Assessing systemic, developmental, and reproductive toxicity and estrogenicity of Korean red ginseng extract G1899 in juvenile Sprague-Dawley Rats.

Background: Korean red ginseng (KRG) is a product from ginseng roots, which is enriched with ginsenosides and has been utilized for a long time as an adaptogen to alleviate various physiological or disease conditions. While KRG is generally considered safe, conducting a thorough toxicological assessment of the spray-dried powder G1899 during the juvenile period is essential to establish its safety profile. This study aimed to assess the safety of G1899 during the juvenile period using Sprague-Dawley rats. Methods: Two studies were conducted separately: a juvenile toxicity study and a uterotrophic bioassay. To assess the potential toxicity at systemic, postnatal developmental, and reproductive levels, G1899 was orally gavaged once a day in post-weaning juvenile Sprague-Dawley (SD) rats at 0, 1250, 2500, or 5000 mg/kg/day. Estrogenicity was assessed by orally gavaging G1899 in immature female SD rats at 0, 2500, or 5000 mg/kg/day on postnatal days (PND) 19-21, followed by a uterotrophic bioassay. These studies were conducted in accordance with the Good Laboratory Practice (GLP) regulations and regulatory test guidelines. Results: Regarding juvenile toxicity, no abnormalities related to the G1899 treatment were observed in any group during the experiment. Moreover, no uterotrophic responses were observed in the dosed female group. Based on these results, the no observed adverse effect level (NOAEL) of G1899 was determined to be at least 5000 mg/kg/day for general systemic function, developmental/reproductive function, and estrogenic activity. Conclusion: Our results suggest that G1899 is not toxic to juveniles at doses of up to 5000 mg/kg/day.

Centrifugal-Gravity-Enforced Deposition of MXene Electrodes for High-Performance and Ultrastable Microsupercapacitors.

Two-dimensional (2D) transition metal carbides, known as MXenes, have captured much attention for their excellent electrical conductivity and electrochemical capability. However, the susceptibility of MXenes to oxidation, particularly Ti3C2Tx transforming into titanium dioxide upon exposure to ambient air, hinders their utilization for extended operational life cycles. This work introduces a simple and straightforward method for producing ultrathin MXene electrode films tailored for energy storage applications, employing centrifugal-gravity force. Our approach significantly suppresses the oxidation phenomenon that arises in MXene materials and also effectively prevents the recrystallization of potentially residual LiF during the film formation. Additionally, the utilization of this MXene electrode in an all-solid-state microsupercapacitor (MSC) with an interdigitated pattern demonstrates an exceptionally improved and stable electrochemical performance. This includes a high volumetric capacitance of approximately 467 F cm-3, an energy density of around 65 mWh cm-3, and impressive long-term cycle stability, retaining about 94% capacity after 10 000 cycles. Moreover, a downsized MSC device exhibits remarkable mechanical durability, retaining over 98% capacity even when folded and sustaining stability over extended periods. Therefore, we believe that this study provides valuable insights for advancing highly integrated energy storage devices, ensuring exceptional electrochemical efficiency and prolonged functionality in diverse environments, whether ambient or humid.

Effect of Bias Potential on the Interface of a Solid Electrolyte and Electrode during XPS Depth Profiling Analysis.

Depth profiling is an essential method to investigate the physical and chemical properties of a solid electrolyte and electrolyte/electrode interface. In conventional depth profiling, various spectroscopic tools such as X-ray photoelectron spectroscopy (XPS) and secondary ion mass spectroscopy (SIMS) are utilized to monitor the chemical states along with ion bombardment to etch a sample. Nevertheless, the ion bombardment during depth profiling results in an inevitable systematic error, i.e., the accumulation of mobile ions at the electrolyte/electrode interface, known as the ion pile-up phenomenon. Here, we propose a novel method using bias potential, the substrate-bias method, to prevent the ion pile-up phenomena during depth profiling of a solid electrolyte. When the positive bias potential is applied on the substrate (electrode), the number of accumulating ions at the electrolyte/electrode interface is significantly reduced. The in-depth XPS analysis with the biased electrode reveals not only the suppression of the ion pile-up phenomena but also the altered chemical states at the interfacial region between the electrolyte and electrode depending on the bias. The proposed substrate-bias method can be a good alternative scheme for an efficient yet precise depth profiling technique for a solid electrolyte.

The Effect of κ-Carrageenan on Porcine Sperm Cryo-Survival.

κ-Carrageenan is a sulfated polysaccharide from red seaweed with substantial antioxidant activities. This study aimed to investigate the effect of κ-Carrageenan treatment on frozen-thawed (FT) porcine semen quality. Therefore, the spermatozoa were diluted and cryopreserved in a freezing extender supplemented with 0 (control), 0.2, 0.4, 0.6, and 0.8 mg/mL κ-Carrageenan. Sperm kinematics were assessed immediately after thawing (AT) and post-incubation for 120 min. The viability, acrosome integrity, lipid peroxidation, mitochondrial membrane potential (MMP), and intracellular caspase activity were measured AT. The results indicated that 0.2 mg/mL κ-Carrageenan increased total and progressive motility AT and post-incubation for 120 min (p < 0.05). Moreover, the viable sperm percentage and MMP after 0.2 mg/mL treatment were higher than those after control and other κ-Carrageenan concentration treatments. The proportion of acrosome-intact spermatozoa was significantly higher after 0.2 and 0.4 mg/mL κ-Carrageenan treatment than that after control and other κ-Carrageenan concentration treatments. The intracellular caspase activity was not significantly different among the experimental groups. However, the MDA concentration after 0.2 mg/mL κ-Carrageenan treatment was lower (p < 0.05) than that after the control treatment. Taken together, adding κ-Carrageenan to the porcine semen freezing extender improved the FT sperm quality mainly by influencing membrane stability and protecting against oxidative stress.

Uprighting a mesially impacted mandibular second molar with scissor bite using simple tubes.

Orthodontic uprighting or traction of an impacted mandibular second molar often necessitates invasive interventions. This report aims to illustrate the utilization of nickel-titanium wire segments inserted into small, simple tubes for uprighting mesially impacted mandibular second molars and also for scissor bite correction. The term "simple tube" refers to a tube without a bonding base attached to a tooth surface by covering it with flowable composite resin. Due to the absence of a bonding base, the simple tube is characterized by its diminutive size and minimal profile height, facilitating placement on partially exposed second molars and unconventional positioning to adjust the force geometry. In this case study, mesially-impacted mandibular second molars with scissor bite were uprighted in a 21-year-old male utilizing simple tubes. Simple tubes can be used for molar uprighting and scissor bite correction buccally and lingually.

Engineered Hybrid Vesicles and Cellular Internalization in Mammary Cancer Cells.

Extracellular vesicles play an important role in intercellular communication, with the potential to serve as biomaterials for nanocarriers. Combining such extracellular vesicles and liposomes results in advanced drug delivery carriers. In this study, we attempted to fabricate hybrid vesicles using a membrane fusion method and incorporated an anticancer drug. As a result, we successfully prepared nanosized uniform hybrid vesicles and evaluated their physicochemical characteristics and intracellular uptake mechanisms via endocytosis in various cell lines. Compared to liposomes, the hybrid vesicles showed better physical properties and a relatively higher reduction in cell viability, which was presumably dependent on the specific cell type. These findings suggest that fusion-based hybrid vesicles offer a novel strategy for delivering therapeutic agents and provide insights into the types of extracellular vesicles that are useful in fabricating hybrid vesicles to develop an advanced drug delivery system.

Prognostic Significance of Bulky Nodal Disease in Anal Cancer Management: A Multi Institutional Study.

Purpose: This study aimed to assess the prognostic significance of bulky nodal involvement in patients with anal squamous cell carcinoma treated with definitive chemoradiotherapy. Materials and Methods: We retrospectively analyzed medical records of patients diagnosed with anal squamous cell carcinoma who underwent definitive chemoradiotherapy at three medical centers between 2004 and 2021. Exclusion criteria included distant metastasis at diagnosis, 2D radiotherapy, and salvage treatment for local relapse. Bulky N+ was defined as nodes with a long diameter of 2 cm or greater. Results: A total of 104 patients were included, comprising 51 with N0, 46 with non-bulky N+, and 7 with bulky N+. The median follow-up duration was 54.0 months (range, 6.4-162.2 months). Estimated 5-year progression-free survival (PFS), loco-regional recurrence-free survival (LRRFS), and overall survival (OS) rates for patients with bulky N+ were 42.9%, 42.9%, and 47.6%, respectively. Bulky N+ was significantly associated with inferior PFS, LRRFS and OS compared to patients without or with non-bulky N+, even after multivariate analysis. We proposed a new staging system incorporating bulky N+ as N2 stage, with estimated 5-year LRRFS, PFS, and OS rates of 81.1%, 80.6%, and 86.2% for stage I, 67.7%, 60.9%, and 93.3% for stage II, and 42.9%, 42.9%, and 47.6% for stage III disease, enhancing the predictability of prognosis. Conclusion: Patients with bulky nodal disease treated with standard chemoradiotherapy experienced poor survival outcomes, indicating the potential necessity for further treatment intensification.

Shaping brassinosteroid signaling through scaffold proteins.

Cellular responses to internal and external stimuli are orchestrated by intricate intracellular signaling pathways. To ensure an efficient and specific information flow, cells employ scaffold proteins as critical signaling organizers. With the ability to bind multiple signaling molecules, scaffold proteins can sequester signaling components within specific subcellular domains or modulate the efficiency of signal transduction. Scaffolds can also tune the output of signaling pathways by serving as regulatory targets. This review focuses on scaffold proteins associated with the plant GLYCOGEN SYNTHASE KINASE3-like kinase, BRASSINOSTEROID-INSENSITIVE2 (BIN2) that serve as a key negative regulator of brassinosteroid (BR) signaling. Here we summarize the current understanding of how scaffold proteins actively shape BR signaling outputs and crosstalk in plant cells via interactions with BIN2.

Potent small molecule inhibitors against the 3C protease of foot-and-mouth disease virus.

Foot-and-mouth disease (FMD) is one of the most devastating diseases of livestock which can cause significant economic losses, especially when introduced to FMD-free countries. FMD virus (FMDV) belongs to the family Picornaviridae and is antigenically heterogeneous with seven established serotypes. The prevailing preventive and control strategies are limited to restriction of animal movement and elimination of infected or exposed animals, which can be potentially combined with vaccination. However, FMD vaccination has limitations including delayed protection and lack of cross-protection against different serotypes. Recently, antiviral drug use for FMD outbreaks has increasingly been recognized as a potential tool to augment the existing early response strategies, but limited research has been reported on potential antiviral compounds for FMDV. FMDV 3C protease (3Cpro) cleaves the viral-encoded polyprotein into mature and functional proteins during viral replication. The essential role of viral 3Cpro in viral replication and the high conservation of 3Cpro among different FMDV serotypes make it an excellent target for antiviral drug development. We have previously reported multiple series of inhibitors against picornavirus 3Cpro or 3C-like proteases (3CLpros) encoded by coronaviruses or caliciviruses. In this study, we conducted structure-activity relationship studies for our in-house focused compound library containing 3Cpro or 3CLpro inhibitors against FMDV 3Cpro using enzyme and cell-based assays. Herein, we report the discovery of aldehyde and α-ketoamide inhibitors of FMDV 3Cpro with high potency. These data inform future preclinical studies that are related to the advancement of these compounds further along the drug development pathway.IMPORTANCEFood-and-mouth disease (FMD) virus (FMDV) causes devastating disease in cloven-hoofed animals with a significant economic impact. Emergency response to FMD outbreaks to limit FMD spread is critical, and the use of antivirals may overcome the limitations of existing control measures by providing immediate protection for susceptible animals. FMDV encodes 3C protease (3Cpro), which is essential for virus replication and an attractive target for antiviral drug discovery. Here, we report a structure-activity relationship study on multiple series of protease inhibitors and identified potent inhibitors of FMDV 3Cpro. Our results suggest that these compounds have the potential for further development as FMD antivirals.

Subjective memory complaints and medication adherence among hypertensive Korean older adults with multimorbidity: mediating effect of depression and social support.

BACKGROUND & AIM(S): Medication adherence (MA) is a key factor in maintaining adequate blood pressure and preventing complications. However, some older adults experience difficulties in taking medicine properly due to declines in cognitive function. Although subjective memory complaints (SMC) are recognized as early markers of cognitive impairment, previous studies concerning the relationship between MA and cognitive function have focused only on objective cognitive function. Furthermore, while depression has a high correlation with SMC, low MA, and social support, there is limited evidence on their relationship. This study aims to understand the effect of SMC on MA and the mediating effect of depression and social support. METHOD(S): This study is a descriptive cross-sectional investigation. A sample of 195 community-dwelling hypertensive older adults with multimorbidity from 3 community senior centers in Gwangju, South Korea were recruited through convenience sampling. Data was collected through face-to-face survey from January to March 2018. The PROCESS macro v4.2 program [Model 6] was used to analyze the mediating effect of depression and social support in the relationship between SMC and MA. Data analysis was performed using SPSS/WIN 26.0 and STATA MP 17.0. RESULTS: The average MA was 6.74. There were significant differences in MA according to awareness of prescribed drugs, awareness of side effects, insomnia, and healthcare accessibility. SMC was positively correlated with depression, while social support and MA were negatively correlated. While depression was a significant mediator of the effect of SMC on MA, the mediating effect of social support was not significant. The multiple mediation effect of depression and social support was not significant. CONCLUSION: The results suggest that medication management of older adults in community settings should be accompanied by a comprehensive health assessment of associated factors. Health professionals should explore strategies to improve memory as well as prevent and alleviate depression to increase MA among hypertensive older adults with multimorbidity.

Disparities in the association between ambient temperature and preterm birth according to individual and regional characteristics: a nationwide time-stratified case-crossover study.

BACKGROUND: Several studies have reported that climate change elevates heat exposure in pregnant women and high temperatures during pregnancy are associated with preterm births (PTBs). Although the association might be disproportionate, related evidence remains sparse. We evaluated the disproportionate risk of PTB associated with ambient temperature during pregnancy by individual and regional characteristics in South Korea. METHODS: We collected data on birth certificates and daily mean temperatures during the period from 2011 to 2019. A time-stratified case-crossover design was used to investigate the association between temperature and PTB and stratified analyses were conducted to examine the effect modification of individual and regional characteristics. RESULTS: A total of 160,067 singleton PTBs were recorded in Korea from 2011 to 2019. A 5℃ increase in the mean temperature during the last four weeks before delivery was associated with an increased risk of PTB with an odds ratio (OR) of 1.03 (95% confidence interval [CI]: 1.02, 1.05), and the association was more evident in mothers aged ≥35 years (OR: 1.06 [95% CI: 1.03, 1.10]) and with low education levels (OR: 1.04 [95% CI: 1.02, 1.05]). Additionally, the estimated risk was evident in districts with lower medical resources and more prominent disparities were shown by individual and regional characteristics in rural areas than in urban areas. CONCLUSIONS: This study provides evidence that the risk of PTB related to ambient temperature is disproportionate by individual and regional characteristics and suggests the need for public health policies to alleviate the disparities, especially in rural areas.

Promising Effect of the Children in Disaster: Evaluation and Recovery Intervention on Trauma Symptoms and Quality of Life for Children and Adolescents: A Controlled Study.

OBJECTIVE: The Children in Disaster: Evaluation and Recovery (CIDER) program in Korea was developed to treat children and adolescents exposed to trauma. This study aimed to demonstrate the effectiveness of the CIDER through a comparison with controls. METHODS: A total of 85 participants consisted of the intervention group (n=41) and control group (n=44). We assessed the changes in trauma-related symptoms, depression, anxiety, and improvements in quality of life before and after the intervention. RESULTS: In total, bullying and school violence (44.7%) were the most common trauma, followed by sexual abuse (17.6%). Acute stress disorder and post-traumatic stress disorder (PTSD) accounted for 41.2%, and attention-deficit/hyperactivity disorder (ADHD) and developmental disorder were the most common comorbidities (51.8%). The symptoms of trauma, depression, anxiety, and quality of life improved significantly in the intervention group, while the control group did not show significant changes. CONCLUSION: Compared with the control group, the CIDER improved symptoms and quality of life in children and adolescents who had experienced trauma. The CIDER program was practical and easy to apply, even for different ages, types of traumas, and comorbidities.

Quantitative and qualitative mutational impact of ionizing radiation on normal cells.

The comprehensive genomic impact of ionizing radiation (IR), a carcinogen, on healthy somatic cells remains unclear. Using large-scale whole-genome sequencing (WGS) of clones expanded from irradiated murine and human single cells, we revealed that IR induces a characteristic spectrum of short insertions or deletions (indels) and structural variations (SVs), including balanced inversions, translocations, composite SVs (deletion-insertion, deletion-inversion, and deletion-translocation composites), and complex genomic rearrangements (CGRs), including chromoplexy, chromothripsis, and SV by breakage-fusion-bridge cycles. Our findings suggest that 1 Gy IR exposure causes an average of 2.33 mutational events per Gb genome, comprising 2.15 indels, 0.17 SVs, and 0.01 CGRs, despite a high level of inter-cellular stochasticity. The mutational burden was dependent on total irradiation dose, regardless of dose rate or cell type. The findings were further validated in IR-induced secondary cancers and single cells without clonalization. Overall, our study highlights a comprehensive and clear picture of IR effects on normal mammalian genomes.

Gadolinium-Based Magnetic Resonance Theranostic Agent with Gallic Acid as an Anti-Neuroinflammatory and Antioxidant Agent.

Studies in the field have actively pursued the incorporation of diverse biological functionalities into gadolinium-based contrast agents, aiming at the amalgamation of MRI imaging and therapeutic capabilities. In this research, we present the development of Gd-Ga, an anti-neuroinflammatory MR contrast agent strategically designed to target inflammatory mediators for comprehensive imaging diagnosis and targeted lesion treatment. Gd-Ga is a gadolinium complex composed of 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetylamide (DO3A) conjugated with gallic acid (3,4,5-trihydroxybenzoic acid). Upon intravenous administration in LPS-induced mouse models, Gd-Ga demonstrated a remarkable three-fold increase in signal-to-noise (SNR) variation compared to Gd-DOTA, particularly evident in both the cortex and hippocampus 30 min post-MR monitoring. In-depth investigations, both in vitro and in vivo, into the anti-neuroinflammatory properties of Gd-Ga revealed significantly reduced protein expression levels of pro-inflammatory mediators compared to the LPS group. The alignment between in silico predictions and phantom studies indicates that Gd-Ga acts as an anti-neuroinflammatory agent by directly binding to MD2. Additionally, the robust antioxidant activity of Gd-Ga was confirmed by its effective scavenging of NO and ROS. Our collective findings emphasize the immense potential of this theranostic complex, where a polyphenol serves as an anti-inflammatory drug, presenting an exceptionally efficient platform for the diagnosis and treatment of neuroinflammation.

Efficacy of Moxibustion for Cancer-Related Fatigue in Patients with Breast Cancer: A Systematic Review and Meta-Analysis.

INTRODUCTION: Breast cancer is the most commonly diagnosed cancer worldwide, and most patients experience fatigue. However, there are no effective treatments for cancer-related fatigue (CRF). Several randomized controlled trials (RCTs) have suggested that moxibustion improves CRF. We conducted a systematic review and meta-analysis to compare the differences in fatigue scale scores, quality of life, and clinical efficacy in patients with breast cancer who developed CRF and did versus did not receive moxibustion. METHODS: RCTs were searched in 7 databases using a standardized search method from database inception to March 2023, and RCTs that met the inclusion criteria were selected. RESULTS: Among 1337 initially identified RCTs, 10 RCTs involving 744 participants were selected for this study. The meta-analysis involved assessment of the revised Piper Fatigue Scale scores, Cancer Fatigue Scale scores, Karnofsky Performance Scale scores, Athens Insomnia Scale scores, clinical efficacy, and Qi deficiency syndrome scale scores. Compared with the control, moxibustion was associated with significantly better Piper Fatigue Scale scores (P < 0.0001), quality of life [Karnofsky Performance Scale scores (P < 0.0001)], clinical efficacy (P = 0.0007), and Qi deficiency syndrome scale scores (P = 0.02). CONCLUSIONS: Moxibustion improves CRF in patients with breast cancer. The efficacy of moxibustion should be further examined by high-quality studies in various countries with patients subdivided by their breast cancer treatment status. REGISTRATION: PROSPERO ID: CRD42023451292.

Incidence and case fatality of acute myocardial infarction in Korea, 2011-2020.

OBJECTIVES: Cardiovascular diseases are a leading cause of mortality worldwide, and acute myocardial infarction (AMI) is particularly fatal condition. We evaluated the incidence and case fatality rates of AMI in Korea from 2011 to 2020. METHODS: We utilized data from the National Health Insurance Services to calculate crude, age-standardized, and age-specific incidence rates, along with 30-day and 1-year case fatality rates, of AMI from 2011 to 2020. Age-standardized incidence rates were determined using direct standardization to the 2005 population. RESULTS: The crude incidence rate of AMI per 100,000 person-years consistently increased from 44.7 in 2011 to 68.3 in 2019, before decreasing slightly to 66.2 in 2020. The age-standardized incidence rate of AMI displayed a 19% rise from 2011 to 2019, followed by a slight decline in 2020. The increasing trend for AMI incidence was more pronounced in males than in females. Both 30-day and 1-year case fatality rates remained stable among younger individuals but showed a decrease among older individuals. There was a minor surge in case fatality in 2020, particularly among recurrent AMI cases. CONCLUSIONS: Over the past decade, the AMI incidence rate in Korea has consistently increased, with a slight downturn in 2020. The case fatality rate has remained relatively stable except for a minor increase in 2020. This study provides data for continuous surveillance, the implementation of targeted interventions, and the advancement of research aimed at AMI in Korea.

Incidence and case fatality of stroke in Korea, 2011-2020.

OBJECTIVES: Stroke remains the second leading cause of death in Korea. This study was designed to estimate the crude, age-adjusted and age-specific incidence rates, as well as the case fatality rate of stroke, in Korea from 2011 to 2020. METHODS: We utilized data from the National Health Insurance Services from January 1, 2002 to December 31, 2020, to calculate incidence rates and 30-day and 1-year case fatality rates of stroke. Additionally, we determined sex and age-specific incidence rates and computed age-standardized incidence rates by direct standardization to the 2005 population. RESULTS: The crude incidence rate of stroke hovered around 200 (per 100,000 person-years) from 2011 to 2015, then surged to 218.4 in 2019, before marginally declining to 208.0 in 2020. Conversely, the age-standardized incidence rate consistently decreased by 25% between 2011 and 2020. When stratified by sex, the crude incidence rate increased between 2011 and 2019 for both sexes, followed by a decrease in 2020. Age-standardized incidence rates displayed a downward trend throughout the study period for both sexes. Across all age groups, the 30-day and 1-year case fatality rates of stroke consistently decreased from 2011 to 2019, only to increase in 2020. CONCLUSIONS: Despite a decrease in the age-standardized incidence rate, the total number of stroke events in Korea continues to rise due to the rapidly aging population. Moreover, 2020 witnessed a decrease in incidence but an increase in case fatality rates.

Heat wave exposure and increased heat-related hospitalizations in young children in South Korea: A time-series study.

BACKGROUND: Numerous studies have investigated the association between heat wave exposure increased heat-related hospitalizations in the general population. However, little is known about heat-related morbidity in young children who are more vulnerable than the general population. Therefore, we aimed to evaluate the association between hospitalization for heat-related illness in children and heat wave exposure in South Korea. METHODS: We used the National Health Insurance Service (NHIS) database, which provides medical records from 2015 to 2019 in South Korea. We defined daily hospitalizations for heat-related illness of children younger than five years during the summer period (June to August). We considered the definition of heat waves considering the absolute temperature and percentile. A total of 12 different heat waves were used. A time-series analysis was used to investigate the association between heat wave exposure and heat-related hospitalization among children younger than five years. We used a two-stage design involving a meta-analysis after modeling by each region. RESULTS: We included 16,879 daily heat-related hospitalizations among children younger than five years. Overall, heat wave exposure within two days was most related for heat-related hospitalizations in young children. The relative risk (RR) due to heat wave exposure within two days (lag2) (12 definitions: 70th to 90th percentile of maximum temperature) ranged from 1.038 (95% confidence interval (CI): 0.971, 1.110) to 1.083 (95% CI: 1.036, 1.133). We found that boys were more vulnerable to heat exposure than girls. In addition, we found that urban areas were more vulnerable to heat exposure than rural areas. CONCLUSIONS: In our study, heat wave exposure during summer was found to be associated with an increased risk of hospitalization for heat-related illness among children younger than five years. Our findings suggest the need for summer heat wave management and prevention for children.

Five-Day Spacing of Two Fractionated Ablative Radiotherapies Enhances Antitumor Immunity.

PURPOSE: This study aimed to enhance tumor control and abscopal effects by applying diverse stereotactic ablative radiation therapy (SABR) schedules. METHODS AND MATERIALS: FSaII, CT-26, and 4T1 cells were used for tumor growth delay and lung metastases analysis after 1- or 5-day intervals radiation therapy (RT) with 40, 20, and 20 Gy, respectively. Immunodeficient BALB/c-nude, immunocompetent C3H, and BALB/c mouse models were used. For immune monitoring, FSaII tumors were analyzed using flow cytometry, immunofluorescence staining, and real-time quantitative reverse transcription polymerase chain reaction. The spleens were used for the ELISpot assay and flow cytometry to determine effector CD8 T cells. For abscopal effect analysis in CT-26 tumors, the volume of the nonirradiated secondary tumors was measured after primary tumors were irradiated with 1-day or 5-day intervals. RESULTS: Contrary to the high-dose 1-day interval RT, the 5-day interval RT significantly delayed tumor growth in immunocompetent mice, which was not observed in immunodeficient mice. In addition, the 5-day interval RT significantly reduced the number of lung metastases in FSaII and CT-26 tumors. Five-day spacing was more effective than 1-day interval in enhancing the antitumor immunity via increasing the secretion of tumor-specific IFN-γ, activating the CD8 T cells, and suppressing the monocytic myeloid-derived suppressor cells. The 5-day spacing inhibited nonirradiated secondary tumor growth more effectively than did the 1-day interval. CONCLUSIONS: Compared with the 1-day interval RT, the 5-day interval RT scheme demonstrated enhanced antitumor immunity of CD8 T cells associated with inhibition of myeloid-derived suppressor cells. Enhancing antitumor immunity leads to significant improvements in both primary tumor control and the abscopal effect.

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: Meta-Analysis and International Stereotactic Radiosurgery Society Practice Guidelines.

This systematic review and meta-analysis reports on outcomes and hepatic toxicity rates after stereotactic body radiation therapy (SBRT) for liver-confined hepatocellular carcinoma (HCC) and presents consensus guidelines regarding appropriate patient management. Using the Preferred Reporting Items for Systemic Review and Meta-Analyses guidelines, a systematic review was performed from articles reporting outcomes at ≥5 years published before October 2022 from the Embase, MEDLINE, Cochrane, and Scopus databases with the following search terms: ("stereotactic body radiotherapy" OR "SBRT" OR "SABR" OR "stereotactic ablative radiotherapy") AND ("hepatocellular carcinoma" OR "HCC"). An aggregated data meta-analysis was conducted to assess overall survival (OS) and local control (LC) using weighted random effects models. In addition, individual patient data analyses incorporating data from 6 institutions were conducted as their own subgroup analyses. Seventeen observational studies, comprising 1889 patients with HCC treated with ≤9 SBRT fractions, between 2003 and 2019, were included in the aggregated data meta-analysis. The 3- and 5-year OS rates after SBRT were 57% (95% confidence interval [CI], 47%-66%) and 40% (95% CI, 29%-51%), respectively. The 3- and 5-year LC rates after SBRT were 84% (95% CI, 77%-90%) and 82% (95% CI, 74%-88%), respectively. Tumor size was the only prognostic factor for LC. Tumor size and region were significantly associated with OS. Five-year LC and OS rates of 79% (95% CI, 0.74-0.84) and 25% (95% CI, 0.20-0.30), respectively, were observed in the individual patient data analyses. Factors prognostic for improved OS were tumor size <3 cm, Eastern region, Child-Pugh score ≤B7, and the Barcelona Clinic Liver Cancer stage of 0 and A. The incidence of severe hepatic toxicity varied according to the criteria applied. SBRT is an effective treatment modality for patients with HCC with mature follow-up. Clinical practice guidelines were developed on behalf of the International Stereotactic Radiosurgery Society (ISRS).