A novel computational pathology approach for identifying gene signatures prognostic of disease-free survival for papillary thyroid carcinomas.

INTRODUCTION: Papillary thyroid carcinoma (PTC) is the most prevalent form of thyroid cancer, with the classical and follicular variants representing most cases. Despite generally favorable prognoses, approximately 10% of patients experience recurrence post-surgery and radioactive iodine therapy. Attempts to stratify risk of recurrence have relied on gene expression-based prognostic and predictive signatures with a focus on mutations of well-known driver genes, while hallmarks of tumor morphology have been ignored. OBJECTIVES: We introduce a new computational pathology approach to develop prognostic gene signatures for PTC that is informed by quantitative features of tumor and immune cell morphology. METHODS: We quantified nuclear and immune-related features of tumor morphology to develop a pathomic signature, which was then used to inform an RNA-expression signature model provides a notable advancement in risk stratification compared to both standalone and pathology-informed gene-expression signatures. RESULTS: There was a 17.8% improvement in the C-index (from 0.605 to 0.783) for 123 cPTCs and 15% (from 0.576 to 0.726) for 38 fvPTCs compared to the standalone gene-expression signature. Hazard ratios also improved for cPTCs from 0.89 (0.67,0.99) to 4.43 (3.65,6.68) and fvPTC from 0.98 (0.76,1.32) to 2.28 (1.87,3.64). We validated the image-based risk model on an independent cohort of 32 cPTCs with hazard ratio 1.8 (1.534,2.167).

Artificial intelligence in neuro-oncology: advances and challenges in brain tumor diagnosis, prognosis, and precision treatment.

This review delves into the most recent advancements in applying artificial intelligence (AI) within neuro-oncology, specifically emphasizing work on gliomas, a class of brain tumors that represent a significant global health issue. AI has brought transformative innovations to brain tumor management, utilizing imaging, histopathological, and genomic tools for efficient detection, categorization, outcome prediction, and treatment planning. Assessing its influence across all facets of malignant brain tumor management- diagnosis, prognosis, and therapy- AI models outperform human evaluations in terms of accuracy and specificity. Their ability to discern molecular aspects from imaging may reduce reliance on invasive diagnostics and may accelerate the time to molecular diagnoses. The review covers AI techniques, from classical machine learning to deep learning, highlighting current applications and challenges. Promising directions for future research include multimodal data integration, generative AI, large medical language models, precise tumor delineation and characterization, and addressing racial and gender disparities. Adaptive personalized treatment strategies are also emphasized for optimizing clinical outcomes. Ethical, legal, and social implications are discussed, advocating for transparency and fairness in AI integration for neuro-oncology and providing a holistic understanding of its transformative impact on patient care.

Computational pathology identifies immune-mediated collagen disruption to predict clinical outcomes in gynecologic malignancies.

BACKGROUND: The role of immune cells in collagen degradation within the tumor microenvironment (TME) is unclear. Immune cells, particularly tumor-infiltrating lymphocytes (TILs), are known to alter the extracellular matrix, affecting cancer progression and patient survival. However, the quantitative evaluation of the immune modulatory impact on collagen architecture within the TME remains limited. METHODS: We introduce CollaTIL, a computational pathology method that quantitatively characterizes the immune-collagen relationship within the TME of gynecologic cancers, including high-grade serous ovarian (HGSOC), cervical squamous cell carcinoma (CSCC), and endometrial carcinomas. CollaTIL aims to investigate immune modulatory impact on collagen architecture within the TME, aiming to uncover the interplay between the immune system and tumor progression. RESULTS: We observe that an increased immune infiltrate is associated with chaotic collagen architecture and higher entropy, while immune sparse TME exhibits ordered collagen and lower entropy. Importantly, CollaTIL-associated features that stratify disease risk are linked with gene signatures corresponding to TCA-Cycle in CSCC, and amino acid metabolism, and macrophages in HGSOC. CONCLUSIONS: CollaTIL uncovers a relationship between immune infiltration and collagen structure in the TME of gynecologic cancers. Integrating CollaTIL with genomic analysis offers promising opportunities for future therapeutic strategies and enhanced prognostic assessments in gynecologic oncology.

The role of cells that are part of our immune system in altering the structure of the protein collagen within cancers is not fully understood, particularly within cancers that affect women such as ovarian, cervical and uterine cancers. Here, we developed a computer-based method called CollaTIL to explore how immune cells influence collagen in these tumors and affect their growth. We found that a higher presence of immune cells leads to less organized collagen in the tumor. Conversely, when there are fewer immune cells, the collagen tends to be more structured. Additionally, CollaTIL identifies patterns that predict patient outcomes in these cancers. These findings not only enhance our understanding of tumor biology but also may be useful in helping clinicians to predict which patients are at risk of their disease progressing.

Machine learning driven index of tumor multinucleation correlates with survival and suppressed anti-tumor immunity in head and neck squamous cell carcinoma patients.

OBJECTIVES: Matching treatment intensity to tumor biology is critical to precision oncology for head and neck squamous cell carcinoma (HNSCC) patients. We sought to identify biological features of tumor cell multinucleation, previously shown by us to correlate with survival in oropharyngeal (OP) SCC using a machine learning approach. MATERIALS AND METHODS: Hematoxylin and eosin images from an institutional OPSCC cohort formed the training set (DTr). TCGA HNSCC patients (oral cavity, oropharynx and larynx/hypopharynx) formed the validation set (DV). Deep learning models were trained in DTr to calculate a multinucleation index (MuNI) score. Gene set enrichment analysis (GSEA) was then used to explore correlations between MuNI and tumor biology. RESULTS: MuNI correlated with overall survival. A multivariable nomogram that included MuNI, age, race, sex, T/N stage, and smoking status yielded a C-index of 0.65, and MuNI was prognostic of overall survival (2.25, 1.07-4.71, 0.03), independent of the other variables. High MuNI scores correlated with depletion of effector immunocyte subsets across all HNSCC sites independent of HPV and TP53 mutational status although the correlations were strongest in wild-type TP53 tumors potentially due to aberrant mitotic events and activation of DNA-repair mechanisms. CONCLUSION: MuNI is associated with survival in HNSCC across subsites. This may be driven by an association between high levels of multinucleation and a suppressive (potentially exhausted) tumor immune microenvironment. Mechanistic studies examining the link between multinucleation and tumor immunity will be required to characterize biological drivers of multinucleation and their impact on treatment response and outcomes.

Computational Image and Molecular Analysis Reveal Unique Prognostic Features of Immune Architecture in African Versus European American Women with Endometrial Cancer.

Endometrial cancer (EC) disproportionately affects African American (AA) women in terms of progression and death. In our study, we sought to employ computerized image and bioinformatic analysis to tease out morphologic and molecular differences in EC between AA and European-American (EA) populations. We identified the differences in immune cell spatial patterns between AA and EA populations with markers of tumor biology, including histologic and molecular subtypes. The models performed best when they were trained and validated using data from the same population. Unsupervised clustering revealed a distinct association between immune cell features and known molecular subtypes of endometrial cancer that varied between AA and EA populations. Our genomic analysis revealed two distinct and novel gene sets with mutations associated with improved prognosis in AA and EA patients. Our study findings suggest the need for population-specific risk prediction models for women with endometrial cancer.

SYSMut: decoding the functional significance of rare somatic mutations in cancer.

Current tailored-therapy efforts in cancer are largely focused on a small number of highly recurrently mutated driver genes but therapeutic targeting of these oncogenes remains challenging. However, the vast number of genes mutated infrequently across cancers has received less attention, in part, due to a lack of understanding of their biological significance. We present SYSMut, an extendable systems biology platform that can robustly infer the biologic consequences of somatic mutations by integrating routine multiomics profiles in primary tumors. We establish SYSMut's improved performance vis-à-vis state-of-the-art driver gene identification methodologies by recapitulating the functional impact of known driver genes, while additionally identifying novel functionally impactful mutated genes across 29 cancers. Subsequent application of SYSMut on low-frequency gene mutations in head and neck squamous cell (HNSC) cancers, followed by molecular and pharmacogenetic validation, revealed the lipidogenic network as a novel therapeutic vulnerability in aggressive HNSC cancers. SYSMut is thus a robust scalable framework that enables the discovery of new targetable avenues in cancer.

H3K9 methylation drives resistance to androgen receptor-antagonist therapy in prostate cancer.

Antiandrogen strategies remain the prostate cancer treatment backbone, but drug resistance develops. We show that androgen blockade in prostate cancer leads to derepression of retroelements (REs) followed by a double-stranded RNA (dsRNA)-stimulated interferon response that blocks tumor growth. A forward genetic approach identified H3K9 trimethylation (H3K9me3) as an essential epigenetic adaptation to antiandrogens, which enabled transcriptional silencing of REs that otherwise stimulate interferon signaling and glucocorticoid receptor expression. Elevated expression of terminal H3K9me3 writers was associated with poor patient hormonal therapy outcomes. Forced expression of H3K9me3 writers conferred resistance, whereas inhibiting H3K9-trimethylation writers and readers restored RE expression, blocking antiandrogen resistance. Our work reveals a drug resistance axis that integrates multiple cellular signaling elements and identifies potential pharmacologic vulnerabilities.

Untangling a complex web: Computational analyses of tumor molecular profiles to decode driver mechanisms.

Genome-scale studies focusing on molecular profiling of cancers across tissue types have revealed a plethora of aberrations across the genomic, transcriptomic, and epigenomic scales. The significant molecular heterogeneity across individual tumors even within the same tissue context complicates decoding the key etiologic mechanisms of this disease. Furthermore, it is increasingly likely that biologic mechanisms underlying the pathobiology of cancer involve multiple molecular entities interacting across functional scales. This has motivated the development of computational approaches that integrate molecular measurements with prior biological knowledge in increasingly intricate ways to enable the discovery of driver genomic aberrations across cancers. Here, we review diverse methodological approaches that have powered significant advances in our understanding of the genomic underpinnings of cancer at the cohort and at the individual tumor scales. We outline the key advances and challenges in the computational discovery of cancer mechanisms while motivating the development of systems biology approaches to comprehensively decode the biologic drivers of this complex disease.

Importance Weighted Import Vector Machine for Unsupervised Domain Adaptation.

In real-world applications, the assumption of independent and identical distribution is no longer consistent. To alleviate the significant mismatch between source and target domains, importance weighting import vector machine, which is an adaptive classifier, is proposed. This adaptive probabilistic classification method, which is sparse and computationally efficient, can be used for unsupervised domain adaptation (DA). The effectiveness of the proposed approach is demonstrated via a toy problem, and a real-world cross-domain object recognition task. Even though the sparseness, the proposed method outperforms the state-of-the-art in both unsupervised and semisupervised DA scenarios. We also introduce a reliable importance weighted cross validation (RIWCV), which is an improvement of importance weighted cross validation, for parameter and model selection. The RIWCV avoid falling down in local minimum, by selecting a more reliable combination of the parameters instead of the best parameters.

ISRUC-Sleep: A comprehensive public dataset for sleep researchers.

To facilitate the performance comparison of new methods for sleep patterns analysis, datasets with quality content, publicly-available, are very important and useful. We introduce an open-access comprehensive sleep dataset, called ISRUC-Sleep. The data were obtained from human adults, including healthy subjects, subjects with sleep disorders, and subjects under the effect of sleep medication. Each recording was randomly selected between PSG recordings that were acquired by the Sleep Medicine Centre of the Hospital of Coimbra University (CHUC). The dataset comprises three groups of data: (1) data concerning 100 subjects, with one recording session per subject; (2) data gathered from 8 subjects; two recording sessions were performed per subject, and (3) data collected from one recording session related to 10 healthy subjects. The polysomnography (PSG) recordings, associated with each subject, were visually scored by two human experts. Comparing the existing sleep-related public datasets, ISRUC-Sleep provides data of a reasonable number of subjects with different characteristics such as: data useful for studies involving changes in the PSG signals over time; and data of healthy subjects useful for studies involving comparison of healthy subjects with the patients, suffering from sleep disorders. This dataset was created aiming to complement existing datasets by providing easy-to-apply data collection with some characteristics not covered yet. ISRUC-Sleep can be useful for analysis of new contributions: (i) in biomedical signal processing; (ii) in development of ASSC methods; and (iii) on sleep physiology studies. To evaluate and compare new contributions, which use this dataset as a benchmark, results of applying a subject-independent automatic sleep stage classification (ASSC) method on ISRUC-Sleep dataset are presented.

A two-step automatic sleep stage classification method with dubious range detection.

BACKGROUND: The limitations of the current systems of automatic sleep stage classification (ASSC) are essentially related to the similarities between epochs from different sleep stages and the subjects' variability. Several studies have already identified the situations with the highest likelihood of misclassification in sleep scoring. Here, we took advantage of such information to develop an ASSC system based on knowledge of subjects' variability of some indicators that characterize sleep stages and on the American Academy of Sleep Medicine (AASM) rules. METHODS: An ASSC system consisting of a two-step classifier is proposed. In the first step, epochs are classified using support vector machines (SVMs) spread into different nodes of a decision tree. In the post-processing step, the epochs suspected of misclassification (dubious classification) are tagged, and a new classification is suggested. Identification and correction are based on the AASM rules, and on misclassifications most commonly found/reported in automatic sleep staging. Six electroencephalographic and two electrooculographic channels were used to classify wake, non-rapid eye movement (NREM) sleep--N1, N2 and N3, and rapid eye movement (REM) sleep. RESULTS: The proposed system was tested in a dataset of 14 clinical polysomnographic records of subjects suspected of apnea disorders. Wake and REM epochs not falling in the dubious range, are classified with accuracy levels compatible with the requirements for clinical applications. The suggested correction assigned to the epochs that are tagged as dubious enhances the global results of all sleep stages. CONCLUSIONS: This approach provides reliable sleep staging results for non-dubious epochs.

Adaptive automatic sleep stage classification under covariate shift.

Current automatic sleep stage classification (ASSC) methods that rely on polysomnographic (PSG) signals suffer from inter-subject differences that make them unreliable in facing with new and different subjects. A novel adaptive sleep scoring method based on unsupervised domain adaptation, aiming to be robust to inter-subject variability, is proposed. We assume that the sleep quality variants follow a covariate shift model, where only the sleep features distribution change in the training and test phases. The maximum overlap discrete wavelet transform (MODWT) is applied to extract relevant features from EEG, EOG and EMG signals. A set of significant features are selected by minimum-redundancy maximum-relevance (mRMR) which is a powerful feature selection method. Finally, an instance-weighting method, namely the importance weighted kernel logistic regression (IWKLR) is applied for the purpose of obtaining adaptation in classification. The classification results using leave one out cross-validation (LOOCV), show that the proposed method performs at the state-of-the art in the field of ASSC.

Efficient feature selection for sleep staging based on maximal overlap discrete wavelet transform and SVM.

In this paper, a novel algorithm is proposed with application in sleep/awake detection and in multiclass sleep stage classification (awake, non rapid eye movement (NREM) sleep and REM sleep). In turn, NREM is further divided into three stages denoted here by S1, S2, and S3. Six electroencephalographic (EEG) and two electro-oculographic (EOG) channels were used in this study. The maximum overlap discrete wavelet transform (MODWT) with the multi-resolution Analysis is applied to extract relevant features from EEG and EOG signals. The extracted feature set is transformed and normalized to reduce the effect of extreme values of features. A set of significant features are selected by mRMR which is a powerful feature selection method. Finally the selected feature set is classified using support vector machines (SVMs). The system achieved 95.0% of average accuracy for sleep/awake detection. As concerns the multiclass case, the average accuracy of sleep stages classification was 93.0%.