Artificial intelligence for ultrasound microflow imaging in breast cancer diagnosis.

PURPOSE: To develop and evaluate artificial intelligence (AI) algorithms for ultrasound (US) microflow imaging (MFI) in breast cancer diagnosis. MATERIALS AND METHODS: We retrospectively collected a dataset consisting of 516 breast lesions (364 benign and 152 malignant) in 471 women who underwent B-mode US and MFI. The internal dataset was split into training (n = 410) and test datasets (n = 106) for developing AI algorithms from deep convolutional neural networks from MFI. AI algorithms were trained to provide malignancy risk (0-100%). The developed AI algorithms were further validated with an independent external dataset of 264 lesions (229 benign and 35 malignant). The diagnostic performance of B-mode US, AI algorithms, or their combinations was evaluated by calculating the area under the receiver operating characteristic curve (AUROC). RESULTS: The AUROC of the developed three AI algorithms (0.955-0.966) was higher than that of B-mode US (0.842, P < 0.0001). The AUROC of the AI algorithms on the external validation dataset (0.892-0.920) was similar to that of the test dataset. Among the AI algorithms, no significant difference was found in all performance metrics combined with or without B-mode US. Combined B-mode US and AI algorithms had a higher AUROC (0.963-0.972) than that of B-mode US (P < 0.0001). Combining B-mode US and AI algorithms significantly decreased the false-positive rate of BI-RADS category 4A lesions from 87% to 13% (P < 0.0001). CONCLUSION: AI-based MFI diagnosed breast cancers with better performance than B-mode US, eliminating 74% of false-positive diagnoses in BI-RADS category 4A lesions.

MRI-based breast cancer radiogenomics using RNA profiling: association with subtypes in a single-center prospective study.

BACKGROUND: There are few prospective studies on the correlations between MRI features and whole RNA-sequencing data in breast cancer according to molecular subtypes. The purpose of our study was to explore the association between genetic profiles and MRI phenotypes of breast cancer and to identify imaging markers that influences the prognosis and treatment according to subtypes. METHODS: From June 2017 to August 2018, MRIs of 95 women with invasive breast cancer were prospectively analyzed, using the breast imaging-reporting and data system and texture analysis. Whole RNA obtained from surgical specimens was analyzed using next-generation sequencing. The association between MRI features and gene expression profiles was analyzed in the entire tumor and subtypes. Gene networks, enriched functions, and canonical pathways were analyzed using Ingenuity Pathway Analysis. The P value for differential expression was obtained using a parametric F test comparing nested linear models and adjusted for multiple testing by reporting Q value. RESULTS: In 95 participants (mean age, 53 years ± 11 [standard deviation]), mass lesion type was associated with upregulation of CCL3L1 (sevenfold) and irregular mass shape was associated with downregulation of MIR421 (sixfold). In estrogen receptor-positive cancer with mass lesion type, CCL3L1 (21-fold), SNHG12 (11-fold), and MIR206 (sevenfold) were upregulated, and MIR597 (265-fold), MIR126 (12-fold), and SOX17 (fivefold) were downregulated. In triple-negative breast cancer with increased standard deviation of texture analysis on precontrast T1-weighted imaging, CLEC3A (23-fold), SRGN (13-fold), HSPG2 (sevenfold), KMT2D (fivefold), and VMP1 (fivefold) were upregulated, and IGLC2 (73-fold) and PRDX4 (sevenfold) were downregulated (all, P < 0.05 and Q < 0.1). Gene network and functional analysis showed that mass type estrogen receptor-positive cancers were associated with cell growth, anti-estrogen resistance, and poor survival. CONCLUSION: MRI characteristics are associated with the different expressions of genes related to metastasis, anti-drug resistance, and prognosis, depending on the molecular subtypes of breast cancer.

Diagnostic value of mammography for accompanying non-mass enhancement on preoperative breast MRI.

BACKGROUND: Successful surgical treatment for localized breast cancer can depend on accurate diagnosis for accompanying non-mass enhancement (NME) on preoperative breast magnetic resonance imaging (MRI). PURPOSE: To evaluate the diagnostic value of mammography for accompanying NME adjacent to index cancer on preoperative breast MRI. MATERIAL AND METHODS: Among 569 consecutive patients who underwent preoperative breast MRI from January 2016 to August 2018 for ultrasound-guided biopsy-proven breast cancer, 471 patients who underwent initial mammography and subsequent surgery were finally included. Two radiologists retrospectively reviewed preoperative MRI findings of the 471 patients and detected accompanying NME adjacent to index cancer. MRI, mammography, and histopathology findings of the accompanying NME were evaluated using Pearson's chi-square test, Mann-Whitney U test, and logistic regression analysis. The area under the receiver operating characteristic curve (AUC) of MRI and combined MRI and mammography was calculated in differentiating benign from malignant accompanying NME. The reference standard was surgical pathologic findings. RESULTS: MRI revealed 93 accompanying NME lesions in 92 (19.5%) of the 471 patients, showing 55 (59.1%) malignant and 38 (40.9%) benign lesions. On multivariate analysis, malignant NME lesions were more associated with mammography-positive findings (P = 0.000), clumped or clustered ring internal enhancement (P = 0.015), and extensive intraductal component presence of index tumor (P = 0.007) compared with benign lesions. The AUC increased after correlation with mammography showing 0.649 (95% confidence interval [CI] 0.533-0.765) for MRI and 0.833 (95% CI 0.747-0.919) for combined MRI and mammography. CONCLUSION: Mammography is valuable in predicting malignancy for accompanying NME on preoperative breast MRI.

Fucoidan Independently Enhances Activity in Human Immune Cells and Has a Cytostatic Effect on Prostate Cancer Cells in the Presence of Nivolumab.

Fucoidan compounds may increase immune activity and are known to have cancer inhibitory effects in vitro and in vivo. In this study, we aimed to investigate the effect of fucoidan compounds on ex vivo human peripheral blood mononuclear cells (PBMCs), and to determine their cancer cell killing activity both solely, and in combination with an immune-checkpoint inhibitor drug, Nivolumab. Proliferation of PBMCs and interferon gamma (IFNγ) release were assessed in the presence of fucoidan compounds extracted from Fucus vesiculosus, Undaria pinnatifida and Macrocystis pyrifera. Total cell numbers and cell killing activity were assessed using a hormone resistant prostate cancer cell line, PC3. All fucoidan compounds activated PBMCs, and increased the effects of Nivolumab. All fucoidan compounds had significant direct cytostatic effects on PC3 cells, reducing cancer cell numbers, and PBMCs exhibited cell killing activity as measured by apoptosis. However, there was no fucoidan mediated increase in the cell killing activity. In conclusion, fucoidan compounds promoted proliferation and activity of PBMCs and added to the effects of Nivolumab. Fucoidan compounds all had a direct cytostatic effect on PC3 cells, as shown through their proliferation reduction, while their killing was not increased.

Anti-Inflammatory Activity of Fucoidan Extracts In Vitro.

Fucoidans are sulfated, complex, fucose-rich polymers found in brown seaweeds. Fucoidans have been shown to have multiple bioactivities, including anti-inflammatory effects, and are known to inhibit inflammatory processes via a number of pathways such as selectin blockade and enzyme inhibition, and have demonstrated inhibition of inflammatory pathologies in vivo. In this current investigation, fucoidan extracts from Undaria pinnatifida, Fucus vesiculosus, Macrocystis pyrifera, Ascophyllum nodosum, and Laminaria japonica were assessed for modulation of pro-inflammatory cytokine production (TNF-α, IL-1ß, and IL-6) by human peripheral blood mononuclear cells (PBMCs) and in a human macrophage line (THP-1). Fucoidan extracts exhibited no signs of cytotoxicity in THP-1 cells after incubation of 48 h. Additionally, all fucoidan extracts reduced cytokine production in LPS stimulated PBMCs and human THP-1 cells in a dose-dependent fashion. Notably, the 5-30 kDa subfraction from Macrocystis pyrifera was a highly effective inhibitor at lower concentrations. Fucoidan extracts from all species had significant anti-inflammatory effects, but the lowest molecular weight subfractions had maximal effects at low concentrations. These observations on various fucoidan extracts offer insight into strategies that improve their efficacy against inflammation-related pathology. Further studies should be conducted to elucidate the mechanism of action of these extracts.

Radiogenomic Analysis of Breast Cancer by Using B-Mode and Vascular US and RNA Sequencing.

Background Radiogenomic investigations for breast cancer provide an understanding of tumor heterogeneity and discover image phenotypes of genetic variation. However, there is little research on the correlations between US features of breast cancer and whole-transcriptome profiling. Purpose To explore US phenotypes reflecting genetic alteration relevant to breast cancer treatment and prognosis by comparing US images of tumor with their RNA sequencing results. Materials and Methods From January to October 2016, B-mode and vascular US images in 31 women (mean age, 49 years ± 9 [standard deviation]) with breast cancer were prospectively analyzed. B-mode features included size, shape, echo pattern, orientation, margin, and calcifications. Vascular features were evaluated by using microvascular US and contrast agent-enhanced US: vascular index, vessel morphologic features, distribution, penetrating vessels, enhancement degree, order, margin, internal homogeneity, and perfusion defect. RNA sequencing was conducted with total RNA obtained from a surgical specimen by using next-generation sequencing. US features were compared with gene expression profiles, and ingenuity pathway analysis was used to analyze gene networks, enriched functions, and canonical pathways associated with breast cancer. The P value for differential expression was extracted by using a parametric F test comparing nested linear models. Results Thirteen US features were associated with various patterns of 340 genes (P < .05). Nonparallel orientation at B-mode US was associated with upregulation of TFF1 (log twofold change [log2FC] = 4.0; P < .001), TFF3 (log2FC = 2.5; P < .001), AREG (log2FC = 2.6; P = .005), and AGR3 (log2FC = 2.6; P = .003). Complex vessel morphologic structure was associated with upregulation of FZD8 (log2FC = 2.0; P = .01) and downregulation of IGF1R (log2FC = -2.0; P = .006) and CRIPAK (log2FC = -2.4; P = .01). The top networks with regard to orientation or vessel morphologic structure were associated with cell cycle, death, and proliferation. Conclusion Compared with RNA sequencing, B-mode and vascular US features reflected genomic alterations associated with hormone receptor status, angiogenesis, or prognosis in breast cancer. © RSNA, 2020 Online supplemental material is available for this article.

Fucoidan and Lung Function: Value in Viral Infection.

Compromised lung function is a feature of both infection driven and non-infective pathologies. Viral infections-including the current pandemic strain SARS-CoV-2-that affect lung function can cause both acute and long-term chronic damage. SARS-CoV-2 infection suppresses innate immunity and promotes an inflammatory response. Targeting these aspects of SARS-CoV-2 is important as the pandemic affects greater proportions of the population. In clinical and animal studies, fucoidans have been shown to increase innate immunity and decrease inflammation. In addition, dietary fucoidan has been shown to attenuate pulmonary damage in a model of acute viral infection. Direct inhibition of SARS-CoV-2 in vitro has been described, but is not universal. This short review summarizes the current research on fucoidan with regard to viral lung infections and lung damage.

Oral Fucoidan Attenuates Lung Pathology and Clinical Signs in a Severe Influenza a Mouse Model.

Fucoidans are known to be effective inhibitors of inflammation, and of virus binding and cellular entry. Undaria pinnatifida-derived fucoidan (UPF) was assessed in a severe influenza A (H1N1, PR8) infection model in mice. Initially, UPF was gavaged at 3.52 mg daily in a treatment model. Gross lung pathology (consolidation) was significantly reduced as compared to controls. UPF was then presented as a feed supplement at a rate of either nil, 3.52 mg/day or 7.04 mg/day in a prophylactic model, dosed three days before infection. A significant improvement was observed in the clinical signs of ill-health, as well as a reduction in gross lung pathology in animals treated with the higher dose, although there was no significant reduction in lung viral titres.

Micro RNA Expression after Ingestion of Fucoidan; A Clinical Study.

Fucoidans are a class of fucose-rich sulfated polysaccharides derived from brown macroalgae that exert a range of biological activities in vitro and in vivo. To generate an unbiased assessment of pathways and processes affected by fucoidan, a placebo-controlled double-blind pilot study was performed in healthy volunteers. Blood samples were taken immediately before and 24 h after ingestion of a single dose of 1 g of Undaria pinnatifida fucoidan (UPF) or placebo. Levels of isolated miRNAs were analyzed using Taqman Open Array Human MicroRNA panels. Out of 754 miRNAs screened, UPF affected a total of 53 miRNAs. Pathway analysis using the TALOS data analysis tool predicted 29 different pathways and processes that were largely grouped into cell surface receptor signaling, cancer-related pathways, the majority of which were previously associated with fucoidans. However, this analysis also identified nine pathways and processes that have not been associated with fucoidans before. Overall, this study illustrates that even a single dose of fucoidans has the potential to affect the expression of genes related to fundamental cellular processes. Moreover, it confirms previous data that fucoidans influence immunity, cancer cells, inflammation, and neurological function.

Can enhancement types on preoperative MRI reflect prognostic factors and surgical outcomes in invasive breast cancer?

OBJECTIVES: This study was conducted in order to evaluate whether enhancement types on preoperative MRI can reflect prognostic factors and surgical outcomes in invasive breast cancer. METHODS: Among 484 consecutive patients who underwent preoperative breast MRI from October 2014 to July 2017 for biopsy-proven breast cancer, 313 patients with 315 invasive breast cancers who underwent subsequent surgery were finally included in this study. Two radiologists retrospectively reviewed preoperative MRI findings of these 315 lesions and categorized them to mass, nonmass, and combined type according to enhancement features. Combined type was defined as coexisted mass and nonmass enhancement. Histopathologic results focusing on prognostic factors and surgical outcomes were compared among the three types of lesion using Pearson's chi-square, linear-by-linear association, Kruskal-Wallis, one-way ANOVA test, and multinomial logistic regression. RESULTS: Of the cancers analyzed, 198 (62.9%) were mass, 59 (18.7%) were nonmass, and 58 (18.4%) were combined type. The nonmass type showed the smallest invasive tumor size (p < 0.001) and the most common positive HER2 receptor status (p = 0.001). The combined type had the most frequent lymphovascular invasion (p = 0.011), axillary lymph node-positive status (p = 0.031), operation changes (p < 0.001), and first resection margin-positive status (p < 0.001). Initial operation of mastectomy was more frequent in the nonmass and combined types than that in the mass type (p < 0.001). But HER2 receptor status and operation changes showed no statistical significance on multivariate analysis. CONCLUSIONS: Enhancement types on preoperative MRI reflect different prognostic factors and surgical outcomes in invasive breast cancer. KEY POINTS: • Morphologic features of contrast media uptake on contrast-enhanced MRI may be related with fundamental biological differences of invasive breast cancers. • Mass or nonmass enhancement type on preoperative MRI might reflect different prognostic factors and surgical outcomes in invasive breast cancer. • The combined mass and nonmass enhancement type might be associated with poorer prognosis and worse surgical outcomes.

Therapies from Fucoidan: New Developments.

Since our last review in 2015, the study and use of fucoidan has extended in several research areas. Clinical use of fucoidan for the treatment of renal disease has become available and human safety studies have been undertaken on radiolabeled fucoidan for the purpose of imaging thrombi. Fucoidan has been incorporated into an increasing number of commercially available supplements and topical treatments. In addition, new measuring techniques are now available to assess the biologically relevant uptake of fucoidans and to assist in production. Microbiome modulation and anti-pathogenic effects are increasingly promising applications for fucoidans, due to the need for alternative approaches to antibiotic use in the food chain. This review outlines promising new developments in fucoidan research, including potential future therapeutic use.

New Doppler imaging technique for assessing angiogenesis in breast tumors: correlation with immunohistochemically analyzed microvessels density.

BACKGROUND: Microvessel density (MVD) is associated with grade and prognosis in breast tumors. However, conventional color Doppler flow (CDF) imaging has been limited to represent MVD of breast tumors. PURPOSE: To evaluate whether a new Doppler imaging technique (AngioPLUS) can represent MVD of breast tumors. MATERIAL AND METHODS: The institutional review board approved this retrospective study, and patients' informed consent was waived. CDF and AngioPLUS were available in pathologically confirmed 55 breast tumors of 53 women. For each lesion, vascular flow patterns (distribution and amount) of both Doppler images were retrospectively reviewed, and MVD was measured using immunohistochemical analysis of the biopsied tissue sections. MVD was subcategorized as low or high group with reference to the median. The associations between the Doppler features and MVD were evaluated using Fisher's exact test and Student's t test. RESULTS: Of the 55 masses, 28 (50.9%) were benign and 27 (49.1%) were malignant. Vascular flow distribution and amount of both Doppler imaging were different between the benign and malignant lesions (CDF, P = 0.020 and P = 0.010; AngioPLUS, P = 0.002 and P = 0.005). MVD had no significant relationships with CDF features, but vascular flow distribution on AngioPLUS showed significant differences between the lesions with low and high MVD ( P = 0.020); Combined distribution was more frequent in the high MVD lesions than in the low MVD lesions (17/28, 60.7% vs. 6/27, 22.2%). CONCLUSION: Our data confirmed the correlation between a new Doppler imaging technique, AngioPLUS, and MVD. We suggest that AngioPLUS can be used for assessing MVD in breast tumors.

Comparison of the Diagnostic Performance of Power Doppler Ultrasound and a New Microvascular Doppler Ultrasound Technique (AngioPLUS) for Differentiating Benign and Malignant Breast Masses.

This study was performed to compare the diagnostic performance of power Doppler ultrasound (US) and a new microvascular Doppler US technique (AngioPLUS; SuperSonic Imagine, Aix-en-Provence, France) for differentiating benign and malignant breast masses. Power Doppler US and AngioPLUS findings were available in 124 breast masses with confirmed pathologic results (benign, 80 [64.5%]; malignant, 44 [35.5%]). The diagnostic performance of each tool was calculated to distinguish benign from malignant masses using a receiver operating characteristic curve analysis and compared. The area under the curve showed that AngioPLUS was superior to power Doppler US in differentiating benign from malignant breast masses, but the difference was not statistically significant.

Complications and Radiologic Features of Breast Augmentation via Injection of Aquafilling Gel.

Many attempts have been made to augment breasts using injectable materials; however, various complications are associated with these materials. Aquafilling gel (Aquafilling, Podebrady, Czech Republic) is a new soft tissue filler that has been used as an implant material for the face and lip and recently for breast augmentation. This article describes 3 cases of augmentation mammoplasty using Aquafilling gel, focusing on their complications and radiologic features.

3D Printed Micrometer-Scale Polymer Mounts for Single Crystal Analysis.

3D printed micrometer-scale polymer mounts for single crystal analysis have been prepared by photopolymerization using digital light projection stereolithography (DLP-SLA), with a commercially available digital light projection stereolithography printer (US$4000) and 3DM-ABS resin (US$150 per liter). The polymer mounts were prepared in batches of 49 in 1 h 15 min, which allowed for rapid prototyping and testing of new crystal mounting designs, with a resin cost of 0.2¢ US per mount. The suitability of the 3D printed mounts for single crystal crystallography has been demonstrated through their use in Cu Kα X-ray diffraction experiments of Rochelle salt (sodium potassium tartrate), the protein lysozyme, and has been employed for routine crystallographic analysis of organic and inorganic materials.

Shear-Wave Elastography for Papillary Thyroid Carcinoma can Improve Prediction of Cervical Lymph Node Metastasis.

BACKGROUND: This study aimed to investigate whether the elasticity index of shear-wave elastography (SWE) can predict cervical lymph node (LN) metastasis of papillary thyroid carcinoma (PTC). METHODS: This retrospective study included 363 patients with a surgical diagnosis of PTC who underwent preoperative SWE evaluation. The elasticity indices of PTC (E mean, E max, E min, E ratio-p, and E ratio-m) and gray-scale ultrasound (US) parameters (extrathyroidal extension, multifocality, and cervical LN metastasis) were correlated with the pathologic staging parameters. The optimal cutoff values for the elasticity indices were determined for the prediction of cervical LN metastasis, and diagnostic performance was compared between gray-scale US and the combined application of gray-scale US and SWE. RESULTS: The findings showed E mean and E max to be associated with central LN metastasis (P = 0.037) and E min to be associated with lateral LN metastasis (P = 0.015). An E mean value higher than 124 kPa or an E max value higher than 138 kPa with suspicious gray-scale US findings improved the sensitivity and area under the curve (AUC) for predicting central LN metastasis (sensitivity, 45.4 and 44.6 % vs. 28 %, P < 0.001; AUC, 0.659 and 0.667 vs. 0.615, P = 0.011 and 0.019), whereas an E min value higher than 63 kPa with suspicious gray-scale US findings improved the sensitivity and AUC for predicting lateral LN metastasis (sensitivity, 95.8 vs. 75 %, P = 0.025; AUC, 0.924 vs. 0.871, P = 0.047). CONCLUSION: The quantitative elasticity index of PTC on preoperative SWE could be useful for predicting cervical LN metastasis.

Feasibility of 5-minute delayed transition phase imaging with 30° flip angle in gadoxetic acid-enhanced 3D gradient-echo MRI of liver, compared with 20-minute delayed hepatocyte phase MRI with standard 10° flip angle.

OBJECTIVE: The purpose of this study was to compare 5-minute delayed transitional phase imaging using a 30° flip angle (hereafter, 5 min-FA30) and 20-minute hepatocyte phase imaging using a 10° flip angle (hereafter, 20 min-FA10) in gadoxetic acid-enhanced MRI for focal hepatic lesion detection and lesion-to-liver contrast-to-noise ratio (CNR), and to determine whether 5 min-FA30 could replace 20 min-FA10 with a 15-minute time saving. MATERIALS AND METHODS: One hundred sixteen patients with 282 focal hepatic lesions (size range, 0.2-12.5 cm; malignant, n = 146; benign, n = 136) underwent gadoxetic acid-enhanced MRI with 5 min-FA30 and 20 min-FA10 with a 3D T1-weighted gradient-echo sequence. Three radiologists independently assessed the presence of focal hepatic lesions using a 4-point scale, and detection sensitivity of focal hepatic lesions was calculated. Lesion-to-liver CNRs were calculated and compared in two image groups. RESULTS: There was no significant difference in detection sensitivity of focal hepatic lesions for all three readers between 5 min-FA30 (mean, 95.4%) and 20 min-FA10 (mean, 95.6%), irrespective of lesion size or malignancy. The mean CNR on 5 min-FA30 (167.9 ± 84.1) was significantly higher than that on 20 min-FA10 (160.2 ± 79.5). However, the mean CNR difference between the two image groups was relatively small (7.8 ± 41.9). CONCLUSION: Compared with 20 min-FA10, 5 min-FA30 provided higher CNR and similar sensitivity. These findings indicate that 5 min-FA30 could replace 20-min delayed hepatocyte phase imaging using a 10° flip angle with similar diagnostic performance and 15 minutes of time saving.

Tracing binding modes in hit-to-lead optimization: chameleon-like poses of aspartic protease inhibitors.

Successful lead optimization in structure-based drug discovery depends on the correct deduction and interpretation of the underlying structure-activity relationships (SAR) to facilitate efficient decision-making on the next candidates to be synthesized. Consequently, the question arises, how frequently a binding mode (re)-validation is required, to ensure not to be misled by invalid assumptions on the binding geometry. We present an example in which minor chemical modifications within one inhibitor series lead to surprisingly different binding modes. X-ray structure determination of eight inhibitors derived from one core scaffold resulted in four different binding modes in the aspartic protease endothiapepsin, a well-established surrogate for e.g. renin and ß-secretase. In addition, we suggest an empirical metrics that might serve as an indicator during lead optimization to qualify compounds as candidates for structural revalidation.

Protein-nucleic acid complexes and the role of mass spectrometry in their structure determination.

Mass spectrometry is now established as a powerful tool for the study of the stoichiometry, interactions, dynamics, and subunit architecture of large protein assemblies and their subcomplexes. Recent evidence has suggested that the 3D structure of protein complexes can be maintained intact in the gas phase, highlighting the potential of ion mobility to contribute to structural biology. A key challenge is to integrate the compositional and structural information from ion mobility mass spectrometry with molecular modelling approaches to produce 3D models of intact protein complexes. In this review, we focus on the mass spectrometry of protein-nucleic acid assemblies with particular attention to the application of ion mobility, an emerging technique in structural studies. We also discuss the challenges that lie ahead for the full integration of ion mobility mass spectrometry with structural biology.