The Association between Low Fetal Fraction of Non-Invasive Prenatal Testing and Adverse Pregnancy Outcomes for Placental Compromise.

(1) Background: Non-invasive prenatal testing (NIPT) is a screening test for fetal aneuploidy using cell-free fetal DNA. The fetal fragments (FF) of cell-free DNA (cfDNA) are derived from apoptotic trophoblast of the placenta. The level of fetal cfDNA is known to be influenced by gestational age, multiple pregnancies, maternal weight, and height. (2) Methods: This study is a single-center retrospective observational study which examines the relationship between the fetal fraction (FF) of cell-free DNA in non-invasive prenatal testing (NIPT) and adverse pregnancy outcomes in singleton pregnancies. A total of 1393 samples were collected between 10 weeks and 6 days, and 25 weeks and 3 days of gestation. (3) Results: Hypertensive disease of pregnancy (HDP) occurred more frequently in the low FF group than the normal FF group (5.17% vs. 1.91%, p = 0.001). Although the rates of small for gestational age (SGA) and placental abruption did not significantly differ between groups, the composite outcome was significantly higher in the low FF group (7.76% vs. 3.64%, p = 0.002). Furthermore, women who later experienced complications such as HDP or gestational diabetes mellitus (GDM) had significantly lower plasma FF levels compared to those without complications (p < 0.001). After adjustments, the low FF group exhibited a significantly higher likelihood of placental compromise (adjusted odds ratio: 1.946). (4) Conclusions: Low FF in NIPT during the first and early second trimesters is associated with adverse pregnancy outcomes, particularly HDP, suggesting its potential as a predictive marker for such outcomes.

Advanced Immunomodulatory Biomaterials for Therapeutic Applications.

The multifaceted biological defense system modulating complex immune responses against pathogens and foreign materials plays a critical role in tissue homeostasis and disease progression. Recently developed biomaterials that can specifically regulate immune responses, nanoparticles, graphene, and functional hydrogels have contributed to the advancement of tissue engineering as well as disease treatment. The interaction between innate and adaptive immunity, collectively determining immune responses, can be regulated by mechanobiological recognition and adaptation of immune cells to the extracellular microenvironment. Therefore, applying immunomodulation to tissue regeneration and cancer therapy involves manipulating the properties of biomaterials by tailoring their composition in the context of the immune system. This review provides a comprehensive overview of how the physicochemical attributes of biomaterials determine immune responses, focusing on the physical properties that influence innate and adaptive immunity. This review also underscores the critical aspect of biomaterial-based immune engineering for the development of novel therapeutics and emphasizes the importance of understanding the biomaterials-mediated immunological mechanisms and their role in modulating the immune system.

MRI Scoring Systems for Predicting Isocitrate Dehydrogenase Mutation and Chromosome 1p/19q Codeletion in Adult-type Diffuse Glioma Lacking Contrast Enhancement.

Background According to 2021 World Health Organization criteria, adult-type diffuse gliomas include glioblastoma, isocitrate dehydrogenase (IDH)-wildtype; oligodendroglioma, IDH-mutant and 1p/19q-codeleted; and astrocytoma, IDH-mutant, even when contrast enhancement is lacking. Purpose To develop and validate simple scoring systems for predicting IDH and subsequent 1p/19q codeletion status in gliomas without contrast enhancement using standard clinical MRI sequences. Materials and Methods This retrospective study included adult-type diffuse gliomas lacking contrast at contrast-enhanced MRI from two tertiary referral hospitals between January 2012 and April 2022 with diagnoses confirmed at pathology. IDH status was predicted primarily by using T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign, followed by 1p/19q codeletion prediction. A visual rating of MRI features, apparent diffusion coefficient (ADC) ratio, and relative cerebral blood volume was measured. Scoring systems were developed through univariable and multivariable logistic regressions and underwent calibration and discrimination, including internal and external validation. Results For the internal validation cohort, 237 patients were included (mean age, 44.4 years ± 14.4 [SD]; 136 male patients; 193 patients in IDH prediction and 163 patients in 1p/19q prediction). For the external validation cohort, 35 patients were included (46.1 years ± 15.3; 20 male patients; 28 patients in IDH prediction and 24 patients in 1p/19q prediction). The T2-FLAIR mismatch sign demonstrated 100% specificity and 100% positive predictive value for IDH mutation. IDH status prediction scoring system for tumors without mismatch sign included age, ADC ratio, and morphologic characteristics, whereas 1p/19q codeletion prediction for IDH-mutant gliomas included ADC ratio, cortical involvement, and mismatch sign. For IDH status and 1p/19q codeletion prediction, bootstrap-corrected areas under the receiver operating characteristic curve were 0.86 (95% CI: 0.81, 0.90) and 0.73 (95% CI: 0.65, 0.81), respectively, whereas at external validation they were 0.99 (95% CI: 0.98, 1.0) and 0.88 (95% CI: 0.63, 1.0). Conclusion The T2-FLAIR mismatch sign and scoring systems using standard clinical MRI predicted IDH and 1p/19q codeletion status in gliomas lacking contrast enhancement. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Badve and Hodges in this issue.

Exploration of neuroanatomical characteristics to differentiate prodromal Alzheimer's disease from cognitively unimpaired amyloid-positive individuals.

Differentiating clinical stages based solely on positive findings from amyloid PET is challenging. We aimed to investigate the neuroanatomical characteristics at the whole-brain level that differentiate prodromal Alzheimer's disease (AD) from cognitively unimpaired amyloid-positive individuals (CU A+) in relation to amyloid deposition and regional atrophy. We included 45 CU A+ participants and 135 participants with amyloid-positive prodromal AD matched 1:3 by age, sex, and education. All participants underwent 18F-florbetaben positron emission tomography and 3D structural T1-weighted magnetic resonance imaging. We compared the standardized uptake value ratios (SUVRs) and volumes in 80 regions of interest (ROIs) between CU A+ and prodromal AD groups using independent t-tests, and employed the least absolute selection and shrinkage operator (LASSO) logistic regression model to identify ROIs associated with prodromal AD in relation to amyloid deposition, regional atrophy, and their interaction. After applying False Discovery Rate correction at < 0.1, there were no differences in global and regional SUVR between CU A+ and prodromal AD groups. Regional volume differences between the two groups were observed in the amygdala, hippocampus, entorhinal cortex, insula, parahippocampal gyrus, and inferior temporal and parietal cortices. LASSO logistic regression model showed significant associations between prodromal AD and atrophy in the entorhinal cortex, inferior parietal cortex, both amygdalae, and left hippocampus. The mean SUVR in the right superior parietal cortex (beta coefficient = 0.0172) and its interaction with the regional volume (0.0672) were also selected in the LASSO model. The mean SUVR in the right superior parietal cortex was associated with an increased likelihood of prodromal AD (Odds ratio [OR] 1.602, p = 0.014), particularly in participants with lower regional volume (OR 3.389, p < 0.001). Only regional volume differences, not amyloid deposition, were observed between CU A+ and prodromal AD. The reduced volume in the superior parietal cortex may play a significant role in the progression to prodromal AD through its interaction with amyloid deposition in that region.

Inhibition of DAPK3 Suppresses Radiation-Induced Cellular Senescence by Activation of a PGC1α-Dependent Metabolism Pathway in Brain Endothelial Cells.

In the brain, environmental changes, such as neuroinflammation, can induce senescence, characterized by the decreased proliferation of neurons and dendrites and synaptic and vascular damage, resulting in cognitive decline. Senescence promotes neuroinflammatory disorders by senescence-associated secretory phenotypes and reactive oxygen species. In human brain microvascular endothelial cells (HBMVECs), we demonstrate that chronological aging and irradiation increase death-associated protein kinase 3 (DAPK3) expression. To confirm the role of DAPK3 in HBMVEC senescence, we disrupted DAPK3 activity using small interfering RNA (siRNA) or a dominant-negative mutant (DAPK3-P216S), which reduced cellular senescence phenotypes, as assessed by changes in tube formation, senescence-associated beta-galactosidase activity, and cell proliferation. In endothelial cells, DAPK3 promotes cellular senescence by regulating the phosphorylation and inactivation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) via the protein kinase B pathway, resulting in the decreased expression of mitochondrial metabolism-associated genes, such as ATP5G1, BDNF, and COX5A. Our studies show that DAPK3 is involved in cellular senescence and PGC1α regulation, suggesting that DAPK3 regulation may be important for treating aging-related brain diseases or the response to radiation therapy.

Toxicology and safety study of L-tryptophan and its impurities for use in swine.

L-tryptophan, an essential amino acid for physiological processes, metabolism, development, and growth of organisms, is widely utilized in animal nutrition and human health as a feed additive and nutritional supplement, respectively. Despite its known benefits, safety concerns have arisen due to an eosinophilia-myalgia syndrome (EMS) outbreak linked to L-tryptophan consumed by humans. Extensive research has established that the EMS outbreak was caused by an L-tryptophan product that contained certain impurities. Therefore, safety validations are imperative to endorse the use of L-tryptophan as a supplement or a feed additive. This study was conducted in tertiary hybrid [(Landrace × Yorkshire) × Duroc] pigs to assess general toxicity and potential risks for EMS-related symptoms associated with L-tryptophan used as a feed additive. Our investigation elucidated the relationship between L-tryptophan and EMS in swine. No mortalities or clinical signs were observed in any animals during the administration period, and the test substance did not induce toxic effects. Hematological analysis and histopathological examination revealed no changes in EMS-related parameters, such as eosinophil counts, lung lesions, skin lesions, or muscle atrophy. Furthermore, no test substance-related changes occurred in other general toxicological parameters. Through analyzing the tissues and organs of swine, most of the L-tryptophan impurities that may cause EMS were not retained. Based on these findings, we concluded that incorporating L-tryptophan and its impurities into the diet does not induce EMS in swine. Consequently, L-tryptophan may be used as a feed additive throughout all growth stages of swine without safety concerns.

Novel Amidine Derivative K1586 Sensitizes Colorectal Cancer Cells to Ionizing Radiation by Inducing Chk1 Instability.

Checkpoint kinase 1 (Chk1) is a key mediator of the DNA damage response that regulates cell cycle progression, DNA damage repair, and DNA replication. Small-molecule Chk1 inhibitors sensitize cancer cells to genotoxic agents and have shown preclinical activity as single agents in cancers characterized by high levels of replication stress. However, the underlying genetic determinants of Chk1-inhibitor sensitivity remain unclear. Although treatment options for advanced colorectal cancer are limited, radiotherapy is effective. Here, we report that exposure to a novel amidine derivative, K1586, leads to an initial reduction in the proliferative potential of colorectal cancer cells. Cell cycle analysis revealed that the length of the G2/M phase increased with K1586 exposure as a result of Chk1 instability. Exposure to K1586 enhanced the degradation of Chk1 in a time- and dose-dependent manner, increasing replication stress and sensitizing colorectal cancer cells to radiation. Taken together, the results suggest that a novel amidine derivative may have potential as a radiotherapy-sensitization agent that targets Chk1.

Brain-Permeable Immunoproteasome-Targeting Macrocyclic Peptide Epoxyketones for Alzheimer's Disease.

Previously, we demonstrated that linear peptide epoxyketones targeting the immunoproteasome (iP) could ameliorate cognitive deficits in mouse models of Alzheimer's disease (AD) independently of amyloid deposition. We also reported the first iP-targeting macrocyclic peptide epoxyketones, which exhibit improved metabolic stability compared with their linear counterparts. Here, we prepared additional macrocyclic peptide epoxyketones and compared them with existing macrocyclic iP inhibitors by assessing Caco2 cell-based permeability and microsomal stability, providing the four best macrocyclic iP inhibitors. We then evaluated the four compounds using the Ames test and the potency assays in BV2 cells, selecting compound 5 as our AD drug lead. When 5 was administered intravenously (40 mg/kg) or orally (150 mg/kg) into healthy BALB/c mice, we observed considerable iP inhibition in the mouse brain, indicating good blood-brain barrier permeability and target engagement. Combined results suggest that 5 is a promising AD drug lead that may need further investigation.

Imaging Genomics of Glioma Revisited: Analytic Methods to Understand Spatial and Temporal Heterogeneity.

An improved understanding of the cellular and molecular biologic processes responsible for brain tumor development, growth, and resistance to therapy is fundamental to improving clinical outcomes. Imaging genomics is the study of the relationships between microscopic, genetic, and molecular biologic features and macroscopic imaging features. Imaging genomics is beginning to shift clinical paradigms for diagnosing and treating brain tumors. This article provides an overview of imaging genomics in gliomas, in which imaging data including hallmarks such as IDH-mutation, MGMT methylation, and EGFR-mutation status can provide critical insights into the pretreatment and posttreatment stages. This article will accomplish the following: 1) review the methods used in imaging genomics, including visual analysis, quantitative analysis, and radiomics analysis; 2) recommend suitable analytic methods for imaging genomics according to biologic characteristics; 3) discuss the clinical applicability of imaging genomics; and 4) introduce subregional tumor habitat analysis with the goal of guiding future radiogenetics research endeavors toward translation into critically needed clinical applications.

COVID-19 (SARS-CoV-2) mRNA vaccination does not affect basal sex hormone levels (follicle-stimulating hormone, luteinizing hormone, estradiol) in reproductive-age women.

Objective: People vaccinated with the coronavirus disease 2019 (COVID-19) (severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2]) mRNA vaccine have reported experiencing various adverse effects. For instance, reproductive-age women have presented with complaints of abnormal uterine bleeding or menstrual cycle changes. We speculated that differences in basal sex hormone levels before and after vaccination may be present in women who experienced irregular bleeding or menstrual cycle changes; thus, this study aimed to investigate the differences in basal sex hormone levels of women before and after two doses of SARS-CoV-2 mRNA vaccination. Methods: This retrospective study included patients who received SARS-CoV-2 mRNA vaccines between January 2021 and February 2022 at a single center. In an outpatient setting, patients were queried regarding their menstrual cycle, the date of SARS-CoV-2 mRNA vaccination, vaccination type, and vaccination side effects. Differences in basal hormone levels (menstrual cycle days 2-3, follicle-stimulating hormone [FSH], luteinizing hormone [LH], and estradiol) before and after vaccination were compared. Results: Among the 326 patients, patients with no laboratory records of the hormones were excluded. The median time interval between SARS-CoV-2 mRNA vaccination and the laboratory test day was 79 days (interquartile range, 44 to 127). A comparative analysis of these hormones before and after vaccination revealed no significant differences. Subgroup analyses based on age and reported adverse events also found no statistically significant differences. Conclusion: This study showed no significant differences in basal hormone levels (FSH, LH, and estradiol) before and after SARS-CoV-2 mRNA vaccination.

Deep learning-based metastasis detection in patients with lung cancer to enhance reproducibility and reduce workload in brain metastasis screening with MRI: a multi-center study.

OBJECTIVES: To assess whether a deep learning-based system (DLS) with black-blood imaging for brain metastasis (BM) improves the diagnostic workflow in a multi-center setting. MATERIALS AND METHODS: In this retrospective study, a DLS was developed in 101 patients and validated on 264 consecutive patients (with lung cancer) having newly developed BM from two tertiary university hospitals, which performed black-blood imaging between January 2020 and April 2021. Four neuroradiologists independently evaluated BM either with segmented masks and BM counts provided (with DLS) or not provided (without DLS) on a clinical trial imaging management system (CTIMS). To assess reading reproducibility, BM count agreement between the readers and the reference standard were calculated using limits of agreement (LoA). Readers' workload was assessed with reading time, which was automatically measured on CTIMS, and were compared between with and without DLS using linear mixed models considering the imaging center. RESULTS: In the validation cohort, the detection sensitivity and positive predictive value of the DLS were 90.2% (95% confidence interval [CI]: 88.1-92.2) and 88.2% (95% CI: 85.7-90.4), respectively. The difference between the readers and the reference counts was larger without DLS (LoA: -0.281, 95% CI: -2.888, 2.325) than with DLS (LoA: -0.163, 95% CI: -2.692, 2.367). The reading time was reduced from mean 66.9 s (interquartile range: 43.2-90.6) to 57.3 s (interquartile range: 33.6-81.0) (P <.001) in the with DLS group, regardless of the imaging center. CONCLUSION: Deep learning-based BM detection and counting with black-blood imaging improved reproducibility and reduced reading time, on multi-center validation.

Improving Diagnostic Performance of MRI for Temporal Lobe Epilepsy With Deep Learning-Based Image Reconstruction in Patients With Suspected Focal Epilepsy.

OBJECTIVE: To evaluate the diagnostic performance and image quality of 1.5-mm slice thickness MRI with deep learning-based image reconstruction (1.5-mm MRI + DLR) compared to routine 3-mm slice thickness MRI (routine MRI) and 1.5-mm slice thickness MRI without DLR (1.5-mm MRI without DLR) for evaluating temporal lobe epilepsy (TLE). MATERIALS AND METHODS: This retrospective study included 117 MR image sets comprising 1.5-mm MRI + DLR, 1.5-mm MRI without DLR, and routine MRI from 117 consecutive patients (mean age, 41 years; 61 female; 34 patients with TLE and 83 without TLE). Two neuroradiologists evaluated the presence of hippocampal or temporal lobe lesions, volume loss, signal abnormalities, loss of internal structure of the hippocampus, and lesion conspicuity in the temporal lobe. Reference standards for TLE were independently constructed by neurologists using clinical and radiological findings. Subjective image quality, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were analyzed. Performance in diagnosing TLE, lesion findings, and image quality were compared among the three protocols. RESULTS: The pooled sensitivity of 1.5-mm MRI + DLR (91.2%) for diagnosing TLE was higher than that of routine MRI (72.1%, P < 0.001). In the subgroup analysis, 1.5-mm MRI + DLR showed higher sensitivity for hippocampal lesions than routine MRI (92.7% vs. 75.0%, P = 0.001), with improved depiction of hippocampal T2 high signal intensity change (P = 0.016) and loss of internal structure (P < 0.001). However, the pooled specificity of 1.5-mm MRI + DLR (76.5%) was lower than that of routine MRI (89.2%, P = 0.004). Compared with 1.5-mm MRI without DLR, 1.5-mm MRI + DLR resulted in significantly improved pooled accuracy (91.2% vs. 73.1%, P = 0.010), image quality, SNR, and CNR (all, P < 0.001). CONCLUSION: The use of 1.5-mm MRI + DLR enhanced the performance of MRI in diagnosing TLE, particularly in hippocampal evaluation, because of improved depiction of hippocampal abnormalities and enhanced image quality.

Durvalumab Consolidation After Chemoradiotherapy in Elderly Patients With Unresectable Stage III NSCLC: A Real-World Multicenter Study.

BACKGROUND: The PACIFIC trial demonstrated survival benefit of durvalumab after concurrent chemoradiotherapy (CCRT) in unresectable stage III non-small-cell lung cancer. Data on the effectiveness and safety of durvalumab in elderly patients is lacking. METHODS: This retrospective study was conducted between September 2017 and September 2022. Progression-free survival (PFS), overall survival (OS), recurrence patterns, first subsequent treatment after recurrence, factors associated with survival outcomes, and adverse events (AEs) were compared. RESULTS: Of the 286 patients, 120 (42.0%) were ≥ 70 years and 166 (58.0%) were < 70 years. The median PFS (17.7 vs. 19.4 months; P = .43) and median OS (35.7 months vs. not reached; P = .13) were similar between 2 groups. Proportion of patients who completed durvalumab was lower in elderly patients (27.5% vs. 39.2%; P = .040). In elderly patients, ECOG PS 0 or 1 was associated with better PFS, and being male and having received a cisplatin-based regimen during CCRT were factors associated with better and worse OS, respectively. In patients aged < 70 years, a PD-L1 ≥ 50% was associated with improved PFS and OS. Elderly patients experienced more treatment-related AEs, grade 3/4 AEs, permanent discontinuation of durvalumab, and treatment-related deaths. Among the AEs leading to permanent discontinuation or death, pulmonary AE was significantly more common in elderly patients. CONCLUSION: Durvalumab demonstrated similar outcomes in elderly compared to younger patients. However, AEs were more common in elderly patients. Thus, judicious selection of patients and chemotherapy regimens, coupled with careful AE monitoring, are important factors for ensuring optimal durvalumab treatment.

Pectoralis Muscle Area as a Predictor of Mortality in Patients Hospitalized with Bronchiectasis Exacerbation.

INTRODUCTION: Data on factors related to mortality in patients with bronchiectasis exacerbation are insufficient. Computed tomography (CT) can measure the pectoralis muscle area (PMA) and is a useful tool to diagnose sarcopenia. This study aimed to evaluate whether PMA can predict mortality in patients with bronchiectasis exacerbation. METHODS: Patients hospitalized due to bronchiectasis exacerbation at a single center were retrospectively divided into survivors and non-survivors based on 1-year mortality. Thereafter, a comparison of the clinical and radiologic characteristics was conducted between the two groups. RESULTS: A total of 66 (14%) patients died at 1 year. In the multivariate analysis, age, BMI <18.4 kg/m2, sex-specific PMA quartile, ≥3 exacerbations in the previous year, serum albumin <3.5 g/dL, cystic bronchiectasis, tuberculosis-destroyed lung, and diabetes mellitus were independent predictors for the 1-year mortality in patients hospitalized with bronchiectasis exacerbation. A lower PMA was associated with a lower overall survival rate in the survival analysis according to sex-specific quartiles of PMA. PMA had the highest area under the curve during assessment of prognostic performance in predicting the 1-year mortality. The lowest sex-specific PMA quartile group exhibited higher disease severity than the highest quartile group. CONCLUSIONS: CT-derived PMA was an independent predictor of 1-year mortality in patients hospitalized with bronchiectasis exacerbation. Patients with lower PMA exhibited higher disease severity. These findings suggest that PMA might be a useful marker for providing additional information regarding prognosis of patients with bronchiectasis exacerbation.

Noninvasive factors predicting the maintenance of pregnancy for more than 4 weeks after rescue cerclage in singleton pregnancies with cervical dilatation and prolapsed membrane.

Studies on noninvasive factors and predicting the maintenance of pregnancy, and those comparing the usefulness of these factors with invasive amniotic fluid markers in predicting the maintenance of pregnancy following rescue cerclage, are lacking. Therefore, this study aimed to determine whether C-reactive protein (CRP) levels, White blood cell (WBC) count, absolute neutrophil count (ANC), and platelet-to-lymphocyte ratio (PLR) in maternal blood, which are noninvasive and readily available clinical markers, can predict the maintenance of pregnancy following rescue cerclage in patients with cervical insufficiency (CI). A total of 142 singleton pregnant women (15-28 wk) who underwent rescue cerclage for CI were retrospectively evaluated. The interleukin (IL)-6 concentration in the amniotic fluid; CRP levels, WBC count, ANC, and PLR in the maternal peripheral blood; and degree of cervical dilatation were evaluated before cerclage. The primary outcome was whether the pregnancy was maintained for >4 weeks after rescue cerclage. Among the 142 patients, prolonged pregnancy for >4 weeks following emergent cerclage was observed in 107 (75.35%), while 35 (24.65%) gave birth within 4 weeks. This study demonstrated that the degree of cervical dilatation at diagnosis; WBC count, ANC, and CRP levels in the maternal peripheral blood; and IL-6 concentration in the amniotic fluid significantly differed between the successful and failure groups (all P < .05). The area under the curve (AUC) of the amniotic fluid IL-6 concentration was .795 for the prediction of spontaneous preterm birth within 4 weeks after rescue cerclage. Additionally, the AUC of the CRP level, cervical dilatation, WBC count, ANC, and PLR were .795, .703, .695, .682, and .625, respectively. These findings suggest that the preoperative CRP levels can be considered a useful noninvasive marker comparable to amniotic fluid IL-6 concentration for identifying pregnant women with CI at high risk of spontaneous preterm birth following rescue cerclage.

Diffsig: Associating Risk Factors with Mutational Signatures.

BACKGROUND: Somatic mutational signatures elucidate molecular vulnerabilities to therapy, and therefore detecting signatures and classifying tumors with respect to signatures has clinical value. However, identifying the etiology of the mutational signatures remains a statistical challenge, with both small sample sizes and high variability in classification algorithms posing barriers. As a result, few signatures have been strongly linked to particular risk factors. METHODS: Here, we develop a statistical model, Diffsig, for estimating the association of one or more continuous or categorical risk factors with DNA mutational signatures. Diffsig takes into account the uncertainty associated with assigning signatures to samples as well as multiple risk factors' simultaneous effect on observed DNA mutations. RESULTS: We applied Diffsig to breast cancer data to assess relationships between five established breast-relevant mutational signatures and etiologic variables, confirming known mechanisms of cancer development. In simulation, our model was capable of accurately estimating expected associations in a variety of contexts. CONCLUSIONS: Diffsig allows researchers to quantify and perform inference on the associations of risk factors with mutational signatures. IMPACT: We expect Diffsig to provide more robust associations of risk factors with signatures to lead to better understanding of the tumor development process and improved models of tumorigenesis.

Clinical impact of pleural fluid carcinoembryonic antigen on therapeutic strategy and efficacy in lung adenocarcinoma patients with malignant pleural effusion.

BACKGROUND/AIMS: Epidermal growth factor receptor (EGFR) mutation is important in determining the treatment strategy for advanced lung cancer patients with malignant pleural effusion (MPE). Contrary to serum carcinoembryonic antigen (S-CEA) levels, the associations between pleural fluid CEA (PF-CEA) levels and EGFR mutation status as well as between PF-CEA levels and treatment efficacy have rarely been investigated in lung adenocarcinoma patients with MPE. METHODS: This retrospective study enrolled lung adenocarcinoma patients with MPE and available PF-CEA levels and EGFR mutation results. The patients were categorized based on PF-CEA levels: < 10 ng/mL, 10-100 ng/mL, 100-500 ng/mL, and ≥ 500 ng/mL. The association between PF-CEA levels and EGFR mutation status as well as their therapeutic impact on overall survival was compared among the four groups. RESULTS: This study included 188 patients. PF-CEA level was found to be an independent predictor of EGFR mutation but not S-CEA level. The EGFR mutation rates were higher as the PF-CEA levels increased, regardless of cytology results or sample types. Among EGFR-mutant lung adenocarcinoma patients receiving EGFR-tyrosine kinase inhibitor (TKI) treatment, those with high PF-CEA levels had significantly better survival outcomes than those with low PF-CEA levels. CONCLUSION: High PF-CEA levels were associated with high EGFR mutation rate and may lead to a favorable clinical outcome of EGFR-TKI treatment in EGFR-mutant lung adenocarcinoma patients with MPE. These findings highlight the importance of actively investigating EGFR mutation detection in patients with suspected MPE and elevated PF-CEA levels despite negative cytology results.