Normal tissue complication probability model of temporal lobe injury following re-irradiation of IMRT for local recurrent nasopharyngeal carcinoma.

Purpose: We tried to establish the normal tissue complication probability (NTCP) model of temporal lobe injury of recurrent nasopharyngeal carcinoma (NPC) patients after two courses of intensity modulated radiotherapy (IMRT) to provide more reliable dose-volume data reference to set the temporal lobe tolerance dose for recurrent NPC patients in the future. Methods and materials: Recurrent NPC patients were randomly divided into training data set and validation data set in a ratio of 2:1, All the temporal lobes (TLs) were re-contoured as R/L structures and named separately in the MIM system. The dose distribution of the initial IMRT plan was deformed into the second course planning CT via MIM software to get the deformed dose. Equivalent dose of TLs in 2Gy fractions was calculated via linear quadratic model, using an α/ß=3 for temporal lobes. NTCP model that correlated the irradiated volume of the temporal lobe and? the clinical variables were evaluated in a multivariate prediction model using AUC analysis. Results: From Jan. 2010 to Dec. 2020, 78 patients were enrolled into our study. Among which 26 (33.3%) developed TLI. The most important factors affecting TLI was the sum-dose d1.5cc of TL, while the possible clinical factors did not reach statistically significant differences in multivariate analysis. According to NTCP model, the TD5 and TD50 EQD2 dose of sum-dose d1.5cc were 65.26Gy (46.72-80.69Gy) and 125.25Gy (89.51-152.18Gy), respectively. For the accumulated EQD2 dose, the area under ROC shadow was 0.8702 (0.7577-0.9828) in model validation, p<0.001. Conclusion: In this study, a NTCP model of temporal lobe injury after a second course of IMRT for recurrent nasopharyngeal carcinoma was established. TD5 and TD50 doses of temporal lobe injury after re-RT were obtained according to the model, and the model was verified by validation set data.

Development of porous structure for broadening Bragg-peak in scanning carbon-ion radiotherapy: Monte Carlo simulation and experimental validation.

PURPOSE: The present study aimed to develop a porous structure with plug-ins (PSP) to broaden the Bragg peak width (BPW, defined as the distance in water between the proximal and distal 80% dose) of the carbon ion beam while maintaining a sharp distal falloff width (DFW, defined as the distance along the beam axis where the dose in water reduces from 80% to 20%). METHODS: The binary voxel models of porous structure (PS) and PSP were established in the Monte Carlo code FLUKA and the corresponding physical models were manufactured by 3D printing. Both experiment and simulation were performed for evaluating the modulation capacity of PS and PSP. BPWs and DFWs derived from each integral depth dose curves were compared. Fluence homogeneity of 430 MeV/u carbon-ion beam passing through the PSP was recorded by analyzing radiochromic films at six different locations downstream the PSP in the experiment. Additionally, by changing the beam spot size and incident position on the PSP, totally 48 different carbon-ion beams were simulated and corresponding deviations of beam metrics were evaluated to test the modulating stability of PSP. RESULTS: According to the measurement data, the use of PSP resulted in an average increase of 0.63 mm in BPW and a decrease of 0.74 mm in DFW compared to PS. The 2D radiation field inhomogeneities were lower than 3 % when the beam passing through a ≥ 10 cm PMMA medium. Furthermore, employing a spot size of ≥ 6 mm ensures that beam metric deviations, including BPW, DFW, and range, remain within a deviation of 0.1 mm across various incident positions. CONCLUSION: The developed PSP demonstrated its capability to effectively broaden the BPW of carbon ion beams while maintaining a sharp DFW comparing to PS. The superior performance of PSP, indicates its potential for clinical use in the future.

Up modulation of dose-averaged linear energy transfer by simultaneous integrated boost in carbon-ion radiotherapy for pancreatic carcinoma.

BACKGROUND: Local recurrence in locally advanced pancreatic cancer (LAPC) after carbon-ion radiotherapy (CIRT) may partly attribute to low dose-averaged linear energy transfer (LETd), despite high CIRT dose. PURPOSE: This study aimed to investigate the approaches to up-modulate the CIRT LETd and to evaluate the corresponding oxygen enhancement ratio (OER) reduction. METHODS: 10 LAPCs that had been irradiated by CIRT with 67.5 Gy (RBE) in 15 fractions were selected. Their original plans were taken as the control plan for the LETd and OER investigations. Our considerations for up-modulating LETd were: (1) to deliver high doses to gross tumor volume core (GTVcore), while keeping dose constraints of the gastrointestinal (GI) tract in tolerance; (2) to put more Bragg-peak (BP) within the modulated targets; (3) to increase the BP density, high doses were necessary; (4) CIRT LETd could be effectively increased to small volumes; and (5) simultaneous integrated boost technique (SIB) could achieve the aforementioned tasks. The LETd and the corresponding OER distributions of each type of SIB plan were evaluated. RESULTS: We delivered up to 100 Gy (RBE) to GTVcore using SIB. The mean LETd of GTV increased significantly by 21.3% from 47.8 to 58.0 keV/µm (p < 0.05). Meanwhile, the mean OER of GTVcore decreased by 6.6%, from 1.51 to 1.41 (p < 0.05). The GI LETdS in all modulated plans were not more than those in the original plans. CONCLUSIONS: SIB could effectively increase CIRT LETd to LAPC, thus producing reduced OER, which may effectively overcome the radioresistance of LAPCs.

Prediction of death rates for cardiovascular diseases and cancers.

Background: To estimate cardiovascular and cancer death rates by regions and time periods. Design: Novel statistical methods were used to analyze clinical surveillance data. Methods: A multicenter, population-based medical survey was performed. Annual recorded deaths from cardiovascular diseases were analyzed for all 195 countries of the world. It is challenging to model such data; few mathematical models can be applied because cardiovascular disease and cancer data are generally not normally distributed. Results: A novel approach to assessing the biosystem reliability is introduced and has been found to be particularly suitable for analyzing multiregion environmental and healthcare systems. While traditional methods for analyzing temporal observations of multiregion processes do not deal with dimensionality efficiently, our methodology has been shown to be able to cope with this challenge. Conclusions: Our novel methodology can be applied to public health and clinical survey data.

Proton and Carbon Ion Radiation Therapy Decreased Severe Lymphopenia by Reducing Thoracic Vertebra and Aortic Doses in Non-Small Cell Lung Cancer Versus Intensity Modulated Radiation Therapy.

PURPOSE: Lymphopenia is a common adverse effect of radiation therapy (RT). Little is known about the difference in lymphopenia between intensity modulated (photon) radiation therapy (IMRT) and proton and carbon ion radiation therapy (PCIRT). This study aimed to investigate lymphopenia differences between IMRT and PCIRT in non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Clinical and dosimetric parameters were collected from 343 patients who received definitive IMRT or PCIRT for NSCLC. Severe lymphopenia (SRL) was defined as an absolute lymphocyte count (ALC) ≤0.5 × 103 cells/µL. Overall survival (OS) was analyzed using the Kaplan-Meier method. Propensity score matching was performed between the IMRT and PCIRT groups. Least absolute shrinkage and selection operator analysis was used to select appropriate dosimetric parameters. Univariate and multivariate logistic regression analyses were conducted to identify the predictors of SRL. RESULTS: Compared with the IMRT group, the PCIRT group was less likely to develop SRL (P < .001). Compared with the non-SRL group, the SRL group showed significant association with poorer OS, with a median survival time of 29.2 versus 15.0 months (P = .046). IMRT was an independent risk factor of SRL (P = .004). A lower ALC before RT (P = .030) and larger planning target volume (PTV) (P = .002) were also significant independent risk factors for SRL. Moreover, the majority of dosimetric parameters of organs at risk in PCIRT were lower than those in IMRT (P < .001). Thoracic vertebra V5 (P = .002) and aorta V5 (P = .026) were identified as independent risk predictors of SRL after adding dosimetric parameters to the regression model. CONCLUSIONS: Compared with IMRT, PCIRT could reduce SRL incidence, possibly by limiting thoracic vertebra and aortic doses, and SRL was associated with poor outcomes in patients with NSCLC.

Carbon ion radiotherapy with pencil beam scanning for hepatocellular carcinoma: Long-term outcomes from a phase I trial.

This study evaluates the feasibility of the pencil beam scanning technique of carbon ion radiotherapy (CIRT) in the setting of hepatocellular carcinoma (HCC) and establishes the maximum tolerated dose (MTD) calculated by the Local Effect Model version I (LEM-I) with a dose escalation plan. The escalated relative biological effectiveness-weighted dose levels included 55, 60, 65, and 70 Gy in 10 fractions. Active motion management techniques were employed, and several measures were applied to mitigate the interplay effect induced by a moving target. CIRT was planned with the LEM-I-based treatment planning system and delivered by raster scanning. Offline PET/CT imaging was used to verify the beam range. Offline adaptive replanning was performed whenever required. Twenty-three patients with a median tumor size of 4.3 cm (range, 1.7-8.5 cm) were enrolled in the present study. The median follow-up time was 56.1 months (range, 5.7-74.4 months). No dose limiting toxicity was observed until 70 Gy, and MTD had not been reached. No patients experienced radiation-induced liver disease within 6 months after the completion of CIRT. The overall survival rates at 1, 3, and 5 years were 91.3%, 81.9%, and 67.1% after CIRT, respectively. The local progression-free survival and progression-free survival rates at 1, 3 and 5 years were 100%, 94.4%, and 94.4% and 73.6%, 59.2%, and 37.0%, respectively. The raster scanning technique could be used to treat HCC. However, caution should be exercised to mitigate the interplay effect. CIRT up to 70 Gy in 10 fractions over 2 weeks was safe and effective for HCC.

Cross-regulation of Wnt/β-catenin and NF-κB signaling pathway and their involvement in the differentiation of mesenchymal stem cells / 口腔医学

@#Both Wnt/β-catenin signaling pathway and NF-κB signaling pathway are highly conservative pathways that regulate a variety of biological processes, and their cross-regulation have attracted attention in many biological and medical research fields. In this review, we summarize the cross-regulation between Wnt/β-catenin signaling pathway and NF-κB signaling pathway and discuss their involvement in the multi-directional differentiation of mesenchymal stem cells.

Pencil Beam Scanning Carbon Ion Radiotherapy for Hepatocellular Carcinoma.

Purpose: Carbon ion radiotherapy (CIRT) has emerged as a promising treatment modality for hepatocellular carcinoma (HCC). However, evidence of using the pencil beam scanning (PBS) technique to treat moving liver tumors remains lacking. The present study investigated the efficacy and toxicity of PBS CIRT in patients with HCC. Methods: Between January 2016 and October 2021, 90 consecutive HCC patients treated with definitive CIRT in our center were retrospectively analyzed. Fifty-eight patients received relative biological effectiveness-weighted doses of 50-70 Gy in 10 fractions, and 32 received 60-67.5 Gy in 15 fractions, which were determined by the tumor location and normal tissue constraints. Active motion-management techniques and necessary strategies were adopted to mitigate interplay effects efficiently. Oncologic outcomes and toxicities were evaluated. Results: The median follow-up time was 28.6 months (range 5.7-74.6 months). The objective response rate was 75.0% for all 90 patients with 100 treated lesions. The overall survival rates at 1-, 2- and 3-years were 97.8%, 83.3% and 75.4%, respectively. The local control rates at 1-, 2- and 3-years were 96.4%, 96.4% and 93.1%, respectively. Radiation-induced liver disease was not documented, and 4 patients (4.4%) had their Child-Pugh score elevated by 1 point after CIRT. No grade 3 or higher acute non-hematological toxicities were observed. Six patients (6.7%) experienced grade 3 or higher late toxicities. Conclusion: The active scanning technique was clinically feasible to treat HCC by applying necessary mitigation measures for interplay effects. The desirable oncologic outcomes as well as favorable toxicity profiles presented in this study will be a valuable reference for other carbon-ion centers using the PBS technique and local effect model-based system, and add to a growing body of evidence about the role of CIRT in the management of HCC.

A Transformer-Based Approach Combining Deep Learning Network and Spatial-Temporal Information for Raw EEG Classification.

The attention mechanism of the Transformer has the advantage of extracting feature correlation in the long-sequence data and visualizing the model. As time-series data, the spatial and temporal dependencies of the EEG signals between the time points and the different channels contain important information for accurate classification. So far, Transformer-based approaches have not been widely explored in motor-imagery EEG classification and visualization, especially lacking general models based on cross-individual validation. Taking advantage of the Transformer model and the spatial-temporal characteristics of the EEG signals, we designed Transformer-based models for classifications of motor imagery EEG based on the PhysioNet dataset. With 3s EEG data, our models obtained the best classification accuracy of 83.31%, 74.44%, and 64.22% on two-, three-, and four-class motor-imagery tasks in cross-individual validation, which outperformed other state-of-the-art models by 0.88%, 2.11%, and 1.06%. The inclusion of the positional embedding modules in the Transformer could improve the EEG classification performance. Furthermore, the visualization results of attention weights provided insights into the working mechanism of the Transformer-based networks during motor imagery tasks. The topography of the attention weights revealed a pattern of event-related desynchronization (ERD) which was consistent with the results from the spectral analysis of Mu and beta rhythm over the sensorimotor areas. Together, our deep learning methods not only provide novel and powerful tools for classifying and understanding EEG data but also have broad applications for brain-computer interface (BCI) systems.

The influence of beam optics asymmetric distribution on dose in scanning carbon-ion radiotherapy.

PURPOSE: To quantify the influence of beam optics asymmetric distribution on dose. METHODS: Nine reference cubic targets and corresponding plans with modulation widths (M) of 3, 6, and 9 cm and with center depths (CDs) of 6, 12, and 24 cm were generated by the treatment planning system (TPS). The Monte Carlo code FLUKA was used for simulating the dose distribution from the aforementioned original plans and the dose perturbation by varying ±5%, ±15%, ±20%, ±25%, and ±40% in spot full width half maximum to the X-direction while keeping consistent in the Y-direction. The dosimetric comparisons in dose deviation, γ-index analysis, lateral penumbra, and flatness were evaluated. RESULTS: The largest 3D absolute mean deviation was 15.0% ± 20.9% (mean ± standard deviation) in M3CD6, whereas with the variation from -15% to +20%, the values were below 5% for all cube plans. The lowest 2D γ-index passing rate was 80.6% with criteria of 2%-2 mm by a +40% variation in M3CD6. For the M9CD24 with a -40% variation, the maximum 1D dose deviations were 5.6% and 15.7% in the high-dose region and the edge of the radiation field, respectively. The maximum deviations of penumbra and flatness were 3.4 mm and 11.4%, respectively. CONCLUSIONS: The scenario of beam optics asymmetric showed relatively slight influence on the global dose distribution but severely affected dose on the edge of the radiation field. For scanning carbon-ion therapy facilities, beam spot lateral profile settings in TPS base data should be properly handled when beam optics asymmetry variation is over 15%.

Exosomes Derived From Human Gingival Mesenchymal Stem Cells Attenuate the Inflammatory Response in Periodontal Ligament Stem Cells.

This study aimed to explore the effects of exosomes derived from human gingival mesenchymal stem cells (GMSC-Exo) on the inflammatory response of periodontal ligament stem cells (PDLSCs) in an inflammatory microenvironment in order to restore the regenerative potential of PDLSCs, which promotes periodontal tissue regeneration in patients with periodontitis. Periodontitis is a chronic infectious disease characterized by periodontal tissue inflammation and alveolar bone destruction. PDLSCs are regarded as promising seed cells for restoring periodontal tissue defects because of their ability to regenerate cementum/PDL-like tissue and alveolar bone. However, PDLSCs in the inflammatory environment show significantly attenuated regenerative potential. GMSC-Exo have been reported to have anti-inflammatory and immunosuppressive properties. In this study, we investigated the effects of GMSC-Exo on the inflammatory response of PDLSCs induced by lipopolysaccharides (LPS). LPS was used to simulate the inflammatory microenvironment of periodontitis in vitro. GMSC-Exo were extracted from the culture supernatant of GMSCs by ultracentrifugation. We found that GMSC-Exo attenuated the inflammatory response of PDLSCs induced by LPS. Furthermore, compared to treatment with LPS, treatment with GMSC-Exo attenuated the expression of NF-κB signaling and Wnt5a in LPS-induced PDLSCs. In conclusion, we confirmed that GMSC-Exo could suppress the inflammatory response of PDLSCs by regulating the expression of NF-κB signaling and Wnt5a, which paves the way for the establishment of a therapeutic approach for periodontitis.

Identifying Visual Attention Features Accurately Discerning Between Autism and Typically Developing: a Deep Learning Framework.

Atypical visual attention is a hallmark of autism spectrum disorder (ASD). Identifying the attention features accurately discerning between people with ASD and typically developing (TD) at the individual level remains a challenge. In this study, we developed a new systematic framework combining high accuracy deep learning classification, deep learning segmentation, image ablation and a direct measurement of classification ability to identify the discriminative features for autism identification. Our two-stream model achieved the state-of-the-art performance with a classification accuracy of 0.95. Using this framework, two new categories of features, Food & drink and Outdoor-objects, were identified as discriminative attention features, in addition to the previously reported features including Center-object and Human-faces, etc. Altered attention to the new categories helps to understand related atypical behaviors in ASD. Importantly, the area under curve (AUC) based on the combined top-9 features identified in this study was 0.92, allowing an accurate classification at the individual level. We also obtained a small but informative dataset of 12 images with an AUC of 0.86, suggesting a potentially efficient approach for the clinical diagnosis of ASD. Together, our deep learning framework based on VGG-16 provides a novel and powerful tool to recognize and understand abnormal visual attention in ASD, which will, in turn, facilitate the identification of biomarkers for ASD.

Indications of IMRT, PRT and CIRT for HCC from comparisons of dosimetry and normal tissue complication possibility.

PURPOSE: To identify the indications for hepatocellular carcinoma (HCC) irradiated by intensity-modulated photon radiotherapy (IMRT), proton radiotherapy (PRT) or carbon-ion radiotherapy (CIRT) by comparing of dosimetric parameters and incidences of classic radiation-induced liver disease (RILD). METHODS: In all, 40 HCCs were divided into group A (tumors located > 1 cm away from gastrointestinal [GI] tract), and group B (tumors located < 1 cm away from GI tract). The prescribed curative doses were 60 Gy (relative biological effectiveness [RBE]) in 10 fractions for group A, and 67.5 Gy (RBE) in 15 fractions for group B. IMRT, PRT and CIRT plans were separately generated to reach the curative doses and coverage. Dosimetric parameters evaluated were mean dose to normal liver (MDTNL) and the volume of normal liver receiving more than 1 Gy (RBE) (V1). Lyman-Kutcher-Burman model was used to determine the incidences of classic RILD, and Power model of non-linear regression, to estimate the tumor volume that could be irradiated with the curative doses within dose constraint of MDTNL. RESULTS: With comparable target doses, the MDTNL (Gy [RBE]) were 18.8 ± 3.7, 13.5 ± 3.1 and 12.8 ± 2.7 in group A and 24.9 ± 7.1, 18.2 ± 3.7 and 17.5 ± 3.7 in group B, respectively, for IMRT, PRT and CIRT. The classic RILD incidences (%) were 22.3 ± 30.0 in IMRT, 2.3 ± 4.9 in PRT and 1.2 ± 2.4 in CIRT. V1 (%) were 89.9 ± 8.8, 43.0 ± 10.2 and 45.9 ± 8.8, respectively, for IMRT, PRT and CIRT. CONCLUSIONS: PRT and CIRT could spare the liver more than IMRT. IMRT could deliver the curative doses to HCC up to a diameter of 7.9 cm; PRT, up to 13.2 cm; and CIRT, up to 14.8 cm.

One-Year Efficacy and Safety of Proton-Beam Irradiation Combined with Intravitreal Conbercept for Refractory or Recurrent Polypoidal Choroidal Vasculopathy: A Pilot Study.

INTRODUCTION: To investigate the efficacy and safety of proton-beam irradiation (PBI) combined with intravitreal conbercept (IVC) injection for refractory or recurrent polypoidal choroidal vasculopathy (PCV). METHODS: A prospective interventional clinical trial included 12 patients with refractory PCV (defined as persistent exudation or fluid after six consecutive injections at monthly intervals and/or photodynamic therapy) or recurrent PCV (defined as new exudative signs after six monthly injections and/or photodynamic therapy) treated between January 2019 and September 2020. Every patient underwent single PBI (14 GyE) with concomitant IVC (0.5 mg) within 1 week and further doses of IVC were administered pro re nata. RESULTS: By the 12-month follow-up, the subretinal fluid was completely absorbed in 9 eyes (81.8%). The angiographic regression and closure rates of the polyps were 60% (12/20) and 90% (18/20), respectively. The mean number of IVC injections was 3.1 ± 1.37. The mean BCVA improved by 20 letters (P = 0.006). The mean central macular thickness (CMT) decreased from 476.50 ± 123.63 µm to 317.70 ± 89.34 µm (P = 0.004). The areas of branching vascular networks and polyps decreased by 37.2% and 72.3%, respectively. Radiation retinopathy was observed in five eyes, but no systemic adverse events were observed. CONCLUSION: PBI combined with IVC appears to promote polyp regression and closure, reduce CMT, and improve BCVA, with a favorable safety profile, after 12 months. Therefore, PBI may be a useful adjuvant therapy for patients with refractory or recurrent PCV. TRIAL REGISTRATION: Proton-Beam Irradiation Combined with Intravitreal Conbercept for Refractory or Recurrent Polypoidal Choroidal Vasculopathy: Prospective Phase II Clinical Study (ChiCTR2000038987).

Dosimetric comparison between carbon, proton and photon radiation for renal retroperitoneal soft tissue sarcoma recurrence or metastasis after radical nephrectomy.

OBJECTIVE: To compare the dosimetric difference between various modalities in the radiation treatment for renal retroperitoneal soft tissue sarcoma recurrence or metastasis (RRSTSRM) after radical nephrectomy, and assess the dosimetric advantage on protecting the organs at risk (OARs) in the carbon and proton radiotherapy for the patients with a single kidney. METHODS: A total of 12 patients with RRSTSRM who underwent radical nephrectomy were enrolled in this study. Carbon, proton, and photon radiotherapy were implemented for treatment planning. The prescription dose was fulfilled by simultaneously integrated boosting technique, with giving the planning target volume-1 (PTV-1) 51Gy (RBE) and planning target volume-2 (PTV-2) 60 Gy (RBE). Doses in the patient's spinal cord, stomach, duodenum, bowel, colon, and contralateral kidney were evaluated. The normal tissue complication probability (NTCP) of the duodenum, bowel, colon, and contralateral kidney was derived under Lyman-Kutcher-Burman (LKB) estimation. RESULTS: In the carbon plans, the percentage volume of 95% prescription dose (V95%) covering PTV-1 (PTV-2) was 95.93% ± 3.42% (95.61% ± 4.26%). No significant dosimetric difference on the target was obtained between the four radiation modalities (P > .05). The percentage volume of receiving 40 Gy (RBE) [V40Gy (RBE)] in the duodenum could be reduced from 12.94% ± 15.99% in the IMRT plans to 6.36% ± 8.79% (8.44% ± 12.35%) in the carbon (proton) plans (P < .05). The V40Gy (RBE) in the bowel could be reduced from 13.48% ± 13.12% in the IMRT plans to 7.04% ± 9.32% (7.34% ± 9.89%) in the carbon (proton) plans (P < .05). The mean value of NTCP for the duodenum was 0.43 ± 0.47 (0.45 ± 0.48) by using carbon (proton) radiation. The value was 0.05 (0.03) lower than the IMRT plans on average, with a reduction of 0.20 (0.13) for the patients with lesions <5 mm away from the duodenum. The mean doses of the contralateral kidney were 0.28 ± 0.37 Gy (RBE) [0.28 ± 0.40 Gy (RBE)] in the IMCT (IMPT) plans, which was 92.43% (92.43%) lower than the value in the IMRT plans respectively (P < .05). CONCLUSION: Compared to the conventional radiation techniques, particle radiotherapy of carbon and proton could significantly spare more OARs in the treatment for RRSTSRM after radical nephrectomy. Patients, especially those whose residuals are close to the duodenum would potentially benefit from the particle radiation therapy for RRSTSRM on the decrease in radiation-related side-effect.

Clinical Implementation of a 6D Treatment Chair for Fixed Ion Beam Lines.

PURPOSE: To verify the practicality and safety of a treatment chair with six degrees of freedom (6DTC) through demonstrating the efficacy of the workflow in clinical settings and analyzing the obtained technical data, including intra-fraction patient movement during the use of the 6DTC. MATERIALS AND METHODS: A clinical study was designed and conducted to test the clinical treatment workflow and the safety of the 6DTC. Based on the demonstrated dosimetric advantages, fifteen patients with head and neck tumors were selected and treated with the 6DTC. The positional error at the first beam position (PE-B1) and the second beam position (PE-B2) were analyzed and compared with the results from daily quality assurance (QA) procedures of the 6DTC and imaging system performed each day before clinical treatment. The intra-fraction patient movement was derived from the total patient alignment positional error and the QA data based on a Gaussian distribution formulism. RESULTS: The QA results showed sub-millimeter mechanical accuracy of the 6DTC over the course of the clinical study. For 150 patient treatment fractions, the mean deviations between PE-B1 and PE-B2 were 0.13mm (SD 0.88mm), 0.25mm (SD 1.17mm), -0.57mm (SD 0.85mm), 0.02° (SD 0.35°), 0.00° (SD 0.37°), and -0.02° (SD 0.37°) in the x, y, z (translational), and u, v, w (rotational) directions, respectively. The calculated intra-fraction patient movement was -0.08mm (SD 0.56mm), 0.71mm (SD 1.12mm), -0.52mm (SD 0.84mm), 0.10° (SD 0.32°), 0.09° (SD 0.36°), and -0.04° (SD 0.36°) in the x, y, z, u, v, w directions, respectively. CONCLUSIONS: The performance stability of the 6DTC was satisfactory. The position accuracy and intra-fraction patient movement in an upright posture with the 6DTC were verified and found adequate for clinical implementation.

Effect of gingival mesenchymal stem cell-derived exosomes on inflammatory macrophages in a high-lipid microenvironment.

OBJECTIVE: The aim of this study was to examine the effect of gingival mesenchymal stem cells derived exosomes (GMSC-Exos) on lipopolysaccharide/interferon-gamma (LPS/INF-γ)-induced inflammatory macrophages in a high-lipid microenvironment. MATERIALS AND METHODS: Exosomes were obtained by culturing gingival mesenchymal stem cells (GMSCs) in alpha-MEM with exosome-free fetal bovine serum for 48 h. The control group was produced in vitro by inducing human acute monocytic leukemia cells (THP-1 cells) into naïve macrophages (M0). Inflammatory macrophages (M1) were made by activating M0 macrophages with LPS/IFN-γ. These M1 macrophages were treated with oxidized low-density lipoprotein (ox-LDL) to create the high-lipid group, of which some macrophages were further treated with GMSC-Exos for 24 h to form the GMSC-Exos group. Supernatants were collected, and total RNA were extracted for downstream analysis. The expression of surface markers in macrophages were analyzed by flow cytometry. The lipid accumulation level was assessed by oil red O staining. RESULTS: Exosomes were successfully isolated from GMSC medium. The GMSC-Exos group showed lower Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß), and cluster of differentiation 86 (CD86) expression levels than the high-lipid group, and the highest levels of Interleukin-10 (IL-10) among all groups. The GMSC-Exos group showed significant reductions in TNF-α levels than the high-lipid group, and significant escalations in IL-10 levels than the other two groups. Oil red o Staining showed that lipid accumulation in macrophages was inhibited in the GMSC-Exos group. CONCLUSIONS: GMSC-Exos reduce the release level and expression of inflammatory factors, inhibit lipid accumulation, and promote the polarization of pro-inflammatory macrophages into anti-inflammatory phenotype in a high-lipid microenvironment.

Development of an isocentric rotating chair positioner to treat patients of head and neck cancer at upright seated position with multiple nonplanar fields in a fixed carbon-ion beamline.

PURPOSE: An isocentric rotating chair for a positioner was developed as a nongantry solution to provide multiple nonplanar radiation fields with a maximum tilt of 20 ∘ for treating head and neck cancer patients at an upright seated position in a fixed carbon-ion beamline. METHODS: The preclinical validation of the chair was present for this study funded by a grant through the Shanghai Proton and Heavy Ion Center (SPHIC) in Shanghai, China. The chair was installed in SPHIC. A concept of parallel kinematic was adopted to build the chair. Three movement subunits of the chair are a Stewart hexapod platform and two modules for three-dimensional translation and 360 ∘ rotation. This chair can position patients with a tilt up to 20 ∘ over a continuous 360 ∘ rotation. Any weak structures within each subunit were investigated by industrial static/dynamic simulations of used materials. After manufactured subunits were assembled in a factory, a series of executed six degree-of-freedom (DoF) displacements were measured by using a laser-based dynamic tracking system (LDTS) for the initial validation. Deviations between measured and required displacements, referred to as displacement deviation, were used to evaluate the displacement accuracy of the chair. After satisfying the initial validation in the factory, the chair was disassembled and installed in our treatment room. The displacement accuracy of the chair was revalidated by using the LDTS. Then, an integration validation of the chair was conducted to position a head phantom by using our image-guided radiotherapy (IGRT) system. Because the positioning accuracy of our IGRT system achieved a clinical tolerance of 1.0 mm and 1.0 ∘ only for a pitch/roll of <5 ∘ , the integration validation was conducted on 36 planned fields with a 5 ∘ tilt evenly over 360 ∘ rotation. RESULTS: To fulfill the general purpose of positioner, the chair allows the execution of any displacement over a cubic treatment volume with a length of 500 mm. Materials selected by simulations met required strengths under all circumstances of the clinical usage. The displacement accuracy of the chair satisfied the tolerance of 0.3 mm in-translation and 0.3 ∘ in-rotation during the initial validation in the factory. After the chair was installed in our institute, a linear displacement deviation of +/-0.6 mm was observed over +/-200 mm displacements in horizontal X/Y axes. After correcting the linear deviation, the displacement deviations of the chair for horizontal and vertical X/Y/Z axes were within 0.5 mm and 0.5 ∘ for its revalidation. During the integration validation, the displacement deviation of the chair was 0.8 mm and 0.6 ∘ when positioning a head phantom for the 36 fields with a 5 ∘ tilt. CONCLUSIONS: The chair achieved the required clinical tolerance for the clinical application. The tilt angle was limited to within 5 ∘ to treat patients through a specific treatment workflow with a proper daily quality assurance program during a clinical trial, started in May 2019. An integration validation with a 20 ∘ tilt will be conducted in the near future to realize the full potential of the isocentric rotating chair.

Performance of a 6D Treatment Chair for Patient Positioning in an Upright Posture for Fixed Ion Beam Lines.

Purpose: To evaluate the mechanical accuracy and the robustness of position alignment under x-ray-based image guidance of a treatment chair with six degrees of freedom (6DTC) which was developed for patient treatment in an upright posture at fixed horizontal beam lines in particle (proton, carbon ion, or others) radiotherapy facilities. Method and Material: The positional accuracy including translational and axial rotational accuracy of the 6DTC was evaluated by using a Vicon Motion Capture System (VMCS). Stability of the chair rotation isocenter was determined by a CCD camera with an in-house developed software. The tests were carried out to examine two key motion components of the 6DTC: a floor/rail-mount 360°-rotating platform and a 6-degree-of-freedom (6DOF) platform. The measurement results were compared to that of a commercial clinical robot couch. The accuracy of position alignment, simulating the actual clinical protocol, through an Image-guided Radiation Therapy (IGRT) system was studied at the pre-treatment position and beam specific treatment position. Results: The translational accuracy was 0.12 mm (SD 0.07 mm) for the 6DOF platform. The rotational accuracy was 0.04° (SD 0.03°) and 0.02° (SD 0.02°) for the 6DOF platform and the 360° -rotating platform, respectively. The displacement between the chair rotation center and the room isocenter center was no more than 0.18 mm in all three rotational axes. Combined with an x-ray-based IGRT system, the treatment alignment test with a rigid phantom yielded a total positional accuracy of 0.23 mm (SD 0.17 mm) and 0.14° (SD 0.14°) at treatment position. Conclusions: On the basis of the rigid phantom study, the 6DTC showed comparable accuracy to the robot treatment couch. Combining with the IGRT, the 6DTC can provide position alignment with submillimeter accuracy for rigid phantom in upright posture.

QT Interval Dispersion as a Predictor of Clinical Outcome in Acute Ischemic Stroke.

Background and Purpose: QT dispersion (QTd) abnormalities are widely documented in stroke patients. This study aims to investigate the association between QTd and clinical outcomes in IS patients. Methods: IS patients registered in the Blood Pressure and Clinical Outcome in transient ischemic attack (TIA) or IS (BOSS) registry between 2012 and 2014 within 24 h of onset were analyzed. In this prospective observational study, we identified 1,522 IS cases with adequate electrocardiographic evaluations to assess QTd after the index stroke. Patients were classified into four groups based on the quartile of QTd, with the lowest group as the reference. The primary stroke outcome was defined as a modified Rankin Scale score ≥3 at 1-year. Multiple logistic regressions were utilized to investigate the association between QTd and outcome events. Results: The mean QTd across all cases was 57 ms (40-83). Functional dependency or death was documented in 214 (14.98%) cases at 1 year. After adjusting for confounders, the prevalence of death and major disability (mRS ≥ 3) showed significant differences according to the quartile of QTd, with the risk of death and major disability (mRS ≥ 3) at 1 year being significantly higher for patients in Q4 than for those in Q1 (adjusted OR = 1.626, 95% CI:1.033-2.560). However, there were no significant correlation between QTd and the event outcomes at 1 year. Conclusions: QTd was associated with poor functional outcomes at 1 year. QTd is a useful surrogate marker for adverse functional prognosis, which might help to stratify risk in patients with acute IS.