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.

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.

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.

Variable Stiffness and Damping Mechanism for CPR Manikin to Simulate Mechanical Properties of Human Chest.

OBJECTIVE: This study introduces a novel system that can simulate diverse mechanical properties of the human chest to enhance the experience of CPR training by reflecting realistic chest conditions of patients. METHODS: The proposed system consists of Variable stiffness mechanisms (VSMs) and Variable damper (VD) utilizing stretching silicone bands and dashpot dampers with controllable valves to modulate stiffness and damping, respectively. Cyclic loading was applied with a robot manipulator to the system. Compression force and displacement were measured and analyzed to evaluate the system's mechanical response. Long-term stability of the system was also validated. RESULTS: A non-linear response of the human chest under compression is realized through this design. Test results indicated non-linear force-displacement curves with hysteresis, similar to those observed in the chest of patients. Controlling the VSM and VD allowed for intentional changes in the slope and area of curves that are related to stiffness and damping, respectively. Stiffness and damping of the system were computed using performance test results. The stiffness ranged from 5.34 N/mm to 13.59 N/mm and the damping ranges from 0.127 N[Formula: see text] s/mm to 0.511 N[Formula: see text] s/mm. These properties cover a significant portion of the reported mechanical properties of the human chests. The system demonstrated satisfactory stability even when it was subjected to maximum stiffness conditions of the long-term compression test. CONCLUSION: The system is capable of emulating the mechanical properties and behavior of the human chests, thereby enhancing the CPR training experience.

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.

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.

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.

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.

Development of artificial intelligence-driven biosignal-sensitive cardiopulmonary resuscitation robot.

AIM OF THE STUDY: We evaluated whether an artificial intelligence (AI)-driven robot cardiopulmonary resuscitation (CPR) could improve hemodynamic parameters and clinical outcomes. METHODS: We developed an AI-driven CPR robot which utilizes an integrated feedback system with an AI model predicting carotid blood flow (CBF). Twelve pigs were assigned to the AI robot group (n = 6) and the LUCAS 3 group (n = 6). They underwent 6 min of CPR after 7 min of ventricular fibrillation. In the AI robot group, the robot explored for the optimal compression position, depth and rate during the first 270-second period, and continued CPR with the optimal setup during the next 90-second period and beyond. The primary outcome was CBF during the last 90-second period. The secondary outcomes were coronary perfusion pressure (CPP), end-tidal carbon dioxide level (ETCO2) and return of spontaneous circulation (ROSC). RESULTS: The AI model's prediction performance was excellent (Pearson correlation coefficient = 0.98). CBF did not differ between the two groups [estimate and standard error (SE), -23.210 ± 20.193, P = 0.250]. CPP, ETCO2 level and rate of ROSC also did not show difference [estimate and SE, -0.214 ± 7.245, P = 0.976 for CPP; estimate and SE, 1.745 ± 3.199, P = 0.585 for ETCO2; 5/6 (83.3%) vs. 4/6 (66.7%), P = 1.000 for ROSC). CONCLUSION: This study provides proof of concept that an AI-driven CPR robot in porcine cardiac arrest is feasible. Compared to a LUCAS 3, an AI-driven CPR robot produced comparable hemodynamic and clinical outcomes.

Removal of circulating mitochondrial N-formyl peptides via immobilized antibody therapy restores sepsis-induced neutrophil dysfunction.

During recovery from septic shock, circulating mitochondrial N-formyl peptides (mtFPs) predispose to secondary infection by occupying formyl peptide receptor 1 (FPR1) on the neutrophil (polymorphonuclear leukocyte, PMN) membrane, suppressing cytosolic calcium ([Ca2+]i)-dependent responses to secondarily encountered bacteria. However, no study has yet investigated therapeutic clearance of circulating mtFPs in clinical settings. Thus, we studied how to remove mtFPs from septic-shock plasma and whether such removal could preserve cell-surface FPR1 and restore sepsis-induced PMN dysfunction by normalizing [Ca2+]i flux. In in vitro model systems, mtFP removal rescued PMN FPR1-mediated [Ca2+]i flux and chemotaxis that had been suppressed by prior mtFP exposure. However, PMN functional recovery occurred in a stepwise fashion over 30 - 90 minutes. Intracellular Ca2+-calmodulin appears to contribute to this delay. In ex vivo model systems using blood samples obtained from patients with septic shock, anti-mtFP antibodies alone failed to eliminate mtFPs from septic-shock plasma or inhibit mtFP activity. We therefore created a beads-based anti-mtFP antibody cocktail (bb-AMfpA) by combining protein A/sepharose with antibodies specific for the most potent human mtFP chemoattractants. The bb-AMfpA treatment successfully removed those active mtFPs from septic-shock plasma. Furthermore, the bb-AMfpA treatment significantly restored chemotactic and bactericidal dysfunction of PMNs obtained from patients with septic shock who developed secondary infections. By clearing circulating mtFPs, the immobilized anti-mtFP antibody therapy prevented mtFP interactions with surface FPR1, thereby restoring [Ca2+]i-dependent PMN antimicrobial function in clinical septic-shock environments. This approach may help prevent the development of secondary, nosocomial infections in patients recovering from septic shock.

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.

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.

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.

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.