WO2025096567A1 - In-beam scanner for proton flash radiotherapy - Google Patents

Abstract

An in-beam scanner for measuring in-spill prompt gamma events and post-spill positron emission events during proton FLASH radiotherapy (FLASH RT). The in-beam scanner may have a cylindrical shape that defines a central bore extending parallel with a longitudinal axis of the in-beam scanner, wherein a target of the proton FLASH RT is configured to be positioned within the central bore of the in-beam scanner for receiving radiation. The in-beam scanner may include a first detector array comprising a first plurality of detectors arranged annularly that has an inner-facing detecting surface that faces the longitudinal axis. The in-beam scanner may include a collimator removably positioned within the central bore and thereby covering the inner-facing detecting surface of each detector of the first detector array.

Description

IN-BEAM SCANNER FOR PROTON FLASII K \mu i tit K \n

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Patent Application No.

63/594,113, filed October 30, 2023, entitled “IN-BEAM SCANNER FOR PROTON FLASH RADIOTHERAPY,” which is expressly incorporated herein by reference in its entirety.

BACKGROUND

[0002] It is broadly acknowledged that proton therapy has not yet delivered on its potential and promises despite that it is generally considered to be the future of radiation oncology. Medical accelerators and beam delivery have gone through several hardware and software transformations. Treatment planning is now a complex, sophisticated and well-established multi-step process assisted by advances in the software modeling of beam interactions in phantoms and patients. However, the in vivo accuracy and related functional imaging efficacy of each irradiation (e.g., proton range verification) has not kept up at the same pace of these developments.

[0003] FLASH therapy or FLASH radiotherapy (FLASH RT) is a modality of ultra-high dose of up to about tens of grays (Gy) delivered in milliseconds or even shorter beam extraction times. It offers unique imaging opportunities and an instantaneous dose rate that is several orders of magnitude higher than what is currently used in conventional clinical radiotherapy. Radiation delivered at high dose rates and high doses (i.e., the FLASH modality) eradicates cancer tissues as well as conventional radiotherapy in which the beam is extracted over tens of seconds, but better spares healthy tissues, as demonstrated in extensive animal studies. Although the same delivered dose can be delivered at conventional and FLASH rates, the biological response of live tissues is different. FLASH delivered radiation differentially better spares healthy tissues over cancer tissues, which is known as the FLASH effect. This difference is yet to be understood. Since it is practically impossible to study how FLASH alters individual cells in patients and animals, current studies have focused on evaluating the recipient’s organs or survival. This is a major weakness of many of the FLASH studies, which are unable to conduct microdosimetry and imaging to identify and assess sub-regions within an organ where FLASH led to less damage and other sub-regions where FLASH didn’t protect. [0004] The FLASH treatment technique has the potentie oncology, thus has received tremendous amounts of attention and is vigorously pursued by many clinical research groups. However, the method must rigorously demonstrate that such radiation delivery indeed reduces the normal tissue toxicities, commonly associated with conventional radiotherapy, and is effective in tumor eradication. The underlying biomedical mechanism responsible for the FLASH positive effects must be understood and fully elucidated if the therapy is to be fully exploited and adopted. But even before then, the impact on medical personnel and instrumentation must be fully characterized so that such fast extraction can be safely experimented with and can ultimately be routinely employed in therapy.

[0005] In proton radiation therapy, protons activate elements in a tissue and create excited or new nuclides, many of them unstable. Excited nuclei and new isotopes emit gamma rays that originate from de-excitation of various nuclei resulting from the proton bombardment. Some new nuclides are positron emitters that initiate positron-electron annihilations. Deexcitations are fast and generate mostly uncorrelated single fast (prompt) gammas of multitude of energies. Positron-emitters (PE) are activated isotopes that undergo a P⁺ decay with a characteristic half-life ranging from seconds to hours, and yield a pair of gammas, each of energy equal to the electron or positron mass of 511 keV. Prompt gamma imaging (PGI) is accomplished by a single photon emission computed tomography (SPECT) camera. Positron emission tomography (PET) exploits the physics of annihilation that yields back-to- back gammas of known energies.

[0006] The amount and the character of radiation emitted by a beam-activated tissue strictly correlates with the quantity of energy and the localization of an impinging beam. By conducting the dosimetry and imaging of the irradiated live tissues one provides a direct feedback regarding where and how much energy was delivered by a therapeutic beam.

SUMMARY

[0007] Described herein is an in-beam scanner for measuring in-spill prompt gamma events and post-spill positron emission events during proton FLASH radiotherapy (FLASH RT). The term “in-beam” refers to the situation that a scanner operates (can acquire data) during the delivery (spill) of therapeutic beam. The in-beam scanner may have a cylindrical shape that defines a central bore extending parallel with a longitudinal axis of the in-beam scanner, wherein a target of the proton FLASH RT is configured to be positioned within the central bore of the in-beam scanner for receiving radiation. It maj conformal alignment with a body. Specifically, flat panels of PET/PGI/SPECT tomography could be also constructed. With time-of-flight and depth-of-interaction features of a scanner, the fidelity of imaging and dosimetry is robust and the detector geometry is more tolerant of imperfect positioning with respect to a body. Smaller panels may be employed as inserts into larger commercial systems to serve as effective “magnifying glass” of improved sensitivity.

[0008] In accordance with an aspect of the disclosure, the in-beam scanner may include a first detector array comprising a first plurality of detectors arranged annularly, wherein the first detector array defines at least a portion of the cylindrical shape of the in-beam scanner, wherein each detector of the first detector array has an inner-facing detecting surface that faces the longitudinal axis, and wherein the inner-facing detecting surface defines a portion of the central bore; and a collimator removably positioned within the central bore and thereby covering the inner-facing detecting surface of each detector of the first detector array. Depending on the targeted area, a gap may be introduced in the scanner to provide a beam access.

[0009] The collimator may be configured to be: (i) installed within the central bore of the in-beam scanner during a first phase of FLASH RT treatment such that the plurality of detectors can detect in-spill prompt gamma events, and (ii) removed from within the central bore of the in-beam scanner during a second phase of FLASH RT treatment such that the plurality of detectors can detect post-spill positron emission events.

[0010] In accordance with another aspect of the disclosure, a method of measuring in-spill prompt gamma events and post-spill positron emission event during FLASH radiotherapy (FLASH RT) using an in-beam scanner is provided using the in-beam scanner. The method includes positioning a target within the central bore of the in-beam scanner; a delivering, to the target, a proton treatment beam at an ultra-high dose and ultra-high rate; detecting, during a first time period, in-spill prompt gamma events using the first detector array, wherein the collimator is positioned within the central bore during the first time period; removing the collimator from within the central bore of the in-beam scanner; and detecting, during a second time period which is after the first time period, post-spill positron emission events using the first detector array.

[0011] This summary is provided to introduce a selection of concepts in a simplified form that is further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed si be used to limit the scope of the claimed subject matter.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The foregoing summary, as well as the following detailed description of illustrative implementations, is better understood when read in conjunction with the appended drawings. To illustrate the implementations, there are shown in the drawings example constructions; however, the implementations are not limited to the specific methods and instrumentalities disclosed. In the drawings:

[0013] FIG. 1 A illustrates an example FLASH-compatible hybrid PET/PGI/SPECT brain scanner in accordance with aspects of the present disclosure;

[0014] FIG. IB illustrates an example collimator for use within the scanner of FIG. 1 A in accordance with aspects of the present disclosure;

[0015] FIG. 2 illustrates additional details of removeable chin and crown sections of the scanner of FIGS. 1A and IB in accordance with aspects of the present disclosure;

[0016] FIG. 3 illustrates a perspective view of the scanner shown in a first clinical setting in accordance with aspects of the present disclosure;

[0017] FIG. 4 illustrates a top-down view of the scanner shown in the first clinical setting in accordance with aspects of the present disclosure;

[0018] FIG. 5 illustrates another perspective view of the scanner shown in the first clinical setting in accordance with aspects of the present disclosure;

[0019] FIG. 6 illustrates a side view of the scanner shown in the first clinical setting in accordance with aspects of the present disclosure;

[0020] FIG. 7 illustrates another perspective view of the scanner shown in the first clinical setting in accordance with aspects of the present disclosure;

[0021] FIG. 8 illustrates a perspective view of the scanner in a housing shown in a second clinical setting in accordance with aspects of the present disclosure;

[0022] FIG. 9 illustrates a perspective view of the scanner in the housing and a patient’s head shown in the second clinical setting in accordance with aspects of the present disclosure; [0023] FIGS. 10A and 10B illustrate the scanner configi third clinical setting in accordance with aspects of the present disclosure;

[0024] FIGS. 11 A, 1 IB, and 11C illustrate the scanner in a fourth clinical setting in accordance with aspects of the present disclosure;

[0025] FIG. 12 is an example operational flow using the scanner in accordance with aspects of the present disclosure; and

[0026] FIG. 13 is an example computing device in accordance with aspects of the present disclosure.

DETAILED DESCRIPTION

[0027] Introduction

[0028] Therapy with a FLASH beam requires a high accuracy of beam delivery and precise monitoring of its effects. A FLASH “shot” creates two distinct time scales and emission types. During a spill, lasting a fraction of a second, radiation is dominated by prompt gammas emitted from a number of activated nuclides. Positron-emitting isotopes are also created by protons and their activity extends past the spill time so data can be collected over minutes. Using in-spill events offers prompt-gamma imaging (PGI) by single-photon emission computed tomography (SPECT) and the post-spill data allows PET imaging. The PGI/SPECT is an in-spill snapshot of activation while PET imaging follows the evolution of the initial activation over time. The in-beam PET/PGI/SPECT imaging and dosimetry of FLASH proton beams have not been attempted despite that they offer immediate assessment of the irradiation and can guide the follow-up treatment. An adaptive FLASH therapy may not only improve the therapy outcome of individual patients but is likely to increase the patient throughput thus may extend such treatment to a much broader population of patients.

[0029] However, before FLASH can be routinely employed in the clinic, the biomedical mechanisms underlying the FLASH effect need to be better understood, that it does indeed reduce normal tissue toxicity, and an understanding of its impact on medical personnel and instrumentation gained. Towards this end, the present disclosure describes use of positron emission tomography (PET) to help in the transition to clinical FLASH therapy, for example, systems and methods for recording PET imaging and dosimetry of a proton FLASH beam.

[0030] More specifically, described herein is a high-sensitivity, in-beam scanner that can be used to collect data from tissues activated in proton therapy, such as FLASH radiotherapy (RT). The disclosed in-beam scanner, and related data pro the FLASH effect through imaging and dosimetry using the in-beam or “activated” positron emission tomography (PET) and prompt gamma imaging (PGI) through single photon emission computed tomography (SPECT).

[0031] The disclosed in-beam scanner is made of scintillating crystals and photodetectors that are read out by fast electronics and data are acquired to a computer for further processing. Prompt gammas and gammas from e⁺e' annihilation of decayed positron emitters interact in crystals and produce scintillating light detected by photodetectors. The time of flight (TOF) of gammas and the position of gamma interactions (a.k.a. the depth of interaction, DOI) are determined from double-ended photodetector readout (i.e., photodetectors mounted and coupled to both ends of scintillating crystals). The readout electronics, with the exception of the photodetectors, are mounted on the “away” side from the patient side. The geometry (i.e., the configuration of crystals and related readout electronics) of the scanner may be adjusted to the location of cancer. For brain tumors a structure surrounding hermetically a head is ideal (FIG 1). It has three parts: a central cylinder (barrel), a crown (corona) flat panel above the head, and a chin (bottom) flat panel. This three-section scanner has higher sensitivity than any other PET scanner proposed or constructed so far. For cancers away from head, one could use flat panel to “sandwich” a body by two, four, or more panels to detect beam-generated gammas (FIGS 11 A - 11C). All these configurations are perfectly suitable for imaging of injected radio-pharmaceuticals.

[0032] To detect in-beam prompt gammas using a SPECT technique, the scanner - configured in any geometry - will be temporarily augmented by collimators that would allow imaging and dosimetry of a therapeutic beam. The collimators will be removed within a minute or so past the beam spill.

[0033] The disclosed in-beam scanner can be used to conduct unprecedented comprehensive studies of time-ordered prompt gammas that are congruent with positron emissions produced in phantoms and biological tissues irradiated by a FLASH beam. By employing low-energy prompt gammas, a snapshot of FLASH beam-produced emissions can be captured during the sub-second-long spill, and, after rapidly removing a collimator, the image evolution can be monitored using activated positron-emitters registered over minutes past the spill. PET/PGI/SPECT data can yield volumetric information of the irradiated tumor and healthy organs that will allow post-irradiation assessments of the beam-induced toxicity, currently the limiting factor of proton therapy. This new technique will provide the in vivo proton range verification and feedback information on the either FLASH or conventional dose rates.

[0034] With reference to FIGS. 1 A, IB and 2, there is illustrated an example FLASH- compatible in-beam PET/PGI/SPECT scanner 100 (hereinafter “scanner 100”). The scanner 100 may be designed having a generally cylindrical shape having and an inner collimator 102 (FIG. IB) with parallel hexagonal holes that can be rapidly removed after a FLASH extraction. The collimator 102 is utilized for a PGESPECT modality but may be removed for PET events. FIGS. 1 A and 2 further illustrate removeable crown 104 and a chin 106 panel sections that may be used to provide brain coverage sensitivity. The crown 104 and chin 106 sections substantially increase the detection efficiency and can also be swung out during the beam but reinstalled immediately after the spill. The design and time-and-motion studies will focus on maximizing the efficiency of employing such a scanner in clinical conditions.

[0035] A core 108 of the scanner 100 may include PET modules assembled out of 8/8 arrays, each made out of Lul.8Y0.2SiO5:Ce (LYSO:Ce) scintillation crystals. Each 64- element LYSO scintillation crystal array may feature 3.0x3. Ox 15 mm3 “pixel” crystals and each pixel crystal may be coupled to a silicon photomultiplier (SiPM), such as a Hamamatsu S14161-3050HS-08. All pixel crystals in the LYSO arrays matched the SiPM pixel pitch that features 8x8 pixels of 3.0 mmx3.0 mm dimensions set 0.2 mm apart. The SiPM photodetectors maybe read out by a high-resolution time-of-flight front-end ASIC readout. For example, the individual channel readout electronics may use a PETsys TOFPET2 ASIC in conjunction with the PETsys FEB/S SiPM readout board and the PETsys FEB/I ASIC interface board. The example scanner 100 may attain 1.5 mm position resolution and 200 ps coincidence time resolution.

[0036] In FLASH extractions the instantaneous intensity may be as much as 1,000 times higher than in conventionally delivered proton beam spills. This poses constraints and challenges for instruments, including detectors surrounding the irradiated tissue and presents opportunities for using the strong and fast signal emitted by isotopes activated by protons (e.g.,15O) and their minimal biological washout. The scanner must function in the spatial and temporal proximity to the beam creating an intense radiation zone, including penetrating low- energy neutrons. The effects of this may be mitigated using timing-sensitive instrumentation and protective shielding. [0037] The PET/PGI/SPECT scanner 100 employs nove a large amount of data for evaluating and guiding therapy. These are large and complex data sets, which are processed and analyzed using machine-learning reconstruction and data assessment algorithms. The data sets are created during the various modes of operation involving in-spill prompt (single) gammas and post-spill back-to-back two 511 keV gammas. In operation, in-spill prompt gammas are measured in an annular PGI/SPECT formed by the collimator 102 inserted into the scanner 100.

[0038] The use of the collimator 102 during a spill and its immediate removal may result in two effectively independent data sets that are reconstructed and use for imaging and dosimetry. The reconstruction may be accomplished by using different software reconstruction packages that are intrinsically connected to Monte Carlo simulations and modeling. Such simulations are used for several aspects of data analysis, such as extracting the nominal dose and for providing potential observables that can be used for guiding both the machine-learning algorithms and for interpreting the measurements. These modern analysis methods of using Monte Carlo training algorithms not only improve the reconstruction fidelity but also allow better interpretation of imaging and the time evolution of PET. For example, there are several multi-variate packages available, e.g., kNN, ANN, BDT, CVN, that can be applied to reconstructing events, finding dosimetric relationships with the beam and relate to imaging using the Castor software package. Each phase of reconstruction and analysis may employ Monte Carlo modeling that enhances results by proper training, classification, and parameters estimation. The combined value of these novel modalities guides proton therapy and for advancing new adaptive radiation treatment protocols. The result produces precision dosimetry of all irradiation modalities (conventional and FLASH).

[0039] The efficiency of detecting in-spill PGI and positron annihilation (i.e., the sensitivity) and the precision of imaging (i.e., the position resolution of the source of gammas) require excellent depth-of-interaction (Doi) and time-of-flight (ToF) resolutions of the detector. In particular, knowledge of an interaction point of registered gammas plays a role in the fidelity of reconstructing the line of response (LOR) formed by two detected gammas originating from their annihilation point. Although other factors are also at play (e.g., the P+ end-point energy, motion, or gamma scattering), the depth of interaction (Doi), i.e., the distance of the gamma interaction to the entry point in the crystal detector, and the time of flight (ToF) can be measured on an event-by-even with higher fidelity. Other factors may be inferred statistically.

[0040] Measurements of Doi by a photon readout from both ends of a crystal (thus the name “the double-ended readout”). The observable that correlates with Doi is the ratio of the amount of light detected from one end to the amount of light detected from the other end. A double-ended readout technique can be utilized as this active method improves the overall collection of photons leading to improved timing and the energy resolutions.

[0041] A Compton-camera arrangement with additional active elements residing on a second, outside ring of detectors may also be used in conjunction with the scanner 100. This may image and measure doses of in-spill prompt gammas using SPECT or an MPECT (i.e., a Multi Photon ECT). Removing the collimator 102 would register post-spill PET imaging and dosimetry. The sensitivity of the scanner 100 opens up a possibility of imaging of a 3-gamma ortho-positroniuim (3 SI state) and a measurement of the ratio of number of 3-gamma to 2- gamma [ortho- to para-positronium (ISO state)] decays that is sensitive to the matter density (e.g., intra versus extra-cellular origins).

[0042] FIGS. 3-7 illustrate additional views of the scanner 100 in a first clinical setting. FIGS 8-9 illustrate the example scanner 100 in a second clinical setting. The scanner 100 may be contained within a housing 800 and the subject may be in a seated position. FIGS. 10A- 10B illustrate the example scanner 100 in a third clinical setting within a positron emission tomography (PET) scanner 1000. FIGS. 11 A-l 1C illustrate the example scanner 100 in a fourth clinical setting within the positron emission tomography (PET) scanner 1000. As evidenced by the FIGS., the scanner 100 may be used in different clinical settings within the scope of the present disclosure.

[0043] FIG. 12 illustrates a flow chart of an example method 1200 for measuring in-spill prompt gamma events and post-spill positron emission event during FLASH radiotherapy (FLASH RT) using the in-beam scanner 100 of the present disclosure. At 1202, a target is positioned within a central bore of the in-beam scanner. For example, as shown in FIGS. 3-7, the head of a patient (or other portion of the body) may be positioned within the in-beam scanner 100. At 1204, a proton treatment beam is delivered to the target at an ultra-high dose and ultra-high rate. At 1206, during a first time period, in-spill prompt gamma events are detected using a detector array of the in-beam scanner. For example, the in-spill prompt gamma events may be detected using the detector within the core 108. At 1208, a collimator is removed from within a central bore of the in-beam scan shown in FIG. IB. At 1210, during a second time period, post-spill positron emission events are detected using a detector array of the in-beam scanner. The second time period may follow the first time period. For example, the post-spill positron emission events may be detected using the detector within the core 108.

[0044] Thus, as is understood from the disclosed apparatuses and methods, the PET/PGI/SPECT scanner 100 will provide many advantages. For example, employing the inbeam PET/PGI/SPECT scanner 100 during and immediately after beam irradiation can benefit from the highest statistics of the short-lived isotopes. In live tissues the imaging will be less blurred by washout and other physiological processes. The in-spill PGESPECT will provide a snapshot of the beam energy deposition. The immediate post-irradiation commencement of PET measurement (although there may be some interference with the removal of a collimator) enables the highest detection efficiency of measuring short-lived positron emitters (such as 150, 13N, or 11C) that are generated following the bombardment of therapeutic beam of protons activation of the targeted (tumor) area. Additionally, in-beam PET imaging largely minimizes errors due to patient repositioning and motion due to the relatively long conventional PET imaging session.

[0045] The PET/PGI/SPECT scanner 100 will extract the maximum information on the deposited energy (the dose) and map where this energy has been deposited. Using proton beam activations resulting in prompt gammas and positron-emitting isotopes, much of such information may be obtained by precision imaging and measurements of the flux and partial energy of emitted gammas using the scanner 100 that surrounds an irradiated body and registers its signals from the proton irradiation itself. Thus, the scanner 100 and associated analysis software will produce unprecedented FLASH data that will help to understand how to cope with such a radiation environment. The scanner 100 may further unravel the FLASH effect and help develop new treatment therapies and protocols.

[0046] FIG. 13 illustrates examples of computer hardware, codes or data 1300 that may include the kinds of software programs, data stores, and hardware that can implement event message processing, context determination, notification generation, and content delivery, as described above according to certain embodiments. As shown, the computing system 1300 includes, without limitation, a central processing unit (CPU) 1305, a network interface 1315, a memory 1320, and storage 1330, each connected to a bus 1317. The computing system 1300 may also include an i/o device interface 1310 connecting i/o devices 1312 (e.g., keyboard, display and mouse devices) to the computing s> elements shown in computing system 1300 may correspond to a physical computing system (e.g., a system in a data center) or may be a virtual computing instance executing within a computing cloud.

[0047] The CPU 1305 retrieves and executes programming instructions stored in the memory 1320 as well as stored in the storage 1330. The bus 1317 is used to transmit programming instructions and application data between the CPU 1305, I/O device interface 1310, storage 1330, network interface 1315, and memory 1320. Note, CPU 1305 is included to be representative of a single CPU, multiple CPUs, a single CPU having multiple processing cores, and the like, and the memory 1320 is generally included to be representative of a random access memory. The storage 1330 may be a disk drive or flash storage device. Although shown as a single unit, the storage 1330 may be a combination of fixed and/or removable storage devices, such as fixed disc drives, removable memory cards, optical storage, network attached storage (NAS), or a storage area-network (SAN).

[0048] Illustratively, the memory 1320 includes one or more of data receiving component 1321, simulation component 1322, reconstruction component 1323 and/or the dosimetric relationship component 1324, all of which are discussed in greater detail above. Further, storage 1330 includes one or more of, in-spill event data 1331, post-spill event data 1332, prompt gamma event data 1333, positron emission event data 1334 and dosimetry data 1335, all of which are also discussed in greater detail above.

[0049] It should be understood that the various techniques described herein may be implemented in connection with hardware components or software components or, where appropriate, with a combination of both. Illustrative types of hardware components that can be used include field-programmable gate arrays (FPGAS), application-specific integrated circuits (ASICS), application-specific standard products (ASSPS), system-on-a-chip systems (SOCS), complex programmable logic devices (CPLDS), etc. The methods and apparatus of the presently disclosed subject matter, or certain aspects or portions thereof, may take the form of program code (i.e., instructions) embodied in tangible media, such as removeable drives (floppy diskettes, CD-ROMS), hard drives, including such on cloud-based environments, or any other machine-readable storage medium where, when the program code is loaded into and executed by a machine, such as a computer, the machine becomes an apparatus for practicing the presently disclosed subject matter. [0050] Although certain implementations may refer to u disclosed subject matter in the context of one or more stand-alone computer systems, the subject matter is not so limited but rather may be implemented in connection with any computing environment, such as a network or distributed computing environment. Still further, aspects of the presently disclosed subject matter may be implemented in or across a plurality of processing chips or devices, and storage may similarly be effected across a plurality of devices. Such devices might include personal computers, network servers, and handheld devices, for example.

[0051] The construction and arrangement of the systems and methods as shown in the various implementations are illustrative only. Although only a few implementations have been described in detail in this disclosure, many modifications are possible (e.g., variations in sizes, dimensions, structures, shapes, and proportions of the various elements, values of parameters, mounting arrangements, use of materials, colors, orientations, etc.). For example, the position of elements may be reversed or otherwise varied, and the nature or number of discrete elements or positions may be altered or varied. Accordingly, all such modifications are intended to be included within the scope of the present disclosure. The order or sequence of any process or method steps may be varied or re-sequenced according to alternative implementations. Other substitutions, modifications, changes, and omissions may be made in the design, operating conditions, and arrangement of the implementations without departing from the scope of the present disclosure.

[0052] When information is transferred or provided over a network or another communications connection (either hardwired, wireless, or a combination of hardwired or wireless) to a machine, the machine properly views the connection as a machine-readable medium. Thus, any such connection is properly termed a machine-readable medium. Combinations of the above are also included within the scope of machine-readable media. Machine-executable instructions include, for example, instructions and data which cause a general-purpose computer, special purpose computer, or special purpose processing machines to perform a certain function or group of functions.

[0053] Although the figures show a specific order of method steps, the order of the steps may differ from what is depicted. Also, two or more steps may be performed concurrently or with partial concurrence. Such variation will depend on the software and hardware systems chosen and on designer choice. All such variations are within the scope of the disclosure. Likewise, software implementations could be accomplished with standard programming techniques with rule-based logic and other logic to accomj processing steps, comparison steps and decision steps.

[0054] It is to be understood that the methods and systems are not limited to specific synthetic methods, specific components, or to particular compositions. It is also to be understood that the terminology used herein is for the purpose of describing particular implementations only and is not intended to be limiting.

[0055] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another implementation includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another implementation. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0056] “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0057] Throughout the description and claims of this specification, the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps. “Exemplary” means “an example of’ and is not intended to convey an indication of a preferred or ideal implementation. “Such as” is not used in a restrictive sense, but for explanatory purposes.

[0058] Disclosed are components that can be used to perform the disclosed methods and systems. These and other components are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these components are disclosed that while specific reference of each various individual and collective combinations and permutation of these may not be explicitly disclosed, each is specifically contemplated and described herein, for all methods and systems. This applies to all aspects of this application including, but not limited to, steps in disclosed methods. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional specific implementation or combination of implementations of the disclosed methods.

Claims

WHAT IS CLAIMED IS:

1. An in-beam scanner for measuring in-spill prompt gamma events and post-spill positron emission events during proton FLASH radiotherapy (FLASH RT), the in-beam scanner having a cylindrical shape that defines a central bore extending parallel with a longitudinal axis of the in-beam scanner, the in-beam scanner comprising: a first detector array comprising a first plurality of detectors arranged annularly, wherein the first detector array defines at least a portion of the cylindrical shape of the in-beam scanner, wherein each detector of the first detector array has an inner-facing detecting surface that faces the longitudinal axis, and wherein the inner-facing detecting surface defines a portion of the central bore; and a collimator removably positioned within the central bore and thereby covering the inner- facing detecting surface of each detector of the first detector array, wherein the collimator is configured to be: (i) installed within the central bore of the inbeam scanner during a first phase of FLASH RT treatment such that the plurality of detectors can detect in-spill prompt gamma events, and (ii) removed from within the central bore of the inbeam scanner during a second phase of FLASH RT treatment such that the plurality of detectors can detect post-spill positron emission events, and wherein a target of the proton FLASH RT is configured to be positioned within the central bore of the in-beam scanner for receiving radiation.

2. The in-beam scanner of claim 1, further comprising a second detector array comprising a second plurality of detectors arranged in a grid, wherein the second detector array is configured to be selectively positioned perpendicular to the longitudinal axis and covering a first open end of the central bore.

3. The in-beam scanner of claim 2, wherein the second detector array is coupled to an articulating mechanism such that the second detector array can be selectively positioned: (i) in a first position wherein the second detector array is perpendicular to the longitudinal axis and covering the first open end of the central bore, or (ii) in a second position wherein the second detector array is not covering the first open end of the central bore.

4. The in-beam scanner of claim 3, further comprising a housing that at least partially encloses the first detector array, wherein the articulating mechanism comprises a shaped arm that is rotatably coupled on a first end to the housing, and wherein the second detector array is fixed to a second end of the shaped arm such that the second detector array can be moved between the first position and the second position.

5. The in-beam scanner of claim 2, further comprising a third detector array comprising a third plurality of detectors arranged in a grid, wherein the third detector array is configured to be selectively positioned perpendicular to the longitudinal axis and covering a second open end of the central bore, the second open end opposite the first open end.

6. The in-beam scanner of claim 5, wherein the third detector array is coupled to an articulating mechanism such that the third detector array can be selectively positioned: (i) in a first position wherein the third detector array is perpendicular to the longitudinal axis and covering the second open end of the central bore, or (ii) in a second position wherein the third detector array is not covering the second open end of the central bore.

7. The in-beam scanner of claim 6, further comprising a housing that at least partially encloses the first detector array, wherein the articulating mechanism comprises a shaped arm that is rotatably coupled on a first end to the housing, and wherein the second detector array is fixed to a second end of the shaped arm such that the second detector array can be moved between the first position and the second position.

8. The in-beam scanner of claim 1, wherein the collimator is formed of a high-density material selected from a group consisting of: tungsten, osmium, iridium, platinum, rhenium, plutonium, gold, or uranium.

9. The in-beam scanner of claim 1 , wherein the collimator comprises a plurality of holes formed therein.

10. The in-beam scanner of claim 9, wherein the plurality of holes are hexagonal in shape.

11. The in-beam scanner of claim 1 , wherein each detector of the first detector array comprises a segmented array of scintillation crystals.

12. The in-beam scanner of claim 11, wherein the scintillation crystals are selected from a group consisting of: LYSO, LSO, BGO, BaF2, GAGG, CeBr3, CaF2, GSO, LaBr3, LGSO, LuAG, LuAP, YAG, YSO, or ZnS.

13. The in-beam scanner of claim 1, wherein each detector of the first detector array is coupled to a respective multi-pixel photodetector.

14. The in-beam scanner of claim 13, wherein the multi-pixel photodetector is a silicon photomultiplier (SiPM).

15. The in-beam scanner of claim 1, wherein the in-bean scanner is adapted for use with injected radio-pharmaceuticals as a standalone detector or in combination with large bore Positron emission tomography (PETs) for magnification imaging.

16. A method of measuring in-spill prompt gamma events and post-spill positron emission event during FLASH radiotherapy (FLASH RT) using an in-beam scanner, the in-beam scanner having a cylindrical shape that defines a central bore extending parallel with a longitudinal axis of the in-beam scanner, the in-beam scanner comprising: (i) a first detector array comprising a first plurality of detectors arranged annularly, the first detector array defining at least a portion of the cylindrical shape of the in-beam scanner, wherein each detector of the first detector array has an inner-facing detecting surface that faces the longitudinal axis, the inner-facing detecting surface defines a portion of the central bore, and (ii) a collimator removably positioned within the central bore and thereby covering the inner-facing detecting surface of each detector of the first detector array, the method comprising: positioning a target within the central bore of the in-beam scanner; a delivering, to the target, a proton treatment beam at an ultra-high dose and ultra-high rate; detecting, during a first time period, in-spill prompt gamma events using the first detector array, wherein the collimator is positioned within the central bore during the first time period; removing the collimator from within the central bore of the in-beam scanner; and detecting, during a second time period which is after the first time period, post-spill positron emission events using the first detector array.

17. The method of claim 16, wherein a first longitudinal gap is formed between at least two neighboring detectors of the first detector array and a second longitudinal gap is formed in the collimator, the first longitudinal gap and the second longitudinal gap configured to align when the collimator is installed such that a proton treatment beam is delivered to the target through the first longitudinal gap and the longitudinal second gap, the first longitudinal gap and the second longitudinal gap extending parallel with the longitudinal axis.

18. The method of claim 16, wherein the in-beam scanner further comprises a second detector array, the second detector array comprising a second plurality of detectors arranged in a grid, wherein the second detector array is coupled to an articulating mechanism, the method further comprising: selectively positioning the second detector array: (i) in a first position wherein the second detector array is perpendicular to a longitudinal axis and covering a first open end of the central bore, or (ii) in a second position wherein the second detector array is not covering the first open end of the central bore.

19. The method of claim 18, wherein the in-beam scanner further comprises a third detector array, the third detector array comprising a third plurality of detectors arranged in a grid, wherein the third detector array is coupled to the articulating mechanism, the method further comprising: selectively positioning the third detector array: (i) in a first position wherein the third detector array is perpendicular to a longitudinal axis and covering a second open end of the central bore that is opposite of the first open end, or (ii) in a second position wherein the third detector array is not covering the second open end of the central bore.

20. The method of claim 16, wherein the collimator is formed of a high-density material selected from a group consisting of: tungsten, osmium, iridium, platinum, rhenium, plutonium, gold, or uranium.

21. The method of claim 16, wherein the collimator comprises a plurality of holes formed therein.

22. The method of claim 21, wherein the plurality of holes are hexagonal in shape.

23. The method of claim 16, wherein each detector of the first detector array comprises a segmented array of scintillation crystals.

24. The method of claim 23, wherein the scintillation crystals are selected from a group consisting of: LYSO, LSO, BGO, BaF2, GAGG, CeBr3, CaF2, GSO, LaBr3, LGSO, LuAG, LuAP, YAG, YSO, or ZnS.

25. The method of claim 16, wherein each detector of the first detector array is coupled to a respective multi-pixel photodetector.

26. The method of claim 25, wherein the multi-pixel photodetector is a silicon photomultiplier (SiPM).

27. The method of claim 16, further comprising using the in-bean scanner with injected radio-pharmaceuticals as a standalone detector or in combination with large bore Positron emission tomography (PETs) for magnification imaging.

28. An in-beam scanner for measuring in-spill prompt gamma events and post-spill positron emission events during proton FLASH radiotherapy (FLASH RT), comprising: a plurality of flat panel detector arrays wherein each detector of the flat panel detector arrays has an inner-facing detecting surface that faces a longitudinal axis and that together generally surround a predetermined area of a subject; wherein plurality of flat panel detector arrays detect in-spill prompt gamma events emissions from a positron emission tomography (PET) scanner.

29. The in-beam scanner of claim 28, wherein each detector of the flat panel detector arrays comprises a segmented array of scintillation crystals.

30. The in-beam scanner of claim 29, wherein the scintillation crystals are selected from a group consisting of: LYSO, LSO, BGO, BaF2, GAGG, CeBr3, CaF2, GSO, LaBr3, LGSO, LuAG, LuAP, YAG, YSO, or ZnS.

31. The in-beam scanner of claim 28, wherein each of the plurality of flat panel detector arrays are coupled to a respective multi-pixel photodetector.

32. The in-beam scanner of claim 31, wherein the multi-pixel photodetector is a silicon photomultiplier (SiPM).

33. The in-beam scanner of claim 28, wherein the in-bean scanner is adapted for use with injected radio-pharmaceuticals as a standalone detector or in combination with large bore Positron emission tomography (PETs) for magnification imaging.