Clinical Radiation Research Articles

Research on new treatment mode of radiotherapy based on pseudo-medical images

Background and objectiveMulti-modal medical images with multiple feature information are beneficial for radiotherapy. A new radiotherapy treatment mode based on triangle generative adversarial network (TGAN) model was proposed to synthesize pseudo-medical images between multi-modal datasets. MethodsCBCT, MRI and CT images of 80 patients with nasopharyngeal carcinoma were selected. The TGAN model based on multi-scale discriminant network was used for data training between different image domains. The generator of the TGAN model refers to cGAN and CycleGAN, and only one generation network can establish the non-linear mapping relationship between multiple image domains. The discriminator used multi-scale discrimination network to guide the generator to synthesize pseudo-medical images that are similar to real images from both shallow and deep aspects. The accuracy of pseudo-medical images was verified in anatomy and dosimetry. ResultsIn the three synthetic directions, namely, CBCT → CT, CBCT → MRI, and MRI → CT, significant differences (p < 0.05) in the three-fold-cross validation results on PSNR and SSIM metrics between the pseudo-medical images obtained based on TGAN and the real images. In the testing stage, for TGAN, the MAE metric results in the three synthesis directions (CBCT → CT, CBCT → MRI, and MRI → CT) were presented as mean (standard deviation), which were 68.67 (5.83), 83.14 (8.48), and 79.96 (7.59), and the NMI metric results were 0.8643 (0.0253), 0.8051 (0.0268), and 0.8146 (0.0267) respectively. In terms of dose verification, the differences in dose distribution between the pseudo-CT obtained by TGAN and the real CT were minimal. The H values of the measurement results of dose uncertainty in PGTV, PGTVnd, PTV1, and PTV2 were 42.510, 43.121, 17.054, and 7.795, respectively (P < 0.05). The differences were statistically significant. The gamma pass rate (2%/2 mm) of pseudo-CT obtained by the new model was 94.94% (0.73%), and the numerical results were better than those of the three other comparison models. ConclusionsThe pseudo-medical images acquired based on TGAN were close to the real images in anatomy and dosimetry. The pseudo-medical images synthesized by the TGAN model have good application prospects in clinical adaptive radiotherapy.

A 2D strip ionization chamber array with high spatiotemporal resolution for proton pencil beam scanning FLASH radiotherapy.

Experimental measurements of two-dimensional (2D) dose rate distributions in proton pencil beam scanning (PBS) FLASH radiation therapy (RT) are currently lacking. In this study, we characterize a newly designed 2D strip-segmented ionization chamber array (SICA) with high spatial and temporal resolution and demonstrate its applications in a modern proton PBS delivery system at both conventional and ultrahigh dose rates. A dedicated research beamline of the Varian ProBeam system was employed to deliver a 250-MeV proton PBS beam with nozzle currents up to 215nA. In the research and clinical beamlines, the spatial, temporal, and dosimetric performances of the SICA were characterized and compared with measurements using parallel-plate ion chambers (IBA PPC05 and PTW Advanced Markus chamber), a 2D scintillator camera (IBA Lynx), Gafchromic films (EBT-XD), and a Faraday cup. A novel reconstruction approach was proposed to enable the measurement of 2D dose and dose rate distributions using such a strip-type detector. The SICA demonstrated a position accuracy of 0.12±0.02mm at a 20-kHz sampling rate (50μs per event) and a linearity of R2 >0.99 for both dose and dose rate with nozzle beam currents ranging from 1 to 215nA. The 2D dose comparison to the film measurement resulted in a gamma passing rate of 99.8% (2mm/2%). A measurement-based proton PBS 2D FLASH dose rate distribution was compared to simulation results and showed a gamma passing rate of 97.3% (2mm/2%). The newly designed SICA demonstrated excellent spatial, temporal, and dosimetric performances and is well suited for commissioning, quality assurance, and a wide range of clinical applications in proton PBS clinical and FLASH-RT.

3,4,5-O-tricaffeoylquinic acid with anti-radiation activity suppresses LPS-induced NLRP3 inflammasome activation via autophagy in THP-1 macrophages

Damage to normal tissues caused by excessive ionizing radiation (IR) exposure is the major side effect of radiotherapy. Several recent studies have shown that IR-induced damage to tissues leads to a systemic immune response and NLRP3 inflammasome activation in immune cells. 3,4,5-O-tricaffeoylquinic acid (tCQA), extracted from the natural plant Azolla imbricata, relieves inflammation and has radioprotective function. Here, we aimed to investigate the inhibitory effect and molecular mechanism of tCQA on IR-induced NLRP3 inflammasome activation. First, the results of ELISA and qPCR assays showed that tCQA has anti-inflammatory effects in THP-1 cell line and healthy human peripheral blood mononuclear cells. Western blotting and ELISA suggested tCQA could inhibit NF-κB/MAPK signaling pathway, NLRP3 expression and the secretion of IL-1β in lipopolysaccharide (LPS)-stimulated THP-1 macrophages. Then, flow cytometry, LDH assay and western blotting demonstrated that tCQA could inhibit LPS- and nigericin-induced Caspase-1 activation and gasdermin D cleavage, thereby suppressing inflammatory cell death. Furthermore, we found that the autophagy inhibitor chloroquine, not the proteasome inhibitor MG132, could counteract the promoting effect of tCQA on NLRP3 degradation and the inhibitory effect on cell death. Western blotting and autophagosome staining results suggested tCQA could significantly enhance LPS-induced autophagic flux in macrophages and ATG5/ATG7 knockdown reverses the inhibitory effect of tCQA on NLRP3 expression and Caspase-1 activation, indicating that tCQA induces NLRP3 degradation via autophagy. Finally, THP-1 macrophages and BALB/c mice were irradiated with 137Cs γ-rays and tCQA could inhibit IR-induced NLRP3 inflammasome activation both in vitro and in vivo. To conclude, tCQA controls inflammation and NLRP3 inflammasome activation in vitro via NF-κB/MAPK signaling pathway and autophagy, meanwhile inhibits IR-induced NLRP3 inflammasome activation in vivo. Overall, our study provides an experimental and theoretical basis for the application of tCQA as a radioprotectant in clinical radiotherapy.

FLASH radiotherapy: an emerging approach in radiation therapy.

FLASH radiotherapy (RT) is a technique involving the delivery of ultra-high dose rate radiation to the target. FLASH-RT has been shown to reduce radiation-induced toxicity in healthy tissues without compromising the anti-cancer effects of treatment compared to conventional radiation therapy. In the present article, we review the published data on FLASH-RT and discuss the current state of knowledge of this novel approach. We also highlight the technological constraints and complexity of FLASH-RT and describe the physics underlying this modality, particularly how technology supports energy transfer by ionising radiation (e.g., beam on/off sequence, pulse-energy load, intervals). We emphasise that current preclinical experience is mostly based on FLASH electrons and that clinical application of FLASH-RT is very limited. The incorporation of FLASH-RT into routine clinical radiotherapy will require the development of devices capable of producing FLASH photon beams.

Development of a novel airbag system of abdominal compression for reducing respiratory motion: preliminary results in healthy volunteers.

This study used cine-magnetic resonance imaging (cine-MRI) to evaluate the safety and efficacy of a novel airbag system combined with a shell-type body fixation system in reducing respiratory motion in normal volunteers. The airbag system consists of a six-sided polygon inflatable airbag, a same shape plate, a stiff air supply tube, an air-supply pump and a digital pressure load cell monitor. Piezoelectric sensors were installed in the plate to detect compression pressure load changes; pressure load data were transferred to the digital pressure load cell monitor through Bluetooth. Five volunteers underwent cine-MRI with and without airbag compression to detect differences in the respiratory motion of the organs. The volunteers’ physiologic signs were stable during the experiment. The maximum inspiration pressure load was 4.48 ± 0.86 kgf (range, 4.00–6.00 kgf), while the minimum expiration pressure load was 3.69 ± 0.95 kgf (range, 2.8–5.3 kgf). Under airbag compression, the right diaphragm movement was reduced from 19.50 ± 6.43 mm to 9.60 ± 3.61 mm (P < 0.05) in the coronal plane and 23.12 ± 6.30 mm to 11.00 ± 3.69 mm (P < 0.05) in the sagittal plane. The left diaphragm, pancreas and liver in the coronal plane and the right kidney and liver in the sagittal plane also showed significant movement reduction. This novel airbag abdominal compression system was found to be safe during the experiment and successful in the reduction of internal organ respiratory motion and promises to be a convenient and efficient tool for clinical radiotherapy.

Chemoradiotherapy in Muscle-invasive Bladder Cancer: 10-yr Follow-up of the Phase 3 Randomised Controlled BC2001 Trial

BackgroundBC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer (MIBC), demonstrated improvement in locoregional control by adding fluorouracil and mitomycin C to radiotherapy (James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477–88). There are limited data on long-term recurrence risk. ObjectiveTo determine whether benefit of adding chemotherapy to radiotherapy for MIBC is maintained in the long term. Design, setting, and participantsA phase 3 randomised controlled 2 × 2 factorial trial was conducted. Between 2001 and 2008, 458 patients with T2-T4a N0M0 MIBC were enrolled; 360 were randomised to radiotherapy (178) or chemoradiotherapy (182), and 218 were randomised to standard whole-bladder radiotherapy (108) or reduced high-dose-volume radiotherapy (111). The median follow-up time was 9.9 yr. The trial is registered (ISRCTN68324339). InterventionRadiotherapy: 55 Gy in 20 fractions over 4 wk or 64 Gy in 32 fractions over 6.5 wk; concurrent chemotherapy: 5-fluorouracil and mitomycin C. Outcome measurements and statistical analysisLocoregional control (primary endpoint), invasive locoregional control, toxicity, rate of salvage cystectomy, disease-free survival (DFS), metastasis-free survival (MFS), bladder cancer–specific survival (BCSS), and overall survival. Cox regression was used. The analysis of efficacy outcomes was by intention to treat. Results and limitationsChemoradiotherapy improved locoregional control (hazard ratio [HR] 0.61 [95% confidence interval {CI} 0.43–0.86], p = 0.004) and invasive locoregional control (HR 0.55 [95% CI 0.36–0.84], p = 0.006). This benefit translated, albeit nonsignificantly, for disease-related outcomes: DFS (HR 0.78 [95% CI 0.60–1.02], p = 0.069), MFS (HR 0.78, [95% CI 0.58–1.05], p = 0.089), overall survival (HR = 0.88 [95% CI 0.69–1.13], p = 0.3), and BCSS (HR 0.79 [95% CI 0.59–1.06], p = 0.11). The 5-yr cystectomy rate was 14% (95% CI 9–21%) with chemoradiotherapy versus 22% (95% CI 16–31%) with radiotherapy alone (HR 0.54, [95% CI 0.31–0.95], p = 0.034). No differences were seen between standard and reduced high-dose-volume radiotherapy. ConclusionsLong-term findings confirm the benefit of adding concomitant 5-fluorouracil and mitomycin C to radiotherapy for MIBC. Patient summaryWe looked at long-term outcomes of a phase 3 clinical trial testing radiotherapy with or without chemotherapy for patients with invasive bladder cancer. We concluded that the benefit of adding chemotherapy to radiotherapy was maintained over 10 yr.

Microbeam Irradiation of the Beating Rodent Heart: An Ex Vivo Study of Acute and Subacute Effects on Cardiac Function

Microbeam radiation therapy (MRT) has shown several advantages compared with conventional broad-beam radiation therapy in small animal models, including a better preservation of normal tissue function and improved drug delivery based on a rapidly increased vascular permeability in the target region. Normal tissue tolerance is the limiting factor in clinical radiation therapy. Knowledge of the normal tissue tolerance of organs at risk is therefore a prerequisite in evaluating any new radiation therapy approach. With an irradiation target in the thoracic cavity, the heart would be the most important organ at risk. We used the ex vivo beating rodent heart in the Langendorff perfusion system at the synchrotron to administer microbeam irradiation (MBI) with a peak dose of 40 or 400 Gy. By continuously recording the electrocardiogram, the left ventricular pressure, and the aortic pressure before, during and after MBI, we were able to assess acute and subacute effects of MBI on electrophysiological and mechanical cardiac function. In addition, we analyzed histologic and ultrastructural sequelae caused by MBI. There were no significant changes in heart rate, heart rate variability, systolic increase of left ventricular pressure or aortic pressure. Moreover, the changes of heart rate, left ventricular pressure and aortic pressure by adding 10-5 mol/L norepinephrine to the perfusate, were also not significant between MBI and sham experiments. However, the rate-pressure product as a surrogate marker for maximum workload after MBI was significantly lower compared with sham-irradiated controls. On the structural level, no severe membranous, sarcomeric, mitochondrial or nuclear changes caused by MBI were detected by desmin immunohistochemistry and electron microscopy. With respect to acute and subacute toxicity, an MBI peak dose up to 400Gy did not result in severe changes in cardiac electrophysiology or mechanics.

Radioprotective effect of X-ray abdominal FLASH irradiation: Adaptation to oxidative damage and inflammatory response may be benefiting factors.

Ultrahigh dose-rate irradiation (FLASH-IR) was reported to be efficient in tumor control while reducing normal tissue radiotoxicity. However, the mechanism of such phenomenon is still unclear. Besides, the FLASH experiments using high energy X-ray, the most common modality in clinical radiotherapy, arerarely reported. This study aims to investigate the radiobiological response using 6 MV X-ray FLASH-IR or conventional dose-rate IR (CONV-IR). The superconducting linac of Chengdu THz Free Electron Laser (CTFEL) facility was used for FLASH-IR, a diamond radiation detector and a CeBr3 scintillation detector were used to monitor the time structure and dose rate of FLASH pulses. BALB/c nude mice received whole abdominal 6 MV X-ray FLASH-IR or CONV-IR, the prescribed dose was 15Gy or 10Gy and the delivered absolute dose was monitored with EBT3 films. The mice were either euthanized 24 h post-IR to evaluate acute tissue responses or followed up for 6weeks to observe late-stage responses and survival probability. Complete blood count, histological analyses, and measurement of cytokine expression and redox status were performed. The mean dose rate of>150Gy/s and instantaneous dose rate of>5.5 × 105 Gy/s was reached in FLASH-IR at the center of mice body. After 6 weeks' follow-up of mice that received 15Gy IR, the FLASH group showed faster body weight recovery and higher survival probability than the CONV group. Histological analysis showed that FLASH-IR induced less acute intestinal damage than CONV-IR. Complete blood count and cytokine concentration measurement found that the inflammatory blood cell counts and pro-inflammatory cytokine concentrations were elevated at the acute stage after both FLASH-IR and CONV-IR. However, FLASH irradiated mice had significantly fewer inflammatory blood cells and diminished pro-inflammatory cytokine at the late stage. Moreover, higher reactive oxygen species (ROS) signal intensities but significantly reduced lipid peroxidation were found in the FLASH group than in the CONV group in the acute stage. The radioprotective effect of 6 MV X-ray FLASH-IR was observed. The differences in inflammatory responses and redox status between the two groups may be the factors responsible for reduced radiotoxicities following FLASH-IR. Further studies are required to thoroughly evaluate the impact of ROS on FLASH effect.

Nanoscale Coordination Polymer Based on Bacterial Derivatives for Enhanced Radiotherapy in Neuroblastoma

Neuroblastoma (NB) is one of the most common extracranial malignancies in children, accounting for 7–8% of childhood malignancies. As one of the main treatments for NB, radiotherapy is limited by various factors in clinics, such as the hypoxia microenvironment in tumor and serious side effects. Herein, we synthesized a kind of nanoscale coordination polymer denoted as Hf@DAP nanoparticles composed of hafnium ion (Hf[Formula: see text] and 2,6-diaminopimelic acid (DAP), one of bacterial derivatives. From the image of transmission electron microscope (TEM), nanoparticles had uniform dispersion. Furthermore, the hydrodynamic diameter measured by dynamic light scattering method was about 190 nm. In this structure, the Hf[Formula: see text] can enhance radiotherapy by effectively enhancing the function of X-ray, and the DAP was a biocompatible ligand for fabricating the nanoscale coordination nanoparticles. Furthermore, Hf@DAP nanoparticles were stable in various mediums and exhibited favorable biocompatibility in various cell lines in vitro. Cell viabilities were tested by cell counting kit (CCK-8) in vitro. There was no obvious cytotoxicity to normal cells, including NIH3T3, RAW264.7, and HUVECs, after incubation with Hf@DAP nanoparticles, indicating biocompatibilities of Hf@DAP nanoparticles. Additionally, a significantly enhanced radiotherapy effect was observed in the N2a cells, a kind of NB cell line, pretreated with Hf@DAP nanoparticles in vitro. The in vivo tumor growth was obviously inhibited in the mice with the combined therapy of Hf@DAP nanoparticles and X-ray, compared with PBS group, Hf@DAP group, and X-ray group. Furthermore, the survival time of the mice in the combined group was significantly prolonged, compared with PBS group. In addition, tissues structures of main organs, such as the lung, liver, spleen, and kidney in these mice, were ordered without the influence of Hf@DAP nanoparticles. Thus, this work proposed a potential radio-sensitizer for further clinical radiotherapy with limited side effects and high efficiency.

Rapid variable flip angle positive susceptibility contrast imaging for clinical metal seeds

Positive susceptibility contrast imaging (PSCI) based on susceptibility mapping exhibits excellent efficacy for visualizing magnetic resonance (MR)-compatible metallic devices because of their high magnetic susceptibility compared to that of human tissues. However, the long-acquisition time required by the two-dimensional fast spin echo (2D FSE)-based PSCI approach, impedes its practical applications in 3D imaging. In this study, a three-dimensional (3D) susceptibility-based variable flip angle (vFA) FSE sequence was proposed to accelerate data acquisition in the clinical radiotherapy applications of ex vivo and in vivo rapid 3D PSCI for the imaging of metal seeds. Here, the proposed scheme applied a 3D modulated vFA technique for refocused imaging with an extended echo-train sequence for sampling data. The scheme integrated the projection-onto-dipole fields (PDF) to remove the background field and accelerate PSCI by using a compressive sensing framework with a variable-densitysampling mask. The experiments involved some gelatin phantoms, porcine tissues and patients with scapular tumors and brachytherapy seeds. All of the experimental results showed that the proposed scheme could accelerate data acquisition of 3D PSCI at the reduction factors of 2 ∼ 5 while accurately localizing the actual positions of the brachytherapy seeds in the ex vivo and in vivo applications. The results were compared with those of the existing methods, including susceptibility gradient mapping using the original resolution (SUMO) and gradient echo acquisition for superparamagnetic particle (GRASP).

Quantitative comparison of different dosimetry methods in orthovoltage X-ray therapy

Gamma index metric is frequently used for dose verification in quality control (QC) procedures for clinical radiation therapy. Monte Carlo (MC) simulations and radiochromic films can be used to validate complex dose plans for recording dose distributions in irradiated volume. When metal artifacts are present in the anatomical region of interest, a quantitative comparison of planned and experimental (mathematical simulation/physical study) dose using the gamma index metric and its 2D derivative may allow better weighted dose planning decisions. The purpose of this study was to use the gamma index derivative - 2D-dose/distance index (2DDI) to compare quantitatively different dosimetry methods used for evaluating dose distributions in orthovoltage X-ray therapy. 2DDI was validated by assessing the program's capabilities when comparing Monte Carlo simulated (FLUKA) dose distribution with EBT3 and RTQA2 film dosimetry. The proposed 2D-dose/distance index was found to be sensitive enough to assess dose discrepancies and dose distribution misalignments between two dosimetry methods that were also used to verify doses in objects with metal artifacts inside. The findings imply that 2DDI could be used for quality control in orthovoltage radiotherapy in complex cases involving metal artifacts in the anatomic region of interest.

Applications of Machine Learning to Improve the Clinical Viability of Compton Camera Based in vivo Range Verification in Proton Radiotherapy.

We studied the application of a deep, fully connected Neural Network (NN) to process prompt gamma (PG) data measured by a Compton camera (CC) during the delivery of clinical proton radiotherapy beams. The network identifies 1) recorded “bad” PG events arising from background noise during the measurement, and 2) the correct ordering of PG interactions in the CC to help improve the fidelity of “good” data used for image reconstruction. PG emission from a tissue-equivalent target during irradiation with a 150 MeV proton beam delivered at clinical dose rates was measured with a prototype CC. Images were reconstructed from both the raw measured data and the measured data that was further processed with a neural network (NN) trained to identify “good” and “bad” PG events and predict the ordering of individual interactions within the good PG events. We determine if NN processing of the CC data could improve the reconstructed PG images to a level in which they could provide clinically useful information about the in vivo range and range shifts of the proton beams delivered at full clinical dose rates. Results showed that a deep, fully connected NN improved the achievable contrast to noise ratio (CNR) in our images by more than a factor of 8x. This allowed the path, range, and lateral width of the clinical proton beam within a tissue equivalent target to easily be identified from the PG images, even at the highest dose rates of a 150 MeV proton beam used for clinical treatments. On average, shifts in the beam range as small as 3 mm could be identified. However, when limited by the amount of PG data measured with our prototype CC during the delivery of a single proton pencil beam (~1 × 109 protons), the uncertainty in the reconstructed PG images limited the identification of range shift to ~5 mm. Substantial improvements in CC images were obtained during clinical beam delivery through NN pre-processing of the measured PG data. We believe this shows the potential of NNs to help improve and push CC-based PG imaging toward eventual clinical application for proton RT treatment delivery verification.

Magnetron Sputtered CsPbCl3 Perovskite Detectors as Real-Time Dosimeters for Clinical Radiotherapy

The aim of this study is to investigate the feasibility of manufacturing thin real-time relative dosimeters for clinical radiotherapy (RT) with potential applications for transmission monitoring in vivo dosimetry and pre-treatment dose verifications. Thin (≈1μm) layers of a high sensitivity, wide bandgap semiconductor, the inorganic perovskite CsPbCl3, have been grown for the first time by magnetron sputtering on plastic substrates equipped with electrode arrays. Prototype devices have been tested in real-time configuration to evaluate the dose delivered by a 6MV photon beam from a linear accelerator. Linearity of the charge with the dose has been verified over three order of magnitudes, linearity of the current signal with the dose rate has been also successfully tested in the range 0.5-4.3Gy/min. The combination of high sensitivity per unit volume and wide bandgap provides high signal-to-noise ratios, up to 70, even at moderate applied voltages. The Schottky diode configuration allows the detector to operate without bias voltage (null bias).The blocking-barrier structure allows to confine the active volume within sub-millimetric sizes, a quite attractive feature in view to increase granularity and achieve the high spatial resolutions required in modern RT techniques. All the above-mentioned features indeed pave the way to a novel generation of flexible, transmission, real time dosimeters for clinical radiotherapy.

Gross Tumor Volume Definition and Comparative Assessment for Esophageal Squamous Cell Carcinoma From 3D 18F-FDG PET/CT by Deep Learning-Based Method.

BackgroundThe accurate definition of gross tumor volume (GTV) of esophageal squamous cell carcinoma (ESCC) can promote precise irradiation field determination, and further achieve the radiotherapy curative effect. This retrospective study is intended to assess the applicability of leveraging deep learning-based method to automatically define the GTV from 3D 18F-FDG PET/CT images of patients diagnosed with ESCC.MethodsWe perform experiments on a clinical cohort with 164 18F-FDG PET/CT scans. The state-of-the-art esophageal GTV segmentation deep neural net is first employed to delineate the lesion area on PET/CT images. Afterwards, we propose a novel equivalent truncated elliptical cone integral method (ETECIM) to estimate the GTV value. Indexes of Dice similarity coefficient (DSC), Hausdorff distance (HD), and mean surface distance (MSD) are used to evaluate the segmentation performance. Conformity index (CI), degree of inclusion (DI), and motion vector (MV) are used to assess the differences between predicted and ground truth tumors. Statistical differences in the GTV, DI, and position are also determined.ResultsWe perform 4-fold cross-validation for evaluation, reporting the values of DSC, HD, and MSD as 0.72 ± 0.02, 11.87 ± 4.20 mm, and 2.43 ± 0.60 mm (mean ± standard deviation), respectively. Pearson correlations (R2) achieve 0.8434, 0.8004, 0.9239, and 0.7119 for each fold cross-validation, and there is no significant difference (t = 1.193, p = 0.235) between the predicted and ground truth GTVs. For DI, a significant difference is found (t = −2.263, p = 0.009). For position assessment, there is no significant difference (left-right in x direction: t = 0.102, p = 0.919, anterior–posterior in y direction: t = 0.221, p = 0.826, and cranial–caudal in z direction: t = 0.569, p = 0.570) between the predicted and ground truth GTVs. The median of CI is 0.63, and the gotten MV is small.ConclusionsThe predicted tumors correspond well with the manual ground truth. The proposed GTV estimation approach ETECIM is more precise than the most commonly used voxel volume summation method. The ground truth GTVs can be solved out due to the good linear correlation with the predicted results. Deep learning-based method shows its promising in GTV definition and clinical radiotherapy application.

Emerging nanozymes for potentiating radiotherapy and radiation protection

While radiotherapy is a mainstay therapeutic modality for malignant tumor, the intrinsic tumor resistance to radiotherapy, as well as the concomitant radiation injury to adjacent healthy tissues, greatly limits the efficacy of cancer radiotherapy. As a result, the development of novel radioenhancers and radioprotectants is highly desired for clinical radiotherapy. In recent years, nanozymes have inspired ever-growing research interest because of their multi-enzyme activities and microenvironment-responsive feature. In view of the significant progress of nanozymes in radiation medicine, we, in this review, systematically illustrate the impressive progress of nanozymes for potentiating radiotherapy and radiation protection. First, the types of nanozymes used in tumor radiotherapy are briefly discussed. Subsequently, the main strategies of nanozymes to enhance the radiotherapy efficiency, including promoting the generation of reactive oxygen species (ROS), relieving hypoxia in tumor microenvironment and combining with other cancer therapeutic regimens, are summarized. Finally, the advances of typical nanozymes for preventing radiation-induced hematopoietic damage and gastrointestinal damage are highlighted.

Robust radiosensitization of hemoglobin-curcumin nanoparticles suppresses hypoxic hepatocellular carcinoma

BackgroundRadioresistance inducing by hypoxic microenvironment of hepatocellular carcinoma is a major obstacle to clinical radiotherapy. Advanced nanomedicine provides an alternative to alleviate the hypoxia extent of solid tumor, even to achieve effective synergistic treatment when combined with chemotherapy or radiotherapy.ResultsHerein, we developed a self-assembled nanoparticle based on hemoglobin and curcumin for photoacoustic imaging and radiotherapy of hypoxic hepatocellular carcinoma. The fabricated nanoparticles inhibited hepatoma migration and vascular mimics, and enhanced the radiosensitivity of hypoxic hepatoma cells in vitro via repressing cell proliferation and DNA damage repair, as well as inducing apoptosis. Benefit from oxygen-carrying hemoglobin combined with polyphenolic curcumin, the nanoparticles also effectively enhanced the photoacoustic contrast and the efficacy of radiotherapy for hepatocellular carcinoma in vivo.ConclusionsTogether, the current study offered a radiosensitization platform for optimizing the efficacy of nanomedicines on hypoxic radioresistant tumor.Graphical

Effects of BMI1 Gene on Regulating Apoptosis, Invasion, and Migration of HEC-1B Cells Induced by Ionizing Radiation.

The aim of this study was to examine the role of B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1) gene in regulating the apoptosis, invasion, and migration of human endometrial adenocarcinoma cell line (HEC-1B) cells induced by ionizing radiation. The expression of BMI1 mRNA was detected by quantitative real-time polymerase chain reaction (qRT-PCR), and the positive expression of BMI1 was detected by immunohistochemistry (IHC) staining. HEC-1 B cells were randomly divided into three groups: control group, BMI1 overexpression group, and BMI1 inhibitor group. Cell proliferation was detected by cell counting kit-8 (CCK-8); cell migration and invasion were detected by Transwell test; cell apoptosis was detected by flow cytometry; and the expression of MMP2, MMP7, MMP9, Rock1, RhoA, P53, P21, and Bax protein was detected by the western blot. The results suggested that the expression of BMI1 mRNA and tissue positive in endometrial cancer tissues was increased significantly. After ionizing radiation, compared with the control group, the proliferation, cell migration, and invasion of HEC-1B cells were increased significantly in the BMI1 overexpression group, while the proliferation, cell migration, and invasion of HEC-1B cells were decreased significantly in BMI1 inhibitor group. The apoptosis rate of BMI1 overexpression group was decreased significantly, while the BMI1 inhibitor group was increased significantly. The levels of MMP2, MMP7, MMP9, Rock1, RhoA and p53, p21, Bax protein in BMI1 overexpression group were significantly increased, while the levels of MMP2, MMP7, MMP9, Rock1, RhoA and p53, p21, Bax protein in BMI1 inhibitor group were significantly decreased. BMI1 is highly expressed in endometrial cancer tissues, and inhibiting BMI1 expression can reduce the proliferation, migration, and invasion of HEC-1B cells after ionizing radiation and promote apoptosis, which offers new insights into the clinical radiotherapy of tumors.

Targeting Protein Arginine Methyltransferase 5 Suppresses Radiation-induced Neuroendocrine Differentiation and Sensitizes Prostate Cancer Cells to Radiation.

Prostate cancer remains the second leading cause of cancer death among American men. Radiotherapy is a potentially curative treatment for localized prostate cancer, and failure to control localized disease contributes to the majority of prostate cancer deaths. Neuroendocrine differentiation (NED) in prostate cancer, a process by which prostate adenocarcinoma cells transdifferentiate into neuroendocrine-like (NE-like) cells, is an emerging mechanism of resistance to cancer therapies and contributes to disease progression. NED also occurs in response to treatment to promote the development of treatment-induced neuroendocrine prostate cancer (NEPC), a highly aggressive and terminal stage disease. We previously demonstrated that by mimicking clinical radiotherapy protocol, fractionated ionizing radiation (FIR) induces prostate cancer cells to undergo NED in vitro and in vivo. Here, we performed transcriptomic analysis and confirmed that FIR-induced NE-like cells share some features of clinical NEPC, suggesting that FIR-induced NED represents a clinically relevant model. Furthermore, we demonstrated that protein arginine methyltransferase 5 (PRMT5), a master epigenetic regulator of the DNA damage response and a putative oncogene in prostate cancer, along with its cofactors pICln and MEP50, mediate FIR-induced NED. Knockdown of PRMT5, pICln, or MEP50 during FIR-induced NED and sensitized prostate cancer cells to radiation. Significantly, PRMT5 knockdown in prostate cancer xenograft tumors in mice during FIR prevented NED, enhanced tumor killing, significantly reduced and delayed tumor recurrence, and prolonged overall survival. Collectively, our results demonstrate that PRMT5 promotes FIR-induced NED and suggests that targeting PRMT5 may be a novel and effective radiosensitization approach for prostate cancer radiotherapy.

Study on esophageal cancer radiotherapy dosimetry and position verification for volumetric modulated arc therapy

BackgroundThis study analyzed the respective advantages and disadvantages by comparing volumetric modulated arc therapy (VMAT) and intensity modulated radiotherapy (IMRT) on the dose distribution and position verification distribution characteristics in esophageal cancer radiotherapy, in order to provide the reference for the clinical radiotherapy technology optimization of esophageal cancer. MethodsA total of 56 cases of patients with esophageal cancer were selected and applied to the Pinnacle three-dimensional radiation treatment planning system (TPS), in order to design a VMAT plan and IMRT plan under the guidance of image-guided radiotherapy (IGRT). The dosimetry and position verification difference were compared between the two groups. ResultsRevealed that the target dose distribution of the VMAT plan and IMRT plan meets the requirements in clinical dosimetry for all 56 patients in this study. Under the premise of similar target coverage, the conformal index (CI) of the VMAT plan, homogeneity index (HI), target volume, BODY-PTV radiated volume and spinal cord Dmax, bilateral lung V5, V20 and mean lung dose (MLD), monitor unit (MU) and treatment time (TT), as well as position verification and others, were obviously superior to those in the IMRT plan; and the difference was statistically significant. ConclusionCBCT guided VMAT is a potential effective treatment for esophageal cancer and may be more effective and safer than IMRT.

Stereotactic body radiotherapy optimization to reduce the risk of carotid blowout syndrome using normal tissue complication probability objectives.

PurposeTo determine the possibility of further improving clinical stereotactic body radiotherapy (SBRT) plans using normal tissue complication probability (NTCP) objectives in order to minimize the risk for carotid blowout syndrome (CBOS).Methods10 patients with inoperable locally recurrent head and neck cancer, who underwent SBRT using CyberKnife were analyzed. For each patient, three treatment plans were examined: (1) cone‐based without delineation of the ipsilateral internal carotid (clinical plan used to treat the patients); (2) cone‐based with the carotid retrospectively delineated and spared; and (3) Iris‐based with carotid sparing. The dose–volume histograms of the target and primary organs at risk were calculated. The three sets of plans were compared based on dosimetric and TCP/NTCP (tumor control and normal tissue complication probabilities) metrics. For the NTCP values of carotid, the relative seriality model was used with the following parameters: D 50 = 40 Gy, γ = 0.75, and s = 1.0.ResultsAcross the 10 patient plans, the average TCP did not significantly change when the plans were re‐optimized to spare the carotid. The estimated risk of CBOS was significantly decreased in the re‐optimized plans, by 14.9% ± 7.4% for the cone‐based plans and 17.7% ± 7.1% for the iris‐based plans (p = 0.002 for both). The iris‐based plans had significant (p = 0.02) reduced CBOS risk and delivery time (20.1% ± 7.4% time reduction, p = 0.002) compared to the cone‐based plans.ConclusionA significant improvement in the quality of the clinical plans could be achieved through the delineation of the internal carotids and the use of more modern treatment delivery modalities. In this way, for the same target coverage, a significant reduction in the risk of CBOS could be achieved. The range of risk reduction varied depending on the proximity of carotid artery to the target.