Physics in Medicine & Biology

Internationally, reference dosimetry for clinical proton beams largely follows the guidelines published by the International Atomic Energy Agency (IAEA TRS-398 Rev. 1 (2024). This approach yields a relative standard uncertainty of 1.7% (k = 1) on the absorbed dose to water determined under reference conditions. The new IPEM code of practice presented here, enables the relative standard uncertainty on the absorbed dose to water measured under reference conditions to be reduced to 1.0% (k = 1). This improvement is based on the absorbed dose to water calibration service for proton beams provided by the National Physical Laboratory (NPL), the UK's primary standards laboratory. This significantly reduced uncertainty is achieved through the use of a primary standard level graphite calorimeter to derive absorbed dose to water directly in the clinical department's beam. This eliminates the need for beam quality correction factors (${k_{Q,{Q_0}}}$) as required by the IAEA TRS-398 approach. The portable primary standard level graphite calorimeter, developed over a number of years at the NPL, is sufficiently robust to be useable in the proton beams of clinical facilities both in the UK and overseas. The new code of practice involves performing reference dosimetry measurements directly traceable to the primary standard level graphite calorimeter in a clinical proton beam. Calibration of an ionisation chamber is performed in the centre of a standard test volume (STV) of dose, defined here to be a 10 × 10 × 10 cm volume in water, centred at a depth of 15 cm. Further STVs at reduced and increased depths are also utilised. The designated ionisation chambers are Roos-type plane-parallel chambers. This article provides all the necessary background material, formalism, and specifications of reference conditions required to implement reference dosimetry according to this new code of practice. The Annexes provide a detailed review of ion recombination and how this should be assessed (Annex A1) and detailed work instructions for creating and delivering the STVs (Annex A2).

Objective. This paper introduces a novel PET imaging methodology called 3-dimensional positron imaging (3Dπ), which integrates total-body coverage, time-of-flight (TOF) technology, ultra-low dose imaging capabilities, and ultra-fast readout electronics inspired by emerging technology from the DarkSide collaboration. Approach. The study evaluates the performance of 3Dπ using Monte Carlo simulations based on NEMA NU 2-2018 protocols. The methodology employs a homogenous, monolithic scintillator composed of liquid argon (LAr) doped with xenon (Xe) with silicon photomultipliers (SiPMs) operating at cryogenic temperatures. Main results. Substantial improvements in system performance are observed, with the 3Dπ system achieving a noise equivalent count rate of 3.2 Mcps at 17.3 kBq ml⁻¹, continuing to increase up to 4.3 Mcps at 40 kBq ml⁻¹. Spatial resolution measurements show an average FWHM of 2.7 mm across both axial positions. The system exhibits superior sensitivity, with values reaching 373 kcps MBq⁻¹ with a line source at the center of the field of view. Additionally, 3Dπ achieves a TOF resolution of 151 ps at 5.3 kBq ml⁻¹, highlighting its potential to produce high-quality images with reduced noise levels. Significance. The study underscores the potential of 3Dπ in improving PET imaging performance, offering the potential for shorter scan times and reduced radiation exposure for patients. The Xe-doped LAr offers advantages such as fast scintillation, enhanced light yield, and cost-effectiveness. Future research will focus on optimizing system geometry and further refining reconstruction algorithms to exploit the strengths of 3Dπ for clinical applications.

Objective. X-ray computed tomography employing low-dose x-ray source is actively researched to reduce radiation exposure. However, the reduced photon count in low-dose x-ray sources leads to severe noise artifacts in analytic reconstruction methods like filtered backprojection. Recently, deep learning (DL)-based approaches employing uni-domain networks, either in the image-domain or projection-domain, have demonstrated remarkable effectiveness in reducing image noise and Poisson noise caused by low-dose x-ray source. Furthermore, dual-domain networks that integrate image-domain and projection-domain networks are being developed to surpass the performance of uni-domain networks. Despite this advancement, dual-domain networks require twice the computational resources of uni-domain networks, even though their underlying network architectures are not substantially different. Approach. The U-Net architecture, a type of Hourglass network, comprises encoder and decoder modules. The encoder extracts meaningful representations from the input data, while the decoder uses these representations to reconstruct the target data. In dual-domain networks, however, encoders and decoders are redundantly utilized due to the sequential use of two networks, leading to increased computational demands. To address this issue, this study proposes a cross-domain DL approach that leverages analytical domain transfer functions. These functions enable the transfer of features extracted by an encoder trained in input domain to target domain, thereby reducing redundant computations. The target data is then reconstructed using a decoder trained in the corresponding domain, optimizing resource efficiency without compromising performance. Main results. The proposed cross-domain network, comprising a projection-domain encoder and an image-domain decoder, demonstrated effective performance by leveraging the domain transfer function, achieving comparable results with only half the trainable parameters of dual-domain networks. Moreover, the proposed method outperformed conventional iterative reconstruction techniques and existing DL approaches in reconstruction quality. Significance. The proposed network leverages the transfer function to bypass redundant encoder and decoder modules, enabling direct connections between different domains. This approach not only surpasses the performance of dual-domain networks but also significantly reduces the number of required parameters. By facilitating the transfer of primal representations across domains, the method achieves synergistic effects, delivering high quality reconstruction images with reduced radiation doses.

Objective. Computational uncertainty and variability of power absorption and temperature rise in humans for radiofrequency (RF) exposure is a critical factor in ensuring human protection. This aspect has been emphasized as a priority. However, accurately modeling head tissue composition and assigning tissue dielectric and thermal properties remains a challenging task. This study investigated the impact of segmentation-based versus segmentation-free models for assessing localized RF exposure. Approach. Two computational head models were compared: one employing traditional tissue segmentation and the other leveraging deep learning to estimate tissue dielectric and thermal properties directly from magnetic resonance images. The finite-difference time-domain method and the bioheat transfer equation was solved to assess temperature rise for local exposure. Inter-subject variability and dosimetric uncertainties were analyzed across multiple frequencies. Main results. The comparison between the two methods for head modeling demonstrated strong consistency, with differences in peak temperature rise of 7.6 ± 6.4%. The segmentation-free model showed reduced inter-subject variability, particularly at higher frequencies where superficial heating dominates. The maximum relative standard deviation in the inter-subject variability of heating factor was 15.0% at 3 GHz and decreased with increasing frequencies. Significance. This study highlights the advantages of segmentation-free deep-learning models for RF dosimetry, particularly in reducing inter-subject variability and improving computational efficiency. While the differences between the two models are relatively small compared to overall dosimetric uncertainty, segmentation-free models offer a promising approach for refining individual-specific exposure assessments. These findings contribute to improving the accuracy and consistency of human protection guidelines against RF electromagnetic field exposure.

Objective. Fast computation of daily reoptimization is key for an efficient online adaptive proton therapy workflow. Various approaches aim to expedite this process, often compromising daily dose. This study compares Massachusetts General Hospital's (MGH's) online dose reoptimization approach, Paul Scherrer Institute's (PSI's) online replanning workflow and a full reoptimization adaptive workflow for head and neck cancer (H&N) patients. Approach. Ten H&N patients (PSI:5, MGH:5) with daily cone beam computed tomographys (CBCTs) were included. Synthetic CTs were created by deforming the planning CT to each CBCT. Targets and organs at risk (OARs) were deformed on daily images. Three adaptive approaches were investigated: (i) an online dose reoptimization approach modifying the fluence of a subset of beamlets, (ii) full reoptimization adaptive workflow modifying the fluence of all beamlets, and (iii) a full online replanning approach, allowing the optimizer to modify both fluence and position of all beamlets. Two non-adapted (NA) scenarios were simulated by recalculating the original plan on the daily image using: Monte Carlo for NA_MGH and raycasting algorithm for NA_PSI. Main results. All adaptive scenarios from both institutions achieved the prescribed daily target dose, with further improvements from online replanning. For all patients, low-dose CTV D_98% shows mean daily deviations of −2.2%, −1.1%, and 0.4% for workflows (i), (ii), and (iii), respectively. For the online adaptive scenarios, plan optimization averages 2.2 min for (iii) and 2.4 for (i) while the full dose reoptimization requires 72 min. The OA_MGH20% dose reoptimization approach produced results comparable to online replanning for most patients and fractions. However, for one patient, differences up to 11% in low-dose CTV D_98% occurred. Significance. Despite significant anatomical changes, all three adaptive approaches ensure target coverage without compromising OAR sparing. Our data suggests 20% dose reoptimization suffices, for most cases, yielding comparable results to online replanning with a marginal time increase due to Monte Carlo. For optimal daily adaptation, a rapid online replanning is preferable.

Acoustic holography can be used to construct an arbitrary wavefront at a desired 2D plane or 3D volume by beam shaping an emitted field and is a relatively new technique in the field of biomedical applications. Acoustic holography was first theorized in 1985 following Gabor's work in creating optical holograms in the 1940s. Recent developments in 3D printing have led to an easier and faster way to manufacture monolithic acoustic holographic lenses that can be attached to single-element transducers. As ultrasound passes through the lens material, a phase shift is applied to the waves, causing an interference pattern at the 2D image plane or 3D volume, which forms the desired pressure field. This technology has many applications already in use and has become of increasing interest for the biomedical community, particularly for treating regions that are notoriously difficult to operate on, such as the brain. Acoustic holograms could provide a non-invasive, precise, and patient specific way to deliver drugs, induce hyperthermia, or create tissue cell patterns. However, there are still limitations in acoustic holography, such as the difficulties in creating 3D holograms and the passivity of monolithic lenses. This review aims to outline the biomedical applications of acoustic holograms reported to date and discuss their current limitations and the future work that is needed for them to reach their full potential in the biomedical community.

There has been an increase in the availability and utilization of commercially available 3D printers in radiotherapy, with applications in phantoms, brachytherapy applicators, bolus, compensators, and immobilization devices. Additive manufacturing in the form of 3D printing has the advantage of rapid production of personalized patient specific prints or customized phantoms within a short timeframe. One of the barriers to uptake has been the lack of guidance. The aim of this topical review is to present the radiotherapy applications and provide guidance on important areas for establishing a 3D printing service in a radiotherapy department including procurement, commissioning, material selection, establishment of relevant quality assurance, multidisciplinary team creation and training.

FLASH radiotherapy employs ultra-high dose rates of $>\!\!40$ Gy s⁻¹, which may reduce normal tissue complication as compared to conventional dose rate treatments, while still ensuring the same level of tumour control. The potential benefit this can offer to patients has been the cause of great interest within the radiation oncology community, but this has not translated to a direct understanding of the FLASH effect. The oxygen depletion and inter-track interaction hypotheses are currently the leading explanations as to the mechanisms behind FLASH, but these are still not well understood, with many questions remaining about the exact underpinnings of FLASH and the treatment parameters required to optimally induce it. Monte Carlo simulations may hold the key to unlocking the mystery behind FLASH, allowing for analysis of the underpinning mechanisms at a fundamental level, where the interactions between individual radiation particles, DNA strands and chemical species can be studied. Currently, however, there is still a great deal of disagreement in simulation findings and the importance of the different mechanisms they support. This review discusses current studies into the mechanisms of FLASH using the Monte Carlo method. The simulation parameters and results for all major investigations are provided. Discussion primarily revolves around the oxygen depletion and inter-track interactions hypotheses, though other, more novel, theories are also mentioned. A general list of recommendations for future simulations is provided, informed by the articles discussed. This review highlights some of the useful parameters and simulation methodologies that may be required to finally understand the FLASH effect.

In recent decades, medical image registration technology has undergone significant development, becoming one of the core technologies in medical image analysis. With the rise of deep learning, deep learning-based medical image registration methods have achieved revolutionary improvements in processing speed and automation, showing great potential, especially in unsupervised learning. This paper briefly introduces the core concepts of deep learning-based unsupervised image registration, followed by an in-depth discussion of innovative network architectures and a detailed review of these studies, highlighting their unique contributions. Additionally, this paper explores commonly used loss functions, datasets, and evaluation metrics. Finally, we discuss the main challenges faced by various categories and propose potential future research topics. This paper surveys the latest advancements in unsupervised deep neural network-based medical image registration methods, aiming to help active readers interested in this field gain a deep understanding of this exciting area.

Effective dose was created as a radiological protection dose quantity linked to risk to enable planning of radiological protection for the control of exposure. Its application and usage has evolved from occupational and public exposure during work with radiation sources to medicine and applications in patient dosimetry. Effective dose is the sum of doses to organs and tissues within the body weighted according to their sensitivity to radiation for induction of stochastic effects determined from epidemiological studies of exposed populations. It is based on radiation risks averaged over the population and formulated using reference phantoms. Effective dose has been adopted by the medical community for application to patients and has been instrumental in raising awareness of doses from medical imaging. However, although effective dose can be used for comparison of doses from different medical procedures, it is not designed for application to individual patients. The reasons being that organ doses vary with the stature of the patient and the radiation risks depend on the age and sex of the patient. Moves to more personalised medicine have created a desire for a more individualised approach to patient dosimetry, although support for this progression is not universal. This paper traces the evolution of effective dose and its applications. It reflects on how well effective dose provides a measure of risk for individual patients and examines ways in which a more personalised approach might be developed with reference to computed tomography. It considers differences in dose relating to the sizes of patients and looks at variations in risks of cancer incidence within a population with an age distribution typical of patients and examines how this relates to the risk profile. Possible options for improving the individualisation of dosimetry are discussed.

Objective. Utilizing prompt gammas in preclinical pinhole-collimated PET avoids image degradation due to positron range blurring and photon down scatter, enables multi-isotope PET and can improve counting statistics for low-abundance positron emitters. This was earlier reported for 124I, 89Zr and simultaneous 124I -18F PET using the VECTor scanner (MILabs, The Netherlands), demonstrating sub-mm resolution despite long positron ranges. The aim of the present study is to investigate if such sub-mm PET imaging is also feasible for a large variety of other isotopes including those with extremely high energy prompt gammas (>1 MeV) or with complex emission spectra of prompt gammas. Approach. We use Monte Carlo simulations to assess achievable image resolutions and uniformity across a broad range of spectrum types and emitted prompt gamma energies (603 keV - 2.2 MeV), using 52Mn, 94Tc, 89Zr, 44Sc, 86Y, 72As, 124I, 38K, and 66Ga. Main results. Our results indicate that sub-millimeter resolution imaging may be feasible for almost all isotopes investigated, with the currently used cluster pinhole collimators. At prompt gamma energies of 603 keV of 124I, an image resolution of ~0.65 mm was achieved, while for emissions at 703, 744, 834, and 909 keV of 94Tc, 52Mn, 72As, and 89Zr, respectively, ~0.7 mm resolution was obtained. Finally, at ultra-high energies of 1.2 (44Sc) and 1.4 MeV (52Mn) resolutions of ~0.75 mm and ~0.8 mm could still be achieved although ring artifacts were observed at the highest energies (1.4 MeV). For 38K (2.2 MeV), an image resolution of 1.2 mm was achieved utilizing its 2.2 MeV prompt emission. Significance. This work shows that current cluster pinhole collimators are suitable for sub-mm resolution prompt PET up till at least 1.4 MeV. This may open up new avenues to developing new tracer applications and therapies utilizing these PET isotopes.

Objective: In particle therapy (PT), several methods are being investigated to help reduce range margins and identify deviations from the original treatment plan, such as prompt-gamma (PG) imaging with Compton cameras (CC). To reconstruct the images, the Origin Ensemble (OE) algorithm is commonly used. In the context of PT, artifacts and strong noise often affect CC images. To improve the ability of OE to identify range shifts, and also to enhance image quality, we propose to regularize OE using beam a-priori knowledge (beam prior).
Approach: We implemented the beam prior to OE using the class of Gibbs' distribution functions. For evaluation, Monte-Carlo simulations of centered and off-center beams with therapeutic energies impinging on a PMMA target were conducted in GATE. To introduce range shifts, air layers were introduced into the target. In addition, the effect of a bone layer, closer to a realistic scenario, was investigated. OE with the beam prior (BP-OE) and conventional OE (reference) were compared using the spill-over-ratio (SOR) as well as shifts in the distal falloff in projections using cubic splines with Chebyshev nodes.
Main results: BP-OE improved the shift estimates by up to 11% compared to conventional OE for centered and up to 250% with off-centered beams. BP-OE
decreased the image noise level, improving the SOR significantly by up to 96%.
Significance: BP-OE applied to CC data can improve shift estimations compared to conventional OE. The developed Gibbs-based regularization framework also allows
further prior functions to be included into OE, for instance, smoothing or edge-preserving priors. BP-OE could be extended to PET-based range verification or multiple-beam scenarios.

Objective: Clinical implementation of in-beam PET monitoring in proton therapy requires the integration of an online fast and reliable dose calculation engine. This manuscript reports on the achievement of real-time reconstruction of 3D dose and activity maps with proton range verification from experimental in-beam PET measurements. 

Approach: Several cylindrical homogeneous PMMA phantoms were irradiated with a monoenergetic 70-MeV proton beam in a clinical facility. Additionally, PMMA range-shifting foils of varying thicknesses were placed at the proximal surface of the phantom to investigate range shift prediction capabilities. PET activity was measured using a state-of-the-art in-house developed six-module PET scanner equipped with online PET reconstruction capabilities. For real-time dose estimation, we integrated this system with an in-beam dose estimation (IDE) algorithm, which combines a GPU-based 3D reconstruction algorithm with a dictionary-based software, capable of estimating deposited doses from the 3D PET activity images. The range shift prediction performance has been quantitatively studied in terms of the minimum dose to be delivered and the maximum acquisition time.

Main results: With this framework, 3D dose maps were accurately reconstructed and displayed with a delay as short as one second. For a dose fraction of 8.4 Gy at the Bragg peak maximum, range shifts as small as 1 mm could be detected. The quantitative analysis shows that accumulating 20 seconds of statistics from the start of the irradiation, doses down to 1 Gy could be estimated online with total uncertainties smaller than 2 mm. 

Significance. The hardware and software combination employed in this work can deliver dose maps and accurately predict range shifts after short acquisition times and small doses, suggesting that real-time monitoring and dose reconstruction during proton therapy are within reach. Future work will focus on testing the methodology in more complex clinical scenarios and on upgrading the PET prototype for increased sensitivity.

Objective: Radiotherapy planning requires significant expertise to balance tumor control and organ-at-risk (OAR) sparing. Automated planning can improve both efficiency and quality. This study introduces GPT-Plan, a novel multi-agent system powered by the GPT-4 family of large language models (LLMs), for automating the iterative radiotherapy plan optimization. Approach: GPT-Plan uses LLM-driven agents, mimicking the collaborative clinical workflow of a dosimetrist and physicist, to iteratively generate and evaluate text-based radiotherapy plans based on predefined criteria. Supporting tools assist the agents by leveraging historical plans, mitigating LLM hallucinations, and balancing exploration and exploitation. Performance was evaluated on 12 lung (IMRT) and 5 cervical (VMAT) cancer cases, benchmarked against the ECHO auto-planning method and manual plans. The impact of historical plan retrieval on efficiency was also assessed. Results: For IMRT lung cancer cases, GPT-Plan generated high-quality plans, demonstrating superior target coverage and homogeneity compared to ECHO while maintaining comparable or better OAR sparing. For VMAT cervical cancer cases, plan quality was comparable to a senior physicist and consistently superior to a junior physicist, particularly for OAR sparing. Retrieving historical plans significantly reduced the number of required optimization iterations for lung cases (p < 0.01) and yielded iteration counts comparable to those of the senior physicist for cervical cases (p=0.313). Occasional LLM hallucinations have been mitigated by self-reflection mechanisms. One limitation was the inaccuracy of vision-based LLMs in interpreting dose images. Significance: This pioneering study demonstrates the feasibility of automating radiotherapy planning using LLM-powered agents for complex treatment decision-making tasks. While challenges remain in addressing LLM limitations, ongoing advancements hold potential for further refining and expanding GPT-Plan's capabilities.&#xD;

Objective. Cone beam computed tomography (CBCT) has become an essential tool in head and neck cancer (HNC) radiotherapy (RT) treatment delivery. Automatic segmentation of the organs at risk (OARs) on CBCT can trigger and accelerate treatment replanning but is still a challenge due to the poor soft tissue contrast, artifacts, and limited field-of-view of these images, alongside the lack of large, annotated datasets to train deep learning models. This study aims to develop a comprehensive framework to segment 25 HN OARs on CBCT to facilitate treatment replanning.&#xD;Approach. The proposed framework was developed in three steps: (i) refining an in-house framework to segment 25 OARs on computed tomography (CT); (ii) training a deep learning model to segment the same OARs on synthetic CT (sCT) images derived from CBCT using contours propagated from CT as ground truth, integrating high-contrast information from CT and texture features of sCT; and (iii) validating the clinical relevance of sCT segmentations through a dosimetric analysis on an external cohort. &#xD;Main results. Most OARs achieved a Dice Score Coefficient over 70%, with mean Average Surface Distances of 1.30 mm for CT and 1.27 mm for sCT. The dosimetric analysis demonstrated a strong agreement in the mean dose and D2 (%) values, with most OARs showing non-significant differences between automatic CT and sCT segmentations. &#xD;Significance. These results support the feasibility and clinical relevance of using deep learning models for OAR segmentation on both CT and CBCT for HNC RT.&#xD;

Internationally, reference dosimetry for clinical proton beams largely follows the guidelines published by the International Atomic Energy Agency (IAEA TRS-398 Rev. 1 (2024). This approach yields a relative standard uncertainty of 1.7% (k = 1) on the absorbed dose to water determined under reference conditions. The new IPEM code of practice presented here, enables the relative standard uncertainty on the absorbed dose to water measured under reference conditions to be reduced to 1.0% (k = 1). This improvement is based on the absorbed dose to water calibration service for proton beams provided by the National Physical Laboratory (NPL), the UK's primary standards laboratory. This significantly reduced uncertainty is achieved through the use of a primary standard level graphite calorimeter to derive absorbed dose to water directly in the clinical department's beam. This eliminates the need for beam quality correction factors (${k_{Q,{Q_0}}}$) as required by the IAEA TRS-398 approach. The portable primary standard level graphite calorimeter, developed over a number of years at the NPL, is sufficiently robust to be useable in the proton beams of clinical facilities both in the UK and overseas. The new code of practice involves performing reference dosimetry measurements directly traceable to the primary standard level graphite calorimeter in a clinical proton beam. Calibration of an ionisation chamber is performed in the centre of a standard test volume (STV) of dose, defined here to be a 10 × 10 × 10 cm volume in water, centred at a depth of 15 cm. Further STVs at reduced and increased depths are also utilised. The designated ionisation chambers are Roos-type plane-parallel chambers. This article provides all the necessary background material, formalism, and specifications of reference conditions required to implement reference dosimetry according to this new code of practice. The Annexes provide a detailed review of ion recombination and how this should be assessed (Annex A1) and detailed work instructions for creating and delivering the STVs (Annex A2).

Objective. Utilizing prompt gammas in preclinical pinhole-collimated PET avoids image degradation due to positron range blurring and photon down scatter, enables multi-isotope PET and can improve counting statistics for low-abundance positron emitters. This was earlier reported for 124I, 89Zr and simultaneous 124I -18F PET using the VECTor scanner (MILabs, The Netherlands), demonstrating sub-mm resolution despite long positron ranges. The aim of the present study is to investigate if such sub-mm PET imaging is also feasible for a large variety of other isotopes including those with extremely high energy prompt gammas (>1 MeV) or with complex emission spectra of prompt gammas. Approach. We use Monte Carlo simulations to assess achievable image resolutions and uniformity across a broad range of spectrum types and emitted prompt gamma energies (603 keV - 2.2 MeV), using 52Mn, 94Tc, 89Zr, 44Sc, 86Y, 72As, 124I, 38K, and 66Ga. Main results. Our results indicate that sub-millimeter resolution imaging may be feasible for almost all isotopes investigated, with the currently used cluster pinhole collimators. At prompt gamma energies of 603 keV of 124I, an image resolution of ~0.65 mm was achieved, while for emissions at 703, 744, 834, and 909 keV of 94Tc, 52Mn, 72As, and 89Zr, respectively, ~0.7 mm resolution was obtained. Finally, at ultra-high energies of 1.2 (44Sc) and 1.4 MeV (52Mn) resolutions of ~0.75 mm and ~0.8 mm could still be achieved although ring artifacts were observed at the highest energies (1.4 MeV). For 38K (2.2 MeV), an image resolution of 1.2 mm was achieved utilizing its 2.2 MeV prompt emission. Significance. This work shows that current cluster pinhole collimators are suitable for sub-mm resolution prompt PET up till at least 1.4 MeV. This may open up new avenues to developing new tracer applications and therapies utilizing these PET isotopes.

Objective: In particle therapy (PT), several methods are being investigated to help reduce range margins and identify deviations from the original treatment plan, such as prompt-gamma (PG) imaging with Compton cameras (CC). To reconstruct the images, the Origin Ensemble (OE) algorithm is commonly used. In the context of PT, artifacts and strong noise often affect CC images. To improve the ability of OE to identify range shifts, and also to enhance image quality, we propose to regularize OE using beam a-priori knowledge (beam prior).&#xD;Approach: We implemented the beam prior to OE using the class of Gibbs' distribution functions. For evaluation, Monte-Carlo simulations of centered and off-center beams with therapeutic energies impinging on a PMMA target were conducted in GATE. To introduce range shifts, air layers were introduced into the target. In addition, the effect of a bone layer, closer to a realistic scenario, was investigated. OE with the beam prior (BP-OE) and conventional OE (reference) were compared using the spill-over-ratio (SOR) as well as shifts in the distal falloff in projections using cubic splines with Chebyshev nodes.&#xD;Main results: BP-OE improved the shift estimates by up to 11% compared to conventional OE for centered and up to 250% with off-centered beams. BP-OE&#xD;decreased the image noise level, improving the SOR significantly by up to 96%.&#xD;Significance: BP-OE applied to CC data can improve shift estimations compared to conventional OE. The developed Gibbs-based regularization framework also allows&#xD;further prior functions to be included into OE, for instance, smoothing or edge-preserving priors. BP-OE could be extended to PET-based range verification or multiple-beam scenarios.

Objective: Clinical implementation of in-beam PET monitoring in proton therapy requires the integration of an online fast and reliable dose calculation engine. This manuscript reports on the achievement of real-time reconstruction of 3D dose and activity maps with proton range verification from experimental in-beam PET measurements. &#xD;&#xD;Approach: Several cylindrical homogeneous PMMA phantoms were irradiated with a monoenergetic 70-MeV proton beam in a clinical facility. Additionally, PMMA range-shifting foils of varying thicknesses were placed at the proximal surface of the phantom to investigate range shift prediction capabilities. PET activity was measured using a state-of-the-art in-house developed six-module PET scanner equipped with online PET reconstruction capabilities. For real-time dose estimation, we integrated this system with an in-beam dose estimation (IDE) algorithm, which combines a GPU-based 3D reconstruction algorithm with a dictionary-based software, capable of estimating deposited doses from the 3D PET activity images. The range shift prediction performance has been quantitatively studied in terms of the minimum dose to be delivered and the maximum acquisition time.&#xD;&#xD;Main results: With this framework, 3D dose maps were accurately reconstructed and displayed with a delay as short as one second. For a dose fraction of 8.4 Gy at the Bragg peak maximum, range shifts as small as 1 mm could be detected. The quantitative analysis shows that accumulating 20 seconds of statistics from the start of the irradiation, doses down to 1 Gy could be estimated online with total uncertainties smaller than 2 mm. &#xD;&#xD;Significance. The hardware and software combination employed in this work can deliver dose maps and accurately predict range shifts after short acquisition times and small doses, suggesting that real-time monitoring and dose reconstruction during proton therapy are within reach. Future work will focus on testing the methodology in more complex clinical scenarios and on upgrading the PET prototype for increased sensitivity.&#xD;

Objective. Fast computation of daily reoptimization is key for an efficient online adaptive proton therapy workflow. Various approaches aim to expedite this process, often compromising daily dose. This study compares Massachusetts General Hospital's (MGH's) online dose reoptimization approach, Paul Scherrer Institute's (PSI's) online replanning workflow and a full reoptimization adaptive workflow for head and neck cancer (H&N) patients. Approach. Ten H&N patients (PSI:5, MGH:5) with daily cone beam computed tomographys (CBCTs) were included. Synthetic CTs were created by deforming the planning CT to each CBCT. Targets and organs at risk (OARs) were deformed on daily images. Three adaptive approaches were investigated: (i) an online dose reoptimization approach modifying the fluence of a subset of beamlets, (ii) full reoptimization adaptive workflow modifying the fluence of all beamlets, and (iii) a full online replanning approach, allowing the optimizer to modify both fluence and position of all beamlets. Two non-adapted (NA) scenarios were simulated by recalculating the original plan on the daily image using: Monte Carlo for NA_MGH and raycasting algorithm for NA_PSI. Main results. All adaptive scenarios from both institutions achieved the prescribed daily target dose, with further improvements from online replanning. For all patients, low-dose CTV D_98% shows mean daily deviations of −2.2%, −1.1%, and 0.4% for workflows (i), (ii), and (iii), respectively. For the online adaptive scenarios, plan optimization averages 2.2 min for (iii) and 2.4 for (i) while the full dose reoptimization requires 72 min. The OA_MGH20% dose reoptimization approach produced results comparable to online replanning for most patients and fractions. However, for one patient, differences up to 11% in low-dose CTV D_98% occurred. Significance. Despite significant anatomical changes, all three adaptive approaches ensure target coverage without compromising OAR sparing. Our data suggests 20% dose reoptimization suffices, for most cases, yielding comparable results to online replanning with a marginal time increase due to Monte Carlo. For optimal daily adaptation, a rapid online replanning is preferable.

Objective. Cone beam computed tomography (CBCT) has become an essential tool in head and neck cancer (HNC) radiotherapy (RT) treatment delivery. Automatic segmentation of the organs at risk (OARs) on CBCT can trigger and accelerate treatment replanning but is still a challenge due to the poor soft tissue contrast, artifacts, and limited field-of-view of these images, alongside the lack of large, annotated datasets to train deep learning models. This study aims to develop a comprehensive framework to segment 25 HN OARs on CBCT to facilitate treatment replanning.&#xD;Approach. The proposed framework was developed in three steps: (i) refining an in-house framework to segment 25 OARs on computed tomography (CT); (ii) training a deep learning model to segment the same OARs on synthetic CT (sCT) images derived from CBCT using contours propagated from CT as ground truth, integrating high-contrast information from CT and texture features of sCT; and (iii) validating the clinical relevance of sCT segmentations through a dosimetric analysis on an external cohort. &#xD;Main results. Most OARs achieved a Dice Score Coefficient over 70%, with mean Average Surface Distances of 1.30 mm for CT and 1.27 mm for sCT. The dosimetric analysis demonstrated a strong agreement in the mean dose and D2 (%) values, with most OARs showing non-significant differences between automatic CT and sCT segmentations. &#xD;Significance. These results support the feasibility and clinical relevance of using deep learning models for OAR segmentation on both CT and CBCT for HNC RT.&#xD;

Objective. Tracking tumors with multi-leaf collimators and x-ray imaging can be a cost-effective motion management method to reduce internal target volume margins for lung cancer patients, sparing normal tissues while ensuring target coverage. To realize that, accurate tumor localization on x-ray images is essential. We aimed to develop a systematic method for automatically generating tumor segmentation ground truth (GT) on cone-beam computed tomography (CBCT) projections and use it to help refine and validate our patient-specific AI-based tumor localization model. Approach. To obtain the tumor segmentation GT on CBCT projections, we propose a 4DCBCT-aided GT generation pipeline consisting of three steps: breathing phase extraction and 10-phase 4DCBCT reconstruction, manual segmentation on phase 50% followed by deformable contour propagation to other phases, and forward projection of the 3D segmentation to the CBCT projection of the corresponding phase. We then used the CBCT projections from one fraction in the angular range of [$-10^{\circ}$, 10^∘] and [80^∘, 100^∘] to refine a Retina U-Net baseline model, which was pretrained on 1140231 digitally reconstructed radiographs generated from a public lung dataset for automatic tumor delineation on projections, and used later-fraction CBCT projections in the same angular range for testing. Six LMU University Hospital patient CBCT projection sets were reserved for validation and 11 for testing. Tracking accuracy was evaluated as the center-of-mass (COM) error and the Dice similarity coefficient (DSC) between the predicted and ground-truth segmentations. Main results. Over the 11 testing patients, each with around 40 CBCT projections tested, the patient refined models had a mean COM error of 2.3 ± 0.9 mm/4.2 ± 1.7 mm and a mean DSC of 0.83 ± 0.06/0.72 ± 0.13 for angles within [$-10^{\circ}$, 10^∘] / [80^∘, 100^∘]. The mean inference time was 68 ms/frame. The patient-specific training segmentation loss was found to be correlated to the segmentation performance at [$-10^{\circ}$, 10^∘]. Significance. Our proposed approach allows patient-specific real-time markerless lung tumor tracking, which could be validated thanks to the novel 4DCBCT-aided GT generation approach.

Objective. Uveal melanomas and retinoblastomas can be treated with ophthalmic beta-emitting ruthenium-106/rhodium-106 applicators. The applicator manufacturer provides a datasheet of the dosimetric properties of each applicator set, but the source strengths and 3D dose distributions should be verified by the end user with independent measurements. Approach. The purpose of this work was to calibrate diamond detector against low energy electron beam and determine necessary correction factors in the geometry of ophthalmic applicators to be able to perform quality assurance (QA) measurements for the applicators. Two separate sets of applicators were evaluated. Main results. The results showed good agreement with manufacturers' specifications. An average agreement of 3% to the manufacturer's reference data was observed: measured dose rate/reference = 0.97 ± 0.04 (mean ± SD), range 0.90–1.05. Significance. It can be concluded that megavoltage electron beam is suitable for calibration of a diamond detector. After calibration, detector can be used for an absolute dose measurement of a ruthenium-106/rhodium-106 applicator with sufficient performance to detect deviations larger than 10% in the QA before clinical use.

Objective. To assess the performance of a probabilistic deep learning based algorithm for predicting inter-fraction anatomical changes in head and neck patients. Approach. A probabilistic daily anatomy model (DAM) for head and neck patients DAM (DAM_HN) is built on the variational autoencoder architecture. The model approximates the generative joint conditional probability distribution of the repeat computed tomography (rCT) images and their corresponding masks on the planning CT images (pCT) and their masks. The model outputs deformation vector fields, which are used to produce possible rCTs and associated masks. The dataset is composed of 93 patients (i.e. 315 pCT–rCT pairs), 9 (i.e. 27 pairs) of which were set aside for final testing. The performance of the model is assessed based on the reconstruction accuracy and the generative performance for the set aside patients. Main results. The model achieves a DICE score of 0.83 and an image similarity score normalized cross-correlation of 0.60 on the test set. The generated parotid glands, spinal cord and constrictor muscle volume change distributions and center of mass shift distributions were also assessed. For all organs, the medians of the distributions are close to the true ones, and the distributions are broad enough to encompass the real observed changes. Moreover, the generated images display anatomical changes in line with the literature reported ones, such as the medial shifts of the parotids glands. Significance. DAM_HN is capable of generating realistic anatomies observed during the course of the treatment and has applications in anatomical robust optimization, treatment planning based on plan library approaches and robustness evaluation against inter-fractional changes.

Objective:&#xD;Magnetic Resonance Imaging (MRI) is a non-invasive imaging technique that provides high soft tissue contrast, playing a vital role in disease diagnosis and treatment planning. However, due to limitations in imaging hardware, scan time, and patient compliance, the resolution of MRI images is often insufficient. Super-resolution (SR) techniques can enhance MRI resolution, reveal more detailed anatomical information, and improve the identification of complex structures, while also reducing scan time and patient discomfort. However, traditional population-based models trained on large datasets may introduce artifacts or hallucinated structures, which compromise their reliability in clinical applications.&#xD;&#xD;Approach:&#xD;To address these challenges, we propose a patient-specific Knowledge Transfer Implicit Neural Representation (KT-INR) super-resolution model. The KT-INR model integrates a dual-head Implicit Neural Network (INR) with a pre-trained Generative Adversarial Network (GAN) model trained on a large-scale dataset. Anatomical information from different MRI sequences of the same patient, combined with the super-resolution mappings learned by the GAN model on population-based dataset, is transferred as prior knowledge to the INR. This integration enhances both the performance and reliability of the super resolution model.&#xD;&#xD;Main Results:&#xD;We validated the effectiveness of the KT-INR model across three distinct clinical super-resolution tasks on the BRATS dataset. For Task 1, KT-INR achieved an average SSIM, PSNR, and LPIPS of 0.9813, 36.845, and 0.0186, respectively. In comparison, a state-of-the-art super resolution technique, ArSSR, attained average values of 0.9689, 33.4557, and 0.0309 for the same metrics. The experimental results demonstrate that KT-INR outperforms all other methods across all tasks and evaluation metrics, with particularly remarkable performance in resolving fine anatomical details.&#xD;&#xD;Significance:&#xD;The KT-INR model significantly enhances the reliability of super-resolution results, effectively addressing the hallucination effects commonly seen in traditional models. It provides a robust solution for patient-specific MRI super-resolution.