PET/MRI of hypoxia and vascular function in ER-positive breast cancer: correlations with immunohistochemistry.

OBJECTIVES: To explore the relationship between indices of hypoxia and vascular function from 18F-fluoromisonidazole ([18F]-FMISO)-PET/MRI with immunohistochemical markers of hypoxia and vascularity in oestrogen receptor-positive (ER +) breast cancer. METHODS: Women aged > 18 years with biopsy-confirmed, treatment-naïve primary ER + breast cancer underwent [18F]-FMISO-PET/MRI prior to surgery. Parameters of vascular function were derived from DCE-MRI using the extended Tofts model, whilst hypoxia was assessed using the [18F]-FMISO influx rate constant, Ki. Histological tumour sections were stained with CD31, hypoxia-inducible factor (HIF)-1α, and carbonic anhydrase IX (CAIX). The number of tumour microvessels, median vessel diameter, and microvessel density (MVD) were obtained from CD31 immunohistochemistry. HIF-1α and CAIX expression were assessed using histoscores obtained by multiplying the percentage of positive cells stained by the staining intensity. Regression analysis was used to study associations between imaging and immunohistochemistry variables. RESULTS: Of the lesions examined, 14/22 (64%) were ductal cancers, grade 2 or 3 (19/22; 86%), with 17/22 (77%) HER2-negative. [18F]-FMISO Ki associated negatively with vessel diameter (p = 0.03), MVD (p = 0.02), and CAIX expression (p = 0.002), whilst no significant relationships were found between DCE-MRI pharmacokinetic parameters and immunohistochemical variables. HIF-1α did not significantly associate with any PET/MR imaging indices. CONCLUSION: Hypoxia measured by [18F]-FMISO-PET was associated with increased CAIX expression, low MVD, and smaller vessel diameters in ER + breast cancer, further corroborating the link between inadequate vascularity and hypoxia in ER + breast cancer. KEY POINTS: • Hypoxia, measured by [18F]-FMISO-PET, was associated with low microvessel density and small vessel diameters, corroborating the link between inadequate vascularity and hypoxia in ER + breast cancer. • Increased CAIX expression was associated with higher levels of hypoxia measured by [18F]-FMISO-PET. • Morphologic and functional abnormalities of the tumour microvasculature are the major determinants of hypoxia in cancers and support the previously reported perfusion-driven character of hypoxia in breast carcinomas.

Sodium accumulation in breast cancer predicts malignancy and treatment response.

BACKGROUND: Breast cancer remains a leading cause of death in women and novel imaging biomarkers are urgently required. Here, we demonstrate the diagnostic and treatment-monitoring potential of non-invasive sodium (23Na) MRI in preclinical models of breast cancer. METHODS: Female Rag2-/- Il2rg-/- and Balb/c mice bearing orthotopic breast tumours (MDA-MB-231, EMT6 and 4T1) underwent MRI as part of a randomised, controlled, interventional study. Tumour biology was probed using ex vivo fluorescence microscopy and electrophysiology. RESULTS: 23Na MRI revealed elevated sodium concentration ([Na+]) in tumours vs non-tumour regions. Complementary proton-based diffusion-weighted imaging (DWI) linked elevated tumour [Na+] to increased cellularity. Combining 23Na MRI and DWI measurements enabled superior classification accuracy of tumour vs non-tumour regions compared with either parameter alone. Ex vivo assessment of isolated tumour slices confirmed elevated intracellular [Na+] ([Na+]i); extracellular [Na+] ([Na+]e) remained unchanged. Treatment with specific inward Na+ conductance inhibitors (cariporide, eslicarbazepine acetate) did not affect tumour [Na+]. Nonetheless, effective treatment with docetaxel reduced tumour [Na+], whereas DWI measures were unchanged. CONCLUSIONS: Orthotopic breast cancer models exhibit elevated tumour [Na+] that is driven by aberrantly elevated [Na+]i. Moreover, 23Na MRI enhances the diagnostic capability of DWI and represents a novel, non-invasive biomarker of treatment response with superior sensitivity compared to DWI alone.

Machine Learning for Workflow Applications in Screening Mammography: Systematic Review and Meta-Analysis.

Background Advances in computer processing and improvements in data availability have led to the development of machine learning (ML) techniques for mammographic imaging. Purpose To evaluate the reported performance of stand-alone ML applications for screening mammography workflow. Materials and Methods Ovid Embase, Ovid Medline, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science literature databases were searched for relevant studies published from January 2012 to September 2020. The study was registered with the PROSPERO International Prospective Register of Systematic Reviews (protocol no. CRD42019156016). Stand-alone technology was defined as a ML algorithm that can be used independently of a human reader. Studies were quality assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 and the Prediction Model Risk of Bias Assessment Tool, and reporting was evaluated using the Checklist for Artificial Intelligence in Medical Imaging. A primary meta-analysis included the top-performing algorithm and corresponding reader performance from which pooled summary estimates for the area under the receiver operating characteristic curve (AUC) were calculated using a bivariate model. Results Fourteen articles were included, which detailed 15 studies for stand-alone detection (n = 8) and triage (n = 7). Triage studies reported that 17%-91% of normal mammograms identified could be read by adapted screening, while "missing" an estimated 0%-7% of cancers. In total, an estimated 185 252 cases from three countries with more than 39 readers were included in the primary meta-analysis. The pooled sensitivity, specificity, and AUC was 75.4% (95% CI: 65.6, 83.2; P = .11), 90.6% (95% CI: 82.9, 95.0; P = .40), and 0.89 (95% CI: 0.84, 0.98), respectively, for algorithms, and 73.0% (95% CI: 60.7, 82.6), 88.6% (95% CI: 72.4, 95.8), and 0.85 (95% CI: 0.78, 0.97), respectively, for readers. Conclusion Machine learning (ML) algorithms that demonstrate a stand-alone application in mammographic screening workflows achieve or even exceed human reader detection performance and improve efficiency. However, this evidence is from a small number of retrospective studies. Therefore, further rigorous independent external prospective testing of ML algorithms to assess performance at preassigned thresholds is required to support these claims. ©RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Whitman and Moseley in this issue.

Adoption of artificial intelligence in breast imaging: evaluation, ethical constraints and limitations.

Retrospective studies have shown artificial intelligence (AI) algorithms can match as well as enhance radiologist's performance in breast screening. These tools can facilitate tasks not feasible by humans such as the automatic triage of patients and prediction of treatment outcomes. Breast imaging faces growing pressure with the exponential growth in imaging requests and a predicted reduced workforce to provide reports. Solutions to alleviate these pressures are being sought with an increasing interest in the adoption of AI to improve workflow efficiency as well as patient outcomes. Vast quantities of data are needed to test and monitor AI algorithms before and after their incorporation into healthcare systems. Availability of data is currently limited, although strategies are being devised to harness the data that already exists within healthcare institutions. Challenges that underpin the realisation of AI into everyday breast imaging cannot be underestimated and the provision of guidance from national agencies to tackle these challenges, taking into account views from a societal, industrial and healthcare prospective is essential. This review provides background on the evaluation and use of AI in breast imaging in addition to exploring key ethical, technical, legal and regulatory challenges that have been identified so far.

Hypoxia and perfusion in breast cancer: simultaneous assessment using PET/MR imaging.

OBJECTIVES: Hypoxia is associated with poor prognosis and treatment resistance in breast cancer. However, the temporally variant nature of hypoxia can complicate interpretation of imaging findings. We explored the relationship between hypoxia and vascular function in breast tumours through combined 18F-fluoromisonidazole (18 F-FMISO) PET/MRI, with simultaneous assessment circumventing the effect of temporal variation in hypoxia and perfusion. METHODS: Women with histologically confirmed, primary breast cancer underwent a simultaneous 18F-FMISO-PET/MR examination. Tumour hypoxia was assessed using influx rate constant Ki and hypoxic fractions (%HF), while parameters of vascular function (Ktrans, kep, ve, vp) and cellularity (ADC) were derived from dynamic contrast-enhanced (DCE) and diffusion-weighted (DW)-MRI, respectively. Additional correlates included histological subtype, grade and size. Relationships between imaging variables were assessed using Pearson correlation (r). RESULTS: Twenty-nine women with 32 lesions were assessed. Hypoxic fractions > 1% were observed in 6/32 (19%) cancers, while 18/32 (56%) tumours showed a %HF of zero. The presence of hypoxia in lesions was independent of histological subtype or grade. Mean tumour Ktrans correlated negatively with Ki (r = - 0.38, p = 0.04) and %HF (r = - 0.33, p = 0.04), though parametric maps exhibited intratumoural heterogeneity with hypoxic regions colocalising with both hypo- and hyperperfused areas. No correlation was observed between ADC and DCE-MRI or PET parameters. %HF correlated positively with lesion size (r = 0.63, p = 0.001). CONCLUSION: Hypoxia measured by 18F-FMISO-PET correlated negatively with Ktrans from DCE-MRI, supporting the hypothesis of perfusion-driven hypoxia in breast cancer. Intratumoural hypoxia-perfusion relationships were heterogeneous, suggesting that combined assessment may be needed for disease characterisation, which could be achieved using simultaneous multimodality imaging. KEY POINTS: • At the tumour level, hypoxia measured by 18F-FMISO-PET was negatively correlated with perfusion measured by DCE-MRI, which supports the hypothesis of perfusion-driven hypoxia in breast cancer. • No associations were observed between 18F-FMISO-PET parameters and tumour histology or grade, but tumour hypoxic fractions increased with lesion size. • Intratumoural hypoxia-perfusion relationships were heterogeneous, suggesting that the combined hypoxia-perfusion status of tumours may need to be considered for disease characterisation, which can be achieved via simultaneous multimodality imaging as reported here.

Dynamic contrast-enhanced computed tomography for the diagnosis of solitary pulmonary nodules: a systematic review and meta-analysis.

INTRODUCTION: A systematic review and meta-analysis were performed to determine the diagnostic performance of dynamic contrast-enhanced computed tomography (DCE-CT) for the differentiation between malignant and benign pulmonary nodules. METHODS: Ovid MEDLINE and EMBASE were searched for studies published up to October 2018 on the diagnostic accuracy of DCE-CT for the characterisation of pulmonary nodules. For the index test, studies with a minimum of a pre- and post-contrast computed tomography scan were evaluated. Studies with a reference standard of biopsy for malignancy, and biopsy or 2-year follow-up for benign disease were included. Study bias was assessed using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies). The sensitivities, specificities, and diagnostic odds ratios were determined along with 95% confidence intervals (CIs) using a bivariate random effects model. RESULTS: Twenty-three studies were included, including 2397 study participants with 2514 nodules of which 55.3% were malignant (1389/2514). The pooled accuracy results were sensitivity 94.8% (95% CI 91.5; 96.9), specificity 75.5% (69.4; 80.6), and diagnostic odds ratio 56.6 (24.2-88.9). QUADAS 2 assessment showed intermediate/high risk of bias in a large proportion of the studies (52-78% across the domains). No difference was present in sensitivity or specificity between subgroups when studies were split based on CT technique, sample size, nodule size, or publication date. CONCLUSION: DCE-CT has a high diagnostic accuracy for the diagnosis of pulmonary nodules although study quality was indeterminate in a large number of cases. KEY POINTS: • The pooled accuracy results were sensitivity 95.1% and specificity 73.8% although individual studies showed wide ranges of values. • This is comparable to the results of previous meta-analyses of PET/CT (positron emission tomography/computed tomography) diagnostic accuracy for the diagnosis of solitary pulmonary nodules. • Robust direct comparative accuracy and cost-effectiveness studies are warranted to determine the optimal use of DCE-CT and PET/CT in the diagnosis of SPNs.

A Meta-analysis of the Diagnostic Performance of Diffusion MRI for Breast Lesion Characterization.

Background Various techniques are available to assess diffusion properties of breast lesions as a marker of malignancy at MRI. The diagnostic performance of these diffusion markers has not been comprehensively assessed. Purpose To compare by meta-analysis the diagnostic performance of parameters from diffusion-weighted imaging (DWI), diffusion-tensor imaging (DTI), and intravoxel incoherent motion (IVIM) in the differential diagnosis of malignant and benign breast lesions. Materials and Methods PubMed and Embase databases were searched from January to March 2018 for studies in English that assessed the diagnostic performance of DWI, DTI, and IVIM in the breast. Studies were reviewed according to eligibility and exclusion criteria. Publication bias and heterogeneity between studies were assessed. Pooled summary estimates for sensitivity, specificity, and area under the curve were obtained for each parameter by using a bivariate model. A subanalysis investigated the effect of MRI parameters on diagnostic performance by using a Student t test or a one-way analysis of variance. Results From 73 eligible studies, 6791 lesions (3930 malignant and 2861 benign) were included. Publication bias was evident for studies that evaluated apparent diffusion coefficient (ADC). Significant heterogeneity (P < .05) was present for all parameters except the perfusion fraction (f). The pooled sensitivity, specificity, and area under the curve for ADC was 89%, 82%, and 0.92, respectively. The highest performing parameter for DTI was the prime diffusion coefficient (λ1), and pooled sensitivity, specificity, and area under the curve was 93%, 90%, and 0.94, respectively. The highest performing parameter for IVIM was tissue diffusivity (D), and the pooled sensitivity, specificity, and area under the curve was 88%, 79%, and 0.90. Choice of MRI parameters had no significant effect on diagnostic performance. Conclusion Diffusion-weighted imaging, diffusion-tensor imaging, and intravoxel incoherent motion have comparable diagnostic accuracy with high sensitivity and specificity. Intravoxel incoherent motion is comparable to apparent diffusion coefficient. Diffusion-tensor imaging is potentially promising but to date the number of studies is limited. © RSNA, 2019 Online supplemental material is available for this article.

23Na MRI: inter-reader reproducibility of normal fibroglandular sodium concentration measurements at 3 T.

BACKGROUND: To study the reproducibility of 23Na magnetic resonance imaging (MRI) measurements from breast tissue in healthy volunteers. METHODS: Using a dual-tuned bilateral 23Na/1H breast coil at 3-T MRI, high-resolution 23Na MRI three-dimensional cones sequences were used to quantify total sodium concentration (TSC) and fluid-attenuated sodium concentration (FASC). B1-corrected TSC and FASC maps were created. Two readers manually measured mean, minimum and maximum TSC and mean FASC values using two sampling methods: large regions of interest (LROIs) and small regions of interest (SROIs) encompassing fibroglandular tissue (FGT) and the highest signal area at the level of the nipple, respectively. The reproducibility of the measurements and correlations between density, age and FGT apparent diffusion coefficient (ADC) values were evaluatedss. RESULTS: Nine healthy volunteers were included. The inter-reader reproducibility of TSC and FASC using SROIs and LROIs was excellent (intraclass coefficient range 0.945-0.979, p < 0.001), except for the minimum TSC LROI measurements (p = 0.369). The mean/minimum LROI TSC and mean LROI FASC values were lower than the respective SROI values (p < 0.001); the maximum LROI TSC values were higher than the SROI TSC values (p = 0.009). TSC correlated inversely with age but not with FGT ADCs. The mean and maximum FGT TSC and FASC values were higher in dense breasts in comparison to non-dense breasts (p < 0.020). CONCLUSIONS: The chosen sampling method and the selected descriptive value affect the measured TSC and FASC values, although the inter-reader reproducibility of the measurements is in general excellent. RELEVANCE STATEMENT: 23Na MRI at 3 T allows the quantification of TSC and FASC sodium concentrations. The sodium measurements should be obtained consistently in a uniform manner. KEY POINTS: • 23Na MRI allows the quantification of total and fluid-attenuated sodium concentrations (TSC/FASC). • Sampling method (large/small region of interest) affects the TSC and FASC values. • Dense breasts have higher TSC and FASC values than non-dense breasts. • The inter-reader reproducibility of TSC and FASC measurements was, in general, excellent. • The results suggest the importance of stratifying the sodium measurements protocol.

Evaluation of pretreatment ADC values as predictors of treatment response to neoadjuvant chemotherapy in patients with breast cancer - a multicenter study.

BACKGROUND: Magnetic resonance imaging (MRI) can be used to diagnose breast cancer. Diffusion weighted imaging (DWI) and the apparent diffusion coefficient (ADC) can reflect tumor microstructure in a non-invasive manner. The correct prediction of response of neoadjuvant chemotherapy (NAC) is crucial for clinical routine. Our aim was to compare ADC values between patients with pathological complete response (pCR) and non-responders based upon a multi-center design to improve the correct patient selection, which patient would more benefit from NAC and which patient would not. METHODS: For this study, data from 4 centers (from Japan, Brazil, Spain and United Kingdom) were retrospectively acquired. The time period was overall 2003-2019. The patient sample comprises 250 patients (all female; median age, 50.5). In every case, pretreatment breast MRI with DWI was performed. pCR was assessed by experienced pathologists in every center using the surgical specimen in the clinical routine work up. pCR was defined as no residual invasive disease in either breast or axillary lymph nodes after NAC. ADC values between the group with pCR and those with no pCR were compared using the Mann-Whitney U test (two-group comparisons). Univariable and multivariabe logistic regression analysis was performed to predict pCR status. RESULTS: Overall, 83 patients (33.2%) achieved pCR. The ADC values of the patient group with pCR were lower compared with patients without pCR (0.98 ± 0.23 × 10- 3 mm2/s versus 1.07 ± 0.24 × 10- 3 mm2/s, p = 0.02). The ADC value achieved an odds ratio of 4.65 (95% CI 1.40-15.49) in univariable analysis and of 3.0 (95% CI 0.85-10.63) in multivariable analysis (overall sample) to be associated with pCR status. The odds ratios differed in the subgroup analyses in accordance with the molecular subtype. CONCLUSIONS: The pretreatment ADC-value is associated with pathological complete response after NAC in breast cancer patients. This could aid in clinical routine to reduce treatment toxicity for patients, who would not benefit from NAC. However, this must be tested in further studies, as the overlap of the ADC values in both groups is too high for clinical prediction.

Improving the image quality of DWI in breast cancer: comparison of multi-shot DWI using multiplexed sensitivity encoding to conventional single-shot echo-planar imaging DWI.

OBJECTIVE: To compare diffusion-weighted images (DWI) acquired using single-shot echo-planar imaging (ss-EPI) and multiplexed sensitivity encoding (MUSE) in breast cancer. METHODS: 20 females with pathologically confirmed breast cancer (age 51 ± 12 years) were imaged with ss-EPI-DWI and MUSE-DWI. ADC, normalised ADC (nADC), blur and distortion metrics and qualitative image quality scores were compared. The Crété-Roffet and Mattes mutual information metrics were used to evaluate blurring and distortion, respectively. In a breast phantom, six permutations of MUSE-DWI with varying parallel acceleration factor and number of shots were compared. Differences in ADC and nADC were compared using the coefficient of variation in the phantom and a paired t-test in patients. Differences in blur, distortion and qualitative metrics were analysed using a Wilcoxon signed-rank test. RESULTS: There was a low coefficient of variation (<2%) in ADC between ss-EPI-DWI and all MUSE-DWI permutations acquired using the phantom. 22 malignant and three benign lesions were identified in 20 patients. ADC values measured using MUSE were significantly lower compared to ss-EPI for malignant but not benign lesions (p < 0.001, p = 0.21). nADC values were not significantly different (p = 0.62, p = 0.28). Blurring and distortion improved with number of shots and acceleration factor, and significantly improved with MUSE in patients (p < 0.001, p = 0.002). Qualitatively, image quality improved using MUSE. CONCLUSION: MUSE improves the image quality of breast DWI compared to ss-EPI. ADVANCES IN KNOWLEDGE: MUSE-DWI has superior image quality and reduced blurring and distortion compared to ss-EPI-DWI in breast cancer.

Hyperpolarized Carbon-13 MRI for Early Response Assessment of Neoadjuvant Chemotherapy in Breast Cancer Patients.

Hyperpolarized 13C-MRI is an emerging tool for probing tissue metabolism by measuring 13C-label exchange between intravenously injected hyperpolarized [1-13C]pyruvate and endogenous tissue lactate. Here, we demonstrate that hyperpolarized 13C-MRI can be used to detect early response to neoadjuvant therapy in breast cancer. Seven patients underwent multiparametric 1H-MRI and hyperpolarized 13C-MRI before and 7-11 days after commencing treatment. An increase in the lactate-to-pyruvate ratio of approximately 20% identified three patients who, following 5-6 cycles of treatment, showed pathological complete response. This ratio correlated with gene expression of the pyruvate transporter MCT1 and lactate dehydrogenase A (LDHA), the enzyme catalyzing label exchange between pyruvate and lactate. Analysis of approximately 2,000 breast tumors showed that overexpression of LDHA and the hypoxia marker CAIX was associated with reduced relapse-free and overall survival. Hyperpolarized 13C-MRI represents a promising method for monitoring very early treatment response in breast cancer and has demonstrated prognostic potential. SIGNIFICANCE: Hyperpolarized carbon-13 MRI allows response assessment in patients with breast cancer after 7-11 days of neoadjuvant chemotherapy and outperformed state-of-the-art and research quantitative proton MRI techniques.