Physically constrained neural networks for inferring physiological system models.

Systems biology and systems neurophysiology in particular have recently emerged as powerful tools for a number of key applications in the biomedical sciences. Nevertheless, such models are often based on complex combinations of multiscale (and possibly multiphysics) strategies that require ad hoc computational strategies and pose extremely high computational demands. Recent developments in the field of deep neural networks have demonstrated the possibility of formulating nonlinear, universal approximators to estimate solutions to highly nonlinear and complex problems with significant speed and accuracy advantages in comparison with traditional models. After synthetic data validation, we use so-called physically constrained neural networks (PINN) to simultaneously solve the biologically plausible Hodgkin-Huxley model and infer its parameters and hidden time-courses from real data under both variable and constant current stimulation, demonstrating extremely low variability across spikes and faithful signal reconstruction. The parameter ranges we obtain are also compatible with prior knowledge. We demonstrate that detailed biological knowledge can be provided to a neural network, making it able to fit complex dynamics over both simulated and real data.

Spatiotemporal learning of dynamic positron emission tomography data improves diagnostic accuracy in breast cancer.

Positron emission tomography (PET) can reveal metabolic activity in a voxelwise manner. PET analysis is commonly performed in a static manner by analyzing the standardized uptake value (SUV) obtained from the plateau region of PET acquisitions. A dynamic PET acquisition can provide a map of the spatiotemporal concentration of the tracer in vivo, hence conveying information about radiotracer delivery to tissue, its interaction with the target and washout. Therefore, tissue-specific biochemical properties are embedded in the shape of time activity curves (TACs), which are generally used for kinetic analysis. Conventionally, TACs are employed along with information about blood plasma activity concentration, i.e., the arterial input function (AIF), and specific compartmental models to obtain a full quantitative analysis of PET data. The main drawback of this approach is the need for invasive procedures requiring arterial blood sample collection during the whole PET scan. In this paper, we address the challenge of improving PET diagnostic accuracy through an alternative approach based on the analysis of time signal intensity patterns. Specifically, we demonstrate the diagnostic potential of tissue TACs provided by dynamic PET acquisition using various deep learning models. Our framework is shown to outperform the discriminative potential of classical SUV analysis, hence paving the way for more accurate PET-based lesion discrimination without additional acquisition time or invasive procedures. Clinical Relevance- The diagnostic accuracy of dynamic PET data exploited by deep-learning based time signal intensity pattern analysis is superior to that of static SUV imaging.

Radiomics in breast cancer classification and prediction.

Breast Cancer (BC) is the common form of cancer in women. Its diagnosis and screening are usually performed through different imaging modalities such as mammography, magnetic resonance imaging and ultrasound. However, mammography and ultrasound-imaging techniques have limited sensitivity and specificity both in identifying lesions and in differentiating malign from benign lesions, especially in presence of dense breast parenchyma. Due to the higher resolution of magnetic resonance images, MRI represents the method with the higher specificity and sensitivity among all the available tools, in both lesions' identification and diagnosis. However, especially for diagnosis, even MRI has limitations that are only partially solved if combined with mammography. Unfortunately, due to the limits of all these imaging tools, in order to have a certain diagnosis, patients often receive painful and costly bioptics procedures. In this context, several computational approaches have been developed to increase sensitivity, while maintaining the same specificity, in BC diagnosis and screening. Amongst these, radiomics has been increasingly gaining ground in oncology to improve cancer diagnosis, prognosis and treatment. Radiomics derives multiple quantitative features from single or multiple medical imaging modalities, highlighting image traits which are not visible to the naked eye and hence significantly augmenting the discriminatory and predictive potential of medical imaging. This review article aims to summarize the state of the art in radiomics-based BC research. The dominating evidence extracted from the literature points towards a high potential of radiomics in disentangling malignant from benign breast lesions, classifying BC types and grades and also in predicting treatment response and recurrence risk. In the era of personalized medicine, radiomics has the potential to improve diagnosis, prognosis, prediction, monitoring, image-based intervention, and assessment of therapeutic response in BC.

Deep computational pathology in breast cancer.

Deep Learning (DL) algorithms are a set of techniques that exploit large and/or complex real-world datasets for cross-domain and cross-discipline prediction and classification tasks. DL architectures excel in computer vision tasks, and in particular image processing and interpretation. This has prompted a wave of disruptingly innovative applications in medical imaging, where DL strategies have the potential to vastly outperform human experts. This is particularly relevant in the context of histopathology, where whole slide imaging (WSI) of stained tissue in conjuction with DL algorithms for their interpretation, selection and cancer staging are beginning to play an ever increasing role in supporting human operators in visual assessments. This has the potential to reduce everyday workload as well as to increase precision and reproducibility across observers, centers, staining techniques and even pathologies. In this paper we introduce the most common DL architectures used in image analysis, with a focus on histopathological image analysis in general and in breast histology in particular. We briefly review how, state-of-art DL architectures compare to human performance on across a number of critical tasks such as mitotic count, tubules analysis and nuclear pleomorphism analysis. Also, the development of DL algorithms specialized to pathology images have been enormously fueled by a number of world-wide challenges based on large, multicentric image databases which are now publicly available. In turn, this has allowed most recent efforts to shift more and more towards semi-supervised learning methods, which provide greater flexibility and applicability. We also review all major repositories of manually labelled pathology images in breast cancer and provide an in-depth discussion of the challenges specific to training DL architectures to interpret WSI data, as well as a review of the state-of-the-art methods for interpretation of images generated from immunohistochemical analysis of breast lesions. We finally discuss the future challenges and opportunities which the adoption of DL paradigms is most likely to pose in the field of pathology for breast cancer detection, diagnosis, staging and prognosis. This review is intended as a comprehensive stepping stone into the field of modern computational pathology for a transdisciplinary readership across technical and medical disciplines.

A novel approach for geographical risk mapping of morbidity and mortality rates: the case of Val D'Agri, Italy.

While associations between exposure to air pollutants and increased morbidity and mortality are well established, few rigorous studies on this issue are available. The aim of the current study is to implement a new approach to the spatial analysis of mortality and morbidity, based on testing for the presence of the same association in other areas of similar size. Additionally, we perform a case study in Val d'Agri (VA), an area of Basilicata Region, Southern Italy, where oil and natural gas extraction began in 1998. In order to examine the spatial distribution of morbidity and mortality in the region of interest, Hospital discharge (2001-2013) and mortality (2003-2014) rates for the main environment-related diseases were calculated. In addition, a comparison between the period 1980-1998 and the period 1999-2014 was performed for cardiovascular disease mortality. For the period under study, a neutral scenario emerged for cancer and respiratory diseases, where we found no differences in morbidity and mortality as compared to the national benchmark. In some cases significantly lower values (as compared to the nation-wide benchmark) were found. Conversely, a slight excess in morbidity and mortality (as compared to the nation-wide benchmark) emerged for cardiovascular diseases. Still, this excess was common to a number of municipalities in the surroundings of VA, and appeared to be already present in 1980. Higher rates of cardiovascular diseases, lower rates of neoplastic disorders no differences in mortality for respiratory causes (as compared to the nation-wide benchmark) were found in multiple areas of the region, and were therefore not specific to VA. In summary, our data do not support the hypothesis of a role of industrial activities related to oil extraction in VA in determining mortality and morbidity patterns and trends.

Novel insights into breast cancer progression and metastasis: A multidisciplinary opportunity to transition from biology to clinical oncology.

According to the most recent epidemiological studies, breast cancer shows the highest incidence and the second leading cause of death in women. Cancer progression and metastasis are the main events related to poor survival of breast cancer patients. This can be explained by the presence of highly resistant to chemo- and radiotherapy stem cells in many breast tumor tissues. In this context, numerous studies highlighted the possible involvement of epithelial to mesenchymal transition phenomenon as biological program to generate cancer stem cells, and thus participate to both metastatic and drug resistance process. Therefore, the comprehension of mechanisms (both cellular and molecular) involved in breast cancer occurrence and progression can lay the foundation for the development of new diagnostic and therapeutical protocols. In this review, we reported the most important findings in the field of breast cancer highlighting the most recent data concerning breast tumor biology, diagnosis and therapy.

An Ad Hoc Random Initialization Deep Neural Network Architecture for Discriminating Malignant Breast Cancer Lesions in Mammographic Images.

Breast cancer is one of the most common cancers in women, with more than 1,300,000 cases and 450,000 deaths each year worldwide. In this context, recent studies showed that early breast cancer detection, along with suitable treatment, could significantly reduce breast cancer death rates in the long term. X-ray mammography is still the instrument of choice in breast cancer screening. In this context, the false-positive and false-negative rates commonly achieved by radiologists are extremely arduous to estimate and control although some authors have estimated figures of up to 20% of total diagnoses or more. The introduction of novel artificial intelligence (AI) technologies applied to the diagnosis and, possibly, prognosis of breast cancer could revolutionize the current status of the management of the breast cancer patient by assisting the radiologist in clinical image interpretation. Lately, a breakthrough in the AI field has been brought about by the introduction of deep learning techniques in general and of convolutional neural networks in particular. Such techniques require no a priori feature space definition from the operator and are able to achieve classification performances which can even surpass human experts. In this paper, we design and validate an ad hoc CNN architecture specialized in breast lesion classification from imaging data only. We explore a total of 260 model architectures in a train-validation-test split in order to propose a model selection criterion which can pose the emphasis on reducing false negatives while still retaining acceptable accuracy. We achieve an area under the receiver operatic characteristics curve of 0.785 (accuracy 71.19%) on the test set, demonstrating how an ad hoc random initialization architecture can and should be fine tuned to a specific problem, especially in biomedical applications.

A random initialization deep neural network for discriminating malignant breast cancer lesions.

Breast cancer is one of the most common cancer in women, with more than 1,300,000 cases and 450,000 deaths each year worldwide. Recent studies show that early breast cancer detection, along with suitable treatment, could significantly reduce breast cancer death rates in the long-term. While the consequences of a false positive diagnosis can be psychologically and socioeconomically burdensome, the result of a false negative diagnosis can be devastating, especially in terms of health detriment. In this context, the false positive and false negative rates commonly achieved by radiologists are extremely arduous to estimate and control, and some authors have estimated figures of up to 20% of total diagnoses or more. Novel ideas in computer-assisted diagnosis have been prompted by the introduction of deep learning techniques in general and of convolutional neural networks (CNN) in particular. In this paper, we design and validate an ad-hoc CNN architecture specialized in breast lesion classification and heuristically explore possible parameter combinations and architecture styles in order to propose a model selection criterion which can pose the emphasis on reducing false negatives while still retaining acceptable accuracy. We achieve good classification performance on the validation and test set, demonstrating how an ad-hoc, random initialization CNN architecture can provide practical aid in the classification and staging of breast cancer.

Quantitative analysis of basal and interim PET/CT images for predicting tumor recurrence in patients with Hodgkin's lymphoma.

OBJECTIVES: The qualitative analysis of interim PET has been reported to be useful for predicting the outcome of Hodgkin's lymphoma (HL) after chemotherapy. As the next step, our study aims to present a quantitative analysis on the basis of both a basal (PET/CT0) and an interim (PET/CT2) scan to improve the prognostic value of imaging in HL patients. PATIENTS AND METHODS: A cohort of 68 patients undergoing a basal and an interim scan with F-fluorodeoxyglucose after two cycles of chemotherapy consisting of adriamycin, bleomycin, vinblastine, and dacarbazine were examined. Two subsets of patients with a positive and a negative interim scan were selected. RESULTS: In patients with a negative scan, a total of 108 lymph node lesions showing a good response to chemotherapy were contoured, whereas in the remaining patients with positive scans, six responder and 12 relapsing lymph node lesions were contoured. Standardized uptake value (SUV) and Hounsfield unit (HU) values were included in the volumes contoured on coregistered basal and interim scans and included in a database. A linear regression model was used to identify the predictor of relapse at the lesion level. The support vector machine analysis and bootstrap approach were used to determine the model capability. The predictive models were presented as nomograms on the basis of basal or both basal and interim studies. SUV at the basal/interim study and basal HU values were predictors of a poor prognosis. In particular, the higher points were associated with lower values of SUV and HU at baseline and the higher values of SUV at the interim study. Using the bootstrap and support vector machine approach, the cut-off of the model increased up to 89%. CONCLUSION: The novel tool enables estimation of the risk of tumor relapse after chemotherapy in HL patients on the basis of basal and interim PET/CT scans including SUV and densitometric information.