Potential therapeutic targets of gastric cancer explored under endogenous network modeling of clinical data.

Improvement in the survival rate of gastric cancer, a prevalent global malignancy and the leading cause of cancer-related mortality calls for more avenues in molecular therapy. This work aims to comprehend drug resistance and explore multiple-drug combinations for enhanced therapeutic treatment. An endogenous network modeling clinic data with core gastric cancer molecules, functional modules, and pathways is constructed, which is then transformed into dynamics equations for in-silicon studies. Principal component analysis, hierarchical clustering, and K-means clustering are utilized to map the attractor domains of the stochastic model to the normal and pathological phenotypes identified from the clinical data. The analyses demonstrate gastric cancer as a cluster of stable states emerging within the stochastic dynamics and elucidate the cause of resistance to anti-VEGF monotherapy in cancer treatment as the limitation of the single pathway in preventing cancer progression. The feasibility of multiple objectives of therapy targeting specified molecules and/or pathways is explored. This study verifies the rationality of the platform of endogenous network modeling, which contributes to the development of cross-functional multi-target combinations in clinical trials.

4F-Indole Enhances the Susceptibility of Pseudomonas aeruginosa to Aminoglycoside Antibiotics.

Infections caused by multidrug-resistant bacteria are becoming increasingly serious. The aminoglycoside antibiotics have been widely used to treat severe Gram-negative bacterial infections. Here, we reported that a class of small molecules, namely, halogenated indoles, can resensitize Pseudomonas aeruginosa PAO1 to aminoglycoside antibiotics such as gentamicin, kanamycin, tobramycin, amikacin, neomycin, ribosomalin sulfate, and cisomicin. We selected 4F-indole as a representative of halogenated indoles to investigate its mechanism and found that the two-component system (TCS) PmrA/PmrB inhibited the expression of multidrug efflux pump MexXY-OprM, allowing kanamycin to act intracellularly. Moreover, 4F-indole inhibited the biosynthesis of several virulence factors, such as pyocyanin, type III secretion system (T3SS), and type VI secretion system (T6SS) exported effectors, and reduced the swimming and twitching motility by suppressing the expression of flagella and type IV pili. This study suggests that the combination of 4F-indole and kanamycin can be more effective against P. aeruginosa PAO1 and affect its multiple physiological activities, providing a novel insight into the reactivation of aminoglycoside antibiotics. IMPORTANCE Infections caused by Pseudomonas aeruginosa have become a major public health crisis. Its resistance to existing antibiotics causes clinical infections that are hard to cure. In this study, we found that halogenated indoles in combination with aminoglycoside antibiotics could be more effective than antibiotics alone against P. aeruginosa PAO1 and preliminarily revealed the mechanism of the 4F-indole-induced regulatory effect. Moreover, the regulatory effect of 4F-indole on different physiological behaviors of P. aeruginosa PAO1 was analyzed by combined transcriptomics and metabolomics. We explain that 4F-indole has potential as a novel antibiotic adjuvant, thus slowing down the further development of bacterial resistance.

Evaluating the accumulated dose distribution of organs at risk in combined radiotherapy for cervical carcinoma based on deformable image registration.

OBJECTIVE: To evaluate the feasibility and value of deformable image registration (DIR) in calculating the cumulative doses of organs at risk (OARs) in the combined radiotherapy of cervical cancer. PATIENTS AND METHODS: Thirty cervical cancer patients treated with external beam radiotherapy (EBRT) combined with intracavitary brachytherapy (ICBT) were reviewed. The simulation CT images of EBRT and ICBT were imported into Varian Velocity 4.1 for the DIR-based dose accumulation. Cumulative dose-volume parameters of D2cc for rectum and bladder were compared between the direct addition (DA) and DIR methods. The quantitative parameters were measured to evaluate the accuracy of DIR. RESULTS: The three-dimensional cumulative dose distribution of the tumor and OARs were graphically well illustrated by composite isodose lines. In combined EBRT and ICBT, the mean cumulative bladder D2cc calculated by DIR and DA was 86.13 Gy and 86.27 Gy, respectively. The mean cumulative rectal D2cc calculated by DIR and DA was 72.97 Gy and 73.90 Gy, respectively. No significant differences were noted between these two methods (p > 0.05). As to the parameters used to evaluate the DIR accuracy, the mean DSC, Jacobian, MDA (mm) and Hausdorff distance (mm) were 0.79, 1.0, 3.84, and 22.01 respectively for the bladder and 0.53, 1.2, 7.31, and 29.58 respectively for the rectum. In this study, the DSC seemed to be slightly lower compared with previous studies. CONCLUSION: Dose accumulation based on DIR might be an alternative method to illustrate and evaluate the cumulative doses of the OARs in combined radiotherapy for cervical cancer. However, DIR should be used with caution before overcoming the relevant limitations.

Does radiation therapy need more than two photon energies from Linac?

Purpose: Modern Linacs are equipped with multiple photon energies for radiation therapy, and proper energy is chosen for each case based on tumor characteristics and patient anatomy. The aim of this study is to investigate whether it is necessary to have more than two photons energies. Methods: The principle of photon energy synthesis is presented. It is shown that a photon beam of any intermediate energy (Esyn) can be synthesized from a linear combination of a low energy (Elow) and a high energy (Ehigh). The principle is validated on a wide range of scenarios: different intermediate photon energies on the same Linac; between Linacs from the same manufacturer or different manufacturers; open and wedge beams; and extensive photon energies available from published reference data. In addition, 3D dose distributions in water phantom are compared using Gamma analysis. The method is further demonstrated in clinical cases of various tumor sites and multiple treatment modalities. Experimental measurements are performed for IMRT plans and they are analyzed using the standard clinical protocol. Results: The synthesis coefficients vary with energy and field size. The root mean square error (RMSE) is within 1.1% for open and wedge fields. Excellent agreement was observed for British Journal of Radiology (BJR) data with an average RMSE of 0.11%. The 3D Gamma analysis shows a good match for all field sizes in the water phantom and all treatment modalities for the five clinical cases. The minimum gamma passing rate of 95.7% was achieved at 1%/1mm criteria for two measured dose distributions of IMRT plans. Conclusion: A Linac with two photon energies is capable of producing dosimetrically equivalent plans of any energy in-between through the photon energy synthesis, supporting the notion that there is no need to equip more than two photon energies on each Linac. This can significantly reduce the cost of equipment for radiation therapy.

Comparison of Ray Tracing and Monte Carlo Calculation Algorithms for Spine Lesions Treated With CyberKnife.

Purpose: This study attempts to evaluate Ray Tracing (RT) and Monte Carlo (MC) algorithms for CyberKnife treatments of spine lesions and determine whether the MC algorithm is necessary for all spine treatment and compare the RT algorithm and MC algorithm at various spine lesion sites. Methods: The CyberKnife is used for stereotactic body radiotherapy for lesions in the cervical spine (30), thoracic spine (50), lumbar spine (30), and sacral spine (15). Dose was calculated using RT and MC algorithms for patients planned with the same beam angles and monitor units. Dose-volume histograms of the target and selected critical structures are evaluated. Results: The average target coverage of prescribed dose with MC algorithms was 94.80%, 88.47%, 92.52%, and 93.41%, respectively, in cervical, thoracic, lumbar, and sacral spine. For the thoracic spine, the RT algorithm significantly overestimates the percentage volume of the target covered by the prescribed dose, as well as overestimates doses to organs at risk in most cases, including lung, spinal cord, and esophagus. For cervical, lumbar, and sacral spine, the differences of the target coverage of prescription dose were generally less than 3% between the RT and MC algorithms. The differences of doses to organs at risk varied with lesion sites and surrounding organs. Conclusions: In the thoracic spine lesions with beams through air cavities, RT algorithm should be limited and verified with MC algorithm, but the RT algorithm is adequate for treatment of cervical, lumbar, and sacral spine lesions without or with a small amount of beams passing through the lungs.

A feasibility study for in vivo treatment verification of IMRT using Monte Carlo dose calculation and deep learning-based modelling of EPID detector response.

BACKGROUND: This paper describes the development of a predicted electronic portal imaging device (EPID) transmission image (TI) using Monte Carlo (MC) and deep learning (DL). The measured and predicted TI were compared for two-dimensional in vivo radiotherapy treatment verification. METHODS: The plan CT was pre-processed and combined with solid water and then imported into PRIMO. The MC method was used to calculate the dose distribution of the combined CT. The U-net neural network-based deep learning model was trained to predict EPID TI based on the dose distribution of solid water calculated by PRIMO. The predicted TI was compared with the measured TI for two-dimensional in vivo treatment verification. RESULTS: The EPID TI of 1500 IMRT fields were acquired, among which 1200, 150, and 150 fields were used as the training set, the validation set, and the test set, respectively. A comparison of the predicted and measured TI was carried out using global gamma analyses of 3%/3 mm and 2%/2 mm (5% threshold) to validate the model's accuracy. The gamma pass rates were greater than 96.7% and 92.3%, and the mean gamma values were 0.21 and 0.32, respectively. CONCLUSIONS: Our method facilitates the modelling process more easily and increases the calculation accuracy when using the MC algorithm to simulate the EPID response, and has potential to be used for in vivo treatment verification in the clinic.

Assessment of Delivery Quality Assurance for Stereotactic Radiosurgery With Cyberknife.

PURPOSE: The purpose of this study is to establish and assess a practical delivery quality assurance method for stereotactic radiosurgery with Cyberknife by analyzing the geometric and dosimetric accuracies obtained using a PTW31016 PinPoint ionization chamber and EBT3 films. Moreover, this study also explores the relationship between the parameters of plan complexity, target volume, and deliverability parameters and provides a valuable reference for improving plan optimization and validation. METHODS: One hundred fifty cases of delivery quality assurance plans were performed on Cyberknife to assess point dose and planar dose distribution, respectively, using a PTW31016 PinPoint ionization chamber and Gafchromic EBT3 films. The measured chamber doses were compared with the planned mean doses in the sensitive volume of the chamber, and the measured planar doses were compared with the calculated dose distribution using gamma index analysis. The gamma passing rates were evaluated using the criteria of 3%/1 mm and 2%/2 mm. The statistical significance of the correlations between the complexity metrics, target volume, and the gamma passing rate were analyzed using Spearman's rank correlation coefficient. RESULTS: For point dose comparison, the averaged dose differences (± standard deviations) were 1.6 ± 0.73% for all the cases. For planar dose distribution, the mean gamma passing rate for 3%/1 mm, and 2%/2 mm evaluation criteria were 94.26% ± 1.89%, and 93.86% ± 2.16%, respectively. The gamma passing rates were higher than 90% for all the delivery quality assurance plans with the criteria of 3%/1 mm and 2%/2 mm. The difference in point dose was lowly correlated with volume of PTV, number of beams, and treatment time for 150 DQA plans, and highly correlated with volume of PTV for 18 DQA plans of small target. DQA gamma passing rate (2%/2 mm) was a moderate significant correlation for the number of nodes, number of beams and treatment time, and a low correlation with MU. CONCLUSION: PTW31016 PinPoint ionization chamber and EBT3 film can be used for routine Cyberknife delivery quality assurance. The point dose difference should be within 3%. The gamma passing rate should be higher than 90% for the criteria of 3%/1 mm and 2%/2 mm. In addition, the plan complexity and PTV volume were found to have some influence on the plan deliverability.

A method for in vivo treatment verification of IMRT and VMAT based on electronic portal imaging device.

BACKGROUND: Intensity-modulated radiation therapy (IMRT) and volume-modulated arc therapy (VMAT) are rather complex treatment techniques and require patient-specific quality assurance procedures. Electronic portal imaging devices (EPID) are increasingly used in the verification of radiation therapy (RT). This work aims to develop a novel model to predict the EPID transmission image (TI) with fluence maps from the RT plan. The predicted TI is compared with the measured TI for in vivo treatment verification. METHODS: The fluence map was extracted from the RT plan and corrections of penumbra, response, global field output, attenuation, and scatter were applied before the TI was calculated. The parameters used in the model were calculated separately for central axis and off-axis points using a series of EPID measurement data. Our model was evaluated using a CIRS thorax phantom and 20 clinical plans (10 IMRT and 10 VMAT) optimized for head and neck, breast, and rectum treatments. RESULTS: Comparisons of the predicted and measured images were carried out using a global gamma analysis of 3%/2 mm (10% threshold) to validate the accuracy of the model. The gamma pass rates for IMRT and VMAT were greater than 97.2% and 94.5% at 3%/2 mm, respectively. CONCLUSION: We have developed an accurate and straightforward EPID-based quality assurance model that can potentially be used for in vivo treatment verification of the IMRT and VMAT delivery.

Development of an Electronic Portal Imaging Device Dosimetry Method.

Support arm backscatter and off-axis effects of an electronic portal imaging device (EPID) are challenging for radiotherapy quality assurance. Aiming at the issue, we proposed a simple yet effective method with correction matrices to rectify backscatter and off-axis responses for EPID images. First, we measured the square fields with ionization chamber array (ICA) and EPID simultaneously. Second, we calculated the dose-to-pixel value ratio and used it as the correction matrix of the corresponding field. Third, the correction value of the large field was replaced with that of the same point in the small field to generate a correction matrix suitable for different EPID images. Finally, we rectified the EPID image with the correction matrix, and then the processed EPID images were converted into the absolute dose. The calculated dose was compared with the measured dose via ICA. The gamma pass rates of 3%/3 mm and 2%/2 mm (5% threshold) were 99.6% ± 0.94% and 95.48% ± 1.03%, and the average gamma values were 0.28 ± 0.04 and 0.42 ± 0.05, respectively. Experimental results verified our method accurately corrected EPID images and converted pixel values into absolute dose values such that EPID was an efficient radiotherapy dosimetry tool.

Auxiliary Structures-Assisted Radiotherapy Improvement for Advanced Left Breast Cancer.

BACKGROUND: To improve the quality of plan for the radiation treatment of advanced left breast cancer by introducing the auxiliary structures (ASs) which are used to spare the regions with no intact delineated structures adjacent to the target volume. METHODS: CT data from 20 patients with left-sided advanced breast cancer were selected. An AS designated as A1 was created to spare the regions of the aorta, pulmonary artery, superior vena ava, and contralateral tissue of the upper chest and neck, and another, designated as A2, was created in the regions of the cardia and fundus of the stomach, left liver lobe, and splenic flexure of the colon. IMRT and VMAT plans were created for cases with and without the use of the AS dose constraints in plan optimization. Dosimetric parameters of the target and organs at risk (OARs) were compared between the separated groups. RESULTS: With the use of AS dose constraints, both the IMRT and VMAT plans were clinically acceptable and deliverable, even showing a slight improvement in dose distribution of both the target and OARs compared with the AS-unused plans. The ASs significantly realized the dose sparing for the regions and brought a better conformity index (p < 0.05) and homogeneity index (p < 0.05) in VMAT plans. In addition, the volume receiving at least 20 Gy (V20) for the heart (p < 0.05), V40 for the left lung (p < 0.05), and V40 for the axillary-lateral thoracic vessel juncture region (p < 0.05) were all lower in VMAT plans. CONCLUSION: The use of the defined AS dose constraints in plan optimization was effective in sparing the indicated regions, improving the target dose distribution, and sparing OARs for advanced left breast cancer radiotherapy, especially those that utilize VMAT plans.

Stem Cell-Based Therapy for Experimental Ischemic Stroke: A Preclinical Systematic Review.

Stem cell transplantation offers promise in the treatment of ischemic stroke. Here we utilized systematic review, meta-analysis, and meta-regression to study the biological effect of stem cell treatments in animal models of ischemic stroke. A total of 98 eligible publications were included by searching PubMed, EMBASE, and Web of Science from inception to August 1, 2020. There are about 141 comparisons, involving 5,200 animals, that examined the effect of stem cell transplantation on neurological function and infarct volume as primary outcome measures in animal models for stroke. Stem cell-based therapy can improve both neurological function (effect size, -3.37; 95% confidence interval, -3.83 to -2.90) and infarct volume (effect size, -11.37; 95% confidence interval, -12.89 to -9.85) compared with controls. These results suggest that stem cell therapy could improve neurological function deficits and infarct volume, exerting potential neuroprotective effect for experimental ischemic stroke, but further clinical studies are still needed.

Neuroprotective Effect of Astragaloside IV on Cerebral Ischemia/Reperfusion Injury Rats Through Sirt1/Mapt Pathway.

Background: Ischemic stroke is a common disease with poor prognosis, which has become one of the leading causes of morbidity and mortality worldwide. Astragaloside IV (AS-IV) is the main bioactive ingredient of Astragali Radix (which has been used for ischemic stroke for thousands of years) and has been found to have multiple bioactivities in the nervous system. In the present study, we aimed to explore the neuroprotective effects of AS-IV in rats with cerebral ischemia/reperfusion (CIR) injury targeting the Sirt1/Mapt pathway. Methods: Sprague-Dawley rats (male, 250-280 g) were randomly divided into the Sham group, middle cerebral artery occlusion/reperfusion (MCAO/R) group, AS-IV group, MCAO/R + EX527 (SIRT1-specific inhibitor) group, and AS-IV + EX527 group. Each group was further assigned into several subgroups according to ischemic time (6 h, 1 d, 3 d, and 7 days). The CIR injury was induced in MCAO/R group, AS-IV group, MCAO/R + EX527 group, and AS-IV + EX527 group by MCAO surgery in accordance with the modified Zea Longa criteria. Modified Neurological Severity Scores (mNSS) were used to evaluate the neurological deficits; TTC (2,3,5-triphenyltetrazolium chloride) staining was used to detect cerebral infarction area; Western Blot was used to assess the protein levels of SIRT1, acetylated MAPT (ac-MAPT), phosphorylated MAPT (p-MAPT), and total MAPT (t-MAPT); Real-time Quantitative Polymerase Chain Reaction (qRT-PCR) was used in the detection of Sirt1 and Mapt transcriptions. Results: Compared with the MCAO/R group, AS-IV can significantly improve the neurological dysfunction (p < 0.05), reduce the infarction area (p < 0.05), raise the expression of SIRT1 (p < 0.05), and alleviate the abnormal hyperacetylation and hyperphosphorylation of MAPT (p < 0.05). While compared with the AS-IV group, AS-IV + EX527 group showed higher mNSS scores (p < 0.05), more severe cerebral infarction (p < 0.05), lower SIRT1 expression (p < 0.01), and higher ac-MAPT and p-MAPT levels (p < 0.05). Conclusion: AS-IV can improve the neurological deficit after CIR injury in rats and reduce the cerebral infarction area, which exerts neuroprotective effects probably through the Sirt1/Mapt pathway.

Preclinical systematic review of ginsenoside Rg1 for cognitive impairment in Alzheimer's disease.

Ginseng has been used for the treatment of aging and memory impairment for thousands of years. Several studies have found that ginsenoside Rg1, as one of the main active components of ginseng, could potentially improve cognitive function in several different animal models. A preclinical systematic review to evaluate the efficacy and mechanisms of ginsenoside Rg1 for ameliorating cognitive impairments in Alzheimer's disease is reported here. We searched six databases from their inceptions to January 2019. Thirty-two studies were selected, which included a total of 1,643 animals. According to various cognitive behavioral tests, the results of the meta-analyses showed that ginsenoside Rg1 significantly improved cognitive behavioral impairments in most Alzheimer's disease models (P < 0.05), but there were no significant effects in animals with neuronal degeneration induced by chronic stress or in SAMP8 transgenic mice. The potential mechanisms included antioxidant and anti-inflammatory effects, amelioration of Alzheimer's disease-related pathology, synapse protection, and up-regulation of nerve cells via multiple signaling pathways.

The Preliminary Results of 3-Dimensional Printed Individual Template Assisted 192Ir High-Dose Rate Interstitial Brachytherapy for Central Recurrent Gynecologic Cancer.

OBJECTIVE: To evaluate the feasibility and safety of high dose rate interstitial brachytherapy (HDR-IB) assisted with 3-dimensional printing individual template (3D-PIT) for central pelvic recurrent gynecologic cancer (CR-GYN). METHODS: Totally 32 patients diagnosed with CR-GYN received iridium-192(192Ir) HDR-IB assisted with 3D-PIT that was classified in 2 types(Type I: transvaginal template/ applicator, and Type II: transvaginal combined transperineal template). The prescribed dose to gross tumor volume (GTV) was 10-36 Gy in 2-6 fractions. We rely on a few dosimetric parameters for quality control. The short-term efficacy was evaluated by RECIST v1.1, and the adverse event was evaluated by CTCAE V4.0. RESULTS: The median V100, D100 and D90 of per fraction among all the patients were 88.9%±9.8%, 3.45Gy±0.54 Gy, and 5.79Gy±0.32 Gy, respectively. Dosimetric comparison between preplan and treatment plan of 20/32 patients with Type II 3D-PIT showed no significant difference in GTV volume, V100, D100, D90, conformation index (CI) and homogeneity index (HI). No severe treatment complications occurred. Grade 3 or 4 late toxicities (fistula) were observed in 3 patients (9%). The local response rate (complete remission, CR + partial remission, PR) was 84.4% (27/32) 1 month after completion of treatment. The median time to progression (TTP) was 15.4 months (95% CI 11.3- 19.6 months), 1-year local control (LC) rate were 51.7%. CONCLUSIONS: HDR-IB assisted by 3D-PIT was a reliable modality for CR-GYN due to the clinical feasibility and accepted complications.

Multi-task autoencoder based classification-regression model for patient-specific VMAT QA.

Patient-specific quality assurance (PSQA) of volumetric modulated arc therapy (VMAT) to assure accurate treatment delivery is resource-intensive and time-consuming. Recently, machine learning has been increasingly investigated in PSQA results prediction. However, the classification performance of models at different criteria needs further improvement and clinical validation (CV), especially for predicting plans with low gamma passing rates (GPRs). In this study, we developed and validated a novel multi-task model called autoencoder based classification-regression (ACLR) for VMAT PSQA. The classification and regression were integrated into one model, both parts were trained alternatively while minimizing a defined loss function. The classification was used as an intermediate result to improve the regression accuracy. Different tasks of GPRs prediction and classification based on different criteria were trained simultaneously. Balanced sampling techniques were used to improve the prediction accuracy and classification sensitivity for the unbalanced VMAT plans. Fifty-four metrics were selected as inputs to describe the plan modulation-complexity and delivery-characteristics, while the outputs were PSQA GPRs. A total of 426 clinically delivered VMAT plans were used for technical validation (TV), and another 150 VMAT plans were used for CV to evaluate the generalization performance of the model. The ACLR performance was compared with the Poisson Lasso (PL) model and found significant improvement in prediction accuracy. In TV, the absolute prediction error (APE) of ACLR was 1.76%, 2.60%, and 4.66% at 3%/3 mm, 3%/2 mm, and 2%/2 mm, respectively; whereas the APE of PL was 2.10%, 3.04%, and 5.29% at 3%/3 mm, 3%/2 mm, and 2%/2 mm, respectively. No significant difference was found between CV and TV in prediction accuracy. ACLR model set with 3%/3 mm can achieve 100% sensitivity and 83% specificity. The ACLR model could classify the unbalanced VMAT QA results accurately, and it can be readily applied in clinical practice for virtual VMAT QA.

Extracts or Active Components from Acorus gramineus Aiton for Cognitive Function Impairment: Preclinical Evidence and Possible Mechanisms.

Extracts or active components from Acorus gramineus Aiton (EAAGA) have been clinically used for cognition impairment more than hundreds of years and are still used in modern times in China and elsewhere worldwide. Previous studies reported that EAAGA improves cognition impairment in animal models. Here, we conducted a preclinical systematic review to assess the current evidence of EAAGA for cognition impairment. We searched 7 databases up until June 2019. Methodological quality for each included studies was accessed according to the CAMARADES 10-item checklist. The primary outcome measures were neurobehavioral function scores evaluated by the Morris water maze test, electrical Y-maze test, step-down test, radial eight-arm maze test, and step-through test. The secondary outcome measures were mechanisms of EAAGA for cognition function. Finally, 34 studies involving 1431 animals were identified. The quality score of studies range from 1 to 6, and the median was 3.32. Compared with controls, the results of the meta-analysis indicated EAAGA exerted a significant effect in decreasing the escape latency and error times and in increasing the length of time spent in the platform quadrant and the number of platform crossings representing learning ability and memory function (all P < 0.01). The possible mechanisms of EAAGA are largely through anti-inflammatory, antioxidant, antiapoptosis activities, inhibition of neurotoxicity, regulating synaptic plasticity, protecting cerebrovascular, stimulating cholinergic system, and suppressing astrocyte activation. In conclusion, EAAGA exert potential neuroprotective effects in experimental cognition impairment, and EAAGA could be a candidate for cognition impairment treatment and further clinical trials.

Analysis of long-term outcome of image-guided volumetric modulated arc therapy (VMAT) for primary malignant tumor of the cervical spine.

OBJECTIVE: Retrospective analysis of the long-term clinical outcome and acute toxicity of the primary malignant tumor of cervical spine receiving CBCT image-guided VMAT. METHODS: Thirty patients with primary malignant tumor of the cervical spine included in our center, from December 2013 to January 2016, 28 patients were retrospectively studied. The prescription dosage 95% PTV volume dose was 44 Gy, 2.0 Gy/fraction, and a total of 22 times. The median PGTV synchronized volume dose was 60 Gy (45-62.1 Gy), median 2.5 Gy (2-2.7 Gy)/fraction. In volumetric modulated, two arc volumetric modulated arc therapy (VMAT) was used, with spinal cord dosage DMAX< 45 Gy. Early response rate and acute toxicities were analyzed. RESULT: The follow-up duration was 6-76 months (median 53 months). At the end of follow-up of June 1, 2019, 78.6% (22/28) patients were still alive. 3 and 5-y local control rates were 67.3% and 56.5% while 3 and 5-y OS were both 78.6% in the whole group of patients, respectively. Fourteen patients with chordoma 5-y local control rates and OS were 57.1% and 85.7%, respectively. Nine patients with giant-cell tumor of bone had a 5-y local control rate and OS were 77.8% and 85.7%, respectively. The response rate for moderate pain or above was 80% (8/10). Eleven patients (39.3%) suffered from grade 1 acute skin toxicity. Twenty-four patients (85.7%) had grade 1/2 mucositis. No radiation-induced spinal cord injury was found. CONCLUSION: The image-guided VMAT for primary malignant tumor of the cervical spine provided a satisfactory long-term local control rate.

Sanhua Decoction, a Classic Herbal Prescription, Exerts Neuroprotection Through Regulating Phosphorylated Tau Level and Promoting Adult Endogenous Neurogenesis After Cerebral Ischemia/Reperfusion Injury.

Background: Ischemia stroke is the leading cause of death and long-term disability. Sanhua Decoction (SHD), a classic Chinese herbal prescription, has been used for ischemic stroke for about thousands of years. Here, we aim to investigate the neuroprotective effects of SHD on cerebral ischemia/reperfusion (CIR) injury rat models. Methods: The male Sprague-Dawley rats (body weight, 250-280 g; age, 7-8 weeks) were randomly divided into sham group, CIR group, and SHD group and were further divided into subgroups according to different time points at 6 h, 1, 3, 7, 14, 21, and 28 d, respectively. The SHD group received intragastric administration of SHD at 10 g kg-1 d-1. The focal CIR models were induced by middle cerebral artery occlusion according to Longa's method, while sham group had the same operation without suture insertion. Neurological deficit score (NDS) was evaluated using the Longa's scale. BrdU, doublecortin (DCX), and glial fibrillary acidic protein (GFAP) were used to label proliferation, migration, and differentiation of nerve cells before being observed by immunofluorescence. The expression of reelin, total tau (t-tau), and phosphorylated tau (p-tau) were evaluated by western blot and RT-qPCR. Results: SHD can significantly improve NDS at 1, 3, 7, and 14 d (p < 0.05), increase the number of BrdU positive and BrdU/DCX positive cells in subventricular zone at 3, 7, and 14 d (p < 0.05), upregulate BrdU/GFAP positive cells in the ischemic penumbra at 28 d after CIR (p < 0.05), and reduce p-tau level at 1, 3, 7, and 14 d (p < 0.05). There was no significant difference on reelin and t-tau level between three groups at each time points after CIR. Conclusions: SHD exerts neuroprotection probably by regulating p-tau level and promoting the proliferation, migration, and differentiation of endogenous neural stem cells, accompanying with neurobehavioral recovery.

Set-up error and dosimetric analysis of HexaPOD evo RT 6D couch combined with cone beam CT image-guided intensity-modulated radiotherapy for primary malignant tumor of the cervical spine.

PURPOSE: To investigate the set-up error and consequent dosimetric change in HexaPOD evo RT 6D couch under image-guided intensity-modulated radiotherapy (IG-IMRT) for primary malignant tumor of the cervical spine. METHODS: Ten cases with primary malignant tumor of the cervical spine were treated with intensity-modulated radiotherapy (IMRT) in our hospital from August 2013 to November 2014. The X-ray volumetric images (XVI) were scanned and obtained by cone-beam CT (CBCT). The six directions (6D) of set-up errors of translation and rotation were obtained by planned CT image registration. HexaPOD evo RT 6D couch made online correction of the set-up error, and then the CBCT was conducted to obtain the residual error. RESULTS: We performed set-up error and dosimetric analysis. First, for the set-up error analysis, the average error in three translation directions of 6D set-up error of the primary tumor of the cervical spine was <2 mm, whereas the single maximum error (absolute value) is 7.0 mm. Among average errors of rotation direction, Rotation X (RX) direction 0.67° ± 0.04°, Rotation Y (RY) direction 1.06° ± 0.06°, Rotation Z (RZ) direction 0.78° ± 0.05°; and the single maximum error in three rotation directions were 2.8°, 3.8°, and 2.9°, respectively. On three directions (X, Y, Z axis), the extended distance from clinical target volume (CTV) to planning target volume (PTV) was 3.45, 3.17, and 3.90 mm by calculating, respectively. Then, for the dosimetric analysis, the parameters, including plan sum PTV D98 and D95, planning gross tumor volume D98 and D95, V100% of the plan sum were significantly lower than the treatment plan. Moreover, Dmax of the spinal cord was significantly higher than the treatment plan. CONCLUSION: 6D set-up error correction system should be used for accurate position calibration of precise radiotherapy for patients with malignant tumor of the cervical spine.

Machine Learning for Patient-Specific Quality Assurance of VMAT: Prediction and Classification Accuracy.

PURPOSE: To assess the accuracy of machine learning to predict and classify quality assurance (QA) results for volumetric modulated arc therapy (VMAT) plans. METHODS AND MATERIALS: Three hundred three VMAT plans, including 176 gynecologic cancer and 127 head and neck cancer plans, were chosen in this study. Fifty-four complexity metrics were extracted from the QA plans and considered as inputs. Patient-specific QA was performed, and gamma passing rates (GPRs) were used as outputs. One Poisson lasso (PL) regression model was developed, aiming to predict individual GPR, and 1 random forest (RF) classification model was developed to classify QA results as "pass" or "fail." Both technical validation (TV) and clinical validation (CV) were used to evaluate the model reliability. GPR prediction accuracy of PL and classification performance of PL and RF were evaluated. RESULTS: In TV, the mean prediction error of PL was 1.81%, 2.39%, and 4.18% at 3%/3 mm, 3%/2 mm, and 2%/2 mm, respectively. No significant differences in prediction errors between TV and CV were observed. In QA results classification, PL had a higher specificity (accurately identifying plans that can pass QA), whereas RF had a higher sensitivity (accurately identifying plans that may fail QA). By using 90% as the action limit at a 3%/2 mm criterion, the specificity of PL and RF was 97.5% and 87.7% in TV and 100% and 71.4% in CV, respectively. The sensitivity of PL and RF was 31.6% and 100% in TV and 33.3% and 100% in CV, respectively. With 100% sensitivity, the QA workload of 81.2% of plans in TV and 62.5% of plans in CV could be reduced by RF. CONCLUSIONS: The PL model could accurately predict GPR for most VMAT plans. The RF model with 100% sensitivity was preferred for QA results classification. Machine learning can be a useful tool to assist VMAT QA and reduce QA workload.