Molecular mechanism for strengthening E-cadherin adhesion using a monoclonal antibody.

E-cadherin (Ecad) is an essential cell-cell adhesion protein with tumor suppression properties. The adhesive state of Ecad can be modified by the monoclonal antibody 19A11, which has potential applications in reducing cancer metastasis. Using X-ray crystallography, we determine the structure of 19A11 Fab bound to Ecad and show that the antibody binds to the first extracellular domain of Ecad near its primary adhesive motif: the strand-swap dimer interface. Molecular dynamics simulations and single-molecule atomic force microscopy demonstrate that 19A11 interacts with Ecad in two distinct modes: one that strengthens the strand-swap dimer and one that does not alter adhesion. We show that adhesion is strengthened by the formation of a salt bridge between 19A11 and Ecad, which in turn stabilizes the swapped ß-strand and its complementary binding pocket. Our results identify mechanistic principles for engineering antibodies to enhance Ecad adhesion.

Accuracy of an Artificial Intelligence System for Interval Breast Cancer Detection at Screening Mammography.

Background Artificial intelligence (AI) systems can be used to identify interval breast cancers, although the localizations are not always accurate. Purpose To evaluate AI localizations of interval cancers (ICs) on screening mammograms by IC category and histopathologic characteristics. Materials and Methods A screening mammography data set (median patient age, 57 years [IQR, 52-64 years]) that had been assessed by two human readers from January 2011 to December 2018 was retrospectively analyzed using a commercial AI system. The AI outputs were lesion locations (heatmaps) and the highest per-lesion risk score (range, 0-100) assigned to each case. AI heatmaps were considered false positive (FP) if they occurred on normal screening mammograms or on IC screening mammograms (ie, in patients subsequently diagnosed with IC) but outside the cancer boundary. A panel of consultant radiology experts classified ICs as normal or benign (true negative [TN]), uncertain (minimal signs of malignancy [MS]), or suspicious (false negative [FN]). Several specificity and sensitivity thresholds were applied. Mann-Whitney U tests, Kruskal-Wallis tests, and χ2 tests were used to compare groups. Results A total of 2052 screening mammograms (514 ICs and 1548 normal mammograms) were included. The median AI risk score was 50 (IQR, 32-82) for TN ICs, 76 (IQR, 41-90) for ICs with MS, and 89 (IQR, 81-95) for FN ICs (P = .005). Higher median AI scores were observed for invasive tumors (62 [IQR, 39-88]) than for noninvasive tumors (33 [IQR, 20-55]; P < .01) and for high-grade (grade 2-3) tumors (62 [IQR, 40-87]) than for low-grade (grade 0-1) tumors (45 [IQR, 26-81]; P = .02). At the 96% specificity threshold, the AI algorithm flagged 121 of 514 (23.5%) ICs and correctly localized the IC in 93 of 121 (76.9%) cases, with 48 FP heatmaps on the mammograms for ICs (rate, 0.093 per case) and 74 FP heatmaps on normal mammograms (rate, 0.048 per case). The AI algorithm correctly localized a lower proportion of TN ICs (54 of 427; 12.6%) than ICs with MS (35 of 76; 46%) and FN ICs (four of eight; 50% [95% CI: 13, 88]; P < .001). The AI algorithm localized a higher proportion of node-positive than node-negative cancers (P = .03). However, no evidence of a difference by cancer type (P = .09), grade (P = .27), or hormone receptor status (P = .12) was found. At 89.8% specificity and 79% sensitivity thresholds, AI detection increased to 181 (35.2%) and 256 (49.8%) of the 514 ICs, respectively, with FP heatmaps on 158 (10.2%) and 307 (19.8%) of the 1548 normal mammograms. Conclusion Use of a standalone AI system improved early cancer detection by correctly identifying some cancers missed by two human readers, with no differences based on histopathologic features except for node-positive cancers. © RSNA, 2024 Supplemental material is available for this article.

Fast and High-Resolution T2 Mapping Based on Echo Merging Plus k-t Undersampling with Reduced Refocusing Flip Angles (TEMPURA) as Methods for Human Renal MRI.

PURPOSE: To develop a highly accelerated multi-echo spin-echo method, TEMPURA, for reducing the acquisition time and/or increasing spatial resolution for kidney T2 mapping. METHODS: TEMPURA merges several adjacent echoes into one k-space by either combining independent echoes or sharing one echo between k-spaces. The combined k-space is reconstructed based on compressed sensing theory. Reduced flip angles are used for the refocusing pulses, and the extended phase graph algorithm is used to correct the effects of indirect echoes. Two sequences were developed: a fast breath-hold sequence; and a high-resolution sequence. The performance was evaluated prospectively on a phantom, 16 healthy subjects, and two patients with different types of renal tumors. RESULTS: The fast TEMPURA method reduced the acquisition time from 3-5 min to one breath-hold (18 s). Phantom measurements showed that fast TEMPURA had a mean absolute percentage error (MAPE) of 8.2%, which was comparable to a standardized respiratory-triggered sequence (7.4%), but much lower than a sequence accelerated by purely k-t undersampling (21.8%). High-resolution TEMPURA reduced the in-plane voxel size from 3 × 3 to 1 × 1 mm2, resulting in improved visualization of the detailed anatomical structure. In vivo T2 measurements demonstrated good agreement (fast: MAPE = 1.3%-2.5%; high-resolution: MAPE = 2.8%-3.3%) and high correlation coefficients (fast: R = 0.85-0.98; high-resolution: 0.82-0.96) with the standardized method, outperforming k-t undersampling alone (MAPE = 3.3-4.5%, R = 0.57-0.59). CONCLUSION: TEMPURA provides fast and high-resolution renal T2 measurements. It has the potential to improve clinical throughput and delineate intratumoral heterogeneity and tissue habitats at unprecedented spatial resolution.

Improvements in Between-Vendor MRI Harmonization of Renal T2 Mapping using Stimulated Echo Compensation.

BACKGROUND: T2 mapping is valuable to evaluate pathophysiology in kidney disease. However, variations in T2 relaxation time measurements across MR scanners and vendors may occur requiring additional correction. PURPOSE: To harmonize renal T2 measurements between MR vendor platforms, and use an extended-phase-graph-based fitting method ("StimFit") to correct stimulated echoes and reduce between-vendor variations. STUDY TYPE: Prospective. SUBJECTS: 8 healthy "travelling" volunteers (37.5% female, 32 ± 6 years) imaged on four MRI systems across three vendors at four sites, 10 healthy volunteers (50% female, 32 ± 8 years) scanned multiple times on a given MR scanner for repeatability evaluation. ISMRM/NIST system phantom scanned for evaluation of T2 accuracy. FIELD STRENGTH/SEQUENCE: 3T, multiecho spin-echo sequence. ASSESSMENT: T2 images fit using conventional monoexponential fitting and "StimFit." Mean absolute percentage error (MAPE) of phantom measurements with reference T2 values. Average cortex and medulla T2 values compared between MR vendors, with masks obtained from T2 -weighted images and T1 maps. Full-width-at-half-maximum (FWHM) T2 distributions to evaluate local homogeneity of measurements. STATISTICAL TESTS: Coefficient of variation (CV), linear mixed-effects model, analysis of variance, student's t-tests, Bland-Altman plots, P-value <0.05 considered statistically significant. RESULTS: In the ISMRM/NIST phantom, "StimFit" reduced the MAPE from 4.9%, 9.1%, 24.4%, and 18.1% for the four sites (three vendors) to 3.3%, 3.0%, 6.6%, and 4.1%, respectively. In vivo, there was a significant difference in kidney T2 measurements between vendors using a monoexponential fit, but not with "StimFit" (P = 0.86 and 0.92, cortex and medulla, respectively). The intervendor CVs of T2 measures were reduced from 8.0% to 2.6% (cortex) and 7.1% to 2.8% (medulla) with StimFit, resulting in no significant differences for the CVs of intravendor repeat acquisitions (P = 0.13 and 0.05). "StimFit" significantly reduced the FWHM of T2 distributions in the cortex and whole kidney. DATA CONCLUSION: Stimulated-echo correction reduces renal T2 variation across MR vendor platforms. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Breast density effect on the sensitivity of digital screening mammography in a UK cohort.

OBJECTIVES: To assess the performance of breast cancer screening by category of breast density and age in a UK screening cohort. METHODS: Raw full-field digital mammography data from a single site in the UK, forming a consecutive 3-year cohort of women aged 50 to 70 years from 2016 to 2018, were obtained retrospectively. Breast density was assessed using Volpara software. Examinations were grouped by density category and age group (50-60 and 61-70 years) to analyse screening performance. Statistical analysis was performed to determine the association between density categories and age groups. Volumetric breast density was assessed as a binary classifier of interval cancers (ICs) to find an optimal density threshold. RESULTS: Forty-nine thousand nine-hundred forty-eight screening examinations (409 screen-detected cancers (SDCs) and 205 ICs) were included in the analysis. Mammographic sensitivity, SDC/(SDC + IC), decreased with increasing breast density from 75.0% for density a (p = 0.839, comparisons made to category b), to 73.5%, 59.8% (p = 0.001), and 51.3% (p < 0.001) in categories b, c, and d, respectively. IC rates were highest in the densest categories with rates of 1.8 (p = 0.039), 3.2, 5.7 (p < 0.001), and 7.9 (p < 0.001) per thousand for categories a, b, c, and d, respectively. The recall rate increased with breast density, leading to more false positive recalls, especially in the younger age group. There was no significant difference between the optimal density threshold found, 6.85, and that Volpara defined as the b/c boundary, 7.5. CONCLUSIONS: The performance of screening is significantly reduced with increasing density with IC rates in the densest category four times higher than in women with fatty breasts. False positives are a particular issue for the younger subgroup without prior examinations. CLINICAL RELEVANCE STATEMENT: In women attending screening there is significant underdiagnosis of breast cancer in those with dense breasts, most marked in the highest density category but still three times higher than in women with fatty breasts in the second highest category. KEY POINTS: Breast density can mask cancers leading to underdiagnosis on mammography. Interval cancer rate increased with breast density categories 'a' to 'd'; 1.8 to 7.9 per thousand. Recall rates increased with increasing breast density, leading to more false positive recalls.

Inside-out regulation of E-cadherin conformation and adhesion.

Cadherin cell-cell adhesion proteins play key roles in tissue morphogenesis and wound healing. Cadherin ectodomains bind in two conformations, X-dimers and strand-swap dimers, with different adhesive properties. However, the mechanisms by which cells regulate ectodomain conformation are unknown. Cadherin intracellular regions associate with several actin-binding proteins including vinculin, which are believed to tune cell-cell adhesion by remodeling the actin cytoskeleton. Here, we show at the single-molecule level, that vinculin association with the cadherin cytoplasmic region allosterically converts weak X-dimers into strong strand-swap dimers and that this process is mediated by myosin II-dependent changes in cytoskeletal tension. We also show that in epithelial cells, ∼70% of apical cadherins exist as strand-swap dimers while the remaining form X-dimers, providing two cadherin pools with different adhesive properties. Our results demonstrate the inside-out regulation of cadherin conformation and establish a mechanistic role for vinculin in this process.

Mammography Breast Cancer Screening Triage Using Deep Learning: A UK Retrospective Study.

Background Breast screening enables early detection of cancers; however, most women have normal mammograms, resulting in repetitive and resource-intensive reading tasks. Purpose To investigate if deep learning (DL) algorithms can be used to triage mammograms by identifying normal results to reduce workload or flag cancers that may be overlooked. Materials and Methods In this retrospective study, three commercial DL algorithms were investigated using consecutive mammograms from two UK Breast Screening Program sites from January 2015 to December 2017 and January 2017 to December 2018 on devices from two mammography vendors. Normal mammograms with a 3-year follow-up and histopathologically proven cancer detected at screening, the subsequent round, or in the 3-year interval were included. Two algorithm thresholds were set: in scenario A, 99.0% sensitivity for rule-out triage to a lone reader, and in scenario B, approximately 1.0% additional recall providing a rule-in triage for further assessment. Both thresholds were then applied to the screening workflow in scenario C. The sensitivity and specificity were used to assess the overall predictive performance of each DL algorithm. Results The data set comprised 78 849 patients (median age, 59 years [IQR, 53-63 years]) and 887 screening-detected, 439 interval, and 688 subsequent screening round-detected cancers. In scenario A (rule-out triage), models DL-1, DL-2, and DL-3 triaged 35.0% (27 565 of 78 849), 53.2% (41 937 of 78 849), and 55.6% (43 869 of 78 849) of mammograms, respectively, with 0.0% (0 of 887) to 0.1% (one of 887) of screening-detected cancers undetected. In scenario B, DL algorithms triaged in 4.6% (20 of 439) to 8.2% (36 of 439) of interval and 5.2% (36 of 688) to 6.1% (42 of 688) of subsequent-round cancers when applied after the routine double-reading workflow. Combining both approaches in scenario C resulted in an overall noninferior specificity (difference, -0.9%; P < .001) and superior sensitivity (difference, 2.7%; P < .001) for the adaptive workflow compared with routine double reading for all three algorithms. Conclusion Rule-out and rule-in DL-adapted triage workflows can improve the efficiency and efficacy of mammography breast cancer screening. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Nishikawa and Lu in this issue.

A Phase II study of neoadjuvant axitinib for reducing the extent of venous tumour thrombus in clear cell renal cell cancer with venous invasion (NAXIVA).

BACKGROUND: Surgery for renal cell carcinoma (RCC) with venous tumour thrombus (VTT) extension into the renal vein (RV) and/or inferior vena cava (IVC) has high peri-surgical morbidity/mortality. NAXIVA assessed the response of VTT to axitinib, a potent tyrosine kinase inhibitor. METHODS: NAXIVA was a single-arm, multi-centre, Phase 2 study. In total, 20 patients with resectable clear cell RCC and VTT received upto 8 weeks of pre-surgical axitinib. The primary endpoint was percentage of evaluable patients with VTT improvement by Mayo level on MRI. Secondary endpoints were percentage change in surgical approach and VTT length, response rate (RECISTv1.1) and surgical morbidity. RESULTS: In all, 35% (7/20) patients with VTT had a reduction in Mayo level with axitinib: 37.5% (6/16) with IVC VTT and 25% (1/4) with RV-only VTT. No patients had an increase in Mayo level. In total, 75% (15/20) of patients had a reduction in VTT length. Overall, 41.2% (7/17) of patients who underwent surgery had less invasive surgery than originally planned. Non-responders exhibited lower baseline microvessel density (CD31), higher Ki67 and exhausted or regulatory T-cell phenotype. CONCLUSIONS: NAXIVA provides the first Level II evidence that axitinib downstages VTT in a significant proportion of patients leading to reduction in the extent of surgery. CLINICAL TRIAL REGISTRATION: NCT03494816.

Dynamic biomarker and imaging changes from a phase II study of pre- and post-surgical sunitinib.

OBJECTIVE: To explore translational biological and imaging biomarkers for sunitinib treatment before and after debulking nephrectomy in the NeoSun (European Union Drug Regulating Authorities Clinical Trials Database [EudraCT] number: 2005-004502-82) single-centre, single-arm, single-agent, Phase II trial. PATIENTS AND METHODS: Treatment-naïve patients with metastatic renal cell carcinoma (mRCC) received 50 mg once daily sunitinib for 12 days pre-surgically, then post-surgery on 4 week-on, 2 week-off, repeating 6-week cycles until disease progression in a single arm phase II trial. Structural and dynamic contrast-enhanced magnet resonance imaging (DCE-MRI) and research blood sampling were performed at baseline and after 12 days. Computed tomography imaging was performed at baseline and post-surgery then every two cycles. The primary endpoint was objective response rate (Response Evaluation Criteria In Solid Tumors [RECIST]) excluding the resected kidney. Secondary endpoints included changes in DCE-MRI of the tumour following pre-surgery sunitinib, overall survival (OS), progression-free survival (PFS), response duration, surgical morbidity/mortality, and toxicity. Translational and imaging endpoints were exploratory. RESULTS: A total of 14 patients received pre-surgery sunitinib, 71% (10/14) took the planned 12 doses. All underwent nephrectomy, and 13 recommenced sunitinib postoperatively. In all, 58.3% (seven of 12) of patients achieved partial or complete response (PR or CR) (95% confidence interval 27.7-84.8%). The median OS was 33.7 months and median PFS was 15.7 months. Amongst those achieving a PR or CR, the median response duration was 8.7 months. No unexpected surgical complications, sunitinib-related toxicities, or surgical delays occurred. Within the translational endpoints, pre-surgical sunitinib significantly increased necrosis, and reduced cluster of differentiation-31 (CD31), Ki67, circulating vascular endothelial growth factor-C (VEGF-C), and transfer constant (KTrans , measured using DCE-MRI; all P < 0.05). There was a trend for improved OS in patients with high baseline plasma VEGF-C expression (P = 0.02). Reduction in radiological tumour volume after pre-surgical sunitinib correlated with high percentage of solid tumour components at baseline (Spearman's coefficient ρ = 0.69, P = 0.02). Conversely, the percentage tumour volume reduction correlated with lower baseline percentage necrosis (coefficient = -0.51, P = 0.03). CONCLUSION: Neoadjuvant studies such as the NeoSun can safely and effectively explore translational biological and imaging endpoints.

Quantification and reduction of cross-vendor variation in multicenter DWI MR imaging: results of the Cancer Core Europe imaging task force.

OBJECTIVES: In the Cancer Core Europe Consortium (CCE), standardized biomarkers are required for therapy monitoring oncologic multicenter clinical trials. Multiparametric functional MRI and particularly diffusion-weighted MRI offer evident advantages for noninvasive characterization of tumor viability compared to CT and RECIST. A quantification of the inter- and intraindividual variation occurring in this setting using different hardware is missing. In this study, the MRI protocol including DWI was standardized and the residual variability of measurement parameters quantified. METHODS: Phantom and volunteer measurements (single-shot T2w and DW-EPI) were performed at the seven CCE sites using the MR hardware produced by three different vendors. Repeated measurements were performed at the sites and across the sites including a traveling volunteer, comparing qualitative and quantitative ROI-based results including an explorative radiomics analysis. RESULTS: For DWI/ADC phantom measurements using a central post-processing algorithm, the maximum deviation could be decreased to 2%. However, there is no significant difference compared to a decentralized ADC value calculation at the respective MRI devices. In volunteers, the measurement variation in 2 repeated scans did not exceed 11% for ADC and is below 20% for single-shot T2w in systematic liver ROIs. The measurement variation between sites amounted to 20% for ADC and < 25% for single-shot T2w. Explorative radiomics classification experiments yield better results for ADC than for single-shot T2w. CONCLUSION: Harmonization of MR acquisition and post-processing parameters results in acceptable standard deviations for MR/DW imaging. MRI could be the tool in oncologic multicenter trials to overcome the limitations of RECIST-based response evaluation. KEY POINTS: • Harmonizing acquisition parameters and post-processing homogenization, standardized protocols result in acceptable standard deviations for multicenter MR-DWI studies. • Total measurement variation does not to exceed 11% for ADC in repeated measurements in repeated MR acquisitions, and below 20% for an identical volunteer travelling between sites. • Radiomic classification experiments were able to identify stable features allowing for reliable discrimination of different physiological tissue samples, even when using heterogeneous imaging data.

Subtractive NCE-MRA: Improved background suppression using robust regression-based weighted subtraction.

PURPOSE: To correct the intensity difference of static background signal between bright blood images and dark blood images in subtractive non-contrast-enhanced MR angiography using robust regression, thereby improving static background signal suppression on subtracted angiograms. METHODS: Robust regression (RR), using iteratively reweighted least squares, is used to calculate the regression coefficient of background tissues from a scatter plot showing the voxel intensity of bright blood images versus dark blood images. The weighting function is based on either the Euclidean distance from the estimated regression line or the deviation angle. Results from RR using the deviation angle (RRDA), conventional RR using the Euclidean distance, and ordinary leastsquares regression were compared with reference values determined manually by two observers. Performance was evaluated over studies using different sequences, including 36 thoracic flow-sensitive dephasing data sets, 13 iliac flow-sensitive dephasing data sets, and 26 femoral fresh blood imaging data sets. RESULTS: RR deviation angle achieved robust and accurate performance in all types of images, with small bias, small mean absolute error, and high-correlation coefficients with reference values. Background tissues, such as muscle, veins, and bladder, were suppressed while the vascular signal was preserved. Euclidean distance gave good performance for thoracic and iliac flow-sensitive dephasing, but could not suppress background tissues in femoral fresh blood imaging. Ordinary least squares regression was sensitive to outliers and overestimated regression coefficients in thoracic flow-sensitive dephasing. CONCLUSION: Weighted subtraction using RR was able to acquire the regression coefficients of background signal and improve background suppression of subtractive non-contrast-enhanced MR angiography techniques. RR deviation angle has the most robust and accurate overall performance among three regression methods.

Highly accelerated subtractive femoral non-contrast-enhanced MRA using compressed sensing with k-space subtraction, phase and intensity correction.

PURPOSE: To develop an improved reconstruction method, k-space subtraction with phase and intensity correction (KSPIC), for highly accelerated, subtractive, non-contrast-enhanced MRA. METHODS: The KSPIC method is based on k-space subtraction of complex raw data. It applies a phase-correction procedure to restore the polarity of negative signals caused by subtraction and an intensity-correction procedure to improve background suppression and thereby sparsity. Ten retrospectively undersampled data sets and 10 groups of prospectively undersampled data sets were acquired in 12 healthy volunteers. The performance of KSPIC was compared with another improved reconstruction based on combined magnitude subtraction, as well as with conventional k-space subtraction reconstruction and magnitude subtraction reconstruction, both using quantitative metrics and using subjective quality scoring. RESULTS: In the quantitative evaluation, KSPIC had the best performance in terms of peak SNR, structural similarity index measure, contrast-to-noise ratio of artery-to-background and sharpness, especially at high acceleration factors. The KSPIC method also had the highest subjective scores for all acceleration factors in terms of vessel delineation, image noise and artifact, and background contamination. The acquisition can be accelerated by a factor of 20 without significant decreases of subjective scores. The optimal size of the phase-correction region was found to be 12-20 pixels in this study. CONCLUSION: Compared with combined magnitude subtraction and conventional reconstructions, KSPIC has the best performance in all of the quantitative and qualitative measurements, permitting good image quality to be maintained up to higher accelerations. The KSPIC method has the potential to further reduce the acquisition time of subtractive MRA for clinical examinations.

MRI features of the normal prostatic peripheral zone: the relationship between age and signal heterogeneity on T2WI, DWI, and DCE sequences.

OBJECTIVES: To assess the multiparametric MRI (mpMRI) appearances of normal peripheral zone (PZ) across age groups in a biopsy-naïve population, where prostate cancer (PCa) was subsequently excluded, and propose a scoring system for background PZ changes. METHODS: This retrospective study included 175 consecutive biopsy-naïve patients (40-74 years) referred with a suspicion of PCa, but with subsequent negative investigations. Patients were grouped by age into categories ≤ 54, 55-59, 60-64, and ≥ 65 years. MpMRI sequences (T2-weighted imaging [T2WI], diffusion-weighted imaging [DWI]/apparent diffusion coefficient [ADC], and dynamic contrast-enhanced imaging [DCE]) were independently evaluated by two uro-radiologists on a proposed 4-point grading scale for background change on each sequence, wherein score 1 mirrored PIRADS-1 change and score 4 represented diffuse background change. Peripheral zone T2WI signal intensity and ADC values were also analyzed for trends relating to age. RESULTS: There was a negative correlation between age and assigned background PZ scores for each mpMRI sequence: T2WI: r = - 0.52, DWI: r = - 0.49, DCE: r = - 0.45, p < 0.001. Patients aged ≤ 54 years had mean scores of 3.0 (T2WI), 2.7 (DWI), and 3.1 (DCE), whilst patients ≥ 65 years had significantly lower mean scores of 1.7, 1.4, and 1.9, respectively. There was moderate inter-reader agreement for all scores (range κ = 0.43-0.58). Statistically significant positive correlations were found for age versus normalized T2WI signal intensity (r = 0.2, p = 0.009) and age versus ADC values (r = 0.33, p = 0.001). CONCLUSION: The normal PZ in younger patients (≤ 54 years) demonstrates significantly lower T2WI signal intensity, lower ADC values, and diffuse enhancement on DCE, which may hinder diagnostic interpretation in these patients. The proposed standardized PZ background scoring system may help convey the potential for diagnostic uncertainty to clinicians. KEY POINTS: • Significant, positive correlations were found between increasing age and higher normalized T2-weighted signal intensity and mean ADC values of the prostatic peripheral zone. • Younger men exhibit lower T2-weighted imaging signal intensity, lower ADC values, and diffuse enhancement on dynamic contrast-enhanced imaging, which may hinder MRI interpretation. • A scoring system is proposed which aims towards a standardized assessment of the normal background PZ. This may help convey the potential for diagnostic uncertainty to clinicians.

Simultaneous MRI water-fat separation and quantitative susceptibility mapping of carotid artery plaque pre- and post-ultrasmall superparamagnetic iron oxide-uptake.

PURPOSE: Imaging carotid artery plaques to identify features of vulnerability typically requires a multicontrast MRI protocol. The identification of regions of inflammation with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles requires separate pre- and postcontrast scans. We propose a method of joint water-fat separation and quantitative susceptibility mapping (QSM) to aid classification of atherosclerotic plaques and offer a positive contrast mechanism in USPIO-imaging. METHODS: Ten healthy volunteers (3 women and 7 men; aged, 30.7 ± 10.7 years) were imaged at 1.5T to develop an acquisition and postprocessing protocol. Five patients (1 woman and 4 men; mean age, 71 ± 7.5 years) with moderate to severe luminal stenosis were imaged pre- and postadministration of a USPIO contrast agent. We used a multiecho gradient echo acquisition to perform water/fat separation and subsequently QSM. The results were compared with a conventional multicontrast MRI protocol, CT images, and histopathology data. RESULTS: In the volunteer scans, a multiecho gradient echo acquisition with bipolar readout gradients demonstrated to be a reliable acquisition methodology to produce high-quality susceptibility maps in conjunction with the proposed postprocessing methodology. In the patient study, water/fat separation provided a tool to identify lipid-rich necrotic cores and QSM provided a qualitative and quantitative evaluation of plaque features and positive contrast when evaluating USPIO uptake. Plaque calcification could be identified by strong diamagnetism (-1.27 ± 0.71 ppm), while USPIO uptake demonstrated a strong paramagnetism (1.32 ± 0.61 ppm). CONCLUSION: QSM was able to identify multiple plaque features in a single acquisition, providing positive contrast for plaques demonstrating USPIO uptake and negative contrast for calcification.

Removing rician bias in diffusional kurtosis of the prostate using real-data reconstruction.

PURPOSE: To compare prostate diffusional kurtosis imaging (DKI) metrics generated using phase-corrected real data with those generated using magnitude data with and without noise compensation (NC). METHODS: Diffusion-weighted images were acquired at 3T in 16 prostate cancer patients, measuring 6 b-values (0-1500 s/mm2 ), each acquired with 6 signal averages along 3 diffusion directions, with noise-only images acquired to allow NC. In addition to conventional magnitude averaging, phase-corrected real data were averaged in an attempt to reduce rician noise-bias, with a range of phase-correction low-pass filter (LPF) sizes (8-128 pixels) tested. Each method was also tested using simulations. Pixelwise maps of apparent diffusion (D) and apparent kurtosis (K) were calculated for magnitude data with and without NC and phase-corrected real data. Average values were compared in tumor, normal transition zone (NTZ), and normal peripheral zone (NPZ). RESULTS: Simulations indicated LPF size can strongly affect K metrics, where 64-pixel LPFs produced accurate metrics. Relative to metrics estimated from magnitude data without NC, median NC K were lower (P < 0.0001) by 6/11/8% in tumor/NPZ/NTZ, 64-LPF real-data K were lower (P < 0.0001) by 4/10/7%, respectively. CONCLUSION: Compared with magnitude data with NC, phase-corrected real data can produce similar K, although the choice of phase-correction LPF should be chosen carefully.

Diffusion-weighted MRI in Advanced Epithelial Ovarian Cancer: Apparent Diffusion Coefficient as a Response Marker.

Background Treatment of advanced epithelial ovarian cancer results in a relapse rate of 75%. Early markers of response would enable optimization of management and improved outcome in both primary and recurrent disease. Purpose To assess the apparent diffusion coefficient (ADC), derived from diffusion-weighted MRI, as an indicator of response, progression-free survival (PFS), and overall survival. Materials and Methods This prospective multicenter trial (from 2012-2016) recruited participants with stage III or IV ovarian, primary peritoneal, or fallopian tube cancer (newly diagnosed, cohort one; relapsed, cohort two) scheduled for platinum-based chemotherapy, with interval debulking surgery in cohort one. Cohort one underwent two baseline MRI examinations separated by 0-7 days to assess ADC repeatability; an additional MRI was performed after three treatment cycles. Cohort two underwent imaging at baseline and after one and three treatment cycles. ADC changes in responders and nonresponders were compared (Wilcoxon rank sum tests). PFS and overall survival were assessed by using a multivariable Cox model. Results A total of 125 participants (median age, 63.3 years [interquartile range, 57.0-70.7 years]; 125 women; cohort one, n = 47; cohort two, n = 78) were included. Baseline ADC (range, 77-258 × 10-5mm2s-1) was repeatable (upper and lower 95% limits of agreement of 12 × 10-5mm2s-1 [95% confidence interval {CI}: 6 × 10-5mm2s-1 to 18 × 10-5mm2s-1] and -15 × 10-5mm2s-1 [95% CI: -21 × 10-5mm2s-1 to -9 × 10-5mm2s-1]). ADC increased in 47% of cohort two after one treatment cycle, and in 58% and 53% of cohorts one and two, respectively, after three cycles. Percentage change from baseline differed between responders and nonresponders after three cycles (16.6% vs 3.9%; P = .02 [biochemical response definition]; 19.0% vs 6.2%; P = .04 [radiologic definition]). ADC increase after one cycle was associated with longer PFS in cohort two (adjusted hazard ratio, 0.86; 95% CI: 0.75, 0.98; P = .03). ADC change was not indicative of overall survival for either cohort. Conclusion After three cycles of platinum-based chemotherapy, apparent diffusion coefficient (ADC) changes are indicative of response. After one treatment cycle, increased ADC is indicative of improved progression-free survival in relapsed disease. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

Subtractive non-contrast-enhanced MRI of lower limb veins using multiple flow-dependent preparation strategies.

PURPOSE: To evaluate the performance of acceleration-dependent vascular anatomy for non-contrast-enhanced MR venography (ADVANCE-MRV) in femoral veins and to investigate whether venous signal uniformity can be improved by applying multiple acquisitions with different flow suppressions or multiple flow suppressions in 1 acquisition. METHODS: The ADVANCE-MRV method uses flow-sensitized modules to acquire a dark-artery image set and a dark-artery vein set, which are subsequently subtracted. Ten healthy volunteers were imaged using the ADVANCE-MRV sequence with improved venous suppression uniformity in the dark-artery vein images achieved by applying multiple flow suppressions in the same acquisition or by combining multiple images acquired with different flow suppressions. The performance of the improved technique was also evaluated in 13 patients with lower-limb deep venous thrombosis. RESULTS: Multiple-preparation and multiple-acquisition approaches all improved venous signal uniformity and reduced the signal void artifacts observed in the original ADVANCE-MRV images. The multiple-acquisition approaches achieved excellent blood signal uniformity and intensity, albeit at the cost of an increase in the total acquisition time. The double-preparation approach demonstrated good performance in all measurements, providing a good compromise between signal uniformity and acquisition time. The blood signal spatial variation and its variation using different gradient amplitudes were reduced by 20% and 29%. All patient images showed uniform and bright venous signal in nonoccluded sections of vein. CONCLUSION: The enhanced ADVANCE-MRV methods substantially improved signal uniformity in healthy volunteers and patients with known deep venous thrombosis. The double-preparation approach gave good-quality femoral vein images, providing improved venous signal uniformity without increasing acquisition time in comparison to the original sequence.

Non-invasive assessment of glioma microstructure using VERDICT MRI: correlation with histology.

PURPOSE: This prospective study evaluated the use of vascular, extracellular and restricted diffusion for cytometry in tumours (VERDICT) MRI to investigate the tissue microstructure in glioma. VERDICT-derived parameters were correlated with both histological features and tumour subtype and were also used to explore the peritumoural region. METHODS: Fourteen consecutive treatment-naïve patients (43.5 years ± 15.1 years, six males, eight females) with suspected glioma underwent diffusion-weighted imaging including VERDICT modelling. Tumour cell radius and intracellular and combined extracellular/vascular volumes were estimated using a framework based on linearisation and convex optimisation. An experienced neuroradiologist outlined the peritumoural oedema, enhancing tumour and necrosis on T2-weighted imaging and contrast-enhanced T1-weighted imaging. The same regions of interest were applied to the co-registered VERDICT maps to calculate the microstructure parameters. Pathology sections were analysed with semi-automated software to measure cellularity and cell size. RESULTS: VERDICT parameters were successfully calculated in all patients. The imaging-derived results showed a larger intracellular volume fraction in high-grade glioma compared to low-grade glioma (0.13 ± 0.07 vs. 0.08 ± 0.02, respectively; p = 0.05) and a trend towards a smaller extracellular/vascular volume fraction (0.88 ± 0.07 vs. 0.92 ± 0.04, respectively; p = 0.10). The conventional apparent diffusion coefficient was higher in low-grade gliomas compared to high-grade gliomas, but this difference was not statistically significant (1.22 ± 0.13 × 10-3 mm2/s vs. 0.98 ± 0.38 × 10-3 mm2/s, respectively; p = 0.18). CONCLUSION: This feasibility study demonstrated that VERDICT MRI can be used to explore the tissue microstructure of glioma using an abbreviated protocol. The VERDICT parameters of tissue structure correlated with those derived on histology. The method shows promise as a potential test for diagnostic stratification and treatment response monitoring in the future. KEY POINTS: • VERDICT MRI is an advanced diffusion technique which has been correlated with histopathological findings obtained at surgery from patients with glioma in this study. • The intracellular volume fraction measured with VERDICT was larger in high-grade tumours compared to that in low-grade tumours. • The results were complementary to measurements from conventional diffusion-weighted imaging, and the technique could be performed in a clinically feasible timescale.

Diagnostic evaluation of magnetization transfer and diffusion kurtosis imaging for prostate cancer detection in a re-biopsy population.

OBJECTIVE: To evaluate diffusion kurtosis imaging (DKI) and magnetisation transfer imaging (MTI) compared to standard MRI for prostate cancer assessment in a re-biopsy population. METHODS: Thirty-patients were imaged at 3 T including DKI (Kapp and Dapp) with b-values 150/450/800/1150/1500 s/mm2 and MTI performed with and without MT saturation. Patients underwent transperineal biopsy based on prospectively defined MRI targets. Receiver-operating characteristic (ROC) analyses assessed the parameters and Wilcoxon-signed ranked test assessed relationships between metrics. RESULTS: Twenty patients had ≥ 1 core positive for cancer in a total of 26 MRI targets (Gleason 3+3 in 8, 3+4 in 12, ≥ 4+3 in 6): 13 peripheral (PZ) and 13 transition zone (TZ). The apparent diffusion coefficient (ADC) and Dapp were significantly lower and the Kapp and MT ratio (MTR) significantly higher in tumour versus benign tissue (all p ≤ 0.005); ROC values 0.767-1.000. Normal TZ had: lower ADC and Dapp and higher Kapp and MTR compared to normal PZ. MTR showed a moderate correlation to Kapp (r = 0.570) and Dapp (r = -0.537) in normal tissue but a poor correlation in tumours. No parameter separated low-grade (Gleason 3+3) from high-grade (≥ 3+4) disease for either PZ (p = 0.414-0.825) or TZ (p = 0.148-0.825). CONCLUSION: ADC, Dapp, Kapp and MTR all distinguished benign tissue from tumour, but none reliably differentiated low- from high-grade disease. KEY POINTS: • MTR was significantly higher in PZ and TZ tumours versus normal tissue • K app was significantly lower and D app higher for PZ and TZ tumours • There was no incremental value for DKI/MTI over mono-exponential ADC parameters • No parameter could consistently differentiate low-grade (Gleason 3+3) from high-grade (≥ 3+4) disease • Divergent MTR/DKI values in TZ tumours suggests they offer different functional information.

Biophysical basis of cadherin mediated cell-cell adhesion.

Classical cadherin transmembrane cell-cell adhesion proteins play essential roles in tissue morphogenesis and in mediating tissue integrity. Cadherin ectodomains from opposing cells interact to form load-bearing trans dimers that mechanically couple cells. Cell-cell adhesion is believed to be strengthened by cis clustering of cadherins on the same cell surface. This review summarizes biophysical studies of the structure, interaction kinetics and biomechanics of classical cadherin ectodomains. We first discuss the structure and equilibrium binding kinetics of classical cadherin trans and cis dimers. We then discuss how mechanical stimuli alters the kinetics of cadherin interaction and tunes adhesion. Finally, we highlight open questions on the role of mechanical forces in influencing cadherin structure, function and organization on the cell surface.