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BACKGROUND: Uterine corpus endometrial carcinoma (UCEC) is a prevalent gynecologic malignancy with a favorable prognosis if detected early. However, there is a lack of accurate and reliable early detection tests for UCEC. This study aims to develop a precise and non-invasive diagnostic method for UCEC using circulating cell-free DNA (cfDNA) fragmentomics. METHODS: Peripheral blood samples were collected from all participants, and cfDNA was extracted for analysis. Low-coverage whole-genome sequencing was performed to obtain cfDNA fragmentomics data. A robust machine learning model was developed using these features to differentiate between UCEC and healthy conditions. RESULTS: The cfDNA fragmentomics-based model showed high predictive power for UCEC detection in training (n = 133; AUC 0.991) and validation cohorts (n = 89; AUC 0.994). The model manifested a specificity of 95.5% and a sensitivity of 98.5% in the training cohort, and a specificity of 95.5% and a sensitivity of 97.8% in the validation cohort. Physiological variables and preanalytical procedures had no significant impact on the classifier's outcomes. In terms of clinical benefit, our model would identify 99% of Chinese UCEC patients at stage I, compared to 21% under standard care, potentially raising the 5-year survival rate from 84 to 95%. CONCLUSION: This study presents a novel approach for the early detection of UCEC using cfDNA fragmentomics and machine learning showing promising sensitivity and specificity. Using this model in clinical practice could significantly improve UCEC management and control, enabling early intervention and better patient outcomes. Further optimization and validation of this approach are warranted to establish its clinical utility.
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Ácidos Nucleicos Libres de Células , Detección Precoz del Cáncer , Neoplasias Endometriales , Humanos , Femenino , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/sangre , Neoplasias Endometriales/genética , Persona de Mediana Edad , Ácidos Nucleicos Libres de Células/sangre , Detección Precoz del Cáncer/métodos , Anciano , Aprendizaje Automático , Adulto , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Sensibilidad y EspecificidadRESUMEN
Colorectal cancer (CRC) is frequently diagnosed in advanced stages, highlighting the need for developing approaches for early detection. Liquid biopsy using cell-free DNA (cfDNA) fragmentomics is a promising approach, but the clinical application is hindered by complexity and cost. This study aimed to develop an integrated model using cfDNA fragmentomics for accurate, cost-effective early-stage CRC detection. Plasma cfDNA was extracted and sequenced from a training cohort of 360 participants, including 176 CRC patients and 184 healthy controls. An ensemble stacked model comprising five machine learning models was employed to distinguish CRC patients from healthy controls using five cfDNA fragmentomic features. The model was validated in an independent cohort of 236 participants (117 CRC patients and 119 controls) and a prospective cohort of 242 participants (129 CRC patients and 113 controls). The ensemble stacked model showed remarkable discriminatory power between CRC patients and controls, outperforming all base models and achieving a high area under the ROC curve (AUC) of 0.986 in the validation cohort. It reached 94.88% sensitivity and 98% specificity for detecting CRC in the validation cohort, with sensitivity increasing as cancer progressed. The model also demonstrated consistently high accuracy in within-run and between-run tests and across various conditions in healthy individuals. In the prospective cohort, it achieved 91.47% sensitivity and 95.58% specificity. This integrated model capitalizes on the multiplex nature of cfDNA fragmentomics to achieve high sensitivity and robustness, offering significant promise for early CRC detection and broad patient benefit.
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BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) and systemic inflammation response index (SIRI) at admission are independent diagnostic biomarkers in stroke-associated pneumonia (SAP). Our study aimed to investigate the association between NLR, SIRI, specifically follow-up NLR and SIRI, and SAP, as well as their relationship with functional outcomes. PATIENTS AND METHODS: We retrospectively included 451 consecutive intracerebral hemorrhage patients from May 2017 to May 2019. We conducted univariate and multivariable analyses to identify the factors independently associated with SAP and poor functional outcomes. RESULTS: Compared to 127 (28.16%) patients diagnosed with SAP, those without SAP had both lower baseline and follow-up NLR and SIRI values ( P <0.001). After adjustments, we found that baseline NLR [OR, 1.039 (95% CI, 1.003-1.077); P =0.036] and follow-up NLR [OR, 1.054 (95% CI, 1.011-1.098); P =0.012] were independently associated with SAP. The follow-up NLR was also associated with a higher mRS [OR, 1.124 (95% CI, 1.025-1.233); P =0.013] and lower ADL-MBI score [OR, 1.167 (95% CI, 1.057-1.289); P =0.002] at discharge. Multivariable analysis indicated that advanced age and nasogastric tube feeding were independently associated with SAP ( P <0.05). We constructed a dynamic nomogram to identify SAP risk. Further subgroup analysis revealed that baseline NLR [OR, 1.062 (95% CI, 1.007-1.120); P =0.026] is independently associated with SAP in the nasogastric feeding group, while follow-up NLR [OR, 1.080 (95% CI, 1.024-1.139); P =0.005] was associated with the occurrence of SAP in non-nasogastric feeding patients. CONCLUSIONS: We found elevated baseline and follow-up NLR values were associated with SAP occurrence, and increasing follow-up NLR indicated poor functional outcomes. Inflammatory markers at different stages may offer individualized guidance for patients receiving various treatments.
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Hemorragia Cerebral , Linfocitos , Neutrófilos , Neumonía , Humanos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios Retrospectivos , Estudios de Casos y Controles , Hemorragia Cerebral/sangre , Neumonía/sangre , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/inmunologíaRESUMEN
The postmenopausal decrease in circulating estradiol (E2) levels has been shown to contribute to several adverse physiological and psychiatric effects. To elucidate the molecular effects of E2 on the brain, we examined differential gene expression and DNA methylation (DNAm) patterns in the nonhuman primate brain following ovariectomy (Ov) and subsequent subcutaneous bioidentical E2 chronic treatment. We identified several dysregulated molecular networks, including MAPK signaling and dopaminergic synapse response, that are associated with ovariectomy and shared across two different brain areas, the occipital cortex (OC) and prefrontal cortex (PFC). The finding that hypomethylation (p = 1.6 × 10-51) and upregulation (p = 3.8 × 10-3) of UBE2M across both brain regions provide strong evidence for molecular differences in the brain induced by E2 depletion. Additionally, differential expression (p = 1.9 × 10-4; interaction p = 3.5 × 10-2) of LTBR in the PFC provides further support for the role E2 plays in the brain, by demonstrating that the regulation of some genes that are altered by ovariectomy may also be modulated by Ov followed by hormone replacement therapy (HRT). These results present real opportunities to understand the specific biological mechanisms that are altered with depleted E2. Given E2's potential role in cognitive decline and neuroinflammation, our findings could lead to the discovery of novel therapeutics to slow cognitive decline. Together, this work represents a major step toward understanding molecular changes in the brain that are caused by ovariectomy and how E2 treatment may revert or protect against the negative neuro-related consequences caused by a depletion in estrogen as women approach menopause.
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OBJECTIVES: To compare the performance of the multiparametric magnetic resonance imaging (mpMRI) radiomics and 18F-Prostate-specific membrane antigen (PSMA)-1007 PET/CT radiomics model in diagnosing extracapsular extension (EPE) in prostate cancer (PCa), and to evaluate the performance of a multimodal radiomics model combining mpMRI and PET/CT in predicting EPE. METHODS: We included 197 patients with PCa who underwent preoperative mpMRI and PET/CT before surgery. mpMRI and PET/CT images were segmented to delineate the regions of interest and extract radiomics features. PET/CT, mpMRI, and multimodal radiomics models were constructed based on maximum correlation, minimum redundancy, and logistic regression analyses. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) and indices derived from the confusion matrix. RESULTS: AUC values for the mpMRI, PET/CT, and multimodal radiomics models were 0.85 (95% CI, 0.78-0.90), 0.73 (0.64-0.80), and 0.83 (0.75-0.89), respectively, in the training cohort and 0.74 (0.61-0.85), 0.62 (0.48-0.74), and 0.77 (0.64-0.87), respectively, in the testing cohort. The net reclassification improvement demonstrated that the mpMRI radiomics model outperformed the PET/CT one in predicting EPE, with better clinical benefits. The multimodal radiomics model performed better than the single PET/CT radiomics model (P < .05). CONCLUSION: The mpMRI and 18F-PSMA-PET/CT combination enhanced the predictive power of EPE in patients with PCa. The multimodal radiomics model will become a reliable and robust tool to assist urologists and radiologists in making preoperative decisions. ADVANCES IN KNOWLEDGE: This study presents the first application of multimodal radiomics based on PET/CT and MRI for predicting EPE.
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Imágenes de Resonancia Magnética Multiparamétrica , Neoplasias de la Próstata , Masculino , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Próstata , Extensión Extranodal , Radiómica , Neoplasias de la Próstata/cirugía , Imagen por Resonancia Magnética/métodosRESUMEN
OBJECTIVE: Radiomics can reflect the heterogeneity within the focus. We aim to explore whether radiomics can predict recurrent intracerebral hemorrhage (RICH) and develop an online dynamic nomogram to predict it. METHODS: This retrospective study collected the clinical and radiomics features of patients with spontaneous intracerebral hemorrhage seen in our hospital from October 2013 to October 2016. We used the minimum redundancy maximum relevancy and the least absolute shrinkage and selection operator methods to screen radiomics features and calculate the Rad-score. We use the univariate and multivariate analyses to screen clinical predictors. Optimal clinical features and Rad-score were used to construct different logistics regression models called the clinical model, radiomics model, and combined-logistic regression model. DeLong testing was performed to compare performance among different models. The model with the best predictive performance was used to construct an online dynamic nomogram. RESULTS: Overall, 304 patients with intracerebral hemorrhage were enrolled in this study. Fourteen radiomics features were selected to calculate the Rad-score. The patients with RICH had a significantly higher Rad-score than those without (0.5 vs. -0.8; P< 0.001). The predictive performance of the combined-logistic regression model with Rad-score was better than that of the clinical model for both the training (area under the receiver operating curve, 0.81 vs. 0.71; P = 0.02) and testing (area under the receiver operating curve, 0.65 vs. 0.58; P = 0.04) cohorts statistically. CONCLUSIONS: Radiomics features were determined related to RICH. Adding Rad-score into conventional clinical models significantly improves the prediction efficiency. We developed an online dynamic nomogram to accurately and conveniently evaluate RICH.
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Nomogramas , Radiómica , Humanos , Estudios Retrospectivos , Hemorragia Cerebral/diagnóstico por imagen , HospitalesRESUMEN
Objective: Post-stroke hyperglycemia as a common phenomenon is associated with unfavorable outcomes. Focusing on admission hyperglycemia, other markers of dysglycemia were overlooked. This study aimed to explore the contribution of acute phase blood glucose levels in combination with other radiological signs to the prognostication of functional outcomes in patients with spontaneous intracerebral hemorrhage (sICH). Methods: Consecutive patients with sICH with at least five random plasma glucose measurements and complete radiological data during hospitalization were included. We calculated the average, maximum, minimum, standard deviation, and coefficient of variation of blood glucose levels for each patient. Radiological data, including island, black hole, blend, and satellite signs were collected. Functional outcomes were evaluated using the Barthel index. Unfavorable outcomes were defined as a Barthel index score ≤ 60. Univariate and multivariate analyses were performed to identify independent predictors of unfavorable outcomes. Results: Two hundred and thirty-eight patients (mean age 58.5, 163 men and 75 women) were included, and 71 had a history of diabetes. Unfavorable outcomes occurred in 107 patients (45.0%) at 3 months. Multivariate logistic regression analysis demonstrated that maximum blood glucose levels (odds ratio, 1.256; 95% confidence interval, 1.124â1.404; p < 0.001) and island sign (odds ratio, 2.701; 95% confidence interval, 1.322â5.521; p = 0.006) were independent predictors of unfavorable outcomes in the nondiabetic group. Meanwhile, patients without diabetes who experienced hematoma expansion had higher average (p = 0.036) and maximum blood glucose levels (p = 0.014). Interpretation: Maximum blood glucose levels and island sign were independently associated with unfavorable outcomes in patients without diabetes, whereas no glycemic variability indices were associated with unfavorable outcomes. Glucose levels influenced hematoma expansion and functional outcomes, particularly in patients without diabetes with sICH. Thus, clinical management of blood glucose levels should be strengthened for patients with sICH with or without a history of diabetes.
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Background: Hypertension is a common comorbidity in patients with unruptured intracranial aneurysms and is closely associated with the rupture of aneurysms. However, only a few studies have focused on the rupture risk of aneurysms comorbid with hypertension. This retrospective study aimed to construct prediction models for the rupture of middle cerebral artery (MCA) aneurysm associated with hypertension using machine learning (ML) algorithms, and the constructed models were externally validated with multicenter datasets. Methods: We included 322 MCA aneurysm patients comorbid with hypertension who were being treated in four hospitals. All participants underwent computed tomography angiography (CTA), and aneurysm morphological features were measured. Clinical characteristics included sex, age, smoking, and hypertension history. Based on the clinical and morphological characteristics, the training datasets (n=277) were used to fit the ML algorithms to construct prediction models, which were externally validated with the testing datasets (n=45). The prediction performances of the models were assessed by receiver operating characteristic (ROC) curves. Results: The areas under the ROC curve (AUCs) of the k-nearest-neighbor (KNN), neural network (NNet), support vector machine (SVM) and logistic regression (LR) models in the training datasets were 0.83 [95% confidence interval (CI): 0.78-0.88], 0.87 (95% CI: 0.82-0.92), 0.91 (95% CI: 0.88-0.95), and 0.83 (95% CI: 0.77-0.88), respectively, and in the testing datasets were 0.74 (95% CI: 0.59-0.89), 0.82 (95% CI: 0.69-0.94), 0.73 (95% CI: 0.58-0.88), and 0.76 (95% CI: 0.61-0.90), respectively. The aspect ratio (AR) was ranked as the most important variable in the ML models except for NNet. Further analysis showed that the AR had good diagnostic performance, with AUC values of 0.75 in the training datasets and 0.77 in the testing datasets. Conclusions: The ML models performed reasonably accurately in predicting MCA aneurysm rupture comorbid with hypertension. AR was demonstrated as the leading predictor for the rupture of MCA aneurysm with hypertension.
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OBJECTIVES: Aberrantly expressed circular RNAs (circRNAs) have been detected in many types of tumors. Hence, they are currently investigated as candidate biomarkers for diagnostic and potential targets for therapy in cancers. The objective of this study was to assess the expression profile of circRNA in lung adenocarcinoma (LUAD). METHODS: This study included 14 pairs of postoperative lung adenocarcinoma specimens, including cancer tissues and matched adjacent tissues. Second-generation sequencing was applied to the specimens to determine the circRNA expression in them among the 5242 distinct circRNAs detected. RESULTS: We identified a total of 18 significantly dysregulated circRNAs in the LUAD tissues: upregulation in four and downregulation in 14. ROC (The receiver operating characteristic curve) further suggested that hsa_circ_0120106, has_circ_0007342, has_circ_0005937, and circRNA_0000826 could potentially be used as biomarkers in the diagnosis of LUAD. Furthermore, study of the circRNA-microRNA (miRNA)-messenger RNA (mRNA) revealed interactions between the 18 dysregulated circRNA and several cancer-related miRNAs. Finally, a further Kyoto Encyclopedia of Genes and Genomes analysis showed that the cell cycle phase transition, p53 signaling pathway, AMP-activated protein kinase (AMPK) relative signaling pathway, and so on were key putative pathways in the process of LUAD. CONCLUSIONS: These findings demonstrated the correlation between abnormality in circRNA expression and LUAD, which lays the foundation of making CircRNAs candidate biomarkers in the diagnosis of LUAD.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , MicroARNs , Humanos , ARN Circular/genética , MicroARNs/genética , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Biomarcadores , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologíaRESUMEN
The efficacy of immunotherapy in advanced HER2-mutated non-small-cell lung cancer (NSCLC) remains incomprehensively studied. A total of 107 NSCLC patients with de novo HER2 mutations were retrospectively studied at Guangdong Lung Cancer Institute [GLCI cohort, exon 20 insertions (ex20ins): 71.0%] to compare clinical/molecular features and immune checkpoint inhibitor (ICI)-based therapy efficacy between patients with ex20ins and non-ex20ins. Two external cohorts (TCGA, n = 21; META-ICI, n = 30) were used for validation. In the GLCI cohort, 68.2% of patients displayed programmed death-ligand 1 (PD-L1) expression < 1%. Compared with ex20ins patients, non-ex20ins patients had more concurrent mutations in the GLCI cohort (P < 0.01) and a higher tumour mutation burden in the TCGA cohort (P = 0.03). Under ICI-based therapy, advanced NSCLC patients with non-ex20ins had potentially superior progression-free survival [median: 13.0 vs. 3.6 months, adjusted hazard ratio (HR): 0.31, 95% confidence interval (CI): 0.11-0.83] and overall survival (median: 27.5 vs. 8.1 months, adjusted HR: 0.39, 95% CI: 0.13-1.18) to ex20ins patients, consistent with findings in the META-ICI cohort. ICI-based therapy may serve as an option for advanced HER2-mutated NSCLC, with potentially better efficacy in non-ex20ins patients. Further investigations are warranted in clinical practice.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estudios Retrospectivos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Genómica , Mutación/genéticaRESUMEN
Mutations in epidermal growth factor receptor and anaplastic lymphoma kinase are common driver events in non-small cell lung cancer (NSCLC), which are associated with a high frequency of bone metastases (BMs). While the bone marrow represents a specialized immune microenvironment, the immune repertoire of BMs remains unknown. Considering the higher incidence of BMs in driver gene-positive NSCLCs, and the unique biology of the bone, herein, we assessed the infiltrating immune cells and T cell receptor (TCR) profile of BMs in driver-positive NSCLCs. Immune profile of BMs in driver gene-positive NSCLC were assessed in 10 patients, where 6 had driver gene-positive mutation. TCR and bulk RNA sequencing were performed on malignant bone samples. The diversity and clonality of the TCR repertoire were analyzed. The cellular components were inferred from bulk gene expression profiles computationally by CIBERSORT. Although BMs were generally regarded as immune-cold tumors, immune cell composition analyses showed co-existence of cytotoxic and suppressor immune cells in driver-positive BM samples, as compared to primary lung. Analysis of the TCR repertoire indicated a trend of higher diversity and similar clonality in the driver-positive compared with the driver-negative subsets. In addition, we identified two cases that showed the opposite response to immune checkpoint blockade. A comparison of these two patients' BM samples showed more highly amplified clones, fewer M2 macrophages and more activated natural killer cells in the responder. In summary, BMs in NSCLC are heterogeneous in their immune microenvironment, which might be related to differential clinical outcomes to immune checkpoint blockade.
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Neoplasias Óseas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Pulmón/patología , Neoplasias Óseas/genética , Receptores de Antígenos de Linfocitos T/genética , Microambiente Tumoral/genéticaRESUMEN
BACKGROUND: Post-stroke epilepsy (PSE) is one of the major sequelae of stroke. Inflammation has been implicated in the development of stroke. The study aimed to explore the relationship between neutrophil-to-lymphocyte ratio (NLR) levels and epilepsy in patients with primary intracerebral hemorrhage (ICH). METHODS: A retrospective study was performed on 1132 patients with first-time ICH. Blood samples were obtained at admission after ICH. Patients included in the study were classified into three groups according to NLR tertiles. Logistic regression was used to analyze the relationship between NLR levels and the occurrence of PSE. RESULTS: The occurrence of PSE was significantly correlated with NLR levels (r = 0.118, P < 0.001). Patients with PSE had higher NLR levels than those without PSE. After adjusting for potential confounders, high NLR was independently associated with an increased risk of PSE (OR = 1.861, 95% CI 1.032-3.355, P = 0.039). Neutrophil-to-lymphocyte ratio levels were independently associated with the occurrence of PSE in the poor functional outcome group, while this association was not significant in the favorable functional outcome group. The model (cortical involvement + hematoma volume + early seizures + NLR) showed good prognostic performance. CONCLUSION: High NLR at admission is associated with an increased risk of PSE, which suggests that NLR may play a role in risk stratification in patients with ICH.
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Epilepsia , Accidente Cerebrovascular , Humanos , Neutrófilos , Estudios Retrospectivos , Hemorragia Cerebral/complicaciones , Linfocitos , Accidente Cerebrovascular/complicaciones , Epilepsia/complicacionesRESUMEN
PURPOSE: Pathologic complete response (pCR) rates of patients with triple-negative breast cancer who were administered docetaxel plus carboplatin were significantly higher than those of patients administered epirubicin/cyclophosphamide followed by docetaxel in the neoadjuvant NeoCART trial. Here, we performed a preplanned secondary analysis of the homologous recombination deficiency (HRD) score as a predictor of the pCR in patients with triple-negative breast cancer from the NeoCART cohort. METHODS: Pretherapeutic tumor tissues were assessed retrospectively by DNA extraction and sequencing. BRCA1/2 mutations were evaluated in both somatic and germline forms. HRD scores were calculated from genome-wide allele-specific copy number results and comprised telomeric allelic imbalance, loss of heterozygosity, and large-scale state transitions. High HRD scores were defined as ≥ 38, and HRD was defined as either a high HRD score or a deleterious BRCA1/2 mutation. RESULTS: HRD testing was completed for 43 (79.6%) of 54 NeoCART cohort patients. Thirty of 43 (69.8%) tumors had high HRD scores, and eight patients had BRCA-mutated tumors. No significant association between BRCA1/2 mutation status and pCR was observed either in the general population or in the two treatment arms. Docetaxel plus carboplatin group patients who achieved pCR had higher HRD scores than non-pCR patients, and this difference approached significance (61.69 ± 24.26 v 39.44 ± 22.83, P = .061). No significant correlations between HRD scores and pCR (61.29 ± 24.02 v 53.21 ± 24.31, P = .480) or residual cancer burden 0/1 (62.50 ± 22.50 v 51.85 ± 24.74, P = .324) were observed in the epirubicin/cyclophosphamide followed by docetaxel group. CONCLUSION: HRD is a potential predictive biomarker for clinical benefit from neoadjuvant carboplatin-based chemotherapy and provides a possibility for screening the optimum chemotherapy backbone to combine with immunotherapy.
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Neoplasias de la Mama Triple Negativas , Humanos , Carboplatino/uso terapéutico , Mutación , Epirrubicina/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Docetaxel/uso terapéutico , Terapia Neoadyuvante/métodos , Estudios Retrospectivos , Proteína BRCA1/genética , Recombinación Homóloga/genética , Ciclofosfamida/uso terapéuticoRESUMEN
The postmenopausal decrease in circulating estradiol (E2) levels has been shown to contribute to several adverse physiological and psychiatric effects. To elucidate the molecular effects of E2 on the brain, we examined differential gene expression and DNA methylation (DNAm) patterns in the nonhuman primate brain following ovariectomy (Ov) and subsequent E2 treatment. We identified several dysregulated molecular networks, including MAPK signaling and dopaminergic synapse response, that are associated with ovariectomy and shared across two different brain areas, the occipital cortex (OC) and prefrontal cortex (PFC). The finding that hypomethylation (p=1.6×10-51) and upregulation (p=3.8×10-3) of UBE2M across both brain regions, provide strong evidence for molecular differences in the brain induced by E2 depletion. Additionally, differential expression (p=1.9×10-4; interaction p=3.5×10-2) of LTBR in the PFC, provides further support for the role E2 plays in the brain, by demonstrating that the regulation of some genes that are altered by ovariectomy may also be modulated by Ov followed by hormone replacement therapy (HRT). These results present real opportunities to understand the specific biological mechanisms that are altered with depleted E2. Given E2's potential role in cognitive decline and neuroinflammation, our findings could lead to the discovery of novel therapeutics to slow cognitive decline. Together, this work represents a major step towards understanding molecular changes in the brain that are caused by ovariectomy and how E2 treatment may revert or protect against the negative neuro-related consequences caused by a depletion in estrogen as women approach menopause.
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BACKGROUND: Due to the blood-brain barrier, plasma is not an ideal source to evaluate the genetic characteristics of central nervous system tumors. Thus, cerebrospinal fluid (CSF) is becoming an alternative biopsy type to evaluate the genetic landscape of intracranial tumors. We aimed to explore the genetic profiles of CSF-derived circulating tumor DNA (ctDNA) to predict intracranial tumor responses and monitor mutational evolution during the treatment of non-small cell lung cancer (NSCLC) patients with brain metastases. METHODS: We conducted a prospective study of 92 newly diagnosed NSCLC patients with brain metastases. Paired CSF and plasma samples were collected at baseline, 8 weeks after treatment initiation, and disease progression. All samples underwent next-generation sequencing of 425 cancer-related genes. RESULTS: At baseline, the positive detection rates of ctDNA in CSF, plasma, and extracranial tumors were 63.7% (58/91), 91.1% (82/90), and 100% (58/58), respectively. A high level of genetic heterogeneity was observed between paired CSF and plasma, while concordance in driver mutations was also observed. A higher number of unique copy number variations was detected in CSF-ctDNA than in plasma. ctDNA positivity of CSF samples at baseline was associated with poor outcomes (HR=2.565, P=0.003). Moreover, patients with ≥ 50% reductions in the concentrations of CSF ctDNA after 8 weeks of treatment had significantly longer intracranial progression-free survivals (PFS) than patients with < 50% reductions in CSF ctDNA concentrations (13.27 months vs 6.13 months, HR=0.308, P=0.017). A ≥ 50% reduction in CSF ctDNA concentrations had better concordance with radiographic intracranial tumor responses than plasma. A ≥ 50% reduction in plasma ctDNA concentrations was also associated with longer extracranial PFS (11.57 months vs 6.20 months, HR=0.406, P=0.033). Based on clonal evolution analyses, the accumulation of subclonal mutations in CSF ctDNA was observed after 8 weeks of treatment. The clonal mutations that remained in more than 80% in CSF after 8 weeks also predicted shorter intracranial PFS (HR=3.785, P=0.039). CONCLUSIONS: CSF ctDNA exhibited unique genetic profiles of brain metastases, and dynamic changes in CSF ctDNA could better predict intracranial tumor responses and track clonal evolution during treatment in NSCLC patients with brain metastases. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03257735.
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Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Encéfalo/patología , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , ADN Tumoral Circulante/genética , Variaciones en el Número de Copia de ADN , Perfil Genético , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Estudios ProspectivosRESUMEN
The goal of this study is to identify pharmacological inhibitors that target a recently identified novel mediator of breast cancer brain metastasis (BCBM), truncated glioma-associated oncogene homolog 1 (tGLI1). Inhibitors of tGLI1 are not yet available. To identify compounds that selectively kill tGLI1-expressing breast cancer, we screened 1527 compounds using two sets of isogenic breast cancer and brain-tropic breast cancer cell lines engineered to stably express the control, GLI1, or tGLI1 vector, and identified the FDA-approved antifungal ketoconazole (KCZ) to selectively target tGLI1-positive breast cancer cells and breast cancer stem cells, but not tGLI1-negative breast cancer and normal cells. KCZ's effects are dependent on tGLI1. Two experimental mouse metastasis studies have demonstrated that systemic KCZ administration prevented the preferential brain metastasis of tGLI1-positive breast cancer and suppressed the progression of established tGLI1-positive BCBM without liver toxicities. We further developed six KCZ derivatives, two of which (KCZ-5 and KCZ-7) retained tGLI1-selectivity in vitro. KCZ-7 exhibited higher blood-brain barrier penetration than KCZ/KCZ-5 and more effectively reduced the BCBM frequency. In contrast, itraconazole, another FDA-approved antifungal, failed to suppress BCBM. The mechanistic studies suggest that KCZ and KCZ-7 inhibit tGLI1's ability to bind to DNA, activate its target stemness genes Nanog and OCT4, and promote tumor proliferation and angiogenesis. Our study establishes the rationale for using KCZ and KCZ-7 for treating and preventing BCBM and identifies their mechanism of action.
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BACKGROUND: PET-based radiomics features could predict the biological characteristics of primary prostate cancer (PCa). However, the optimal thresholds to predict the biological characteristics of PCa are unknown. This study aimed to compare the predictive power of 18F-PSMA-1007 PET radiomics features at different thresholds for predicting multiple biological characteristics. METHODS: One hundred and seventy-three PCa patients with complete preoperative 18F-PSMA-1007 PET examination and clinical data before surgery were collected. The prostate lesions' volumes of interest were semi-automatically sketched with thresholds of 30%, 40%, 50%, and 60% maximum standardized uptake value (SUVmax). The radiomics features were respectively extracted. The prediction models of Gleason score (GS), extracapsular extension (ECE), and vascular invasion (VI) were established using the support vector machine. The performance of models from different thresholding regions was assessed using receiver operating characteristic curve and confusion matrix-derived indexes. RESULTS: For predicting GS, the 50% SUVmax model showed the best predictive performance in training (AUC, 0.82 [95%CI 0.74-0.88]) and testing cohorts (AUC, 0.80 [95%CI 0.66-0.90]). For predicting ECE, the 40% SUVmax model exhibit the best predictive performance (AUC, 0.77 [95%CI 0.68-0.84] and 0.77 [95%CI 0.63-0.88]). As for VI, the 50% SUVmax model had the best predictive performance (AUC, 0.74 [95%CI 0.65-0.82] and 0.74 [95%CI 0.56-0.82]). CONCLUSION: The 18F-1007-PSMA PET-based radiomics features at 40-50% SUVmax showed the best predictive performance for multiple PCa biological characteristics evaluation. Compared to the single PSA model, radiomics features may provide additional benefits in predicting the biological characteristics of PCa.
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Neoplasias Primarias Múltiples , Neoplasias de la Próstata , Radioisótopos de Flúor , Humanos , Aprendizaje Automático , Masculino , Niacinamida/análogos & derivados , Oligopéptidos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Próstata , Antígeno Prostático Específico , Neoplasias de la Próstata/diagnóstico por imagenRESUMEN
Introduction: BRAF variants were reported resistant mechanisms to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant NSCLC. Nevertheless, characteristics and subsequent treatment strategies of such patients remain unclear. Methods: From October 2016 to May 2020, patients with advanced NSCLC for whom next-generation sequencing detected mutations of both BRAF and EGFR were retrospectively included. From June 2020 to January 2021, patients with EGFR-mutant NSCLC who acquired the BRAF V600E mutation after progression on osimertinib were prospectively enrolled to explore the efficacy and safety of EGFR plus BARF co-inhibition. Results: A total of 58 patients were retrospectively identified and five prospectively included. BRAF variants were acquired after a median time of 22.7 months from initial diagnosis. The frequency of variations in TP53, PIK3CA, RB1, MET, LRP1B, APC, CDKN2A, MYC, ERBB2, and SMAD4 was all more than 10%; these mutations affected the cell cycle or p53 pathway and the EGFR downstream and bypass pathways. The median progression-free survival was 5.0 months for patients on chemotherapy and 2.1 months for those on TKIs not targeting both of EGFR and BRAF (p = 0.019). The median PFS was 7.8 months in five patients who received EGFR plus BRAF co-inhibitory drugs. RAS signaling was activated on disease progression. Conclusions: Variations in the EGFR downstream and bypass pathways were frequent in patients with dual mutations of EGFR and BRAF. The efficacies of TKIs not targeting both EGFR and BRAF were inferior to chemotherapy. EGFR plus BRAF co-inhibition improved efficacy. Such treatment strategies should be further explored.
RESUMEN
BACKGROUND: Most existing studies have focused on the correlation between white matter lesion (WML) and baseline intraventricular hemorrhage (IVH) in patients with intracerebral hemorrhage (ICH), whereas few studies have investigated the relationship between WML severity and delayed IVH after admission. This study aimed to investigate the correlation between WML severity and delayed IVH and to verify the association between WML and baseline IVH. METHODS: A total of 480 patients with spontaneous ICH from February 2018 to October 2020 were selected. WML was scored using the Van Swieten Scale, with scores of 0-2 representing nonslight WML and scores of 3-4 representing moderate-severe WML. We determined the presence of IVH on baseline (< 6 h) and follow-up computed tomography (< 72 h) images. Univariate analysis and multiple logistic regression were used to analyze the influencing factors of baseline and delayed IVH. RESULTS: Among 480 patients with ICH, 172 (35.8%) had baseline IVH, and there was a higher proportion of moderate-severe WML in patients with baseline IVH (20.3%) than in those without baseline IVH (12.7%) (P = 0.025). Among 308 patients without baseline IVH, delayed IVH was found in 40 patients (12.9%), whose proportion of moderate-severe WML (25.0%) was higher than that in patients without delayed IVH (10.8%) (P = 0.012). Multiple logistic regression results showed that moderate-severe WML was independently correlated with baseline IVH (P = 0.006, odds ratio = 2.266, 95% confidence interval = 1.270-4.042) and delayed IVH (P = 0.002, odds ratio = 7.009, 95% confidence interval = 12.086-23.552). CONCLUSIONS: Moderate-severe WML was an independent risk factor for delayed IVH as well as baseline IVH.