Adjuvant therapeutic strategy decision support for an elderly population with localized breast cancer: A monocentric cohort retrospective study.

Guidelines for the management of elderly patients with early breast cancer are scarce. Additional adjuvant systemic treatment to surgery for early breast cancer in elderly populations is challenged by increasing comorbidities with age. In non-metastatic settings, treatment decisions are often made under considerable uncertainty; this commonly leads to undertreatment and, consequently, poorer outcomes. This study aimed to develop a decision support tool that can help to identify candidate adjuvant post-surgery treatment schemes for elderly breast cancer patients based on tumor and patient characteristics. Our approach was to generate predictions of patient outcomes for different courses of action; these predictions can, in turn, be used to inform clinical decisions for new patients. We used a cohort of elderly patients (≥ 70 years) who underwent surgery with curative intent for early breast cancer to train the models. We tested seven classification algorithms using 5-fold cross-validation, with 80% of the data being randomly selected for training and the remaining 20% for testing. We assessed model performance using accuracy, precision, recall, F1-score, and AUC score. We used an autoencoder to perform dimensionality reduction prior to classification. We observed consistently better performance using logistic regression and linear discriminant analysis models when compared to the other models we tested. Classification performance generally improved when an autoencoder was used, except for when we predicted the need for adjuvant treatment. We obtained overall best results using a logistic regression model without autoencoding to predict the need for adjuvant treatment (F1-score = 0.869).

Mature tertiary lymphoid structures are key niches of tumour-specific immune responses in pancreatic ductal adenocarcinomas.

OBJECTIVE: To better understand the immune microenvironment of pancreatic ductal adenocarcinomas (PDACs), here we explored the relevance of T and B cell compartmentalisation into tertiary lymphoid structures (TLSs) for the generation of local antitumour immunity. DESIGN: We characterised the functional states and spatial organisation of PDAC-infiltrating T and B cells using single-cell RNA sequencing (scRNA-seq), flow cytometry, multicolour immunofluorescence, gene expression profiling of microdissected TLSs, as well as in vitro assays. In addition, we performed a pan-cancer analysis of tumour-infiltrating T cells using scRNA-seq and sc T cell receptor sequencing datasets from eight cancer types. To evaluate the clinical relevance of our findings, we used PDAC bulk RNA-seq data from The Cancer Genome Atlas and the PRINCE chemoimmunotherapy trial. RESULTS: We found that a subset of PDACs harbours fully developed TLSs where B cells proliferate and differentiate into plasma cells. These mature TLSs also support T cell activity and are enriched with tumour-reactive T cells. Importantly, we showed that chronically activated, tumour-reactive T cells exposed to fibroblast-derived TGF-ß may act as TLS organisers by producing the B cell chemoattractant CXCL13. Identification of highly similar subsets of clonally expanded CXCL13 + tumour-infiltrating T cells across multiple cancer types further indicated a conserved link between tumour-antigen recognition and the allocation of B cells within sheltered hubs in the tumour microenvironment. Finally, we showed that the expression of a gene signature reflecting mature TLSs was enriched in pretreatment biopsies from PDAC patients with longer survival after receiving different chemoimmunotherapy regimens. CONCLUSION: We provided a framework for understanding the biological role of PDAC-associated TLSs and revealed their potential to guide the selection of patients for future immunotherapy trials.

[The medical informatics initiative and rare diseases: next-generation routine data for diagnosis, therapy selection and research]. / Die Medizininformatik-Initiative und Seltene Erkrankungen: Routinedaten der nächsten Generation für Diagnose, Therapiewahl und Forschung.

People with rare diseases (RDs) have particular potential to benefit from digitisation in the healthcare system. The National Action Alliance for People with Rare Diseases (NAMSE) has campaigned for SE to be specifically taken into account in the digitisation of the healthcare system in Germany. The topic was addressed within the Medical Informatics Initiative (MII) of the Federal Ministry of Education and Research (BMBF). Here, starting with university hospitals, a digital infrastructure is currently being established for the data protection-compliant multiple use of standardised care and research data. Since 2020, part of the initiative has been the CORD-MI project (Collaboration on Rare Diseases) in which university hospitals and other partners throughout Germany have joined forces to improve patient care and research in the field of rare diseases.This article highlights how the MII takes into account the concerns of SE and what opportunities the "new routine data" obtained offer. A SE module was included in the "MII core data set" - an information model based on the data standard fast healthcare interoperability resources (FHIR). Data collected in the context of care and research routines can thus be exchanged between the participating institutions in the future and support, for example, diagnosis, therapy selection and research projects in the field of SE. The CORD-MI project has set itself the goal of obtaining insights into the care situation of people with SE with the help of exemplary questions and then drawing conclusions for further necessary steps in the area of digitalisation.

Data-Driven Identification of Biomarkers for In Situ Monitoring of Drug Treatment in Bladder Cancer Organoids.

Three-dimensional (3D) organoid culture recapitulating patient-specific histopathological and molecular diversity offers great promise for precision medicine in cancer. In this study, we established label-free imaging procedures, including Raman microspectroscopy (RMS) and fluorescence lifetime imaging microscopy (FLIM), for in situ cellular analysis and metabolic monitoring of drug treatment efficacy. Primary tumor and urine specimens were utilized to generate bladder cancer organoids, which were further treated with various concentrations of pharmaceutical agents relevant for the treatment of bladder cancer (i.e., cisplatin, venetoclax). Direct cellular response upon drug treatment was monitored by RMS. Raman spectra of treated and untreated bladder cancer organoids were compared using multivariate data analysis to monitor the impact of drugs on subcellular structures such as nuclei and mitochondria based on shifts and intensity changes of specific molecular vibrations. The effects of different drugs on cell metabolism were assessed by the local autofluorophore environment of NADH and FAD, determined by multiexponential fitting of lifetime decays. Data-driven neural network and data validation analyses (k-means clustering) were performed to retrieve additional and non-biased biomarkers for the classification of drug-specific responsiveness. Together, FLIM and RMS allowed for non-invasive and molecular-sensitive monitoring of tumor-drug interactions, providing the potential to determine and optimize patient-specific treatment efficacy.

Predicting drug sensitivity of cancer cells based on DNA methylation levels.

Cancer cell lines, which are cell cultures derived from tumor samples, represent one of the least expensive and most studied preclinical models for drug development. Accurately predicting drug responses for a given cell line based on molecular features may help to optimize drug-development pipelines and explain mechanisms behind treatment responses. In this study, we focus on DNA methylation profiles as one type of molecular feature that is known to drive tumorigenesis and modulate treatment responses. Using genome-wide, DNA methylation profiles from 987 cell lines in the Genomics of Drug Sensitivity in Cancer database, we used machine-learning algorithms to evaluate the potential to predict cytotoxic responses for eight anti-cancer drugs. We compared the performance of five classification algorithms and four regression algorithms representing diverse methodologies, including tree-, probability-, kernel-, ensemble-, and distance-based approaches. We artificially subsampled the data to varying degrees, aiming to understand whether training based on relatively extreme outcomes would yield improved performance. When using classification or regression algorithms to predict discrete or continuous responses, respectively, we consistently observed excellent predictive performance when the training and test sets consisted of cell-line data. Classification algorithms performed best when we trained the models using cell lines with relatively extreme drug-response values, attaining area-under-the-receiver-operating-characteristic-curve values as high as 0.97. The regression algorithms performed best when we trained the models using the full range of drug-response values, although this depended on the performance metrics we used. Finally, we used patient data from The Cancer Genome Atlas to evaluate the feasibility of classifying clinical responses for human tumors based on models derived from cell lines. Generally, the algorithms were unable to identify patterns that predicted patient responses reliably; however, predictions by the Random Forests algorithm were significantly correlated with Temozolomide responses for low-grade gliomas.

Physiological and socioeconomic characteristics predict COVID-19 mortality and resource utilization in Brazil.

BACKGROUND: Given the severity and scope of the current COVID-19 pandemic, it is critical to determine predictive features of COVID-19 mortality and medical resource usage to effectively inform health, risk-based physical distancing, and work accommodation policies. Non-clinical sociodemographic features are important explanatory variables of COVID-19 outcomes, revealing existing disparities in large health care systems. METHODS AND FINDINGS: We use nation-wide multicenter data of COVID-19 patients in Brazil to predict mortality and ventilator usage. The dataset contains hospitalized patients who tested positive for COVID-19 and had either recovered or were deceased between March 1 and June 30, 2020. A total of 113,214 patients with 50,387 deceased, were included. Both interpretable (sparse versions of Logistic Regression and Support Vector Machines) and state-of-the-art non-interpretable (Gradient Boosted Decision Trees and Random Forest) classification methods are employed. Death from COVID-19 was strongly associated with demographics, socioeconomic factors, and comorbidities. Variables highly predictive of mortality included geographic location of the hospital (OR = 2.2 for Northeast region, OR = 2.1 for North region); renal (OR = 2.0) and liver (OR = 1.7) chronic disease; immunosuppression (OR = 1.7); obesity (OR = 1.7); neurological (OR = 1.6), cardiovascular (OR = 1.5), and hematologic (OR = 1.2) disease; diabetes (OR = 1.4); chronic pneumopathy (OR = 1.4); immunosuppression (OR = 1.3); respiratory symptoms, ranging from respiratory discomfort (OR = 1.4) and dyspnea (OR = 1.3) to oxygen saturation less than 95% (OR = 1.7); hospitalization in a public hospital (OR = 1.2); and self-reported patient illiteracy (OR = 1.1). Validation accuracies (AUC) for predicting mortality and ventilation need reach 79% and 70%, respectively, when using only pre-admission variables. Models that use post-admission disease progression information reach accuracies (AUC) of 86% and 87% for predicting mortality and ventilation use, respectively. CONCLUSIONS: The results highlight the predictive power of socioeconomic information in assessing COVID-19 mortality and medical resource allocation, and shed light on existing disparities in the Brazilian health care system during the COVID-19 pandemic.

A pan-cancer analysis of progression mechanisms and drug sensitivity in cancer cell lines.

Biomarker discovery involves identifying genetic abnormalities within a tumor. However, one of the main challenges in defining such therapeutic targets is accounting for the molecular heterogeneity of cancer. By integrating somatic mutation and gene expression data from hundreds of heterogeneous cell lines from the Cancer Cell Line Encyclopedia (CCLE), we identify sequences of genetic events that may help explain common patterns of oncogenesis across 22 tumor types, and evaluate the general effect of late-stage mutations on drug sensitivity and resistance mechanisms. Through gene enrichment analysis, we find several cancer-specific and immune pathways that are significantly enriched in each of our three proposed phases of cancer progression. By further analyzing the drug activity area associated with compounds that target the BRAF oncogene, a known predictor of drug sensitivity for several compounds used in cancer treatment, we verify that the acquisition of new driver mutations interferes with the targeted drug mechanism, meaning that cells without late-stage mutations generally respond better to drugs.

No-shows in appointment scheduling - a systematic literature review.

No-show appointments significantly impact the functioning of healthcare institutions, and much research has been performed to uncover and analyze the factors that influence no-show behavior. In spite of the growing body of literature on this issue, no synthesis of the state-of-the-art is presently available and no systematic literature review (SLR) exists that encompasses all medical specialties. This paper provides a SLR of no-shows in appointment scheduling in which the characteristics of existing studies are analyzed, results regarding which factors have a higher impact on missed appointment rates are synthetized, and comparisons with previous findings are performed. A total of 727 articles and review papers were retrieved from the Scopus database (which includes MEDLINE), 105 of which were selected for identification and analysis. The results indicate that the average no-show rate is of the order of 23%, being highest in the African continent (43.0%) and lowest in Oceania (13.2%). Our analysis also identified patient characteristics that were more frequently associated with no-show behavior: adults of younger age; lower socioeconomic status; place of residence is distant from the clinic; no private insurance. Furthermore, the most commonly reported significant determinants of no-show were high lead time and prior no-show history.

Integrating mutation and gene expression cross-sectional data to infer cancer progression.

BACKGROUND: A major problem in identifying the best therapeutic targets for cancer is the molecular heterogeneity of the disease. Cancer is often caused by an accumulation of mutations which produce irreversible damage to the cell's control mechanisms of survival and proliferation. Different mutations may affect these cellular anachronisms through a combination of molecular interactions which may be dynamically changing during cancer progression. It has been previously shown that cancer accumulates mutations over time. In this paper we address the problem of cancer heterogeneity by modeling cancer progression using somatic mutation and gene expression cross-sectional data. RESULTS: We propose a novel formulation of integrating somatic mutation and gene expression data to infer the temporal sequence of events from cross-sectional data. Using a mixed integer linear program we model the interaction between groups of different mutated genes and the resulting modifications at the gene expression level. Our approach identifies a partition of mutation events which gradually produce gene expression changes to a partition of genes over time. The proposed formulation is tested using both simulated data and real breast cancer data with matched somatic mutations and gene expression measurements from The Cancer Genome Atlas. First, we classify the genes as oncogenes or tumor suppressors based on the frequency of driver mutations. As expected, the most frequently mutated genes in breast cancer are PIK3CA and TP53 genes. Then, we select those genes with most frequent driver mutations and a set of genes known to play roles in cancer development. Furthermore, we apply the proposed mixed integer linear program to identify the temporal order in which genes mutate and, simultaneously, the changes they produce at the gene expression level during cancer progression. In addition, we are able to identify known causal relationships between mutations and gene expression changes in PI3K/AKT and TP53 pathways. CONCLUSIONS: This paper proposes a new model to infer the temporal sequence in which mutations occur and lead to changes at the gene expression level during cancer progression. The approach is general and can be applied to any data sets with available somatic mutations and gene expression measurements.