Radiomics in cone-beam breast CT for the prediction of axillary lymph node metastasis in breast cancer: a multi-center multi-device study.

OBJECTIVES: To develop a radiomics model in contrast-enhanced cone-beam breast CT (CE-CBBCT) for preoperative prediction of axillary lymph node (ALN) status and metastatic burden of breast cancer. METHODS: Two hundred and seventy-four patients who underwent CE-CBBCT examination with two scanners between 2012 and 2021 from two institutions were enrolled. The primary tumor was annotated in each patient image, from which 1781 radiomics features were extracted with PyRadiomics. After feature selection, support vector machine models were developed to predict ALN status and metastatic burden. To avoid overfitting on a specific patient subset, 100 randomly stratified splits were made to assign the patients to either training/fine-tuning or test set. Area under the receiver operating characteristic curve (AUC) of these radiomics models was compared to those obtained when training the models only with clinical features and combined clinical-radiomics descriptors. Ground truth was established by histopathology. RESULTS: One hundred and eighteen patients had ALN metastasis (N + (≥ 1)). Of these, 74 had low burden (N + (1~2)) and 44 high burden (N + (≥ 3)). The remaining 156 patients had none (N0). AUC values across the 100 test repeats in predicting ALN status (N0/N + (≥ 1)) were 0.75 ± 0.05 (0.67~0.93, radiomics model), 0.68 ± 0.07 (0.53~0.85, clinical model), and 0.74 ± 0.05 (0.67~0.88, combined model). For metastatic burden prediction (N + (1~2)/N + (≥ 3)), AUC values were 0.65 ± 0.10 (0.50~0.88, radiomics model), 0.55 ± 0.10 (0.40~0.80, clinical model), and 0.64 ± 0.09 (0.50~0.90, combined model), with all the ranges spanning 0.5. In both cases, the radiomics model was significantly better than the clinical model (both p < 0.01) and comparable with the combined model (p = 0.56 and 0.64). CONCLUSIONS: Radiomics features of primary tumors could have potential in predicting ALN metastasis in CE-CBBCT imaging. CLINICAL RELEVANCE STATEMENT: The findings support potential clinical use of radiomics for predicting axillary lymph node metastasis in breast cancer patients and addressing the limited axilla coverage of cone-beam breast CT. KEY POINTS: • Contrast-enhanced cone-beam breast CT-based radiomics could have potential to predict N0 vs. N + (≥ 1) and, to a limited extent, N + (1~2) vs. N + (≥ 3) from primary tumor, and this could help address the limited axilla coverage, pending future verifications on larger cohorts. • The average AUC of radiomics and combined models was significantly higher than that of clinical models but showed no significant difference between themselves. • Radiomics features descriptive of tumor texture were found informative on axillary lymph node status, highlighting a higher heterogeneity for tumor with positive axillary lymph node.

Radiomics nomogram for predicting axillary lymph node metastasis-a potential method to address the limitation of axilla coverage in cone-beam breast CT: a bi-center retrospective study.

PURPOSE: Cone-beam breast CT (CBBCT) has an inherent limitation that the axilla cannot be imaged in its entirety. We aimed to develop and validate a nomogram based on clinical factors and contrast-enhanced (CE) CBBCT radiomics features to predict axillary lymph node (ALN) metastasis and complement limited axilla coverage. MATERIAL AND METHODS: This retrospective study included 312 patients with breast cancer from two hospitals who underwent CE-CBBCT examination in a clinical trial (NCT01792999) during 2012-2020. Patients from TCIH comprised training set (n = 176) and validation set (n = 43), and patients from SYSUCC comprised external test set (n = 93). 3D ROIs were delineated manually and radiomics features were extracted by 3D Slicer software. RadScore was calculated and radiomics model was constructed after feature selection. Clinical model was built on independent predictors. Nomogram was developed with independent clinical predictors and RadScore. Diagnostic performance was compared among three models by ROC curve, and decision curve analysis (DCA) was used to evaluate the clinical utility of nomogram. RESULTS: A total of 139 patients were ALN positive and 173 patients were negative. Twelve radiomics features remained after feature selection. Location and focality were selected as independent predictors for ALN status. The AUC of nomogram in external test set was higher than that of clinical model (0.80 vs. 0.66, p = 0.012). DCA demonstrated that the nomogram had higher overall net benefit than that of clinical model. CONCLUSION: The nomogram combined CE-CBBCT-based radiomics features and clinical factors could have potential in distinguishing ALN positive from negative and addressing the limitation of axilla coverage in CBBCT.

Promoting the Recruitment, Engagement, and Reinvigoration of Effector T Cells via an Injectable Hydrogel with a Supramolecular Binding Capability for Cancer Immunotherapy.

T cells play a basic and key role in immunotherapy against solid tumors, and efficiently recruiting them into neoplastic foci and sustaining long-term effector function are consistent goals that remain a critical challenge. Here, an injectable alginate-based hydrogel with abundant ß-cyclodextrin (ALG-ßCD) sites is developed and intratumorally injected to recruit CCR9+ CD8+ T cells (a subset of T cells with robust antitumor activity) via the trapped chemokine CCL25. In the meantime, an intravenously injected adamantane-decorated anti-PD1 antibody (Ad-aPD1) would hitchhike on recruited CCR9+ CD8+ T cells to achieve the improved intratumoral accumulation of Ad-aPD1. Moreover, the Ad-PD1 and Ad-PDL1 antibodies are immobilized in the ALG-ßCD hydrogel through supramolecular host-guest interactions of Ad and ßCD, which facilitate engagement between CD8+ T cells and tumor cells and reinvigorate CD8+ T cells to avoid exhaustion. Based on this treatment strategy, T cell-mediated anticancer activity is promoted at multiple levels, eventually achieving superior antitumor efficacy in both orthotopic and postsurgical B16-F10 tumor models.

Inhibiting zero-order light of a spatial light modulator with voltage optimization.

The crucial zero-order light due to the pixelation effect of spatial light modulator (SLM) has been a serious issue in the field of light modulation, especially in applications with a high numerical aperture optical system. In this investigation, we report that by properly adjusting the high-level and low-level pixel voltages of an SLM, the zero-order light caused by the pixelation effect of an SLM can be significantly eliminated. The method is further validated under an inverted fluorescence microscope. The experimental results show that the zero-order light can be inhibited up to 91.3%, accompanied by an improvement of the modulation efficiency from 77.5% to 92.6%.

Multi-Focal Laser Direct Writing through Spatial Light Modulation Guided by Scalable Vector Graphics.

Multi-focal laser direct writing (LDW) based on phase-only spatial light modulation (SLM) can realize flexible and parallel nanofabrication with high-throughput potential. In this investigation, a novel approach of combining two-photon absorption, SLM, and vector path-guided by scalable vector graphics (SVGs), termed SVG-guided SLM LDW, was developed and preliminarily tested for fast, flexible, and parallel nanofabrication. Three laser focuses were independently controlled with different paths, which were optimized according to the SVG to improve fabrication and promote time efficiency. The minimum structure width could be as low as 81 nm. Accompanied by a translation stage, a carp structure of 18.10 µm × 24.56 µm was fabricated. This method shows the possibility of developing LDW techniques toward fully electrical systems, and provides a potential way to efficiently engrave complex structures on nanoscales.

Biomimetic Nanoparticle with Glutathione Depletion and Amplified ROS Generation Capabilities for Synergistic Chemo-Sonodynamic Therapy in Squamous Cell Carcinomas.

Nanomedicines for combining chemotherapy and sonodynamic therapy (SDT) have enormous potential in squamous cell carcinoma treatment. However, the therapeutic efficacy of noninvasive SDT is severely limited because the generation of reactive oxygen species (ROS) by sonosensitizers is highly dependent on the levels of intracellular excess glutathione (GSH) in the tumor cells. To overcome this barrier, a red blood cell (RBC) membrane-camouflaged nanomedicine consisting of GSH-sensitive polyphosphoester (SS-PPE) and ROS-sensitive polyphosphoester (S-PPE) was designed for the simultaneous delivery of the sonosensitizer hematoporphyrin (HMME) and chemotherapeutic agent docetaxel (DTXL) for effectively enhanced antitumor efficacy. In vitro and in vivo studies demonstrated that HMME-driven ROS generation under ultrasound (US) inhibited SCC7 cell proliferation and accelerated DTXL release to further kill tumor cells via the hydrophobic-hydrophilic transition of the nanoparticle core. Meanwhile, the disulfide bond of SS-PPE effectively consumes GSH to prevent ROS consumption. This biomimetic nanomedicine provides GSH depletion and amplified ROS generation capabilities to achieve a novel synergistic chemo-SDT strategy for squamous cell carcinomas.

Flow Cytometry with Anti-Diffraction Light Sheet (ADLS) by Spatial Light Modulation.

Flow cytometry is a widespread and powerful technique whose resolution is determined by its capacity to accurately distinguish fluorescently positive populations from negative ones. However, most informative results are discarded while performing the measurements of conventional flow cytometry, e.g., the cell size, shape, morphology, and distribution or location of labeled exosomes within the unpurified biological samples. Herein, we propose a novel approach using an anti-diffraction light sheet with anisotroic feature to excite fluorescent tags. Constituted by an anti-diffraction Bessel-Gaussian beam array, the light sheet is 12 µm wide, 12 µm high, and has a thickness of ~0.8 µm. The intensity profile of the excited fluorescent signal can, therefore, reflect the size and allow samples in the range from O (100 nm) to 10 µm (e.g., blood cells) to be transported via hydrodynamic focusing in a microfluidic chip. The sampling rate is 500 kHz, which provides a capability of high throughput without sacrificing the spatial resolution. Consequently, the proposed anti-diffraction light sheet flow cytometry (ADLSFC) can obtain more informative results than the conventional methodologies, and is able to provide multiple characteristics (e.g., the size and distribution of fluorescent signal) helping to distinguish the target samples from the complex backgrounds.

Accuracy of Preoperative Contrast-enhanced Cone Beam Breast CT in Assessment of Residual Tumor after Neoadjuvant Chemotherapy: A Comparative Study with Breast MRI.

RATIONALE AND OBJECTIVES: To compare the accuracy of preoperative contrast-enhanced cone beam breast CT (CE-CBBCT) and MRI in assessment of residual tumor after neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: Residual tumor assessments in 91 female patients were performed on preoperative CE-CBBCT and MRI images after NAC. The agreements of tumor size between imaging and pathology were tested by Intraclass Correlation Coefficient (ICC). Subgroup analyses were set according to ductal carcinoma in situ (DCIS), calcifications and molecular subtypes. Correlated-samples Wilcoxon Signed-rank test was used to analyze the difference between imaging and pathology in total and subgroups. AUC, sensitivity, specificity, PPV, and NPV were calculated to compare the performance of CE-CBBCT and MRI in predicting pathological complete response (pCR). RESULTS: Comparing with pathology, the agreement on CE-CBBCT was good (ICC = 0.64, 95% CI, 0.35-0.78), whereas on MRI was moderate (ICC = 0.59, 95% CI, 0.36-0.77), and overestimation on CE-CBBCT was less than that on MRI (median (interquartile range, IQR): 0.24 [0.00, 1.31] cm vs. 0.67 [0.00, 1.81] cm; p = 0.000). In subgroup analysis, CE-CBBCT showed superior accuracy than MRI when residual DCIS (p = 0.000) and calcifications (p = 0.000) contained, as well as luminal A (p = 0.043) and luminal B (p = 0.009) breast cancer. CE-CBBCT and MRI performed comparable in predicting pCR, AUCs were 0.749 and 0.733 respectively (p > 0.05). CONCLUSION: CE-CBBCT showed superior accuracy in assessment of residual tumor compared with MRI, especially when residual DCIS or calcifications contained and luminal subtype. The performance of preoperative CE-CBBCT in predicting pCR was comparable to MRI. CE-CBBCT could be an alternative method used for preoperative assessment after NAC.

A Magnetically Driven Amoeba-Like Nanorobot for Whole-Process Active Drug Transport.

The passive diffusion performance of nanocarriers results in inefficient drug transport across multiple biological barriers and consequently cancer therapy failure. Here, a magnetically driven amoeba-like nanorobot (amNR) is presented for whole-process active drug transport. The amNR is actively extravasated from blood vessels and penetrated into deep tumor tissue through a magnetically driven deformation effect. Moreover, the acidic microenvironment of deep tumor tissue uncovers the masked targeting ligand of amNR to achieve active tumor cell uptake. Furthermore, the amNR rapidly releases the encapsulated doxorubicin (DOX) after alternating magnetic field application. The amNRs eventually deliver DOX into ≈92.3% of tumor cells and completely delay tumor growth with an inhibition rate of 96.1%. The deformable amNRs, with the assistance of magnetic field application, provide a facile strategy for whole-process active drug transport.

Comparison of malignant calcification identification between breast cone-beam computed tomography and digital mammography.

BACKGROUND: Calcifications are important abnormal findings in breast imaging and help in the diagnosis of breast cancer. PURPOSE: To compare breast cone-beam computed tomography (CBCT) with digital mammography (DM) in terms of the ability to identify malignant calcifications. MATERIAL AND METHODS: In total, 115 paired examinations were performed utilizing breast CBCT and DM; 86 pathology-proven malignant lesions with calcifications detected on DM and 29 randomly selected breasts without calcifications were reviewed by three radiologists. The ability to detect calcifications was assessed on CBCT images. The characterization agreement of two imaging modalities was evaluated by the kappa coefficient. For breast CBCT images, the parameters for the display of calcifications were recorded. The Kruskal-Wallis test was used to compare the preferred slice thickness chosen by each of the three radiologists. The degree of calcification clarity was compared between two modalities using the Mann-Whitney U-test. RESULTS: The combined sensitivity and specificity of three radiologists in 85 DM-detected calcifications detection on breast CBCT images were 98.43% (251/255) and 98.85% (86/87), respectively. CBCT images showed substantial agreement with mammograms in terms of the characterization of calcifications morphology (k = 0.703; P < 0.05) and distribution (k = 0.629; P < 0.05). CBCT images with a slice thickness of 0.273 mm and three-dimensional maximum-intensity projection (3D-MIP) were more beneficial for calcifications identification. No statistically significant difference was found between standard DM views and CBCT images for three radiologists on calcification display clarity. CONCLUSION: CBCT images were comparable to mammograms in calcification identification and may be sufficient for malignant calcifications detection and characterization.

Self-assembling ferrimagnetic fluorescent micelles for bioimaging guided efficient magnetic hyperthermia therapy.

Multifunctional magnet-fluorescent nanocomposites are widely applied in biomedical applications. Incorporating biocompatible quantum dots with highly ferrimagnetic magnetic nanoparticles into one nanoplatform for achieving efficient magnetic hyperthermia therapy (MHT) is very important. Herein, we reported an amphiphilic block copolymer with a flowable hydrophobic chain to encapsulate highly ferrimagnetic magnetic nanoparticles and ZnS/InP quantum dots via a facile self-assembly method. The obtained ferrimagnetic fluorescent micelle (FMFM) exhibited a uniform diameter of about 180 nm. In stark contrast, larger aggregation (400 nm in diameter) inevitably occurred using common poly(D,L-lactide) (PLA)-based amphiphilic block copolymer with a rigid hydrophobic chain, which was readily cleared by the reticuloendothelial system (RES). The flowable FMFM exhibited long-term colloidal stability within one month and desired fluorescent stability within 84 h. Benefiting from the high ferrimagnetism, the FMFM revealed excellent magnetic heating effect and magnetic resonance imaging capability. With accurate manipulation under an external magnetic field, FMFM realized in vitro enhanced fluorescence imaging sensitivity and accumulation efficiency at the tumor region, achieving in vitro and vivo improved MHT efficacy.

In Situ Programming of Nanovaccines for Lymph Node-Targeted Delivery and Cancer Immunotherapy.

In situ cancer vaccines consisting of antigens and adjuvants are a promising cancer treatment modality; however, the convenient manufacture of vaccines in vivo and their efficient delivery to lymph nodes (LNs) remains a major challenge. Herein, we outline a facile approach to simultaneously achieve the in situ programming of vaccines via two synergetic nanomedicines, Tu-NPFN and Ln-NPR848. Tu-NPFN (∼100 nm) generated a large number of antigens under an alternating magnetic field, and Ln-NPR848 (∼35 nm) encapsulating adjuvant R848 captured a portion of generated antigens for the manufacture of nanovaccines in situ and LN-targeted delivery, which significantly promoted the uptake and maturation of dendritic cells to initiate potent anticancer immune responses. Notably, combined with an anti-CTLA4 antibody (aCTLA-4), this therapy completely eradicated distant tumors in some mice and exerted a long-term immune memory effect on tumor metastasis. This study provides a generalizable strategy for in situ cancer vaccination.

Mixing and Flow Transition in an Optimized Electrokinetic Turbulent Micromixer.

Micromixer is a key element in a lab on a chip for broad applications in the analysis and measurement of chemistry and engineering. Previous investigations reported that electrokinetic (EK) turbulence could be realized in a "Y" type micromixer with a cross-sectional dimension of 100 µm order. Although the ultrafast turbulent mixing can be generated at a bulk flow Reynolds number on the order of unity, the micromixer has not been optimized. In this investigation, we systematically investigated the influence of electric field intensity, AC frequency, electric conductivity ratio, and channel width at the entrance on the mixing effect and transition electric Rayleigh number in the "Y" type electrokinetic turbulent micromixer. It is found that the optimal mixing is realized in a 350 µm wide micromixer, under 100 kHz and 1.14 × 105 V/m AC electric field, with an electric conductivity ratio of 1:3000. Under these conditions, a degree of mixedness of 0.93 can be achieved at 84 µm from the entrance and 100 ms. A further investigation of the critical electric field and the critical electric Rayleigh number indicates that the most unstable condition of EK flow instability is inconsistent with that of the optimal mixing in EK turbulence. To predict the evolution of EK flow under high Raσ and guide the design of EK turbulent micromixers, it is necessary to apply a computational turbulence model instead of linear instability analysis.

Comparison of background parenchymal enhancement (BPE) on contrast-enhanced cone-beam breast CT (CE-CBBCT) and breast MRI.

OBJECTIVES: To compare the background parenchymal enhancement (BPE) levels on contrast-enhanced cone-beam breast CT (CE-CBBCT) and MRI, evaluate inter-reader reliability, and analyze the relationship between clinical factors and BPE level on CE-CBBCT. METHODS: In this retrospective study, patients who underwent both CE-CBBCT and MRI were analyzed. BPE levels on CE-CBBCT and MRI were assessed by five specialists independently in random fashion, with a wash-out period of 4 weeks. Weighted kappa was used to analyze the agreement between CE-CBBCT and MRI, and intraclass correlation coefficient (ICC) was used to evaluate the inter-reader reliability for each modality. The association between BPE level on CE-CBBCT and clinical factors was evaluated by univariate and multivariate logistic regression. RESULTS: A total of 221 patients from January 2017 to April 2021 were enrolled. CE-CBBCT showed substantial agreement (weighted kappa = 0.690) with MRI for BPE evaluation, with good degree of inter-reader reliability on both CE-CBBCT (ICC = 0.712) and MRI (ICC = 0.757). Based on majority reports, BPE levels on CE-CBBCT were lower than MRI (p < 0.001). BPE level on CE-CBBCT was significantly associated with menstrual status (odds ratio, OR = 0.125), breast density (OR = 2.308), and previously treated breast cancer (OR = 0.052) (all p < 0.05). BPE level for premenopausal patients was associated with menstrual cycle, with lower BPE level for the 2nd week of menstrual cycle (OR = 0.246). CONCLUSIONS: CE-CBBCT showed substantial agreement and comparable inter-reader reliability with MRI for BPE evaluation, indicating that the corresponding BI-RADS lexicons could be used to describe BPE level on CE-CBBCT. The 2nd week of menstrual cycle timing is suggested as the optimal examination period for CE-CBBCT. KEY POINTS: • CE-CBBCT showed substantial agreement and comparable inter-reader reliability with MRI for BPE evaluation. • Menstrual status, breast density, and previously treated breast cancer were associated with the BPE level on CE-CBBCT images. • The 2ndweek of the menstrual cycle is suggested as the optimal examination period for CE-CBBCT.

Non-iterative multifold strip segmentation phase method for six-dimensional optical field modulation.

In this Letter, we propose a non-iterative multifold strip segmentation phase method for a spatial light modulator (SLM) to generate multifocal spots of diverse beams (Airy, spiral, perfect vortex, and Bessel-Gaussian beams) in a high-numerical-aperture system, with up to 6D controllability. The method is further validated by an inverted fluorescence microscope. By adjusting the bright and dark voltage parameters of the SLM, zero-order light caused by the pixelation effect of the SLM has been successfully eliminated. We hope this research provides a more flexible and powerful approach for the rapid modulation of multi-focus light fields in the development of biomedicine and lithography.

Dedicated breast CT: state of the art-Part I. Historical evolution and technical aspects.

Dedicated breast CT is an emerging 3D isotropic imaging technology for breast, which overcomes the limitations of 2D compression mammography and limited angle tomosynthesis while providing some of the advantages of magnetic resonance imaging. This first installment in a 2-part review describes the evolution of dedicated breast CT beginning with a historical perspective and progressing to the present day. Moreover, it provides an overview of state-of-the-art technology. Particular emphasis is placed on technical limitations in scan protocol, radiation dose, breast coverage, patient comfort, and image artifact. Proposed methods of how to address these technical challenges are also discussed. KEY POINTS: • Advantages of breast CT include no tissue overlap, improved patient comfort, rapid acquisition, and concurrent assessment of microcalcifications and contrast enhancement. • Current clinical and prototype dedicated breast CT systems differ in acquisition modes, imaging techniques, and detector types. • There are still details to be decided regarding breast CT techniques, such as scan protocol, radiation dose, breast coverage, patient comfort, and image artifact.

Dedicated breast CT: state of the art-Part II. Clinical application and future outlook.

Dedicated breast CT is being increasingly used for breast imaging. This technique provides images with no compression, removal of tissue overlap, rapid acquisition, and available simultaneous assessment of microcalcifications and contrast enhancement. In this second installment in a 2-part review, the current status of clinical applications and ongoing efforts to develop new imaging systems are discussed, with particular emphasis on how to achieve optimized practice including lesion detection and characterization, response to therapy monitoring, density assessment, intervention, and implant evaluation. The potential for future screening with breast CT is also addressed. KEY POINTS: • Dedicated breast CT is an emerging modality with enormous potential in the future of breast imaging by addressing numerous clinical needs from diagnosis to treatment. • Breast CT shows either noninferiority or superiority with mammography and numerical comparability to MRI after contrast administration in diagnostic statistics, demonstrates excellent performance in lesion characterization, density assessment, and intervention, and exhibits promise in implant evaluation, while potential application to breast cancer screening is still controversial. • New imaging modalities such as phase-contrast breast CT, spectral breast CT, and hybrid imaging are in the progress of R & D.

A tumor acidity-driven transformable polymeric nanoassembly with deep tumor penetration and membrane-anchoring capability for targeted photodynamic therapy.

In recent years, directly damaging cell membrane therapeutic modalities have attracted great attention in the field of cancer therapy due to their critical role in guaranteeing essential cellular function. In this study, the transformable nanoassembly PEG-Ce6@PAEMA, consisting of the photosensitizer polyethylene glycol-chlorin-e6 (PEG-Ce6) and tumor pH-sensitive polymer poly(2-azepane ethyl methacrylate) (PAEMA), was developed for highly efficient membrane-targeted photodynamic therapy. The PAEMA core is rapidly protonated at the acidic tumor pH, resulting in the disassembly of PEG-Ce6@PAEMA and regeneration of PEG-Ce6. Subsequently, the resultant PEG-Ce6 with a very small size (~2.6 kDa) ensures deep penetration into tumor tissue and direct and rapid anchoring to the cancer cell membrane, eventually achieving superior tumor growth inhibition under light irradiation. Thus, this tumor acidity-driven transformable polymeric nanoassembly provides a simple but efficient strategy for membrane targeting cancer therapy.