Afebrile status at the time of emergency department visit is associated with delayed antibiotic therapy in patients with sepsis (revised).

OBJECTIVES: To determine whether there is a difference in antibiotic administration time and prognosis in afebrile sepsis patients compared to febrile sepsis patients. METHODS: This was retrospective multicenter observational study. Data collected from three referral hospitals. Data were collected from May 2014 through February 2016 under the SEPSIS-2 criteria and from March 2016 to April 2020 under the newly released SEPSIS-3 criteria. Patients were divided into two groups based on body temperature: afebrile (<37.3 °C) and febrile (≥37.3 °C). The relationship between initial body temperature and 28-day mortality were analyzed using multivariable logistic regression. The subgroup analysis was conducted on patients with complete Hour-1 bundle performance records. RESULTS: We included 4293 patients in this study. Initial body temperatures in 28-day survivors were significantly higher than in 28-day non-survivors (37.5 °C ± 1.2 °C versus 37.1 °C ± 1.2 °C, p < 0.01). Multivariable logistic regression analysis was performed in afebrile and febrile sepsis patients. Adjusted odds ratio of afebrile sepsis patients for 28-day mortality was 1.76 (95% Confidence interval 1.46-2.12). As a result of performing the Hour-1 bundle, the number of patients who received antibiotics within 1 h was smaller in the afebrile sepsis patients (323/2076, 15.6%) than in the febrile sepsis patients (395/2156, 18.3%) (p = 0.02). In the subgroup analysis of patients with complete Hour-1 bundle performance records adjusted odds ratio of afebrile sepsis patients for 28-day mortality was 1.68 (95% Confidence interval 1.34-2.11). The febrile sepsis patients received antibiotics faster than the afebrile sepsis patients (175.5 ± 207.9 versus 209.3 ± 277.9, p < 0.01). CONCLUSIONS: Afebrile sepsis patients were associated with higher 28-day mortality compared to their febrile counterparts and were delayed in receiving antibiotics. This underscores the need for improved early detection and treatment strategies for the afebrile sepsis patients.

Prognostic Evaluation and Survival Prediction for Combined Hepatocellular-Cholangiocarcinoma Following Hepatectomy.

Purpose: This study aimed to assess prognostic factors associated with combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and to predict 5-year survival based on these factors. Materials and Methods: Patients who underwent definitive hepatectomy from 2006 to 2022 at a single institution was retrospectively analyzed. Inclusion criteria involved a pathologically confirmed diagnosis of cHCC-CCA. Results: A total of 80 patients with diagnosed cHCC-CCA were included in the analysis. The median progression-free survival (PFS) was 15.6 months, while distant metastasis-free survival (DMFS), hepatic progression-free survival (HPFS), and overall survival (OS) were 50.8, 21.5, and 85.1 months, respectively. In 52 cases of recurrence, intrahepatic recurrence was the most common initial recurrence (34/52), with distant metastasis in 17 cases. Factors associated with poor DMFS included tumor necrosis, lymphovascular invasion (LVI), perineural invasion and histologic compact type. Postoperative CA19-9, tumor necrosis, LVI, and close/positive margin were associated with poor overall survival. LVI emerged as a key factor affecting both DMFS and OS, with a 5-year OS of 93.3% for patients without LVI compared to 35.8% with LVI. Based on these factors, a nomogram predicting 3-year and 5-year DMFS and OS was developed, demonstrating high concordance with actual survival in the cohort (Harrell C-index 0.809 for OS, 0.801 for DMFS, respectively). Conclusion: The prognosis of cHCC-CCA is notably poor when combined with lymphovascular invasion. Given the significant impact of adverse features, accurate outcome prediction is crucial. Moreover, consideration of adjuvant therapy may be warranted for patients exhibiting poor survival and increased risk of local recurrence or distant metastasis.

Evidence-based clinical recommendations for hypofractionated radiotherapy: exploring efficacy and safety - Part 2. Lung (non-small cell lung cancer).

Several recent studies have investigated the use of hypofractionated radiotherapy (HFRT) for various cancers. However, HFRT for non-small cell lung cancer (NSCLC) with or without concurrent chemotherapy is not yet widely used because of concerns about serious side effects and the lack of evidence for improved treatment results. Investigations of HFRT with concurrent chemotherapy in NSCLC have usually been performed in single-arm studies and with a small number of patients, so there are not yet sufficient data. Therefore, the Korean Society for Radiation Oncology Practice Guidelines Committee planned this review article to summarize the evidence on HFRT so far and provide it to radiation oncology clinicians. In summary, HFRT has demonstrated promising results, and the reviewed data support its feasibility and comparable efficacy for the treatment of locally advanced NSCLC. The incidence and severity of esophageal toxicity have been identified as major concerns, particularly when treating large fraction sizes. Strategies, such as esophagus-sparing techniques, image guidance, and dose constraints, may help mitigate this problem and improve treatment tolerability. Continued research and clinical trials are essential to refine treatment strategies, identify optimal patient selection criteria, and enhance therapeutic outcomes.

Multi-omics analysis sandbox toolkit for swift derivations of clinically relevant genesets and biomarkers.

The utilization of multi-omics research has gained popularity in clinical investigations. However, effectively managing and merging extensive and diverse datasets presents a challenge due to its intricacy. This research introduces a Multi-Omics Analysis Sandbox Toolkit, an online platform designed to facilitate the exploration, integration, and visualization of datasets ranging from single-omics to multi-omics. This platform establishes connections between clinical data and omics information, allowing for versatile analysis and storage of both single and multi-omics data. Additionally, users can repeatedly utilize and exchange their findings within the platform. This toolkit offers diverse alternatives for data selection and gene set analysis. It also presents visualization outputs, potential candidates, and annotations. Furthermore, this platform empowers users to collaborate by sharing their datasets, analyses, and conclusions with others, thus enhancing its utility as a collaborative research tool. This Multi-Omics Analysis Sandbox Toolkit stands as a valuable asset in comprehensively grasping the influence of diverse factors in diseases and pinpointing potential biomarkers.

Trends in breast, colon, pancreatic, and uterine cancers in women during the COVID-19 pandemic in North Carolina.

IMPORTANCE: The COVID-19 pandemic led to reductions in primary care and cancer screening visits, which may delay detection of some cancers. The impact on incidence has not been fully quantified. We examined change in cancer incidence to determine how the COVID-19 pandemic may have altered the characteristics of cancers diagnosed among women. METHODS: This study included female patients aged ≥18 years and diagnosed with breast (n = 9489), colon (n = 958), pancreatic (n = 669), or uterine (n = 1991) cancer at three hospitals in North Carolina. Using interrupted time series, we compared incidence of cancers diagnosed between March 2020 and November 2020 (during pandemic) with cancers diagnosed between January 2016 and February 2020 (pre-pandemic). RESULTS: During the pandemic, incidence of breast and uterine cancers was significantly lower than expected compared to pre-pandemic (breast-18%, p = 0.03; uterine -20%, p = 0.05). Proportions of advanced pathologic stage and hormone receptor-negative breast cancers, and advanced clinical stage and large size uterine cancers were more prevalent during the pandemic. No significant changes in incidence were detected for pancreatic (-20%, p = 0.08) or colon (+14%, p = 0.30) cancers. CONCLUSION AND RELEVANCE: In women, the COVID-19 pandemic resulted in a significant reduction in the incidence of breast and uterine cancers, but not colon or pancreatic cancers. A change in the proportion of poor prognosis breast and uterine cancers suggests that some cancers that otherwise would have been diagnosed at an earlier stage will be detected in later years. Continued analysis of long-term trends is needed to understand the full impact of the pandemic on cancer incidence and outcomes.

Evidence-based clinical recommendations for hypofractionated radiotherapy: exploring efficacy and safety - Part 1. Brain and head and neck.

Advances in radiotherapy (RT) techniques, including intensity-modulated RT and image-guided RT, have allowed hypofractionation, increasing the fraction size over the conventional dose of 1.8-2.0 Gy. Hypofractionation offers advantages such as shorter treatment times, improved compliance, and under specific conditions, particularly in tumors with a low α/ß ratio, higher efficacy. It was initially explored for use in RT for prostate cancer and adjuvant RT for breast cancer, and its application has been extended to various other malignancies. Hypofractionated RT (HFRT) may also be effective in patients who are unable to undergo conventional treatment owing to poor performance status, comorbidities, or old age. The treatment of brain tumors with HFRT is relatively common because brain stereotactic radiosurgery has been performed for over two decades. However, re-irradiation of recurrent lesions and treatment of elderly or frail patients are areas under investigation. HFRT for head and neck cancer has not been widely used because of concerns regarding late toxicity. Thus, we aimed to provide a comprehensive summary of the current evidence for HFRT for brain tumors and head and neck cancer and to offer practical recommendations to clinicians faced with the challenge of choosing new treatment options.

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.

Kallistatin deficiency exacerbates neuronal damage after cardiac arrest.

The purpose of study was to evaluate that kallistatin deficiency causes excessive production of reactive oxygen species and exacerbates neuronal injury after cardiac arrest. For in vitro study, kallistatin knockdown human neuronal cells were given ischemia-reperfusion injury, and the oxidative stress and apoptosis were evaluated. For clinical study, cardiac arrest survivors admitted to the ICU were divided into the good (CPC 1-2) and poor (CPC 3-5) 6-month neurological outcome groups. The serum level of kallistatin, Nox-1, H2O2 were measured. Nox-1 and H2O2 levels were increased in the kallistatin knockdown human neuronal cells with ischemia-reperfusion injury (p < 0.001) and caspase-3 was elevated and apoptosis was promoted (SERPINA4 siRNA: p < 0.01). Among a total of 62 cardiac arrest survivors (16 good, 46 poor), serum kallistatin were lower, and Nox-1 were higher in the poor neurological group at all time points after admission to the ICU (p = 0.013 at admission; p = 0.020 at 24 h; p = 0.011 at 72 h). At 72 h, H2O2 were higher in the poor neurological group (p = 0.038). Kallistatin deficiency exacerbates neuronal ischemia-reperfusion injury and low serum kallistatin levels were associated with poor neurological outcomes in cardiac arrest survivors.

Highly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis.

Despite intensive clinical and scientific efforts, the mortality rate of sepsis remains high due to the lack of precise biomarkers for patient stratification and therapeutic guidance. Secreted human tryptophanyl-tRNA synthetase 1 (WARS1), an endogenous ligand for Toll-like receptor (TLR) 2 and TLR4 against infection, activates the genes that signify the hyperinflammatory sepsis phenotype. High plasma WARS1 levels stratified the early death of critically ill patients with sepsis, along with elevated levels of cytokines, chemokines, and lactate, as well as increased numbers of absolute neutrophils and monocytes, and higher Sequential Organ Failure Assessment (SOFA) scores. These symptoms were recapitulated in severely ill septic mice with hypercytokinemia. Further, injection of WARS1 into mildly septic mice worsened morbidity and mortality. We created an anti-human WARS1-neutralizing antibody that suppresses proinflammatory cytokine expression in marmosets with endotoxemia. Administration of this antibody into severe septic mice attenuated cytokine storm, organ failure, and early mortality. With antibiotics, the antibody almost completely prevented fatalities. These data imply that blood-circulating WARS1-guided anti-WARS1 therapy may provide a novel theranostic strategy for life-threatening systemic hyperinflammatory sepsis.

Diagnostic assessments and treatment results of well-differentiated gastric-type adenocarcinoma of the uterine cervix (Adenoma malignum): A multicenter retrospective analysis of KROG 22-03 study.

OBJECTIVE: Among cervical adenocarcinomas, well-differentiated gastric adenocarcinoma of the uterine cervix (WD-GAS), previously termed adenoma malignum (minimal deviation adenocarcinoma) is not well understood. Because of its rarity and difficulty in diagnosis, there is no standard care for WD-GAS. Thus, we conducted the first multicenter retrospective study on WD-GAS to clarify prognostic factors for long-term survival and recurrence. METHODS: Patients diagnosed with WD-GAS at eight hospitals participated in this multi-center study. Overall survival (OS) and recurrence-free survival (RFS) were calculated with the Kaplan-Meier method. Additionally, OS between the early and advanced FIGO stage groups were compared with the log-rank test. Cox regression analysis was conducted to identify significant factors associated with recurrence-free survival (RFS). RESULTS: A total of 73 patients from eight hospitals in South Korea were included in the analysis. The median follow-up period was 44.8 months, and all patients underwent curative surgical intervention as the primary treatment. Recurrence was observed in 17 patients (23.3%). Ten patients had locoregional recurrence, four patients had distant metastasis, and three patients presented with both locoregional recurrence and distant metastasis. The Cox regression analysis identified several statistically significant factors associated with RFS, including vaginal invasion (VI), parametrial invasion (PMI), resection margin (RM), and nodal and lymphovascular invasion (LVI). When considering these five factors together, patients without any of the factors exhibited recurrence-free survival (RFS) of 97.0% at three years and those with more than one of these factors had a 3-year RFS of 65.4% (P < 0.001). CONCLUSION: WD-GAS showed relatively high locoregional recurrence rate. Positive PMI, VI, RM, nodal involvement, and LVI were associated with a significant increase in recurrence or distant metastasis rates.

A remote-controlled automatic chest compression device capable of moving compression position during CPR: A pilot study in a mannequin and a swine model of cardiac arrest.

BACKGROUND: Recently, we developed a chest compression device that can move the chest compression position without interruption during CPR and be remotely controlled to minimize rescuer exposure to infectious diseases. The purpose of this study was to compare its performance with conventional mechanical CPR device in a mannequin and a swine model of cardiac arrest. MATERIALS AND METHODS: A prototype of a remote-controlled automatic chest compression device (ROSCER) that can change the chest compression position without interruption during CPR was developed, and its performance was compared with LUCAS 3 in a mannequin and a swine model of cardiac arrest. In a swine model of cardiac arrest, 16 male pigs were randomly assigned into the two groups, ROSCER CPR (n = 8) and LUCAS 3 CPR (n = 8), respectively. During 5 minutes of CPR, hemodynamic parameters including aortic pressure, right atrial pressure, coronary perfusion pressure, common carotid blood flow, and end-tidal carbon dioxide partial pressure were measured. RESULTS: In the compression performance test using a mannequin, compression depth, compression time, decompression time, and plateau time were almost equal between ROSCER and LUCAS 3. In a swine model of cardiac arrest, coronary perfusion pressure showed no difference between the two groups (p = 0.409). Systolic aortic pressure and carotid blood flow were higher in the LUCAS 3 group than in the ROSCER group during 5 minutes of CPR (p < 0.001, p = 0.008, respectively). End-tidal CO2 level of the ROSCER group was initially lower than that of the LUCAS 3 group, but was higher over time (p = 0.022). A Kaplan-Meier survival analysis for ROSC also showed no difference between the two groups (p = 0.46). CONCLUSION: The prototype of a remote-controlled automated chest compression device can move the chest compression position without interruption during CPR. In a mannequin and a swine model of cardiac arrest, the device showed no inferior performance to a conventional mechanical CPR device.

SECRETED TRYPTOPHANYL-tRNA SYNTHETASE 1 IS A PROGNOSTIC MARKER IN SEPSIS PATIENTS WITHOUT MONOCYTOPENIA.

ABSTRACT: Objective: This study aimed to test whether the prognostic value of tryptophanyl-tRNA synthetase 1 (WARS1) for 28-day mortality in patients with sepsis was affected by monocytopenia. Methods: A prospective analysis of retrospectively collected samples from 74 sepsis patients was performed. WARS1, C-reactive protein (CRP), and procalcitonin were measured at admission and 24 and 72 h after admission. The prognostic value of WARS1, CRP, and procalcitonin for 28-day mortality was compared using repeated measures analysis of variance and the area under the receiver operating characteristic curve (AUROC). All analyses were performed in patients with or without monocytopenia, defined as an absolute monocyte count less than 0.1 × 10 9 cells/L. Results: WARS1 levels differed significantly between survivors and nonsurvivors when all patients and patients without monocytopenia were assessed ( P = 0.008, P < 0.001, respectively). In contrast, the WARS1 level did not differ between survivors and nonsurvivors with monocytopenia. C-reactive protein and procalcitonin levels were not different between survivors and nonsurvivors regardless of whether they had monocytopenia. The AUROCs of WARS1 at admission and 24 h for mortality were significantly higher in patients without monocytopenia (0.830, 0.818) than in patients with monocytopenia (0.232, 0.196; P < 0.001, both). When patients without monocytopenia were analyzed, the AUROCs of WARS1 for mortality were 0.830 and 0.818 at admission and 24 h, respectively, which were significantly higher than those of CRP (0.586, 0.653) and procalcitonin (0.456, 0.453) at the same time points ( P = 0.024 and 0.034, respectively). Conclusion: WARS1 is a useful biomarker for prognosis in sepsis patients without monocytopenia.

A general one-pot, solvent-free solid-state synthesis of biocompatible metal nanoparticles using dextran as a tool: Evaluation of their catalytic and anti-cancer activities.

We propose a general green method coupled with a solid-state vibration ball milling strategy for the synthesis of various metal nanoparticles (MNPs), employing a polymeric carbohydrate dextran (Dx) as a reducing and stabilizing molecule. The synthesis of size-controlled Dx-based MNPs (Dx@MNPs), featuring comparatively narrow size distributions, was achieved by controlling the mass ratio of the reactants, reaction time, frequency of the vibration ball mill, and molecular weight of Dx. Notably, this process was conducted at ambient temperatures, without the aid of solvents and accelerating agents, such as NaOH, and conventional reductants as well as stabilizers. Thermal properties of the resulting Dx@MNPs nanocomposites were extensively investigated, highlighting the influence of metal precursors and reaction conditions. Furthermore, the catalytic activity of synthesized nanocomposites was evaluated through the reduction reaction of 4-nitrophenol, exhibiting great catalytic performance. In addition, we demonstrated the excellent biocompatibility of the as-prepared Dx@MNPs toward human embryonic kidney (HEK-293) cells, revealing their potential for anticancer activities. This novel green method for synthesizing biocompatible MNPs with Dx expands the horizons of carbohydrate-based materials as well as MNP nanocomposites for large-scale synthesis and controlled size distribution for various industrial and biomedical applications.

Total neoadjuvant therapy with short-course radiotherapy Versus long-course neoadjuvant chemoradiotherapy in Locally Advanced Rectal cancer, Korean trial (TV-LARK trial): study protocol of a multicentre randomized controlled trial.

BACKGROUND: For locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT) may enhance tumour response, reduce recurrence, and improve patient compliance compared to upfront surgery. Recent studies have shown that chemoradiotherapy (CRT) followed by consolidation chemotherapy leads to higher rate of pathologic complete response (pCR) than induction chemotherapy followed by CRT. However, an optimal TNT regimen that maximise the pCR rate and minimise toxicity has not been established. Therefore, the aim of this trial was to investigate whether preoperative short-course radiotherapy followed by chemotherapy with four cycles of CAPOX can double the pCR rate compared to a standard schedule of long-course preoperative CRT in patients with LARC. METHODS: This is a multi-centre, prospective, open label, randomised controlled trial. Patients with clinical primary tumour stage 3 and higher or regional node-involved rectal cancer located within 10 cm from the anal verge were randomly assigned equally to short-course radiotherapy (25 Gy in 5 fractions over 1 week) followed by four cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) (TNT) or CRT (50.4 Gy in 28 fractions over 5 weeks, concurrently with concomitant oral capecitabine 825 mg/m2 twice a day). After preoperative treatment, total mesorectal excision was performed 2-4 weeks in the TNT group and 6-10 weeks in the CRT group, followed by optional additional adjuvant chemotherapy. The primary endpoint is the pCR rate, and secondary endpoints include disease-related treatment failure, quality of life, and cost-effectiveness. Assuming a pCR rate of 28% and 15% in the TNT and CRT groups, respectively, and one-side alpha error rate of 0.025 and power of 80%, 348 patients will be enrolled considering 10% dropout rate. DISCUSSION: The TV-LARK trial will evaluate the superiority of employed TNT regimen against the standard CRT regimen for patients with LARC. We aimed to identify a TNT regimen that will improve the pCR rate and decrease systemic recurrence in these patients. TRIAL REGISTRATION: Cris.nih.go.kr ID: KCT0007169 (April 08, 2022). The posted information will be updated as needed to reflect the protocol amendments and study progress.

Comparison of initial and sequential salvage brain-directed treatment in patients with 1-4 vs. 5-10 brain metastases from breast cancer (KROG 16-12).

PURPOSE: We aimed to compare the initial and salvage brain-directed treatment and overall survival (OS) between patients with 1-4 brain metastases (BMs) and those with 5-10 from breast cancer (BC). We also organized a decision tree to select the initial whole-brain radiotherapy (WBRT) for these patients. METHODS: Between 2008 and 2014, 471 patients were diagnosed with 1-10 BMs. They were divided into two groups based on the number of BM: 1-4 BMs (n = 337) and 5-10 BMs (n = 134). Median follow-up duration was 14.0 months. RESULTS: Stereotactic radiosurgery (SRS)/fractionated stereotactic radiotherapy (FSRT) was the most common treatment modality (n = 120, 36%) in the 1-4 BMs group. In contrast, 80% (n = 107) of patients with 5-10 BMs were treated with WBRT. The median OS of the entire cohort, 1-4 BMs, and 5-10 BMs was 18.0, 20.9, and 13.9 months, respectively. In the multivariate analysis, the number of BM and WBRT were not associated with OS, whereas triple-negative BC and extracranial metastasis decreased OS. Physicians determined the initial WBRT based on four variables in the following order: number and location of BM, primary tumor control, and performance status. Salvage brain-directed treatment (n = 184), mainly SRS/FSRT (n = 109, 59%), prolonged OS by a median of 14.3 months. CONCLUSION: The initial brain-directed treatment differed notably according to the number of BM, which was chosen based on four clinical factors. In patients with ≤ 10 BMs, the number of BM and WBRT did not affect OS. The major salvage brain-directed treatment modality was SRS/FSRT and increased OS.

Battery-Free, Wireless, Cuff-Type, Multimodal Physical Sensor for Continuous Temperature and Strain Monitoring of Nerve.

Peripheral nerve injuries cause various disabilities related to loss of motor and sensory functions. The treatment of these injuries typically requires surgical operations for improving functional recovery of the nerve. However, capabilities for continuous nerve monitoring remain a challenge. Herein, a battery-free, wireless, cuff-type, implantable, multimodal physical sensing platform for continuous in vivo monitoring of temperature and strain from the injured nerve is introduced. The thin, soft temperature, and strain sensors wrapped around the nerve exhibit good sensitivity, excellent stability, high linearity, and minimum hysteresis in relevant ranges. In particular, the strain sensor integrated with circuits for temperature compensation provides reliable, accurate strain monitoring with negligible temperature dependence. The system enables power harvesting and data communication to wireless, multiple implanted devices wrapped around the nerve. Experimental evaluations, verified by numerical simulations, with animal tests, demonstrate the feasibility and stability of the sensor system, which has great potential for continuous in vivo nerve monitoring from an early stage to complete regeneration.

Treatment outcomes of stereotactic body radiation therapy for pulmonary metastasis from sarcoma: a multicenter, retrospective study.

PURPOSE: The aim of this study was to evaluate the treatment outcomes and potential dose-response relationship of stereotactic body radiation therapy (SBRT) for pulmonary metastasis of sarcoma. MATERIALS AND METHODS: A retrospective review of 39 patients and 71 lesions treated with SBRT from two institutions was performed. The patients had oligometastatic or oligoprogressive disease, or were receiving palliation. Doses of 20-60 Gy were delivered in 1-5 fractions. The local control per tumor (LCpT) was evaluated according to the biologically effective dose with an α/ß ratio of 10 (BED10) of the prescribed dose (BED10 ≥ 100 Gy vs. BED10 < 100 Gy). Clinical outcomes per patient, including local control per patient (LCpP), pulmonary progression-free rate (PPFR), any progression-free rate (APFR), and overall survival (OS) were investigated. RESULTS: The median follow-up period was 27.2 months. The 1-, 2-, and 3-year LCpT rates for the entire cohort were 100.0%, 88.3%, and 73.6%, respectively. There was no observed difference in LCpT between the two BED10 groups (p = 0.180). The 3-year LCpP, PPFR, APFR, and OS rates were 78.1%, 22.7%, 12.9%, and 83.7%, respectively. Five (12.8%) patients with oligometastasis had long-term disease-free intervals, with a median survival period of 40.7 months. Factors that were associated with a worse prognosis were oligoprogression (vs. oligometastasis), multiple pulmonary metastases, and simultaneous extrathoracic metastasis. CONCLUSION: SBRT for pulmonary metastasis of sarcoma is effective. Some selected patients may achieve durable response. Considerations of SBRT indication and disease extent may be needed as they may influence the prognosis.

Evaluation of Radiation Sensitivity Differences in Mouse Liver Tumor Organoids Using CRISPR/Cas9-Mediated Gene Mutation.

BACKGROUND: To assess the radiosensitivity of liver tumors harboring different genetic mutations, mouse liver tumors were generated in vivo through the hydrodynamic injection of clustered regularly interspaced short palindromic repeat/caspase 9 (CRISPR/Cas9) constructs encoding single-guide RNAs (sgRNAs) targeting Tp53, Pten, Nf1, Nf2, Tsc2, Cdkn2a, or Rb1. METHODS: The plasmid vectors were delivered to the liver of adult C57BL/6 mice via hydrodynamic tail vein injection. The vectors were injected into 10 mice in each group. Organoids were generated from mouse liver tumors. The radiation response of the organoids was assessed using an ATP cell viability assay. RESULTS: The mean survival period of mice injected with vectors targeting Nf2 (4.8 months) was lower than that of other mice. Hematoxylin and eosin staining, immunohistochemical (IHC) staining, and target sequencing analyses revealed that mouse liver tumors harbored the expected mutations. Tumor organoids were established from mouse liver tumors. Histological evaluation revealed marked morphological similarities between the mouse liver tumors and the generated tumor organoids. Moreover, IHC staining indicated that the parental tumor protein expression pattern was maintained in the organoids. The results of the ATP cell viability assay revealed that the tumor organoids with mutated Nf2 were more resistant to high-dose radiation than those with other gene mutations. CONCLUSIONS: This study developed a radiation response assessment system for mouse tumors with mutant target genes using CRISPR/Cas9 and organoids. The Tp53 and Pten double mutation in combination with the Nf2 mutation increased the radiation resistance of tumors. The system used in this study can aid in elucidating the mechanism underlying differential intrinsic radiation sensitivity of individual tumors.

Whole-Genome Sequencing Reveals Mutational Signatures Related to Radiation-Induced Sarcomas and DNA-Damage-Repair Pathways.

Radiation-induced sarcoma (RIS) is a rare but serious late complication arising from radiotherapy. Despite unfavorable clinical outcomes, the genomic footprints of ionizing radiation in RIS development remain largely unknown. Hence, this study aimed to characterize RIS genomes and the genomic alterations in them. We analyzed whole-genome sequencing in 11 RIS genomes matched with normal genomes to identify somatic alterations potentially associated with RIS development. Furthermore, the abundance of mutations, mutation signatures, and structural variants in RIS were compared with those in radiation-naïve spontaneous sarcomas. The mutation abundance in RIS genomes, including one hypermutated genome, was variable. Cancer-related genes might show different types of genomic alterations. For instance, NF1, NF2, NOTCH1, NOTCH2, PIK3CA, RB1, and TP53 showed singleton somatic mutations; MYC, CDKN2A, RB1, and NF1 showed recurrent copy number alterations; and NF2, ARID1B, and RAD51B showed recurrent structural variations. The genomic footprints of nonhomologous end joining are prevalent at indels of RIS genomes compared with those in spontaneous sarcoma genomes, representing the genomic hallmark of RIS genomes. In addition, frequent chromothripsis was identified along with predisposing germline variants in the DNA-damage-repair pathways in RIS genomes. The characterization of RIS genomes on a whole-genome sequencing scale highlighted that the nonhomologous end joining pathway was associated with tumorigenesis, and it might pave the way for the development of advanced diagnostic and therapeutic strategies for RIS.