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BACKGROUND: Triple-negative breast cancer (TNBC) is highly heterogeneous, resulting in different responses to neoadjuvant chemotherapy (NAC) and prognoses among patients. This study sought to characterize the heterogeneity of TNBC on MRI and develop a radiogenomic model for predicting both pathological complete response (pCR) and prognosis. MATERIALS AND METHODS: In this retrospective study, TNBC patients who underwent neoadjuvant chemotherapy at Fudan University Shanghai Cancer Center were enrolled as the radiomic development cohort (n = 315); among these patients, those whose genetic data were available were enrolled as the radiogenomic development cohort (n = 98). The study population of the two cohorts was randomly divided into a training set and a validation set at a ratio of 7:3. The external validation cohort (n = 77) included patients from the DUKE and I-SPY 1 databases. Spatial heterogeneity was characterized using features from the intratumoral subregions and peritumoral region. Hemodynamic heterogeneity was characterized by kinetic features from the tumor body. Three radiomics models were developed by logistic regression after selecting features. Model 1 included subregional and peritumoral features, Model 2 included kinetic features, and Model 3 integrated the features of Model 1 and Model 2. Two fusion models were developed by further integrating pathological and genomic features (PRM: pathology-radiomics model; GPRM: genomics-pathology-radiomics model). Model performance was assessed with the AUC and decision curve analysis. Prognostic implications were assessed with KaplanâMeier curves and multivariate Cox regression. RESULTS: Among the radiomic models, the multiregional model representing multiscale heterogeneity (Model 3) exhibited better pCR prediction, with AUCs of 0.87, 0.79, and 0.78 in the training, internal validation, and external validation sets, respectively. The GPRM showed the best performance for predicting pCR in the training (AUC = 0.97, P = 0.015) and validation sets (AUC = 0.93, P = 0.019). Model 3, PRM and GPRM could stratify patients by disease-free survival, and a predicted nonpCR was associated with poor prognosis (P = 0.034, 0.001 and 0.019, respectively). CONCLUSION: Multiscale heterogeneity characterized by DCE-MRI could effectively predict the pCR and prognosis of TNBC patients. The radiogenomic model could serve as a valuable biomarker to improve the prediction performance.
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Imagen por Resonancia Magnética , Terapia Neoadyuvante , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/diagnóstico por imagen , Femenino , Terapia Neoadyuvante/métodos , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Imagen por Resonancia Magnética/métodos , Pronóstico , AncianoRESUMEN
PURPOSE: To investigate whether a radiomics model based on mammography (MG) and magnetic resonance imaging (MRI) can be used to predict disease-free survival (DFS) after phyllodes tumor (PT) surgery. METHOD: About 131 PT patients who underwent MG and MRI before surgery between January 2010 and December 2020 were retrospectively enrolled, including 15 patients with recurrence and metastasis and 116 without recurrence. 884 and 3138 radiomic features were extracted from MG and MR images, respectively. Then, multiple radiomics models were established to predict the recurrence risk of the patients by applying a support vector machine classifier. The area under the ROC curve (AUC) was calculated to evaluate model performance. After dividing the patients into high- and low-risk groups based on the predicted radiomics scores, survival analysis was conducted to compare differences between the groups. RESULTS: In total, 3 MG-related and 5 MRI-related radiomic models were established; the prediction performance of the T1WI feature fusion model was the best, with an AUC value of 0.93. After combining the features of MG and MRI, the AUC increased to 0.95. Furthermore, the MG, MRI and all-image radiomic models had statistically significant differences in survival between the high- and low-risk groups (P < .001). All-image radiomics model showed higher survival performance than the MG and MRI radiomics models alone. CONCLUSIONS: Radiomics features based on preoperative MG and MR images can predict DFS after PT surgery, and the prediction score of the image radiomics model can be used as a potential indicator of recurrence risk.
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BACKGROUND: Notch1 signaling inhibiton with N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester] (DAPT) treatment could promote brain recovery and the intervention effect is different between striatum (STR) and cortex (CTX), which might be accounted for different changes of glial activities, but the in-depth mechanism is still unknown. The purpose of this study was to identify whether DAPT could modulate microglial subtype shifts and astroglial-endfeet aquaporin-4 (AQP4) mediated waste solute drainage. METHODS: Sprague-Dawley rats (n=10) were subjected to 90min of middle cerebral artery occlusion (MCAO) and were treated with DAPT (n=5) or act as control with no treatment (n=5). Two groups of rats underwent MRI scans at 24h and 4 week, and sacrificed at 4 week after stroke for immunofluorescence (IF). RESULTS: Compared with control rats, MRI data showed structural recovery in ipsilateral STR but not CTX. And IF showed decreased pro-inflammatory M1 microglia and increased anti-inflammatory M2 microglia in striatal lesion core and peri-lesions of STR, CTX. Meanwhile, IF showed decreased AQP4 polarity in ischemic brain tissue, however, AQP4 polarity in striatal peri-lesions of DAPT treated rats was higher than that in control rats but shows no difference in cortical peri-lesions between control and treated rats. CONCLUSIONS: The present study indicated that DAPT could promote protective microglia subtype shift and striatal astrocyte mediated waste solute drainage, that the later might be the major contributor of waste solute metabolism and one of the accounts for discrepant recovery of STR and CTX.
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Acuaporina 4 , Astrocitos , Dipéptidos , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media , Microglía , Ratas Sprague-Dawley , Receptor Notch1 , Recuperación de la Función , Transducción de Señal , Animales , Acuaporina 4/metabolismo , Receptor Notch1/metabolismo , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/fisiopatología , Masculino , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/patología , Microglía/metabolismo , Microglía/efectos de los fármacos , Microglía/patología , Dipéptidos/farmacología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Factores de Tiempo , Fármacos Neuroprotectores/farmacología , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/fisiopatología , Accidente Cerebrovascular Isquémico/patologíaRESUMEN
BACKGROUND AND AIM: The spatial distribution and interactions of cells in the tumor immune microenvironment (TIME) might be related to the different responses of triple-negative breast cancer (TNBC) to immunomodulators. The potential of multiplex IHC (m-IHC) in evaluating the TIME has been reported, but the efficacy is insufficient. We aimed to research whether m-IHC results could be used to reflect the TIME, and thus to predict prognosis and complement the TNBC subtyping system. METHODS: The clinical, imaging, and prognosis data for 86 TNBC patients were retrospectively reviewed. CD3, CD4, CD8, Foxp3, PD-L1, and Pan-CK markers were stained by m-IHC. Particular cell spatial distributions and interactions in the TIME were evaluated with the HALO multispectral analysis platform. Then, we calculated the prognostic value of components of the TIME and their correlations with TNBC transcriptomic subtypes and MRI radiomic features reflecting TNBC subtypes. RESULTS: The components of the TIME score were established by m-IHC and demonstrated positive prognostic value for TNBC (p = 0.0047, 0.039, <0.0001 for DMFS, RFS, and OS). The score was calculated from several indicators, including Treg% in the tumor core (TC) or stromal area (SA), PD-L1+ cell% in the SA, CD3 + cell% in the TC, and PD-L1+ /CD8+ cells in the invasive margin and SA. According to the TNBC subtyping system, a few TIME indicators were significantly different in different subtypes and significantly correlated with MRI radiomic features reflecting TNBC subtypes. CONCLUSION: We demonstrated that the m-IHC-based quantitative score and indicators related to the spatial distribution and interactions of cells in the TIME can aid in the accurate diagnosis of TNBC in terms of prognosis and classification.
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Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/patología , Antígeno B7-H1 , Estudios Retrospectivos , Pronóstico , Microambiente Tumoral , Biomarcadores de TumorRESUMEN
Intratumor heterogeneity (ITH) profoundly affects therapeutic responses and clinical outcomes. However, the widespread methods for assessing ITH based on genomic sequencing or pathological slides, which rely on limited tissue samples, may lead to inaccuracies due to potential sampling biases. Using a newly established multicenter breast cancer radio-multiomic dataset (n = 1474) encompassing radiomic features extracted from dynamic contrast-enhanced magnetic resonance images, we formulated a noninvasive radiomics methodology to effectively investigate ITH. Imaging ITH (IITH) was associated with genomic and pathological ITH, predicting poor prognosis independently in breast cancer. Through multiomic analysis, we identified activated oncogenic pathways and metabolic dysregulation in high-IITH tumors. Integrated metabolomic and transcriptomic analyses highlighted ferroptosis as a vulnerability and potential therapeutic target of high-IITH tumors. Collectively, this work emphasizes the superiority of radiomics in capturing ITH. Furthermore, we provide insights into the biological basis of IITH and propose therapeutic targets for breast cancers with elevated IITH.
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Neoplasias de la Mama , Multiómica , Humanos , Femenino , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/genética , Genómica , Perfilación de la Expresión Génica/métodos , FenotipoRESUMEN
Inhibition of Notch1 signaling has been shown to promote astrocyte-derived neurogenesis after stroke. To investigate the regulatory role of Notch1 signaling in this process, in this study, we used a rat model of stroke based on middle cerebral artery occlusion and assessed the behavior of reactive astrocytes post-stroke. We used the γ-secretase inhibitor N-[N-(3,5-diuorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester (DAPT) to block Notch1 signaling at 1, 4, and 7 days after injury. Our results showed that only administration of DAPT at 4 days after stroke promoted astrocyte-derived neurogenesis, as manifested by recovery of white matter fiber bundle integrity on magnetic resonance imaging, which is consistent with recovery of neurologic function. These findings suggest that inhibition of Notch1 signaling at the subacute stage post-stroke mediates neural repair by promoting astrocyte-derived neurogenesis.
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Background and objectives: The glymphatic system is a recently discovered cerebrospinal fluid transport system and little is known about its dynamic changes after stroke. This study aimed to dynamically observe the structural and functional changes of the impaired glymphatic system in the thalamus after ischemic stroke by pathology and MRI. Materials and methods: Ischemic stroke was induced by the middle cerebral artery occlusion (MCAO) model. A total of 20 Sprague-Dawley rats were randomly assigned into four groups: sham, MCAO 1 week, MCAO 2 week, and MCAO 2 month. All rats successively underwent neurological examination, dynamic contrast-enhanced MRI (DCE-MRI), and immunofluorescence staining. Immunofluorescence staining of glial fibrillary acidic protein (GFAP), aquaporin-4 (AQP4), ionized calcium-binding adaptor molecule 1 (Iba1), and beta-amyloid precursor protein (APP) were done in thalamus ventroposterior nucleus. Results: The astrocyte and microglial activation and the APP deposition in the MCAO 2 week group were the highest (P < 0.05 for all). The AQP4 polarization rates of the MCAO 2 week and 2 month groups were the lowest (P < 0.05 for all). Although there was no correlation between histological changes and MRI metrics in all four groups (P > 0.05 for all), the tendency of the APP deposition was nearly consistent with the one of the contrast agent retention in DCE-MRI. Conclusion: The glymphatic system in the thalamus was severely impaired at 2nd week after MCAO, and may be revealed by DCE-MRI. This study may provide a relevant theoretical basis for making a thorough inquiry of the mechanism of brain injury after stroke and clinical treatment of ischemic stroke and help readers appreciate the importance of DCE-MRI.
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Background: The upgrade of high-risk breast lesions (HRLs) is closely related to subsequent treatment, but the current predictors for upgrade are limited to intratumoral features of single imaging mode. Methods: We retrospectively reviewed 230 HRLs detected by mammography, ultrasound, and magnetic resonance imaging (MRI) before biopsy at the Fudan University Cancer Hospital from January 2017 to March 2018. The clinical features, imaging data according to the Breast Imaging Reporting and Data System (BI-RADS) lexicon, and tumor upgrade situation were received. Based on the different risks of upgrade reported, the lesions were classified into high-risk I [HR-I, with atypical hyperplasia (AH)] and high-risk II (HR-II, without AH). We analyzed the association between clinicopathological and imaging factors and upgrade. We used the receiver operating characteristic (ROC) curve to compare the efficacy of three imaging modes for predicting upgrade. Results: We included 230 HRLs in 230 women in the study, and the overall upgrade rate was 20.4% (47/230). The upgrade rate was higher in HR-I compared to HR-II (38.5% vs. 4.1%, P<0.01). In patients with AH, estrogen receptor-positive (ER+) patients accounted for 81.0% (64/79). For all HRLs and HR-I, in clinical characteristics, age, maximum size of lesion, and menopausal status were significantly associated with upgrade (P<0.05). In imaging factors, MRI background parenchymal enhancement (BPE), signs of MRI and ultrasound were significantly correlated with upgrade (P<0.05). Patients with negative MRI or ultrasound manifestations had lower upgrade rates (P<0.01). For HR-II, only BPE showed a significant difference between groups (P=0.001). Multifactorial analysis of all HRLs showed that age and BPE were independent predictors of upgrade (P<0.01). The areas under the ROC cure (AUCs) for predicting upgrade in mammography, ultrasound, and MRI were 0.606, 0.590, and 0.913, respectively, indicating that MRI diagnosis was significantly better than mammography and ultrasound (P<0.001). Conclusions: HRLs with AH had a higher rate of upgrade and increased ER expression. Among three imaging modes, MRI was more effective than ultrasound and mammography in diagnosing the upgrade of HRLs. Older age and moderate to marked BPE can indicate malignant upgrade. MRI can provide a certain value for the diagnosis and follow-up of HRLs.
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Background: Ischemic stroke is one of the leading causes of human death and disability. Brain edema and peri-infarct astrocyte reactivity are crucial pathological changes, both involving aquaporin-4 (AQP4). Studies revealed that acute inhibition of AQP4 after stroke diminishes brain edema, however, its effect on peri-infarct astrocyte reactivity and the subacute outcome is unclear. And if diffusion-weighted imaging (DWI) could reflect the AQP4 expression patterns is uncertain. Methods: Rats were subjected to middle cerebral artery occlusion (MCAO) and allocated randomly to TGN 020-treated and control groups. One day after stroke, brain swelling and lesion volumes of the rats were checked using T2-weighted imaging (T2-WI). Fourteen days after stroke, the rats successively underwent neurological examination, T2-WI and DWI with standard b-values and ultra-high b-values, apparent diffusion coefficient (ADC) was calculated correspondingly. Finally, the rats' brains were acquired and used for glial fibrillary acidic protein (GFAP) and AQP4 immunoreactive analysis. Results: At 1 day after stroke, the TGN-020-treated animals exhibited reduced brain swelling and lesion volumes compared with those in the control group. At 14 days after stroke, the TGN-020-treated animals showed fewer neurological function deficits and smaller lesion volumes. In the peri-infarct region, the control group showed evident astrogliosis and AQP4 depolarization, which were reduced significantly in the TGN-020 group. In addition, the ultra-high b-values of ADC (ADCuh) in the peri-infarct region of the TGN-020 group was higher than that of the control group. Furthermore, correlation analysis revealed that peri-infarct AQP4 polarization correlated negatively with astrogliosis extent, and ADCuh correlated positively with AQP4 polarization. Conclusion: We found that acutely inhibiting AQP4 using TGN-020 promoted neurological recovery by diminishing brain edema at the early stage and attenuating peri-infarct astrogliosis and AQP4 depolarization at the subacute stage after stroke. Moreover, ADCuh could reflect the AQP4 polarization.
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Edema Encefálico , Gliosis , Infarto de la Arteria Cerebral Media , Animales , Acuaporina 4/biosíntesis , Edema Encefálico/diagnóstico por imagen , Edema Encefálico/metabolismo , Edema Encefálico/patología , Edema Encefálico/prevención & control , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Gliosis/diagnóstico por imagen , Gliosis/metabolismo , Gliosis/patología , Gliosis/prevención & control , Infarto de la Arteria Cerebral Media/diagnóstico por imagen , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Imagen por Resonancia Magnética , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Ratas , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Tiadiazoles/uso terapéuticoRESUMEN
BACKGROUND: Multimodal CT, including CT angiography (CTA) and CT perfusion (CTP), was increasingly used in stroke triage. This study was to determine the relationship between a new integrated parameter-both collateral circulation and relative permeability surface (PS)-and the hemorrhagic transformation (HT) in acute ischemic stroke (AIS) with middle cerebral artery occlusion (MCAO). METHODS: We retrospectively reviewed consecutive AIS patients with MCAO who underwent baseline CTA/CTP within 4 h of symptom onset and follow-up susceptibility-weighted imaging (SWI) within 3 weeks. Collateral circulation was assessed on the baseline CTA. Baseline CTP data were postprocessed to generate PS parameter. The patients with poor collateral circulation and at the same time with high relative PS were classified as the group of both poor collateral circulation and high relative PS. HT was defined according to European Cooperative Acute Stroke Study II criteria on follow-up SWI imaging. Multivariate logistic regression analysis was performed using HT as an outcome variable. RESULTS: The group of patients with both poor collateral circulation and high relative PS was thirteen and thirty-three (52%) developed HT of the final cohort sixty-three AIS patients with MCAO. Multivariate logistic analysis revealed the new integrated parameter-both collateral circulation and relative PS (odds ratio, 16.59; 95% confidence interval, 13.09-19.10; P < 0.001) was independent predictor of HT. The area under the curve was 0.85 (95% confidence interval, 0.81-0.89). The sensitivity was 57%, specificity 97% and positive predictive value 92%, negative predictive value 58%. CONCLUSIONS: For AIS patients with MCAO, these with poor collateral circulation on CTA and at the same time with high relative PS on CTP were at high risk for HT.
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Background: Together with cerebral small vessel disease (CSVD), large vessel atherosclerosis is considered to be an equally important risk factor in the progression of vascular cognitive impairment. This article aims to investigate whether carotid atherosclerotic calcification is associated with the increased risk of post-stroke cognitive impairment (PSCI). Methods: A total of 128 patients (mean age: 62.1 ± 12.2 years, 37 women) suffering from ischemic stroke underwent brain/neck computer tomography angiography examination. The presence and characteristic of carotid calcification (size, number and location) were analyzed on computer tomography angiography. White matter hyperintensity (WMH) was assessed using Fazekas scales. PSCI was diagnosed based on a battery of neuropsychological assessments implemented 6-12 months after stroke. Results: Among 128 patients, 26 developed post-stroke dementia and 96 had carotid calcification. Logistic regression found carotid calcification (odds ratio [OR] = 7.15, 95% confidence interval [CI]: 1.07-47.69) and carotid artery stenosis (OR = 6.42, 95% CI: 1.03-40.15) both significantly increased the risk for post-stroke dementia. Moreover, multiple, thick/mixed, and surface calcifications exhibited an increasing trend in PSCI (P trend = 0.004, 0.016, 0.045, respectively). The prediction model for post-stroke dementia including carotid calcification (area under curve = 0.67), WMH (area under curve = 0.67) and other covariates yielded an area under curve (AUC) of 0.90 (95% CI: 0.82-0.99). Conclusion: Our findings demonstrated that the quantity and location of carotid calcifications were independent indicators for PSCI. The significant role of large vessel atherosclerosis in PSCI should be concerned in future study.
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BACKGROUND: Pathomechanism of secondary degeneration in remote regions after ischemic stroke has not been totally clarified. Contrast-enhanced MRI with injecting Gd-DTPA in cisterna magna (CM) is regarded as an efficient method to measure glymphatic system function in brain. Our research aimed at evaluating glymphatic system changes in secondary degeneration areas by contrast-enhanced MRI. METHODS: Ischemic stroke was induced by left middle cerebral artery occlusion (MCAO) model. A total of 12 Sprague-Dawley rats were randomly divided into three groups: control group with sham operations (n=4), the group of acute phase (1 day after MCAO) (n=4), and the group of subacute phase (7 days after MCAO) (n=4). Contrast-enhanced MRI was performed in 1days or 7days after operations respectively. All rats received an intrathecal injection of Gd-DTPA (2µl/min, totally 20µl) and high-resolution 3D T1-weighted MRI for 6 h. The time course of the signal-to-noise ratio (SNR) in substantia Nigra (SN) and ventral thalamic nucleus (VTN) was evaluated between two hemispheres in all rats. RESULTS: In control group without ischemia, time-to-peak of SNR in SN was earlier than that in VTN. There were no differences of SNR between two hemispheres after intrathecal Gd-DTPA administration. In the group of acute phase, MRI revealed similar time course and time-to-peak of SNR between ipsilateral and contralateral VTN, while a tendency of higher SNR in ipsilateral SN than contralateral SN at 4h, 5h, 6h after Gd-DTPA injection. And time-to-peak of SNR was similar in bilateral SN. In the group of subacute phase, time-to-peak of SNR was similar in bilateral VTN, while longer in ipsilateral SN compared with contralateral side. In addition, SNR in T1WI in ipsilateral was significantly higher than SNR in contralateral SN and VTN at 5h (VTN, P= 0.003; SN, P=0.004) and 6h (VTN, P=0.015; SN, P=0.006) after Gd-DTPA injection. CONCLUSION: Glymphatic system was impaired in ipsilateral SN and VTN after ischemic stroke, which may contribute to neural degeneration.