WO2018213809A1

WO2018213809A1 - Particle therapy aided by microbubbles and ultrasound

Info

Publication number: WO2018213809A1
Application number: PCT/US2018/033546
Authority: WO
Inventors: Sarah Kathryn Patch
Original assignee: Sarah Kathryn Patch
Priority date: 2017-05-19
Filing date: 2018-05-18
Publication date: 2018-11-22

Abstract

A particle beam range verification method includes acquiring at least one ultrasound image of target tissue that has been exposed to a particle beam, and obtaining range information for the particle beam from a change in ultrasound contrast due to destruction, by the particle beam, of microbubbles deposited in the target tissue. A particle treatment method includes delivering microbubbles to target tissue, and exposing the target tissue to a particle beam to cause damage to the target tissue, including damage caused by destruction of microbubbles by the particle beam. A microbubble-enhanced ultrasound imaging method includes acquiring an ultrasound image series of target tissue during at least one of wash-in of microbubbles to the target tissue and wash-out of the microbubbles from the target tissue, and deriving therefrom at least one of a wash-in rate and a wash-out rate indicating response of target tissue to particle treatment.

Description

PARTICLE THERAPY AIDED BY MICROBUBBLES AND ULTRASOUND

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of priority from U.S.

Provisional Application Serial No. 62/508,683 filed May 19, 2017, which is incorporated herein by reference in its entirety.

BACKGROUND

[0002] Certain forms of cancer may advantageously be treated with particle therapy. In particle therapy, a particle accelerator delivers a beam of energetic particles, such as protons or other positive ions, that is aimed at the tumor to damage the tumor. More specifically, the energetic particles damage DNA of the cancerous cells. Cancerous cells are generally less capable of DNA repair than normal cells, and cancerous cells are therefore more sensitive to the particle treatment than normal cells.

[0003] When treating a tumor internally in the patient's body, e.g., a tumor located in an organ, the particle beam must pass through healthy tissue to reach the tumor. This portion of the patient's tissue may also be damaged by the particle beam. However, the damage to surrounding healthy tissue is usually less than if other forms of radiation therapy, such as x-ray therapy. In particle therapy, the greatest damage occurs at the so- called Bragg peak of the particle beam, and the energy of the particle beam can be tuned to place the Bragg peak at a certain depth in the patient's body. Collisions between the energetic particles and the patient's tissue ultimately stop the particles, such that there is very little effect on the tissue located downstream from the Bragg peak.

[0004] Particle therapy is performed according to a treatment plan that outlines which locations are to be exposed to the particle beam, from which directions this treatment should take place, and which beam energy is required to reach the targeted locations. The treatment plan relies on pre-treatment imaging of the patient and is typically generated with millimeter precision. Unfortunately, organs of a patient may shift by centimeters between pre-treatment imaging and particle treatment, and treatment plans therefore frequently favor particle beam angles that minimize overall collateral damage to healthy tissue near the tumor in the event of a discrepancy between the actual anatomy and the anatomy imaged prior to treatment. SUMMARY

[0005] In an embodiment, a particle beam range verification method includes (a) acquiring at least one ultrasound image of target tissue that has been exposed to a particle beam, wherein the target tissue contains microbubbles that enhance contrast of the ultrasound image, and (b) obtaining range information for the particle beam from change in the contrast due to destruction of at least some of the microbubbles by the particle beam.

[0006] In an embodiment, a particle treatment method includes delivering microbubbles to target tissue, and exposing the target tissue to a particle beam to cause damage to the target tissue, wherein the damage includes damage caused by destruction of at least some of the microbubbles by the particle beam.

[0007] In an embodiment, a microbubble-enhanced ultrasound imaging method includes acquiring an ultrasound image series of target tissue during at least one of wash-in rate of microbubbles to the target tissue and wash-out rate of the microbubbles from the target tissue, and deriving, from the ultrasound image series, at least one of a wash-in rate and a wash-out rate indicating response of target tissue to particle treatment.

[0008] In an embodiment, a range verification system includes machine- readable instructions encoded in non-transitory memory. The machine-readable instructions are configured to, upon execution by at least one processor, (a) command an ultrasound imager to acquire at least one ultrasound image of target tissue that has been exposed to the particle beam, and (b) determine range information for the particle beam from change in contrast of the at least one ultrasound image due to destruction, by the particle beam, of microbubbles deposited in the target tissue.

[0009] In an embodiment, a system for enhancing particle treatment with particle-induced microbubble cavitation includes machine-readable instructions encoded in non-transitory memory, that, upon execution by at least one processor, command a beam modulator to deliver a series of particle bunches, of a phase-bunched particle beam, to the target tissue at a delivery frequency that resonantly drives oscillation of at least some of the microbubbles to induce cavitation thereof.

[0010] In an embodiment, a microbubble-enhanced ultrasound imaging system for assessing response of target tissue to particle treatment includes machine- readable instructions encoded in non-transitory memory, that, upon execution by at least one processor, (a) command an ultrasound imager to acquire an ultrasound image series of target tissue during at least one of wash-in rate of microbubbles to the target tissue and wash-out rate of the microbubbles from the target tissue, and (b) derive at least one of a wash-in rate and a wash-out rate from the ultrasound image series.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 illustrates a particle treatment apparatus that is aided by ultrasound imaging and microbubbles, according to one embodiment.

[0012] FIG. 2 illustrates an ultrasound imaging system for microbubble- enhanced use in particle treatment, according to one embodiment.

[0013] FIG. 3 illustrates one example configuration of the ultrasound imaging system of FIG. 2 relative to a particle beam.

[0014] FIG. 4 illustrates another example configuration of the ultrasound imaging system of FIG. 2 relative to a particle beam.

[0015] FIG. 5 shows an example configuration of the ultrasound imaging system of FIG. 2 for microbubble-enhanced ultrasound imaging in particle therapy of prostate cancer.

[0016] FIG. 6 illustrates, by example, ultrasound contrast enhancement by microbubbles.

[0017] FIG. 7 illustrates a microbubble-enhanced ultrasound imaging method, according to one embodiment.

[0018] FIG. 8 shows one example contrast curve derived from ultrasound images acquired during wash-in of microbubbles to target tissue.

[0019] FIG. 9 shows one example contrast curve derived from ultrasound images acquired during wash-out of microbubbles from target tissue.

[0020] FIG. 10 illustrates a microbubble-enhanced ultrasound imaging system for verifying range of a particle beam in a particle treatment, according to one embodiment.

[0021] FIG. 11 shows one pair of ultrasound images that illustrate an example of change in ultrasound contrast caused by microbubble destruction by a particle beam.

[0022] FIG. 12 illustrates a microbubble-enhanced ultrasound imaging method for verifying range of a particle beam in a particle treatment, according to one embodiment. [0023] FIG. 13 illustrates a microbubble-enhanced ultrasound imaging method for monitoring wash-in of microbubbles to target tissue and verifying range of a particle beam in a particle treatment of target tissue, according to one embodiment.

[0024] FIG. 14 illustrates a particle treatment method that is enhanced by particle-induced microbubble destruction, according to one embodiment.

[0025] FIG. 15 illustrates a particle treatment apparatus that is enhanced by particle-induced microbubble cavitation, according to one embodiment.

[0026] FIG. 16 illustrates a particle treatment apparatus that is enhanced by particle-induced microbubble cavitation resonantly driven by a phase-bunched particle beam, according to one embodiment.

[0027] FIG. 17 illustrates two particle generators configured to produce a phase-bunched particle beam characterized by a delivery frequency that is less than the frequency applied by a radio-frequency cavity, according to one embodiment.

[0028] FIG. 18 illustrates a microbubble-enhanced particle treatment method that utilizes microbubble-enhanced ultrasound imaging to verify the range of a particle beam, according to one embodiment.

[0029] FIG. 19 illustrates a system for processing of microbubble-enhanced ultrasound images to verify the range of a particle beam in a particle treatment, according to one embodiment.

[0030] FIG. 20 illustrates one system for enhancing particle treatment with particle-induced microbubble cavitation, according to one embodiment.

[0031] FIG. 21 illustrates a system for processing microbubble-enhanced ultrasound images to assess a response of target tissue to particle treatment, according to one embodiment.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0032] The present disclosure is concerned with the use of microbubbles and/or ultrasound to guide, enhance, or otherwise assist particle therapy. Ultrasound imaging is inexpensive and non-ionizing. Ultrasound imaging is compatible with particle therapy systems as long as the ultrasound transducer or transducers are placed outside the particle beam. Ultrasound imaging may therefore be performed during particle therapy, although it may be preferred to acquire the ultrasound images during downtime of the particle beam delivery to avoid electromagnetic interference from the particle beam in the ultrasound images. The contrast in an ultrasound image may be enhanced by the presence of microbubbles in the imaged tissue. In addition to enhancing ultrasound imaging, microbubbles may enhance damage to target tissue caused by a particle beam.

Microbubbles may be used to chemically damage the target tissue or mechanically damage the target tissue. Chemical damage may result from the breakage of microbubbles loaded with drugs, such as radiosensitizing drugs. Radio sensitizing drugs enhance tissue damage created by the particle beam. Breakage of such drug-carrying microbubbles may be caused by the particle beam or a pulse of focused ultrasound. Mechanical damage may result from violent cavitation events of microbubbles, for example induced by the particle beam.

[0033] FIG. 1 illustrates one particle treatment apparatus 100 that is aided by ultrasound imaging and microbubbles. Apparatus 100 includes a particle generator 110, an ultrasound imager 120, and a controller 130. Particle generator 110 delivers a particle beam 112 to target tissue 192 of a patient 190. Particle generator 110 is, for example, a synchrotron, a cyclotron, a synchro-cyclotron, a laser-driven accelerator, a next- generation laser-driven accelerator, or a linear accelerator. Particle beam 112 is, for example, a beam of protons or other positive ions, e.g., helium or carbon ions. Particle beam 112 may be a continuous particle beam, a phase-bunched particle beam, or a pulsed particle beam. Target tissue 192 may be a tumor, for example in the prostate, liver, pancreas, breast, or another organ of patient 190. However, the presently disclosed systems and methods are not limited to treatment of cancerous tissue and may also be applied to non-cancerous target tissue 192. Ultrasound imager 120 is positioned outside the path of particle beam 112 to acquire ultrasound images of target tissue 192 and, optionally, surrounding regions. Controller 130 controls (a) delivery of particle beam 112 by particle generator 110 and (b) ultrasound image acquisition by ultrasound imager 120.

[0034] Herein, a "phase-bunched" particle beam refers to a continuous beam that has been accelerated by a radio-frequency field. Phase-bunching occurs when a particle generator uses a radio-frequency electromagnetic fields (for example a radio- frequency cavity) to accelerate the continuous particle beam. The peaks and valleys of the radio-frequency field cause bunching of the particles of the particle beam, such that the bunching is in phase with the radio-frequency field.

[0035] In one scenario, microbubbles 140 are administered to patient 190 to enhance or help guide particle therapy. Microbubbles 140 may be administered intravenously and spread throughout patient 190 via the vascular system of patient 190. Microbubbles 140 may scatter ultrasound at a relatively high rate compared to the tissue of patient 190. The presence of microbubbles 140 in tissue imaged by ultrasound imager 120 may therefore lead to an increased contrast in the ultrasound images. Since microbubbles 140 are transported by the vascular system, microbubbles 140 may help highlight vascularity in the ultrasound images and, in some implementations, provide additional health indicators of the vascularity of target tissue 192, for example via evaluation of the rate of wash-in of microbubbles 140 to target tissue 192 or the rate of wash-out of microbubbles 140 from target tissue. The state of vascularity of a tumor may be used as an indicator of the health of the tumor tissue, and destruction of a tumor' s vascularity can be one objective of particle therapy.

[0036] Particle beam 112 may break microbubbles 140 in its path. In one scenario, the type of microbubbles 140 is selected such that particle beam 112 has sufficient stopping power to destroy microbubbles 140 only within a certain distance from the Bragg peak of particle beam 112. In this scenario, ultrasound imaging of target tissue 192 may be used to verify the range of particle beam 112 (i.e., check the alignment of particle beam 112 relative to target tissue 192), since destruction of microbubbles 140 by particle beam 112 affects the contrast in the ultrasound images.

[0037] Microbubbles 140 may cooperate with particle beam 112 and/or ultrasound emitted by ultrasound imager 120 (or another ultrasound transducer) to chemically or mechanically enhance damage to target tissue 192 during treatment by apparatus 100. In treatment scenarios that utilize microbubbles 140 to enhance damage to target tissue 192 or verify the range of particle beam 112, apparatus 100 may utilize ultrasound imager 120 to monitor the wash-in of microbubbles 140 to target tissue 192. In such scenarios, apparatus 100 may be configured to initiate range verification and/or treatment only when a sufficient amount of microbubbles 140 are present in or near target tissue 192.

[0038] FIG. 2 illustrates one ultrasound imaging system 200 for microbubble- enhanced use in particle treatment. Ultrasound imaging system 200 includes an ultrasound imager 220 and a controller 230, embodiments of ultrasound imager 120 and controller 130, respectively. Ultrasound imaging system 200 may be coupled with particle generator 110, and optionally a microbubble delivery manager 240, to form a particle treatment apparatus 202. Particle treatment apparatus 202 is an embodiment of particle treatment apparatus 100. Alternatively, ultrasound imaging system 200 is configured to cooperate with a particle generator 110 provided by a third party.

[0039] Ultrasound imager 220 is configured to acquire one or more ultrasound images 228 of target tissue 192 that, at least during portions of the particle treatment, contains microbubbles 140. Ultrasound imager 220 includes an ultrasound transducer array 222 that emits ultrasound toward target tissue and, in a spatially resolved manner, detects ultrasound scattered back to ultrasound transducer array 222, to generate an ultrasound image 228. Ultrasound images 228 may, in addition to target tissue 192, show tissue of patient 190 that is adjacent to target tissue 192. Controller 230 controls image acquisition by ultrasound imager 220.

[0040] In an embodiment, controller 230 is configured to cooperate with microbubble delivery manager 240 to coordinate acquisition of ultrasound images 228 with delivery of microbubbles 140 to target tissue 192. For example, controller 230 may initiate acquisition of ultrasound images 228 upon receipt of an input from microbubble delivery manager 240 indicating that microbubbles 140 have been administered to patient 190. In one implementation, microbubble delivery manager 240 is a person who manages the administering of microbubbles 140 to patient 190, in which case microbubble delivery manager 240 may manually notify controller 230 that microbubbles 140 have been administered or are about to be administered to patient 190. Alternatively, in this implementation, controller 230 may notify microbubble delivery manager 240 to administer microbubbles 140. In another implementation, microbubble delivery manager 240 is an automatic system that, with or without assistance from an operator, administers microbubbles 140 to patient 190. In this implementation, controller 230 may control administering of microbubbles 140 by microbubble delivery manager 240, or microbubble delivery manager 240 may communicate a signal, e.g., an electronic signal, to controller 230 indicating that microbubbles 140 have been administered or are about to be administered to patient 190.

[0041] In certain embodiments, controller 230 is further configured to control at least aspects of delivery of particle beam 112 by particle generator 110 to target tissue 192. For example, controller 230 may initiate, halt, and/or adjust delivery of particle beam 112 to target tissue 192 based upon ultrasound image(s) 228 and/or based upon input received from microbubble delivery manager 240. [0042] Without departing from the scope hereof, controller 230 may be provided as a standalone product configured to cooperate with an ultrasound imager 220 and, optionally, one or both of particle generator 110 and microbubble delivery manager 240 provided by a third party. Controller 230 may be implemented as a processor and a non-transitory memory having encoded therein machine-readable instructions that, upon execution by the processor, perform the functionality of controller 230 as discussed above. Without departing from the scope hereof, this non-transitory memory with the machine-readable instructions encoded therein may be provided as a standalone software product configured for implementation on a third-party computer. Also without departing from the scope hereof, controller 230 may be implemented as two or more modules on different systems. For example, one portion of controller 230 may reside in particle generator 110 while another portion of controller 230 resides in ultrasound imager 220 and yet another portion of controller 230 is external to both particle generator 110 and ultrasound imager 220.

[0043] FIG. 3 illustrates one configuration 300 of ultrasound imaging system 200 relative to particle beam 112. In configuration 300, the image plane 324 of ultrasound transducer array 222 is oriented substantially orthogonal to the propagation direction of particle beam 112. The field of view 326 of ultrasound transducer array 222 encompasses target tissue 192 and a portion of the path of particle beam 112 leading to target tissue 192. FIG. 3 also shows a two-dimensional (2D) ultrasound image 380 which is an example of ultrasound images 228 that ultrasound transducer array 222 may capture in configuration 300. In the example shown in FIG. 3, Bragg peak 312 is within target tissue 192. If, however, particle beam 112 was either slightly undershooting and thus placing Bragg peak 312 short of target tissue 192, or slight overshooting and thus placing Bragg peak 312 beyond target tissue 192, 2D ultrasound image 380 will likely provide information about the location of Bragg peak 312 since the plane of ultrasound image 380 is parallel to the propagation direction of particle beam 112. In other words, configuration 300 may allow for determining the longitudinal range of particle beam 112 from a 2D ultrasound image.

[0044] Controller 230 may affect capture of a stack of 2D ultrasound images by ultrasound transducer array 222 to provide three-dimensional (3D) imagery of target tissue 192 and, optionally, adjacent tissue. Furthermore, without departing from the scope hereof, ultrasound transducer array 222 may be capable of beamforming such that controller 230 may electronically adjust the orientation of image plane 324.

[0045] FIG. 4 illustrates another configuration 400 of ultrasound imaging system 200 relative to particle beam 112. In configuration 400, the image plane 324 of ultrasound transducer array 222 is oriented at an oblique angle to the propagation direction of particle beam 112, such that particle beam 112 passes through an image plane of ultrasound transducer array 222. The field of view 326 of ultrasound transducer 222 encompasses target tissue 192 and a short segment of the path of particle beam 112 as it passes through the image plane of ultrasound transducer array 222 in configuration 400. FIG. 4 also shows a 2D ultrasound image 480 which is an example of ultrasound images 228 that ultrasound transducer array 222 may capture in configuration 400. In the example shown in FIG. 4, Bragg peak 312 is aligned with target tissue 192 in the dimensions transverse to the propagation direction of particle beam 112. Configuration 400 is well suited for determining the location of particle beam 112. However, in configuration 400, determination of the longitudinal range of particle beam 112 may require capture of a stack of 2D ultrasound images 480 collectively forming a 3D ultrasound image of target tissue 192 and adjacent tissue.

[0046] FIG. 5 shows one configuration 500 of ultrasound imaging system 200 for microbubble-enhanced ultrasound imaging in particle therapy of prostate cancer. In configuration 500, a transrectal ultrasound transducer array 522 is positioned in rectum 596 via a rectal catheter (not shown in FIG. 5). Transrectal ultrasound transducer array 522 is an embodiment of transrectal transducer array 222. Particle beam 112 may be directed through hip bone 580 and pelvis 582 to a tumor 592 in prostate 594, as indicated by particle beam 112(1). The propagation direction of particle beam 112(1) prevents direct particle exposure to bladder 598 and rectum 596 in the event that the longitudinal range of particle beam 112(1) is not properly aligned with tumor 592. However, hip bone 580 may suffer damage in this arrangement. In an alternative arrangement, particle beam 112 passes between hip bone 580 and bladder 598 to reach tumor 592, see particle beam 112(2). This arrangement avoids damage to hip bone 580 but is more sensitive to range errors in particle beam 112(2). For example, a range error may cause damage to rectum 596. Although not shown in FIG. 5, transrectal ultrasound transducer array 522 may be equipped with an acoustic matching material that spaces transrectal ultrasound transducer array 522 apart from the anterior wall of rectum 596 to prevent damage to transrectal ultrasound transducer array 522 in case of particle beam range error. Similarly, hydrogel spaces may be implanted into the patient to increase distance between prostate 594 and the radiosensitive rectum 596.

[0047] FIG. 6 illustrates ultrasound contrast enhancement by microbubbles 140. FIG. 6 shows two ultrasound images 600 and 610 of a liver. Ultrasound images 600 and 610 are examples of ultrasound image 228. Ultrasound image 600 is acquired without the presence of microbubbles 140, whereas ultrasound image 610 is acquired after delivering microbubbles 140 to the imaged tissue. It is evident that microbubbles 140 enhance the contrast and, in particular, highlights vascular structure.

[0048] FIG. 7 illustrates one microbubble-enhanced ultrasound imaging method 700. Method 700 may be performed by ultrasound imaging system 200 or particle treatment apparatus 202. In a step 710, method 700 monitors ultrasound contrast in ultrasound images during wash-in of microbubbles to target tissue, or during wash-out of microbubbles from the target tissue. In one example of step 710, ultrasound imager 220 monitors wash-in of microbubbles 140 to target tissue 192 upon or after administering of microbubble 140 to patient 190 via, for example, an intravenous injection. In another example of step 710, ultrasound imager 220 monitors wash-out of microbubbles 140 from target tissue 192 after administering of microbubble 140 to patient 190. Step 710 may include a step 712 of acquiring an ultrasound image series during the microbubble wash- in or wash-out. In one example of step 712, controller 230 commands ultrasound transducer array 222 of ultrasound imager 220 to capture a series of ultrasound images 228 of target tissue 192 during wash-in or wash-out of microbubbles 140.

[0049] Method 700 may further include a step 702 of administering microbubbles 140. Microbubble delivery manager 240 may perform step 702.

[0050] In an embodiment, method 700 further includes a step 720 of deriving a wash- in or wash-out rate from the ultrasound image series acquired in step 712. In one example of step 720, controller 230 processes a series of ultrasound images 228 to derive therefrom a rate of microbubble wash-in or wash-out.

[0051] FIG. 8 shows one example contrast curve 810 derived from ultrasound images 228 acquired during wash-in of microbubbles 140 to target tissue 192. Contrast curve 810 is an example of data generated by controller 230 in step 720 based upon a series of ultrasound images 228 captured by ultrasound transducer array 222 in step 712. [0052] FIG. 8 plots contrast curve 810 as contrast 804 versus time 802 after administering of microbubbles 140 to patient 190. In one scenario, contrast 804 is derived from a local region of interest in ultrasound images 228, wherein the local region of interest is associated with target tissue 192. FIG. 6 shows an example region interest 620 in ultrasound images 600 and 610. In another scenario, contrast 804 takes into

consideration the full view of ultrasound image 228. Contrast 804 may represent (a) a difference between maximum and minimum ultrasound signal within an ultrasound image 228 of a local region thereof, (b) an absolute maximum or absolute average ultrasound signal value within an ultrasound image 228 of a local region thereof, (c) a maximum or average ultrasound signal value within an ultrasound image 228 of a local region thereof relative to a reference value, or (d) another metric derived from an ultrasound image 228 indicative of ultrasound contrast or signal.

[0053] Contrast curve 810 increases from an initial level 824 to steady-state level 822 that is substantially maintained for a period of time. Contrast curve 810 exhibits a rate 830 of increase between initial level 824 and steady-state level 822. Rate 830 is an example of a microbubble wash-in rate determined by controller 230 in step 720.

[0054] FIG. 9 shows one example contrast curve 910 derived from ultrasound images 228 acquired during wash-out of microbubbles 140 from target tissue 192.

Contrast curve 910 is an example of data generated by controller 230 in step 720 based upon a series of ultrasound images 228 captured by ultrasound transducer array 222 in step 712. Contrast curve 910 decreases from an initial level 924 to a final level 922. Initial level 924 and final level 922 may be substantially the same as steady-state level 822 and initial level 824, respectively. Contrast curve 910 exhibits a rate 930 of decrease between initial level 924 and final level 922. Rate 930 is an example of a microbubble wash-out rate determined by controller 230 in step 720.

[0055] Referring again to FIG. 7, method 700 may perform a step 730 after step 720. Step 730 assesses the response of target tissue 192 to a particle treatment, such as exposure to particle beam 112, based upon the wash- in rate and/or wash-out rate determined in step 720. Wash-in and wash-out rates indicate perfusion, which is an indicator of tumor health. For example, aggressively growing tumors need a robust blood supply and are therefore generally associated with a high wash-in rate. Overgrown tumors, on the other hand, often have a necrotic core which is essentially dead and therefore is associated with little blood flow if any. Step 730 may be performed manually by a person receiving the wash-in rate and/or wash-out rate from controller 230.

Alternatively, an embodiment of controller 230 that includes a correspondence between the wash-in rate and/or wash-out rate and a treatment outcome, may assess a treatment outcome based upon the wash-in rate and/or wash-out rate. This assessment may be a prediction of the treatment outcome based upon the wash-in rate and/or wash-out rate. In cases where there is a known correspondence between treatment outcome and the wash-in rate and/or wash-out rate, the assessment may be used to select nonresponsive patients and refer them to alternative treatment.

[0056] In one scenario, particle therapy by particle treatment apparatus 202 includes performing method 700, with step 720, before and after treatment of target tissue 192 with particle beam 112. In this scenario, step 730 may assess the response of target tissue 192 to particle treatment based upon a comparison of a wash-in or wash-out rate determined in step 720 before particle treatment to a wash-in or wash-out rate determined in step 720 after particle treatment. In a scenario where method 700 is applied to hypofractionated particle treatment, step 730 may, after delivery of a fraction, assess the response of target tissue 192 to the fraction by comparing a wash-in or wash-out rate determined in step 720 for the current fraction to a baseline wash-in or wash-out rate determined in step 720 for a previous fraction. If the assessed response deviates from the expected response, the hypofractionated treatment plan may be modified. Step 730 may also assess the response of non-target tissue, such as tissue near target tissue 192, to particle treatment. For example, particle treatment may be stopped or modified if the damage to non-target tissue exceeds a certain level.

[0057] Certain embodiments of method 700 further include a step 740 of outputting a signal when the ultrasound contrast reaches a threshold contrast. Controller 230 may perform step 740. In one such embodiment, method 700 performs step 740 during wash-in of microbubbles 140 and outputs a signal indicating that contrast 804 of contrast curve 810 has reached steady-state level 822 or a slightly lower threshold level 820 (see FIG. 8) associated with a sufficient amount of microbubbles 140 in target tissue 192. In this embodiment, method 700 may further include a step 750 of initiating a particle treatment session, such as a particle treatment that is enhanced by the presence of microbubbles 140 in or near target tissue 192. For example, microbubbles 140 may be loaded with radiosensitizing drugs that are released to target tissue 192 when

microbubbles 140 are broken by particle beam 112. In one example of step 740, controller 230 outputs a signal to particle generator 110 when the amount of microbubbles 140 in target tissue 192 is deemed sufficient.

[0058] Herein, a "particle treatment session" refers to the treatment applied between placing patient 190 in the particle treatment apparatus and removing patient 190 from the particle treatment apparatus. A particle treatment plan may be limited to only one treatment session. Alternatively, the particle treatment plan may be a fractionated treatment plan with multiple fractions respectively delivered over multiple respective days or multiple respective placements of patient 190 in the particle treatment apparatus.

[0059] In another embodiment, method 700 performs step 740 during washout of microbubbles 140 from target tissue 192. In this embodiment, step 740 may output a signal indicating that contrast 804 of contrast curve 910 has dropped below a threshold level 920 (see FIG. 9) corresponding to a lower limit on the acceptable amount of microbubbles 140 in target tissue 192. This embodiment of method 700 may further include a step 760 of re- administering microbubbles 140. In one example of step 760, controller 230 outputs a signal to microbubble delivery manager 240 indicating that microbubbles 140 should be re-administered.

[0060] FIG. 10 illustrates one microbubble-enhanced ultrasound imaging system 1000 for verifying range of a particle beam in a particle treatment. Ultrasound imaging system 1000 is an embodiment of ultrasound imaging system 200 that implements controller 230 as a controller 1030. Ultrasound imaging system 1000 may be coupled with particle generator 110, and optionally microbubble delivery manager 240 to form a particle treatment apparatus 1002. Particle treatment apparatus 1002 is an embodiment of particle treatment apparatus 202.

[0061] System 1000 is capable of online range verification for pulsed, continuous, and phase-bunched particle beams 112. System 1000 provides an attractive alternative to range determination relying on pre-treatment imaging of patient 190, and system 1000 is capable of preventing the delivery of damaging radiation doses to the wrong location of patient 190. System 1000 facilitates taking full advantage of the millimeter accuracy of treatment plans even in the event that the anatomy of patient 190 should shift during treatment. System 1000 is particularly advantageous when particle beam 112 is a continuous or phase-bunched particle beam. While it is possible to determine the range of a pulsed particle beam using thermoacoustics, continuous and phase-bunched particle beams require a different technique since these beams do not generate the sudden heat required for thermoacoustic range verification.

[0062] Controller 1030 is adapted to cooperate with ultrasound imager 220 to evaluate the range of particle beam 112 relative to target tissue 192. Controller 1030 includes ultrasound image acquisition controller 1032 and range evaluator 1034.

Ultrasound image acquisition controller 1032 controls acquisition of ultrasound images 228 by ultrasound imager 220. Range evaluator 1034 processes one or more ultrasound images 228, captured by ultrasound transducer array 222, to obtain range information for particle beam 112. Range evaluator 1034 obtains the range information based upon a change in ultrasound contrast caused by destruction of microbubbles 140 by particle beam 112. The composition and particle energy of particle beam 112 may be cooperatively configured with the structure of microbubbles 140 to ensure that particle beam 112 destroys at least some of microbubbles 140 in the path of particle beam 112.

[0063] In certain scenarios, the composition and energy of particle beam 112 are cooperatively configured with the structure of microbubbles 140 to achieve maximum microbubble destruction at the Bragg peak of particle beam 112. In these scenarios, the portion of particle beam 112 having maximum microbubble destruction capability substantially coincides with the portion of particle beam 112 having the greatest therapeutic effect on tissue. For example, microbubbles 140 and particle beam 112 may be cooperatively configured to reach threshold for destruction of microbubbles 140 only for microbubbles 140 that are no more than 5-10 millimeters from the Bragg peak of particle beam 112. Thus, in these scenarios, identification of the location of maximum microbubble destruction by particle beam 112 directly indicates the location of greatest therapeutic effect. In one such scenario, microbubbles 140 are gas- or air- filled bubbles with monolayer lipid shells, and particle beam 112 is a proton beam.

[0064] FIG. 11 shows one pair of ultrasound images 1100 and 1110 that illustrate an example of change in ultrasound contrast caused by microbubble destruction by a particle beam. Ultrasound images 1100 and 1110 are examples of ultrasound images 228. Both of ultrasound images 1100 and 1110 are captured by ultrasound transducer array 222 while microbubbles 140 are present in and near target tissue 192. The contrast in both of ultrasound images 1100 and 1110 is therefore enhanced by ultrasound, as discussed above for ultrasound image 610. However, ultrasound image 1100 is captured before exposure to particle beam 112, and ultrasound image 1110 is captured after exposure to particle beam 112 and resulting destruction of microbubbles 140 in a local region 1120. This destruction of microbubbles 140 is evident by region 1120 in ultrasound image 1100 being dark relative to the surrounding tissue and, in particular, relative to the same region in ultrasound image 1100.

[0065] Referring again to FIG. 10, range evaluator 1034 may process one or more ultrasound images 228 acquired by ultrasound imager 220 to identify or at least search for a local region of reduced ultrasound contrast, so as to obtain range information for particle beam 112.

[0066] In an embodiment, controller 1030 includes a comparator 1036 that compares range information determined by range evaluator 1034 to a target range 1090 received, for example, from an operator or from a treatment planning system (not shown in FIG. 10). Target range 1090 coincides with the location of at least a portion of target tissue 192. Based upon the range information determined by range evaluator 1034, comparator 1036 determines if the range of particle beam 112 matches target range 1090. Comparator 1036 may co-register ultrasound images 228 acquired by ultrasound imager 120 during a particle treatment session with planning computed-tomography (CT) images acquired in a pre-treatment imaging procedure. Such co-registration allows for determination of the range of particle beam 112 in the room coordinates used to develop the treatment plan. For some treatment sites, such as the prostate, ultrasound images 228 clearly visualize the treatment volume. In such cases, comparison to planning CT images may not be required, and comparator 1036 may verify the range of particle beam 112 from ultrasound images 228 acquired during the particle treatment session without comparison to the planning CT images. Controller 1030 may further include a notifier 1038 that notifies particle generator 110 if comparator 1036 determines that the range of particle beam 112 deviates from target range 1090. Alternatively, controller 1030 may be in at least partial control of particle generator 110 and configured to halt and/or adjust delivery of particle beam 112 by particle generator 110, if the range of particle beam 112 deviates from target range 1090, so as to align the range of particle beam 112 with target range 1090.

[0067] In certain embodiments, ultrasound image acquisition controller 1032 includes a monitoring unit 1040, and controller 1030 further includes one or both of a wash-in evaluator 1042 and a wash-out evaluator 1044. Such embodiments of controller 1030 are capable of performing method 700. Monitoring unit 1040 is configured to command ultrasound imager 220 to perform step 710 and, optionally, step 740 of method 700. Wash-in evaluator 1042 and a wash-out evaluator 1044 are configured to perform step 720. Controller 1030 may further be configured to perform step 730. In an alternative embodiment, a person or an external system performs step 730.

[0068] Controller 1030 may also include a timing module 1050 that coordinates the timing of acquisition of ultrasound images 228, as commanded by ultrasound image acquisition controller 1032, with (a) delivery of microbubbles 140 by microbubble delivery manager 240 to patient 190 and/or (b) exposure of patient 190 to particle beam 112. In one implementation, timing module 1050 is configured to prevent or reduce electromagnetic interference from particle beam 112 on ultrasound images 228 used by controller 1030 to make determinations. In this implementation, timing module 1050 is configured to ensure that ultrasound images 228, processed by any one of range evaluator 1034, wash-in evaluator 1042, and wash-out evaluator 1044, are captured while particle beam 112 is not being delivered to patient 190, or while the gantry magnets are in a quiescent state. Timing module 1050 may limit capture of ultrasound images 228 to time periods not coinciding with delivery of particle beam 112 to patient 190.

Alternatively, timing module 1050 may eliminate, from consideration by any one of range evaluator 1034, wash-in evaluator 1042, and wash-out evaluator 1044, ultrasound images 228 acquired while patient 190 is being exposed to particle beam 112.

[0069] Without departing from the scope hereof, controller 1030 may be provided as a standalone product configured to cooperate with an ultrasound imager 220 and, optionally, one or both of particle generator 110 and microbubble delivery manager 240 provided by a third party. Controller 1030 may be implemented as a processor and a non-transitory memory having encoded therein machine-readable instructions that, upon execution by the processor, perform the functionality of controller 1030 as discussed above. Without departing from the scope hereof, this non-transitory memory with the machine-readable instructions encoded therein may be provided as a standalone software product configured for implementation on a third-party computer.

[0070] FIG. 12 illustrates one microbubble-enhanced ultrasound imaging method 1200 for verifying range of a particle beam in a particle treatment. Certain embodiments of method 1200 further control a particle generator, used in the particle treatment, according to the range verification. Method 1200 is performed by microbubble-enhanced ultrasound imaging system 1000 or particle treatment apparatus 1002, for example. Method 1200 includes steps 1210 and 1220.

[0071] Step 1210 acquires at least one ultrasound image of target tissue 192 that (a) has been exposed to the particle beam and (b) contains microbubbles 140 that enhance contrast of the ultrasound image. Without departing from the scope hereof, each of the at least one ultrasound image may show not only target tissue 192 but also other tissue near target tissue 192. In one example of step 1210, ultrasound image acquisition controller 1032 commands ultrasound imager 220 to acquire, using ultrasound transducer array 222, at least one ultrasound image 228 of target tissue 192 and, optionally, tissue near target tissue 192. Each ultrasound image 228 may be a 2D ultrasound image, for example acquired with ultrasound transducer array 222 arranged according to

configuration 300 or 400, or a 3D ultrasound image. The 3D ultrasound image may be composed of a stack of 2D ultrasound images.

[0072] Step 1220 obtains range information for the particle beam from a contrast change in the ultrasound image(s) acquired in step 1210, wherein the contrast change is due to destruction of at least some of microbubbles 140 by the particle beam. In one example of step 1220, range evaluator 1034 processes at least one ultrasound image 228, acquired in step 1210, to obtain range information for particle beam 112 relative to target tissue 192. Step 1220 may be configured to evaluate the ultrasound contrast at the location of target tissue 192 to determine if the ultrasound contrast changes at this location. Alternatively, step 1220 may consider a larger region and identify a location where the ultrasound contrast does change, if such a location exists within the region viewed by the ultrasound image(s).

[0073] In an embodiment, step 1220 includes a step 1226 of ascertaining a local decrease in an ultrasound signal and attributing this local decrease to destruction of at least some of microbubbles 140 by the particle beam. In one example of step 1226, range evaluator 1034 identifies, in one or more ultrasound images 228, a dark region that is similar to local region 1120 of ultrasound image 1110. Range evaluator 1034 then attributes the decreased ultrasound signal in the dark region to destruction of at least some of microbubbles 140 by particle beam 112.

[0074] Step 1220 may implement one or both of steps 1222 and 1224. Step 1222 compares ultrasound images captured before and after exposure of patient 190 to the particle beam, to determine the contrast change. To minimize flow of microbubbles 140 between the before and after ultrasound images considered by step 1222, these before and after ultrasound images may be captured within 0.1 seconds of an exposure of patient 190 to the particle beam. In one example of step 1220 implementing step 1222, range evaluator 1034 compares ultrasound images 1100 and 1110 to determine that the contrast has changed in the location of local region 1120. Range evaluator 1034 may compare the ultrasound signal in a region of interest (ROI) 1150, or in an ROI 1152, of ultrasound images 1100 and 1110 to determine that the ultrasound signal within ROI 1150, or ROI 1152, is lower in ultrasound image 1110 than in ultrasound image 1100. ROIs 1150 and 1152 are example ROIs depicted in FIG. 11. Step 1224 compares different regions of one ultrasound image to determine the change in contrast. To minimize flow of microbubbles 140 between (a) exposure of patient 190 to the particle beam and (b) capture of the ultrasound image considered by step 1224, this ultrasound image may be captured within 0.1 seconds of the exposure of patient 190 to the particle beam. In one example of step 1220 implementing step 1224, range evaluator 1034 compares different ROIs of ultrasound image 1110 (e.g., ROIs 1150 and 1140) to determine that the contrast is different in the location of local region 1120. ROI 1140 is depicted in FIG. 11.

[0075] In one embodiment, method 1200 further includes a step 1230. Based upon the range information obtained in step 1220, step 1230 determines if the range of the particle beam matches a target range associated with at least a portion of the target tissue. In one example of step 1230, comparator 1036 compares the range information, obtained in step 1220, to target range 1090, to determine is the range of particle beam 112 matches target range 1090.

[0076] Method 1200 may further include a step 1240 of notifying the particle generator system, producing the particle beam, if the range of the particle beam deviates from the target range. In one example of step 1240, notifier 1038 notifies particle generator 110 if step 1230 determines that the range of particle beam 112 deviates from target range 1090. In embodiments of system 1000 where controller 1030 is equipped to control at least aspects of particle generator 110, this notification may be an internal communication within controller 1030. Optionally, after performing step 1240, method 1200 proceeds to perform a step 1250 that halts and/or adjusts exposure of patient 190 to the particle beam. In one example of step 1250, particle generator 110 halts and/or adjusts exposure of patient 190 to particle beam 112, upon receipt of a notification from notifier 1038. In another example of step 1250, controller 1030 halts and/or adjusts exposure of patient 190 to particle beam 112, upon generation of a notification by notifier 1038.

[0077] A particle treatment session typically includes sequential treatment of different portions of target tissue 192. For example, a stack of different layers of target tissue 192 may be treated sequentially. In one scenario, a particle treatment session includes performing method 1200 for each different target tissue portion, to be sequentially treated, to ensure that the particle beam is properly aligned to each new target range.

[0078] FIG. 13 illustrates one microbubble-enhanced ultrasound imaging method 1300 for monitoring wash-in of microbubbles 140 to target tissue 192 and verifying range of a particle beam in a particle treatment of target tissue 192. Method 1300 may further control (a) a particle generator, used in the particle treatment, according to the range verification. In addition, one embodiment of method 1300 is configured to at least contribute to the management of microbubble delivery to the patient. Method 1300 is performed by microbubble-enhanced ultrasound imaging system 1000 or particle treatment apparatus 1002, for example. Method 1300 combines method 1200 with an embodiment of method 700. Method 1300 includes steps 1310, 1320, and 1330.

[0079] Step 1310 monitors, via ultrasound images, wash- in of microbubbles 140 to target tissue 192. Step 1310 is an embodiment of step 710. In one example of step 1310, monitoring unit 1040 commands ultrasound imager 220 to acquire a series of ultrasound images 228 during wash-in of microbubbles 140 to target tissue 192, while wash-in evaluator 1042 evaluates the contrast in ultrasound images 228 and compares the contrast to a threshold contrast. The threshold contrast may be similar to threshold level 820 or steady-state level 822.

[0080] Method 1300 may include step 702 of administering microbubbles 140 to patient 190, as discussed above in reference to FIG. 7.

[0081] Upon determining in step 1310, during or after the wash-in of microbubbles 140 to target tissue 192, that the contrast in the ultrasound images exceeds a threshold contrast, step 1320 communicates an output signal (e.g., a trigger signal) to the particle generator producing the particle beam for the particle treatment. In one example of step 1320, when wash-in evaluator 1042 has determined that the contrast in ultrasound images 228 exceeds the threshold contrast, controller 1030 sends a trigger signal to particle generator 110. In embodiments of system 1000 where controller 1030 controls at least aspects of particle generator 110, the signal of step 1320 may be communicated internally within controller 1030.

[0082] Step 1320 simultaneously prompts (a) the performance of step 1330 and (b) delivery of particle beam 112 to patient 190. In one embodiment, method 1300 includes a step 1360. In step 1360, the particle generator initiates exposure of patient 190 to the particle beam, upon receipt of the output signal generated in step 1320. In one example of step 1360, particle generator 110 receives a trigger signal from controller 1030 and, upon receipt of this trigger signal, initiates exposure of patient 190 to particle beam 112.

[0083] Step 1330 performs steps 1210, 1220, and 1230 to determine if the range of the particle beam matches a target range. In one example of step 1330, controller 1030 cooperates with ultrasound imager 220 to determine if the range of particle beam 112 matches target range 1090.

[0084] Method 1300 may include one or more steps performed according to the outcome of step 1330. This optional portion of method 1300 starts with a decision step 1340 that may be performed by controller 1030. In decision step 1340, if step 1330 determines that the range of the particle beam deviates from the target range, method 1300 proceeds to step 1240 and, optionally, step 1250. In one implementation, if method 1300 adjusts the particle beam in step 1250, method 1300 may return to step 1330 to reevaluate the range of the particle beam. In this implementation, method 1300 may further include, before potentially returning to step 1330, a decision step 1350 that evaluates if the ultrasound image contrast is sufficient to satisfactorily perform the range verification of step 1330. Decision step 1350 acquires one or more ultrasound images of target tissue 192 (and, optionally, adjacent tissue) to determine if the ultrasound image contrast exceeds the threshold contrast of step 1320. Decision step 1350 may be performed by controller 1030, utilizing monitoring unit 1040 and wash-in evaluator 1042, in cooperation with ultrasound imager 220, in a manner similar to that discussed above in reference to steps 1310 and 1320. If decision step 1350 finds that the ultrasound contrast is sufficient, method 1300 returns to step 1330. Otherwise, method 1300 may return to step 702 or indicate to microbubble delivery manager 240 that it is necessary to re- administer microbubbles 140 to patient 190.

[0085] Referring again to decision step 1340, if step 1330 determines that the range of the particle beam matches the target range, method 1300 continues exposure of patient 190 to particle beam 112. In an embodiment, step 1320 initiated exposure of patient 190 to a test beam, as opposed to the actual treatment beam intended to have therapeutic effect. In this embodiment, method 1300 may, if decision step 1340 indicates that the range of the particle beam matches the target range, proceed to a step 1342 of switching from the test beam to the treatment beam. In one example of step 1342, particle generator 110 switches from delivery of a test beam to delivery of a treatment beam.

[0086] In one scenario, method 1300 utilizes microbubbles 140 that carry drugs that enhance the particle treatment, such as radio sensitizing drugs. The particle beam may release the drugs to target tissue 192 when destroying the microbubbles.

However, it is also possible to break the microbubbles with a focused ultrasound pulse. Thus, in one embodiment, method 1300 includes a step 1370 of applying ultrasound to break at least some of microbubbles 140 and release the drugs carried by these microbubbles 140. Method 1300 may perform step 1370 if decision step 1340 indicates that the range of the particle beam matches the target range. In one example of step 1340, controller 1030 commands ultrasound transducer array 222, or another transducer, to apply a strong pulse of ultrasound focused on target tissue 192.

[0087] As discussed above in reference to method 1200, a particle treatment session typically includes sequential treatment of different portions of target tissue 192. In one scenario, a particle treatment session includes performing method 1300 for each different target tissue portion, to be sequentially treated, to ensure that the particle beam is properly aligned to each new target range.

[0088] FIG. 14 illustrates one particle treatment method 1400 that is enhanced by particle-induced microbubble destruction. Method 1400 includes a step 1410 of exposing target tissue 192 to a particle beam to damage the target tissue, wherein the damage includes damage from destruction of at least some of microbubbles 140 induced by the particle beam. The damage caused by destruction of microbubbles 140 may be mechanical, chemical, or both. One implementation of method 1400 utilizes

microbubbles 140 that are loaded with radiosensitizing drugs. Upon destruction of microbubbles 140 by the particle beam in step 1410, the radiosensitizing drugs are released to target tissue 192 to chemically enhance effectiveness of particle therapy delivered to target tissue 192. Another implementation of method 1400 utilizes microbubbles 140 that do not carry radiosensitizing drugs. In this implementation, the particle beam induces cavitation of at least some of microbubbles 140, and the pressure bursts associated with the cavitation events mechanically damage target tissue 192. Yet another implementation of method 1400 utilizes microbubbles 140 that are loaded with radiosensitizing drugs, and the particle beam induces cavitation of at least some of microbubbles 140. Upon cavitation of microbubbles 140, the radiosensitizing drugs are released to target tissue 192 to chemically enhance damage to target tissue 192, and the pressure bursts associated with the cavitation events mechanically damage target tissue 192, which aids in transporting drugs to target tissue 192.

[0089] Microbubbles 140 may be located in the vasculature of target tissue 192, such that the pressure pulses associated with cavitation of microbubbles 140 damage the vasculature of target tissue 192. However, microbubbles 140 may also be outside the vasculature of target tissue 192 and thus damage other portions of target tissue 192. For example, the vasculature of a tumor may be leaky such that microbubbles 140, transported to the tumor via the vascular system of patient 190, may leak out of the vasculature and instead reside in non- vascular tissue of the tumor. In one example of step 1410, particle generator 110 exposes target tissue 192 to particle beam 112 after microbubble 140 have been administered to patient 190.

[0090] In one scenario, method 1400 uses microbubbles 140 that are gas- or air- filled bubbles with monolayer lipid shells and a particle beam 112 that is a proton beam. As discussed above in reference to FIG. 10, this scenario may provide the greatest amount of microbubble destruction (e.g., cavitation events) at the Bragg peak of the particle beam.

[0091] Step 1410 may include one, two, or all of steps 1412, 1414, and 1416. In step 1412, the particle beam induces destruction (e.g., cavitation) of at least some of microbubbles 140 when one or more particles of the particle beam passes through each such microbubble. The particles may break bonds of lipid shells of the bubbles to induce the destruction.

[0092] In step 1414, the particle beam induces destruction (e.g., cavitation) of at least some of microbubbles 140 by deforming each such microbubble with a pressure pulse generated by deceleration of one or more particles of the particle beam as the particle beam is stopped by target tissue 192.

[0093] In step 1416, the particle generator delivers a series of particle bunches to the target tissue at a delivery frequency. The particle bunches resonantly drive oscillation of at least some of microbubbles 140 at the delivery frequency. For at least some microbubbles 140, this oscillation leads to cavitation of the microbubble. The series of particle bunches may be bunches of a phase-bunched particle beam. Herein, "delivery frequency" refers to the frequency of a temporal pattern of a particle beam. The delivery frequency may be the frequency at which individual particle bunches arrive at target tissue 192. However, the delivery frequency may also be an undertone of the arrival frequency of particle bunches. For example, if the particle beam includes groups of particle bunches (e.g., 3 particle bunches in each group with a longer pause between groups), the delivery frequency may be the frequency at which the groups arrive to target tissue 192.

[0094] In certain embodiments, method 1400 further includes step 702 of administering microbubbles 140 to patient 190. Method 1400 may be configured to perform step 1410 when sufficient microbubbles 140 are present in target tissue 192.

[0095] FIG. 15 illustrates one particle treatment apparatus 1500 that is enhanced by particle-induced microbubble destruction. Particle treatment apparatus 1500 is configured to perform method 1400. Particle treatment apparatus 1500 is similar to particle treatment apparatus 202, except for (a) requiring inclusion of particle generator 110, (b) not requiring ultrasound imaging 220, and (c) replacing controller 230 with a controller 1530. Controller 1530 is configured to control at least aspects of generation of particle beam 112 by particle generator 110 and delivery of particle beam 112 to target tissue 192. In operation, controller 1530 commands particle generator 110 to perform step 1410.

[0096] Controller 1530 may be communicatively coupled with microbubble delivery manager 240 to coordinate the exposure of target tissue 192, in step 1410, with the administering of microbubbles 140 to patient 190, in step 702, so as to ensure that microbubbles 140 are present in target tissue 192 during step 1510. In one embodiment, controller 1530 further includes at least some of the functionality of controller 230 discussed above in reference to FIGS. 2 and 7. In this embodiment, controller 1530 may (a) command ultrasound imager 220 to acquire ultrasound images 228 of target tissue 192 and, optionally, other tissue near target tissue 192, and (b) process ultrasound images 228 to determine when a sufficient amount of microbubbles 140 are present in target tissue 192 for step 1510 to be effective. In another embodiment, controller 1530 further includes at least some of the functionality of controller 1030 discussed above in reference to FIGS. 10, 12, and 13. In this embodiment, controller 1530 may cooperate with ultrasound imager 220 to perform method 1200 so as to verify the range of particle beam 112 before commanding particle generator 110 to perform step 1510. In yet another embodiment, controller 1530 further includes at least some of the functionality of both controller 230 and controller 1030. In this embodiment, controller 1530 may cooperate with ultrasound imager 220 to (a) ensure the presence of a sufficient amount of microbubbles 140 and (b) verify the range of particle beam 112 prior to (c) commanding particle generator 110 to perform step 1510.

[0097] Without departing from the scope hereof, controller 1530 may be provided as a standalone product configured to cooperate with a particle generator 110 and, optionally, one or both of ultrasound imager 220 and microbubble delivery manager 240 provided by a third party. Controller 1530 may be implemented as a processor and a non-transitory memory having encoded therein machine-readable instructions that, upon execution by the processor, perform the functionality of controller 1530 as discussed above. Without departing from the scope hereof, this non-transitory memory with the machine-readable instructions encoded therein may be provided as a standalone software product configured for implementation on a third-party computer. Also without departing from the scope hereof, controller 1530 may be implemented as two or more modules on different systems. For example, one portion of controller 1530 may reside in particle generator 110 while another portion of controller 1530 resides in ultrasound imager 220 and yet another portion of controller 1530 is external to both particle generator 110 and ultrasound imager 220.

[0098] FIG. 16 illustrates one particle treatment apparatus 1600 that is enhanced by particle-induced microbubble cavitation resonantly driven by a phase- bunched particle beam. Particle treatment apparatus 1600 is an embodiment of particle treatment apparatus 1500. Particle treatment apparatus 1600 is configured to perform an embodiment of method 1400 that implements step 1416. Particle treatment apparatus 1600 implements particle generator 110 and controller 1530 as particle generator 1610 and controller 1630, respectively. Particle generator 1610 includes a particle accelerator 1622 and a beam modulator 1624. Particle accelerator 1622 includes a particle source 1621 and a radio-frequency cavity 1623. Controller 1630 includes a bunch selector 1634.

[0099] In operation, particle accelerator 1622 uses particle source 1621 to produce a continuous particle beam 1611 and then uses radio-frequency cavity 1623 to accelerate the continuous particle beam 1611 to a desired energy. It is understood that particle accelerator 1622 may include additional acceleration components, such as a static electric field. Acceleration of continuous particle beam 1611 by radio-frequency cavity

1623 produces a phase-bunched particle beam 1612. The frequency of particle bunches in phase-bunched particle beam 1612 is the radio-frequency applied by radio-frequency cavity 1623. Bunch selector 1634 controls beam modulator 1624 to select only some of the particle bunches of phase-bunched particle beam 1612 for delivery to patient 190. Beam modulator 1624 thereby produces a phase-bunched particle beam 1614

characterized by a delivery frequency that is less than the frequency of particle bunches of phase-bunched particle beam 1612. The delivery frequency is set to resonantly drive oscillation of microbubbles 140 to induce cavitation of microbubbles 140.

[00100] In a first example, bunch selector 1634 commands beam modulator

1624 to select every N'th particle bunch of phase-bunched particle beam 1612 (wherein N is a positive integer), such that the delivery frequency associated with phase-bunched particle beam 1614 is reduced by a factor of N relative to the frequency of particle bunches in phase-bunched particle beam 1612. In a second example, bunch selector 1634 commands beam modulator 1624 to alternatingly (a) select N subsequent particle bunches of phase-bunched particle beam 1612 and (b) deselect N subsequent particle bunches of phase-bunched particle beam 1612. The resulting phase-bunched particle beam 1614 has groups of N particle bunches. These groups occur at a delivery frequency that is reduced by a factor of 2N relative to the frequency of particle bunches in phase-bunched particle beam 1612. This second example may achieve the same delivery frequency as the first example. However, regardless of the value of N, the second example deselects only half of the particle bunches of phase-bunched particle beam 1612. Thus, for values of N greater than one, the second example will deliver more particles to target tissue 192 than the first example and therefore be able to provide the same dose in a shorter duration. In one embodiment, radio frequency cavity 1623 applies a frequency in the range between 8 and 100 MHz, whereas the delivery frequency associated with phase-bunched particle beam 1614 is in the range between 1 and 5 MHz. This range of delivery frequencies is expected to be suitable for resonantly driving oscillation of microbubbles 140 to induce their cavitation. In one scenario, microbubbles 140 and particle beam 112 are

cooperatively configured to reach the microbubbles' cavitation threshold only for microbubbles 140 that are no more than 5-10 millimeters from the Bragg peak of particle beam 112. In this scenario, microbubbles 140 may be gas- or air-filled bubbles with monolayer lipid shells, and each of phased-bunched particle beams 1612 and 1614 may be a proton beam.

[00101] Controller 1630 may further include an acceleration control unit 1632 that controls the radio-frequency applied by radio-frequency cavity 1623.

[00102] Without departing from the scope hereof, beam modulator 1624 and controller 1630 may be provided as a standalone system configured to cooperate with a particle accelerator 1622 provided by a third party, so as to form particle treatment apparatus 1600. Furthermore, controller 1630 may be provided as a standalone product configured to cooperate with a particle generator 1610 and, optionally, one or both of ultrasound imager 220 and microbubble delivery manager 240 provided by a third party. Controller 1630 may be implemented as a processor and a non-transitory memory having encoded therein machine-readable instructions that, upon execution by the processor, perform the functionality of controller 1630 as discussed above. Without departing from the scope hereof, this non-transitory memory with the machine-readable instructions encoded therein may be provided as a standalone software product configured for implementation on a third-party computer.

[00103] In modified embodiment, not depicted in FIG. 16, beam modulator 1624 is placed between source 1621 and radio-frequency cavity 1623. In this

embodiment, beam modulator 1624 selects segments of continuous particle beam 1611 for acceleration by radio-frequency cavity 1623 and subsequent delivery to patient 190. Each segment selected by beam modulator 1624 corresponds to one or more bunches of phase-bunched particle beam 1614, such that phase-bunched particle beam 1614 produced in this alternative embodiment has properties equivalent to phase-bunched particle beam 1614 produced in the embodiment depicted in FIG. 16.

[00104] FIG. 17 illustrates two particle generators 1700 and 1750 configured to produce phase-bunched particle beam 1614 characterized by a delivery frequency that is less than the frequency applied by radio-frequency cavity 1623. Each of particle generators 1700 and 1750 is an embodiment of particle generator 1610 that implements beam modulator 1624 as an electrostatic sweeper 1724. Electrostatic sweeper 1724 is an electrostatic octupole sweeper, for example. The positioning of electrostatic sweeper 1724 is different in particle generators 1700 and 1750. In particle generator 1700, electrostatic sweeper 1724 is positioned after particle accelerator 1622 and operates on phase-bunched particle beam 1612. In particle generator 1750, electrostatic sweeper 1724 is positioned between particle source 1621 and radio-frequency cavity 1623, such that electrostatic sweeper 1724 operates on continuous particle beam 1611. Particle generator 1750 may facilitate use of a less powerful electrostatic sweeper 1724, than that used in particle generator 1700, since continuous particle beam 1611 is less energetic than phase-bunched particle beam 1612.

[00105] In particle generator 1700, electrostatic sweeper 1724 applies a temporally varying electrostatic field (at the desired delivery frequency) to phase-bunched particle beam 1612 to select only some of particle bunches 1710, of phase-bunched particle beam 1612, for delivery to target tissue 192. Electrostatic sweeper 1724 may dump the remaining particle bunches 1710 or recirculate the remaining particle bunches 1710 in particle accelerator 1622. In the example depicted in FIG. 17, electrostatic sweeper 1724 selects two adjacent particle bunches 1710 for each particle bunch group 1716. Between each particle bunch group 1716, electrostatic sweeper 1724 deselects two adjacent particle bunches 1710. In this example, the resulting delivery frequency of phase-bunched particle beam 1614 is reduced by a factor of four relative to the frequency of particles bunches 1710 of phase-bunched particle beam 1612. However, the delivery dose is only reduced by a factor of two.

[00106] In particle generator 1750, electrostatic sweeper 1724 applies a temporally varying electrostatic field (at the desired delivery frequency) to continuous particle beam 1611 to select only certain segments of continuous particle beam 1611, for acceleration by radio-frequency cavity 1623 and delivery to target tissue 192.

Electrostatic sweeper 1724 may dump the remaining segments of continuous particle beam 1611. In the example depicted in FIG. 17, electrostatic sweeper 1724 selects segments 1751 of continuous particle beam 1611 that, after acceleration by radio- frequency cavity 1623 correspond to two adjacent particle bunches 1710 for each particle bunch group 1716. Between each selected segment 1751 , electrostatic sweeper 1724 deselects segments of similar length. In this example, the resulting delivery frequency of phase-bunched particle beam 1614 is reduced by a factor of four relative to the frequency that particles bunches 1710 of phase-bunched particle beam 1614 would have had in the absence of electrostatic sweeper 1724. However, the delivery dose is only reduced by a factor of two.

[00107] FIG. 18 illustrates one microbubble-enhanced particle treatment method 1800 that utilizes microbubble-enhanced ultrasound imaging to verify the range of a particle beam. Method 1800 may further utilize microbubble-enhanced ultrasound imaging to ensure that a sufficient amount of microbubbles are present in the target tissue. Method 1800 is similar to method 1300 and includes method 1400. Method 1800 is performed by particle treatment apparatus 1500 or 1600, for example. As compared to method 1300, method 1800 does not require (but may include) steps 1310 and 1320, method 1800 further includes step 1410, method 1800 replaces step 1330 with a step 1810, method 1800 replaces optional step 1360 with a required step 1860 that may include performing step 1410, and method 1800 requires steps 1240 and 1250.

[00108] Step 1810 performs ultrasound imaging of target tissue 192 to obtain range information from change in ultrasound image contrast due to destruction of at least some of microbubbles 140 by the particle beam. Step 1810 may be performed by ultrasound imager 220 in cooperation with controller 1530 or 1630. Step 1860 is similar to step 1360 except that step 1860 may include a step 1862 of performing step 1410, as discussed above in reference to FIGS. 14 and 15. Method 1800 performs step 1410 after verifying the range in decision step 1340 and, optionally, switching from a test beam to a treatment beam in step 1342. In embodiments of method 1800 where step 1860 includes step 1862, method 1800 merely continues the performance of step 1410 upon verifying the range in decision step 1340.

[00109] FIG. 19 illustrates one system 1900 for processing of microbubble- enhanced ultrasound images to verify the range of a particle beam in a particle treatment. System 1900 is an embodiment of controller 1030. System 1900 includes a processor 1910, a non-transitory memory 1920, and an interface 1990. Memory 1920 includes machine-readable instructions 1930 and a data storage 1980. Instructions 1930 include ultrasound imaging instructions 1932 and range evaluation instructions 1936.

[00110] Upon execution by processor 1910, ultrasound imaging instructions 1932 perform the functionality of ultrasound image acquisition controller 1032.

Ultrasound imaging instructions 1932 are configured to (a) communicate with an ultrasound imager (e.g., ultrasound imager 220) via interface 1990 and (b) store one or more ultrasound images 228 to data storage 1980. Ultrasound imaging instructions 1932 may include monitoring instructions 1934 that, upon execution by processor 1910, perform the functionality of monitoring unit 1040. [00111] Upon execution by processor 1910, range evaluation instructions 1936 perform the functionality of range evaluator 1034 based upon one or more ultrasound images 228 retrieved from data storage 1980.

[00112] Instructions 1930 may further include comparison instructions 1940 and notification instructions 1942 that, upon execution by processor 1910, perform the functionality of comparator 1036 and notifier 1038, respectively. Range evaluation instructions 1936 are configured to retrieve target range 1090 from data storage 1980 (or receive target range 1090 via interface 1990) to compare a particle beam range to target range 1090. Notification instructions 1942 are configured to output notifications via interface 1990.

[00113] In an embodiment, instructions 1930 also include one or both of wash- in evaluation instructions 1950 and wash-out evaluation instructions 1952 that, upon execution by processor 1910, perform the functionality of wash-in evaluator 1042 and wash-out evaluator 1044. Wash-in evaluation instructions 1950 and wash-out evaluation instructions 1952 may be configured to retrieve contrast thresholds 1986 from data storage 1980 or receive contrast thresholds 1986 via interface 1990.

[00114] In certain embodiments, instructions 1930 further include timing instructions 1960 that, upon execution by processor 1910, perform the functionality of timing module 1050.

[00115] FIG. 20 illustrates one system 2000 for enhancing particle treatment with particle-induced microbubble cavitation. System 2000 is an embodiment of controller 1630. System 2000 includes processor 1910, non-transitory memory 2020, and interface 1990. Memory 2020 includes machine-readable instructions 2030 and a data storage 2080. Instructions 2030 include bunch selection instructions 2032 that, upon execution by processor 1910, perform the functionality of bunch selector 1634. Bunch selection instructions 2032 are configured to communicate with a beam modulator (e.g., beam modulator 1624) via interface 1990 to impose a delivery frequency 2082 retrieved from data storage 2080 or received via interface 1990.

[00116] In an embodiment, instructions 2030 further include acceleration control instructions 2034 that, upon execution by processor 1910, perform the functionality of acceleration control unit 1632. Acceleration control instructions 2034 are configured to communicate with a radio-frequency cavity (e.g., radio-frequency cavity 1623) via interface 1990 to accelerate a continuous particle beam with an acceleration frequency 2084 retrieved from data storage 2080 or received via interface 1990.

[00117] Instructions 2030 may further include one or more of ultrasound imaging instructions 1932, range evaluation instructions 1936, comparison instructions 1940, notification instructions 1942, wash-in evaluation instructions 1950, wash-out evaluation instructions 1952, and timing instructions 1960, as discussed above in reference to FIG. 19.

[00118] FIG. 21 illustrates one system 2100 for processing microbubble- enhanced ultrasound images to assess a response of target tissue 192 to particle treatment. System 2100 is an embodiment of controller 230 configured to perform an embodiment of method 700 that includes steps 720 and 730. In certain embodiments, system 2100 implements an embodiment of controller 230 configured to further perform step 740 and, optionally, one or both of steps 740 and 750. In one embodiment, system 2100 forms an embodiment of controller 1030 configured to perform method 1300.

[00119] System 2100 includes processor 1910, non-transitory memory 2120, and interface 1990. Memory 2120 includes machine-readable instructions 2130 and a data storage 2180. Instructions 2130 include ultrasound imaging instructions 1932 with monitoring instructions 1934. Instructions 2130 also include (a) at least one of wash-in evaluation instructions 1950 and wash-out evaluation instructions 1952, and (b) response evaluation instructions 2154.

[00120] Upon execution by processor 1910, ultrasound imaging instructions 1932 and monitoring instructions 1934 perform steps 710 and 712, utilizing data storage 2180 for storage of ultrasound images 228. Upon execution by processor 1910, wash-in evaluation instructions 1950 and/or wash-out evaluation instructions 1952 (a) retrieve ultrasound images 228 from data storage, (b) perform step 720, and (c) store a wash-in rate 2182 and/or a wash-out rate 2184 to data storage 2180. Upon execution by processor 1910, response evaluation instructions 2154 perform step 730 based upon a wash- in rate 2182 and/or a wash-out rate 2184 retrieved from data storage 2180.

[00121] In an embodiment, instructions 2130 further include range evaluation instructions 1936, comparison instructions 1940, and notification instructions 1942 configured as discussed above in reference to FIG. 19. In an embodiment, execution by processor 1910 of ultrasound imaging instructions 1932 (including monitoring instructions 1934) and wash-in evaluation instructions 1950 may include performing steps 1310 and 1320.

[00122] Combinations of features

[00123] Features described above as well as those claimed below may be combined in various ways without departing from the scope hereof. For example, it will be appreciated that aspects of one system or method relating to particle therapy, described herein, may incorporate or swap features of another system or method relating to particle therapy described herein. The following examples illustrate possible, non-limiting combinations of embodiments described above. It should be clear that many other changes and modifications may be made to the systems and methods described herein without departing from the spirit and scope of this invention:

[00124] (Al) A particle beam range verification method may include (a) acquiring at least one ultrasound image of target tissue that has been exposed to a particle beam, wherein the target tissue contains microbubbles that enhance contrast of the ultrasound image, and obtaining range information for the particle beam from change in the contrast due to destruction of at least some of the microbubbles by the particle beam.

[00125] (A2) The method denoted as (Al) may further include (i) based upon the range information, determining if range of the particle beam matches a target range associated with at least a portion of the target tissue, and (ii) if the range of the particle beam deviates from the target range, communicating with a particle generator that produces the particle beam.

[00126] (A3) The method denoted as (A2) may include repeating the steps of acquiring and obtaining for each of a plurality of tissue layers treated by successive exposures of the target tissue to the particle beam, and notifying the particle generator for each tissue layer where the range information indicates that the range of the particle beam deviates from the target range.

[00127] (A4) Either of the methods denoted as (A2) and (A3) may further include, upon communicating with the particle generator, halting, adjusting, or halting and adjusting exposure of a patient, associated with the target tissue, to the particle beam.

[00128] (A5) In any of the methods denoted as (Al) through (A4), the step of acquiring may include acquiring a first ultrasound image of the target tissue prior to an exposure of the target tissue to the particle beam, acquiring a second ultrasound image of the target tissue after the exposure, and comparing the first and second ultrasound images to determine the change in the contrast.

[00129] (A6) The method denoted as (A5) may include acquiring each of the first and second ultrasound images within less than 0.1 seconds of the exposure, to minimize flow of the microbubbles between acquisition of the first and second ultrasound image.

[00130] (A7) In any of the methods denoted as (Al) through (A6), the step of obtaining may include attributing a local decrease in ultrasound signal from the target tissue to destruction of at least some of the microbubbles by the particle beam, wherein the local decrease is ascertained from the at least one ultrasound image.

[00131] (A8) In the method denoted as (A7), the step of obtaining may include comparing different spatial regions of a single ultrasound image to ascertain the local decrease, the single ultrasound image being one of the at least one ultrasound image.

[00132] (A9) In the method denoted as (A18), the step of acquiring may include acquiring the single ultrasound image within 0.1 seconds of the exposure, to minimize flow of the microbubbles between the exposure and acquisition of the single ultrasound image.

[00133] (A10) Any of the methods denoted as (Al) through (A9) may further include monitoring, via ultrasound imaging, wash-in of the microbubbles to the target tissue, and, when ultrasound contrast observed in the step of monitoring exceeds a threshold contrast, communicating an output signal to a particle generator configured to produce the particle beam.

[00134] (Al l) The method denoted as (A10) may further include initiating exposure of patient, associated with the target tissue, to the particle beam upon receipt of the output signal by the particle generator.

[00135] (A12) Any of the methods denoted as (Al) through (Al l) may further include acquiring an ultrasound image series of the target tissue during at least one of wash-in rate of the microbubbles to the target tissue and wash-out of the microbubbles from the target tissue to determine at least one of a wash-in rate and a wash-out rate.

[00136] (A13) Any of the methods denoted as (Al) through (A12) may further include recording a pre-treatment microbubble-enhanced ultrasound image prior to commencing at least a portion of a particle treatment session utilizing the range information, capturing a subsequent microbubble-enhanced ultrasound image during or after the portion of the particle treatment session, and comparing the subsequent microbubble-enhanced ultrasound image to the pre-treatment microbubble-enhanced ultrasound image to evaluate response of the target tissue to the portion of the particle treatment session.

[00137] (A14) In the method denoted as (A13), the portion of the particle treatment session may include one particle treatment fraction of a hypofractionated particle treatment plan.

[00138] (A15) In the method denoted as (A13), the portion of the particle treatment session may be one of a plurality of particle beam exposures associated with treatment of a respective plurality of layers of the target tissue.

[00139] (A16) In any of the methods denoted as (A13) through (A15), the step of comparing may further include evaluating response of non-target tissue to the particle beam.

[00140] (A17) In any of the methods denoted as (Al) through (A16), the particle beam may be a continuous particle beam or a phase-bunched particle beam.

[00141] (A18) In any of the methods denoted as (Al) through (A17), in the step of acquiring, the at least one ultrasound image may be a two-dimensional ultrasound image of layer that intersects the particle beam.

[00142] (A19) In any of the methods denoted as (Al) through (A17), in the step of acquiring, the at least one ultrasound image may be a two-dimensional ultrasound image of layer that contains the particle beam for an extended propagation length of the particle beam.

[00143] (A20) In any of the methods denoted as (Al) through (A17)„ in the step of acquiring, the at least one ultrasound image may be a three-dimensional ultrasound image.

[00144] (A21) In the method denoted as (A20), the step of acquiring may include acquiring a series of two-dimensional ultrasound images to compose the three- dimensional ultrasound image.

[00145] (A22) Any of the methods denoted as (Al) through (A21) may further include exposing the target tissue to the particle beam, wherein the step of exposing includes breaking at least some of the microbubbles to release, to the target tissue, drugs carried by microbubbles, and wherein the drugs being configured to enhance damage to the target tissue from exposure to the particle beam. [00146] (A23) Any of the methods denoted as (Al) through (A22) may further include, after the step of obtaining range information, applying ultrasound to the microbubbles to break the microbubbles and thereby release, to the target tissue, drugs carried by the microbubbles, to enhance damage to the target tissue from exposure to the particle beam.

[00147] (A24) In any of the methods denoted as (Al) through (A23), the microbubbles and the particle beam may be cooperatively configured to reach threshold for said destruction at a first distance from Bragg peak of the particle beam, wherein the first distance is in range between 5 and 10 millimeters.

[00148] (A25) In the method denoted as (A24), the microbubbles may be gas- filled or air-filled bubbles with monolayer lipid shells, the particle beam being a proton beam.

[00149] (Bl) A particle treatment method may include delivering microbubbles to target tissue, and exposing the target tissue to a particle beam to cause damage to the target tissue, wherein the damage includes damage caused by destruction of at least some of the microbubbles by the particle beam.

[00150] (B2) In the method denoted as (Bl), the microbubbles may carry drugs, and the step of exposing may further include releasing, upon the destruction, the drugs to the target tissue to chemically enhance the damage.

[00151] (B3) Either of the methods denoted as (Bl) and (B2) may further include monitoring wash-in of the microbubbles to the target tissue with ultrasound images, and, if a threshold amount of the microbubbles are present in the target tissue, as evidence by the ultrasound images, communicating a trigger signal to a particle generator, configured to produce the particle beam, so as to initiate the step of exposing.

[00152] (B4) Any of the methods denoted as (Bl) through (B3) may further include acquiring an ultrasound image series of the target tissue during at least one of wash-in of the microbubbles to the target tissue and wash-out of the microbubbles from the target tissue.

[00153] (B5) In any of the methods denoted as (Bl) through (B4), the step of exposing may further include mechanically damaging the target tissue by inducing cavitation of at least some of the microbubbles with the particle beam. [00154] (B6) In the method denoted as (B5), the microbubbles may carry drugs, and the step of exposing may further include releasing, upon the cavitation, the drugs to the target tissue to chemically enhance the damage.

[00155] (B7) In either of the methods denoted as (B5) and (B6), the particle beam may be a continuous particle beam or a phase-bunched particle beam, and the step of exposing may include inducing, for each of at least some of the microbubbles, the cavitation when one or more particles of the particle beam pass through the microbubble.

[00156] (B8) In any of the methods denoted as (B5) through (B7), the particle beam may be a continuous particle beam or a phase-bunched particle beam, and the step of exposing may include, for each of at least some of the microbubbles, inducing the cavitation by deforming the microbubble with a pressure pulse generated by deceleration of one or more particles of the particle beam.

[00157] (B9) Any of the methods denoted as (B5) through (B8) may further include radio-frequency accelerating particles to generate a phase-bunched particle beam, and, in the step of exposing, delivering a series of particle bunches of the particle beam to the target tissue at a delivery frequency that resonantly drives oscillation of at least some of the microbubbles to induce said cavitation thereof.

[00158] (B10) In the method denoted as (B9), the delivery frequency may be in the range between 1 and 5 MHz.

[00159] (Bl 1) The method denoted as (B9) may further include (a) in the step of radio-frequency accelerating particles, applying a radio frequency to a continuous particle beam to generate a phase-bunched particle beam with an initial series of particle bunches, wherein the radio-frequency is greater than the delivery frequency, and (b) sweeping the phase-bunched particle beam at the delivery frequency to select only a subset of the initial series of particle bunches for delivery to the target tissue, wherein the subset includes a modulated series of particle bunches and the modulated series includes a regularly repeating pattern of particle bunches that repeats itself at the delivery frequency.

[00160] (B12) In the method denoted as (Bl 1), the radio frequency may be in the range between 8 and 100 MHz, and the delivery frequency may be in the range between 1 and 5 MHz.

[00161] (B13) The method denoted as (B9) may further include (a) sweeping a continuous particle beam to select, at the delivery frequency, segments of the continuous particle beam, and (b) in the step of radio-frequency accelerating particles after the step of sweeping, applying a radio frequency to each of the segments to generate a phase- bunched particle beam, wherein the radio-frequency is greater than the delivery frequency and the phase-bunched particle beam including a series of groups of particle bunches, wherein each of the groups is formed from a respective one of the segments.

[00162] (B14) In the method denoted as (B13), the radio frequency may be in the range between 8 and 100 MHz, and the delivery frequency may be in the range between 1 and 5 MHz.

[00163] (B 15) Any of the methods denoted as (B 1 ) through (B 14) may further include ultrasound imaging the target tissue to obtain range information from change in ultrasound image contrast due to destruction of at least some of the microbubbles by the particle beam.

[00164] (B16) In any of the methods denoted as (Bl) through (B15), the microbubbles and the particle beam may be cooperatively configured to reach threshold for the destruction at a first distance from Bragg peak of the particle beam, wherein the first distance is in the range between 5 and 10 millimeters.

[00165] (B17) In the method denoted as (B16), the microbubbles may be gas- filled or air-filled bubbles with monolayer lipid shells, and the particle beam may be a proton beam.

[00166] (CI) A microbubble-enhanced ultrasound imaging method may include acquiring an ultrasound image series of target tissue during at least one of wash-in of microbubbles to the target tissue and wash-out of the microbubbles from the target tissue, and deriving, from the ultrasound image series, at least one of a wash-in rate and a wash-out rate indicating response of target tissue to particle treatment.

[00167] (C2) The method denoted as (CI) may further include evaluating the response of the target tissue to the particle treatment based upon at least one of the wash- in rate and the wash-out rate.

[00168] (Dl) A range verification system may include machine-readable instructions encoded in non-transitory memory, wherein the machine-readable instructions are configured to, upon execution by at least one processor, (a) command an ultrasound imager to acquire at least one ultrasound image of target tissue that has been exposed to a particle beam, and (b) determine range information for the particle beam from change in contrast of the at least one ultrasound image due to destruction, by the particle beam, of microbubbles deposited in the target tissue. [00169] (D2) The system denoted as (Dl) may further include the ultrasound imager.

[00170] (D3) In either of the systems denoted as (Dl) and (D2), the machine- readable instructions may further include instructions that, upon execution by the at least one processor, (i) determine if range of the particle beam matches a target range associated with at least a portion of the target tissue, and (ii) notify a particle generator producing the particle beam when the range of the particle beam deviates from the target range.

[00171] (D4) In any of the systems denoted as (Dl) through (D3), the machine- readable instructions may further include imaging instructions that, when executed by the at least one processor and upon receiving a signal indicating that microbubbles have been administered to patient associated with the target tissue, (I) command the ultrasound imager to image wash-in of the microbubbles to the target tissue, (II) monitor contrast in the ultrasound images during the wash-in, and (III) when the contrast reaches a threshold contrast, generate a trigger signal.

[00172] (D5) A particle treatment system may include the range verification systems denoted as (D4) and a particle generator for generating the particle beam according to the trigger signal.

[00173] (D6) A particle treatment system may include any of the range verification systems denoted as (Dl) through (D4) and a particle generator for generating the particle beam.

[00174] (El) A system for enhancing particle treatment with particle-induced microbubble cavitation may include machine-readable instructions encoded in non- transitory memory, that, upon execution by at least one processor, command a beam modulator to deliver a series of particle bunches, of a phase-bunched particle beam, to the target tissue at a delivery frequency that resonantly drives oscillation of at least some of the microbubbles to induce cavitation thereof.

[00175] (E2) In the system denoted as (El), the machine-readable instructions may be configured to command the beam modulator to select, for delivery to the target tissue, only a subset of an initial series of particle bunches of the phase-bunched particle beam, wherein the subset includes a modulated series of particle bunches and the modulated series includes a regularly repeating pattern of particle bunches that repeats itself at the delivery frequency [00176] (E3) In either of the systems denoted as (El) and (E2), the machine- readable instructions may be configured to set the delivery frequency in range between 1 and 5 MHz.

[00177] (E4) Any of the systems denoted as (El) through (E3) may further include the beam modulator, wherein the beam modulator is an electrostatic sweeper.

[00178] (E5) A particle treatment system may include any of the systems denoted as (El) through (E4) and a particle accelerator configured to generate the phase- bunched particle beam.

[00179] (E6) In the particle treatment system denoted as (E5), the machine- readable instructions may further include instructions that, when executed by the at least one processor, command a radio-frequency cavity of the particle accelerator to operate at a radio-frequency that exceeds the delivery frequency.

[00180] (E7) In the particle treatment system denoted as (E6), the radio frequency may be in the range between 8 and 100 MHz, and the delivery frequency may be in the range between 1 and 5 MHz.

[00181] (Fl) A microbubble-enhanced ultrasound imaging system for assessing response of target tissue to particle treatment may include machine-readable instructions encoded in non-transitory memory, that, upon execution by at least one processor, (a) command an ultrasound imager to acquire an ultrasound image series of target tissue during at least one of wash-in of microbubbles to the target tissue and wash-out of the microbubbles from the target tissue, and (b) derive at least one of a wash-in rate and a wash-out rate from the ultrasound image series.

[00182] (F2) In the system denoted as (Fl), the machine-readable instructions may further include instructions that, when executed by the at least one processor, assess response of the target tissue to the particle treatment based upon at least one of the wash- in rate and the wash-out rate.

[00183] (F3) Either of the systems denoted as (Fl) and (F2) may further include the ultrasound imager.

[00184] Changes may be made in the above systems and methods without departing from the scope hereof. It should thus be noted that the matter contained in the above description and shown in the accompanying drawings should be interpreted as illustrative and not in a limiting sense. The following claims are intended to cover generic and specific features described herein, as well as all statements of the scope of the present systems and methods, which, as a matter of language, might be said to fall therebetween.

Claims

CLAIMS What is claimed is:

1. A particle beam range verification method, comprising:

acquiring at least one ultrasound image of target tissue that has been exposed to a particle beam, the target tissue containing microbubbles that enhance contrast of the ultrasound image; and

obtaining range information for the particle beam from change in the contrast due to destruction of at least some of the microbubbles by the particle beam.

2. The method of claim 1, further comprising:

based upon the range information, determining if range of the particle beam

matches a target range associated with at least a portion of the target tissue; and

if the range of the particle beam deviates from the target range, communicating with a particle generator that produces the particle beam.

3. The method of claim 2, comprising:

repeating the steps of acquiring and obtaining for each of a plurality of tissue layers treated by successive exposures of the target tissue to the particle beam; and

notifying the particle generator for each tissue layer where the range information indicates that the range of the particle beam deviates from the target range.

4. The method of claim 2, further comprising, upon communicating with the particle generator, halting, adjusting, or halting and adjusting exposure of a patient, associated with the target tissue, to the particle beam.

5. The method of claim 1, the step of acquiring comprising:

acquiring a first ultrasound image of the target tissue prior to an exposure of the target tissue to the particle beam;

acquiring a second ultrasound image of the target tissue after the exposure; and comparing the first and second ultrasound images to determine the change in the contrast.

6. The method of claim 5, comprising acquiring each of the first and second ultrasound images within less than 0.1 seconds of the exposure, to minimize flow of the microbubbles between acquisition of the first and second ultrasound image.

7. The method of claim 1, the step of obtaining comprising attributing a local decrease in ultrasound signal from the target tissue to destruction of at least some of the microbubbles by the particle beam, the local decrease being ascertained from the at least one ultrasound image.

8. The method of claim 7, the step of obtaining comprising comparing different spatial regions of a single ultrasound image to ascertain the local decrease, the single ultrasound image being one of the at least one ultrasound image.

9. The method of claim 8, the step of acquiring comprising acquiring the single ultrasound image within 0.1 seconds of the exposure, to minimize flow of the microbubbles between the exposure and acquisition of the single ultrasound image.

10. The method of claim 1, further comprising:

monitoring, via ultrasound imaging, wash-in of the microbubbles to the target tissue; and

when ultrasound contrast observed in the step of monitoring exceeds a threshold contrast, communicating an output signal to a particle generator configured to produce the particle beam.

11. The method of claim 10, further comprising initiating exposure of patient, associated with the target tissue, to the particle beam upon receipt of the output signal by the particle generator.

12. The method of claim 1, further comprising acquiring an ultrasound image series of the target tissue during at least one of wash-in rate of the microbubbles to the target tissue and wash-out of the microbubbles from the target tissue to determine at least one of a wash-in rate and a wash-out rate.

13. The method of claim 1, further comprising: recording a pre-treatment microbubble-enhanced ultrasound image prior to commencing at least a portion of a particle treatment session utilizing the range information;

capturing a subsequent microbubble-enhanced ultrasound image during or after the portion of the particle treatment session; and

comparing the subsequent microbubble-enhanced ultrasound image to the pre- treatment microbubble-enhanced ultrasound image to evaluate response of the target tissue to the portion of the particle treatment session.

14. The method of claim 13, the portion of the particle treatment session being one particle treatment fraction of a hypofractionated particle treatment plan.

15. The method of claim 13, the portion of the particle treatment session being one of a plurality of particle beam exposures associated with treatment of a respective plurality of layers of the target tissue.

16. The method of claim 13, the step of comparing further comprising evaluating response of non-target tissue to the particle beam.

17. The method of claim 1, the particle beam being a continuous particle beam or a phase-bunched particle beam.

18. The method of claim 1, in the step of acquiring, the at least one ultrasound image being a two-dimensional ultrasound image of layer that intersects the particle beam.

19. The method of claim 1, in the step of acquiring, the at least one ultrasound image being a two-dimensional ultrasound image of layer that contains the particle beam for an extended propagation length of the particle beam.

20. The method of claim 1, in the step of acquiring, the at least one ultrasound image being a three-dimensional ultrasound image.

21. The method of claim 20, the step of acquiring comprising acquiring a series of two-dimensional ultrasound images to compose the three-dimensional ultrasound image.

22. The method of claim 1, further comprising exposing the target tissue to the particle beam, the step of exposing including breaking at least some of the microbubbles to release, to the target tissue, drugs carried by microbubbles, the drugs being configured to enhance damage to the target tissue from exposure to the particle beam.

23. The method of claim 1, further comprising, after the step of obtaining range information, applying ultrasound to the microbubbles to break the microbubbles and thereby release, to the target tissue, drugs carried by the microbubbles, to enhance damage to the target tissue from exposure to the particle beam.

24. The method of claim 1, the microbubbles and the particle beam being cooperatively configured to reach threshold for said destruction at a first distance from Bragg peak of the particle beam, the first distance being in range between 5 and 10 millimeters.

25. The method of claim 24, the microbubbles being gas-filled or air- filled bubbles with monolayer lipid shells, the particle beam being a proton beam.

26. A particle treatment method, comprising:

delivering microbubbles to target tissue; and

exposing the target tissue to a particle beam to cause damage to the target tissue, the damage including damage caused by destruction of at least some of the microbubbles by the particle beam.

27. The method of claim 26, the microbubbles carrying drugs, the step of exposing further comprising releasing, upon said destruction, the drugs to the target tissue to chemically enhance the damage.

28. The method of claim 26, further comprising:

monitoring wash-in of the microbubbles to the target tissue with ultrasound

images; and

if a threshold amount of the microbubbles are present in the target tissue, as

evidence by the ultrasound images, communicating a trigger signal to a particle generator, configured to produce the particle beam, so as to initiate the step of exposing.

29. The method of claim 28, further comprising acquiring an ultrasound image series of the target tissue during at least one of wash-in of the microbubbles to the target tissue and wash-out of the microbubbles from the target tissue.

30. The method of claim 26, the step of exposing further comprising mechanically damaging the target tissue by inducing cavitation of at least some of the microbubbles with the particle beam.

31. The method of claim 30, the microbubbles carrying drugs, the step of exposing further comprising releasing, upon said cavitation, the drugs to the target tissue to chemically enhance the damage.

32. The method of claim 30, the particle beam being a continuous particle beam or a phase-bunched particle beam, the step of exposing comprising inducing, for each of at least some of the microbubbles, said cavitation when one or more particles of the particle beam pass through the microbubble.

33. The method of claim 30, the particle beam being a continuous particle beam or a phase-bunched particle beam, the step of exposing comprising, for each of at least some of the microbubbles, inducing said cavitation by deforming the microbubble with a pressure pulse generated by deceleration of one or more particles of the particle beam.

34. The method of claim 30, further comprising:

radio-frequency accelerating particles to generate a phase-bunched particle beam; and

in the step of exposing, delivering a series of particle bunches, of the particle beam, to the target tissue at a delivery frequency that resonantly drives oscillation of at least some of the microbubbles to induce said cavitation thereof.

35. The method of claim 34, the delivery frequency being in range between 1 and 5 MHz.

36. The method of claim 34, further comprising: in the step of radio-frequency accelerating particles, applying a radio frequency to a continuous particle beam to generate a phase-bunched particle beam with an initial series of particle bunches, the radio-frequency being greater than the delivery frequency; and

sweeping the phase-bunched particle beam at the delivery frequency to select only a subset of the initial series of particle bunches for delivery to the target tissue, the subset including a modulated series of particle bunches, the modulated series including a regularly repeating pattern of particle bunches that repeats itself at the delivery frequency.

37. The method of claim 36, the radio frequency being in range between 8 and 100 MHz, the delivery frequency being in range between 1 and 5 MHz.

38. The method of claim 34, further comprising:

sweeping a continuous particle beam to select, at the delivery frequency, segments of the continuous particle beam; and

in the step of radio-frequency accelerating particles after the step of sweeping, applying a radio frequency to each of the segments to generate a phase- bunched particle beam, the radio-frequency being greater than the delivery frequency, the phase-bunched particle beam including a series of groups of particle bunches, each of the groups being formed from a respective one of the segments.

39. The method of claim 38, the radio frequency being in range between 8 and 100 MHz, the delivery frequency being in range between 1 and 5 MHz.

40. The method of claim 26, further comprising ultrasound imaging the target tissue to obtain range information from change in ultrasound image contrast due to destruction of at least some of the microbubbles by the particle beam.

41. The method of claim 26, the microbubbles and the particle beam being cooperatively configured to reach threshold for said destruction at a first distance from Bragg peak of the particle beam, the first distance being in range between 5 and 10 millimeters.

42. The method of claim 41 , the microbubbles being gas-filled or air- filled bubbles with monolayer lipid shells, the particle beam being a proton beam.

43. A microbubble-enhanced ultrasound imaging method, comprising:

acquiring an ultrasound image series of target tissue during at least one of wash-in of microbubbles to the target tissue and wash-out of the microbubbles from the target tissue; and

deriving, from the ultrasound image series, at least one of a wash-in rate and a wash-out rate indicating response of target tissue to particle treatment.

44. The method of claim 43, further comprising evaluating the response of the target tissue to the particle treatment based upon at least one of the wash-in rate and the wash-out rate.

45. A range verification system, comprising machine-readable instructions encoded in non-transitory memory, the machine-readable instructions being configured to, upon execution by at least one processor:

command an ultrasound imager to acquire at least one ultrasound image of target tissue that has been exposed to a particle beam; and

determine range information for the particle beam from change in contrast of the at least one ultrasound image due to destruction, by the particle beam, of microbubbles deposited in the target tissue.

46. The system of claim 45, further comprising the ultrasound imager.

47. The system of claim 45, the machine-readable instructions further comprising instructions that, upon execution by the at least one processor:

determine if range of the particle beam matches a target range associated with at least a portion of the target tissue; and

notify a particle generator producing the particle beam when the range of the particle beam deviates from the target range.

48. The system of claim 45, the machine-readable instructions further comprising imaging instructions that, when executed by the at least one processor and upon receiving a signal indicating that microbubbles have been administered to patient associated with the target tissue: command the ultrasound imager to image wash-in of the microbubbles to the target tissue;

monitor contrast in the ultrasound images during the wash-in; and

when the contrast reaches a threshold contrast, generate a trigger signal.

49. A particle treatment system, comprising:

the range verification system of claim 48; and

a particle generator for generating the particle beam according to the trigger signal.

50. The system of claim 49, further comprising the ultrasound imager.

51. A particle treatment system, comprising:

the range verification system of claim 45 ; and

a particle generator for generating the particle beam.

52. The system of claim 51, further comprising the ultrasound imager.

53. A system for enhancing particle treatment with particle- induced microbubble cavitation, comprising machine-readable instructions encoded in non- transitory memory, that, upon execution by at least one processor:

command a beam modulator to deliver a series of particle bunches, of a phase- bunched particle beam, to the target tissue at a delivery frequency that resonantly drives oscillation of at least some of the microbubbles to induce cavitation thereof.

54. The system of claim 53, the machine-readable instructions being configured to command the beam modulator to select, for delivery to the target tissue, only a subset of an initial series of particle bunches of the phase-bunched particle beam, the subset including a modulated series of particle bunches, the modulated series including a regularly repeating pattern of particle bunches that repeats itself at the delivery frequency.

55. The system of claim 53, the machine-readable instructions being configured to set the delivery frequency in range between 1 and 5 MHz.

56. The system of claim 53, further comprising the beam modulator, the beam modulator being an electrostatic sweeper.

57. A particle treatment system, comprising:

the system of claim 56; and

a particle accelerator configured to generate the phase-bunched particle beam.

58. The particle treatment system of claim 57, the machine-readable instructions further comprising instructions that, when executed by the at least one processor, command a radio-frequency cavity of the particle accelerator to operate at a radio-frequency that exceeds the delivery frequency.

59. The particle treatment system of claim 58, the radio frequency being in range between 8 and 100 MHz, the delivery frequency being in range between 1 and 5 MHz.

60. A microbubble-enhanced ultrasound imaging system for assessing response of target tissue to particle treatment, comprising machine-readable instructions encoded in non-transitory memory, that, upon execution by at least one processor:

command an ultrasound imager to acquire an ultrasound image series of target tissue during at least one of wash-in of microbubbles to the target tissue and wash-out of the microbubbles from the target tissue; and derive at least one of a wash-in rate and a wash-out rate from the ultrasound image series.

61. The system of claim 60, the machine-readable instructions further comprising instructions that, when executed by the at least one processor, assess response of the target tissue to the particle treatment based upon at least one of the wash-in rate and the wash-out rate.

62. The system of claim 60, further comprising the ultrasound imager.