Artificial Intelligence-Based Mitosis Scoring in Breast Cancer: Clinical Application.

In recent years, artificial intelligence (AI) has demonstrated exceptional performance in mitosis identification and quantification. However, the implementation of AI in clinical practice needs to be evaluated against the existing methods. This study is aimed at assessing the optimal method of using AI-based mitotic figure scoring in breast cancer (BC). We utilized whole slide images from a large cohort of BC with extended follow-up comprising a discovery (n = 1715) and a validation (n = 859) set (Nottingham cohort). The Cancer Genome Atlas of breast invasive carcinoma (TCGA-BRCA) cohort (n = 757) was used as an external test set. Employing automated mitosis detection, the mitotic count was assessed using 3 different methods, the mitotic count per tumor area (MCT; calculated by dividing the number of mitotic figures by the total tumor area), the mitotic index (MI; defined as the average number of mitotic figures per 1000 malignant cells), and the mitotic activity index (MAI; defined as the number of mitotic figures in 3 mm2 area within the mitotic hotspot). These automated metrics were evaluated and compared based on their correlation with the well-established visual scoring method of the Nottingham grading system and Ki67 score, clinicopathologic parameters, and patient outcomes. AI-based mitotic scores derived from the 3 methods (MCT, MI, and MAI) were significantly correlated with the clinicopathologic characteristics and patient survival (P < .001). However, the mitotic counts and the derived cutoffs varied significantly between the 3 methods. Only MAI and MCT were positively correlated with the gold standard visual scoring method used in Nottingham grading system (r = 0.8 and r = 0.7, respectively) and Ki67 scores (r = 0.69 and r = 0.55, respectively), and MAI was the only independent predictor of survival (P < .05) in multivariate Cox regression analysis. For clinical applications, the optimum method of scoring mitosis using AI needs to be considered. MAI can provide reliable and reproducible results and can accurately quantify mitotic figures in BC.

Deciphering the Morphology of Tumor-Stromal Features in Invasive Breast Cancer Using Artificial Intelligence.

Tumor-associated stroma in breast cancer (BC) is complex and exhibits a high degree of heterogeneity. To date, no standardized assessment method has been established. Artificial intelligence (AI) could provide an objective morphologic assessment of tumors and stroma, with the potential to identify new features not discernible by visual microscopy. In this study, we used AI to assess the clinical significance of (1) stroma-to-tumor ratio (S:TR) and (2) the spatial arrangement of stromal cells, tumor cell density, and tumor burden in BC. Whole-slide images of a large cohort (n = 1968) of well-characterized luminal BC cases were examined. Region and cell-level annotation was performed, and supervised deep learning models were applied for automated quantification of tumor and stromal features. S:TR was calculated in terms of surface area and cell count ratio, and the S:TR heterogeneity and spatial distribution were also assessed. Tumor cell density and tumor size were used to estimate tumor burden. Cases were divided into discovery (n = 1027) and test (n = 941) sets for validation of the findings. In the whole cohort, the stroma-to-tumor mean surface area ratio was 0.74, and stromal cell density heterogeneity score was high (0.7/1). BC with high S:TR showed features characteristic of good prognosis and longer patient survival in both the discovery and test sets. Heterogeneous spatial distribution of S:TR areas was predictive of worse outcome. Higher tumor burden was associated with aggressive tumor behavior and shorter survival and was an independent predictor of worse outcome (BC-specific survival; hazard ratio: 1.7, P = .03, 95% CI, 1.04-2.83 and distant metastasis-free survival; hazard ratio: 1.64, P = .04, 95% CI, 1.01-2.62) superior to absolute tumor size. The study concludes that AI provides a tool to assess major and subtle morphologic stromal features in BC with prognostic implications. Tumor burden is more prognostically informative than tumor size.

Biomarkers for site-specific response to neoadjuvant chemotherapy in epithelial ovarian cancer: relating MRI changes to tumour cell load and necrosis.

BACKGROUND: Diffusion-weighted magnetic resonance imaging (DW-MRI) potentially interrogates site-specific response to neoadjuvant chemotherapy (NAC) in epithelial ovarian cancer (EOC). METHODS: Participants with newly diagnosed EOC due for platinum-based chemotherapy and interval debulking surgery were recruited prospectively in a multicentre study (n = 47 participants). Apparent diffusion coefficient (ADC) and solid tumour volume (up to 10 lesions per participant) were obtained from DW-MRI before and after NAC (including double-baseline for repeatability assessment in n = 19). Anatomically matched lesions were analysed after surgical excision (65 lesions obtained from 25 participants). A trained algorithm determined tumour cell fraction, percentage tumour and percentage necrosis on histology. Whole-lesion post-NAC ADC and pre/post-NAC ADC changes were compared with histological metrics (residual tumour/necrosis) for each tumour site (ovarian, omental, peritoneal, lymph node). RESULTS: Tumour volume reduced at all sites after NAC. ADC increased between pre- and post-NAC measurements. Post-NAC ADC correlated negatively with tumour cell fraction. Pre/post-NAC changes in ADC correlated positively with percentage necrosis. Significant correlations were driven by peritoneal lesions. CONCLUSIONS: Following NAC in EOC, the ADC (measured using DW-MRI) increases differentially at disease sites despite similar tumour shrinkage, making its utility site-specific. After NAC, ADC correlates negatively with tumour cell fraction; change in ADC correlates positively with percentage necrosis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01505829.

Locality Sensitive Deep Learning for Detection and Classification of Nuclei in Routine Colon Cancer Histology Images.

Detection and classification of cell nuclei in histopathology images of cancerous tissue stained with the standard hematoxylin and eosin stain is a challenging task due to cellular heterogeneity. Deep learning approaches have been shown to produce encouraging results on histopathology images in various studies. In this paper, we propose a Spatially Constrained Convolutional Neural Network (SC-CNN) to perform nucleus detection. SC-CNN regresses the likelihood of a pixel being the center of a nucleus, where high probability values are spatially constrained to locate in the vicinity of the centers of nuclei. For classification of nuclei, we propose a novel Neighboring Ensemble Predictor (NEP) coupled with CNN to more accurately predict the class label of detected cell nuclei. The proposed approaches for detection and classification do not require segmentation of nuclei. We have evaluated them on a large dataset of colorectal adenocarcinoma images, consisting of more than 20,000 annotated nuclei belonging to four different classes. Our results show that the joint detection and classification of the proposed SC-CNN and NEP produces the highest average F1 score as compared to other recently published approaches. Prospectively, the proposed methods could offer benefit to pathology practice in terms of quantitative analysis of tissue constituents in whole-slide images, and potentially lead to a better understanding of cancer.

Robust normalization protocols for multiplexed fluorescence bioimage analysis.

study of mapping and interaction of co-localized proteins at a sub-cellular level is important for understanding complex biological phenomena. One of the recent techniques to map co-localized proteins is to use the standard immuno-fluorescence microscopy in a cyclic manner (Nat Biotechnol 24:1270-8, 2006; Proc Natl Acad Sci 110:11982-7, 2013). Unfortunately, these techniques suffer from variability in intensity and positioning of signals from protein markers within a run and across different runs. Therefore, it is necessary to standardize protocols for preprocessing of the multiplexed bioimaging (MBI) data from multiple runs to a comparable scale before any further analysis can be performed on the data. In this paper, we compare various normalization protocols and propose on the basis of the obtained results, a robust normalization technique that produces consistent results on the MBI data collected from different runs using the Toponome Imaging System (TIS). Normalization results produced by the proposed method on a sample TIS data set for colorectal cancer patients were ranked favorably by two pathologists and two biologists. We show that the proposed method produces higher between class Kullback-Leibler (KL) divergence and lower within class KL divergence on a distribution of cell phenotypes from colorectal cancer and histologically normal samples.