Background: Drug permeability across the blood-brain barrier (BBB) is a critical challenge for successful drug discovery which has led to multiple efforts to develop in silico predictive models. Most of the in silico models are based on the molecular descriptors of the drugs. In this work, we compare the ability of sequential feature selection and genetic algorithms in selecting the most relevant descriptors and hence enhancing the permeability prediction accuracy.Methods: Five different classifiers were initially trained on a dataset using eight molecular descriptors. Then, sequential feature selection and genetic algorithms were performed separately and the same classifiers were trained using the descriptors chosen by each algorithm.Results: The highest overall accuracy obtained without feature selection was 94.98%. This accuracy increased with sequential feature selection and genetic algorithms on multiple classifiers. However, the highest accuracy (96.23%) was obtained after performing genetic algorithm on the feature vector. Moreover, genetic algorithm with a fitness function based on the performance of a support vector machine led to an increase in the accuracy of all the tested classifiers unlike sequential feature selection.Conclusions: The findings show that genetic algorithm is a more robust approach than sequential feature selection in choosing the most relevant molecular descriptors involved in the permeability across the blood-brain barrier. The results also highlight the importance of the polar surface area of drugs in crossing the BBB.

Colorectal cancer liver metastases (CLM) are the most common type of distant metastases originating from the abdomen and are characterized by a high recurrence rate after curative resection. It has been previously reported that CLM presenting a low cluster of differentiation 3 (CD3) positive T-cell infiltration density concurrent with a high major histocompatibility complex class I (MHC-I) expression were associated with poor clinical outcomes. In this study, we attempt to noninvasively predict whether a CLM exhibit the CD3 Low MHC High immunological profile using preoperative CT images. To this end, we propose an ensemble network combining multiple Attentive Interpretable Tabular learning (TabNet) models, trained using CT-derived radiomic features. A total of 160 CLM were included in this study and randomly divided between a training set (n=130) and a hold-out test set (n=30). The proposed model yielded good prediction performance on the test set with an accuracy of 70.0% [95% confidence interval 53.6%-86.4%] and an area under the curve of 69.4% [52.9%-85.9%]. It also outperformed other off-the-shelf machine learning models. We finally demonstrated that the predicted immune profile was associated with a shorter disease-specific survival (p = .023) and time-to-recurrence (p = .020), showing the value of assessing the immune response.

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Colorectal cancer (CRC) continues to be a leading cause of cancer-related death in the developed world due to metastatic progression of the disease. In an effort to improve the understanding of tumor biology and developing prognostic tools, it was found that CD3+ tumor infiltrating lymphocytes (TIL) had a very strong prognostic value in primary CRC as well as in colorectal liver metastases (CLM). Quantification of TILs remains labor intensive and requires tissue samples, hence being of limited use in the pre-operative period or in the context of non-operable disease. Computed tomography (CT) images however are widely available for patients with CLM. In this study, we propose a pipeline to predict CD3 T-cell infiltration in CLM from pre-operative CT images. Radiomic features were extracted from 58 automatically segmented CLM lesions. Subsequently, dimensionality reduction was performed by training an autoencoder (AE) on the full feature set. We then used AE bottleneck embeddings to predict CD3 T-cell density, stratified into two categories: CD3 hi and CD3 low . For this, we implemented a 1D convolutional neural network (1D-CNN) and compared its performance against five machine learning models using 5-fold cross-validation. Results showed that the proposed 1D-CNN outperformed the other trained models achieving a mean accuracy of 0.69 (standard deviation [SD], 0.01) and a mean area under the receiver operating curve (AUROC) of 0.75 (SD, 0.02) on the validation set. Our findings demonstrate a relationship between CT radiomic features and CD3 tumor infiltration status with the potential of noninvasively determining CD3 status from preoperative CT images.

Background Finding a noninvasive radiomic surrogate of tumor immune features could help identify patients more likely to respond to novel immune checkpoint inhibitors. Particularly, CD73 is an ectonucleotidase that catalyzes the breakdown of extracellular AMP into immunosuppressive adenosine, which can be blocked by therapeutic antibodies. High CD73 expression in colorectal cancer liver metastasis (CRLM) resected with curative intent is associated with early recurrence and shorter patient survival. The aim of this study was hence to evaluate whether machine learning analysis of preoperative liver CT-scan could estimate high vs low CD73 expression in CRLM and whether such radiomic score would have a prognostic significance. Methods We trained an Attentive Interpretable Tabular Learning (TabNet) model to predict, from preoperative CT images, stratified expression levels of CD73 (CD73High vs. CD73Low) assessed by immunofluorescence (IF) on tissue microarrays. Radiomic features were extracted from 160 segmented CRLM of 122 patients with matched IF data, preprocessed and used to train the predictive model. We applied a five-fold cross-validation and validated the performance on a hold-out test set. Results TabNet provided areas under the receiver operating characteristic curve of 0.95 (95% CI 0.87 to 1.0) and 0.79 (0.65 to 0.92) on the training and hold-out test sets respectively, and outperformed other machine learning models. The TabNet-derived score, termed rad-CD73, was positively correlated with CD73 histological expression in matched CRLM (Spearman’s ρ = 0.6004; P < 0.0001). The median time to recurrence (TTR) and disease-specific survival (DSS) after CRLM resection in rad-CD73High vs rad-CD73Low patients was 13.0 vs 23.6 months (P = 0.0098) and 53.4 vs 126.0 months (P = 0.0222), respectively. The prognostic value of rad-CD73 was independent of the standard clinical risk score, for both TTR (HR = 2.11, 95% CI 1.30 to 3.45, P < 0.005) and DSS (HR = 1.88, 95% CI 1.11 to 3.18, P = 0.020). Conclusions Our findings reveal promising results for non-invasive CT-scan-based prediction of CD73 expression in CRLM and warrant further validation as to whether rad-CD73 could assist oncologists as a biomarker of prognosis and response to immunotherapies targeting the adenosine pathway.