Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a dismal prognosis. Despite efforts to improve therapy outcomes in PDAC, overall survival remains at 2 to 5 years following initial diagnosis. To date, there are no established predictive or prognostic biomarkers for PDAC tumors. The availability of digitized H&E stained whole slide images (WSI) has led to an uptake in deep learning-based approaches toward comprehensive, automatic interrogation of tumor-specific attributes for disease diagnosis and prognosis. However, a significant challenge with the interrogation of large WSIs (gigabytes in size) is that only a small portion of the tissue (i.e. ROIs) contains information pertinent to diagnosis or prognosis. In this work, we investigated whether “highattention” ROIs (i.e. patch regions) identified by an attention-driven model to differentiate tumor from benign regions, may also be associated with survival outcomes in PDAC patients. The attention model was developed using a total of n = 461 WSI of H&E-stained pancreatic tumors, from two public repositories. Our approach first identifies attention maps (i.e. ROIs) using clustering-constrained-attention multiple-instance learning (CLAM), on WSI labeled as PDAC versus benign pancreas. Subsequently, the learned attention maps are employed within a LASSO regularized Cox-hazard proportional model to distinguish between high and low survival-risk groups of PDAC patients. Results were evaluated via a log-rank test and compared with established demographic variables (age, sex, race) to predict survival risk. While individual demographic variables did not demonstrate significant differences in survival risk, the attention-driven WSI features yielded significant stratification of low and highrisk groups in both the training (p = 0.0014, Hazard Ratio (HR), 2.0 (95 % Confidence Interval (CI) 1.3 -3.1)) and the test set (p = 0.0012 HR = 2.0 (95 % CI 1.3 -2.6)). Following a large, multi-institutional validation, our deep-learning approach may allow for designing more precise prognostic and predictive histopathological biomarkers for PDAC tumors.
High-grade gliomas are aggressive forms of brain cancer associated with a poor prognosis of 12-15 months. The mutation of isocitrate dehydrogenase I (IDH) and O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation are biomarkers relevant to disease classification and prognosis. Current methods to identify patients’ molecular status are expensive and can be resource prohibitive. Morphological attributes as captured on histopathology contain rich phenotypic information indicative of the underlying molecular processes. Recently, deep learning methods have demonstrated diagnostic and prognostic value via computational analysis of histopathology to incorporate complex and subvisual morphometric features that may not be visually accessible to pathologists. We hypothesize that a computational deep learning approach applied to Hematoxylin and Eosin (H&E)-stained digitized tissue slides will be able to reliably predict the molecular (IDH, MGMT) status in high-grade glioma patients. Specifically, we present a deep learning approach that employs self-supervised and multiple instance learning, on a total of n=325 H&E stained high-grade glioma slides, for identifying (a) IDHmutant versus IDH-wild-type (WT) and (b) MGMT promoter methylated versus unmethylated tumors. The approach addressed challenges of patch selection and the unbalanced instances that arise from only subregions of whole-slide images providing diagnostic value. The deep learning approach achieved accuracy values of 91.17 (+/- 3.47) and 86.11 (+/- 4.45), for the prediction of IDH mutation and MGMT promoter methylation status respectively, demonstrating an improvement of over 5% compared to the reported accuracy values in previous studies.
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