Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical. METHODS: We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety. FINDINGS: Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special T cell population, TCF1+ PD-1+ CD8+ stem-like T cells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9 months (95% CI, 5.4-9.3). CONCLUSIONS: These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation. FUNDING: This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).

Clinical characteristics of extracorporeal cardiopulmonary resuscitation in China: a multicenter retrospective study.

PURPOSE: Extracorporeal cardiopulmonary resuscitation (ECPR) might markedly increase the survival of selected patients with refractory cardiac arrest. But the application situation and indications remained unclear. MATERIALS AND METHODS: We respectively reviwed all adult patients who underwent ECPR from January 2017 to March 2021. Patient characteristics, initiation and management of ECMO, complications, and outcomes were collected and compared between the survivors and nonsurvivors. LASSO regression was used to screen risk factors. Multivariate logistic regression was performed with several parameters screened by LASSO regression. RESULTS: Data were reported from 42 ECMO centers covering 19 provinces of China. A total of 648 patients were included in the study, including 491 (75.8%) males. There were 11 ECPR centers in 2017, and the number increased to 42 in 2020. The number of patients received ECPR increased from 33 in 2017 to 274 in 2020, and the survival rate increased from 24.2% to 33.6%. Neurological complications, renal replacement therapy, epinephrine dosage after ECMO, recovery of spontaneous circulation before ECMO, lactate clearance and shockable rhythm were risk factors independently associated with outcomes of whole process. Sex, recovery of spontaneous circulation before ECMO, lactate, shockable rhythm and causes of arrest were pre-ECMO risk factors independently affecting outcomes. CONCLUSIONS: From January 2017 to March 2021, the numbers of ECPR centers and cases in mainland China increased gradually over time, as well as the survival rate. Pre-ECMO risk factors, especially recovery of spontaneous circulation before ECMO, shockable rhythm and lactate, are as important as post-ECMO management,. Neurological complications are vital risk factors after ECMO that deserved close attention. TRIAL REGISTRATION: NCT04158479, registered on 2019/11/08. https://clinicaltrials.gov/NCT04158479.

Development and validation of an automated Tomotherapy planning method for cervical cancer.

PURPOSE: This study aimed to develop an automated Tomotherapy (TOMO) planning method for cervical cancer treatment, and to validate its feasibility and effectiveness. MATERIALS AND METHODS: The study enrolled 30 cervical cancer patients treated with TOMO at our center. Utilizing scripting and Python environment within the RayStation (RaySearch Labs, Sweden) treatment planning system (TPS), we developed automated planning methods for TOMO and volumetric modulated arc therapy (VMAT) techniques. The clinical manual TOMO (M-TOMO) plans for the 30 patients were re-optimized using automated planning scripts for both TOMO and VMAT, creating automated TOMO (A-TOMO) and automated VMAT (A-VMAT) plans. We compared A-TOMO with M-TOMO and A-VMAT plans. The primary evaluated relevant dosimetric parameters and treatment plan efficiency were assessed using the two-sided Wilcoxon signed-rank test for statistical analysis, with a P-value < 0.05 indicating statistical significance. RESULTS: A-TOMO plans maintained similar target dose uniformity compared to M-TOMO plans, with improvements in target conformity and faster dose drop-off outside the target, and demonstrated significant statistical differences (P+ < 0.01). A-TOMO plans also significantly outperformed M-TOMO plans in reducing V50Gy, V40Gy and Dmean for the bladder and rectum, as well as Dmean for the bowel bag, femoral heads, and kidneys (all P+ < 0.05). Additionally, A-TOMO plans demonstrated better consistency in plan quality. Furthermore, the quality of A-TOMO plans was comparable to or superior than A-VMAT plans. In terms of efficiency, A-TOMO significantly reduced the time required for treatment planning to approximately 20 min. CONCLUSION: We have successfully developed an A-TOMO planning method for cervical cancer. Compared to M-TOMO plans, A-TOMO plans improved target conformity and reduced radiation dose to OARs. Additionally, the quality of A-TOMO plans was on par with or surpasses that of A-VMAT plans. The A-TOMO planning method significantly improved the efficiency of treatment planning.

ARDSFlag: an NLP/machine learning algorithm to visualize and detect high-probability ARDS admissions independent of provider recognition and billing codes.

BACKGROUND: Despite the significance and prevalence of acute respiratory distress syndrome (ARDS), its detection remains highly variable and inconsistent. In this work, we aim to develop an algorithm (ARDSFlag) to automate the diagnosis of ARDS based on the Berlin definition. We also aim to develop a visualization tool that helps clinicians efficiently assess ARDS criteria. METHODS: ARDSFlag applies machine learning (ML) and natural language processing (NLP) techniques to evaluate Berlin criteria by incorporating structured and unstructured data in an electronic health record (EHR) system. The study cohort includes 19,534 ICU admissions in the Medical Information Mart for Intensive Care III (MIMIC-III) database. The output is the ARDS diagnosis, onset time, and severity. RESULTS: ARDSFlag includes separate text classifiers trained using large training sets to find evidence of bilateral infiltrates in radiology reports (accuracy of 91.9%±0.5%) and heart failure/fluid overload in radiology reports (accuracy 86.1%±0.5%) and echocardiogram notes (accuracy 98.4%±0.3%). A test set of 300 cases, which was blindly and independently labeled for ARDS by two groups of clinicians, shows that ARDSFlag generates an overall accuracy of 89.0% (specificity = 91.7%, recall = 80.3%, and precision = 75.0%) in detecting ARDS cases. CONCLUSION: To our best knowledge, this is the first study to focus on developing a method to automate the detection of ARDS. Some studies have developed and used other methods to answer other research questions. Expectedly, ARDSFlag generates a significantly higher performance in all accuracy measures compared to those methods.

Predicting regional recurrence and prognosis in stereotactic body radiotherapy-treated clinical stage I non-small cell lung cancer using a radiomics model constructed with surgical data.

BACKGROUND: Risk stratification of regional recurrence (RR) is clinically important in the design of adjuvant treatment and surveillance strategies in patients with clinical stage I non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). PURPOSE: To develop a radiomics model predicting occult lymph node metastasis (OLNM) using surgical data and apply it to the prediction of RR in SBRT-treated early-stage NSCLC patients. METHODS: Patients with clinical stage I NSCLC who underwent curative surgery with systematic lymph node dissection from January 2013 to December 2018 (the training cohort) and from January 2019 to December 2020 (the validation cohort) were included. A pre-operative CT-based radiomics model, a clinical feature model, and a fusion model predicting OLNM were constructed. The performance of the three models was quantified and compared in the training and validation cohorts. Subsequently, the radiomics model was used to predict RR in a cohort of consecutive SBRT-treated early-stage NSCLC patients from two academic medical centers. RESULTS: A total of 769 patients were included. Eight CT features were identified in the radiomics model, achieving areas under the curves (AUCs) of 0.85 (95% CI 0.81-0.89) and 0.83 (95% CI 0.80-0.88) in the training and validation cohorts, respectively. Nevertheless, adding clinical features did not improve the performance of the radiomics model. With a median follow-up of 40.0 (95% CI 35.2-44.8) months, 32 of the 213 patients in the SBRT cohort developed RR and those in the high-risk group based on the radiomics model had a higher cumulative incidence of RR (p<0.001) and shorter regional recurrence-free survival (p=0.02), progression-free survival (p=0.004) and overall survival (p=0.006) than those in the low-risk group. CONCLUSION: The radiomics model based on pathologically confirmed data effectively identified patients with ONLM, which may be useful in the risk stratification among SBRT-treated patients with clinical stage I NSCLC.

MicroRNA-384 radiosensitizes human non-small cell lung cancer by impairing DNA damage response and repair signaling, which is inhibited by NF-κB.

OBJECTIVE: Radiotherapy has achieved remarkable effects in treating non-small cell lung cancer (NSCLC). However, radioresistance remains the major obstacle to achieving good outcomes. This study aims at identifying potential targets for radiosensitizing NSCLC and elucidating the underlying mechanisms. METHODS: Lentivirus-based infection and CRISPR/Cas9 technology were used to modulate the expression of microRNA-384 (miR-384). Cell clonogenic formation assays and a xenograft tumor model were used to analyze radiosensitivity in NSCLC cells. Fluorescence-activated cell sorting was used to assess the cell cycle and cell death. Immunofluorescence staining, Comet assays, and homologous recombination or non-homologous end-joining I-SceI/GFP reporter assays were used to study DNA damage and repair. Western blotting and quantitative real-time polymerase chain reaction were used to identify the targets of miR-384. Chromatin immunoprecipitation and polymerase chain reaction were performed to evaluate upstream regulators of miR-384. RESULTS: MiR-384 was downregulated in NSCLC. Overexpression of miR-384 increased the radiosensitivity of NSCLC cells in vitro and in vivo, whereas knockout of miR-384 led to radioresistance. Upregulation of miR-384 radiosensitized NSCLC cells by decreasing G2/M cell cycle arrest, inhibiting DNA damage repair, and consequently increasing cell death; miR-384 depletion had the opposite effects. Further investigation revealed that ATM, Ku70, and Ku80 were direct targets of miR-384. Moreover, miR-384 was repressed by NF-κB. CONCLUSIONS: MiR-384 is an ionizing radiation-responsive gene repressed by NF-κB. MiR-384 enhances the radiosensitivity of NSCLC cells via targeting ATM, Ku80, and Ku70, which impairs DNA damage repair. Therefore, miR-384 may serve as a novel radiosensitizer for NSCLC.

Two distinct age-prognosis patterns in patients with esophageal cancer undergoing surgical and radiotherapy treatments: a combined analysis of 3JECROG and SEER databases.

Background: Age is a known prognostic factor for various cancers. However, few studies explored the association between age and prognosis of esophageal cancer (EC) comprehensively, especially from a nonlinear perspective. Design: Retrospective cohort study. Objectives: Our study aims to explore the possible nonlinear associations between age and prognosis in EC patients receiving curative surgery and radiotherapy, respectively. Methods: Cox regression models with restricted cubic splines were used to model the possible nonlinear relationship between age and prognosis in surgical and radiotherapy groups, respectively. Surveillance, Epidemiology, and End Results database was used to validate the age-prognosis patterns found in Jing-Jin-Ji Esophageal and Esophagogastric Cancer Radiotherapy Oncology Group database. Age-prognosis patterns were further validated by survival comparisons between different age subgroups and in subsequent sensitivity and subgroup analyses. Primary endpoint is overall survival. Secondary endpoints are cancer-specific survival and progression-free survival. Results: A total of 56,457 patients from two large cancer databases were included. Patients receiving surgery and radiotherapy showed two distinct nonlinear age-prognosis patterns. Age showed a U-/J-shaped association with prognosis in the radiotherapy group, with a nadir at approximately 65- to 70-years-old. As for surgical cohort, relative risk for all-cause mortality and cancer-specific mortality increased with age with p for nonlinearity <0.05. The above age-prognosis relationships were validated by sensitivity, subgroup, and comparative survival analyses. Youngest and middle-aged patients showed better survival results compared to that of other age subgroups in surgical and radiotherapy cohorts, respectively [Radiotherapy, youngest/middle: hazard ratio (HR) = 1.06, 95% confidence interval (CI): 1.02-1.10, p = 0.001; Radiotherapy, oldest/middle: HR = 1.21, 95% CI: 1.18-1.24, p < 0.001; Surgical, middle/youngest: HR = 1.19, 95% CI: 1.14-1.25, p < 0.001; surgical, oldest/youngest: HR = 1.85, 95% CI: 1.75-1.97, p < 0.001]. Conclusion: Patients receiving surgery and radiotherapy showed two distinct age-prognosis patterns. Younger and middle-aged patients were associated with better survival in surgical and radiotherapy groups, respectively. Additional studies are warranted to explore the underlying mechanisms and clinical implications of this phenomenon.

Global drivers of the conservation-invasion paradox.

The conservation-invasion paradox (CIP) refers to a long-term phenomenon wherein species threatened in their native range can sustain viable populations when introduced to other regions. Understanding the drivers of CIP is helpful for conserving threatened species and managing invasive species, which is unfortunately still lacking. We compiled a global data set of 1071 introduction events, including 960 CIP events (successful establishment of threatened species outside its native range) and 111 non-CIP events (unsuccessful establishment of threatened species outside its native range after introduction), involving 174 terrestrial vertebrates. We then tested the relative importance of various predictors at the location, event, and species levels with generalized linear mixed models and model averaging. Successful CIP events occurred across taxonomic groups and biogeographic realms, especially for the mammal group in the Palearctic and Australia. Locations of successful CIP events had fewer native threat factors, especially less climate warming in invaded regions. The probability of a successful CIP event was highest when species introduction efforts were great and there were more local congeners and fewer natural enemies. These results can inform threatened species ex situ conservation and non-native invasive species mitigation.

Causantes mundiales de la paradoja conservación­invasión Resumen La paradoja de conservación­invasión (PCI) se refiere al evento a largo plazo en el que las especies amenazadas en su distribución nativa puedan mantener poblaciones viables cuando se les introduce a otras regiones. Es de mucha ayuda para la conservación de especies amenazadas y el manejo de especies invasoras entender las causantes de la PCI, entendimiento que todavía es escaso. Compilamos un conjunto mundial de datos de 174 vertebrados terrestres en 1071 eventos de introducción, incluyendo 960 eventos de PCI (el establecimiento exitoso de especies amenazadas fuera de su distribución nativa) y 111 eventos no PCI (el fracaso en el establecimiento de especies amenazadas fuera de su distribución nativa después de la introducción). Después analizamos con modelos lineales mixtos generalizados y promedio de modelos la importancia relativa de varios pronosticadores en la localidad, en el evento y a nivel de especie. Los eventos exitosos de PCI ocurrieron en todos los grupos taxonómicos y en todos los reinos biogeográficos, especialmente para los mamíferos del Paleártico y Australia. Las localidades de los eventos exitosos de PCI tuvieron menos factores nativos de amenaza, especialmente un menor calentamiento climático en las regiones invadidas. La probabilidad de que un evento de PCI sea exitoso fue mayor cuando los esfuerzos de introducción fueron mayores y hubo más congéneres locales y menos enemigos naturales. Estos resultados pueden orientar la conservación ex situ de especies y la mitigación de especies invasoras no nativas.

Validation and development of eDNA metabarcoding primers for comprehensive assessment of Chinese amphibians.

Environmental DNA (eDNA) metabarcoding has emerged as a powerful, non-invasive tool for biodiversity assessments. However, the accuracy and limitations of these assessment techniques are highly dependent on the choice of primer pairs being used. Although several primer sets have been used in eDNA metabarcoding studies of amphibians, there are few comparisons of their reliability and efficiency. Here, we employed lab- and field-tested sets of publicly available and de novo-designed primers in amplifying 83 species of amphibian from all three orders (Anura, Caudata, and Gymnophiona) and 13 families present in China to evaluate the versatility and specificity of these primers sets in amphibian eDNA metabarcoding studies. Three pairs of primers were highly effective, as they could successfully amplify all the major clades of Chinese amphibians in our study. A few non-amphibian taxa were also amplified by these primers, which implies that further optimization of amphibian-specific primers is still needed. The simultaneous use of three primer sets can completely cover all the species obtained by conventional survey methods and has even effectively distinguished quite a number of species (n = 20) in the Wenshan National Nature Reserve. No single primer set could individually detect all of the species from the studied region, indicating that multiple primers might be necessary for a comprehensive survey of Chinese amphibians. Besides, seasonal variations in amphibian species composition were also revealed by eDNA metabarcoding, which was consistent with traditional survey methods. These results indicate that eDNA metabarcoding has the potential to be a powerful tool for studying spatial and temporal community changes in amphibian species richness.

Time-gated single-pixel imaging of Cherenkov emission from a medical linear accelerator.

Cherenkov imaging is an ideal tool for real-time in vivo verification of a radiation therapy dose. Given that radiation is pulsed from a medical linear accelerator (LINAC) together with weak Cherenkov emissions, time-gated high-sensitivity imaging is required for robust measurements. Instead of using an expensive camera system with limited efficiency of detection in each pixel, a single-pixel imaging (SPI) approach that maintains promising sensitivity over the entire spectral band could be used to provide a low-cost and viable alternative. A prototype SPI system was developed and demonstrated here in Cherenkov imaging of LINAC dose delivery to a water tank. Validation experiments were performed using four regular fields and an intensity-modulated radiotherapy (IMRT) delivery plan. The Cherenkov image-based projection percent depth dose curves (pPDDs) were compared to pPDDs simulated by the treatment planning system (TPS), with an overall average error of 0.48, 0.42, 0.65, and 1.08% for the 3, 5, 7, and 9 cm square beams, respectively. The composite image of the IMRT plan achieved a 85.9% pass rate using 3%/3 mm gamma index criteria, in comparing Cherenkov intensity and TPS dose. This study validates the feasibility of applying SPI to the Cherenkov imaging of radiotherapy dose for the first time to our knowledge.

The EGR1/miR-139/NRF2 axis orchestrates radiosensitivity of non-small-cell lung cancer via ferroptosis.

Radiotherapy is one of the predominant treatment modalities for almost all kinds of malignant cancers, including non-small cell lung cancer (NSCLC). Increasing evidence shows that ionizing radiation (IR) induces reactive oxygen species (ROS) leading to lipid peroxidation and subsequently ferroptosis of cancer cells. However, cancer cells evolve multiple mechanisms against ROS biology resulting in resistance to ferroptosis and radiotherapy, of which NRF2 signaling is one of the most studied. In the current research, we identified that microRNA-139 (miR-139) could be a novel radiosensitizer for NSCLC by inhibiting NRF2 signaling. We found that miR-139 possessed great potential as a diagnostic biomarker for NSCLC and multiple other types of cancer. Overexpression of miR-139 increased radiosensitivity of NSCLC cells in vitro and in vivo. MiR-139 directly targeted cJUN and KPNA2 to impair NRF2 signaling resulting in enhanced IR-induced lipid peroxidation and cellular ferroptosis. We proved KPNA2 to be a binding partner of NRF2 that involved in nuclear translocation of NRF2. Moreover, we found that IR induced miR-139 expression through transcriptional factor EGR1. EGR1 bound to the promoter region and transactivated miR-139. Overall, our findings elucidated the effect of EGR1/miR-139/NRF2 in IR-induced ferroptosis of NSCLC cells and provided theoretical support for the potential diagnostic biomarkers and therapeutic targets for the disease.

Apatinib beyond first progression is associated with prolonged overall survival in patients with advanced breast cancer: Results from an observational study.

In the present study, the efficacy and safety of a low dose of apatinib in the treatment of patients with advanced breast cancer (ABC) in a real-world setting were assessed, the impact of continuous anti-angiogenic therapy beyond progression was determined and the factors associated with efficacy were evaluated. A total of 63 patients with ABC who were treated with apatinib and for whom several lines of treatment had failed were retrospectively analyzed in Tangshan People's Hospital (Tangshan, China) between January 2016 and October 2022. Apatinib was administered orally combined with chemotherapy, endocrine therapy, targeted therapy or monotherapy at a dose of 250 mg per day. Apatinib administration was continued in certain patients beyond first progressive disease (PD), and these patients were defined as the continued anti-angiogenic treatment beyond first progression (CABF) group, while those who discontinued apatinib were defined as the non-CABF group. In the evaluation of the first efficacy, the objective response rate was 33.3%. A total of 26 patients continued to receive apatinib post-first PD and were allocated to the CABF group. The median overall survival (OS) time of the 63 patients was 16 months. Log-rank univariate analysis revealed that the OS time was significantly associated with molecular subtype (P=0.014), CABF (P=0.004), and the neutrophil-to-lymphocyte ratio (NLR) (P=0.011). Multivariate Cox regression analysis revealed that being in the non-CABF group and a high NLR were independent risk factors for lower OS time (P=0.017 and P=0.041, respectively). These results support the continued administration of low-dose apatinib beyond progression and the use of NLR as an easily accessible prognostic marker in patients with ABC treated with apatinib.

Hidden hotspots of amphibian biodiversity in China.

Identifying and protecting hotspots of endemism and species richness is crucial for mitigating the global biodiversity crisis. However, our understanding of spatial diversity patterns is far from complete, which severely limits our ability to conserve biodiversity hotspots. Here, we report a comprehensive analysis of amphibian species diversity in China, one of the most species-rich countries on Earth. Our study combines 20 y of field surveys with new molecular analyses of 521 described species and also identifies 100 potential cryptic species. We identify 10 hotspots of amphibian diversity in China, each with exceptional species richness and endemism and with exceptional phylogenetic diversity and phylogenetic endemism (based on a new time-calibrated, species-level phylogeny for Chinese amphibians). These 10 hotspots encompass 59.6% of China's described amphibian species, 49.0% of cryptic species, and 55.6% of species endemic to China. Only four of these 10 hotspots correspond to previously recognized biodiversity hotspots. The six new hotspots include the Nanling Mountains and other mountain ranges in South China. Among the 186 species in the six new hotspots, only 9.7% are well covered by protected areas and most (88.2%) are exposed to high human impacts. Five of the six new hotspots are under very high human pressure and are in urgent need of protection. We also find that patterns of richness in cryptic species are significantly related to those in described species but are not identical.

Multiomics profiling reveals the benefits of gamma-delta (γδ) T lymphocytes for improving the tumor microenvironment, immunotherapy efficacy and prognosis in cervical cancer.

BACKGROUND: As an unconventional subpopulation of T lymphocytes, γδ T cells can recognize antigens independently of major histocompatibility complex restrictions. Recent studies have indicated that γδ T cells play contrasting roles in tumor microenvironments-promoting tumor progression in some cancers (eg, gallbladder and leukemia) while suppressing it in others (eg, lung and gastric). γδ T cells are mainly enriched in peripheral mucosal tissues. As the cervix is a mucosa-rich tissue, the role of γδ T cells in cervical cancer warrants further investigation. METHODS: We employed a multiomics strategy that integrated abundant data from single-cell and bulk transcriptome sequencing, whole exome sequencing, genotyping array, immunohistochemistry, and MRI. RESULTS: Heterogeneity was observed in the level of γδ T-cell infiltration in cervical cancer tissues, mainly associated with the tumor somatic mutational landscape. Definitely, γδ T cells play a beneficial role in the prognosis of patients with cervical cancer. First, γδ T cells exert direct cytotoxic effects in the tumor microenvironment of cervical cancer through the dynamic evolution of cellular states at both poles. Second, higher levels of γδ T-cell infiltration also shape the microenvironment of immune activation with cancer-suppressive properties. We found that these intricate features can be observed by MRI-based radiomics models to non-invasively assess γδ T-cell proportions in tumor tissues in patients. Importantly, patients with high infiltration levels of γδ T cells may be more amenable to immunotherapies including immune checkpoint inhibitors and autologous tumor-infiltrating lymphocyte therapies, than to chemoradiotherapy. CONCLUSIONS: γδ T cells play a beneficial role in antitumor immunity in cervical cancer. The abundance of γδ T cells in cervical cancerous tissue is associated with higher response rates to immunotherapy.

A PET/CT radiomics model for predicting distant metastasis in early-stage non-small cell lung cancer patients treated with stereotactic body radiotherapy: a multicentric study.

OBJECTIVES: Stereotactic body radiotherapy (SBRT) is a treatment option for patients with early-stage non-small cell lung cancer (NSCLC) who are unfit for surgery. Some patients may experience distant metastasis. This study aimed to develop and validate a radiomics model for predicting distant metastasis in patients with early-stage NSCLC treated with SBRT. METHODS: Patients at five institutions were enrolled in this study. Radiomics features were extracted based on the PET/CT images. After feature selection in the training set (from Tianjin), CT-based and PET-based radiomics signatures were built. Models based on CT and PET signatures were built and validated using external datasets (from Zhejiang, Zhengzhou, Shandong, and Shanghai). An integrated model that included CT and PET radiomic signatures was developed. The performance of the proposed model was evaluated in terms of its discrimination, calibration, and clinical utility. Multivariate logistic regression was used to calculate the probability of distant metastases. The cutoff value was obtained using the receiver operator characteristic curve (ROC), and the patients were divided into high- and low-risk groups. Kaplan-Meier analysis was used to evaluate the distant metastasis-free survival (DMFS) of different risk groups. RESULTS: In total, 228 patients were enrolled. The median follow-up time was 31.4 (2.0-111.4) months. The model based on CT radiomics signatures had an area under the curve (AUC) of 0.819 in the training set (n = 139) and 0.786 in the external dataset (n = 89). The PET radiomics model had an AUC of 0.763 for the training set and 0.804 for the external dataset. The model combining CT and PET radiomics had an AUC of 0.835 for the training set and 0.819 for the external dataset. The combined model showed a moderate calibration and a positive net benefit. When the probability of distant metastasis was greater than 0.19, the patient was considered to be at high risk. The DMFS of patients with high- and low-risk was significantly stratified (P < 0.001). CONCLUSIONS: The proposed PET/CT radiomics model can be used to predict distant metastasis in patients with early-stage NSCLC treated with SBRT and provide a reference for clinical decision-making. In this study, the model was established by combining CT and PET radiomics signatures in a moderate-quantity training cohort of early-stage NSCLC patients treated with SBRT and was successfully validated in independent cohorts. Physicians could use this easy-to-use model to assess the risk of distant metastasis after SBRT. Identifying subgroups of patients with different risk factors for distant metastasis is useful for guiding personalized treatment approaches.

Optimization of stereotactic radiotherapy (SRT) planning for brain metastases from lung cancer by Cyberknife system: reducing dose distribution inner ear.

Objective: Through retrospective statistical analysis of radiation distribution in inner ear avoidance for brain metastases from lung cancer by the CyberKnife (CK) system, it can provide a reference for stereotactic radiotherapy (SRT) planning and treatment optimization. Methods: Computed tomography/magnetic resonance imaging data of 44 patients with one brain metastases lesion from lung cancer were used to re-plan and analyze, who had been treated by CK system from April 2021 to April 2022. The prescribed doses of 14-30 Gy in 1-3 fractions was simultaneously delivered to the metastatic lesions. The SRT plans for the same patients were replaned under with and without inner ear avoidance setting. The plan parameters and dose distribution differences were compared between plans. Results: All plans met the dose restrictions. There were no significant differences in the coverage (Coverage), conformity index (CI), mean dose (Dmean), the maximum dose (Dmax) and minimum dose (Dmin) of planning target volume (PTV). With inner ear avoidance setting, the Dmax and Dmean of inner ear area decreased by 13.76% and 12.15% (p<0.01), respectively. The total number of machine nodes and monitor units (MU) increased by 4.63% and 1.06%. Conclusions: During the SRT plan designing for brain metastases from lung cancer, the dose distribution in inner ear area could be reduced by avoidance setting, and the patient's hearing would be well protected.

Dosimetric analysis of brachial plexopathy after stereotactic body radiotherapy: Significance of organ delineation.

OBJECTIVES: Examine the significance of contouring the brachial plexus (BP) for toxicity estimation and select metrics for predicting radiation-induced brachial plexopathy (RIBP) after stereotactic body radiotherapy. MATERIALS AND METHODS: Patients with planning target volume (PTV) ≤ 2 cm from the BP were eligible. The BP was contoured primarily according to the RTOG 1106 atlas, while subclavian-axillary veins (SAV) were contoured according to RTOG 0236. Apical PTVs were classified as anterior (PTV-A) or posterior (PTV-B) PTVs. Variables predicting grade 2 or higher RIBP (RIBP2) were selected through least absolute shrinkage and selection operator regression and logistic regression. RESULTS: Among 137 patients with 140 BPs (median follow-up, 32.1 months), 11 experienced RIBP2. For patients with RIBP2, the maximum physical dose to the BP (BP-Dmax) was 46.5 Gy (median; range, 35.7 to 60.7 Gy). Of these patients, 54.5 % (6/11) satisfied the RTOG limits when using SAV delineation; among them, 83.3 % (5/6) had PTV-B. For patients with PTV-B, the maximum physical dose to SAV (SAV-Dmax) was 11.2 Gy (median) lower than BP-Dmax. Maximum and 0.3 cc biologically effective doses to the BP based on the linear-quadratic-linear model (BP-BEDmax LQL and BP-BED0.3cc LQL, α/ß = 3) were selected as predictive variables with thresholds of 118 and 73 Gy, respectively. CONCLUSION: Contouring SAV may significantly underestimate the RIBP2 risk in dosimetry, especially for patients with PTV-B. BP contouring indicated BP-BED0.3cc LQL and BP-BEDmax LQL as potential predictors of RIBP2.

Can low-dose intravenous bevacizumab be as effective as high-dose bevacizumab for cerebral radiation necrosis?

Although intravenous bevacizumab (IVBEV) is the most promising treatment for cerebral radiation necrosis (CRN), there is no conclusion on the optimal dosage. Our retrospective study aimed to compare the efficacy and safety of high-dose with low-dose IVBEV in treating CRN associated with radiotherapy for brain metastases (BMs). This paper describes 75 patients who were diagnosed with CRN secondary to radiotherapy for BMs, treated with low-dose or high-dose IVBEV and followed up for a minimum of 6 months. The clinical data collected for this study include changes in brain MRI, clinical symptoms, and corticosteroid usage before, during, and after IVBEV treatment. At the 3-month mark following administration of IVBEV, a comparison of two groups revealed that the median percentage decreases in CRN volume on T2-weighted fluid-attenuated inversion recovery and T1-weighted gadolinium contrast-enhanced image (T1CE), as well as the signal ratio reduction on T1CE, were 65.8% versus 64.8% (p = 0.860), 41.2% versus 51.9% (p = 0.396), and 37.4% versus 35.1% (p = 0.271), respectively. Similarly, at 6 months post-IVBEV, the median percentage reductions of the aforementioned parameters were 59.5% versus 62.0% (p = 0.757), 39.1% versus 31.3% (p = 0.851), and 35.4% versus 28.2% (p = 0.083), respectively. Notably, the incidence of grade ≥3 adverse events was higher in the high-dose group (n = 4, 9.8%) than in the low-dose group (n = 0). Among patients with CRN secondary to radiotherapy for BMs, the administration of high-dose IVBEV did not demonstrate superiority over low-dose IVBEV. Moreover, the use of high-dose IVBEV was associated with a higher incidence of grade ≥3 adverse events compared with low-dose IVBEV.

Effect of AQP4 and its palmitoylation on the permeability of exogenous reactive oxygen species: Insights from computational study.

Aquaporin 4 (AQP4) facilitates the transport of reactive oxygen species (ROS). Both cancer cells and the ionizing radiation microenvironment can induce posttranslational modifications (PTMs) in AQP4, which may affect its permeability to ROS. Because this ROS diffusion process is rapid, microscopic, and instantaneous within and outside cells, conventional experimental methods are inadequate for elucidating the molecular mechanisms involved. In this study, computational methods were employed to investigate the permeability of exogenous ROS mediated by radiation in AQP4 at a molecular scale. We constructed a simulation system incorporating AQP4 and AQP4-Cysp13 in a complex lipid environment with ROS. Long-timescale molecular dynamics simulations were conducted to assess the structural stability of both AQP4 and AQP4-Cysp13. Free energy calculations were utilized to determine the ROS transport capability of the two AQP4 proteins. Computational electrophysiology and channel structural analysis quantitatively evaluated changes in ROS transport capacity under various radiation-induced transmembrane voltage microenvironments. Our findings demonstrate the distinct transport capabilities of AQP4 channels for water molecules and various types of ROS and reveal a decrease in transport efficiency when AQP4 undergoes palmitoylation modification. In addition, we have simulated the radiation-induced alteration of cell membrane voltage, which significantly affected the ROS transport capacity. We propose that this research will enhance the understanding of the molecular mechanisms governing the transport of exogenous ROS by AQP4 and elucidate the influence of palmitoylation on ROS transport. This study will also help clarify how different structural features of AQP4 affect the transport of exogenous ROS mediated by radiotherapy, thereby providing a theoretical molecular basis for the development of new treatment strategies that combine with radiotherapy.