Patent Description:
Tumor treating fields (TTFields) are low intensity alternating electric fields within the intermediate frequency range, which may be used to treat tumors as described in <CIT>. TTFields are induced non-invasively into the region of interest by applying AC voltages between transducers placed on the patient's body. Conventionally, a first pair of transducers and a second pair of transducers are placed on the subject's body. AC voltage is applied between the first pair of transducers for a first interval of time to generate an electric field with field lines generally running in the front-back direction. Then, AC voltage is applied between the second pair of transducers for a second interval of time to generate an electric field with field lines generally running in the right-left direction, and the system repeats this sequence.

<CIT> discloses an insulated electrode system for delivering a plurality of tumor treating electromagnetic fields which includes an array of electrode elements for proximate location on a body of a patient, with each electrode element being independently electrically accessible and configured to be dynamically assigned to emanate an electromagnetic field relative to at least one other of the electrode elements.

<CIT> discloses arrays for longitudinal delivery of tumor treating fields to portions of a subject's body that have a longitudinal axis (e.g., the torso, head and arm), in which first and second sets of electrodes are affixed at respective positions longitudinally prior to and subsequent to a target region, whereby an AC electric field is imposed with field lines that run through the target region longitudinally.

<CIT> discloses an apparatus for optimizing treatment using tumor treating fields which changes the applied frequency during the course of treatment based on the determined cell size.

<CIT> discloses a treatment apparatus which includes a plurality of coils configured to generate time-varying magnetic fields that induce electric fields within a subject for treating tumors, with the fields being applied based on computer-assisted modeling using electromagnetic characteristics of the brain, and tissue locations identified as exhibiting disease using imaging data.

One aspect of the invention is directed to an apparatus for detecting and responding to changes in a subject in applying tumor treating fields to a region of interest of the subject's body corresponding to a tumor of the subject's body according to claim <NUM>.

The above aspect of the invention is exemplary, and other aspects and variations of the invention will be apparent from the following detailed description of embodiments.

To provide a subject with an effective TTFields treatment, precise locations at which to place transducers on the subject's body must be generated based on, for example, type, size, and/or location of the cancer in the subject's body. Determining the locations often relies on time- and resource-intensive computer simulations. In addition, existing methods fail to account for changes in the region of interest that occur during real-time treatment (e.g., due to changes in the subject's posture, physiological changes, etc.). Another difficulty is how to differentiate between physiological changes indicating a change in the region of interest and normal changes in the subject's body that occur cyclically over time. Further, there is a need to detect changes in the region of interest quickly so that TTFields treatment can be updated as soon as possible.

The inventor recognized these problems and discovered an approach to track changes in a region of interest of a subject's body during TTFields treatment and to trigger an event (e.g., new MRI; changing locations of transducers, etc.) based on the changes in the region of interest of the subject's body during TTFields treatment. By accounting for the changes in the region of interest of the subject's body in real-time treatment, the accuracy of the locations at which to place the transducers may be improved, thus improving the efficiency of TTFields treatment.

<FIG> is a flowchart depicting an example method <NUM> for applying TTFields to a region of interest of a subject's body corresponding to a tumor of the subject's body. At step S102, the method <NUM> includes locating a first pair of transducers and a second pair of transducers on the subject's body (e.g., the first and second pairs of transducers may be located on a first and second pair of locations of the subject's body, respectively).

At step S104, the method <NUM> includes alternately applying, to the region of interest (e.g., tumor) of the subject's body, a first tumor treating electric field (TTField) between the first pair of locations and a second TTField between the second pair of locations. The first TTField may be produced by applying a first AC voltage generated between the first pair of locations for a time period, generation of the first TTField is ceased, and then the second TTField is produced by applying a second AC voltage between the second pair of locations for a time period.

At step S106, the method <NUM> includes detecting a change in the region of interest of the subject's body. The change in the region of interest may include at least one of a change in the location or a change in volume of the region of interest. Examples of determining a change in region of interest are illustrated in step S216 in <FIG> discussed below. Detecting the change in the region of interest may include monitoring at least one metric with respect to time and comparing the monitored metric to a baseline pattern of the at least one metric with respect to time established for the subject. A change is detected upon detecting a deviation of the monitored at least one metric from the baseline pattern. Establishing the baseline pattern, monitoring the metric(s), and comparing the metric(s) to the baseline pattern are illustrated in <FIG>.

If a change in the region of interest is not detected, the method <NUM> proceeds to step S104. If a change in the region of interest is detected, the method <NUM> proceeds to step S108, which includes ceasing applying TTFields between the first and second pairs of locations.

At step S110, the method <NUM> comprises selecting a third pair of locations and a fourth pair of locations based on the change in the region of interest determined at step S106. The third and fourth pairs of locations are different than the first and second pairs of locations. Then, the method <NUM> may proceed back to step S104 but this time alternately applying, to the region of interest, a third electric field between the third pair of locations of the subject's body and a fourth electric field between the fourth pair of locations of the subject's body. The method <NUM> may continually repeat with each detected change and selected change of locations.

The first pair of locations and the second pair of locations of the method <NUM> may correspond to locations of a first part of the first pair of transducers and a first part of the second pair of transducers, and the first TTField may be applied between the first part of the first pair of transducers and the second electric field between the first part of the second pair of transducers. In another example, the first pair of locations and the second pair of locations of the method <NUM> may correspond to locations of the entire transducers in each transducer pair.

Selecting the third and fourth pairs of locations at step S <NUM> may involve selecting a second part of the first pair of transducers and a second part of the second pair of transducers based on the change in the region of interest determined at step S <NUM>, such that the third electric field is applied between the second part of the first pair of transducers and the fourth electric field is applied between the second part of the second pair of transducers. In one example, the first part of the two pairs of transducers do not overlap with one another, and the second part of the two pairs of transducers do not overlap with one another. In another example, the first part of the two pairs of transducers at least partially overlap with one another, and the second part of the two pairs of transducers at least partially overlap with one another.

Selecting the third and fourth pairs of locations at step S <NUM> may involve re-locating the first and second pairs of transducers to the third and fourth pairs of locations, respectively, so that the third and fourth electric fields are applied between the first pair of transducers located at the third pair of locations and between the second pair of transducers located at the fourth pair of locations. In another embodiment, selecting the third and fourth pairs of locations at step S <NUM> may involve locating a third pair of transducers at the third pair of locations and a fourth pair of transducers at the fourth pair of locations, so that the third and fourth electric fields are applied between the third pair of transducers located at the third pair of locations and between the fourth pair of transducers located at the fourth pair of locations.

<FIG> is a flowchart depicting an example method <NUM> for determining a region of interest and locations of transducers on a subject's body for applying TTFields. At step S202, the method <NUM> includes determining a region of interest of the subject's body corresponding to the tumor (e.g., corresponding to a location and/or volume of the tumor).

The region of interest in the subject's body may be determined by image data <NUM> (e.g., via computer simulations built from the image data <NUM>). The image data <NUM> may include one or more images (e.g., X-ray images, magnetic resonance imaging (MRI), computerized tomography (CT) images, ultrasound images, etc.) of a portion of the subject's body.

Determining the region of interest may incorporate posture information <NUM> of the subject's body. Posture information <NUM> may be detected and/or collected by one or more sensors (e.g., accelerometers, gyroscopes, and/or magnetometers), or determined by user input. Sensor(s) may be located external to the first pair of transducers and the second pair of transducers, or may be part of at least one of the first pair of transducers or the second pair of transducers.

Determining the region of interest may be based on vital signs <NUM> of the subject's body. The vital signs <NUM> may include respiratory signs (e.g., respiratory rate, respiratory volume). Other vital signs may include body temperature, blood pressure, pulse rate, etc..

Determining the region of interest may be based on electric field measurements <NUM>. The electric field measurements <NUM> may include a voltage measurement and a current measurement generated and/or collected for the TTFields applied for a desirable time period prior to a real-time TTFields treatment, and/or during a real-time TTFields treatment.

Determining the region of interest may be based on any combination of two or more factors of the image data <NUM>, posture information <NUM>, vital signs <NUM>, and electric field measurements <NUM>. As an example, the determination of the region of interest may be based on image data <NUM> and posture information <NUM>. In one example, a plurality of regions of interest corresponding to a plurality of postures of the subject are determined. The plurality of regions of interest corresponding to the plurality of postures may be determined prior to real-time TTFields treatment, or may be determined and/or updated during real-time TTFields treatment.

At step S212, a first transducer is positioned at a first location and a second transducer is positioned at a second location. The locations may be selected based on the determined region of interest at step S202 to yield maximum electric field power delivered to the determined region of interest. At step S214, the method <NUM> comprises inducing a TTField between the first and second transducers located at the first and second locations. At step S216, the method <NUM> comprises detecting a change in the region of interest.

The change in the region of interest may be caused by physiological changes <NUM> of the subject's body. Physiological changes may include at least one of a change in tumor size, change in tumor location, weight gain, weight loss, swelling of the body, swelling in a portion of the body, or inflammation, and may be determined by image data and/or other measurements.

The change in the region of interest may be caused by a posture change <NUM>. The posture change <NUM> may include a change from one of a plurality of postures to another of the plurality of postures. The plurality of postures may include at least two of standing, sitting, lying down, or one or more postures in-between standing, sitting, and lying down. In a more specific example, the lying down posture may include the subject lying on at least one of the subject's back, left side, right side, or chest. Posture changes <NUM> may be detected and/collected by one or more sensors, or may be entered by user input.

The change in the region of interest may be caused by a change in vital signs <NUM> of the subject's body. The vital sign change <NUM> may include a change in respiratory signs (e.g., at least one of respiratory rate or respiratory volume) of the subject, as respiratory rate and respiratory volume may change the internal volume of the torso and lead to a change in the region of interest. Other vital signs may include, for example, body temperature, blood pressure, and pulse rate. Vital sign changes <NUM> may be detected by sensors, or entered by user input.

In certain embodiments, the change in the region of interest may be determined based on a detected change in one or more of the factors <NUM>-<NUM> listed above. Additionally, or alternatively, the change in the region of interest may be determined based on a change (<NUM>) in the voltage and/or current of TTFields applied to the region of interest, a resistivity of the subject's body, and/or an impedance of the subject's body. Current measurements are indicative of a current of the TTFields passing through the subject's body between a pair of transducers, as measured at one or more electrodes in the pair of transducers. Voltage measurements are indicative of a voltage applied to the selected pair of transducers to induce the TTFields. A resistivity of the subject's body along a path of the TTField may be calculated based on the voltage and current measurements as discussed below. Further, the voltage and current measurements and/or calculated resistivity may be used to calculate an impedance of the subject's body. The resistivity calculated for one channel (e.g., between a pair of transducers) may be divided by the distance between the pair of transducers to determine an impedance of the subject's body between the pair of transducers. This calculation may be repeated for both channels used to apply alternating TTFields to the region of interest.

At step S226, the method <NUM> includes optionally generating a habit model for the subject based on the data collected at steps S202 and S216. The posture information <NUM>, vital signs <NUM>, posture change <NUM>, vital sign change <NUM>, and current/voltage change <NUM> may be collected and recorded over time during the TTFields treatment and stored with a time stamp. A habit model for the subject may be generated by a machine based on the collected and stored data, with or without additional user input. The habit model may include information regarding time stamp, posture information, and region of interest and may be presented at an output device.

As an example, a habit model may include the following exemplary information:.

At step S228, the method <NUM> may include generating one or more recommendations based on the change in the region of interest obtained at step S216 and/or the habit model generated at step S226. This is similar to step S310 in <FIG>. The recommendations may be for locations on the subject's body at which to place transducers and/or recommended parts of the transducers for applying TTFields. Recommendations may be incorporated in the habit model.

At step S230, the method <NUM> may include adjusting the applied electric field based on the change in the region of interest detected in step S216 and/or the habit model generated at step S226. The adjustment of the electric fields may include adjusting the location of the transducers and/or adjusting the voltage of the TTFields applied to the subject's body. The adjustments may be automatic. As an example, the method <NUM> may change from part <NUM> to part <NUM> of the transducers for applying the electric field at a time when the subject changes posture according to the habit model. In another example, inquiries for confirmation may be presented to the subject on a user device to confirm the change of postures before the TTFields are adjusted.

<FIG> is a flowchart depicting another example method <NUM> for determining locations of transducers on a subject's body for applying TTFields. The method <NUM> includes performing step S216 of <FIG>. At step S302, the method <NUM> includes generating a plurality of regions of interest based on the obtained changes in the region of interest in step S216. This may involve determining a plurality of postures of the subject's body. The step S302 may further comprise selecting a pair of transducers for each region of interest (e.g., for each posture) and applying TTFields to each selected pair of transducers.

At step S304, for each region of interest (e.g., for each posture), the method <NUM> includes receiving a voltage measurement and a current measurement associated with the TTFields induced between the first and the second transducers of the selected pair of transducers. Step S304 may be a computer-implemented step in which current and voltage measurements that were obtained and/or recorded are received at a processing component of a computer.

The current and voltage measurements may be generated and/or collected (e.g., received or accessed from a log file) prior to a real-time treatment of TTFields, or in real-time or near real-time during a treatment period in which TTFields are applied. Such voltage and current measurements may be obtained at regular intervals throughout TTFields treatment.

At step S306, for each region of interest, the method <NUM> includes calculating a resistivity of the subject's body along a path of the TTField between the first transducer and the second transducer based on the received current and voltage measurements. The resistivity of the subject's body along the path of the TTField may be calculated by the following equation: <MAT> Where ρ is the resistivity of the subject's body along the path of the applied TTField in ohm meters (Ωm); E is the magnitude of the electric field of the applied TTField in volts per meter (V/m); and J is the magnitude of the current density of the applied TTField in amperes per square meter (A/m<NUM>).

The calculated resistivity may change over time in which TTFields are applied to the subject's body. Resistivity changes may be the result of, e.g., physiological changes <NUM>, posture changes <NUM>, vital sign changes <NUM>, or changes in placement / attachment of transducers.

At step S308, the method <NUM> includes calculating a power density of the TTFields between the first transducer and the second transducer based on the received current and voltage measurements. The power density of the TTFields may be used to represent the TTFields dose delivered to the corresponding region of interest. The power density of the applied TTFields may be calculated by the following equation: <MAT> Where P is the power density of the applied TTFields; σ is the conductivity of tissue; and E is the magnitude of the electric field of the applied TTFields.

The conductivity of the tissue σ may satisfy the following equation: <MAT>.

Therefore, the power density P may be calculated by Equations <NUM>-<NUM> based on voltage and current measurements of the applied TTFields.

At step S310, the method <NUM> includes selecting and outputting one or more recommended pairs of transducers based on the calculated resistivity and/or the calculated power density. In one example, the selection one or more recommended pairs of transducers is based on the calculated resistivity for each region of interest at step S306. Step S310 may include comparing the calculated resistivities for the plurality of pairs of transducers for each region of interest and, for each region of interest, ranking the plurality of pairs of transducers based on the calculated resistivities. The recommended transducer pairs may be selected based on the ranking. Step S310 may include, for each region of interest, selecting a first pair of transducers based on the ranking of the plurality pairs of transducers, and, for each region of interest, selecting a second pair of transducers from the remaining one or more pairs of transducers based on the ranking. In another example, the selection of the second pair of transducers is based on the selection of the first pair of transducers (e.g., based on an intersection angle with regards to the selected first pair of transducers). The second pair of transducers may be selected such that a first angle between a first line defined by the first part of the first pair of transducers and a second line defined by the first part of the second pair of transducers is approximately <NUM> degrees +/- <NUM> degrees; and a second angle between a third line defined by the second part of the first pair of transducers and a fourth line defined by the second part of the second pair of transducers is approximately <NUM> degrees +/- <NUM> degrees.

Step S310 may include calculating a local minimum power density (LMiPD) for a combination of two pairs of transducers in the plurality pairs of transducers and selecting the layout with a maximum LMiPD. LMiPD represents the lower of two power densities delivered by the TTFields to the region of interest via two pairs of transducers, calculated via Equation.

<FIG> is a flowchart depicting another example method <NUM> for determining the locations of transducers on a subject's body. With reference to <FIG>, method <NUM> includes performing steps S102, S106, and S108 of <FIG>. At step S402, the method <NUM> includes selecting a first set of electrodes of the first pair of transducers and a first set of electrodes of the second pair of transducers. Each transducer may include an array of electrode elements. The electrodes may be individually addressable electrodes, as discussed further below. The selection of these sets of electrodes may be based on the region of interest of the subject's body. At step S404, the method <NUM> includes alternately applying to the region of interest a first TTField between a first set of electrodes of the first pair of transducers and a second TTField between a first set of electrodes of the second pair of transducers. This is similar to step S104 in <FIG>.

At step S406, the method <NUM> includes selecting a second set of electrodes of the first pair of transducers and a second set of electrodes of the second pair of transducers based on the change in region of interest determined at step S106. The selection of the second sets of electrodes of the first pair and second pair of transducers is based on the change in region of interest. A third TTField and a fourth TTField may then be alternately applied to the region of interest between the second set of electrodes of the first pair of transducers and between the second set of electrodes of the second pair of transducers. The first set of electrodes and the second set of electrodes of the first pair of transducers may not overlap with one another, or the first set of electrodes and the second set of electrodes of the first pair of transducers may partially overlap with one another. For example, there may be at least one electrode, e.g., a first electrode, that is in both the first and the second sets of electrodes of the first pair of transducers.

At least one electrode of the first pair of transducers may emit different amounts of non-zero energy during the first and third electric fields, and at least one electrode of the second pair of transducers may emit different amounts of non-zero energy during the second and fourth electric fields. In one example, the at least one electrode in both the first set and the second set of electrodes (e.g., a first electrode) emits energy during the first electric field and during the third electric field. The energy emitted by the first electrode during the first electric field may be different than the energy emitted by the first electrode during the third electric field. As a more specific example, the energy emitted by the first electrode during the first electric field may be a percentage of the energy emitted by the first electrode during the third electric field, the percentage being greater than <NUM>% and less than <NUM>%, or the energy emitted by the first electrode during the third electric field may be a percentage of the energy emitted by the first electrode during the first electric field, the percentage being greater than <NUM>% and less than <NUM>%. In another example, the first electrode emits energy during a first portion in a period of the first electric field and during a first portion in a period of the third electric field. The energy emitted during the first portion in the period of the first electric field may be different than the energy emitted during the first portion in the period of the third electric field.

In an example, the different energy emitted by the first electrode during the first electric field and the third electric field is due to the voltage signal applied to the first electrode being different during the first and third electric field. For example, the first electrode receives different voltage signals for the first and third electric fields. The first electrode may receive a first non-zero voltage during the first electric field and a second non-zero voltage during the third electric field, the first non-zero voltage different from the second non-zero voltage. In another example, the first electrode receives a same amplitude of voltage during the first and third electric fields but during different time segments of periods of the first and third electric fields.

In another example, the different energy emitted by the first electrode during the first electric field and the third electric field is due to a capacitance change of the first electrode. For example, the first electrode has a first capacitance during the first electric field and has a second capacitance during the third electric field. In this example, the first electrode may receive the same voltage signal during the first and third electric fields. Examples of structures in which different energy may be emitted by a first electrode are discussed below with reference to <FIG>.

<FIG> depict examples of determining locations of transducers based on the region of interest for two pairs of transducers to be located. The selection of locations may be based on a plurality of regions of interest associated with a plurality of postures. In <FIG>, a plurality of locations is selected on a torso of the subject's body. First, second, third, and fourth locations <NUM>, <NUM>, <NUM>, and <NUM> are selected to locate transducers when the subject is lying on the left side, and fifth, sixth, seventh, and eighth locations <NUM>, <NUM>, <NUM>, and <NUM> are selected to locate transducers when the subject is standing. Locations <NUM> and <NUM> may form a first pair of locations for a first pair of transducers, and locations <NUM> and <NUM> may form a second pair of locations for a second pair of transducers. Locations <NUM> and <NUM> may form the first pair of locations to locate the first pair (or a third pair) of transducers, and locations <NUM> and <NUM> may form the second pair of locations to locate the second pair (or a fourth pair) of transducers.

In <FIG>, a plurality of electrode elements is integrated in one transducer array <NUM>. The transducer array may be integrated into a helmet or a garment (e.g., hat, shirt, or pants). Multiple pairs of transducers may be selected in the transducer array <NUM>, each transducer having a plurality of electrode elements selected from the transducer array <NUM>. First, second, third, and fourth transducers <NUM>, <NUM>, <NUM>, and <NUM> are selected in the transducer array <NUM> when the subject is lying on the left side, and fifth, sixth, seventh, and eighth transducers <NUM>, <NUM>, <NUM>, and <NUM> are selected when the subject is standing. Transducers <NUM> and <NUM> (or transducers <NUM> and <NUM>) may form the first pair of transducers, and transducers <NUM> and <NUM> (or transducers <NUM> and <NUM>) may form the second pair of transducers.

<FIG> depicts an example transducer with individually selectable electrodes. A first set of electrode elements <NUM> may be selected based on the region of interest, and a second set of electrode elements <NUM> may be selected based on a change in the region of interest. The first set <NUM> includes electrode elements <NUM>, <NUM>, <NUM>, and <NUM>, and the second set <NUM> includes electrode elements <NUM>, <NUM>, <NUM>, and <NUM>. Electrode elements <NUM> and <NUM> are in both sets.

<FIG> depicts an example configuration of a transducer. In this example, the transducer <NUM> includes n electrodes, e.g., <NUM> and <NUM>, and the electrodes <NUM> and <NUM> are wired to switches <NUM>/<NUM>/<NUM>/<NUM> controlled by a controller <NUM>. Each electrode includes two electrode elements. Electrode <NUM> includes electrode elements <NUM> and <NUM> and electrode <NUM> includes electrode elements <NUM> and <NUM>. A controller <NUM> may selectively turn off some switches connected to the electrodes to change the voltage signal applied to the electrodes <NUM> and <NUM> and/or to change a capacitance of the electrodes <NUM> and <NUM>. Examples of the transducer are described in <CIT>.

<FIG> depicts an example configuration of a pair of transducers <NUM> and <NUM>. Both transducers <NUM>/<NUM> may include electrode elements <NUM>/<NUM> positioned on a substrate <NUM>/<NUM> and electrically and mechanically connected through conductive wiring <NUM>/<NUM>. The substrate(s) <NUM>/<NUM> may include cloth, foam, flexible plastic, and/or conductive medical gel. In another example, one or more transducers may include electrode elements that are electrically and mechanically connected without a substrate. Transducers may be affixed to the subject's body or attached/incorporated in garment(s) covering the subject's body.

The transducers <NUM> and <NUM> may be connected to an AC voltage generator <NUM> and a controller <NUM>, which may include a computer having one or more processors <NUM> and memory <NUM>. The memory <NUM> may store instructions that when executed by the one or more processors control the AC voltage generator <NUM> to induce an electric field between the transducers <NUM> and <NUM> and/or cause the computer to perform one or more methods disclosed herein. The controller <NUM> may monitor operations performed by the voltage generator <NUM> and store current/voltage values in memory <NUM>. Other types of information (e.g., temperature values, posture information, vital signs, etc.) may be collected as well (e.g., via sensors <NUM>). Various types of information may be stored in a log file, which may be in the memory <NUM>.

<FIG> depicts an exemplary apparatus <NUM> to determine locations of transducers for applying TTFields according to various embodiments herein. The apparatus <NUM> includes one or more processors <NUM>, a memory <NUM>, and one or more output devices <NUM>. The apparatus <NUM> may be a computer. The apparatus <NUM> may be incorporated into, or separate from and communicatively coupled to, the controller <NUM> of <FIG>. The memory <NUM> is accessible by the one or more processors <NUM>, and the memory <NUM> stores instructions that, when executed by the processor(s) <NUM>, cause the apparatus <NUM> to perform one or more methods disclosed herein. Based on one or more inputs <NUM>, the processor(s) <NUM> may generate and/or rank a plurality of locations for the transducers, and output one or more location recommendations to a user on the output device(s) <NUM>, or output an alert. The one or more inputs <NUM> may include image data, current and voltage measurements, posture information, vital signs, physiological information, and/or user inputs.

<FIG> is a flowchart describing an example computer-implemented method <NUM> of detecting and responding to a change in a subject's body while or after TTFields are induced in the subject's body. At step S1202, the method <NUM> includes receiving one or more measurements. These may include measurement(s) associated with one or more TTFields induced in the subject's body. For example, the step S1202 may comprise receiving current and voltage measurements associated with one or more TTFields induced between at least part of a first transducer located at a first location of the subject's body and at least part of a second transducer located at a second location of the subject's body. The one or more measurements may include measurement(s) associated with the subject's body while the one or more TTFields are induced in the subject's body. For example, the measurement(s) may comprise a temperature associated with the subject's body while TTFields are induced in the subject's body. Other measurements may include those used to determine posture or vital signs of the subject's body.

The measurements received at step S <NUM> may be collected in real-time or near real-time while TTFields are applied. In one example, the AC generator monitors a current and voltage of the AC voltage applied to the pair of transducers and records the current and voltage measurements, for example, in a log file. In another example, one or more sensors separate from the AC generator are used to detect the current and voltage of the TTFields and generate current and voltage measurements for recording in a log file.

Multiple voltage, current, temperature, and/or other measurements may be collected during a treatment session of inducing TTFields in the subject's body. For example, voltage, current, temperature, and/or other measurements may be obtained at regular intervals (e.g., every second, five seconds, thirty seconds, minute, five minutes, ten minutes, thirty minutes, hour, two hours, four hours, or some other interval) throughout TTFields treatments.

At step S1204, the method <NUM> may include receiving an initial data set of at least one metric with respect to time. The at least one metric includes a measurement associated with one or more tumor treating fields induced in the subject's body or associated with the subject's body while one or more tumor treating fields are induced in the subject's body. The initial data set may be a collection of measurement values for at least one metric stored with a time stamp.

In the initial data set, the at least one metric may comprise one or more measurements selected from the group consisting of: a resistivity associated with one or more TTFields induced in the subject's body, a current associated with one or more TTFields induced in the subject's body, a voltage associated with one or more TTFields induced in the subject's body, a differential resistivity between alternating TTFields induced in the subject's body between two pairs of transducer arrays, a sum of resistivities between alternating TTFields induced in the subject's body between two pairs of transducer arrays, an impedance associated with one or more tumor treating fields induced in the subject's body, and a temperature of the subject's body. Other metrics may be received in other embodiments.

Step S1204 may include calculating values of at least one metric (e.g., resistivity, differential resistivity, or resistivity sum) from measurements that were collected or received at step S1202 and associated with corresponding time values. For example, the step S1204 may comprise calculating a resistivity of the subject's body along a path of a TTField between at least part of the first transducer and at least part of the second transducer based on current and voltage measurements received at step S1202 according to Equation <NUM>. As another example, the step S1204 may comprise calculating an impedance associated with one or more TTFields induced in the subject's body, using the calculation techniques discussed above.

Step S1204 may comprise calculating a set of differential resistivities with respect to time from measurements that were collected or received at step S1202. The differential resistivity metric may be a difference between a first resistivity associated with a first TTField induced between at least part of a first pair of transducer arrays at a first pair of locations of the subject's body and a second resistivity associated with a second TTField induced between at least part of a second pair of transducer arrays at a second pair of locations of the subject's body. Calculating a differential resistivity may comprise calculating an absolute value of a difference between first and second calculated resistivities for each time in the initial data set.

Step S1204 may comprise calculating a set of resistivity sums, which involves calculating a sum of first and second calculated resistivities for each time in the initial data set.

At step S1206, the method <NUM> comprises determining a baseline pattern of the at least one metric with respect to time based on the initial data set. The initial data set is indicative of the at least one metric collected during a training period. The term "collected" may refer to the metric(s) either measured (e.g., via sensors) or calculated based on measurements. The "training period" may refer to a period of time during which the at least one metric is collected.

The baseline pattern may comprise a signature in the initial data set that is specific to the subject, representing a cycle related to the subject's unique physiology. The baseline pattern may capture time-dependent changes in the subject's body, such as physiological changes (e.g., sweating, hair growth, etc.), changes based on circadian rhythm (e.g., temperature, hormonal, or other changes in a <NUM> hour cycle), and/or changes in the subject's activities, postures, habits, vital signs, and/or locations (e.g., sleeping, sports, walking, exercising, or sitting at a desk).

The baseline pattern may be a range of values of the at least one metric averaged over a time window or the rate of change of the at least one metric averaged over the time window. For example, a time window average of one or more metrics (e.g., calculated impedance), or of the rate of change of one or more metrics, may be calculated and monitored via comparison of the value of the metric to one or more thresholds. Changes in these time window averages may be correlated with changes in the size of the tumor (<FIG>).

In step S <NUM>, determining the baseline pattern may comprise applying one or more numerical analyses to the initial data set, such as performing a principal component analysis (PCA) on the initial data set. PCA involves decomposing a data set into "principal components" and using the principal components to change the basis on the data, sometimes using only a subset of more significant principal components and ignoring others. Principal components may be computed directly by a computer using the initial data set. The PCA may result in a baseline pattern comprising one or more eigenvectors and their associated eigenvalues, represented by the following equation: <MAT> Where S(t) is the baseline pattern with respect to time; v<NUM>(t), v<NUM>(t), and v<NUM>(t) are eigenvectors representing the principal components determined for the initial data set; and a<NUM>, a<NUM>, and a<NUM> are eigenvalues representing amplitudes for their associated eigenvectors. Each eigenvector vn(t) may be related to physiological conditions in the subject's body, while the corresponding eigenvalue an may be related to the strength or impact of that physiological condition on the data.

At step S <NUM>, the method comprises monitoring the at least one metric with respect to time following the training period (e.g., during later TTFields treatment). The training period may be a period of multiple days during which one or more TTFields treatments are performed on the subject's body. Monitoring the at least one metric may involve receiving and/or calculating the at least one metric, similar to step S <NUM>. At step S1208, monitoring the at least one metric with respect to time may be performed in real-time or near real-time during a time period in which TTFields are induced in the subject's body. Monitoring the at least one metric associated with the TTFields or the subject's body after the training period may include receiving or accessing a log file, which may occur after application of a TTFields treatment is complete. At step S1210, the method may comprise determining whether the monitored at least one metric (e.g., in new data sets) deviates from the predetermined baseline pattern.

At step S1212, the method <NUM> includes triggering an event in response to detecting (at step S1210) a deviation of the monitored at least one metric from the baseline pattern. As an example, at step S1214, the triggered event may include selecting a recommendation for adjusting location(s) of the subject's body for placement of one or more transducers based on the detected deviation. This may involve one or more of the methods discussed above with reference to <FIG>. In another example, at step S1216, the triggered event may include outputting an alert. At step S1216, outputting the alert may include outputting an alert <NUM> indicating that additional imaging of the subject's body is needed. In this way, the method <NUM> may serve to trigger additional imaging as needed in response to physiological changes that could represent a change in the tumor or region of interest in the subject's body. At step S1216, outputting the alert may include outputting an alert <NUM> indicating a change in a tumor of the subject's body.

The process may repeat steps S1208 and S1210 until the monitored metric(s) deviate from the baseline pattern triggering an event at S1212. The process of method <NUM> may begin again from step S1202 to determine a new baseline pattern based on at least one metric collected and/or calculated during a new training period, <NUM>) if additional imaging performed on the subject indicates no change in the tumor, or <NUM>) if transducer pairs are positioned at new locations.

<FIG> is a flowchart describing an example computer-implemented method <NUM> of tracking physiological changes of a subject's body by detecting a deviation of a monitored metric from a baseline. <FIG> is an example process of performing steps S1206, S1208, and S1210 of <FIG>. Steps S1206 and S1208 in <FIG> may comprise steps S1302 and S1304 of <FIG>, respectively. Step S1210 of <FIG> may comprise steps S1306, S1308, and/or S1310 of <FIG>.

At step S1302, the initial data set received at step S104 of <FIG> is decomposed using PCA. At step S1304, the method <NUM> may include collecting one or more additional data sets of the at least one metric with respect to time. At step S1306, the method <NUM> may include decomposing the one or more additional data sets of the at least one metric using, for example, the same PCA decomposition that was used on the initial data set or an altered PCA. At step S1308, the method <NUM> may include comparing the one or more additional data sets to the PCA decomposition of the initial data of S <NUM>. At step S <NUM>, the method <NUM> may include detecting a deviation of one or more additional data sets from the baseline pattern.

In an example, the comparison at S1308 may involve comparing a decomposition (S1306) of the one or more additional data sets to the PCA decomposition (S1302) of the initial data set. For example, the method <NUM> may comprise decomposing at S <NUM> a second data set using PCA to generate a second set of eigenvectors and a second set of eigenvalues, as follows: <MAT> Where S'(t) is the PCA decomposition of the second data set with respect to time; v'<NUM>(t), v'<NUM>(t), and v'<NUM>(t) are eigenvectors representing the principal components determined for the second data set; and a'<NUM>, a'<NUM>, and a'<NUM> are eigenvalues representing amplitudes for the associated eigenvectors.

Using the above PCA decomposition, the comparison at S1308 may comprise comparing eigenvectors extracted from the second data set to those extracted from the initial data set (e.g., comparing vi(t) to v'i(t)). At step S1310, the method <NUM> may comprise detecting a deviation of the second data set from the baseline pattern in response to detecting a new eigenvector v'i(t) (<NUM>) that is not present in the PCA decomposition of the initial data set. For example, the PCA decomposition (baseline pattern) of the initial data set may output a set of three eigenvectors v<NUM>(t), v<NUM>(t), and v<NUM>(t), while the PCA decomposition of the second data set may output a set of four eigenvectors v'<NUM>(t), v'<NUM>(t), v'<NUM>(t), and v'<NUM>(t). The number of eigenvectors (or principal components) extracted from each decomposition may be determined based on the relative impact of each principal component determined by the PCA software. In another example, the step S1306 may comprise decomposing one or more additional data sets via PCA into the same eigenvectors v<NUM>(t), v<NUM>(t), and v<NUM>(t) that were extracted from the PCA (S1302) of the initial data set. In either case, the computer may detect an emergence of a new eigenvector during the decomposition. If an eigenvector emerges after a certain time without a corresponding change in the subject's habits, this may indicate a change at the tumor level.

In another example, the step S1306 may comprise decomposing a second data set into a second set of eigenvalues corresponding to the same set of eigenvectors extracted from the PCA of the initial data set. This PCA decomposition of the second data set may be represented by the following equation: <MAT> Where S'(t) is the PCA decomposition of the second data set with respect to time; v<NUM>(t), v<NUM>(t), and v<NUM>(t) are eigenvectors representing the principal components determined for the initial data set; and a'<NUM>, a'<NUM>, and a'<NUM> are eigenvalues representing amplitudes for these associated eigenvectors based on the decomposition of the second data set. That is, the second data set is decomposed into the same eigenvectors that were identified during PCA of the initial data, and eigenvalues are determined for each of those eigenvectors to most closely fit the second data set. The eigenvalues extracted from the second data set may be compared (S1308) to those extracted from the initial data set (e.g., comparing ai to a'i). At step S1310, the method <NUM> may comprise detecting a deviation of the second data set from the baseline pattern in response to detecting an eigenvalue in the second set of eigenvalues a'i that crosses a threshold (<NUM>) based on the first set of eigenvalues ai. For example, the PCA decomposition of the second data set may output one or more eigenvalues a'<NUM>, a'<NUM>, and a'<NUM> that differ from the corresponding eigenvalues (a<NUM>, a<NUM>, and a<NUM>) for the initial data set by a certain threshold amount or by a certain threshold percentage.

Using the decomposition of Equation <NUM>, the comparison at S1308 may comprise comparing multiple sets of eigenvalues extracted via PCA of multiple sequential data sets to each other and to the eigenvalues extracted from the initial data set. For example, at steps S1304 and S1306, the method <NUM> may comprise collecting multiple data sets of the at least one metric over time and decomposing each of the multiple data sets into another set of eigenvalues corresponding to the same set of eigenvectors extracted from the PCA of the initial data set. At step S1310, the method <NUM> may comprise detecting a deviation of the multiple data sets from the baseline pattern in response to detecting a trend (<NUM>) in the generated eigenvalue a'i of the multiple data sets corresponding to the same eigenvector of the initial data set.

In another example, the comparison at S1308 may involve comparing a signal representing the monitored at least one metric with respect to time to the PCA decomposition (S1302) of the initial data set. For example, the comparison at S1308 may include generating an initial signal representative of at least one metric with respect to time based on the first set of eigenvectors and first set of eigenvalues from the PCA of the initial data set (S1302), and then calculating a difference between this "initial signal" and the corresponding signal of the monitored at least one metric. The "initial signal" may be generated by solving a system of equations using the PCA decomposition of the initial data set (<NUM>) to estimate a signal (the "initial signal") of a metric M taken with respect to time t for the additional data set. At step S1310, the method <NUM> may comprise detecting a deviation in response to detecting that the difference between the initial signal and the corresponding signal of the metric exceeds a threshold (<NUM>).

The decomposition of additional data sets and comparison of the data sets to the initial data set may be carried out sequentially for each new data set in real-time or near real-time during TTFields treatments. If no deviation is detected at S1310, then steps S1304-S1308 repeat.

<FIG> depicts a plot <NUM> of an example baseline pattern <NUM> of a metric <NUM> with respect to time <NUM>. As shown, the baseline pattern <NUM> may represent a <NUM>-hour cycle of the metric <NUM>. Although only one metric <NUM> is illustrated in the plot <NUM>, one or more additional metrics may be monitored at the same time to determine an overall baseline pattern for the subject. The PCA of the initial data set may track a recognizable <NUM>-hour pattern.

<FIG> depicts a computer-implemented method <NUM> for calibrating a system for detecting changes in a subject's body while or after TTFields are induced in the subject's body, which may be performed during the training period. At step <NUM>, the method <NUM> may include outputting a first location at which to locate a first transducer on the subject's body and a second location at which to locate a second transducer on the subject's body. The first location and second location may be output to a user interface. Step S1502 may further include outputting third and fourth locations at which to locate third and fourth transducers on the subject's body.

At step S1504, the method <NUM> includes receiving one or more measurements associated with one or more TTFields induced in the subject's body or associated with the subject's body while the one or more TTFields are induced in the subject's body. In an embodiment with two pairs of transducers, receiving (S1504) the one or more measurements associated with one or more TTFields induced in the subject's body may comprise receiving one or more measurements associated with a first electric field induced between a first pair of transducers located at a first location and a second location on the subject's body and receiving one or more measurements associated with a second electric field induced between a second pair of transducers located at a third location and a fourth location on the subject's body.

At step S1506, the method <NUM> includes determining an initial data set of at least one metric with respect to time based on the one or more measurements received during the training period, as discussed above. At step S1508, the method <NUM> includes performing a PCA on the initial data set to generate a first set of eigenvectors and a first set of eigenvalues. At step S1510, the method <NUM> includes determining a baseline pattern of the at least one metric with respect to time, the baseline pattern comprising at least a portion of the first set of eigenvectors and the first set of eigenvalues. In an example, the baseline pattern may include a subset of the total number of eigenvectors in the first set of eigenvectors and a corresponding subset of the first set of eigenvalues generated via PCA. At step <NUM>, the method <NUM> includes storing the baseline pattern in a memory.

<FIG> depicts an example method <NUM> for correcting for differences in transducer positioning during the process of <FIG>, as the transducers may be removed and replaced on the subject's body periodically. At step S1602, the method <NUM> includes outputting a first location to locate a first transducer on the subject's body and a second location to locate a second transducer on the subject's body. At step S1604, the method <NUM> may include receiving input (e.g., image or video data) corresponding to an actual location of the first transducer on the subject's body and an actual location of the second transducer on the subject's body. At step S1606, the method <NUM> may include comparing the actual location of the first transducer with the first location at which the transducer is to be placed, and comparing the actual location of the second transducer with the second location at which the transducer is to be placed.

At step S1608, the method <NUM> may include correcting for any difference detected between the actual positioning of transducers and the desired first and second locations. In an example, the correction at S1608 may involve adjusting (<NUM>) one or more measurements (e.g., those received at S <NUM>) to correct for at least one of: a difference in positioning between the actual location of the first transducer and the first location, or a difference in positioning between the actual location of the second transducer and the second location. In another example, the correction at S1608 may involve outputting, to a user interface, instructions for correcting a positioning (<NUM>) of at least one of the first transducer or the second transducer.

<FIG> depicts an example computer-implemented method to detect a change in a subject's body while or after TTFields are induced. The method <NUM> includes, at step S1702, receiving current and voltage measurements associated with a first electric field induced in the subject's body, the first electric field passing through a tumor in the subject's body. The method <NUM> includes, at step S1704, receiving current and voltage measurements associated with a second electric field induced in the subject's body, the second electric field passing through the tumor in the subject's body. The method <NUM> includes, at step S1706, calculating a differential resistivity calculated based on the received current and voltage measurements associated with the first and second electric fields. The differential resistivity includes a difference between a first resistivity of the subject's body along a path of the first electric field and a second resistivity of the subject's body along a path of the second electric field.

The method <NUM> includes, at step S1708, determining an initial data set of at least one metric with respect to time, the at least one metric including at least the differential resistivity of S1706. The initial data set is determined based on measurements collected during a training period. The method <NUM> includes, at step S1710, determining a baseline pattern of the at least one metric with respect to time based on the initial data set of S1708.

The method <NUM> includes, at step S1712, determining one or more additional data sets of the at least one metric with respect to time based on measurements collected following the training period. The method <NUM> may include, at step S1714, determining whether the at least one metric associated with the one or more additional data sets deviates from the baseline pattern of S1710. If no deviation is detected, the method <NUM> proceeds back to S1712. If a deviation of the additional data sets from the baseline pattern is detected, the method <NUM> proceeds to step S1716, which includes outputting an alert in response to detecting a deviation of the at least one metric in the one or more additional data sets from the baseline pattern. Step S1716 may include outputting an indication <NUM> that additional imaging of the subject's body is needed, outputting an indication <NUM> of a change in a tumor of the subject's body, or a combination thereof.

<FIG> depict examples of relationships between calculated impedance measurements taken throughout TTFields treatment and tumor size determined via image data. Each of <FIG> provides a plot <NUM> (i.e., 1800A, 1800B, 1800C, 1800D, 1800E, and 1800F) showing trend lines of calculated impedance <NUM> (i.e., 1802A, 1802B, 1802C, 1802D, 1802E, and 1802F) with respect to time and of a determined tumor size <NUM> (i.e., 1804A, 1804B, 1804C, 1804D, 1804E, and 1804F) with respect to time. Each plot <NUM> corresponds to actual measurements / determinations made for one of six patients during clinical trials. The impedance <NUM> is a sum total of the impedance between two channels delivering TTFields (e.g., a first channel between a first pair of transducers and a second channel between a second pair of transducers). The tumor size <NUM> is an estimation of tumor volume calculated based on MRI images from the patients. The trend line for tumor size <NUM> is shown via straight lines connecting multiple tumor size values at different times (corresponding to MRIs taken at distinct points during TTFields treatment). The trend line for impedance <NUM> provides average impedance values taken via window averaging of the impedance over a period of <NUM> days. The measurement shown for each day is an average of impedance values at the current day, the prior <NUM> days, and the following <NUM> days. Times where no impedance values are shown correspond to times in which the transducers were not used or there was no access to the log files.

As illustrated in <FIG>, the calculated impedance <NUM> is correlated to the determined tumor size <NUM>. Thus, impedance measurements can be used to track tumor progression. Changes in impedance values may be used to track changes in the region of interest (e.g., tumor) over time without needing to take an MRI. Calculating and tracking the impedance may be used to <NUM>) determine when a next MRI should be taken, <NUM>) select new pairs of locations for placement of transducers, or both. For example, current and voltage measurements associated with tumor treating fields induced in the subject's body may be received and then used to calculate an impedance associated with the subject's body; the impedance may be monitored with respect to time while TTFields are induced in the subject's body; and upon detecting a deviation of the monitored impedance from a baseline (e.g., impedance values and/or rate of change thereof), an event may be triggered.

Embodiments illustrated under any heading or in any portion of the disclosure may be combined with embodiments illustrated under the same or any other heading or other portion of the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context and as long as the combinations fall within the scope of the claims.

Claim 1:
An apparatus for detecting and responding to changes in a subject in applying tumor treating fields to a region of interest of the subject's body corresponding to a tumor of the subject's body, the apparatus comprising one or more processors (<NUM>) and memory (<NUM>) accessible by the one or more processors (<NUM>) and providing stored instructions that, when executed by the one or more processors (<NUM>), cause the apparatus to:
alternately apply to the region of interest a first electric field between a first pair of locations (<NUM>, <NUM>) of the subject's body and a second electric field between a second pair of locations (<NUM>, <NUM>) of the subject's body;
detect a change in the region of interest;
record changes in the region of interest based on at least one of a posture change of the subject's body, a change in vital signs of the subject's body, a physiological change of the subject's body, a change in the voltage and/or current of the tumor treating fields or a change in the impedance of the subject's body over time;
generate a habit model of the subject's body based on the recorded changes in the region of interest;
cease applying the first and second electric fields;
select, based on the habit model, a third pair of locations (<NUM>, <NUM>) of the subject's body and a fourth pair of locations (<NUM>, <NUM>) of the subject's body, the third and fourth pairs of locations (<NUM>, <NUM>; <NUM>, <NUM>) being different than the first and second pairs of locations (<NUM>, <NUM>; <NUM>, <NUM>); and
alternately apply to the region of interest a third electric field between the third pair of locations (<NUM>, <NUM>) and a fourth electric field between the fourth pair of locations (<NUM>, <NUM>).