Therapeutic Targeting of Glutaminolysis as a Novel Strategy to Combat Cancer Stem Cells.

Rare subpopulations of cancer stem cells (CSCs) have the ability to self-renew and are the primary driving force behind cancer metastatic dissemination and the preeminent hurdle to cancer treatment. As opposed to differentiated, non-malignant tumor offspring, CSCs have sophisticated metabolic patterns that, depending on the kind of cancer, rely mostly on the oxidation of major fuel substrates such as glucose, glutamine, and fatty acids for survival. Glutaminolysis is a series of metabolic reactions that convert glutamine to glutamate and, eventually, α-ketoglutarate, an intermediate in the tricarboxylic acid (TCA) cycle that provides biosynthetic building blocks. These building blocks are mostly utilized in the synthesis of macromolecules and antioxidants for redox homeostasis. A recent study revealed the cellular and molecular interconnections between glutamine and cancer stemness in the cell. Researchers have increasingly focused on glutamine catabolism in their attempt to discover an effective therapy for cancer stem cells. Targeting catalytic enzymes in glutaminolysis, such as glutaminase (GLS), is achievable with small molecule inhibitors, some of which are in early-phase clinical trials and have promising safety profiles. This review summarizes the current findings in glutaminolysis of CSCs and focuses on novel cancer therapies that target glutaminolysis in CSCs.

Prognostic and predictive factors for clinical and radiographic responses in patients with painful bone metastasis treated with magnetic resonance-guided focused ultrasound surgery.

Background: Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is an alternative local therapy for patients with painful bone metastasis. However, little is known about the prognostic and predictive factors of MRgFUS in treating bone metastasis. Materials and methods: This retrospective study analyzed the performance status, treated site, pretreatment pain score, pretreatment tumor volume and lesion coverage volume factor (CVF) of 31 patients who underwent MRgFUS. A numerical rating scale for pain was used at the same time to assess the clinical response. Radiographic responses were evaluated using a modified version of The University of Texas MD Anderson Cancer Center criteria and reference to the MR imaging or computed tomography scans obtained 3 months after treatment. Univariate and multivariate logistic regression analyses were conducted to examine the effect of variables on clinical and radiographic responses. Results: The overall clinical response rate was 83.9% and radiographic response rate was 67.7%. Multivariate logistic regression analysis revealed that the better pretreatment Karnofsky performance status (KPS) (odds ratio: 1.220, 95% confidence interval (CI): 1.033-1.440; p = 0.019) was significantly associated with a more positive clinical response, and that the lesion CVF (odds ratio: 1.183, 95% CI: 1.029-1.183; p = 0.0055) was an independent prognostic factor for radiographic responses. The radiographic response of patients with lesion CVF ≥70% and CVF <70% were 91.7% and 52.6%, respectively (p = 0.0235). Conclusion: The pretreatment KPS was an independent prognostic factor for clinical responses, and lesion CVF was an independent prognostic factor for radiographic responses.

Adaptive control of phase leading compensator parameters applied to respiratory motion compensation system.

PURPOSE: This study evaluates the feasibility of our previously developed Respiratory Motion Compensation System (RMCS) combined with the Phase Lead Compensator (PLC) to eliminate system delays during the compensation of respiration-induced tumor motion. The study objective is to improve the compensation effect of RMCS and the efficay of radiation therapy to reduce its side effects to the patients. MATERIAL AND METHODS: In this study, LabVIEW was used to develop the proposed software for calculating real-time adaptive control parameters, combined with PLC and RMCS for the compensation of total system delay time. Experiments of respiratory motion compensation were performed using 6 pre-recorded human respiration patterns and 7 sets of different sine waves. During the experiments, a respiratory simulation device, Respiratory Motion Simulation System (RMSS), was placed on the RMCS, and the detected target motion signals by the Ultrasound Image Tracking Algorithm (UITA) were transmitted to the RMCS, and the compensation of respiration induced motion was started. Finally, the tracking error of the system is obtained by comparing the encoder signals bwtween RMSS and RMCS. The compensation efficacy is verified by the root mean squared error (RMSE) and the system compensation rate (CR). RESULTS: The experimental results show that the calcuated CR with the simulated respiration patterns is between 42.85% ∼3.53% and 33.76% ∼2.62% in the Right-Left (RL) and Superior-Inferior (SI), respectively, after the RMCS compensation of using the adaptive control parameters in PLC. For the compensation results of human respiration patterns, the CR is between 58.95% ∼8.56% and 62.87% ∼9.05% in RL and SI, respectively. CONCLUSIONS: During the respiratory motion compensation, the influence of the delay time of the entire system (RMCS+RMSS+UITA) on the compensation effect was improved by adding an adaptive control PLC, which reduces compensation error and helps improve efficacy of radiation therapy.

Garcinol downregulates Notch1 signaling via modulating miR-200c and suppresses oncogenic properties of PANC-1 cancer stem-like cells.

Pancreatic cancer represents one of the most aggressive types of malignancy due to its high resistance toward most clinically available treatments. The presence of pancreatic cancer stem-like cells (CSCs) has been attributed to the intrinsically high resistance and highly metastatic potential of this disease. Here, we identified and isolated pancreatic CSCs using the side population (SP) method from human pancreatic cancer cell line, PANC-1. We then compared the SP and non-SP PANC-1 cells genetically. PANC-1 SP cells exhibited CSC properties including enhanced self-renewal ability, increased metastatic potential, and resistance toward gemcitabine treatment. These cancer stem-like phenotypes were supported by their enhanced expression of ABCG2, Oct4, and CD44. A traditional plant-derived antioxidant, garcinol, has been implicated for its anticancer properties. Here, we found that garcinol treatment to PANC-1 SP cells significantly suppressed the stem-like properties of PANC-1 SP cells and metastatic potential by downregulating the expression of Mcl-1, EZH2, ABCG2, Gli-1, and Notch1. More importantly, garcinol treatment led to the upregulation of several tumor suppressor microRNAs, and miR-200c increased by garcinol treatment was found to target and downregulate Notch1. Thus, PANC-1 SP cells may serve as a model for studying drug-resistant pancreatic CSCs, and garcinol has the potential as an antagonist against pancreatic CSCs.

Arrhythmia Evaluation in Wearable ECG Devices.

This study evaluates four databases from PhysioNet: The American Heart Association database (AHADB), Creighton University Ventricular Tachyarrhythmia database (CUDB), MIT-BIH Arrhythmia database (MITDB), and MIT-BIH Noise Stress Test database (NSTDB). The ANSI/AAMI EC57:2012 is used for the evaluation of the algorithms for the supraventricular ectopic beat (SVEB), ventricular ectopic beat (VEB), atrial fibrillation (AF), and ventricular fibrillation (VF) via the evaluation of the sensitivity, positive predictivity and false positive rate. Sample entropy, fast Fourier transform (FFT), and multilayer perceptron neural network with backpropagation training algorithm are selected for the integrated detection algorithms. For this study, the result for SVEB has some improvements compared to a previous study that also utilized ANSI/AAMI EC57. In further, VEB sensitivity and positive predictivity gross evaluations have greater than 80%, except for the positive predictivity of the NSTDB database. For AF gross evaluation of MITDB database, the results show very good classification, excluding the episode sensitivity. In advanced, for VF gross evaluation, the episode sensitivity and positive predictivity for the AHADB, MITDB, and CUDB, have greater than 80%, except for MITDB episode positive predictivity, which is 75%. The achieved results show that the proposed integrated SVEB, VEB, AF, and VF detection algorithm has an accurate classification according to ANSI/AAMI EC57:2012. In conclusion, the proposed integrated detection algorithm can achieve good accuracy in comparison with other previous studies. Furthermore, more advanced algorithms and hardware devices should be performed in future for arrhythmia detection and evaluation.

An autotuning respiration compensation system based on ultrasound image tracking.

The purpose of this study was to develop an ultrasound image tracking algorithm (UITA) for extracting the exact displacement of internal organs caused by respiratory motion. The program can track organ displacements in real time, and analyze the displacement signals associated with organ displacements via a respiration compensating system (RCS). The ultrasound imaging system is noninvasive and has a high spatial resolution and a high frame rate (around 32 frames/s), which reduces the radiation doses that patients receive during computed tomography and X-ray observations. This allows for the continuous noninvasive observation and compensation of organ displacements simultaneously during a radiation therapy session.This study designed a UITA for tracking the motion of a specific target, such as the human diaphragm. Simulated diaphragm motion driven by a respiration simulation system was observed with an ultrasound imaging system, and then the induced diaphragm displacements were calculated by our proposed UITA. These signals were used to adjust the gain of the RCS so that the amplitudes of the compensation signals were close to the target movements. The inclination angle of the ultrasound probe with respect to the surface of the abdomen affects the results of ultrasound image displacement tracking. Therefore, the displacement of the phantom was verified by a LINAC with different inclination-angle settings of the ultrasound probe. The experimental results indicate that the best inclination angle of the ultrasound probe is 40 degrees, since this results in the target displacement of the ultrasound images being close to the actual target motion. The displacement signals of the tracking phantom and the opposing displacement signals created by the RCS were compared to assess the positioning accuracy of our proposed ultrasound image tracking technique combined with the RCS.When the ultrasound probe was inclined by 40 degrees in simulated respiration experiments using sine waves, the correlation between the target displacement on the ultrasound images and the actual target displacement was around 97%, and all of the compensation rates exceeded 94% after activating the RCS. Furthermore, the diaphragm movements on the ultrasound images of three patients could be captured by our image tracking technique. The test results show that our algorithm could achieve precise point locking and tracking functions on the diaphragm. This study has demonstrated the feasibility of the proposed ultrasound image tracking technique combined with the RCS for compensating for organ displacements caused by respiratory motion.This study has shown that the proposed ultrasound image tracking technique combined with the RCS can provide real-time compensation of respiratory motion during radiation therapy, without increasing the overall treatment time. In addition, the system has modest space requirements and is easy to operate.

Recent Advances in Metal-Based NanoEnhancers for Particle Therapy.

Radiotherapy is one of the most common therapeutic regimens for cancer treatment. Over the past decade, proton therapy (PT) has emerged as an advanced type of radiotherapy (RT) that uses proton beams instead of conventional photon RT. Both PT and carbon-ion beam therapy (CIBT) exhibit excellent therapeutic results because of the physical characteristics of the resulting Bragg peaks, which has been exploited for cancer treatment in medical centers worldwide. Although particle therapies show significant advantages to photon RT by minimizing the radiation damage to normal tissue after the tumors, they still cause damage to normal tissue before the tumor. Since the physical mechanisms are different from particle therapy and photon RT, efforts have been made to ameliorate these effects by combining nanomaterials and particle therapies to improve tumor targeting by concentrating the radiation effects. Metallic nanoparticles (MNPs) exhibit many unique properties, such as strong X-ray absorption cross-sections and catalytic activity, and they are considered nano-radioenhancers (NREs) for RT. In this review, we systematically summarize the putative mechanisms involved in NRE-induced radioenhancement in particle therapy and the experimental results in in vitro and in vivo models. We also discuss the potential of translating preclinical metal-based NP-enhanced particle therapy studies into clinical practice using examples of several metal-based NREs, such as SPION, Abraxane, AGuIX, and NBTXR3. Furthermore, the future challenges and development of NREs for PT are presented for clinical translation. Finally, we propose a roadmap to pursue future studies to strengthen the interplay of particle therapy and nanomedicine.

Frontier Review of the Molecular Mechanisms and Current Approaches of Stem Cell-Derived Exosomes.

Exosomes are effective therapeutic vehicles that may transport their substances across cells. They are shown to possess the capacity to affect cell proliferation, migration, anti-apoptosis, anti-scarring, and angiogenesis, via the action of transporting molecular components. Possessing immense potential in regenerative medicine, exosomes, especially stem cell-derived exosomes, have the advantages of low immunogenicity, minimal invasiveness, and broad clinical applicability. Exosome biodistribution and pharmacokinetics may be altered, in response to recent advancements in technology, for the purpose of treating particular illnesses. Yet, prior to clinical application, it is crucial to ascertain the ideal dose and any potential negative consequences of an exosome. This review focuses on the therapeutic potential of stem cell-derived exosomes and further illustrates the molecular mechanisms that underpin their potential in musculoskeletal regeneration, wound healing, female infertility, cardiac recovery, immunomodulation, neurological disease, and metabolic regulation. In addition, we provide a summary of the currently effective techniques for isolating exosomes, and describe the innovations in biomaterials that improve the efficacy of exosome-based treatments. Overall, this paper provides an updated overview of the biological factors found in stem cell-derived exosomes, as well as potential targets for future cell-free therapeutic applications.

Development and evaluation of ultrasound image tracking technology based on Mask R-CNN applied to respiratory motion compensation system.

Background: For respiration induced tumor displacement during a radiation therapy, a common method to prevent the extra radiation is image-guided radiation therapy. Moreover, mask region-based convolutional neural networks (Mask R-CNN) is one of the state-of-the-art (SOTA) object detection frameworks capable of conducting object classification, localization, and pixel-level instance segmentation. Methods: We developed a novel ultrasound image tracking technology based on Mask R-CNN for stable tracking of the detected diaphragm motion and applied to the respiratory motion compensation system (RMCS). For training Mask R-CNN, 1800 ultrasonic images of the human diaphragm are collected. Subsequently, an ultrasonic image tracking algorithm was developed to compute the mean pixel coordinates of the diaphragm detected by Mask R-CNN. These calculated coordinates are then utilized by the RMCS for compensation purposes. The tracking similarity verification experiment of mask ultrasonic imaging tracking algorithm (M-UITA) is performed. Results: The correlation between the input signal and the signal tracked by M-UITA was evaluated during the experiment. The average discrete Fréchet distance was less than 4 mm. Subsequently, a respiratory displacement compensation experiment was conducted. The proposed method was compared to UITA, and the compensation rates of three different respiratory signals were calculated and compared. The experimental results showed that the proposed method achieved a 6.22% improvement in compensation rate compared to UITA. Conclusions: This study introduces a novel method called M-UITA, which offers high tracking precision and excellent stability for monitoring diaphragm movement. Additionally, it eliminates the need for manual parameter adjustments during operation, which is an added advantage.

Effectiveness of Stereotactic Ablative Radiotherapy for Systemic Therapy Respondents with Inoperable Pulmonary Oligometastases and Oligoprogression.

Stereotactic ablative radiotherapy (SABR) may improve survival in patients with inoperable pulmonary oligometastases. However, the impact of pulmonary oligometastatic status after systemic therapy on SABR outcomes remains unclear. Hence, we investigated the outcomes of SABR in 45 patients with 77 lung tumors and the prognostic value of pulmonary oligoprogression. Eligibility criteria were pulmonary oligometastases (defined as ≤5 metastatic lung tumors), controlled extrapulmonary disease (EPD) after front-line systemic therapy, SABR as primary local treatment for inoperable pulmonary metastases, and consecutive imaging follow-up. Oligometastatic lung tumor was classified into controlled or oligoprogressive status. Overall survival (OS), in-field progression-free survival (IFPFS), out-field progression-free survival (OFPFS), and prognostic variables were evaluated. With 21.8 months median follow-up, the median OS, IFPFS, and OFPFS were 28.3, not reached, and 6.5 months, respectively. Two-year OS, IFPFS, and OFPFS rates were 56.0%, 74.2%, and 17.3%, respectively. Oligoprogressive status (p = 0.003), disease-free interval < 24 months (p = 0.041), and biologically effective dose (BED10) < 100 Gy (p = 0.006) were independently associated with inferior OS. BED10 ≥ 100 Gy (p = 0.029) was independently correlated with longer IFPFS. Oligoprogressive status (p = 0.017) and EPD (p = 0.019) were significantly associated with inferior OFPFS. Grade ≥ 2 radiation pneumonitis occurred in four (8.9%) patients. Conclusively, SABR with BED10 ≥ 100 Gy could provide substantial in-field tumor control and longer OS for systemic therapy respondents with inoperable pulmonary oligometastases. Oligoprogressive lung tumors exhibited a higher risk of out-field treatment failure and shorter OS. Hence, systemic therapy should be tailored for patients with oligoprogression to reduce the risk of out-field treatment failure. However, in the absence of effective systemic therapy, SABR is a reasonable alternative to reduce resistant tumor burden.

Feasibility and Toxicity of Interval-Compressed Chemotherapy in Asian Children and Young Adults with Sarcoma.

Twelve Asian patients with sarcoma received interval-compressed (ic-) chemotherapy scheduled every 14 days with a regimen of vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1200-2200 mg/m2) (VDC) alternating with a regimen of ifosfamide (9000 mg/m2) and etoposide (500 mg/m2) (IE), with filgrastim (5-10 mcg/kg/day) between cycles. Carboplatin (800 mg/m2) was added for CIC-rearranged sarcoma. The patients were treated with 129 cycles of ic-VDC/IE with a median interval of 19 days (interquartile range [IQR], 15-24 days. Median nadirs (IQR) were neutrophil count, 134 (30-396) × 106/L at day 11 (10-12), recovery by day 15 (14-17) and platelet count, 35 (23-83) × 109/L at day 11 (10-13), recovery by day 17 (14-21). Fever and bacteremia were observed in 36% and 8% of cycles, respectively. The diagnoses were Ewing sarcoma (6), rhabdomyosarcoma (3), myoepithelial carcinoma (1), malignant peripheral nerve sheath tumor (1), and CIC-DUX4 Sarcoma (1). Seven of the nine patients with measurable tumors responded (one CR and six PR). Interval-compressed chemotherapy is feasible in the treatment of Asian children and young adults with sarcomas.

A Few-Shot Learning Approach Assists in the Prognosis Prediction of Magnetic Resonance-Guided Focused Ultrasound for the Local Control of Bone Metastatic Lesions.

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) constitutes a noninvasive treatment strategy to ablate deep-seated bone metastases. However, limited evidence suggests that, although cytokines are influenced by thermal necrosis, there is still no cytokine threshold for clinical responses. A prediction model to approximate the postablation immune status on the basis of circulating cytokine activation is thus needed. IL-6 and IP-10, which are proinflammatory cytokines, decreased significantly during the acute phase. Wound-healing cytokines such as VEGF and PDGF increased after ablation, but the increase was not statistically significant. In this phase, IL-6, IL-13, IP-10, and eotaxin expression levels diminished the ongoing inflammatory progression in the treated sites. These cytokine changes also correlated with the response rate of primary tumor control after acute periods. The few-shot learning algorithm was applied to test the correlation between cytokine levels and local control (p = 0.036). The best-fitted model included IL-6, IL-13, IP-10, and eotaxin as cytokine parameters from the few-shot selection, and had an accuracy of 85.2%, sensitivity of 88.6%, and AUC of 0.95. The acceptable usage of this model may help predict the acute-phase prognosis of a patient with painful bone metastasis who underwent local MRgFUS. The application of machine learning in bone metastasis is equivalent or better than the current logistic regression.

Retrospective Analysis for Dose Reduction to Organs at Risk with New Personalized Breast Holder (PERSBRA) in Left Breast IMRT.

This study evaluated dose differences in normal organs at risk, such as the lungs, heart, left anterior descending artery (LAD), right coronary artery, left ventricle, and right breast under personalized breast holder (PERSBRA), when using intensity-modulated radiation therapy (IMRT). This study evaluated the radiation protection offered by PERSBRA in left breast cancer radiation therapy. Here, we retrospectively collected data from 24 patients with left breast cancer who underwent breast-conserving surgery as well as IMRT radiotherapy. We compared the dose differences in target coverage and organs at risk with and without PERSBRA. For target coverage, tumor prescribed dose 95% coverage, conformity index, and homogeneity index were evaluated. For organs at risk, we compared the mean heart dose, mean left ventricle dose, LAD maximum and mean dose, mean left lung receiving 20 Gy, 10 Gy, and 5 Gy of left lung volume, maximum and mean coronary artery of the right, maximum of right breast, and mean dose. Good target coverage was achieved with and without PERSBRA. When PERSBRA was used with IMRT, the mean dose of the heart decreased by 42%, the maximum dose of LAD decreased by 26.4%, and the mean dose of LAD decreased by 47.0%. The mean dose of the left ventricle decreased by 54.1%, the volume (V20) of the left lung that received 20 Gy decreased by 22.8%, the volume (V10) of the left lung that received 10 Gy decreased by 19.8%, the volume (V5) of the left lung that received 5 Gy decreased by 15.7%, and the mean dose of the left lung decreased by 23.3%. Using PERSBRA with IMRT greatly decreases the dose to organs at risk (left lung, heart, left ventricle, and LAD). This study found that PERSBRA with IMRT can achieve results similar to deep inspiration breath-hold radiotherapy (DIBH) in terms of reducing the heart radiation dose and the risk of developing heart disease in patients with left breast cancer who cannot undergo DIBH.

Skin Surface Dose for Whole Breast Radiotherapy Using Personalized Breast Holder: Comparison with Various Radiotherapy Techniques and Clinical Experiences.

PURPOSE: Breast immobilization with personalized breast holder (PERSBRA) is a promising approach for normal organ protection during whole breast radiotherapy. The aim of this study is to evaluate the skin surface dose for breast radiotherapy with PERSBRA using different radiotherapy techniques. MATERIALS AND METHODS: We designed PERSBRA with three different mesh sizes (large, fine and solid) and applied them on an anthropomorphic(Rando) phantom. Treatment planning was generated using hybrid, intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) techniques to deliver a prescribed dose of 5000 cGy in 25 fractions accordingly. Dose measurement with EBT3 film and TLD were taken on Rando phantom without PERSBRA, large mesh, fine mesh and solid PERSBRA for (a) tumor doses, (b) surface doses for medial field and lateral field irradiation undergoing hybrid, IMRT, VMAT techniques. RESULTS: The tumor dose deviation was less than five percent between the measured doses of the EBT3 film and the TLD among the different techniques. The application of a PERSBRA was associated with a higher dose of the skin surface. A large mesh size of PERSBRA was associated with a lower surface dose. The findings were consistent among hybrid, IMRT, or VMAT techniques. CONCLUSIONS: Breast immobilization with PERSBRA can reduce heart toxicity but leads to a build-up of skin surface doses, which can be improved with a larger mesh design for common radiotherapy techniques.

Atypical Teratoid/Rhabdoid Tumor in Taiwan: A Nationwide, Population-Based Study.

BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly aggressive embryonal brain tumor most commonly presenting in young children. METHODS: We performed a nationwide, population-based study of AT/RT (ICD-O-3 code: 9508/3) in Taiwan using the Taiwan Cancer Registry Database and the National Death Certificate Database. RESULTS: A total of 47 cases (male/female = 29:18; median age at diagnosis, 23.3 months (IQR: 12.5-87.9)) were diagnosed with AT/RT between 1999 and 2014. AT/RT had higher prevalence in males (61.70%), in children < 36 months (55.32%), and at infratentorial or spinal locations (46.81%). Survival analyses demonstrated that patients ≥ 3 years of age (n = 21 (45%)) had a 5y-OS of 41% (p < 0.0001), treatment with radiotherapy only (n = 5 (11%)) led to a 5y-OS of 60%, treatment with chemotherapy with or without radiotherapy (n = 27 (62%)) was associated with a 5y-OS of 45% (p < 0.0001), and patients with a supratentorial tumor (n = 11 (23%)) had a 5y-OS of 51.95%. Predictors of better survival on univariate Cox proportional hazard modeling and confirmed with multivariate analysis included older age (≥1 year), supratentorial sites, and the administration of radiotherapy, chemotherapy, or both. Gender had no effect on survival. CONCLUSION: Older age, supratentorial site, and treatment with radiotherapy, chemotherapy, or both significantly improves the survival of patients with AT/RT.

The feasibility of an approximate irregular field dose distribution simulation program applied to a respiratory motion compensation system.

PURPOSE: This study optimized our previously proposed simulation program for the approximate irregular field dose distribution (SPAD) and applied it to a respiratory motion compensation system (RMCS) and respiratory motion simulation system (RMSS). The main purpose was to rapidly analyze the two-dimensional dose distribution and evaluate the compensation effect of the RMCS during radiotherapy. METHODS: This study modified the SPAD to improve the rapid analysis of the dose distribution. In the experimental setup, four different respiratory signal patterns were input to the RMSS for actuation, and an ultrasound image tracking algorithm was used to capture the real-time respiratory displacement, which was input to the RMCS for actuation. A linear accelerator simultaneously irradiated the EBT3 film. The gamma passing rate was used to verify the dose similarity between the EBT3 film and the SPAD, and conformity index (CI) and compensation rate (CR) were used to quantify the compensation effect. RESULTS: The Gamma passing rates were 70.48-81.39% (2%/2mm) and 88.23-96.23% (5%/3mm) for various collimator opening patterns. However, the passing rates of the SPAD and EBT3 film ranged from 61.85% to 99.85% at each treatment time point. Under the four different respiratory signal patterns, CR ranged between 21% and 75%. After compensation, the CI for 85%, 90%, and 95% isodose constraints were 0.78, 0.57, and 0.12, respectively. CONCLUSIONS: This study has demonstrated that the dose change during each stage of the treatment process can be analyzed rapidly using the improved SPAD. After compensation, applying the RMCS can reduce the treatment errors caused by respiratory movements.

Tumor motion tracking based on a four-dimensional computed tomography respiratory motion model driven by an ultrasound tracking technique.

BACKGROUND: An ultrasound image tracking algorithm (UITA) was combined with four-dimensional computed tomography (4DCT) to create a real-time tumor motion-conversion model. The real-time position of a lung tumor phantom based on the real-time diaphragm motion trajectories detected by ultrasound imaging in the superior-inferior (SI) and medial-lateral (ML) directions were obtained. METHODS: Three different tumor motion-conversion models were created using a respiratory motion simulation system (RMSS) combined with 4DCT. The tumor tracking error was verified using cone-beam computed tomography (CBCT). The tumor motion-conversion model was produced by using the UITA to monitor the motion trajectories of the diaphragm phantom in the SI direction, and using 4DCT to monitor the motion trajectories of the tumor phantom in the SI and ML directions over the same time period, to obtain parameters for the motion-conversion model such as the tumor center position and the amplitude and phase ratios. RESULTS: The tumor movement was monitored for 90 s using CBCT to determine the real motion trajectories of the tumor phantom and using ultrasound imaging to simultaneously record the diaphragm movement. The absolute error of the motion trajectories of the real and estimated tumor varied between 0.5 and 2.1 mm in the two directions. CONCLUSIONS: This study has demonstrated the feasibility of using ultrasound imaging to track diaphragmatic motion combined with a 4DCT tumor motion-conversion model to track tumor motion in the SI and ML directions. The proposed method makes tracking a lung tumor feasible in real time, including under different breathing conditions.

Simulating the approximate irregular field dose distribution in radiotherapy using an ultrasound tracking technique.

PURPOSE: This study used an ultrasound image tracking algorithm (UITA) in combination with a proposed simulation program for the approximate irregular field dose distribution (SPAD) to assess the feasibility of performing dose distribution simulations for two-dimensional radiotherapy. METHODS: This study created five different types of multileaf collimator openings, and applied a SPAD to analyze the matrix position parameters for each regular field to generate a static program-simulation dose distribution map (PDDM), whose similarity was then compared with a static radiochromic film experimental-measurement dose distribution map (EDDM). A two-dimensional respiration motion simulation system (RMSS) was used to reproduce the respiration motion, and the UITA was used to capture the respiration signals. Respiration signals were input to the SPAD to generate two dynamic PDDMs, which were compared for similarity with the dynamic EDDM. RESULTS: In order to verify the dose distribution between different dose measurement techniques, the gamma passing rate with 2%/2 mm criterion was used for the EDDM and PDDM, the passing rates were between 94.31% and 99.71% in the static field analyses, and between 84.45% and 96.09% for simulations with the UITA signal input and between 89.35% and 97.78% for simulations with the original signal input in the dynamic field analyses. CONCLUSIONS: Static and dynamic dose distribution maps can be simulated based on the proposed matrix position parameters of various fields and by using the UITA to track respiration signals during radiation therapy. The present findings indicate that it is possible to develop a reusable and time-saving dose distribution measurement tool.

Fast Fourier transform combined with phase leading compensator for respiratory motion compensation system.

BACKGROUND: The reduction of the delaying effect in the respiratory motion compensation system (RMCS) is still impossible to completely correct the respiratory waveform of the human body due to each patient has a unique respiratory rate. In order to further improve the effectiveness of radiation therapy, this study evaluates our previously developed RMCS and uses the fast Fourier transform (FFT) algorithm combined with the phase lead compensator (PLC) to further improve the compensation rate (CR) of different respiratory frequencies and patterns of patients. METHODS: In this study, an algorithm of FFT automatic frequency detection was developed by using LabVIEW software, uisng FFT combined with PLC and RMCS to compensate the system delay time. Respiratory motion compensation experiments were performed using pre-recorded respiratory signals of 25 patients. During the experiment, the respiratory motion simulation system (RMSS) was placed on the RMCS, and the pre-recorded patient breathing signals were sent to the RMCS by using our previously developed ultrasound image tracking algorithm (UITA). The tracking error of the RMCS is obtained by comparing the encoder signals of the RMSS and RMCS. The compensation effect is verified by root mean squared error (RMSE) and system CR. RESULTS: The experimental results show that the patient's respiratory patterns compensated by the RMCS after using the proposed FFT combined with PLC control method, the RMSE is between 1.50-5.71 and 3.15-8.31 mm in the right-left (RL) and superior-inferior (SI) directions, respectively. CR is between 72.86-93.25% and 62.3-83.81% in RL and SI, respectively. CONCLUSIONS: This study used FFT combined with PLC control method to apply to RMCS, and used UITA for respiratory motion compensation. Under the automatic frequency detection, the best dominant frequency of the human respiratory waveform can be determinated. In radiotherapy, it can be used to compensate the tumor movement caused by respiratory motion and reduce the radiation damage and side effects of normal tissues nearby the tumor.

Effectiveness of stereotactic ablative radiotherapy in patients with advanced hepatocellular carcinoma unsuitable for transarterial chemoembolization.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) can deliver tumoricidal doses and achieve long-term control in early hepatocellular carcinoma (HCC). However, limited studies have investigated the safety and effectiveness of SABR in patients with advanced diseases that is unsuitable for transarterial chemoembolization (TACE). METHODS: In this observational study, we reviewed the medical records of patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease treated with linear accelerator-based SABR between 2008 and 2016. Their tumors were either refractory to TACE or TACE was contraindicated. Overall survival (OS), in-field progression-free survival (IFPFS), and out-field progression-free survival were calculated using Kaplan-Meier analysis. The Cox regression model was used to examine the effects of variables. Treatment-related toxicities were scored according to the Common Terminology Criteria for Adverse Events (version 4.03) and whether patients developed radiation-induced liver disease (RILD) after SABR. RESULTS: This study included 32 patients. The mean maximal tumor diameter and tumor volumes were 4.7 cm and 135.9 ml, respectively. Patients received linear accelerator-based SABR with a median prescribed dose of 48 Gy (30-60 Gy) in three to six fractions. Based on the assessment of treatment response by using the Response Evaluation Criteria in Solid Tumors (version 1.1), 19% of patients achieved a complete response and 53% achieved a partial response. After a median follow-up of 18.1 months (4.0-65.9 months), 10, 19, and 9 patients experienced in-field failure, out-field hepatic recurrence, and extrahepatic metastases, respectively. The estimated 2-year OS and IFPFS rates were 54.4% and 62.7%, respectively. In a multivariate analysis, a pretreatment Cancer of the Liver Italian Program (CLIP) score of ⩾2 (p = 0.01) was a prognostic factor for shorter OS, and a biologically effective dose (BED) of < 85 Gy10 (p = 0.011) and a Child-Pugh score of ⩾6 (p = 0.014) were prognostic factors for inferior IFPFS. In this study five and eight patients developed classic and nonclassic RILD, respectively. CONCLUSIONS: SABR can serve as a salvage treatment for patients with HCC with BCLC stage C disease unsuitable for TACE, in particular, in those with a baseline CLIP score of ⩽1. A BED10 of ⩾85 Gy is an appropriate prescribed dose for tumor control. Because out-field relapse is the major cause of treatment failure, SABR in combination with novel systemic modalities should be investigated in future studies.