WO2016193125A2

WO2016193125A2 - Cryotherapy systems

Info

Publication number: WO2016193125A2
Application number: PCT/EP2016/061946
Authority: WO
Inventors: Biswaroop CHAKRABARTI; Subhendu Seth; Pallavi Vajinepalli; Payal Keswarpu; Karthik SUBBARAMAN
Original assignee: Koninklijke Philips N.V.
Priority date: 2015-06-03
Filing date: 2016-05-26
Publication date: 2016-12-08
Also published as: WO2016193125A3; CN107690315A

Abstract

A cryo-ablation systems with a probe body (P) having a treatment head (TH) with a tip portion (TP) for contacting tissue at a region of contact and configured for imparting a temperature change to the tissue at said region of contact. A plurality of electrodes (E_j) are arranged spaced apart from said tip portion and around said tip portion, configured to measure an electrical property of the tissue in a neighborhood around said region of contact. Adhesion management means are also envisaged.

Description

CRYOTHERAPY SYSTEMS

FIELD OF THE INVENTION

The invention relates to apparatuses for supporting an in-tissue temperature change operation, method of supporting an in-tissue temperature change operation, computer program elements, and computer readable media.

BACKGROUND OF THE INVENTION

Cervical cancer is the most common cause of cancer deaths among women in relatively low resource settings, such as refugee camps, or countries with relatively low per capita GDP, or similar.

To get on top of this, down-staging efforts (that is, cancer reducing measure) are seen in many developing countries like India, China and these are expected to increase in the future due to large scale screening programs put into place by national health services or UN health agencies. In particular, level 1 evidence (that is, evidence from at least one properly designed randomized controlled trial) shows the benefit of relatively simple ad-hoc treatment ("see and treat" strategies) to achieve down-staging and hence reduce deaths due to cervical cancer or in fact other similar cancer presentations.

Cryotherapy is being considered as the treatment modality for CIN (Cervical intraepithelial neoplasia) treatment for "see and treat", in particular to low resource settings in India, China, Africa, Thailand, etc. In CIN, dysplasia is limited to the epithelium without loss of integrity of basement membrane. One can distinguish further stages of development, namely: CINl which involves dysplasia limited to basal l/3rd, CIN2 which involves growth to basal 2/3rd and CIN3 where the dysplasia has grown the full thickness of the epithelium.

Evidence in these geographies shows that "see and treat" using cryotherapy could be performed by experienced and trained nurses so do not necessarily require attention by a doctor or other highly trained medical specialist.

In a particular cryotherapy procedure called cryo-ablation, abnormal tissue at a lesioned site (e.g. cervix) is destroyed by freezing. A very cold coolant, such as liquid carbon dioxide (-68°C) or Nitrogen (-89°C), circulates through a probe placed on or next to the abnormal tissue. Down to -68°C is achievable at the core of the tissue "ice ball" and about - 20°C is achievable at the edges. Tissue cells held at -20°C for 1 min or more undergo cryo- necrosis.

A particularly effective treatment protocol is a sequence of 3-5-3 mins of "freeze-thaw-refreeze", respectively. The procedure is simple and can be performed by healthcare worker in the field. However, it has few side effects like excessive tissue freezing, avulsion of tissue and hence damage to lot more tissue than needed. This results in patient discomfort such as prolonged (white) discharge.

SUMMARY OF THE INVENTION

There may therefore be a need for alternative apparatus or system to support medical personnel during embolization or similar interventional procedures.

The object of the present invention is solved by the subject matter of the independent claims where further embodiments are incorporated in the dependent claims. It should be noted that the following described aspect of the invention equally applies to the image processing method, the image processing system, to the computer program element and to the computer readable medium.

According to a first aspect of the invention there is provided an apparatus for supporting an in-tissue temperature change operation, comprising:

a probe body having a treatment head with a tip portion for contacting tissue at a region of contact and configured for imparting a temperature change to the tissue at said region of contact, and

a plurality of electrodes (E_j) arranged spaced apart from said tip portion and around said tip portion, configured to measure an electrical property of the tissue in a neighborhood around said region of contact.

Specifically, and according to one embodiment, the apparatus is operable in cooling mode to freeze the tissue below a pre-defined temperature, the apparatus further comprising an estimator module configured to estimate an extent of frozen tissue around the tip based on the measurement of the electrical property.

The spaced apart electrodes allow collecting the measurements in a suitable neighborhood and to estimate the (spatial) extent of frozen tissue not only on the surface of the tissue but also the depth of the amount of frozen tissue without penetrating into the tissue. This is a distinctive advantage of the proposed method over a simple temperature

measurement by a thermometer unit which only allows surface measurements or which would require tissue penetration. The proposed system thus allows relatively painless monitoring how the amount of frozen tissue evolves during the treatment and giving a user a good idea whether the treatment objective has been achieved. The proposed apparatus can thus support even inexperienced staff with only basic medical training. A simple set of instructions accompanying the proposed apparatus will allow a field worker to quickly familiarize themselves on how to use the apparatus and then to be ready to "see-and-treat" in very short time, even under difficult, stressful condition in camps, warzones etc. Significant down- staging rates can be achieved for certain cancer types such as cervix cancer, melanoma treatment etc.

According to one embodiment, the probe is operable in two modes, a cooling mode to cool said tissue, in particular for cryo-ablation, or in a heating mode to heat said tissue, the apparatus in particular including a switching mechanism that allows the probe to switch between said modes.

This allows speeding up operations to quickly dislodge the apparatus in case of adhesion and is allows applying certain treatment protocols that involve a sequence of alternate heating and freezing.

According to one embodiment, the apparatus is operable in cooling mode to freeze the tissue below a pre-defined temperature, the apparatus further comprising an estimator module configured to estimate, after the apparatus ceases to operate in cooling mode, an extent of thawed tissue around the tip based on the measurement of the electrical property. Specifically and according to one embodiment, the alert unit is configured to provide an indication if, after a preset-time period, there still is tissue in the neighborhood that has not yet thawed. This allows for a user to quickly establish the point in time when it is safe to remove the probe from the point of contact with reduced risk for tissue avulsion.

According to a further aspect there is provided a method for supporting an in- tissue temperature change operation, comprising:

imparting a temperature change to tissue at a region of contact with a probe, with a probe having a plurality of spaced apart electrodes arranged around said region contact, collecting a measurement of an electrical property of the tissue in a neighborhood around said region of contact; and

based on the measurement, estimating an extent of tissue affected by the temperature change.

According to a yet further aspect there is provided an apparatus for supporting an in-tissue temperature change operation, comprising: a probe body having a treatment head with a tip portion for contacting tissue at a region of contact and configured for imparting a temperature change to the tissue at said region of contact,

a sensor arrangement configured to measure i) a physical property of the tissue in a neighborhood around said region of contact or ii) a physical property of the tip portion whilst in tissue contact; and

a decision module configured to establish based on a measurement of the physical property whether an adhesion event has occurred in relation to the treatment head and the tissue.

Even inexperienced is supported by the decision module of the proposed apparatus to understand when an adhesion event has occurred. Risk of tissue damage can be reduced.

According to one embodiment the apparatus comprises an adhesion mitigator configured to act on the probe so as to mitigate adhesion between treatment head and the tissue if occurrence of the adhesion event has been established by the decision module.

This helps to quickly and safely dislodge the probe thus increasing efficiency if a large number of patients need treatment in a given time period.

According to one embodiment the apparatus comprises an adhesion mitigator comprising an actuator mechanism operable to move said tip portion whilst in contact with the tissue and whilst said probe operates to change tissue temperature. This allows to quickly and effectively beak adhesion.

Acting on the treatment head other than mechanically is also envisaged. For instance, in one embodiment, where the temperature change imparted by the treatment head comprises cooling said tissue, the action effected by the adhesion mitigator includes ceasing said cooling. More specifically, in one embodiment the cooling stops and the treatment head is actively heated to break the thermally break the adhesion.

A combination of mechanical and thermal action to break the adhesion is also envisaged in some embodiments.

According to one embodiment, said physical property comprises a mechanical property, in particular torque or acceleration/deceleration.

According to one embodiment said physical property comprises an electrical property, in particular an electrical impedance.

According to one embodiment, the treatment head is of a frusto-conical shape and/or wherein the tip portion includes a depression. This shape and the depression at the tip have both been found to reduce the likelihood for adhesion events to occur.

According to one embodiment, the apparatus comprises an alert unit configured to provide an indication if, after a preset-time period, the adhesion event is still in effect. This helps a user even further to safely operate the device without risking tissue damage.

According to one embodiment, the temperature change is suitable for cryo- ablation.

According to a further aspect there is provided a further method for supporting an in-tissue temperature change operation, comprising:

imparting a temperature change to tissue at a region of contact with a probe, measuring i) a physical property of the tissue in a neighborhood around said region of contact or ii) a physical property of the tip portion whilst in tissue contact; and

establishing based on a measurement of the physical property whether an adhesion event has occurred in relation to the treatment head and the tissue.

In sum the proposed apparatuses and methods facilitate:

• preventing or reducing damage to normal tissue by preventing adhesion between cryo- probe tip and tissue

• preventing or reducing avulsion by passively and actively preventing adhesion

• active monitoring of the cryotherapy, thereby limiting exposure of normal tissue and resulting in better prognosis

• making cryotherapy more precise or definitive hence avoiding large tissue destruction and thus avoid above mentioned side effects

• enabling nurses and healthcare workers to perform cryotherapy in low resource

settings and thus enables safe administration of "see and treat" protocols.

BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary embodiments of the invention will now be described with reference to the following drawings wherein:

Figure 1 shows a cryotherapy apparatus according to one embodiment;

Figure 2 shows a plan view along the longitudinal axis on the cryotherapy apparatus as per Figure 1 ;

Figure 3 shows a side elevation of a treatment head of the cryotherapy apparatus as per Figure 1 in contact with tissue;

Figure 4 shows a flow chart for supporting a tissue temperature change operation;

Figures 5A, B show a cryotherapy apparatus according to a different embodiment; and

Figure 6 shows a method for supporting in-tissue temperature change operation according to a second embodiment.

DETAILED DESCRIPTION OF EMBODIMENTS

In the following there are described apparatuses for supporting in-tissue temperature change. More particularly, the apparatuses are suitable for carrying out cryo- ablation in human or animal tissue and include an arrangement treatment monitoring and/or an adhesion management arrangement.

Turning now first to the treatment monitoring arrangement, this is shown schematically in Figure 1 at least partly integrated into a cryo-ablation probe CAA. The probe CAA is arranged to administer cryo-ablation at a lesioned site in human or animal tissue.

Referring to Figure 1 in more detail, there is shown an elongated, in general cylindrical probe body P (shown in side elevation in partial cutaway) which terminates in one end in a metallic treatment head TH. There is a connector module CON at the other end of the elongated probe body P.

The connector module CON includes a first connector CON1 which is arranged to connect the probe to a cryo-source CS. The cryo- source CS may be as simple as a reservoir holding a volume of coolant such as liquid nitrogen or carbon dioxide or a mixture of dimethyl ether and propane. The cryo-source CS is coupled in fluid communication via a suitable conduit like a hose to the cryo-connector CON1.

There is a switching interface SM which allows a user to request and/or to terminate a cryo-ablation operation. The switch may be arranged as a button on the apparatus CAA but physical integration into the cryo-apparatus CAA is not necessary in all

embodiments. For instance, in alternative embodiments there is a remotely operable switch such as a foot pedal in wired or wireless communication with the cryo-apparatus.

The probe body P with the optional housing H is configured and dimensioned so it can be conveniently held in the user's hand. For instance, the dimensions of the cryo probe CAA is about that of a pen or pencil (or "cryo-stick"). The further promote ergonomics, the probe's outer surface structure is configured for sure grip by the user's hand. For instance, in embodiment non-slip areas such as knurlings or other may be arranged on the outer surface of the housing H of the cryo-probe CAA, useful in stress situations where excess perspiration through the (potentially inexperienced) user's hand is not uncommon.

When requested by operation of the switch SM, the coolant is circulating via the cryo-connector CON1 into and out of the probe body P. Specifically, the probe body P incorporates internal tube-work that allows in- and egress of the coolant into and out of the probe body P. The, preferably metallic, treatment head TH is thermally coupled to the coolant circulating within the probe body and so assumes over time the required pre-defined treatment temperature of about -75° to -40°' depending on application.

The cooled treatment head TH, in particular its tip potion TP, is urged by the user into contact with the tissue at the point or region of contact. This region corresponds to at least a part of the diseased site. The tissue, at the point /region of contact, and in a neighborhood thereof, is cooled down to the pre-defined temperature and is eventually cauterized by freezing in order to bring about local cell necrosis to so eliminate or reduce the possibly cancerous neoplasm that has formed at that site. The cryo-probe CAA is configured for external or intra-cavity application (such as CIN treatment).

Now, in order to help the, in particular inexperienced, user of the cryo-probe CAA to determine whether treatment can be aborted at a given site, there is a treatment monitoring functionality, at least partly integrated into the probe CAA. The treatment monitoring functionality comprises a plurality of electrodes El and E2 to collect (possibly intra-cavity) measurements at the tissue. The electrodes El and E2 are held at a pre-defined (preferably user adjustable) distance from the treatment head, in particular from the tip of the treatment head, via a distance element such as a collar portion CP. In particular the electrodes are held at a distance away from an outer surface of the treatment head TH and from the tip TP in particular to span or outline a desired neighborhood around the region of contact.

Connection lines are run, preferably within the housing H, along the probe body P from the electrodes El, E2 to a suitable signal connector CON2. The housing H as shown in Fig 1 is flush with the collar portion CP so the collar is not visible from the outside. But this may not be so in all embodiments as such a construction may turn out too wide to be comfortably held by a user of average hand size. In alternative embodiments, the housing H runs closer to the probe body P for most of its lengths and only diverges (in a gradual or step-like fashion) from the body P near the collar CP to only locally correspond to the width of the collar portion. The cryo-probe CAA may have a (customized) radius of H along the body P depending on average grip sizes.

In one embodiment, but not necessarily all embodiments, the signal connector CON2 is situated at one end of the probe body P, distal from the end where the treatment head TH is situated. The connector CON 2 connects with an estimator module PM.

Connection from the connector CON2 to an input port IN of the estimator module PM may be wireless or wired as the case may be. The readings collected by the electrodes El, E2 are hence transmittable to the estimator module and are processed there. More particularly, whilst the treatment head tip TP is in contact with the tissue (to effect the freezing), so are the terminal portions or electrodes El and E2 with surrounding tissue at the pre-define distance from where the tip is in contact with the tissue. In other words, the treatment head tip TP and the electrodes are in contact with the tissue at the same time albeit at different locations. To ensure concurrent tissue contact of electrodes El, E2 and tip TP, a distance by which the electrodes project forward from the collar portion may be user adjustable to adapt for uneven tissue surfaces. Whilst freezing treatment through or at the treatment head tip TP is ongoing, an electrical property such as voltage or current or, preferably electrical impedance, is measured across the electrodes and the tissue. These measurements are converted by suitable data acquisition circuitry (not shown), such as an A/D converter stage, into digital

measurements and these are then transmitted via electric connector CON2 to the predictor or estimator module PM, the connector CON2 is the input port for the predictor module PM.

Other arrangements are also envisaged, where connector CON2 is formed internal the housing H close to the treatment head H, for instance at the collar portion CP or distance element.

The estimator module PM estimates based on those readings how far the temperature drop has propagated through the tissue from the point of contact with the tip TP. Said differently, these measurements allow estimating an extent of an "ice ball" of frozen tissue that has formed. This, in turn, allows ensuring that an "ablation margin" of sufficient width and/depth has formed around the region/point of contact. If the extent of frozen tissue (by "frozen" we understand herein "frozen below the pre-defined treatment temperature") is deemed sufficient as per the collected electrode readings, this is indicated to the user via an alert module AU or alert unit.

The alert unit AU is configured to drive a suitable transducer TR to so effect sensory rendering of this information. For instance, the transducer may be as simple as a lamp flashing once it is determined that a sufficient amount of tissue in the neighborhood around the region of contact has been sufficiently frozen up. Instead of, or in addition to furnishing an optical indication, the transducer may be arranged as an auditory or haptic transducer. For instance, in the earlier case, a suitable signal sound is emitted via a speaker system and/or the probe is excited to vibrate to indicate to the user that the treatment can be considered complete and can hence be aborted.

Reference is now made to Figure 2 which shows a plan view of the collar- portion CP used to hold the electrodes El and E2 at the pre-defined distance(s) from the tip TP of the treatment head TH. The view as per Figure 2 is along the longitudinal z axis of the probe from the tip of the treatment head.

According to one embodiment and as shown in Figure 2 the collar portion CP includes retainer mechanisms, RM, one for each electrode El or E2. The collar portion CP is essentially a disk formed from a plastic material of suitable flexibility. The retainer mechanisms are arranged as cut-outs in the collar portion. Each cut forms a pattern of repeated hour glass shapes. More particularly, each retainer mechanism RM comprises a series of retainer holes (four are exemplary shown in Figure 4) arranged along a respective radial axis of the disk CP. Each of these holes is suitably dimensioned to correspond to the diameter of the electrode wires. The series of retainer holes are in correspondence via narrow passageways which are formed by opposed neck-portions. Each passageway is, if undisturbed, narrower than the diameter of the electrode wire and hence the electrode is held securely in place once in any one of the retainer holes. If the user wishes to change the distance from the tip portion TP, they gently push or pull the respective electrode either away from the tip or towards it.

Because of the flexibility of the surrounding plastic of the disk CP, the neck-portions will give and allow the electrode to pass from one retainer hole to the neighboring one, essentially clicking into place. In this way a ratchet mechanism is provided that allows changing the distance between the electrode probes and the tip of the treatment head in a simple and effective way. As can be seen in elevation as per Figure 3 the part of the electrode that extends through the collar portion CP and to the outside of the housing H may be formed from thicker, stiffer wire than the connection lines that are run inside the housing towards the connector CON2. This allows easier adjustability of the probe tip-electrode distances. It will be understood by those schooled in the art that the retaining mechanism as shown in Figure 2 is only an exemplary embodiment and other solutions are also envisaged. Specifically, arrangement of the distance element as a disk CP as per Figure 2 is an exemplary embodiment. For instance, the distance element may not be arranged as a (solid) disk as shown in Figure 2 but as a series of discrete, individual arms that extend from the body P as a single opposing pair or, as a plurality of pairs, in star-like arrangement, with each arm having a retainer mechanism RM as described above or similar.

In an alternative embodiment, two parallel non-connected spiral grooved structures are cut into to collar portion CP plane, The spirals originate from the center of the collar portion (close to the tip TP) and spiral outwards towards where the collar portion meets the housing H. This allows for smooth movement of electrodes El, E2 in synchrony for adjusting a desired spacing between the said electrodes for performing the monitoring.

In further embodiments, the electrodes are collectively or individually retractable into the housing H and can be deployed if need be. In one such embodiment, a retractable deploy mechanism such as roller mechanism is arranged in the housing behind the treatment head. The electrodes can then be move inward/outward (relative to the housing H) through openings in the collar portion and past the treatment head TH. One or more contact wheel constructs effect the electrode movement. The inward or outward electrode movement may be spring driven.

Preferably, the electrodes are arranged in a plurality of pairs so at least two electrodes, but more advantageously four or six, are used. The electrode pair(s) El, E2 are alternatively switched to emit (by suitable measurement control circuity - not shown) or receive current sent across the tissue. In other words, each probe functions at times as a receiver and at times as a transmitter of the electric signal through the tissue. The voltage or current readings thus obtained can be used to compute an electrical impedance of the tissue which is known to be relatable to a temperature of the tissue. The signal processing of the electrical readings obtained from the probes can be based on known EIT (electrical impedance tomography) or FIM ("Focused Impedance Measurement") techniques. Preferably, FIM is used as a full reconstruction of the current or voltage distribution in 3D in the tissue and may not be required in all circumstances. More particularly, it is sufficient to learn the temperature at the outer surface of the tissue where the probe contacts the lesion site of the tissue and this can be computed by FIM. As such, with FIM the extent of the ice ball is estimated in only one or two spatial dimensions on the tissue surface but the computations are simplified and can conclude quicker, thus increasing responsiveness. One reason why FIM computations are quicker is that fewer data points are fetched than in tomographic EIT. However, even when only FIM is used, the 2D reconstruction of the impedance distribution on the tissue surface still allows providing a good estimate of the depth down to which tissue has been frozen. This is because the 2D impedance reconstruction on the tissue surface corresponds to a "projection view" of the ice ball currently formed and thus to its diameter. The distance between the electrodes corresponds to the diameter of the ice ball and therefore its depth extension is likewise determined by this diameter due to symmetry. In short, FIM measurements have turned out to provide enough information for present purposes and EIT is hence not necessary but still envisaged herein in some embodiment. Being able to measure (without in-tissue penetration) also the depth of the frozen tissue at any one time rather than merely its surface extension is a distinct advantage of FIM or EIT as used herein over a simple thermometer measurement. Also FIM/EIT allows for tissue characterization which is unavailable in thermometer-based temperature measurements.

FIM has been described by K S Rabbani et al in "Focused Impedance

Measurement (FIM): A New Technique with Improved Zone Localization", Annals of the New York Academy of Sciences, 20 April 1999, Vol 873, Issue 1, pp 408-20.

Particulars of EIT reconstruction are discussed for instance by V A Cherepenin in "Three-dimensional EIT imaging of breast tissues: system design and clinical testing", IEEE Transactions on Medical Imaging, 2002, Vol 21, issue 6, pp 662-667.

With reference to Figure 3, there is shown in more detail the preferably real time monitoring of temperature change propagation through the tissue. The spatial arrangement of the electrodes defines an outer perimeter of the neighborhood (or at least a diameter thereof in case when only two electrodes are used) around the point where the tissue tip TP contacts the tissue. The distance from the tip to the respective electronic probes El and E2 is either fixed or is user adjustable. Once a temperature change is requested by the user, the probe is energized and the cauterization process commences. The temperature drop propagates through the tissue in the form of balls or spheres indicated by dashed lines. In other words each dashed line represents the outer surface of an ice ball that de-marks a respective interface (at different instants) between frozen and not yet frozen tissue. The extent, that is the radius diameter or even the volume of the ice ball can be measured by operating the probes according to an EIT scheme and by processing through an EIT algorithm impedance readings collected by the electrodes at a suitable sample interval.

The distance between opposing probes, in this case El and E2, define the diameter of the ice ball which one is trying to achieve. EIT or FIM impedance measurements can be used by the estimator PM to calculate radius/diameter/ volume of the ice ball formed from a lookup table previously compiled by using calculations involving average tissue (e.g., uterine cervical in CIN) electrical impedance and impedance of ice formed. Monitoring the size of the ice ball helps to decide on the adequacy of treatment. In sum, the measurements collected by the electrodes E1,E2 (suitably spaced apart from each other and the tip TP) allow prediction of the actual ablation margin from ice boundary based on interface between frozen and non- frozen tissue which is associated with a change in electrical impedance and thus predict if a sufficiently wide margin around the lesioned site is of interest, is thawed, or is frozen. The distance between the electrodes form the tip TP is adjustable in to ensure monitoring for the required ablation margin. Overall, the proposed integrated treatment monitoring functionality allows avoiding overtreatment, with improved prognosis and post- treatment presentation of vaginal discharge (frequently reported) can be expected to decrease.

In one embodiment the switching mechanism SM of the cryogenic probe CAA is not only configured to switch on or off freezing mode, but is also configured to switch the probe CAA from freezing mode into heating mode to perform a heating operation where the temperature of the tissue is being actively increased. This is to be distinguished from a simple switching off of the freezing mode which amounts to a mere shutting off circulation of the coolant through the probe body P where the temperature increases due to thermal heat transfer from the ambient temperature. The heating operation can be achieved by using, in one embodiment, heating elements such as heating wires which are arranged inside or outside the metallic treatment head TH. In another embodiment the cryo-source is a heat exchanger which can be switched to cool or to heat. That is, the working liquid is made to circulate as a coolant through the body of the probe to effect the cooling or the working liquid is heated up and made to circulate through the probe body to effect the heating.

The switching interface SM allows the operator to operate the probe in a flash heating mode where freezing and heating operations are applied in alternation. This flash heating functionality can be used to realize so called "freeze-thaw-freeze" protocols. In these protocols, application of cryo-ablation is required for three minutes. Then, subsequently, for five minutes, the probe CAA is switched by switch SM into heating mode and the tissue previously frozen down to under the pre-determined treatment temperature is now made to thaw until a second pre-defined temperature (> 0°, eg +10° or other) is reached. Next, in the final phase, there is another cryo-ablation operation applied at the same site for another three minutes. This alternation between freezing and thawing has been shown to yield effective cauterization results in tissue. The above described freeze-thaw-freeze protocol ("3-5-3") is exemplary and other sequences of time periods than 3min, 5min, 3min are also envisaged. More specifically, some protocols such as 3-5-3, although effective, have been reported to have side effects such as excessive freezing as mentioned above. The proposed EIT or FIM monitoring with the proposed probe CAA may help avoid or at least reduce the side effect and consequently the specific time period pattern may depart from that as prescribed by the protocol.

Flash heating may also be useful when the lesioned site is too large and cannot be effectively cryo-ablated from a single point of contact. The user can then easily move from one treatment point, which has been frozen down to under the pre-determined temperature, to another treatment position by thawing and un-sticking the treatment head and then moving it and applying the freezing operation there.

In these protocols of alternate freezing and thawing, the treatment monitoring arrangement with electronic probes PI and P2 in communication with the estimator module PM can be effectively used not only to estimate the extent of the frozen ball around the treatment site, but conversely can also be used to monitor the extent of thawing as that will likewise impart a change in electrical impedances as measured in the neighborhood.

In this context, the transducer is operated to indicate to the user that the tissue at the tip was successfully thawed and the probe can now be safely removed without danger of damaging tissue. In particular, the transducer can be modulated to indicate to the user that if, after a certain pre-determined waiting time, there is still tissue within the neighborhood, that has not completely thawed yet. For instance, the lamp remains on for as long as there are pockets of tissue in the monitored neighborhood that have not yet thawed. Only when the lamp is off, can the user safely remove the probe CAA. Other transducer modulation schemes may also be used to indicate the same information to the user.

Reference is now made to Figure 4 where a flow chart for a method for supporting in-tissue temperature operation is shown.

At initial step S410 a temperature change is imparted on tissue. This can be achieved by actively applying a freezing operation (such as in cryo-ablation) to tissue at a region of contact with the probe P. Alternatively, an active heating operation is applied to the tissue to promote thawing of previously frozen tissue. Yet alternatively, previously frozen tissue is allowed to thaw on its own, so the temperature change is passively imparted by the ambient temperature gradient.

As explained above, at step S420 an electrical property such as impedance etc, of the tissue in the neighborhood around said point of contact is measured by a plurality of electrodes at least partly surrounding that point/region of contact. The electrodes are spatially set apart from the tip of the probe at the point of contact. An EIT or FIM measuring scheme based on impedances can be used but other measurement schemes are also envisaged herein.

At step S430 an extent of the frozen or, as the case may be, thawed tissue around the region of contact is estimated based on the measurements. More particularly, the spatial extent of an amount of frozen or thawed tissue around said region is estimated. In particular it is established during a cryo-ablation operation whether enough tissue has been frozen or it is established whether there is still some frozen tissue left in a time window after the cryo-ablation operation has been terminated. The collected impedance measurements allow discriminating the impedance property for ice ball region and the non- frozen (normal) tissue. Specifically, impedivity of frozen tissue is of higher magnitude than unfrozen tissue. Thus localization of the frozen/non-frozen tissue interface can be estimated through prior knowledge of both frozen and unfrozen tissue's impedivity. Signal processing at step S430 generally involves suitable signal conditioning such as amplifying /filtering the acquired FIM data and thresholding to discriminate these regions. Furthermore, the ice

accumulation thickness can be measured in particular from the rate of accumulation indicated by the measured electrical property, such as the impedance.

If a certain pre-defined extent/amount of tissue is found, based on those measurements, to be sufficiently affected by the imparted temperature change, a suitable signal is issued at step S440 in form of an alert signal (auditory, haptic or visual or any other). For instance, the signal can be issued if enough tissue has been frozen or conversely, if not all tissue has thawed. If, however, it is determined that the extent of frozen/thawed tissue around the point of contact is not sufficient, the method flow returns to step S410 where temperature change is continued to be imparted. The pre-defined amount of tissue affect by the imparted change is in particular determined by the distance with which the electrodes are held apart from the tip of the probe. That distance may be user adjustable.

In sum, the method can be used to monitor a freezing operation or can be used to monitor thawing after termination of the freezing operation or whilst applying a heating operation to previously frozen tissue.

Reference is now made to Figures 5A and 5B where a cryo-therapy probe according to a different embodiment is shown, including an adhesion management

arrangement.

The general physical layout of the probe according to the second embodiment is similar to the one in Figure 1, with like reference characters indicating like components. In particular there is a cryo-connector CON to connect the probe body P with the cryo-source at an end of the probe body distal to the end where the treatment head TH is located. The probe body P may be housed in a housing H (not shown in Figs 5A, B) similar to the embodiment in Figure 1.

In the embodiment as per Figs 5A, B, the cryo-therapy probe CAA includes an adhesion management arrangement AMS which comprises a sensor arrangement SA that is configured to measure a physical property of the tissue in the neighborhood around the region of contact where the tip of the treatment head contacts the to-be-treated tissue. Alternatively, in addition or instead, it is a physical property of the tip itself which is measured whilst said tip is in contact.

The physical property measured by the sensor arrangement SA is converted by suitable data acquisition circuitry (not shown), such as an A/D converter stage, into digital measurements. The measurements are forwarded to an input port IN of a decision module DM. Similar to the embodiment shown in Figure 1, the input port IN may be formed as an appropriate wired or wireless connector at the same end where the cryo-connector CON is situated. The decision module DM establishes whether, based on the received measurements, adhesion has occurred between the tip TP and the tissue. If, based on the measurement, it is established that there is adhesion, this is indicated by the transducer TR by way of a suitable visual, haptic or auditory indication. The adhesion management sub-system operates preferably in real time whilst the tissue head or in particular its tip TP is in contact with the tissue and whilst the cryo-ablation is applied.

In order to reduce the likelihood for an adhesion to occur in the first place, the probe CAA comprises one or a combination of the following of adhesion avoidance schemes. For instance, in one embodiment, there is a suitable anti-slip coating applied to the treatment head TH, and especially to the tip thereof. In addition to said coating or instead thereof, there is a mechanical actuator mechanism ACM which allows to physically move the treatment head, or in particular the tip thereof, to prevent adhesion to occur. For instance, the actuator mechanism can be arranged as a suitable server motor or stepper motor which imparts a rotatory motion of the treatment head around the longitudinal axis z of the probe body P. For instance, in one embodiment, it is envisaged to apply a continuous rotation whilst the tip is in contact with the tissue and whilst the freezing operation or cryo- ablation operation is applied. A rotation of the treatment head or its tip is particularly advantageous to prevent adhesion, however other movements are not excluded herein. For instance, in one embodiment, the treatment oscillates to and fro in the direction perpendicular to the longitudinal axis of the probe body P. In a typical operation, there will be a minimal baseline movement (such as specific angular velocity) of the cryo-probe tip TP which will help to avoid adhesion whilst tissue cooling is being performed. The baseline movement is relatively small, so it can be practically instantaneously halted (with negligible inertia effects) so that very minimal torque is exerted on tissue in case that adhesion does still occur. The exact specification of this baseline can be determined experimentally. In one embodiment, no matter the movement type (linear or rotatory), the head is comprised of two parts movable relative to each other, with one, terminal part comprising the tip portion, and it is only said terminal part (comprising the tip portion) that is arranged to move (e.g. rotate) and not the entire treatment head.

Figure 5B is a perspective view that shows a more detailed an embodiment of the treatment head TH as envisaged herein equipped with actuator mechanism ACM. It can be seen that, unlike earlier treatment heads, the one proposed herein does not have a pointed tip, but has a rounded tip, and the overall appearance of the head is of frusto-conical shape with a semi- spherical protrusion at the tip TP. In one embodiment, to further reduce the surface where possible adhesion can occur, the tip TP includes, instead of the spherical protrusion, a depression (which is not a through hole) which extends into the treatment head to form an annular lip portion LP around the center point of the tip. This annular shaping of the tip is an alternative to the round protrusion shape mentioned above. Both have been observed by Applicant to significantly reduce the likelihood for adhesion effects to occur.

In addition to the above mentioned measures to reduce the likelihood of adhesion, the probe is equipped with an adhesion mitigator mechanism ADM to mitigate an effect of adhesion, should this still occur. The adhesion mitigator ADM is configured to effect suitable action if the decision module DM establishes that an adhesion event has indeed occurred.

For instance, in one embodiment, the action taken by the adhesion mitigator ADM is to, preferably momentarily, cease the cooling operation and/or notify the user by operating the transducer TR. The adhesion mitigator ADM interfaces with switching interface SM (not shown in Figure 1), to switch the probe CAA into off mode, for instance by shutting off circulation of the coolant through the probe body P. In yet another embodiment and in addition to any of the previous actions, (momentarily) flash heating is used as previously explained above in relation to the first embodiment in Figure 1. That is, not only does the cooling operation cease, but in addition the tip is now actively heated by a heating mechanism to more quickly allow safe dislodging of the tip from the tissue.

In addition thereto, or as an alternative to these thermic measures, a motion such as a specific low amplitude high frequency harmonic movement is applied via the actuator mechanism ACM to the tip TP to dislodge the adhesion.

In either case the decision module decides there is no longer adhesion, the treatment may continue. In sum, the amount of mechanical movement of the head TH (in particular of its tip) and/or the coolant/heating operation of the probe CAA is/are controlled by feedback from the decision module based on processing the measurements collected at the senor.

A number of different embodiments are envisaged for the sensor arrangement to collect the relevant physical property readings and consequently the way that the decision module interprets same. For instance, according to one embodiment, an electrical property is measured which can be correlated to an adhesion event. More particularly, in one embodiment an electrical impedance across the tissue is measured and the sensor arrangement SA is identical to the one explained earlier above in relation to Figure 1 , where a plurality of different electrodes are used spaced at a distance around and from the treatment tip. In this embodiment, EIT or FIM measurements are taken. The electrical impedance is measured around the neighborhood of the contacting treatment head tip. More particularly, in case of an adhesion event, a sudden reduction of electrical impedance is expected to be detectable due to short-circuiting by the metallic cryo-probe (whose electrical behavior is also recorded previously to ease detection). In this embodiment, instead of or in addition to there being the estimator module PM for estimating the extent of frozen tissue, there is now the decision module DM that interprets the impedance measurement to decide whether an adhesion has occurred and whether adhesion mitigation action is to be taken.

In other embodiments, in addition or instead of measuring electrical property as explained earlier, it is a purely mechanical property that is measured, and based thereon a decision is taken as to whether or not adhesion has occurred. For instance in one embodiment, the sensor SA is arranged as a mechanical sensor and is used to measure torque and/or acceleration and/or angular velocity experienced by the treatment head, in particular the tip thereof, whilst the baseline motion is maintained by the actuator mechanism during the treatment. A tell-tale of the adhesion event is then the increased mechanical resistance experienced by the cryo-probe motion due to the torque exerted on the tissue tip when frozen to the tissue. This mechanical resistance may be detected by the (mechanical) sensor SA as a deceleration, decrease angular velocity or increased torque. Based on these mechanical readings, the adhesion mitigator ADM is instructed to effect any one or a combination of the above described adhesion mitigation actions.

The operation of the decision module in respect of the adhesion event can again be based on prior knowledge by using suitable look-up tables or data structures or

functions/formulae, etc, where the functional relationship between the respective physical property (impedance or torque etc.) versus adhesion magnitude is recorded or expressed. As mentioned before in the treatment monitoring embodiment of Fig 1, this prior knowledge can be gathered from experimental data in a prior learning phase. However, this does not exclude embodiments where this relationship is computed from functional expressions/approximations, etc, derived from theoretical considerations. In particular, the prior knowledge allows specifying or quantifying the adhesion mitigation action that needs to be taken. More particularly, based on the magnitude at which the mechanical or electrical property is recorded, the mitigation action can be identified by computation or through look-up operations. Specifically, the amount and/or orientation of torque to be applied to break adhesion or the level of heat to be applied in flash heating and possible the gradient of heat ramp up is computable from the measured magnitude of the mechanical or electrical property.

In one embodiment, a combination of the above described sensor arrangement as both electrical and mechanical, is envisaged herein. In particular a combination of the embodiment of Figures 1, 5 A, B is envisaged, wherein the functionalities of the decision module DM and that of estimation module PM can be integrated into one processing stage.

The cryo-oblation apparatuses as per Figs 1, 5 A, B described above may be used for cryo-ablation of in-situ cervical cancer (mainly, but not only, CIN2 and CIN3) sites but other applications such as dermatological or oral cancer in human or animal patients are also envisaged herein. It will also be noted, that in the above embodiments, which are preferred, the cryo-genic coolant is not brought into direct contact with the to-be-frozen tissue. In particular, there is, preferably, no dispenser mechanism (nozzle, etc.) envisaged herein that sprinkles coolant liquid directly on the tissue. Instead, as envisaged herein, freezing is indirect via heat transfer from the cooled down metallic treatment head/tip onto the tissue. However, direct tissue contact with coolant is envisaged in some alternative embodiments. It is also of note, that the tip TP does preferably not penetrate the tissue (surface) during the cryo-ablation but is made to firmly rest against the tissue. Reference is now made to Fig 6 where a flow chart of a method for supporting an in-tissue temperature change operation is shown. The method is envisaged in particular for adhesion management in case the treatment head of a cryo-ablation apparatus sticks to frozen tissue during treatment application.

At step S610 a temperature change is imparted to tissue at a region of contact with a probe. In particular, the tissue is locally frozen by using cryogenic probe.

At step S620 a physical property of the tissue in a neighborhood around said region of contact is measured. In addition or in the alternative, a physical property of the tip portion TIP is measured whilst in tissue contact. In either case, the measurements are collected during application of the cryo-ablation, that is, whilst the tissue is being cooled down.

Based on measurements of the physical property, it is then established at step S630 whether an adhesion event has occurred in relation to the treatment head and the tissue.

If yes, a corresponding adhesion mitigation action can be taken at step S640 such as mechanical motion of the head/tip of the probe, or instantaneous termination of the cooling and even heating of the head TH, each action designed to break up the adhesion. If no adhesion event is detected, flow returns to step S610 and the same is true if it is determined after application of the adhesion mitigation action that the adhesion has been successfully broken up. In other words the establishing of the adhesion at step S630 is continued preferably in real time at reasonable sampling rate throughout cyro-ablation and whilst the carrying out of the adhesion mitigation action.

Operation of the decision module and the estimator module can be implemented purely in software executed by a general purpose computing unit PU which is configured to receive by suitable interfaces the measurements from the electronic probes or more generally from the sensor arrangement SA. However, the functionalities of these modules may also be implemented in hardware as a suitably programmed FGPA hard wired chip or an SOC ("system on chip") which further includes the necessary conversion circuitry to process the readings received from the respective sensors. In the latter case, which is preferred for field applications, the apparatus is completely autonomous and does not require a general purpose computer for evaluation of the measurements. The hardware chip is integrated into the probe itself. In another embodiment, particularly suitable for field operations, is to arrange only the signal acquisition circuitry in the cryo-therapy probe P itself and to equip the same with a wired or, if preferred, a wireless transmitter which transmits the measurements to a hand-held device such as a laptop, tablet or smart phone, etc. The functionalities of the decision module or the estimator module themselves are then executed on the respective hand held device.

In another exemplary embodiment of the present invention, a computer program or a computer program element is provided that is characterized by being adapted to execute the method steps of the method, according to one of the preceding embodiments, on an appropriate system.

The computer program element might therefore be stored on a computer unit, which might also be part of an embodiment of the present invention. This computing unit may be adapted to perform or induce a performing of the steps of the method described above. Moreover, it may be adapted to operate the components of the above-described apparatus. The computing unit can be adapted to operate automatically and/or to execute the orders of a user. A computer program may be loaded into a working memory of a data processor. The data processor may thus be equipped to carry out the method of the invention.

This exemplary embodiment of the invention covers both, a computer program that right from the beginning uses the invention, and a computer program that by means of an up-date turns an existing program into a program that uses the invention.

Further on, the computer program element might be able to provide all necessary steps to fulfill the procedure of an exemplary embodiment of the method as described above.

According to a further exemplary embodiment of the present invention, a computer readable medium, such as a CD-ROM, is presented wherein the computer readable medium has a computer program element stored on it, which computer program element is described by the preceding section.

A computer program may be stored and/or distributed on a suitable medium (in particular, but not necessarily, a non-transitory medium), such as an optical storage medium or a solid-state medium supplied together with, or as part of other hardware, but may also be distributed in other forms, such as via the internet or other wired or wireless

telecommunication systems.

However, the computer program may also be presented over a network like the

World Wide Web and can be downloaded into the working memory of a data processor from such a network. According to a further exemplary embodiment of the present invention, a medium for making a computer program element available for downloading is provided, which computer program element is arranged to perform a method according to one of the previously described embodiments of the invention.

It has to be noted that embodiments of the invention are described with reference to different subject matters. In particular, some embodiments are described with reference to method type claims, whereas other embodiments are described with reference to the device type claims. However, a person skilled in the art will gather from the above and the following description that, unless otherwise notified, in addition to any combination of features belonging to one type of subject matter, also any combination between features relating to different subject matters, is considered to be disclosed with this application.

However, all features can be combined providing synergetic effects that are more than the simple summation of the features.

While the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. The invention is not limited to the disclosed embodiments. Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing a claimed invention, from a study of the drawings, the disclosure, and the dependent claims.

In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. A single processor or other unit may fulfill the functions of several items re-cited in the claims. The mere fact that certain measures are re-cited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

Claims

CLAIMS:

1. An apparatus (CAA) for supporting an in-tissue temperature change operation, comprising:

a probe body (P) having a treatment head (TH) with a tip portion (TP) for contacting tissue at a region of contact and configured for imparting a temperature change to the tissue at said region of contact; and

2. Apparatus of claim 1, wherein the probe is operable in two modes, a cooling mode to cool said tissue, in particular for cryo-ablation, or in a heating mode to heat said tissue, the apparatus in particular including a switching mechanism (SM) that allows the probe to switch between said modes.

3. Apparatus of any one of the previous claims, wherein the apparatus operates in cooling mode to freeze the tissue below a pre-defined temperature, the apparatus further comprising an estimator module (PM) configured to estimate an extent of frozen tissue around the tip based on the measurement of the electrical property.

4. Apparatus of any one of the previous claims 1-2, wherein the apparatus is operable in cooling mode to freeze the tissue below a pre-defined temperature, the apparatus further comprising an estimator module (PM) configured to estimate, after the apparatus ceases to operate in cooling mode, an extent of thawed tissue around the tip based on the measurement of the electrical property.

5. Apparatus of claim 4, comprising an alert unit (AU) configured to provide an indication if, after a preset-time period, there still is tissue in the neighborhood that has not yet thawed.

6. Method for supporting an in-tissue temperature change operation, comprising: imparting (S410) a temperature change to tissue at a region of contact with a probe;

with a probe having a plurality of spaced apart electrodes (E_j) arranged around said region contact, collecting (S420) a measurement of an electrical property of the tissue in a neighborhood around said region of contact; and

based on the measurement, estimating (S430) an extent of tissue affected by the temperature change.

7. An apparatus (CAA) for supporting an in-tissue temperature change operation, comprising:

a probe body (P) having a treatment head (TH) with a tip portion (TP) for contacting tissue at a region of contact and configured for imparting a temperature change to the tissue at said region of contact;

a sensor arrangement (SA) configured to measure i) a physical property of the tissue in a neighborhood around said region of contact or ii) a physical property of the tip portion (TIP) whilst in tissue contact; and

a decision module (DM) configured to establish based on a measurement of the physical property whether an adhesion event has occurred in relation to the treatment head and the tissue.

8. Apparatus of claim 7, comprising an adhesion mitigator (AM) configured to act on the probe so as to mitigate adhesion between treatment head and the tissue if occurrence of the adhesion event has been established by the decision module (DM).

9. Apparatus of claim 8, adhesion mitigator (AM) comprising an actuator mechanism (AM) operable to move said tip portion whilst in contact with the tissue and whilst said probe operates to change tissue temperature.

10. Apparatus of any one of claims 8 or 9, wherein the temperature change imparted by the treatment head comprises cooling said tissue, wherein the action effected by the adhesion mitigator (AM) includes ceasing said cooling.

11. Apparatus of any one of claims 7-10, wherein said physical property comprises a mechanical property, in particular torque or acceleration/deceleration.

12. Apparatus of any one of claims 7-11, wherein said physical property comprises an electrical property, in particular an electrical impedance.

13. Apparatus of any one of the previous claims 7-12, wherein the treatment head (TH) is of a frusto-conical shape and/or wherein the tip portion (TP) includes a depression.

14. Apparatus of any one of the previous claims 7-13, comprising an alert unit

(AU) configured to provide an indication if, after a preset-time period, the adhesion event is still in effect.

15. Apparatus of any one of the previous claims 7-14, where the temperature change is suitable for cryo-ablation.

16. Method for supporting an in-tissue temperature change operation, comprising:

imparting (S610) a temperature change to tissue at a region of contact with a probe;

measuring (S620) i) a physical property of the tissue in a neighborhood around said region of contact or ii) a physical property of the tip portion (TIP) whilst in tissue contact; and

establishing (S630) based on a measurement of the physical property whether an adhesion event has occurred in relation to the treatment head and the tissue.

17. A computer program element for performing the method steps of claim 6 or 16 on a processing unit (PU).

18. A computer readable medium having stored thereon the program element of claim 17.