Commissioning and Validation of CT Number to SPR Calibration in Carbon Ion Therapy Facility.

Purpose: We performed computed tomography (CT)-stopping power ratio (SPR) calibration in a carbon-ion therapy facility and evaluated SPR estimation accuracy. Materials and Methods: A polybinary tissue model method was used for the calibration of CT numbers and SPR. As a verification by dose calculation, we created a virtual phantom to which the CT-SPR calibration table was applied. Then, SPR was calculated from the change in the range of the treatment planning beam when changing to 19 different CT numbers, and the accuracy of the treatment planning system (TPS) calculation of SPR values from the CT-SPR calibration table was validated. As a verification by measurement, 5 materials (water, milk, olive oil, ethanol, 40% K2HPO4) were placed in a container, and the SPR was obtained by measurement from the change in the range of the beam that passed through the materials. Results: The results of the dose calculations of the TPS showed that the results agreed within 1% for the lower CT numbers up to 1000 HU, but there was a difference of 3.0% in the higher CT number volume. The difference between the SPR calculated by TPS and the SPR caused by the difference in the energy of the incident particles agreed within 0.51%. The accuracy of SPR estimation was measured, and the error was within 2% for all materials tested. Conclusion: These results indicate that the SPR estimation errors are within the range of errors that can be expected in particle therapy. From commissioning and verification results, the CT-SPR calibration table obtained during this commissioning process is clinically applicable.

Evaluation of the availability of single-position treatment with a rotating gantry and the validity of deformable image registration dose assessment for pancreatic cancer carbon-ion radiotherapy.

BACKGROUND: This study aimed to evaluate the clinical acceptability of rotational gantry-based single-position carbon-ion radiotherapy (CIRT) to reduce the gastrointestinal (GI) dose in pancreatic cancer. We also evaluated the usefulness of the deformable image registration (DIR)-based dosimetry method for CIRT. MATERIAL AND METHODS: Fifteen patients with pancreatic cancer were analyzed. The treatment plans were developed for four beam angles in the supine (SP plan) and prone (PR plan) positions. In the case of using multiple positions, the treatment plan was created with two angles for each of the supine and prone position (SP + PR plan). Dose evaluation for multiple positions was performed in two ways: by directly adding the values of the DVH parameters for each position treatment plan (DVH sum), and by calculating the DVH parameters from the accumulative dose distribution created using DIR (DIR sum). The D2cc and D6cc of the stomach and duodenum were recorded for each treatment plan and dosimetry method and compared. RESULTS: There were no significant differences among any of the treatment planning and dosimetry methods (p > 0.05). The DVH parameters for the stomach and duodenum were higher in the PR plan and SP plan, respectively, and DVH sum tended to be between the SP and PR plans. DVH sum and DIR sum, DVH sum tended to be higher for D2cc and DIR sum tended to be higher for D6cc. CONCLUSION: There were no significant differences in the GI dose, which suggests that treatment with a simple workflow performed in one position should be clinically acceptable. In CIRT, DIR-based dosimetry should be carefully considered because of the potential for increased uncertainty due to the steep dose distributions.

A robust treatment planning approach for chest motion in postmastectomy chest wall intensity modulated radiation therapy.

PURPOSE: Chest wall postmastectomy radiation therapy (PMRT) should consider the effects of chest wall respiratory motion. The purpose of this study is to evaluate the effectiveness of robustness planning intensity modulated radiation therapy (IMRT) for respiratory movement, considering respiratory motion as a setup error. MATERIAL AND METHODS: This study analyzed 20 patients who underwent PMRT (10 left and 10 right chest walls). The following three treatment plans were created for each case and compared. The treatment plans are a planning target volume (PTV) plan (PP) that covers the PTV within the body contour with the prescribed dose, a virtual bolus plan (VP) that sets a virtual bolus in contact with the body surface and prescribing the dose that includes the PTV outside the body contour, and a robust plan (RP) that considers respiratory movement as a setup uncertainty and performs robust optimization. The isocenter was shifted to reproduce the chest wall motion pattern and the doses were recalculated for comparison for each treatment plan. RESULT: No significant difference was found between the PP and the RP in terms of the tumor dose in the treatment plan. In contrast, VP had 3.5% higher PTV Dmax and 5.5% lower PTV V95% than RP (p < 0.001). The RP demonstrated significantly higher lung V20Gy and Dmean by 1.4% and 0.4 Gy, respectively, than the PP. The RP showed smaller changes in dose distribution affected by chest wall motion and significantly higher tumor dose coverage than the PP and VP. CONCLUSION: We revealed that the RP demonstrated comparable tumor doses to the PP in treatment planning and was robust for respiratory motion compared to both the PP and the VP. However, the organ at risk dose in the RP was slightly higher; therefore, its clinical use should be carefully considered.

Error on the stopping power ratio of ERKODENT's mouthpiece for head and neck carbon ion radiotherapy treatment.

The errors on the stopping power ratio (SPR) of mouthpiece samples from ERKODENT were evaluated. Erkoflex and Erkoloc-pro from ERKODENT and samples that combined Erkoflex and Erkoloc-pro were computed tomography (CT)-scanned using head and neck (HN) protocol at the East Japan Heavy Ion Center (EJHIC), and the values were averaged to obtain the CT number. The integral depth dose of the Bragg curve with and without these samples was measured for 292.1, 180.9, and 118.8 MeV/u of the carbon-ion pencil beam using an ionization chamber with concentric electrodes at the horizontal port of the EJHIC. The average value of the water equivalent length (WEL) of each sample was obtained from the difference between the range of the Bragg curve and the thickness of the sample. To calculate the difference between the theoretical and measured values, the theoretical CT number and SPR value of the sample were calculated using the stoichiometric calibration method. Compared with the Hounsfield unit (HU)-SPR calibration curve used at the EJHIC, the SPR error on each measured and theoretical value was calculated. The WEL value of the mouthpiece sample had an error of approximately 3.5% in the HU-SPR calibration curve. From this error, it was evaluated that for a mouthpiece with a thickness of 10 mm, a beam range error of approximately 0.4 mm can occur, and for a mouthpiece with a thickness of 30 mm, a beam range error of approximately 1 mm can occur. For a beam passing through the mouthpiece in HN treatment, it would be practical to consider a mouthpiece margin of 1 mm to avoid beam range errors if ions pass through the mouthpiece.

Correcting for the effect of ambient pressure fluctuations on measured output from a linear accelerator with a sealed monitor chamber.

Objective.Ambient pressure fluctuations deform the walls of a sealed monitor chamber in a linear accelerator (LINAC) and affect the output. This study retrospectively quantified the output variations accompanying ambient pressure fluctuations in a LINAC equipped with a sealed monitor chamber and introduced a novel approach of calculating the adjusted output free from the effect of ambient pressure fluctuations.Approach.The output data for the 6 MV and 10 MV X-rays measured between March 2014 and September 2015 were analysed. This period was further divided into four sub-periods according to the output calibrations. Output behaviours were modelled using multiple regression analysis with ambient pressure and the time elapsed since the last calibration as explanatory variables. The output variations accompanying ambient pressure fluctuations were calculated using regression parameters and were subtracted from the measured outputs to obtain the adjusted outputs.Main results.The partial regression coefficients for ambient pressure varied from -2.3 × 10-4to -1.8 × 10-4cGy/MU/hPa for 6 MV and from -1.9 × 10-4to -1.2 × 10-4cGy/MU/hPa for 10 MV X-rays. These partial regression coefficient values were comparable among the four sub-periods and the two x-ray energies, respectively. These findings suggest that the degree of the output variations accompanying ambient pressure fluctuations is independent of x-ray energies and is determined by the internal structure of the chamber and the pressure differential between the inside and outside of the chamber. The adjusted outputs showed a better fit with the time trend line than the measured outputs.Significance.This study demonstrates a novel procedure for obtaining the adjusted outputs and allows precise observation of the output behaviours of a LINAC equipped with a sealed monitor chamber. Combined observation of the measured and adjusted output facilitates the detection of output anomalies, thus contributing to quality control (QC) of LINACs.

Efficacy and safety of miconazole muco-adhesive tablet versus itraconazole in oropharyngeal candidiasis: A randomized, multi-centered, double-blind, phase 3 trial.

Oropharyngeal candidiasis (OPC) is an opportunistic infection treated with anti-fungal agents. Herein, we evaluate the efficacy and safety of miconazole buccal tablets (MBT) and itraconazole capsules in the localized treatment of patients with OPC. In this multi-centered, double-blinded, phase III trial (CTR20130414), both males and non-pregnant females (≥18 years) with OPC were randomized (1:1) to MBT plus placebo (experimental group) or itraconazole capsules plus placebo (control group). The primary endpoint was clinical cure at the end-of-treatment period [visit 4 (V4)] while secondary endpoints were clinical remission rates, partial remission rates, mycological cure, clinical relapse, and adverse events (AEs). All endpoints were statistically analyzed in both the full analysis set (FAS) and per-protocol (PP) set. A total of 431 (experimental: 216; control: 215) subjects were included. At V4, in the FAS set, the clinical cure was achieved in 68% and 59% patients in experimental and control groups, respectively with a treatment difference of 9% [95% confidence interval (CI): -1,19; P < .001] demonstrating non-inferiority of MBT over itraconazole. At V4, mycological cure rates were 68.2% and 42.0% in the experimental group and control groups (P < .001), respectively in FAS. The relapse rates were 5.4% and 6.6%, respectively, in the experimental and control groups. A total of 210 patients experienced AEs during treatment with 47.7% in the experimental group and 49.8% in the control group with no deaths. This study demonstrated that once-daily treatment with MBT was non-inferior to itraconazole with higher mycological cure rates and was tolerable with mild AE in patients with OPC.

Miconazole is an antifungal drug against certain types of fungus or yeast infections. In this study, we showed that treatment with once-daily miconazole buccal tablets was as effective as systemic itraconazole capsules in Chinese patients infected by oropharyngeal candidiasis with minimum side effects.

A Pan-Cancer Analysis Reveals the Prognostic and Immunotherapeutic Value of Stanniocalcin-2 (STC2).

Background: Stanniocalcin-2 (STC2) is a secreted glycoprotein which plays an important role in regulating the homeostasis of calcium, glucose homeostasis, and phosphorus metastasis. Accumulating evidence suggests that STC2 is implicated in cancer mechanisms. However, the effects of STC2 on cancer development and progression across pan-cancer are not yet completely known. Methods: Data were downloaded from The Cancer Genome Atlas database to obtain differentially expressed genes significantly associated with prognosis (key genes). A gene was selected for subsequent correlation studies by integrating the significance of prognosis and the time-dependent ROC curve. Gene expression of different tumor types was analyzed based on the UCSC XENA website. Furthermore, our study investigated the correlation of STC2 expression between prognosis, immune cell infiltration, immune checkpoint genes (ICGs), mismatch repair genes (MMRs), tumor mutation burden (TMB), microsatellite instability (MSI), and drug sensitivity in various malignant tumors. Gene set enrichment analysis (GSEA) was conducted for correlated genes of STC2 to explore potential mechanisms. Results: A total of 3,429 differentially expressed genes and 397 prognosis-related genes were identified from the TCGA database. Twenty-six key genes were found by crossing the former and the latter, and the highest risk gene, STC2, was selected for subsequent correlation studies. STC2 had good diagnostic performance for HNSCC, and was closely related to the survival status and clinicopathological stage of HNSCC patients. In pan-cancer analysis, STC2 was upregulated in 20 cancers and downregulated in seven cancers. STC2 overexpression was overall negatively correlated with overall survival, disease-free survival, disease-specific survival, and progress-free survival. STC2 was profoundly correlated with the tumor immune microenvironment, including immune cell infiltration, ICGs, MMRs, TMB, and MSI. Moreover, STC2 was significantly negatively correlated with the sensitivity or resistance of multiple drugs. Conclusion: STC2 was a potential prognostic biomarker for pan-cancer and a new immunotherapy target.

Development of a quantitative analysis method for assessing patient body surface deformation using an optical surface tracking system.

This study aimed to develop a new method to quantitatively analyze body shape changes in patients during radiotherapy without additional radiation exposure using an optical surface tracking system. This method's accuracy was evaluated using a cubic phantom with a known shift. Surface images of three-dimensionally printed phantoms, which simulated the head and neck shapes of real patients before and after treatment, were used to create a deformation surface area histogram. The near-maximum deformation value covering an area of 2 cm2 in the surface image (Def-2cm2) was calculated. A volumetric modulated arc therapy (VMAT) plan was also created on the pre-treatment phantom, and the dose distribution was recalculated on the post-treatment phantom to compare the dose indices. Surface images of four patients were analyzed to evaluate Def-2cm2 and examine whether this method can be used in clinical cases. Experiments with the cubic phantom resulted in a mean deformation error of 0.08 mm. With head and neck phantoms, the Def-2cm2 value was 17.5 mm, and the dose that covered 95% of the planning target volume in the VMAT plan decreased by 11.7%, indicating that deformation of the body surface may affect the dose distribution. Although analysis of the clinical data showed no clinically relevant deformation in any of the cases, slight skin sagging and respiratory changes in the body surface were observed. The proposed method can quantitatively and accurately evaluate the deformation of a body surface. This method is expected to be used to make decisions regarding modifications to treatment plans.

Technical note: improved positioning protocol for patient setup accuracy in conventional radiotherapy for lung cancer.

This study aimed to investigate an improved setup protocol for maintaining patient setup accuracy, with minimal or no use of image-guided radiation therapy in conventional radiotherapy for lung cancer. A coordinate value for the treatment couch in the anterior-posterior (AP) direction was obtained from the first fraction using bony anatomy image guidance. The coordinate value was invariably used for patient positioning in the second and subsequent treatment fractions. The errors of 2410 setup image sets (anterior and lateral) from 105 patients with lung cancer were analyzed. The systematic and random patient positioning errors in the AP direction were 0.6 ± 1.0 mm. Such errors accounted for 97% of all fractions within ± 2 mm. The protocol resulted in minimal patient setup errors in the AP direction using only one image for guidance; therefore, it may be applied to conventional radiotherapy for lung cancer in case of insufficient image guidance.

Reconstruction of the lncRNA-miRNA-mRNA network based on competitive endogenous RNA reveal functional lncRNAs in Cerebral Infarction.

Functioning as miRNA sponges, long non-coding RNA (lncRNA) exert its pharmacological action via regulating expression of protein-coding genes. However, the lncRNA-mediated ceRNA in cerebral Infarction (CI) remains unclear. In this study, the expression recordsets of mRNA, lncRNA and miRNA of CI samples were obtained from the NCBI GEO datasets separately. The differentially expressed lncRNAs (DELs), miRNAs (DEMis) and mRNAs (DEMs) were identified by limma package in R platform. A total of 267 DELs, 26 DEMis, and 760 DEMs were identified as differentially expressed profiles, with which we constructed the ceRNA network composed of DELs-DEMis-DEMs. Further, clusterProfiler package in R platform is employed for performing Gene Ontology (GO) and KEGG pathway analysis. An aberrant ceRNA network was constructed according to node degrees in CI, including 28 DELs, 19 DEMs and 12 DEMis, from which we extracted the core network, in which 9 nodes were recognized as kernel genes including Tspan3, Eif4a2, rno-miR-208a-3p, rno-miR-194-5p, Pdpn, H3f3b, Stat3, Cd63 and Sdc4. Finally, with the DELs-DEMis-DEMs ceRNA network provided above, we can improve our understanding of the pathogenesis of CI mediated by lncRNA.

Association Between Vitamin D Receptor Gene Polymorphisms and Polycystic Ovary Syndrome Risk: A Meta-Analysis.

Objective: Published studies have demonstrated a closer association between vitamin D receptor (VDR) gene polymorphisms and polycystic ovary syndrome (PCOS) risk, but the results were inconsistent. We therefore performed this meta-analysis to explore the precise associations between VDR gene polymorphisms and PCOS risk. Methods: Five online electronic databases (PubMed, Embase, SCI index, CNKI and Wanfang) were searched. Odds ratios (ORs) with 95% confidence interval (CIs) were calculated to assess the association between VDR Fok I C/T (rs10735810), BsmI A/G (rs1544410), ApaI A/C (rs7975232), and TaqI T/C (rs731236) polymorphisms and PCOS risk. In addition, heterogeneity, accumulative/sensitivity analysis and publication bias were conducted to check the statistical power. Results: Overall, 10 publications (31 independent case-control studies) involving 1,531 patients and 1,174 controls were identified. We found that the C mutation of ApaI A/C was a risk factor for PCOS (C vs. A: OR = 1.20, 95%CI = 1.06-1.35, P < 0.01, I 2 = 29.7%; CC vs. AA: OR = 1.49, 95%CI = 1.17-1.91, P < 0.01, I 2 = 0%; CC vs. AA+AC: OR = 1.36, 95%CI = 1.09-1.69, P = 0.01, I 2 = 12.8%). Moreover, the BsmI A/G polymorphism also showed a dangerous risk for PCOS in Asian population (G vs. A: OR = 1.62, 95%CI = 1.24-2.11, P < 0.01, I 2 = 0%; AG vs. AA: OR = 2.08, 95%CI = 1.26-3.20, P < 0.01, I 2 = 0%; GG vs. AA: OR = 2.21, 95%CI = 1.29-3.77, P < 0.01, I 2 = 0%; AG+GG vs. AA: OR = 2.12, 95%CI = 1.42-3.16, P < 0.01, I 2 = 0%). In addition, no significant association of Fok I C/T, and TaqI T/C polymorphisms was observed. Conclusions: In summary, our meta-analysis suggested that VDR gene polymorphisms contribute to PCOS development, especially in Asian populations.

Novel acridine-based N-acyl-homoserine lactone analogs induce endoreduplication in the human oral squamous carcinoma cell line SAS.

The cytotoxicity of novel acridine-based N-acyl-homoserine lactone (AHL) analogs was investigated on the human oral squamous carcinoma cell line SAS. One analog induced G2/M phase arrest at 5.3-10.6 µM and induced polyploidy at a higher dose (21.2 µM). Importantly, treatment of SAS cells with a combination of the AHL analog and the Jun N-terminal kinase (JNK) inhibitor, SP600125, prevented mitosis and induced polyploidy. The AHL analog synergized with X-irradiation to inhibit clonogenic survival of SAS cells; however, its radiosensitizing effects were relative to not X-irradiation-induced apoptosis but mitotic failure following enhanced expression of Aurora A and B. These results suggest that the active AHL analog showed growth-suppressive and radiosensitizing effects, which involve polyploidy followed by G2/M accumulation and atypical cell death in the SAS cell line.

Functional properties of synthetic N-acyl-L-homoserine lactone analogs of quorum-sensing gram-negative bacteria on the growth of human oral squamous carcinoma cells.

Quorum sensing is defined as the ability of microorganisms to sense their population density via the release of signaling molecules composed of acyl-homoserine lactone (AHL), which is a type of autoinducer (AI). Previous structure-activity relationship (SAR) studies demonstrated that the 3-oxo group, homoserine lactone of L-form, and long acyl side chain have crucial roles in apoptosis induction. Various types of synthetic AI analogs of Pseudomonas aeruginosa were prepared, and SAR study was conducted to determine their effects against human oral squamous carcinoma cells derived from gingival carcinoma Ca9-22 cells and tongue cancer SAS cells. Not only the antiproliferative potential but also the radiation-sensitizing effects against these cells were examined. It was found that antiproliferative activity partly depended on HSL structure and acyl side chain length. Moreover, a few compounds, compound 5 and 87, showed antiproliferative effects against both Ca9-22 and SAS cells, and also induced radiation-sensitizing effects against Ca9-22 cells. Compound 5 alone induced apoptotic cell death accompanied by sub-G1 phase accumulation in cell cycle and caspase-3 activation, and radiation-sensitizing effects of compound 5 could be attributed to enhanced apoptosis induction. In contrast, there were no remarkable alterations in cell cycle distribution in Ca9-22 treated with compound 87 alone or in combination. However, both compounds lack 3-oxo and their acyl side chain lengths are not necessarily long. This SAR study demonstrated that HSL analogs, which lacked the recommended characteristics for apoptosis induction clearly showed antiproliferative and radiation-sensitizing activity in Ca9-22 cells.