Multistain deep learning for prediction of prognosis and therapy response in colorectal cancer.

Although it has long been known that the immune cell composition has a strong prognostic and predictive value in colorectal cancer (CRC), scoring systems such as the immunoscore (IS) or quantification of intraepithelial lymphocytes are only slowly being adopted into clinical routine use and have their limitations. To address this we established and evaluated a multistain deep learning model (MSDLM) utilizing artificial intelligence (AI) to determine the AImmunoscore (AIS) in more than 1,000 patients with CRC. Our model had high prognostic capabilities and outperformed other clinical, molecular and immune cell-based parameters. It could also be used to predict the response to neoadjuvant therapy in patients with rectal cancer. Using an explainable AI approach, we confirmed that the MSDLM's decisions were based on established cellular patterns of anti-tumor immunity. Hence, the AIS could provide clinicians with a valuable decision-making tool based on the tumor immune microenvironment.

Senescence-Associated Molecules and Tumor-Immune-Interactions as Prognostic Biomarkers in Colorectal Cancer.

Background and Aims: The initiation of cellular senescence in response to protumorigenic stimuli counteracts malignant progression in (pre)malignant cells. Besides arresting proliferation, cells entering this terminal differentiation state adopt a characteristic senescence-associated secretory phenotype (SASP) which initiates alterations to their microenvironment and effects immunosurveillance of tumorous lesions. However, some effects mediated by senescent cells contribute to disease progression. Currently, the exploration of senescent cells' impact on the tumor microenvironment and the evaluation of senescence as possible target in colorectal cancer (CRC) therapy demand reliable detection of cellular senescence in vivo. Therefore, specific immunohistochemical biomarkers are required. Our aim is to analyze the clinical implications of senescence detection in colorectal carcinoma and to investigate the interactions of senescent tumor cells and their immune microenvironment in vitro and in vivo. Methods: Senescence was induced in CRC cell lines by low-dose-etoposide treatment and confirmed by Senescence-associated ß-galactosidase (SA-ß-GAL) staining and fluorescence activated cell sorting (FACS) analysis. Co-cultures of senescent cells and immune cells were established. Multiple cell viability assays, electron microscopy and live cell imaging were conducted. Immunohistochemical (IHC) markers of senescence and immune cell subtypes were studied in a cohort of CRC patients by analyzing a tissue micro array (TMA) and performing digital image analysis. Results were compared to disease-specific survival (DSS) and progression-free survival (PFS). Results: Varying expression of senescence markers in tumor cells was associated with in- or decreased survival of CRC patients. Proximity analysis of p21-positive senescent tumor cells and cytotoxic T cells revealed a significantly better prognosis for patients in which these cell types have the possibility to directly interact. In vitro, NK-92 cells (mimicking natural killer T cells) or TALL-104 cells (mimicking both cytotoxic T cells and natural killer T cells) led to dose-dependent specific cytotoxicity in >75 % of the senescent CRC cells but <20 % of the proliferating control CRC cells. This immune cell-mediated senolysis seems to be facilitated via direct cell-cell contact inducing apoptosis and granule exocytosis. Conclusion: Counteracting tumorigenesis, cellular senescence is of significant relevance in CRC. We show the dual role of senescence bearing both beneficial and malignancy-promoting potential in vivo. Absence as well as exceeding expression of senescence markers are associated with bad prognosis in CRC. The antitumorigenic potential of senescence induction is determined by tumor micromilieu and immune cell-mediated elimination of senescent cells.

Multimodal Deep Learning for Prognosis Prediction in Renal Cancer.

BACKGROUND: Clear-cell renal cell carcinoma (ccRCC) is common and associated with substantial mortality. TNM stage and histopathological grading have been the sole determinants of a patient's prognosis for decades and there are few prognostic biomarkers used in clinical routine. Management of ccRCC involves multiple disciplines such as urology, radiology, oncology, and pathology and each of these specialties generates highly complex medical data. Here, artificial intelligence (AI) could prove extremely powerful to extract meaningful information to benefit patients. OBJECTIVE: In the study, we developed and evaluated a multimodal deep learning model (MMDLM) for prognosis prediction in ccRCC. DESIGN SETTING AND PARTICIPANTS: Two mixed cohorts of non-metastatic and metastatic ccRCC patients were used: (1) The Cancer Genome Atlas cohort including 230 patients and (2) the Mainz cohort including 18 patients with ccRCC. For each of these patients, we trained the MMDLM on multiscale histopathological images, CT/MRI scans, and genomic data from whole exome sequencing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcome measurements included Harrell's concordance index (C-index) and also various performance parameters for predicting the 5-year survival status (5YSS). Different visualization techniques were used to make our model more transparent. RESULTS: The MMDLM showed great performance in predicting the prognosis of ccRCC patients with a mean C-index of 0.7791 and a mean accuracy of 83.43%. Training on a combination of data from different sources yielded significantly better results compared to when only one source was used. Furthermore, the MMDLM's prediction was an independent prognostic factor outperforming other clinical parameters. INTERPRETATION: Multimodal deep learning can contribute to prognosis prediction in ccRCC and potentially help to improve the clinical management of this disease. PATIENT SUMMARY: An AI-based computer program can analyze various medical data (microscopic images, CT/MRI scans, and genomic data) simultaneously and thereby predict the survival time of patients with renal cancer.

Deep Learning Predicts Molecular Subtype of Muscle-invasive Bladder Cancer from Conventional Histopathological Slides.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) is the second most common genitourinary malignancy, and is associated with high morbidity and mortality. Recently, molecular subtypes of MIBC have been identified, which have important clinical implications. OBJECTIVE: In the current study, we tried to predict the molecular subtype of MIBC samples from conventional histomorphology alone using deep learning. DESIGN, SETTING, AND PARTICIPANTS: Two cohorts of patients with MIBC were used: (1) The Cancer Genome Atlas Urothelial Bladder Carcinoma dataset including 407 patients and (2) our own cohort including 16 patients with treatment-naïve, primary resected MIBC. This resulted in a total of 423 digital whole slide images of tumor tissue to train, validate, and test the deep learning algorithm to predict the molecular subtype. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Various accuracy measurements including the area under the receiver operating characteristic curves were used to evaluate the deep learning model. A sliding window approach to visualize classification was used. Class activation maps were used to identify image features that are most relevant to call a specific class. RESULTS AND LIMITATIONS: The deep learning model showed great performance in the prediction of the molecular subtype of MIBC patients from hematoxylin and eosin (HE) slides alone-similar to or better than pathology experts. Using different visualization techniques, we identified new histopathological features that were most relevant to our model. CONCLUSIONS: Deep learning can be used to predict important molecular features in MIBC patients from HE slides alone, potentially improving the clinical management of this disease significantly. PATIENT SUMMARY: In patients with bladder cancer, a computer program found changes in the appearance of tumor tissue under the microscope and used these to predict genetic alterations. This could potentially benefit patients.

Prognostic relevance of androgen receptor expression in renal cell carcinomas.

BACKGROUND: Despite rapid discoveries in molecular biology of renal cell carcinoma (RCC) and advances in systemic targeted therapies, development of new diagnostic and therapeutic strategies is urgently needed. The androgen receptor (AR) has been shown to hold prognostic and predicitve value in several malignancies. Here, we studied a possible association between AR expression and prognosis in patients with RCCs. RESULTS: Low AR expression levels were associated with occurrence of distant metastasis and higher tumor stage in papillary and clear-cell RCCs. Importantly, multivariate Cox regression analyses revealed that AR is an independent prognostic factor for cancer-specific survival. MATERIALS AND METHODS: The expression of AR was measured by immunohistochemistry and assessed by digital image analysis using a tissue microarray containing tumor tissue of a large and well-documented series of RCC patients with long-term follow-up information. Chi-squared tests, Kaplan-Meier curves and Cox regression models were used to investigate the possible relationship between AR expression and clinico-pathological characteristics and patient survival. CONCLUSIONS: Patients affected by AR-positive tumors exhibit a favorable prognosis by multiple Cox regression, while loss of AR expression is related to aggressive disease. Therefore, assessing AR expression offers valuable prognostic information that could improve treatment selection for metastatic disease. Moreover, our findings highlight a potential therapeutic use of AR pharmaceuticals in patients with RCCs.