Demonstration of quasi-real-time intrafractional motion in esophageal cancer radiotherapy provided by ExacTrac X-ray snap verification.

OBJECTIVE: To investigate the following hypotheses: (1) ExacTrac X-ray Snap Verification (ET-SV) is an alternative to CBCT for positioning patients with esophageal carcinoma (EC), (2) ET-SV can detect displacement in EC patients during radiotherapy (RT) and (3) EC patients can be feasibly monitored in quasi-real-time with ET-SV during RT. METHODS: Anthropomorphic phantoms and 13 patients were included in this study. CBCT and ET-SV were both implemented before treatment delivery to detect displacement, and their correction results were compared. For the patient tests, positional correction in 3 translational directions and the yaw direction were applied using the ET-SV correction results. The residual error was detected immediately using ET-SV. Finally, to acquire the intrafractional motion, ET-SV was implemented when the gantry was at 0°, 90°, 180° and 270°, respectively. RESULTS: In phantom tests, the maximum value of the difference in displacement between the CBCT and ET systems was 1.16 mm for translation and 0.31° for yaw. According to Bland-Altman analysis of the patient test results, 5% (5/98), 5% (5/98), 5% (5/98), and 4% (4/98) of points were beyond the upper and lower limits of agreement in the AP, SI, LR and yaw directions, respectively. The mean residual error was -0.482 mm, 1.215 mm, 1.0 mm, -0.487°, 0.105°, and 0.003° in the AP, SI, LR, pitch, roll and yaw directions, respectively. The intrafractional displacement ranged from -0.21 mm to 0 mm for translation and from -0.63° to 0.21° for rotation. The mean total translational error for intrafractional motion increased from 0.47 mm to 1.14 mm during the treatment. CONCLUSION: The accuracy of ET-SV for EC RT positional correction is comparable to that of CBCT. Thus, Quasi-real-time intrafractional monitoring can be used to detect EC patient displacement during radiotherapy.

Reproducibility for Hepatocellular Carcinoma CT Radiomic Features: Influence of Delineation Variability Based on 3D-CT, 4D-CT and Multiple-Parameter MR Images.

Purpose: Accurate lesion segmentation is a prerequisite for radiomic feature extraction. It helps to reduce the features variability so as to improve the reporting quality of radiomics study. In this research, we aimed to conduct a radiomic feature reproducibility test of inter-/intra-observer delineation variability in hepatocellular carcinoma using 3D-CT images, 4D-CT images and multiple-parameter MR images. Materials and Methods: For this retrospective study, 19 HCC patients undergoing 3D-CT, 4D-CT and multiple-parameter MR scans were included in this study. The gross tumor volume (GTV) was independently delineated twice by two observers based on contrast-enhanced computed tomography (CECT), maximum intensity projection (MIP), LAVA-Flex, T2W FRFSE and DWI-EPI images. We also delineated the peritumoral region, which was defined as 0 to 5 mm radius surrounding the GTV. 107 radiomic features were automatically extracted from CECT images using 3D-Slicer software. Quartile coefficient of dispersion (QCD) and intraclass correlation coefficient (ICC) were applied to assess the variability of each radiomic feature. QCD<10% and ICC≥0.75 were considered small variations and excellent reliability. Finally, the principal component analysis (PCA) was used to test the feasibility of dimensionality reduction. Results: For tumor tissues, the numbers of radiomic features with QCD<10% indicated no obvious inter-/intra-observer differences or discrepancies in 3D-CT, 4D-CT and multiple-parameter MR delineation. However, the number of radiomic features (mean 89) with ICC≥0.75 was the highest in the multiple-parameter MR group, followed by the 3DCT group (mean 77) and the MIP group (mean 73). The peritumor tissues also showed similar results. A total of 15 and 7 radiomic features presented excellent reproducibility and small variation in tumor and peritumoral tissues, respectively. Two robust features showed excellent reproducibility and small variation in tumor and peritumoral tissues. In addition, the values of the two features both represented statistically significant differences among tumor and peritumoral tissues (P<0.05). The PCA results indicated that the first seven principal components could preserve at least 90% of the variance of the original set of features. Conclusion: Delineation on multiple-parameter MR images could help to improve the reproducibility of the HCC CT radiomic features and weaken the inter-/intra-observer influence.

Optical coherence tomography angiography of flat irregular pigment epithelial detachments in central serous chorioretinopathy.

BACKGROUND: To identify and analyse the character and relationship between flat irregular pigment epithelial detachment feature (FIPED), choroidal thickness and choroidal neovascularisation (CNV) network seen on optical coherence tomography angiography (OCTA) in eyes with central serous chorioretinopathy (CSCR) in Chinese patients. METHOD: In the present study, 152 eyes of 144 Chinese patients, who were previously diagnosed with CSCR, were retrospectively studied. Patients' baseline characteristics, the course of CSCR, best-corrected visual acuity, the pattern of CNV on OCTA, FIPED and choroidal thickness detected by enhanced depth imaging-OCT (EDI-OCT) were analysed. RESULTS: It was disclosed that 7.23% of CSCR patients had CNV. Age and the course of CSCR were found to be correlated with the occurrence of CNV. Among the eyes with CNV network (11 eyes), 100% of them had FIPED, whereas, among the eyes without CNV (141 eyes), 18.04% had FIPED. The maximum width and en-face area of PED were greater in the CNV group compared with that in the non-CNV group (p<0.001). It also was revealed that female gender and a poor vision were risk factors for CNV in eyes with CSCR. The choroidal thickness detected by EDI-OCT was also statistically significant between eyes with CNV and eyes without CNV. The patients who have CNV complicated with FIPED are susceptible to have low vision. CONCLUSION: The present research demonstrated that the majority of CNV cases were linked to FIPED, and the thinner thickness of choroid. The greater width and en-face area of PED may point towards the presence of an underlying CNV network.

Feasibility evaluation of kilovoltage cone-beam computed tomography dose calculation following scatter correction: investigations of phantom and representative tumor sites.

BACKGROUND: To study the feasibility of kilovoltage cone-beam computed tomography (KV-CBCT) dose calculation following scatter correction. METHODS: CIRS 062 and Catphan 504 phantoms were used in this study, and 40 randomly selected subjects representing a variety of cases (ten head cancer cases, ten chest cancer cases, ten abdominal cancer cases and ten pelvic cavity cancer cases) were enrolled. We developed in-house software called the cone-beam CT imaging toolkit (CITK) to improve the quality of CBCT images. We first aligned each planning computed tomography (pCT) image with the corresponding CBCT image using rigid registration after scatter correction. Hounsfield unit-relative electron density (HU-RED) calibration was applied to the CBCT images. The pCT plan was then recalculated on CBCT images. Finally, the dosimetric differences between the two plans were evaluated. The dosimetric parameters included the D98, D2, Dmean, conformity index (CI), homogeneity index (HI) and other organ at risk (OAR) dose parameters of the planning target volume (PTV). The dose distribution index (DDI) and the gamma index were also assessed. Paired Student's t-tests or Wilcoxon rank tests were used to evaluate differences. P<0.05 was considered significant. RESULTS: In the phantom and patient cases, the average dosimetric difference was less than 1% in the PTV and OARs. There was no significant difference in the CI or HI between the two plans. The gamma pass rate of 2%/2 mm was greater than 95% in both plans. There was a significant difference in the DDI between the two plans in the chest group but not in the other groups. CONCLUSIONS: The results suggest that CBCT has high accuracy in dose calculation via scatter correction and HU-RED calibration.

Adhesive Sulfide Solid Electrolyte Interface for Lithium Metal Batteries.

All solid-state Li metal batteries have drawn extensive attention because of the limited side reaction and consequent safety character. The applications of Li metal anodes are indispensable for realizing high energy density but still face many obstacles. One of the critical issues is the contact failure of the solid/solid interface. The rigid interface between a sulfide electrolyte and Li anode cannot afford the volume variation during cycling. Herein, we design an adhesive solid-state electrolyte film, which is supported by hot melt adhesive porous membranes for anode protection. The Li symmetric cells and all solid-state batteries based on adhesive electrolyte layers all exhibit enhanced long cyclic stability and suppressed voltage polarization. The peel strength tests confirm that the electrolyte layers decorated with adhesive components can offer intimate Li metal/electrolyte physical contact and withstand the volume variation of the Li anode. The adhesion force from porous membranes is believed to play a vital role in maintaining solid-solid interfacial contact stability. This work gives a new insight for interface engineering in all solid-state Li metal batteries.

A New Proton Therapy Solution Provides Superior Cardiac Sparing Compared With Photon Therapy in Whole Lung Irradiation for Pediatric Tumor Patients.

OBJECTIVE: Whole lung irradiation (WLI) plays a crucial role in local control in pediatric patients with lung metastases and improves patient survival. The intention of this research was to explore the advantage of cardiac sparing between photons and protons during WLI. We also propose a new solution for cardiac sparing with proton techniques. METHODS: Eleven patients with pediatric tumors and pulmonary metastasis treated with 12 Gy WLI (all received volumetric-modulated arc therapy (VMAT)) in our institute between 2010 and 2019 were retrospectively selected. Each patient was replanned with intensity-modulated radiation therapy (IMRT), helical tomotherapy (HT), and two intensity-modulated proton radiotherapy (IMPT) plans (IMPT-1 and IMPT-2). IMPT-1 considered the whole lung as the planning target volume (PTV), utilizing the anteroposterior technique (0/180°). IMPT-2 was a new proton solution that we proposed in this research. This approach considered the unilateral lung as the PTV, and 3 ipsilateral fields were designed for each lung. Then, IMPT-2 was generated by summing two unilateral lung plans. The primary objective was to obtain adequate coverage (95% of the prescription dose to the PTV) while maximally sparing the dose to the heart. The PTV coverage, conformity index (CI), homogeneity index (HI), and dose-volume statistics of the heart and substructures were assessed by means of the averages of each comparison parameter. RESULTS: All treatment techniques achieved the target volume coverage required by clinical practice. HT yielded the best coverage and homogeneity for the target structure compared with other techniques. The CI from IMRT was excellent. For photon radiation therapy, the HT plan afforded superior dose sparing for the V5, V6, V7, V8, and Dmean of the heart and Dmean of the right ventricle (RV). IMRT displayed the most notable dose reductions in the V9, V10, V11, and V12 of the heart and Dmean of the right atrium (RA). The VMAT plan was the least effective on the heart and substructures. However, compared with photon radiation therapy, IMPT-1 did not show an advantage for heart protection. Interestingly, IMPT-2 provided significant superiority in cardiac sparing, including maximum dose sparing for the V5, V6, V7, V8, V9 and Dmean of the heart and Dmean of the RA, RV, left atrium (LA) and left ventricle (LV) compared to all other techniques. CONCLUSIONS: Considering the complex anatomical relation between target volumes and organs at risk (OARs), IMPT can provide a dose advantage for organs located outside of the target area rather than within or surrounding the area. It is hoped that advances in proton therapy (PT) plan design will lead to further improvements in radiotherapy approaches and provide the best treatment choice for individual patients.

Reproducibility and non-redundancy of radiomic features extracted from arterial phase CT scans in hepatocellular carcinoma patients: impact of tumor segmentation variability.

BACKGROUND: The reproducibility and non-redundancy of radiomic features are challenges in accelerating the clinical translation of radiomics. In this study, we focused on the robustness and non-redundancy of radiomic features extracted from computed tomography (CT) scans in hepatocellular carcinoma (HCC) patients with respect to different tumor segmentation methods. METHODS: Arterial enhanced CT images were retrospectively randomly obtained from 106 patients. As a training data set, 26 HCC patients were used to calculate the features' reproducibility and redundancy. Another data set (55 HCC patients and 25 healthy volunteers) was used for classification. The GrowCut and GraphCut semiautomatic segmentation methods were implemented in 3D Slicer software by two independent observers, and manual delineation was performed by five abdominal radiation oncologists to acquire the gross tumor volume (GTV). Seventy-one radiomic features were extracted from GTVs using Imaging Biomarker Explorer (IBEX) software, including 17 tumor intensity statistical features, 16 shape features and 38 textural features. For each radiomic feature, intraclass correlation coefficient (ICC) and hierarchical clustering were used to quantify its reproducibility and redundancy. Features with ICC values greater than 0.75 were considered reproducible. To generate the number of non-redundancy feature subgroups, the R2 statistic method was used. Then, a classification model was built using a support vector machine (SVM) algorithm with 10-fold cross validation, and area under ROC curve (AUC) was used to evaluate the utility of non-redundant feature extraction by hierarchical clustering. RESULTS: The percentages of excellent reproducible features in the manual delineation group, GraphCut and GrowCut segmentation group were 69% [49], 73% [52] and 79% [56], respectively. Sixty-five percent [46] of the features showed strong robustness for all segmentation methods. The optimal number of cluster subgroup were 9, 13 and 11 for manual delineation, GraphCut and GrowCut segmentation, respectively. The optimal cluster subgroup number was 6 for all groups when the collectively high reproducibility features were selected for clustering. The receiver operating characteristic (ROC) analysis of radiomics classification model with and without feature reduction for healthy liver and HCC had an AUC value of 0.857 and 0.721 respectively. CONCLUSIONS: Our study demonstrates that variations exist in the reproducibility of quantitative imaging features extracted from tumor regions segmented using different methods. The reproducibility and non-redundancy of the radiomic features rely greatly on the tumor segmentation in HCC CT images. We recommend that the most reliable and uniform radiomic features should be selected in the clinical use of radiomics. Classification experiments with feature reduction showed that radiomic features were effective in identifying healthy liver and HCC.

Capability of leaf interdigitation with different inverse planning strategies in Monaco: an investigation of representative tumour sites.

PURPOSE: The aim of this study was to experimentally assess the dosimetric impact of leaf interdigitation using different inverse treatment strategies for representative tumour sites and to identify the situations in which leaf interdigitation can benefit these tumour sites. MATERIAL AND METHODS: Sixty previously treated patients (15 nasopharyngeal carcinoma (NPC), 15 multiple brain metastasis (MBM), 15 cervical cancer and 15 prostate cancer) were re-planned for volumetric modulated arc therapy (VMAT), sliding window IMRT (dMLC) and step-and-shoot IMRT (ssIMRT) with and without leaf interdigitation. Various dosimetric variables, such as PTV coverage, OARs sparing, delivery efficiency and planning time, were evaluated for each plan. In addition, a protocol developed by our group was applied to identify the situations in which leaf interdigitation can achieve benefits in clinical practice. RESULTS: Leaf interdigitation produced few benefits in PTV homogeneity for the MBM VMAT plans and NPC ssIMRT plans. For OARs, sparing was equivalent with and without leaf interdigitation. Leaf interdigitation showed an increase in MUs for dMLC plans and a decrease in MUs for ssIMRT plans. Leaf interdigitation resulted in an increase in segments for dMLC plans and a decrease in segments for NPC and MBM ssIMRT plans. For beam on time, leaf interdigitation showed an increase in MBM dMLC, NPC ssIMRT and prostate ssIMRT plans. In addition, leaf interdigitation saved planning time for VMAT and dMLC plans but increased planning time for ssIMRT plans. CONCLUSION: Leaf interdigitation does not improve plan quality when performing inverse treatment strategies, regardless of whether the target is simple or complex. However, it influences the delivery efficiency and planning time. Based on these observations, our study suggests that leaf interdigitation should be utilized when performing MBM VMAT plans and NPC ssIMRT plans.

[The analysis of mitochondrial DNA haplogroups and variants for Leber's hereditary optic neuropathy in Chinese families carrying the m.14484T >C mutation].

The m.14484T>C mutation in mitochondrial ND6 gene (MT-ND6) is a primary mutation underlying the development of Leber's hereditary optic neuropathy (LHON) , but by itself not enough to cause visual loss. To explore the role of mitochondrial haplogroups on the expression of LHON for the people carrying the m.14484T>C mutation, we performed systematic and extended mutational screening of MT-ND6 gene in a cohort of 1177 Han Chinese patients with LHON. A total of 67 affected subjects carried the homoplasmic m.14484T>C mutation, accounting for 5.7% of this LHON population. The penetrances of optic neuropathy among 51 pedigrees carrying the m.14484T>C mutation ranged from 5.6% to 100.0%, with the average of 21.5%. The sequence analysis of entire mitochondrial genomes of 51 probands exhibited distinct sets of polymorphisms belonging to 18 Eastern Asian haplogroups. The frequencies of haplogroup A and haplogroup F were sig-nificantly less in the LHON mtDNA samples than those in 106 Chinese controls. On the other hand, the haplogroup M10a accounted for 9.8% of the patient's mtDNA samples but was absent in 106 Chinese controls. Strikingly, the average pene-trance (46.13%) of optic neuropathy for the pedigrees carrying mitochondrial haplogroup M10a was higher than those car-rying other mtDNA haplogroups. These observations indicated that mitochondrial haplogroup M10a may increase the risk of visual loss.

Frequency and spectrum of mitochondrial ND6 mutations in 1218 Han Chinese subjects with Leber's hereditary optic neuropathy.

PURPOSE: To investigate the molecular pathogenesis of Leber's hereditary optic neuropathy (LHON) in Chinese families. METHODS: A cohort of 1218 Han Chinese subjects with LHON and 316 control subjects underwent the clinical and genetic evaluation and molecular analysis of mitochondrial (mt)DNA. RESULTS: The age at onset of optic neuropathy in these subjects ranged from 5 to 55 years, with the average of 18 years. Mutational analysis of ND6 gene identified 92 (73 known and 19 novel) variants in these subjects. These variants included 29 (9 novel and 20 known) missense mutations and 63 silence variants. A total of 94 subjects carrying one of the known T14484C, T14502C, and G14459A mutations accounted for 7.7% cases of this cohort, particularly 4.4% for T14484C mutation. Furthermore, eight putative LHON-associated ND6 mutations accounted for 1.1% case of this cohort. Thus, 106 subjects carrying one of ND6 mutations accounted for 8.7% cases of this cohort. Low penetrance of optic neuropathy in pedigrees carrying one of eight putative mutations indicated that the mutation(s) is necessary, but itself insufficient to produce a clinical phenotype. Mitochondrial DNAs in 98 probands carrying the ND6 mutation(s) were widely dispersed among 12 Eastern Asian subhaplogroups. In particular, the occurrences of haplogroups M9, M10, M11, and H2 in patients carrying the ND6 mutations were higher than those in controls. CONCLUSIONS: These data further support that the ND6 gene is the hot spot for mutations associated with LHON. Thus, our findings may provide valuable information for the further understanding of pathophysiology and management of LHON.

Mitochondrial haplotypes may modulate the phenotypic manifestation of the LHON-associated ND1 G3460A mutation in Chinese families.

To investigate the pathophysiology of Leber's hereditary optic neuropathy (LHON), a cohort of 1164 Han Chinese subjects with LHON were screened for ND1 G3460A mutation. A total of 295 subjects from 16 Han Chinese families carrying the G3460A mutation underwent a clinical and genetic evaluation and molecular analysis of mitochondrial (mt)DNA. The incidence of G3460A mutation was 1.4% in this cohort of Chinese subjects with LHON. Twenty-seven (20 males/7 females) of 109 matrilineal relatives among 10 Chinese pedigrees carrying this mutation exhibited a wide range of severity and age-at-onset in visual impairment. Penetrances of optic neuropathy ranged from 7.1% to 50%, with the average of 24.5%. The age-at-onset of 27 affected matrilineal relatives varied from 10 to 40 years, with the average of 22 years. Molecular analysis identified the homoplasmic G3460A mutation and distinct sets of variants belonging to eight haplogroups. Haplogroup M with G3460A mutation was of higher frequency than those in controls. The penetrances of visual loss in families carrying mitochondrial DNA haplogroups A, B and M were higher than those in other families. Furthermore, haplogroup-specific variants tRNA(Ser(AGY)) A12223G, tRNA(Thr) G15927A and tRNA(Glu) A14693G may enhance the penetrance of visual loss in these families. The G3460A mutation occurred through recurrent origins and founder events in Chinese population. Mitochondrial modifiers may modulate the penetrance and expressivity of optic neuropathy among Chinese pedigrees carrying the G3460A mutation. Thus, our findings may provide new insights into the understanding of pathophysiology and valuable information on the management of LHON.