Metabolic heterogeneity in clear cell renal cell carcinoma revealed by single-cell RNA sequencing and spatial transcriptomics.

BACKGROUND: Clear cell renal cell carcinoma is a prototypical tumor characterized by metabolic reprogramming, which extends beyond tumor cells to encompass diverse cell types within the tumor microenvironment. Nonetheless, current research on metabolic reprogramming in renal cell carcinoma mostly focuses on either tumor cells alone or conducts analyses of all cells within the tumor microenvironment as a mixture, thereby failing to precisely identify metabolic changes in different cell types within the tumor microenvironment. METHODS: Gathering 9 major single-cell RNA sequencing databases of clear cell renal cell carcinoma, encompassing 195 samples. Spatial transcriptomics data were selected to conduct metabolic activity analysis with spatial localization. Developing scMet program to convert RNA-seq data into scRNA-seq data for downstream analysis. RESULTS: Diverse cellular entities within the tumor microenvironment exhibit distinct infiltration preferences across varying histological grades and tissue origins. Higher-grade tumors manifest pronounced immunosuppressive traits. The identification of tumor cells in the RNA splicing state reveals an association between the enrichment of this particular cellular population and an unfavorable prognostic outcome. The energy metabolism of CD8+ T cells is pivotal not only for their cytotoxic effector functions but also as a marker of impending cellular exhaustion. Sphingolipid metabolism evinces a correlation with diverse macrophage-specific traits, particularly M2 polarization. The tumor epicenter is characterized by heightened metabolic activity, prominently marked by elevated tricarboxylic acid cycle and glycolysis while the pericapsular milieu showcases a conspicuous enrichment of attributes associated with vasculogenesis, inflammatory responses, and epithelial-mesenchymal transition. The scMet facilitates the transformation of RNA sequencing datasets sourced from TCGA into scRNA sequencing data, maintaining a substantial degree of correlation. CONCLUSIONS: The tumor microenvironment of clear cell renal cell carcinoma demonstrates significant metabolic heterogeneity across various cell types and spatial dimensions. scMet exhibits a notable capability to transform RNA sequencing data into scRNA sequencing data with a high degree of correlation.

miR-622 Increases miR-30a Expression through Inhibition of Hypoxia-Inducible Factor 1α to Improve Metastasis and Chemoresistance in Human Invasive Breast Cancer Cells.

Hypoxia-inducible factor 1α (HIF-1α) plays a pivotal role in the survival, metastasis, and response to treatment of solid tumors. Autophagy serves as a mechanism for tumor cells to eliminate misfolded proteins and damaged organelles, thus promoting invasiveness, metastasis, and resistance to treatment under hypoxic conditions. MicroRNA (miRNA) research underscores the significance of these non-coding molecules in regulating cancer-related protein synthesis across diverse contexts. However, there is limited reporting on miRNA-mediated gene expression studies, especially with respect to epithelial-mesenchymal transition (EMT) and autophagy in the context of hypoxic breast cancer. Our study reveals decreased levels of miRNA-622 (miR-622) and miRNA-30a (miR-30a) in invasive breast cancer cells compared to their non-invasive counterparts. Inducing miR-622 suppresses HIF-1α protein expression, subsequently activating miR-30a transcription. This cascade results in reduced invasiveness and migration of breast cancer cells by inhibiting EMT markers, such as Snail, Slug, and vimentin. Furthermore, miR-30a negatively regulates beclin 1, ATG5, and LC3-II and inhibits Akt protein phosphorylation. Consequently, this improves the sensitivity of invasive MDA-MB-231 cells to docetaxel treatment. In conclusion, our study highlights the therapeutic potential of inducing miR-622 to promote miR-30a expression and thus disrupt HIF-1α-associated EMT and autophagy pathways. This innovative strategy presents a promising approach to the treatment of aggressive breast cancer.

Genetic insights into carbohydrate sulfotransferase 8 and its impact on the immunotherapy efficacy of cancer.

Immune checkpoint blockade (ICB) is a promising therapy for solid tumors, but its effectiveness depends on biomarkers that are not precise. Here, we utilized genome-wide association study to investigate the association between genetic variants and tumor mutation burden to interpret ICB response. We identified 16 variants (p < 5 × 10-8) probed to 17 genes on 9 chromosomes. Subsequent analysis of one of the most significant loci in 19q13.11 suggested that the rs111308825 locus at the enhancer is causal, as its A allele impairs KLF2 binding, leading to lower carbohydrate sulfotransferase 8 (CHST8) expression. Breast cancer cells expressing CHST8 suppress T cell activation, and Chst8 loss attenuates tumor growth in a syngeneic mouse model. Further investigation revealed that programmed death-ligand 1 (PD-L1) and its homologs could be sulfated by CHST8, resulting in M2-like macrophage enrichment in the tumor microenvironment. Finally, we confirmed that low-CHST8 tumors have better ICB response, supporting the genetic effect and clinical value of rs111308825 for ICB efficacy prediction.

Outcomes of covered vs bare metal stents for the treatment of aortoiliac occlusive disease.

OBJECTIVE: We retrospectively compared the clinical outcomes of self-expanding covered stents (CSs) and bare metal stents (BMSs) in the treatment of aortoiliac occlusive disease (AIOD) at a single center between 2016 and 2022. METHODS: All patients with AIOD receiving endovascular therapy at a single center from January 2016 to October 2022 were continuously analyzed, including patients with lesions of all classes according to the Trans-Atlantic Inter-Society Consensus II (TASC-II). Relevant clinical and baseline data were collected, and propensity score matching was performed to compare CSs and BMSs in terms of baseline characteristics, surgical factors, 30-day outcomes, 5-year primary patency, and limb salvage. The follow-up results were analyzed by Kaplan-Meier curves. Cox proportional hazard models were used to identify predictors of primary patency. RESULTS: A total of 209 patients with AIOD were enrolled in the study, including 135 patients (64.6%) in the CS group and 74 patients (35.4%) in the BMS group. Surgical success rates (100% vs 100%; P = 1.00), early (<30-day) mortality rates (0% vs 0%; P = 1.00), cumulative surgical complication rate (12.0% vs 8.0%; P = .891), 5-year primary patency rate (83.4% vs 86.9%; P = .330), secondary patency rate (96% vs 100%; P = .570), and limb salvage rate (100% vs 100%; P = 1.00) did not exhibit significant differences between the two groups. Patients in the CS group had a lower preoperative ankle-brachial index (0.48 ± 0.26 vs 0.52 ± 0.19; P = .032), more cases of complex AIOD (especially TASC D) (47.4% vs 9.5%; P < .001), more chronic total occlusive lesions (77.0% vs 31.1%; P < .001), and more severe calcification (20.7% vs 14.9%; P < .036). After propensity score matching, 50 patients (25 with CS and 25 with BMS) were selected. The results showed that only severe calcification (32.0% vs 8.0%; P = .034) and ankle-brachial index increase (0.45 ± 0.15 vs 0.41 ± 0.22; P = .038) were significantly different between the groups. In terms of surgical factors, patients in the CS group had more use of bilateral femoral or combined brachial artery percutaneous access (60.0% vs 12.0%; P < .001), more number of stents used (2.3 ± 1.2 vs 1.3 ± 0.7; P < .001), longer mean stent length (9.3 ± 3.3 vs 5.8 ± 2.6 cm; P < .001), and more catheter-directed thrombolysis treatment (32.0% vs 4.0%; P = .009). Multivariate Cox survival analysis showed that severe calcification (hazard ratio, 1.32; 95% confidence interval, 1.04-1.85; P = .048) was the only independent predictor of the primary patency rate. CONCLUSIONS: All patients with AIOD who underwent endovascular therapy were included and achieved good outcomes with both CSs and BMSs. The influence of confounding factors in the two groups was minimized by propensity score matching, and the 5-year patency rates were generally similar in the unmatched and matched cohorts. Postoperative hemodynamic improvement was more obvious in patients in the CS group. For more complex lesions, CS is recommended to be preferred. Especially for severe calcification lesions, which is the only independent predictor of primary patency, CS showed obvious advantages. Further studies with more samples are needed to investigate the role of stent types in AIOD treatment.

Identification of hub gene and lncRNA signature related to entotic cell death in cutaneous melanoma for prognostic and immune prediction.

Entotic cell death (ECD), a cell death program observed in cancer cell competition, predominantly occurs in an autophagy protein-dependent, non-apoptotic manner. However, the relationship between cutaneous melanoma (CM) and ECD-associated genes and lncRNAs has remained unclear. This study aimed to elucidate the role and mechanism of ECD-associated genes in CM. To achieve this, 4 mechanism learning algorithms and integrated bioinformatic analyses were employed to identify the core ECD-associated genes and lncRNAs. Subsequently, 2 risk signatures based on ECD-associated genes and hub lncRNAs were constructed for CM patients. As a result, we observed significant differential expression of ECD-associated genes in CM, indicating their potential as valuable predictors for CM patients. Moreover, RHOA was identified as a core ECD-associated gene in CM, and its expression was found to be associated with patients' survival and immune infiltration, suggesting its relevance as a potential therapeutic target. Additionally, this study provided clarification on hub ECD-associated lncRNAs in CM, offering insights into their roles in the disease. Through bioinformatic analyses, we identified 2 risk signatures based on the expression of ECD-associated genes and hub ECD-associated lncRNAs, respectively. Both risk signatures were strongly linked to the prognosis and cancer growth of CM, underscoring their potential as valuable prognostic indicators. Furthermore, mechanistic analyses suggested a significant association between the risk signature and the immune microenvironment in CM, highlighting potential immune-related implications in disease progression. In conclusion, we propose that ECD-associated genes and lncRNAs hold promise as potential targets in CM. Moreover, our findings revealed a significant correlation between ECD and the immune microenvironment, providing crucial insights for guiding individualized treatment strategies in CM.

Genome-Wide Association Studies for Albuminuria of Nondiabetic Taiwanese Population.

INTRODUCTION: Chronic kidney disease, which is defined by a reduced estimated glomerular filtration rate and albuminuria, imposes a large health burden worldwide. Ethnicity-specific associations are frequently observed in genome-wide association studies (GWAS). This study conducts a GWAS of albuminuria in the nondiabetic population of Taiwan. METHODS: Nondiabetic individuals aged 30-70 years without a history of cancer were enrolled from the Taiwan Biobank. A total of 6,768 subjects were subjected to a spot urine examination. After quality control using PLINK and imputation using SHAPEIT and IMPUTE2, a total of 3,638,350 single-nucleotide polymorphisms (SNPs) remained for testing. SNPs with a minor allele frequency of less than 0.1% were excluded. Linear regression was used to determine the relationship between SNPs and log urine albumin-to-creatinine ratio. RESULTS: Six suggestive loci are identified in or near the FCRL3 (p = 2.56 × 10-6), TMEM161 (p = 4.43 × 10-6), EFCAB1 (p = 2.03 × 10-6), ELMOD1 (p = 2.97 × 10-6), RYR3 (p = 1.34 × 10-6), and PIEZO2 (p = 2.19 × 10-7). Genetic variants in the FCRL3 gene that encode a secretory IgA receptor are found to be associated with IgA nephropathy, which can manifest as proteinuria. The PIEZO2 gene encodes a sensor for mechanical forces in mesangial cells and renin-producing cells. Five SNPs with a p-value between 5 × 10-6 and 5 × 10-5 are also identified in five genes that may have a biological role in the development of albuminuria. CONCLUSION: Five new loci and one known suggestive locus for albuminuria are identified in the nondiabetic Taiwanese population.

Early Experience of Online Adaptive Radiation Therapy for Definitive Radiation of Patients With Head and Neck Cancer.

Purpose: The advent of cone beam computed tomography-based online adaptive radiation therapy (oART) has dramatically reduced the barriers of adaptation. We present the first prospective oART experience data in radiation of head and neck cancers (HNC). Methods and Materials: Patients with HNC receiving definitive standard fractionation (chemo)radiation who underwent at least 1 oART session were enrolled in a prospective registry study. The frequency of adaptations was at the discretion of the treating physician. Physicians were given the option of delivering 1 of 2 plans during adaptation: the original radiation plan transposed onto the cone beam computed tomography with adapted contours (scheduled), and a new adapted plan generated from the updated contours (adapted). A paired t test was used to compare the mean doses between scheduled and adapted plans. Results: Twenty-one patients (15 oropharynx, 4 larynx/hypopharynx, 2 other) underwent 43 adaptation sessions (median, 2). The median ART process time was 23 minutes, median physician time at the console was 27 minutes, and median patient time in the vault was 43.5 minutes. The adapted plan was chosen 93% of the time. The mean volume in each planned target volume (PTV) receiving 100% of the prescription dose for the scheduled versus adapted plan for high-risk PTVs was 87.8% versus 95% (P < .01), intermediate-risk PTVs was 87.3% versus 97.9% (P < .01), and low-risk PTVs was 94% versus 97.8% (P < .01), respectively. The mean hotspot was also lower with adaptation: 108.8% versus 106.4% (P < .01). All but 1 organ at risk (11/12) saw a decrease in their dose with the adapted plans, with the mean ipsilateral parotid (P = .013), mean larynx (P < .01), maximum point spinal cord (P < .01), and maximum point brain stem (P = .035) reaching statistical significance. Conclusions: Online ART is feasible for HNC, with significant improvement in target coverage and homogeneity and a modest decrease in doses to several organs at risk.

Bony structure enhanced synthetic CT generation using Dixon sequences for pelvis MR-only radiotherapy.

BACKGROUND: MRI-only radiotherapy planning (MROP) is beneficial to patients by avoiding MRI/CT registration errors, simplifying the radiation treatment simulation workflow and reducing exposure to ionizing radiation. MRI is the primary imaging modality for soft tissue delineation. Treatment planning CTs (i.e., CT simulation scan) are redundant if a synthetic CT (sCT) can be generated from the MRI to provide the patient positioning and electron density information. Unsupervised deep learning (DL) models like CycleGAN are widely used in MR-to-sCT conversion, when paired patient CT and MR image datasets are not available for model training. However, compared to supervised DL models, they cannot guarantee anatomic consistency, especially around bone. PURPOSE: The purpose of this work was to improve the sCT accuracy generated from MRI around bone for MROP. METHODS: To generate more reliable bony structures on sCT images, we proposed to add bony structure constraints in the unsupervised CycleGAN model's loss function and leverage Dixon constructed fat and in-phase (IP) MR images. Dixon images provide better bone contrast than T2-weighted images as inputs to a modified multi-channel CycleGAN. A private dataset with a total of 31 prostate cancer patients were used for training (20) and testing (11). RESULTS: We compared model performance with and without bony structure constraints using single- and multi-channel inputs. Among all the models, multi-channel CycleGAN with bony structure constraints had the lowest mean absolute error, both inside the bone and whole body (50.7 and 145.2 HU). This approach also resulted in the highest Dice similarity coefficient (0.88) of all bony structures compared with the planning CT. CONCLUSION: Modified multi-channel CycleGAN with bony structure constraints, taking Dixon-constructed fat and IP images as inputs, can generate clinically suitable sCT images in both bone and soft tissue. The generated sCT images have the potential to be used for accurate dose calculation and patient positioning in MROP radiation therapy.

Implementation and evaluation of an intelligent automatic treatment planning robot for prostate cancer stereotactic body radiation therapy.

PURPOSE: We previously developed a virtual treatment planner (VTP), an artificial intelligence robot, operating a treatment planning system (TPS). Using deep reinforcement learning guided by human knowledge, we trained the VTP to autonomously adjust relevant parameters in treatment plan optimization, similar to a human planner, to generate high-quality plans for prostate cancer stereotactic body radiation therapy (SBRT). This study describes the clinical implementation and evaluation of VTP. MATERIALS AND METHODS: We integrate VTP with Eclipse TPS using scripting Application Programming Interface. VTP observes dose-volume histograms of relevant structures, decides how to adjust dosimetric constraints, including doses, volumes, and weighting factors, and applies the adjustments to the TPS interface to launch the optimization engine. This process continues until a high-quality plan is achieved. We evaluated VTP's performance using the prostate SBRT case from the 2016 American Association of Medical Dosimetrist/Radiosurgery Society plan study with its plan scoring system, and compared to human-generated plans submitted to the challenge. Using the same scoring system, we also compared the plan quality of 36 prostate SBRT cases (20 planned with IMRT and 16 planned with VMAT) treated at our institution for both VTP and human-generated plans. RESULTS: In the plan study case, VTP achieved a score of 142.1/150.0, ranking the third in the competition (median 134.6). For the clinical cases, VTP achieved 110.6 ± 6.5 for 20 IMRT plans and 126.2 ± 4.7 for 16 VMAT plans, similar to scores of human-generated plans with 110.4 ± 7.0 for IMRT plans and 125.4 ± 4.4 for VMAT plans. The workflow, plan quality and planning time of VTP were reviewed to be satisfactory by experienced physicists. CONCLUSION: We successfully implemented VTP to operate a TPS for autonomous human-like treatment planning for prostate SBRT.

Midterm Outcomes of Kissing Covered Self-Expanding Stents for Reconstruction of Complex Aortoiliac Occlusive Disease.

BACKGROUND: We sought to investigate the midterm results of kissing self-expanding covered stents (SECSs) for the reconstruction of aortic bifurcation in complex aortoiliac occlusive disease. METHODS: Data of consecutive patients who had undergone endovascular treatment for aortoiliac occlusive disease were screened. Only patients with TransAtlantic Inter-Society Consensus (TASC) class C and D lesions treated by bilateral iliac kissing stents (KSs) were included. Midterm primary patency, risk factors, and limb salvage rates were analyzed. Follow-up results were analyzed using the Kaplan-Meier curves. Cox proportional hazards models were used to identify the predictors of primary patency. RESULTS: A total of 48 patients (95.8% men; mean age, 65.3 ± 10.2 years) were treated with kissing SECSs. Of them, 17 patients had TASC-II class C lesions and 31 had class D lesions. There were 38 total occlusive lesions, with a mean occlusive lesion length of 108.2 ± 57.3 mm. The overall mean lesion length was 140.3 ± 60.5 mm, and the mean length of implanted stents in the aortoiliac arteries was 141.9 ± 59.9 mm. The mean diameter of the deployed SECSs was 7.8 ± 0.5 mm. The mean follow-up time was 36.5 ± 15.8 months, and the follow-up rate was 95.8%. At 36 months, the overall primary patency, assisted primary patency, secondary patency, and limb salvage rates were 92.2%, 95.7%, 97.8%, and 100%, respectively. Univariate Cox regression analysis revealed that stent diameter ≤7 mm (hazard ratio [HR]: 9.53; 95% confidence interval [CI] 1.56-57.94, P = 0.014) and severe calcification (HR: 12.66; 95% CI 2.04-78.45, P = 0.006) were significantly associated with restenosis. Multivariate analysis showed severe calcification to be the only significant determinant of restenosis (HR: 12.66; 95% CI 2.04-78.45, P = 0.006). CONCLUSIONS: Kissing SECSs provide good midterm results for the treatment of aortoiliac occlusive disease. A stent diameter >7 mm is a potent protective factor against restenosis. Because severe calcification appears to be the only significant determinant of restenosis, patients with severe calcification require close follow-up.

Clinical experience on patient-specific quality assurance for CBCT-based online adaptive treatment plan.

PURPOSE: Ethos CBCT-based adaptive radiotherapy (ART) system can generate an online adaptive plan by re-optimizing the initial reference plan based on the patient anatomy at the treatment. The optimization process is fully automated without any room for human intervention. Due to the change in anatomy, the ART plan can be significantly different from the initial plan in terms of plan parameters such as the aperture shapes and number of monitor units (MUs). In this study, we investigated the feasibility of using calculation-based patient specific QA for ART plans in conjunction with measurement-based and calculation-based QA for initial plans to establish an action level for the online ART patient-specific QA. METHODS: A cohort of 98 cases treated on CBCT-based ART system were collected for this study. We performed measurement-based QA using ArcCheck and calculation-based QA using Mobius for both the initial plan and the ART plan for analysis. For online the ART plan, Mobius calculation was conducted prior to the delivery, while ArcCheck measurement was delivered on the same day after the treatment. We first investigated the modulation factors (MFs) and MU numbers of the initial plans and ART plans, respectively. The γ passing rates of initial and ART plan QA were analyzed. Then action limits were derived for QA calculation and measurement for both initial and online ART plans, respectively, from 30 randomly selected patient cases, and were evaluated using the other 68 patient cases. RESULTS: The difference in MF between initial plan and ART-plan was 12.9% ± 12.7% which demonstrates their significant difference in plan parameters. Based on the patient QA results, pre-treatment calculation and measurement results are generally well aligned with ArcCheck measurement results for online ART plans, illustrating their feasibility as an indicator of failure in online ART QA measurements. Furthermore, using 30 randomly selected patient cases, the γ analysis action limit derived for initial plans and ART plans are 89.6% and 90.4% in ArcCheck QA (2%/2 mm) and are 92.4% and 93.6% in Mobius QA(3%/2 mm), respectively. According to the calculated action limits, the ArcCheck measurements for all the initial and ART plans passed QA successfully while the Mobius calculation action limits flagged seven and four failure cases respectively for initial plans and ART plans, respectively. CONCLUSION: An ART plan can be substantially different from the initial plan, and therefore a separate session of ART plan QA is needed to ensure treatment safety and quality. The pre-treatment QA calculation via Mobius can serve as a reliable indicator of failure in online ART plan QA. However, given that Ethos ART system is still relatively new, ArcCheck measurement of initial plan is still in practice. It may be skipped as we gain more experience and have better understanding of the system.

Iatrogenic arteriovenous fistula after lumbar discectomy surgery: a case report.

Iatrogenic arteriovenous fistula (IAVF) is an unusual and potentially fatal complication of lumbar spinal surgery. A 62-year-old patient presented with a history of dyspnea, left lower limb edema and coughing. A physical exam showed bilateral basal rales in the lungs, abdominal bruit and bilateral lower limb pitting edema. A computed tomography angiograph revealed an arteriovenous communication between the right internal iliac artery and the left common iliac vein. The patient was diagnosed with an IAVF, which developed post-lumbar disc surgery. The patient underwent a successful endovascular treatment by using covered stent at the common iliac artery with embolism of lumbar artery. The patient's symptoms were relieved 2 months after surgery.

Dual- and multi-energy CT for particle stopping-power estimation: current state, challenges and potential.

Range uncertainty has been a key factor preventing particle radiotherapy from reaching its full physical potential. One of the main contributing sources is the uncertainty in estimating particle stopping power (ρs) within patients. Currently, theρsdistribution in a patient is derived from a single-energy CT (SECT) scan acquired for treatment planning by converting CT number expressed in Hounsfield units (HU) of each voxel toρsusing a Hounsfield look-up table (HLUT), also known as the CT calibration curve. HU andρsshare a linear relationship with electron density but differ in their additional dependence on elemental composition through different physical properties, i.e. effective atomic number and mean excitation energy, respectively. Because of that, the HLUT approach is particularly sensitive to differences in elemental composition between real human tissues and tissue surrogates as well as tissue variations within and among individual patients. The use of dual-energy CT (DECT) forρsprediction has been shown to be effective in reducing the uncertainty inρsestimation compared to SECT. The acquisition of CT data over different x-ray spectra yields additional information on the material elemental composition. Recently, multi-energy CT (MECT) has been explored to deduct material-specific information with higher dimensionality, which has the potential to further improve the accuracy ofρsestimation. Even though various DECT and MECT methods have been proposed and evaluated over the years, these approaches are still only scarcely implemented in routine clinical practice. In this topical review, we aim at accelerating this translation process by providing: (1) a comprehensive review of the existing DECT/MECT methods forρsestimation with their respective strengths and weaknesses; (2) a general review of uncertainties associated with DECT/MECT methods; (3) a general review of different aspects related to clinical implementation of DECT/MECT methods; (4) other potential advanced DECT/MECT applications beyondρsestimation.

The New Kid on the Block: Online Adaptive Radiotherapy in the Treatment of Gynecologic Cancers.

Online adaptive radiation is a new and exciting modality of treatment for gynecologic cancers. Traditional radiation treatments deliver the same radiation plan to cancers with large margins. Improvements in imaging, technology, and artificial intelligence have made it possible to account for changes between treatments and improve the delivery of radiation. These advances can potentially lead to significant benefits in tumor coverage and normal tissue sparing. Gynecologic cancers can uniquely benefit from this technology due to the significant changes in bladder, bowel, and rectum between treatments as well as the changes in tumors commonly seen between treatments. Preliminary studies have shown that online adaptive radiation can maintain coverage of the tumor while sparing nearby organs. Given these potential benefits, numerous clinical trials are ongoing to investigate the clinical benefits of online adaptive radiotherapy. Despite the benefits, implementation of online adaptive radiotherapy requires significant clinical resources. Additionally, the timing and workflow for online adaptive radiotherapy is being optimized. In this review, we discuss the history and evolution of radiation techniques, the logistics and implementation of online adaptive radiation, and the potential benefits of online adaptive radiotherapy for gynecologic cancers.

Impact of residual stenosis on clinical outcomes when performing carotid artery stenting without postdilation.

OBJECTIVE: Many centers consider postdilation if the final angiography after carotid artery stenting (CAS) shows residual stenosis of >30% to 40%. Postdilation has been demonstrated to potentially increase the risk of developing neurologic events. This study aimed to investigate the safety of CAS without postdilation regardless of the degree of residual stenosis. METHODS: We retrospectively investigated 191 patients who underwent transfemoral CAS without postdilation intendedly. All cases underwent mild predilation and self-expanding stent implantation. We divided the patients into a residual stenosis of ≥40% group (n = 69 [36.1%]) and a residual stenosis of <40% group (n = 122 [63.9%]) according to their final angiography. We compared the procedural (within 30 days after CAS) and nonprocedural (afterward) adverse cardiovascular events and in-stent restenosis between the two groups. We also investigated the incidence of perioperative hemodynamic depression between the groups and the changes in residual stenosis over the follow-up time. RESULTS: Patients in the residual stenosis of ≥40% group had a higher preoperative stenosis rate and a greater proportion of severely calcified lesions than those in the <40% group. There was one procedural cardiac death (0.5%), five strokes (2.6%), and four myocardial infarctions (2.1%). A total of 2.9% had stroke or death procedurally in the residual stenosis of ≥40% group and 3.2% in the residual stenosis of <40% group (P > .950). The median nonprocedural follow-up time was 22 months, with a total of six deaths and four strokes. The cumulative 2-year death or stroke rate was 6.2%, with 5.9% in the residual stenosis of ≥40% group versus 6.7% in the residual stenosis of <40% group (P = .507). There were two cases of in-stent restenosis in the residual stenosis of ≥40% group and three in the residual stenosis of <40% group (P = .927). The difference in the peak systolic velocity of the target lesion between groups at 3 months after CAS was no longer present, and residual stenosis stabilized at 10% to 20% at 6 months in both groups. The patients showed an association between increasing hemodynamic depression incidence and residual stenosis in a significantly graded response (P = .021). CONCLUSIONS: Residual stenosis after carotid stenting without postdilation is not associated with a risk of postoperative adverse events. This study provides evidence for the feasibility of a no postdilation strategy for CAS.

MR image reconstruction from undersampled data for image-guided radiation therapy using a patient-specific deep manifold image prior.

Introduction: Recent advancements in radiotherapy (RT) have allowed for the integration of a Magnetic Resonance (MR) imaging scanner with a medical linear accelerator to use MR images for image guidance to position tumors against the treatment beam. Undersampling in MR acquisition is desired to accelerate the imaging process, but unavoidably deteriorates the reconstructed image quality. In RT, a high-quality MR image of a patient is available for treatment planning. In light of this unique clinical scenario, we proposed to exploit the patient-specific image prior to facilitate high-quality MR image reconstruction. Methods: Utilizing the planning MR image, we established a deep auto-encoder to form a manifold of image patches of the patient. The trained manifold was then incorporated as a regularization to restore MR images of the same patient from undersampled data. We performed a simulation study using a patient case, a real patient study with three liver cancer patient cases, and a phantom experimental study using data acquired on an in-house small animal MR scanner. We compared the performance of the proposed method with those of the Fourier transform method, a tight-frame based Compressive Sensing method, and a deep learning method with a patient-generic manifold as the image prior. Results: In the simulation study with 12.5% radial undersampling and 15% increase in noise, our method improved peak-signal-to-noise ratio by 4.46dB and structural similarity index measure by 28% compared to the patient-generic manifold method. In the experimental study, our method outperformed others by producing reconstructions of visually improved image quality.

Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics.

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10-8 and a Bonferroni-corrected p < 4.6 × 10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.

Long Noncoding RNA TPRG1-AS1 Suppresses Migration of Vascular Smooth Muscle Cells and Attenuates Atherogenesis via Interacting With MYH9 Protein.

BACKGROUND: Migration of human aortic smooth muscle cells (HASMCs) contributes to the pathogenesis of atherosclerosis. This study aims to functionally characterize long noncoding RNA TPRG1-AS1 (tumor protein p63 regulated 1, antisense 1) in HASMCs and reveal the underlying mechanism of TPRG1-AS1 in HASMCs migration, neointima formation, and subsequent atherosclerosis. METHODS: The expression of TPRG1-AS1 in atherosclerotic plaques was verified a series of in silico analysis and quantitative real-time polymerase chain reaction analysis. Northern blot, rapid amplification of cDNA ends and Sanger sequencing were used to determine its full length. In vitro transcription-translation assay was used to investigate the protein-coding capacity of TPRG1-AS1. RNA fluorescent in situ hybridization was used to confirm its subcellular localization. Loss- and gain-of-function studies were used to investigate the function of TPRG1-AS1. Furthermore, the effect of TPRG1-AS1 on the pathological response was evaluated in carotid balloon injury model, wire injury model, and atherosclerosis model, respectively. RESULTS: TPRG1-AS1 was significantly increased in atherosclerotic plaques. TPRG1-AS1 did not encode any proteins and its full length was 1279nt, which was bona fide a long noncoding RNA. TPRG1-AS1 was mainly localized in cytoplasmic and perinuclear regions in HASMCs. TPRG1-AS1 directly interacted with MYH9 (myosin heavy chain 9) protein in HASMCs, promoted MYH9 protein degradation through the proteasome pathway, hindered F-actin stress fiber formation, and finally inhibited HASMCs migration. Vascular smooth muscle cell-specific transgenic overexpression of TPRG1-AS1 significantly reduced neointima formation, and attenuated atherosclerosis in apolipoprotein E knockout (Apoe-/-) mice. CONCLUSIONS: This study demonstrated that TPRG1-AS1 inhibited HASMCs migration through interacting with MYH9 protein and consequently suppressed neointima formation and atherosclerosis.

Small animal photon counting cone-beam CT on a preclinical radiation research platform to improve radiation dose calculation accuracy.

Objective.Cone beam CT (CBCT) in preclinical small animal irradiation platforms provides essential information for image guidance and radiation dose calculation for experiment planning. This project developed a photon-counting detector (PCD)-based multi(3)-energy (ME-)CBCT on a small animal irradiator to improve the accuracy of material differentiation and hence dose calculation, and compared to conventional flat panel detector (FPD)-based CBCT.Approach.We constructed a mechanical structure to mount a PCD to an existing preclinical irradiator platform and built a data acquisition pipeline to acquire x-ray projection data with a 100 kVp x-ray beam using three different energy thresholds in a single gantry rotation. We implemented an energy threshold optimization scheme to determine optimal thresholds to balance signal-to-noise ratios (SNRs) among energy channels. Pixel-based detector response calibration was performed to remove ring artifacts in reconstructed CBCT images. Feldkamp-Davis-Kress method was employed to reconstruct CBCT images and a total-variance regularization-based optimization model was used to decompose CBCT images into bone and water material images. We compared dose calculation results using PCD-based ME-CBCT with that of FPD-based CBCT.Main results.The optimal nominal energy thresholds were determined as 26, 56, and 90 keV, under which SNRs in a selected region-of-interest in the water region were 6.11, 5.91 and 5.93 in the three energy channels, respectively. Compared with dose calculation results using FPD-based CBCT, using PCD-based ME-CBCT reduced the mean relative error from 49.5% to 16.4% in bone regions and from 7.5% to 6.9% in soft tissue regions.Significance.PCD-based ME-CBCT is beneficial in improving radiation dose calculation accuracy in experiment planning of preclinical small animal irradiation researches.

Artificial Intelligence in Radiation Therapy.

Artificial intelligence (AI) has great potential to transform the clinical workflow of radiotherapy. Since the introduction of deep neural networks, many AI-based methods have been proposed to address challenges in different aspects of radiotherapy. Commercial vendors have started to release AI-based tools that can be readily integrated to the established clinical workflow. To show the recent progress in AI-aided radiotherapy, we have reviewed AI-based studies in five major aspects of radiotherapy including image reconstruction, image registration, image segmentation, image synthesis, and automatic treatment planning. In each section, we summarized and categorized the recently published methods, followed by a discussion of the challenges, concerns, and future development. Given the rapid development of AI-aided radiotherapy, the efficiency and effectiveness of radiotherapy in the future could be substantially improved through intelligent automation of various aspects of radiotherapy.