Citations

Background: Accurate preoperative characterization of axillary lymph nodes (ALNs) is important in breast cancer, but conventional ultrasound has variable diagnostic performance. We evaluated quantitative shear wave elastography (SWE) for distinguishing reactive from metastatic ALNs, and we explored associations between nodal SWE parameters, breast cancer subtypes, and histological grades. Methods: We prospectively enrolled women with suspicious breast lesions and ALNs identified by clinical ultrasound who were scheduled for biopsy. After exclusions, 141 patients (57 reactive and 84 metastatic ALNs) were included. ElasticNet-regularized logistic regression with nested cross-validation compared clinical ultrasound alone with ultrasound plus SWE. Among 70 patients with metastatic ALNs and immunohistochemical characterization, SWE parameters were compared across surrogate subtypes and histological grades using Kruskal–Wallis tests with Holm adjustments. Results: The combined ultrasound–SWE model achieved an area under the receiver operating characteristic curve of 0.911 (95% CI, 0.859–0.961) compared to 0.798 (95% CI, 0.723–0.873) for ultrasound alone. At the Youden-derived threshold, the combined model achieved 88.1% sensitivity, 82.5% specificity, and 85.8% accuracy. Among metastatic ALNs, SWE parameters, namely Vmean, Vsd, and Vmax, differed significantly across surrogate subtypes, with the most pronounced differences observed between Luminal A and Luminal B tumors, (p = 0.0250, p = 0.0069, and p = 0.0065). No statistically significant differences were detected with histological grades in the five SWE parameters. Conclusions: Quantitative SWE complemented conventional ultrasound for assessing axillary nodal metastasis, with higher cross-validated discrimination for the combined model. Exploratory analyses identified differences in several SWE stiffness metrics between Luminal A and Luminal B tumors; these subtype-associated biomechanical differences require validation in larger cohorts.

A variety of advanced shear wave elastography techniques require the measurement of frequency-resolved phase velocity to properly characterize wave signals where factors such as tissue viscosity or guided wave effects are present. However, when applying these techniques in a dynamic environment where extrinsic motion cannot be limited, nonlinear and nonstationary trends can be expected in the motion signal used for phase velocity estimation. Because such extrinsic motion signals can contaminate a broad range of frequencies, they can produce significant errors in the phase velocity estimates. In this study, we propose a spatiotemporal detrending approach for elastography wave motion signals built from a 2D Whittaker smoother. This smoother has its origins in nonparametric regression and is well suited for fitting nonlinear curves of arbitrary shape. The resulting detrending filter was applied to Lamb wave signals from clinical ultrasound bladder vibrometry measurements. We found that the proposed detrending filter allowed for phase velocity estimates to be made in acquisitions that are otherwise be too corrupted by large motion. This works was supported by a grant from the NIH (DK131685)

Abstract Background Accurate assessment of axillary lymph nodes (ALNs) is a critical step for timely diagnosis of metastasis and proper subsequent intervention in breast cancer patients. Herein, we compare the diagnostic utility of quantitative high-definition microvasculature imaging (qHDMI), shear wave elastography (SWE) and their combination for differentiation of metastatic ALNs from reactive. Methods A total of 85 female patients with suspicious ALNs recommended for fine needle aspiration biopsy (FNAB) were included in the study, and the pathology results were used as the gold standard for labeling the status of each ALN. Three SWE metrics and ten qHDMI-derived biomarkers were used in our analyses. Additionally, age, as well as clinical ultrasound features such as nodal size and cortical thickness were included as clinical factors. The Wilcoxon rank-sum test was utilized to analyze distributional differences in biomarkers between metastatic and reactive ALNs. Multiple elastic-net logistic regression models were developed based on varying combinations of clinical, qHDMI, and SWE feature sets. A 70%/30% train/test split was adopted, and ROC curve analyses were performed to evaluate and compare classification performance. Moreover, distributional differences in qHDMI and SWE biomarkers between ALNs corresponding to breast cancer immunohistochemical subtypes luminal A and B were investigated. Results Of the total of 85 ALNs included in the analysis, 42 were metastatic. Statistically significant (p-value < 0.05) differences were observed in all but one of the qHDMI biomarkers, as well as all the SWE metrics. Test-set discrimination defined by area under ROC curve (AUC) was low for the model using only clinical features (0.62; 95% CI = [0.39,0.84]), with higher performance observed for models using SWE only (0.93; [0.82,1.00]), qHDMI only (0.97; [0.91,1.00]), qHDMI-SWE (0.97; [0.92,1.00]), and qHDMI-SWE plus clinical biomarkers (0.98; [0.94,1.00]). No statistically significant improvements were seen in the combined SWE-qHDMI and SWE-qHDMI-C classification models relative to the qHDMI-only model, although power for comparison was limited. Four qHDMI biomarkers and two SWE measures exhibited statistically significant distributions among breast cancer luminal A and B subtypes. Conclusions qHDMI classification model was able to separate metastatic from reactive ALNs with high accuracy. qHDMI, SWE, and the combined models had improved classification performance over the baseline Clinical model. qHDMI biomarkers can be valuable in determining the malignancy status of suspicious ALNs, providing helpful information regarding breast cancer prognosis.

Abstract Objective . Detrusor overactivity (DO) is a urodynamic observation characterized by fluctuations in detrusor pressure ( P det ) of the bladder. Although detecting DO is important for the management of bladder symptoms, the invasive nature of urodynamic studies (UDS) makes it a source of discomfort and morbidity for patients. Ultrasound bladder vibrometry (UBV) could provide a direct and noninvasive means of detecting DO, due to its sensitivity to changes in elasticity and load in the bladder wall. In this study, we investigated the feasibility and applying UBV toward detecting DO. Approach . UBV and urodynamic study (UDS) measurements were collected in 76 neurogenic bladder patients (23 with DO). Timestamped group velocity squared ( c g 2 ) data series were collected from UBV measurements. Concurrent P det data series were identically analyzed for comparison and validation. A processing approach is developed to separate transient fluctuations in the data series from the larger trend of the data and a DO index is proposed for characterizing the transient peaks observed in the data. Main Results. Applying the DO index as a classifier for DO produced sensitivities and specificities of 0.70 and 0.75 for c g 2 data series and 0.70 and 0.83 for P det data series respectively. Significance . It was found that DO can be feasibly detected from data series of timestamped UBV measurements. Collectively, these initial results are promising, and further refinement to the UBV measurement process is likely to improve and clarify its capabilities for noninvasive detection of DO.

Abstract Abstract 2739 Background: Internal tandem duplication mutations of the FMS-like tyrosine kinase 3 receptor (FLT3-ITD) are among the most frequent mutations in de novo acute myeloblastic leukemia (AML) and result in constitutive activation of the receptor tyrosine kinase. Based on data showing that these mutations negatively affect outcome in AML, FLT3 receptor kinase activity is currently being targeted in the clinic. To date, only FLT3 receptor mutant AML patients have been selected for trials involving FLT3 receptor kinase inhibitors, with surprisingly variable clinical responses. Downstream targets of FLT3 receptor activation, whether by receptor mutation or FLT3 ligand binding, involve Stat5, PI3-kinase/Akt and the Ras/Raf/Erk kinase signal transduction pathways which ultimately affect cell survival and proliferation. Functional characterization of those signaling pathways in mutated versus non-mutated FLT3 receptor (FLT3 -WT) myeloblasts has significant potential to reveal heterogeneity among these genetically defined subgroups and to predict for response to kinase inhibition, independent of FLT3 receptor mutation status. Methods: Modulated single cell network profiling (SCNP) was used to evaluate the activation state of intracellular signaling molecules (i.e. nodes), including phosphorylated (p)-Akt, p-Erk, p-S6, p-Stat5 and cleaved-PARP, at baseline and after treatment with specific modulators [including cytokines (such as IL-27) growth factors (such as FLT3 ligand) and drugs (such as cytosine arabinoside)] in 7 healthy bone marrow mononuclear blasts (BMMb) and leukemic myeloblasts, characterized for FLT3 receptor mutation status, from 44 AML patients (38 FLT-WT and 6 FLT3-ITD), aged >60 years (ECOG trial E3999). A total of 64 node-metrics were analyzed. Results: Signaling profiles differed significantly in FLT3-ITD vs. FLT3-WT AML, and in FLT3-WT vs. BMMb (shown in Figure 1 for a representative node, FLT3 ligand induced p-S6). Specifically, compared to BMMb, FLT3-ITD blasts uniformly showed increased basal p-Stat5 levels, decreased FLT3 ligand-induced activation of P13K and Raf/Ras/Erk pathways, minimal IL-27 induced activation of the Jak/Stat pathway, and higher apoptotic responses to DNA-damaging agents. Two AML samples harboring a low FLT3-ITD mutant burden, however, exhibited a signaling pattern similar to FLT3-WT AML samples. By contrast, FLT3-WT samples displayed heterogeneous signaling profiles, overlapping both with those of FLT3-ITD and BMMb samples, suggesting that a fraction of FLT3-WT AML samples exhibit FLT3 receptor pathway deregulation even without FLT3-ITD. Conclusions This study showed that SCNP, which provides a detailed view of intracellular signaling networks at the single-cell level, subclassified patients with AML beyond their molecularly determined FLT3 mutation status. In particular, a fraction of FLT3-WT AML samples signaled as if containing a FLT3 receptor length mutation while FLT3-ITD samples with low mutational load signaled like FLT3-WT AML samples. The clinical relevance of this observation, both for disease prognosis and response to kinase inhibitors, will be revealed only if AML patients are accrued to kinase inhibition trials irrespective of FLT3 receptor mutation status. The wide range of signaling responses observed in FLT3-WT AML suggests that disease across FLT3-WT patients is heterogeneous, likely promoted through distinct mutations and alterations, giving rise to distinct signaling profiles in individual patients Our data also provide evidence for the co-existence of differentially signaling blast populations in individual patients. The potential impact of signaling heterogeneity on clinical response needs to be assessed and may require an individualized combination of treatment modalities. Disclosure: Rosen: Nodality Inc.: Employment, Equity Ownership. Putta:Nodality Inc.: Employment, Equity Ownership. Gayko:Nodality Inc.: Employment, Equity Ownership. Cesano:Nodality Inc.: Employment, Equity Ownership.