A preliminary study of multispectral Cherenkov imaging and a Fricke-xylenol orange gel film (MCIFF) for online, absolute dose measurement.

BACKGROUND: Cherenkov luminescence imaging has shown potential for relative dose distribution and field verification in radiation therapy. However, to date, limited research utilizing Cherenkov luminescence for absolute dose calibration has been conducted owing to uncertainties arising from camera positioning and tissue surface optical properties. PURPOSE: This paper introduces a novel approach to multispectral Cherenkov luminescence imaging combined with Fricke-xylenol orange gel (FXG) film, termed MCIFF, which can enable online full-field absolute dose measurement. By integrating these two approaches, MCIFF allows for calibration of the ratio between two spectral intensities with absorbed dose, thereby enabling absolute dose measurement. METHODS: All experiments are conducted on a Varian Clinac 23EX, utilizing an electron multiplying charge-coupled device (EMCCD) camera and a two-way image splitter for simultaneous capture of two-spectral Cherenkov imaging. In the first part of this study, the absorbance curves of the prepared FXG film, which receives different doses, are measured using a fluorescence spectrophotometer to verify the correlation between absorbance and dose. In the second part, the FXG film is positioned directly under the radiation beam to corroborate the dose measurement capacity of MCIFF across various beams. In the third part, the feasibility of MCIFF is tested in actual radiotherapy settings via a humanoid model, demonstrating its versatility with various radiotherapy materials. RESULTS: The results of this study indicate that the logarithmic ratios of spectral intensities at wavelengths of 550 ± 50 and 700 ± 100 nm accurately reflect variations in radiation dose (R2 > 0.96) across different radiation beams, particle energies, and dose rates. The slopes of the fitting lines remain consistent under varying beam conditions, with discrepancies of less than 8%. The optical profiles obtained using the MCIFF exhibit a satisfactory level of agreement with the measured results derived from the treatment planning system (TPS) and EBT3 films. Specifically, for photon beams, the lateral distances between the 80% and 20% isodose lines, referred to as the penumbra (P80-20) values, obtained through TPS, EBT3 films, and MCIFF, are determined as 0.537, 0.664, and 0.848 cm, respectively. Similarly, for electron beams, the P80-20 values obtained through TPS, EBT3 films, and MCIFF are found to be 0.432, 0.561, and 0.634 cm, respectively. Furthermore, imaging of the anthropomorphic phantom demonstrates the practical application of MCIFF in real radiotherapy environments. CONCLUSION: By combining an FXG film with Cherenkov luminescence imaging, MCIFF can calibrate Cherenkov luminescence to absorbed dose, filling the gap in online 2D absolute dose measurement methods in clinical practice, and providing a new direction for the clinical application of optical imaging to radiation therapy.

Using the photon isoeffective dose formalism to compare and combine BNCT and CIRT in a head and neck tumour.

Boron Neutron Capture Therapy (BNCT) is a radiotherapy technique based on the enrichment of tumour cells with suitable 10-boron concentration and on subsequent neutron irradiation. Low-energy neutron irradiation produces a localized deposition of radiation dose caused by boron neutron capture reactions. Boron is vehiculated into tumour cells via proper borated formulations, able to accumulate in the malignancy more than in normal tissues. The neutron capture releases two high-LET charged particles (i.e., an alpha particle and a lithium ion), losing their energy in a distance comparable to the average dimension of one cell. Thus BNCT is selective at the cell level and characterized by high biological effectiveness. As the radiation field is due to the interaction of neutrons with the components of biological tissues and with boron, the dosimetry requires a formalism to express the absorbed dose into photon-equivalent units. This work analyzes a clinical case of an adenoid cystic carcinoma treated with carbon-ion radiotherapy (CIRT), located close to optic nerve and deep-seated as a practical example of how to apply the formalism of BNCT photon isoeffective dose and how to evaluate the BNCT dose distribution against CIRT. The example allows presenting different dosimetrical and radiobiological quantities and drawing conclusions on the potential of BNCT stemming on the clinical result of the CIRT. The patient received CIRT with a dose constraint on the optic nerve, affecting the peripheral part of the Planning Target Volume (PTV). After the treatment, the tumour recurred in this low-dose region. BNCT was simulated for the primary tumour, with the goal to calculate the dose distribution in isoeffective units and a Tumour Control Probability (TCP) to be compared with the one of the original treatment. BNCT was then evaluated for the recurrence in the underdosed region which was not optimally covered by charged particles due to the proximity of the optic nerve. Finally, a combined treatment consisting in BNCT and carbon ion therapy was considered to show the consistency and the potential of the model. For the primary tumour, the photon isoeffective dose distribution due to BNCT was evaluated and the resulted TCP was higher than that obtained for the CIRT. The formalism produced values that are consistent with those of carbon-ion. For the recurrence, BNCT dosimetry produces a similar TCP than that of primary tumour. A combined treatment was finally simulated, showing a TCP comparable to the BNCT-alone with overall dosimetric advantage in the most peripheral parts of the treatment volume. Isoeffective dose formalism is a robust tool to analyze BNCT dosimetry and to compare it with the photon-equivalent dose calculated for carbon-ion treatment. This study introduces for the first time the possibility to combine the dosimetry obtained by two different treatment modalities, showing the potential of exploiting the cellular targeting of BNCT combined with the precision of charged particles in delivering an homogeneous dose distribution in deep-seated tumours.

Combined BNCT-CIRT treatment planning for glioblastoma using the effect-based optimization.

Objective. Boron neutron capture therapy (BNCT) and carbon ion radiotherapy (CIRT) are emerging treatment modalities for glioblastoma. In this study, we investigated the methodology and feasibility to combine BNCT and CIRT treatments. The combined treatment plan illustrated how the synergistic utilization of BNCT's biological targeting and CIRT's intensity modulation capabilities could lead to optimized treatment outcomes.Approach. The Monte Carlo toolkit, TOPAS, was employed to calculate the dose distribution for BNCT, while matRad was utilized for the optimization of CIRT. The biological effect-based approach, instead of the dose-based approach, was adopted to develop the combined BNCT-CIRT treatment plans for six patients diagnosed with glioblastoma, considering the different radiosensitivity and fraction. Five optional combined treatment plans with specific BNCT effect proportions for each patient were evaluated to identify the optimal treatment that minimizes damage on normal tissue.Main results. Individual BNCT exhibits a significant effect gradient along with the beam direction in the large tumor, while combined BNCT-CIRT treatments can achieve uniform effect delivery within the clinical target volume (CTV) through the effect filling with reversed gradient by the CIRT part. In addition, the increasing BNCT effect proportion in combined treatments can reduce damage in the normal brain tissue near the CTV. Besides, the combined treatments effectively minimize damage to the skin compared to individual BNCT treatments.Significance. The initial endeavor to combine BNCT and CIRT treatment plans is achieved by the effect-based optimization. The observed advantages of the combined treatment suggest its potential applicability for tumors characterized by pleomorphic, infiltrative, radioresistant and voluminous features.

Calculation of the DNA damage yield and relative biological effectiveness in boron neutron capture therapy via the Monte Carlo track structure simulation.

Objective.Boron neutron capture therapy (BNCT) is an advanced cellular-level hadron therapy that has exhibited remarkable therapeutic efficacy in the treatment of locally invasive malignancies. Despite its clinical success, the intricate nature of relative biological effectiveness (RBE) and mechanisms responsible for DNA damage remains elusive. This work aims to quantify the RBE of compound particles (i.e. alpha and lithium) in BNCT based on the calculation of DNA damage yields via the Monte Carlo track structure (MCTS) simulation.Approach. The TOPAS-nBio toolkit was employed to conduct MCTS simulations. The calculations encompassed four steps: determination of the angle and energy spectra on the nuclear membrane, quantification of the database containing DNA damage yields for ions with specific angle and energy, accumulation of the database and spectra to obtain the DNA damage yields of compound particles, and calculation of the RBE by comparison yields of double-strand break (DSB) with the reference gamma-ray. Furthermore, the impact of cell size and microscopic boron distribution was thoroughly discussed.Main results. The DSB yields induced by compound particles in three types of spherical cells (radius equal to 10, 8, and 6µm) were found to be 13.28, 17.34, 22.15 Gy Gbp-1for boronophenylalanine (BPA), and 1.07, 3.45, 8.32 Gy Gbp-1for sodium borocaptate (BSH). The corresponding DSB-based RBE values were determined to be 1.90, 2.48, 3.16 for BPA and 0.15, 0.49, 1.19 for BSH. The calculated DSB-based RBE showed agreement with experimentally values of compound biological effectiveness for melanoma and gliosarcoma. Besides, the DNA damage yield and DSB-based RBE value exhibited an increasing trend as the cell radius decreased. The impact of the boron concentration ratio on RBE diminished once the drug enrichment surpasses a certain threshold.Significance. This work is potential to provide valuable guidance for accurate biological-weighted dose evaluation in BNCT.

Microdosimetric Analysis for Boron Neutron Capture Therapy via Monte Carlo Track Structure Simulation with Modified Lithium Cross-sections.

Boron neutron capture therapy (BNCT) is a cellular-level hadron therapy achieving therapeutic effects via the synergistic action of multiple particles, including Lithium, alpha, proton, and photon. However, evaluating the relative biological effectiveness (RBE) in BNCT remains challenging. In this research, we performed a microdosimetric calculation for BNCT using the Monte Carlo track structure (MCTS) simulation toolkit, TOPAS-nBio. This paper reports the first attempt to derive the ionization cross-sections of low-energy (>0.025 MeV/u) Lithium for MCTS simulation based on the effective charge cross-section scalation method and phenomenological double-parameter modification. The fitting parameters λ1=1.101,λ2=3.486 were determined to reproduce the range and stopping power data from the ICRU report 73. Besides, the lineal energy spectra of charged particles in BNCT were calculated, and the influence of sensitive volume (SV) size was discussed. Condensed history simulation obtained similar results with MCTS when using Micron-SV while overestimating the lineal energy when using Nano-SV. Furthermore, we found that the microscopic boron distribution can significantly affect the lineal energy for Lithium, while the effect for alpha is minimal. Similar results to the published data by PHITS simulation were observed for the compound particles and monoenergetic protons when using micron-SV. Spectra with nano-SV reflected that the different track densities and absorbed doses in the nucleus together result in the dramatic difference in the macroscopic biological response of BPA and BSH. This work and the developed methodology could impact the research fields in BNCT where understanding radiation effects is crucial, such as the treatment planning system, source evaluation, and new boron drug development.

Use of a neural network-based prediction method to calculate the therapeutic dose in boron neutron capture therapy of patients with glioblastoma.

BACKGROUND: Boron neutron capture therapy (BNCT) is a binary radiotherapy based on the 10 B(n, α)7 Li capture reaction. Nonradioactive isotope 10 B atoms which selectively concentrated in tumor cells will react with low energy neutrons (mainly thermal neutrons) to produce secondary particles with high linear energy transfer, thus depositing dose in tumor cells. In clinical practice, an appropriate treatment plan needs to be set on the basis of the treatment planning system (TPS). Existing BNCT TPSs usually use the Monte Carlo method to determine the three-dimensional (3D) therapeutic dose distribution, which often requires a lot of calculation time due to the complexity of simulating neutron transportation. PURPOSE: A neural network-based BNCT dose prediction method is proposed to achieve the rapid and accurate acquisition of BNCT 3D therapeutic dose distribution for patients with glioblastoma to solve the time-consuming problem of BNCT dose calculation in clinic. METHODS: The clinical data of 122 patients with glioblastoma are collected. Eighteen patients are used as a test set, and the rest are used as a training set. The 3D-UNET is constructed through the design optimization of input and output data sets based on radiation field information and patient CT information to enable the prediction of 3D dose distribution of BNCT. RESULTS: The average mean absolute error of the predicted and simulated equivalent doses of each organ are all less than 1 Gy. For the dose to 95% of the GTV volume (D95 ), the relative deviation between predicted and simulated results are all less than 2%. The average 2 mm/2% gamma index is 89.67%, and the average 3 mm/3% gamma index is 96.78%. The calculation takes about 6 h to simulate the 3D therapeutic dose distribution of a patient with glioblastoma by Monte Carlo method using Intel Xeon E5-2699 v4, whereas the time required by the method proposed in this study is almost less than 1 s using a Titan-V graphics card. CONCLUSIONS: This study proposes a 3D dose prediction method based on 3D-UNET architecture in BNCT, and the feasibility of this method is demonstrated. Results indicate that the method can remarkably reduce the time required for calculation and ensure the accuracy of the predicted 3D therapeutic dose-effect. This work is expected to promote the clinical development of BNCT in the future.

Enhanced Cherenkov imaging for real-time beam visualization by applying a novel carbon quantum dot sheeting in radiotherapy.

BACKGROUND: Cherenkov imaging can be used to visualize the placement of the beam directly on the patient's surface tissue and evaluate the accuracy of treatment planning. However, Cherenkov emission intensity is lower than ambient light. At present, time gating is the only way to realize Cherenkov imaging with ambient light. PURPOSE: This study proposes preparing a novel carbon quantum dot (cQD) sheeting to adjust the wavelength of Cherenkov emission to obtain the optimal wavelength meeting the sensitive detection region of the camera, meanwhile the total optical signal is also increased. By combining a specific filter, this approach might help in using lower-cost camera systems without intensifier-coupled to accomplish in vivo monitoring of the surface beam profile on patients with ambient light. METHODS: The cQD sheetings were prepared by spin coating and UV curing with different concentrations. All experiments were performed on the Varian VitalBeam system and optical emission was captured using an electron multiplying charge-coupled device (EMCCD) camera. To quantify the optical characteristics and certify the improvement of light intensity as well as signal-to-noise ratio (SNR) of cQD sheeting, the first part of the study was carried out on solid water with 6 and 10 MV photon beams. The second part was carried out on an anthropomorphic phantom to explore the applicability of sheeting when using different radiotherapy materials and the imaging effect of sheeting with the impact of ambient light sources. Additionally, thanks to the narrow emission spectrum of the cQD, a band-pass filter was tested to reduce the effect from environmental lights. RESULTS: The experimental results show that the optical intensity collected with sheeting has an excellent linear relationship (R2  > 0.99) with the dose for 6 and 10 MV photons. The full-width half maximum (FWHM) in x and y axis matched with the measured EBT film image, with accuracy in the range of ±1.2 and ±2.7 mm standard deviation, respectively. CQD sheeting can significantly improve the light intensity and SNR of optical images. Using 0.1 mg/ml sheeting as an example, the signal intensity is increased by 209%, and the SNR is increased by 147.71% at 6 MV photons. The imaging on the anthropomorphic phantom verified that cQD sheeting could be applied to different radiotherapy materials. The average optical intensity increased by about 69.25%, 63.72%, and 61.78%, respectively, after adding cQD sheeting to bolus, mask sample and the combination of bolus and mask. Corresponding SNR is improved by about 62.78%, 56.77%, and 68.80%, respectively. Through the sheeting, optical images with SNR > 5 can be obtained in the presence of ambient light and it can be improved through combining with a band-pass filter. When red ambient lights are on, the SNR is increased by about 98.85% after adding a specific filter. CONCLUSION: Through a combination of cQD sheeting and corresponding filter, light intensity and SNR of optical images can be increased significantly, and it shed new light on the promotion of the clinical application of optical imaging to visualize the beam in radiotherapy.

SARU: A self-attention ResUNet to generate synthetic CT images for MR-only BNCT treatment planning.

PURPOSE: Despite the significant physical differences between magnetic resonance imaging (MRI) and computed tomography (CT), the high entropy of MRI data indicates the existence of a surjective transformation from MRI to CT image. However, there is no specific optimization of the network itself in previous MRI/CT translation works, resulting in mistakes in details such as the skull margin and cavity edge. These errors might have moderate effect on conventional radiotherapy, but for boron neutron capture therapy (BNCT), the skin dose will be a critical part of the dose composition. Thus, the purpose of this work is to create a self-attention network that could directly transfer MRI to synthetical computerized tomography (sCT) images with lower inaccuracy at the skin edge and examine the viability of magnetic resonance (MR)-guided BNCT. METHODS: A retrospective analysis was undertaken on 104 patients with brain malignancies who had both CT and MRI as part of their radiation treatment plan. The CT images were deformably registered to the MRI. In the U-shaped generation network, we introduced spatial and channel attention modules, as well as a versatile "Attentional ResBlock," which reduce the parameters while maintaining high performance. We employed five-fold cross-validation to test all patients, compared the proposed network to those used in earlier studies, and used Monte Carlo software to simulate the BNCT process for dosimetric evaluation in test set. RESULTS: Compared with UNet, Pix2Pix, and ResNet, the mean absolute error (MAE) of self-attention ResUNet (SARU) is reduced by 12.91, 17.48, and 9.50 HU, respectively. The "two one-sided tests" show no significant difference in dose-volume histogram (DVH) results. And for all tested cases, the average 2%/2 mm gamma index of UNet, ResNet, Pix2Pix, and SARU were 0.96 ± 0.03, 0.96 ± 0.03, 0.95 ± 0.03, and 0.98 ± 0.01, respectively. The error of skin dose from SARU is much less than the results from other methods. CONCLUSIONS: We have developed a residual U-shape network with an attention mechanism to generate sCT images from MRI for BNCT treatment planning with lower MAE in six organs. There is no significant difference between the dose distribution calculated by sCT and real CT. This solution may greatly simplify the BNCT treatment planning process, lower the BNCT treatment dose, and minimize image feature mismatch.

Screening and Preclinical Evaluation of Novel Radiolabeled Anti-Fibroblast Activation Protein-α Recombinant Antibodies.

Background: Fibroblast activation protein-α (FAPα) is selectively overexpressed in tumor-associated fibroblasts in more than 90% of epithelial tumors, and may be a good target for anticancer treatment, for example, using an anti-FAPα recombinant antibody (rAb) labeled with radionuclides. In the present report, the radiolabeling and preclinical evaluation of novel anti-FAPα rAbs were investigated. Materials and Methods: Two novel anti-FAPα VHHs (AMS002-1 and AMS002-2) with high binding affinity to FAPα were selected from an antibody phage library. The anti-FAPα VHHs were then fused with the Fc fragment of human IgG4 to create two VHH-Fc rAbs. The VHH-Fc rAbs were radiolabeled with 89Zr and 177Lu. The radiolabeled products were evaluated by radioligand-binding assays using FAPα-expressing cells. The biodistribution and tumor-targeting properties were investigated by small-animal PET/CT. AMS002-1-Fc, which showed promising tumor-targeting properties in 89Zr-microPET imaging, was radiolabeled with 177Lu for efficacy study on HT1080 tumor-bearing mice and monitored with SPECT/CT imaging. Results: The two VHH-Fc rAbs with good affinity with KD values in low nanomolar range were identified. Both PET/CT imaging with 89Zr-AMS002-1-Fc rAb and SPECT/CT imaging with 177Lu-AMS002-1-Fc rAb demonstrated highest tumor uptakes at 72 h p.i. and long tumor retention in the preclinical models. Furthermore, ex vivo biodistribution analysis revealed high tumor uptake of 89Zr-AMS002-1-Fc at 48 h p.i. with the value of 6.91% ± 2.08% ID/g. Finally, radioimmunotherapy with 177Lu-AMS002-1-Fc rAb delayed the tumor growth without significant weight loss in mice with HT1080 xenografts. The tumor size of untreated control group was 2.59 times larger compared with the treatment group with 177Lu-AMS002-1-Fc at day 29. Conclusion: 89Zr/177Lu-AMS002-1-Fc represent a pair of promising radiopharmaceuticals for theranostics on FAPα-expressing tumors.

Technical note: Rapid and high-resolution deep learning-based radiopharmaceutical imaging with 3D-CZT Compton camera and sparse projection data.

BACKGROUND: The Compton camera (CC) has great potential in nuclear medicine imaging due to the high detection efficiency and the ability to simultaneously detect multi-energy radioactive sources. However, the finite resolution of the detectors will degrade the images that the real-world CC can obtain. Besides, the CC sometimes can be limited by the detection efficiency, leading to difficulty in using sparse projection data to realize high-resolution reconstruction with short-time measurement, which limits its clinical application for real-time or rapid radiopharmaceutical imaging. PURPOSE: To overcome the difficulty and promote the usage of the CC in radiopharmaceutical imaging, we present a deep learning (DL)-based CC reconstruction method to realize rapid and high-resolution imaging with short-time measurement. METHODS: We developed a DL-based algorithm MCBP-CCnet via Monte Carlo sampling-based back projection and a dedicated convolutional neural network, called CC-Net, to realize the rapid and high-resolution reconstruction with sparse projection data. A CC prototype based on a single three-dimensional position-sensitive CdZnTe (3D-CZT) detector was used to demonstrate the feasibility of our proposed method. The simulations and experiments of radiopharmaceutical imaging used the 3D-CZT CC and [18 F]NaF. A 3D-printing mouse phantom was also further used to evaluate the performance of the proposed method in animal molecular imaging. RESULTS: The simulation and experimental results showed that the proposed method could realize the images reconstruction within 5 s for list-mode projection data and realized a rapid reconstruction within 35 s for experimental radiopharmaceutical imaging based on the 3D-printing mouse phantom, as well as realized the high-resolution imaging with an accuracy of within 0.78 mm in terms of the sparse projection data that only contained hundreds of events. Besides, the deviations between the reconstructed radiative activities and the exact values were less than 1.51%. CONCLUSION: The results demonstrated that the proposed method could realize the rapid and high-resolution CC reconstruction with sparse projection data obtained by the 3D-CZT CC and realize the high-resolution radiopharmaceutical imaging. The study in this paper also demonstrated the potential and feasibility of future applications of a 3D-CZT CC for real-time high-resolution radiopharmaceutical imaging with short-time measurement.

Boron concentration prediction from Compton camera image for boron neutron capture therapy based on generative adversarial network.

Prompt gamma monitoring for the prediction of boron concentration is valuable for the dose calculation of boron neutron capture therapy (BNCT). This work proposes to use generative adversarial network (GAN) to predict the boron distribution based on Compton camera (CC) imaging quickly and provide a scientific basis for its application in BNCT. The BNCT and Compton imaging process was simulated, then the image reconstructed from the simulation and the contour of skin from CT are used as input, and the distribution of boron concentration from PET data is set as the output to train the network. The structural similarity, peak signal-to-noise ratio, and root mean square error of the images generated by the trained network are improved significantly, and the ratio of the boron concentration between the tumor area and the normal tissue is improved from 1.55 to 3.85, which is much closer to the true value of 3.52. The trained network can optimize the original image within 0.83 s, which is much faster than iterative optimization. The proposed method could help to ease the current online monitoring problem of boron concentration on a computational level, thereby promoting the clinical development of BNCT technology.

Radiopharmaceutical imaging based on 3D-CZT Compton camera with 3D-printed mouse phantom.

PURPOSE: The study proposes the use of three-dimensional CdZnTe Compton camera (3D-CZT CC) for radiopharmaceutical imaging and investigates the influence factors using a 3D-printed mouse phantom. METHODS: The event selection method and image reconstruction algorithm are optimized by Monte Carlo simulations and mouse phantom experiments. RESULTS: Simulation results show that the intrinsic energy resolution and spatial resolution of 3D-CZT cause a certain deviation in the calculated Compton scattering angle and Compton axis. Such deviation causes the imaging quality to deteriorate. By selecting events whose distance between Compton and photoelectronic interactions are larger than 10 mm, the mean deviation of the Compton axis could be reduced to less than 10%. Using the ordered origin ensemble algorithm with resolution recovery, the artifacts around organs where the radiopharmaceutical was placed are reduced, and the quality of the reconstruction results are improved compared to the results with simple back projection and origin ensembles algorithms. The phantom study shows that the 3D-CZT CC imaging device could visualize the radiopharmaceuticals distribution by 15 min detection. CONCLUSIONS: Through the analysis of this study, the feasibility of 3D-CZT CC for in-vivo distribution measurement of radiopharmaceuticals is demonstrated, and the quality of reconstruction result has been improved.

Design, synthesis, and preclinical evaluation of a novel bifunctional macrocyclic chelator for theranostics of cancers.

PURPOSE: This study was to design and synthesize a novel bifunctional chelator, named Dar, primarily validated by conjugating to tumor targeting motifs, labeled with radiometals, and performed preclinical evaluation of tumor imaging and cancer therapy in murine tumor models. METHOD: The designed Dar was synthesized and characterized by X-ray crystallography, 1H/13C NMR, and mass spectrometry. Dar-PSMA-617 was conjugated and radiolabeled with 68Ga, 177Lu, and 89Zr. The in vivo behavior of 68 Ga/89Zr-labeled Dar-PSMA-617 were evaluated using micro-PET imaging and biodistribution from image quantitation and tissue radioactivity counting, with 68Ga/89Zr-labeled NOTA/DOTA/DFO-PSMA-617 analogs as controls, respectively. The [177Lu]-Dar-PSMA-617, with [177Lu]-DOTA-PSMA-617 as control, was evaluated in competitive cell uptake, tumor cell internalization, and efflux studies. The treatment efficacy of [177Lu]Lu-Dar-PSMA-617, with [177Lu]Lu-DOTA-PSMA-617 as control, was evaluated in PSMA-positive LNCaP tumor-bearing mice. In addition, the ability of Dar for radiolabeling nanobody was tested by conjugating Dar to KN035 nanobody. The resultant [89Zr]Zr-Dar-KN035 nanobody, with [89Zr]Zr-DFO-KN035 as control, was evaluated by micro-PET imaging and biodistribution in a mouse model bearing MC38&MC38-hPD-L1 colon cancer. RESULTS: 68Ga, 89Zr, and 177Lu-radiolabeled Dar-PSMA-617 complexes were able to be produced under mild condition with high radiochemical yield and purity successfully. [177Lu]Lu-Dar-PSMA-617 had higher cellular uptake yet similar internalization and efflux properties in LNCaP cells, as compared to [177Lu]Lu-DOTA-PSMA-617. Micro-PET images demonstrated significantly higher tumor uptake of [68Ga]Ga-Dar-PSMA-617, than that of the analog [68Ga]Ga-DOTA-PSMA-617. The tumor uptake values of [68Ga]Ga-Dar-PSMA-617 at multiple time points are comparable to that of [68Ga]Ga-NOTA-PSMA-617, although a higher and persistently prolonged kidney retention was resulted in during the study period. The Dar chelator can also successfully mediate the radiolabeling with 89Zr, while the resultant [89Zr]Zr-Dar-PSMA-617 demonstrated a similar biodistribution with [89Zr]Zr-DFO-PSMA-617 measured at 96 h p.i. The treatment with [177Lu]Lu-Dar-PSMA-617 significantly inhibited the tumor growth, showing much better efficacy than that of [177Lu]Lu-DOTA-PSMA-617 at the same injected radioactivity and mass dose. Dar was covalently linked to KN035 nanobody and enabled radiolabeling with 89Zr in high yield and radiochemical purity at room temperature. The resultant [89Zr]Zr-Dar-KN035, with [89Zr]Zr-DFO-KN035 as control, demonstrated superior tumor uptake and detection capability in PET imaging studies. CONCLUSION: The Dar, as a novel bifunctional chelator for medicating the labeling of radiometals onto tumor targeting carriers, was successfully synthesized and chemically characterized. Test radiolabeling, on PSMA-617 and a nanobody as tool targeting molecule carriers, demonstrated the Dar has potential as a universal bifunctional chelator for radiolabeling various radiometals (at least 68Ga, 177Lu, and 89Zr tested) commonly used for clinical imaging and therapy. Using a novel Dar chelator results in altered in vivo behavior of the carriers even though labeled with the same nuclide. This capability makes Dar an alternative to the existing choices for radiolabeling new carrier molecules with various radiometals, especially the radiometals with large radius.

Proton range monitoring based on picosecond detection using a Cherenkov radiation detector: A Monte Carlo study.

In this study, we analyzed the performance of a PbF2 crystal-based detector at proton range monitoring with Monte Carlo simulations. The correlations between the depth-dose and Cherenkov profiles showed that the changes in the peak position in the Cherenkov profiles corresponded to the changes in the corresponding depth-dose profiles. Moreover, the deviations between the changes in the peak positions in the two curves were generally less than 2 mm. The results also showed that the actual proton range could be obtained using flight time information. When the proton energy was 160 MeV, the peak position detected in the Cherenkov profile detected was 14.83 cm with a flight time of 5.3-5.4 ns (starting from the time when protons were emitted), and the actual proton range in polymethyl-methacrylate was 15 cm. Therefore, the accuracy of the proton range measurements could be improved and the absolute range obtained by using the fast and time-sensitive characteristics of the proposed Cherenkov radiator.

Diagnostic Performance of CMR, SPECT, and PET Imaging for the Identification of Coronary Artery Disease: A Meta-Analysis.

Background: Myocardial perfusion imaging modalities, such as cardiac magnetic resonance (CMR), single-photon emission computed tomography (SPECT), and positron emission tomography (PET), are well-established non-invasive diagnostic methods to detect hemodynamically significant coronary artery disease (CAD). The aim of this meta-analysis is to compare CMR, SPECT, and PET in the diagnosis of CAD and to provide evidence for further research and clinical decision-making. Methods: PubMed, Web of Science, EMBASE, and Cochrane Library were searched. Studies that used CMR, SPECT, and/or PET for the diagnosis of CAD were included. Pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio with their respective 95% confidence interval, and the area under the summary receiver operating characteristic (SROC) curve were calculated. Results: A total of 203 articles were identified for inclusion in this meta-analysis. The pooled sensitivity values of CMR, SPECT, and PET were 0.86, 0.83, and 0.85, respectively. Their respective overall specificity values were 0.83, 0.77, and 0.86. Results in subgroup analysis of the performance of SPECT with 201Tl showed the highest pooled sensitivity [0.85 (0.82, 0.88)] and specificity [0.80 (0.75, 0.83)]. 99mTc-tetrofosmin had the lowest sensitivity [0.76 (0.67, 0.82)]. In the subgroup analysis of PET tracers, results indicated that 13N had the lowest pooled sensitivity [0.83 (0.74, 0.89)], and the specificity was the highest [0.91 (0.81, 0.96)]. Conclusion: Our meta-analysis indicates that CMR and PET present better diagnostic performance for the detection of CAD as compared with SPECT.

Effect of spatial distribution of boron and oxygen concentration on DNA damage induced from boron neutron capture therapy using Monte Carlo simulations.

PURPOSE: This paper aims to investigate how the spatial distribution of boron in cells and oxygen concentration affect the DNA damage induced by charged particles in boron neutron capture therapy (BNCT) by Monte Carlo simulations, and further to evaluate the relative biological effectiveness (RBE) of DNA double-strand breaks (DSBs) induction. MATERIALS AND METHODS: The kinetic energy spectra of α, 7Li particles in BNCT arriving at the nucleus surface were obtained from GEANT4 (Geant4 10.05.p01). The DNA damage caused by BNCT was then evaluated using MCDS (MCDS 3.10A). RESULTS: When α or 7Li particles were distributed in the cytomembrane or cytoplasm, the difference in DNA damage of the same types was less than 0.5%. Taking the 137Cs photons as the reference radiation, when the oxygen concentration varied from 0% to 50%, the RBE of 0.54MeV protons and recoil protons varied from 5 to 2, whereas it decreased from 10 to 3 for α or 7Li particles. CONCLUSION: The RBE of DSB induction all charged particles in BNCT decreased with the increase of oxygen concentration. This work indicated that the RBE of different radiation particles of BNCT might be affected by many factors, which should be paid attention to in theoretical research or clinical application.

A bi-tapered and air-gapped beam shaping assembly used for AB-BNCT.

The 7Li(p,n)7Be reaction, which leads to a soft neutron field, is often chosen as the neutron producing reaction used for accelerator-based boron neutron capture therapy (AB-BNCT). This study aims to design a compact beam shaping assembly (BSA) and auxiliary system for a 7Li(p,n)7Be reaction-based neutron source and to evaluate the relationship between the BSA design and the consequent neutron beam quality for further optimization. In this study, five types of moderator shapes for the BSA model were designed. Both the in-air and in-phantom figures of merit were considered to evaluate the performance of the BSA designs. It was found that the BSA with a bi-tapered and air-gapped design could generate a high-intensity epithermal neutron beam, which could be used to treat deep-seated brain tumors within a reasonable time.

Author Correction: Exploring the advantages of intensity-modulated proton therapy: experimental validation of biological effects using two different beam intensity-modulation patterns.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Quantitative evaluation of transmission properties of breast tissue equivalent materials under Compton scatter imaging setup.

To explore the potential of utilizing Compton scattered x-ray photons for imaging applications, it is critical to accurately evaluate scattered x-ray transmission properties of targeted tissue materials. In this study, scattered x-ray transmission of breast tissue equivalent phantoms was evaluated. Firstly, two validations were carried out using a primary x-ray beam at 80 kVp with both experimental measurement (ion chamber with narrow-beam setup) and analytical calculation (Spektr toolkit). The tungsten-anode x-ray spectrum model was thus validated by measuring and calculating the transmission through increasing thickness of 1100 Aluminum filters. Similarly, the composition models of breast tissue equivalent phantoms (CIRS, 012A) were validated by measuring and calculating x-ray transmission for three different breast compositions (BR30/70, BR50/50, and BR70/30). Following validation, transmission properties of Compton scattered x-ray photons were measured with a GOS based linear array detector at the 90° angle from the primary beam. The same study was performed through three independent approaches: experimental measurement, analytical calculation, and Monte Carlo simulation (GEANT4). For all three methods, the scattered x-ray photon transmission as functions of phantom thickness were determined and fit into exponential functions. The transmission curves from all three methods matched reasonably well, with a maximum difference of 6.3% for the estimated effective attenuation coefficients of the BR50/50 phantom. The relative difference among the three methods of estimated attenuation is under 3.5%. As an initial step to develop a novel Compton scatter-based breast imaging system, the quantitative results from this study paved a fundamental base for future work.

Exploring the advantages of intensity-modulated proton therapy: experimental validation of biological effects using two different beam intensity-modulation patterns.

In current treatment plans of intensity-modulated proton therapy, high-energy beams are usually assigned larger weights than low-energy beams. Using this form of beam delivery strategy cannot effectively use the biological advantages of low-energy and high-linear energy transfer (LET) protons present within the Bragg peak. However, the planning optimizer can be adjusted to alter the intensity of each beamlet, thus maintaining an identical target dose while increasing the weights of low-energy beams to elevate the LET therein. The objective of this study was to experimentally validate the enhanced biological effects using a novel beam delivery strategy with elevated LET. We used Monte Carlo and optimization algorithms to generate two different intensity-modulation patterns, namely to form a downslope and a flat dose field in the target. We spatially mapped the biological effects using high-content automated assays by employing an upgraded biophysical system with improved accuracy and precision of collected data. In vitro results in cancer cells show that using two opposed downslope fields results in a more biologically effective dose, which may have the clinical potential to increase the therapeutic index of proton therapy.