine 24 (FIG. 1) and through which liquid nitrogen is
 routed to the probe tip 17. A central tube (not shown) within the probe
 which terminates adjacent to the tip is disposed concentrically within an
 outer return tube (not shown) also within the probe. The central tube
 carries the liquid nitrogen to the tip 17 and has a plurality of holes
 clustered at several locations along its length to allow nitrogen gas that
 may be produced to escape the central tube and return back to the
 cryoprobe machine 24 through the return tube. Any liquid nitrogen that
 reaches the tip 17 remains as liquid nitrogen or is vaporized and returns
 to the cryoprobe machine 24 via the return tube. Concentrically around the
 return tube is a vacuum tube (not shown) which is evacuated for insulating
 the probe. One such cryoprobe is commercially available from Cryomedical
 Sciences, Inc. of Rockville, Md. under the designation 3 mm.times.4
 cm.times.18 cm blunt tip cryoprobe. The illustrative cryoprobe 18a has a
 diameter on the order of 3.0 mm and the actively cooled tip 17 is
 comprised of a suitable thermally conductive material, such as stainless
 steel, and has a length on the order of 4.0 cm.
 Preferably, a layer of electrically insulating material 85 is disposed
 around at least a portion of the cryoprobe 18a. In the illustrative
 embodiment, a thin layer of insulating material, such as Teflon or
 aluminum oxide having a thickness on the order of a few microns, is
 disposed over a portion of the cryoprobe 18a starting at approximately an
 inch from the tip of the cryoprobe and extending back toward the fitting
 19. Use of such an electrically insulating layer 85 advantageously
 improves the sensitivity of impedance measurements.
 In the illustrative embodiment, at least one thermocouple 54 is mounted to
 at least one of the cryoprobes 18a-18n and, preferably, on each of the
 cryoprobes. More preferably, a plurality of thermocouples 54a-54k, such as
 five (only one of which, 54a, is shown), are disposed along a portion of
 each of the cryoprobes 18a-18n, such as along a 2.0 inch length
 longitudinally spaced by from the probe tip by 0.125 inches and from each
 other by 0.5 inches and rotationally spaced from each other by 72.degree..
 As will become apparent, temperature measurements provided by the
 thermocouples 54a-54k may be used to calibrate temperature measurements
 made with thermistor measuring devices 80a-80h supported by the sheath 22a
 and/or to provide probe temperature information for use by the prediction
 processor 36, as will be described. Since the change in resistance of
 thermistors increases significantly, into the Gigaohm range, as
 temperatures decrease below -150.degree. C. and since the thermocouples
 54a-54k are disposed on the probe 18a whereas the thermistors 80a-80h are
 disposed on the sheath 22a, it may be desirable to use the thermocouples
 54a-54k to provide the probe temperature information for use by the
 prediction processor.
 Preferably, the thermocouples 54a-54k are fabricated by a thin-film
 technique and include a first, electrically insulating layer 62 disposed
 over the outer surface of the probe 18a. A low-profile thermocouple
 junction 54a-54k having a thickness on the order of a few microns is
 disposed over the insulating layer 62. Suitable materials for the
 thermocouple junction include iron/constantan, chromel/alumel,
 copper/constantan, chromel/constantan, platinum/rhenium, platinum/rhodium,
 and tungsten/rhenium and suitable application techniques include
 sputtering steps, photoresist metallization steps or a combination of both
 techniques. Thereafter, another thin layer of electrically insulating
 material 66 is applied over the thermocouple junction 54a-54k in order to
 electrically insulate the thermocouple from the sheath 22a or tissue with
 which it may be in contact. Suitable electrically insulating layers 62, 66
 are comprised of aluminum oxide, or silicon oxide, for instance, and have
 a thickness on the order of a few microns. Wires coupling the
 thermocouples 54a-54k to the control unit 14 (FIG. 1) may be fabricated
 according to the same thin-film technique as the thermocouples themselves
 and adapted for connection to standard instrumentation wires at pads
 disposed distal from the probe tip portion 17.
 The sheath 22a is a hollow tubular element having open ends through which
 the cryoprobe 18a extends. Conventionally, a sheath is disposed over a
 portion of a cryoprobe for the purpose of facilitating insertion of the
 cryoprobe into tissue. More particularly, conventional insertion of
 cryoprobes is accomplished by first inserting a hollow needle in the
 desired tissue location. A wire having a hook at one end is directed
 through the hollow needle and the hook is anchored to the tissue.
 Thereafter, the needle is retracted and a series of dilators of increasing
 diameter are guided over the wire until the target tissue location has
 been dilated to a width suitable to accommodate the sheath. The sheath is
 then inserted into the dilator, following which the dilator is removed.
 Finally, the cryoprobe is inserted into the sheath and the sheath is at
 least partially retracted to expose a portion of the cryoprobe, such as on
 the order of one inch.
 In accordance with the present invention, in addition to facilitating
 insertion of the respective cryoprobe 18a in the above-described manner,
 the sheath 22a supports at least one measuring device 80a-80h for
 measuring a parameter of the tissue for use in predicting ice ball
 formation. Examples of parameters measured by the device on the sheath 22a
 include, but are not limited to, temperature, effective thermal
 conductivity, thermal diffusivity and blood perfusion rate.
 In the illustrative embodiment, the sheath 22a includes a plurality of
 parameter measuring devices 80a-80h in the form of thermistors. Preferably
 the sheath 22a has eight thermistors 80a-80h embedded therein and equally
 spaced longitudinally along the forward two inches of the sheath, adjacent
 to the tip portion 17 of the probe 18a. The thermistors are also equally
 spaced radially around the circumference of the sheath 22a. Thus, each
 thermistor is longitudinally spaced from another by 0.25 inches and
 radially by 45.degree..
 It is desirable that the thermistors 80a-80h have only a few ohms of
 resistance at 25.degree. C., that they be relatively low cost, that they
 have a low negative slope to changes in resistance with temperature down
 to cryogenic temperatures, that they be formed from a material which is
 easily heated by passing a current through it, and that they have side by
 side leads that can be easily welded to instrumentation wires 84. Suitable
 thermistors are glass-encapsulated devices of the type sold by Fenwal
 Electronics Incorporated of Milford, Mass. under the product numbers
 112-202EAJ-B01 and 111-202CAK-B01 and having a diameter of 1.14 mm, a
 length of 2.28 mm, a resistance of 2000 ohms at 25.degree. C. and side by
 side leads of 0.10 mm diameter and 9.5 mm length.
 Various techniques for fabricating the sheath 22a and forms of the sheath
 are possible. One sheath 22a, illustrated in FIG. 3, includes an inner
 Teflon tube 86 having an inner diameter slightly larger than, but close
 to, the diameter of the probe 18a and a thickness on the order of
 0.04-0.06 inches. The thermistors 80a-80h are positioned on the inner tube
 86 at the desired locations and are held in place with epoxy or other
 suitable substance. Wires 84 extending from the thermistors are also held
 in place along the length of the inner tube 86 with epoxy. Preferably, a
 plurality of slots or grooves 90 are carved into the inner tube 86 at
 eight equally-spaced locations around the circumference of the tube and
 the thermistors 80a-80h are placed in the grooves. The grooves 90 are
 sized and shaped so that the thermistors 80a-80h extend partially above
 the grooves (i.e., above the outer surface of the inner tube 86 ). Typical
 widths for the grooves 96 are on the order of 0.015-0.060 inches and
 typical depths for the grooves are on the order of 0.008-0.030 inches,
 depending on the dimensions of the particular thermistors.
 A second, outer tube 58 having an inner diameter slightly smaller than the
 outer diameter of the inner tube 86 is positioned over the inner tube 86
 in an interference fit. One way of achieving the interference fit is by
 cooling the inner tube 86 while heating the outer tube 58. With this
 arrangement, the inner tube 86 contracts while the outer tube 58 expands,
 permitting the inner tube to be inserted into the outer tube. When
 temperature equilibrium is reached, the inner tube 86 expands and the
 outer tube 58 contracts, thereby providing an interference fit
 therebetween. Apertures 88 are cut through the outer tube 58 around each
 of the thermistors 80a-80h in order to expose the thermistors 80a-80h and
 thereby to enhance the thermal response time of the thermistors by
 allowing direct thermal contact with the tissue and eliminating any
 intermediate material and its associated temperature drop.
 An alternative sheath 22a' is shown in FIG. 4 to include a relatively thin
 hollow Teflon tube 70 having a diameter slightly larger than the diameter
 of the probe 18a and a thickness on the order of 0.009-0.015 inches. The
 thermistors 80a-80h and wires 84 extending therefrom are arranged in the
 desired pattern on the outer surface of the tube 70 and are held in place
 with epoxy or are adhesively attached to a thin plastic sheet which is in
 turn adhesively attached to the outside of the thin Teflon tube 70.
 Thereafter, a thin Teflon shrink wrap layer 72 is applied over the tube 70
 and the thermistors 80a-80h.
 Once the shrink wrap layer 72 is applied, portions of the layer 72 covering
 the thermistors 80a-80h are removed, such as with a knife or heated tool.
 Cryogenic epoxy cement 74 is then applied to seal the edges of the shrink
 wrap layer 72 around each exposed thermistor 80a-80h. One way of applying
 the epoxy to these regions is with the use of a hypodermic syringe.
 In an other alternative embodiment shown in FIG. 5, a sheath 22a" is
 comprised of a hollow Teflon tube 76, like tube 86 of FIG. 3, having a
 relatively thick wall, on the order of 0.040-0.060 inches. Slots, or
 grooves 78 are cut into the surface of the tube 76 along its length at
 eight equally spaced locations around the circumference of the tube. The
 width of the grooves 78 is selected to permit the thermistors 80a-80h to
 be seated therein and the depth of the grooves 78 is selected to ensure
 that the thermistors extend partially above the outer surface of the tube
 76. In the illustrative embodiment, each groove 78 has a width on the
 order of approximately 0.015-0.060 inches and a depth on the order of
 approximately 0.008-0.030 inches.
 A thin layer 82 of Teflon shrink wrap is then applied over the tube 76 and
 the thermistors 80a-80h. Thereafter, cryogenic epoxy cement 84 is inserted
 into the grooves 78 under the shrink wrap layer 82, such as with the use
 of a hypodermic syringe. Once the epoxy has set, portions of the shrink
 wrap layer 82 covering each of the thermistors 80a-80h are removed to
 expose the thermistors. In view of the various above-described sheath
 embodiments 22a, 22a' and 22a", it will be appreciated by those of
 ordinary skill in the art that various modifications and combinations of
 techniques are possible without departing from the spirit of the
 invention.
 The thermistors 80a-80h supported by the sheath 22 a can be used to measure
 various parameters associated with the tissue, including tissue
 temperature, effective tissue thermal conductivity, blood perfusion rate,
 and thermal diffusivity, for use by the tissue model processor 40 and/or
 prediction processor 36. In order to measure tissue temperature, a known
 current is passed through the measuring thermistor by the thermistor
 circuit 51 and the resulting voltage drop across the thermistor is
 measured. The thermistor voltage drop can be compared to a thermistor
 calibration curve or against a temperature measurement made by one or more
 of the thermocouples 54a-54k, in order to convert the voltage drop into a
 temperature reading. Various arrangements for measuring the voltage across
 the thermistor are possible. As one example, the thermistor is connected
 as one element of a Wheatstone bridge. Alternatively, the thermistor may
 be coupled to a constant current supply or to a digital voltmeter.
 Two thermistors are used to make measurements of effective thermal
 conductivity, thermal diffusivity and blood perfusion rate. One such
 thermistor is located at the measurement site and the second thermistor is
 located at a reference site, preferably approximately 0.5 inches from the
 measurement site. The thermistor circuit 51 (FIG. 1) heats the thermistor
 at the measurement site to a few degrees Celsius above the surrounding
 tissue (i.e., .DELTA.T), which surrounding tissue temperature is known
 from a temperature measurement made by the reference thermistor in the
 manner described above. The electrical energy, .GAMMA., provided by the
 thermistor circuit 51 to the measurement site thermistor in order to
 maintain its temperature elevated by .DELTA.T with respect to the
 surrounding tissue temperature is measured by the readout subsystem 42 or
 by the thermistor circuit itself.
 A set of equations disclosed in an article entitled The Simultaneous
 Measurement of, Thermal Conductivity, Thermal Diffusivity, and Perfusion
 in Small Volumes of Tissue. (Journal of Biomedical Engineering, Valvano et
 al., August 1984, Vol. 106, pages 192-197), allows the effective tissue
 thermal conductivity to be computed according to the following equation:
 ##EQU1##
 where:
 .DELTA.T=volume averaged temperature increase of the measurement thermistor
 relative to the surrounding tissue;
 .GAMMA.=steady state power input provided by the thermistor circuit 51 to
 the measurement thermistor to maintain its temperature at .DELTA.T above
 the surrounding tissue;
 a=spherical radius of the cryoprobe; and
 K.sub.b =thermal conductivity of the thermistor.
 The volume averaged temperature increase .DELTA.T and the steady state
 power input .GAMMA. are known from the thermistor circuit 51. The
 spherical probe radius a and the thermistor thermal conductivity K.sub.b
 may be specified by the probe manufacturer and/or measured. Thus, since
 .DELTA.T, .GAMMA., a and K.sub.b are known values, the effective tissue
 thermal conductivity K.sub.eff can be computed according to the above
 equation (1).
 Additional equations provided in the above-referenced article permit the
 effective tissue thermal conductivity to be used to compute blood
 perfusion rate and thermal diffusivity as follows:
 ##EQU2##
 where:
 .alpha..sub.eff =thermal diffusivity;
 w=blood perfusion rate;
 K.sub.m =thermal conductivity of the tissue without blood flow;
 .beta.=slope of transient power input; and
 C.sub.b1 =blood specific heat.
 Use of the equations (2) and (3) to compute the additional parameters of
 blood perfusion rate and thermal diffusivity may be desirable in
 generating the global tissue model, as will be described.
 The effective tissue thermal conductivity is computed in response to
 measurements made with the thermistors 80a-80h (i.e., the effective tissue
 thermal conductivity is measured) prior to commencement of cryosurgery and
 the results of such "pre-surgery" measurements are used by the tissue
 model processor 40 to model thermal properties of the prostate tissue to
 be treated and by the prediction processor 36 to predict ice ball
 formation by the cryoprobes 18a-18n. Preferably, further measurements are
 made by the thermistors 80a-80h during the cryosurgical procedure. The
 results of such "surgery" measurements are used by the prediction
 processor 36 in order to verify the ice ball formation prediction, as will
 be described.
 Referring to FIG. 6, an illustrative ice ball prediction method performed
 by the tissue model processor 40 and prediction processor 36 of the system
 10 is shown. It will be appreciated by those of ordinary skill in the art
 that the particular sequence of steps shown in the flow diagrams contained
 herein is illustrative only and may be varied without departing from the
 spirit of the invention. Following commencement of the process, the
 operator of the system 10 enters various treatment parameters into the
 system in step 98 corresponding to intended aspects of the cryosurgical
 procedure to be carried out. Specifically, via the user interface 15 of
 the control unit 14, the operator, typically a physician, enters the
 intended relative position or placement of the probes 18a-18n (i.e., probe
 placement relative to other probes and relative to certain anatomical
 features), the depth of penetration of the probes, the duration of
 cryoprobe activation, the activation sequence of the probes, the
 de-activation time of each probe and the operational mode (e.g., a maximum
 freeze run starting at room temperature, with maximum freeze corresponding
 to a probe temperature on the order of -110.degree. C. to -160.degree. C.,
 or a maximum freeze run starting at a -80.degree. C. probe temperature).
 Various ways of describing the cryoprobe positions are possible. As one
 example, the locations of the cryoprobe tips in x, y, z space may be
 specified relative to a point in the prostate plus a vector along each
 cryoprobe if the cryoprobes are not in parallel. Alternatively, the x, y,
 z position of the cryoprobe tip(s) plus the x, y, z position of another
 known location on the cryoprobe(s) may be specified.
 In step 100, the geometry of the region to be modelled by the tissue model
 processor 40 is defined. As will become apparent, the tissue model
 processor 40 is a computer program which is responsive to measurements of
 effective tissue thermal conductivity by the thermistors 80a-80h supported
 by the sheaths 22a-22n for interpolating the effective tissue thermal
 conductivity of the region under treatment, which includes the region
 between and around the cryoprobes 18a-18n. To this end, it is necessary
 that the tissue model processor 40 be provided with information regarding
 the geometry of the treated region (i.e., the geometry of the modelled
 region), including the placement of the cryoprobes relative to each other
 and to the location of certain anatomical features. More particularly,
 this information, which is input by the operator in step 98, is provided
 to the tissue model processor 40 in step 100.
 In step 104, one or more cryoprobes 18a-18n with sheaths 22a-22n are
 inserted into the tissue of the patient targeted for cryosurgery in
 accordance with the treatment parameters entered in step 98. Specifically,
 the probes are inserted according to the placement and depth of
 penetration information entered in step 98.
 The ultrasound probe 60 (FIG. 2) provides a two-dimensional image of the
 prostate to the physician to facilitate placement of the cryoprobes
 18a-18n at the desired locations. The physician may guide the cryoprobes
 to the desired locations by eye (i.e., with use of the ultrasound image)
 or may use an adjustable guide block (not shown) which ensures a specific
 spacing between the probes. The cryoprobes 18a-18n are marked with depth
 indications, by which the physician determines when the specified depth of
 penetration has been reached.
 Pre-surgery in-vivo measurements are made with one or more of the measuring
 devices 80a-80h supported by the cryoprobe sheaths 22a-22n in step 108. In
 one embodiment, the effective tissue thermal conductivity is measured at
 the eight locations of the thermistors 80a-80h on each of five cryoprobes
 18a-18e inserted into the tissue in the manner described above (i.e.,
 using thermistor measurements and equation (1)). Preferably, the thermal
 conductivity data collected in step 106 is curve fitted in step 108 in
 order to determine contour lines having substantially constant thermal
 conductivity characteristics within the modeled region. As one example,
 the measured data is plotted in x, y, z space and the data is examined to
 determine if the variation in measured effective thermal conductivity is
 small or insubstantial. If the variation is small, for example within a
 few percent over the prostate, then the thermal conductivity is assumed in
 the calculation to be constant throughout the entire prostate. However, if
 the variation is substantial, for example in the range of ten percent or
 more, then the data along each sheath is curve fitted, first with standard
 functions, such as exponentials, polynomials, etc., and the function
 providing the best fit is stored for each sheath.
 The global tissue model, which is a characterization of the effective
 thermal conductivity of the tissue under treatment, is generated in step
 110 by the tissue model processor 40 (FIG. 1). The global tissue model is
 generated in response to the geometry data determined in step 100 and the
 curve fitted measurement data derived in step 108. More particularly, in
 response to the measured effective thermal conductivity at the eight
 locations of the thermistors along each of five sheaths covering probes
 inserted into the patient, the relative placement of the sheaths and the
 geometry of the treated region, the effective thermal conductivity of the
 tissue around and between the sheaths is interpolated and stored in
 relation to each portion of the modelled region, thereby providing a
 distribution of effective thermal conductivity around and between the
 probes. Various interpolation schemes, including linear interpolation, are
 possible. As a further alternative, more than one interpolation scheme may
 be used and the results compared to generate the global tissue model. For
 prostates with significant measured variations in effective thermal
 conductivity, points having the same selected values of thermal
 conductivity along the sheaths may be identified by solving the functional
 relationships stored for each sheath. Equations may then be developed
 which describe the x, y, z contours of constant effective thermal
 conductivity in x, y, z space. These equations may then be used to assign
 a value of effective thermal conductivity to each x, y, z block in the
 SINDA calculation space.
 It will be appreciated by those of ordinary skill in the art that the
 global tissue model may characterize additional thermal aspects of the
 treated tissue, including blood perfusion rate and thermal diffusivity. To
 this end, it may be desirable to compute thermal diffusivity and blood
 perfusion rate with equations (2) and (3) above, respectively, in response
 to thermistor measurements, to interpolate these parameters over the
 modelled region and combine the results with the effective tissue thermal
 conductivity in generating the global tissue model.
 In step 112, the prediction processor 36 predicts the formation of ice
 balls in the prostate by calculating the expected temperature versus time
 history of the region. More particularly, the SINDA program of the
 prediction processor 36 breaks down the modelled region (which is defined
 by the user in step 98 ) into a plurality of blocks, some of which are
 occupied by probes according to the probe placement specified in step 98
 and some of which represent tissue. The blocks can be arranged either
 two-dimensionally or three-dimensionally and each block is assigned a
 boundary value condition or equation, following which the temperature
 versus time history is calculated by computing the heat flow in each
 block.
 The initial boundary value for blocks representing portions of a probe
 18a-18n is set equal to the probe temperature measured prior to
 cryosurgery, in step 106, by the thermocouples 54a-54k or thermistors
 80a-80h and input into the SINDA program in step 112. Thus, the probe
 temperature measurements are made once, prior to surgery, and preferably
 by the thermocouples 54a-54k. Another input to the SINDA program is the
 expected temperature time history of each cryoprobe which provides a
 boundary value equation assigned to each block representing a probe.
 Blocks representing tissue are assigned a boundary value condition related
 to the effective thermal conductivity of the tissue. To this end, the
 global tissue model data provides the effective thermal conductivity to
 assign to the blocks representing tissue. Further, blocks corresponding to
 the urethra are assigned a boundary value condition according to the
 expected temperature of a warming fluid passed through the urethra. The
 urethra is maintained at nearly constant temperature during cryosurgery by
 a warmed catheter inserted into the urethra. The blocks in the SINDA
 program representing the catheter are assigned temperatures corresponding
 to a temperature that is set.
 Additional inputs to the SINDA program include the treatment parameters
 entered in step 98, including placement of the probes relative to each
 other and to the treatment region, the activation sequence of the probes,
 the duration of the probe activation, the shutdown timing and sequence for
 the probes and the operational mode of the probes. In step 112, the
 prediction processor 36 computes a prediction of the formation of ice
 balls by each of the cryoprobes 18a-18n inserted into the prostate gland
 50 in response to treatment parameters specified in step 98, the global
 tissue model and the results of the pre-surgery measurements made by the
 thermistors 80a-80h and/or thermocouples 54a-54k.
 In step 116, contours of selected temperatures calculated by the prediction
 processor 36 are used to generate an image illustrating ice ball formation
 on the display 20. More particularly, the display 20 provides a
 representation of the temperature contours within the treated prostate
 gland as a result of activation of the cryoprobes 18a-18n. The displayed
 image may take various forms. In one embodiment, the display 20 provides a
 pictorial representation of the treated prostate gland with the
 temperature contours represented by boundary lines, as shown in FIG. 8.
 Following completion of the process of FIG. 6, the operator, or physician,
 has information regarding precisely how the prostate gland 50 under
 treatment would be frozen upon activation of the cryoprobes 18a-18n in the
 specified manner. With this information, the physician is able to
 determine whether to proceed with, or alter the planned treatment routine
 in order to achieve an optimal area of freezing. For example, where the
 displayed ice ball prediction indicates an excessive area of freezing, the
 physician may alter the treatment routine by activating the cryoprobes
 18a-18n for a shorter duration than otherwise planned. The physician may
 choose to modify the parameters of the treatment routine and repeat steps
 98 through 116 in order to generate a new prediction of ice ball formation
 based on the modified treatment parameters.
 Once the physician is satisfied with the displayed ice ball formation
 prediction, the pre-surgery prediction process of FIG. 6 is completed. The
 actual cryosurgery procedure may follow the process of FIG. 6 immediately
 or at some later time.
 Referring to FIG. 7, the cryosurgical process commences in step 120, with
 activation of the cryoprobes 18a-18n. In step 124, at least one parameter
 associated with the tissue of the patient targeted for cryosurgery is
 measured by the measuring devices 80a-80h on the cryoprobe sheaths
 22a-22n. These measurements are thus, performed during cryosurgery, when
 the cryoprobes are activated and thus, are referred to as "surgery"
 measurements.
 In step 128, the ice ball formation prediction provided in step 112 of FIG.
 6 is verified in response to the surgery measurements made in step 124,
 during cryosurgery. Prediction verification may be based on various
 surgery in-vivo measurements, including tissue temperature and impedance,
 since a correlation between the tissue impedance and ice ball size has
 been demonstrated. Thus, in the latter case, the measurement made in step
 124 is a measurement of tissue impedance made with the impedance circuit
 48 (FIG. 1) in the manner described above. More particularly, from
 measured laboratory data, it has been found that impedance and ice ball
 size can be related by a single curve when ice ball size is plotted
 against impedance. Therefore, impedance data measured at any time during
 cryosurgery may be converted to ice ball size simply by using this plotted
 relationship. Since the prediction model provides as one of its outputs
 the calculated size of the ice ball versus time, and the impedance
 measurements via the plotted relationship also provides a measurement of
 ice ball size versus time, a comparison between calculated results and
 results derived from impedance measurements allows the SINDA model
 predictions to be verified. Tissue temperature measurements may be made
 with either the thermocouples 54a-54k or thermistors 80a-80h in step 124
 and the results used to verify the prediction. As one example, in cases
 where the prediction is based on temperature measurements made with the
 thermocouples 54a-54k, subsequent temperature measurements made with the
 thermistors 80a-80h in step 124 can be used to verify the thermocouple
 temperature measurements on which the prediction is based.
 In step 132, it is determined whether the prediction generated in step 112
 of FIG. 6 requires modification. As one example, if the ice ball
 prediction from step 112 differs from the prediction computed in response
 to measurements in step 128 by more than a predetermined amount, then the
 prediction is updated in step 136 and the updated prediction is displayed
 in step 140. Alternatively, if the ice ball formation prediction generated
 in step 112 of FIG. 6 does not differ from the prediction verification
 determined in step 128 by more than the predetermined amount, then the
 prediction generated in step 112 is subsequently displayed, in step 140.
 In this way, the physician is provided with a real time indication of ice
 ball formation, as the ice ball(s) are formed.
 In certain applications, it may be desirable to repeat the prediction
 verification steps 124-140 at various times during the cryosurgical
 procedure. For example, the prediction may be verified periodically during
 the procedure. Alternatively, a first iteration of the prediction
 verification steps 124-140 may be based on in-vivo measurements of
 temperature made by thermocouples 54a-54k on each of the probes 18a-18n, a
 second iteration of steps 124-140 may be based on temperature measurements
 made by thermistors 80a-80h on each of the sheaths 22a-22n and a final
 iteration of steps 124-140 may be based on impedance measurements made by
 the thermistors. Alternatively, the prediction verification can be based
 on a combination of the measurements of the different parameters.
 FIG. 8 shows an illustrative image provided on the display 20 (FIG. 1) and
 showing the prostate gland 50 having three cryoprobes 18a, 18b and 18c
 inserted therein. The boundary lines 180, 182, 184 and 186 around the
 cryoprobes 18a-18c indicate temperature contours within the prostate gland
 50. Preferably, the temperature contours around the cryoprobes 18a-18n
 show different gradations of temperature, such as by different colors or
 line formats. In the illustrative display, boundary lines 180 and 182
 indicate regions of 0.degree. C. surrounding a single activated cryoprobe
 18a and for two cryoprobes 18a and 18b spaced 1/8 inch apart,
 respectively. Boundary line 184 represents the 0.degree. C. region around
 cryoprobes 18a and 18c in use with one inch between the cryoprobes and
 boundary line 186 represents the 0.degree. C. region around three
 activated cryoprobes 18a, 18c, and 18d spaced one inch apart. The
 physician may select the cancer kill temperature contour to be highlighted
 by a special color.
 It will be appreciated by those of ordinary skill in the art that the
 format of the image provided by the display may be readily varied while
 still providing the physician with the critical information regarding the
 cryosurgical process; namely, temperature contours in the treatment area.
 Further additional information may be readily displayed, including, as
 examples, patient information, measured prostate tissue properties,
 individual or multiple cryoprobe tip temperature histories and impedance
 data. The display 20 may additionally show the rectum and its location
 relative to the prostate gland and the cryoprobes.
 Having described the preferred embodiments of the invention, it will now
 become apparent to one of ordinary skill in the art that other embodiments
 incorporating their concepts may be used. It is felt therefore that these
 embodiments should not be limited to disclosed embodiments but rather
 should be limited only by the spirit and scope of the appended claims. All
 publications and references cited herein are expressly incorporated herein
 by reference in their entirety.