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Consensus Molecular Subtype (CMS) classification of colorectal cancer (CRC) tissues is complicated by RNA degradation upon formalin-fixed paraffin-embedded (FFPE) preservation. Here, we present an FFPE-curated CMS classifier. The CMSFFPE classifier was developed using genes with a high transcript integrity in FFPE-derived RNA. We evaluated the classification accuracy in two FFPE-RNA datasets with matched fresh-frozen (FF) RNA data, and an FF-derived RNA set. An FFPE-RNA application cohort of metastatic CRC patients was established, partly treated with anti-EGFR therapy. Key characteristics per CMS were assessed. Cross-referenced with matched benchmark FF CMS calls, the CMSFFPE classifier strongly improved classification accuracy in two FFPE datasets compared with the original CMSClassifier (63.6% versus 40.9% and 83.3% versus 66.7%, respectively). We recovered CMS-specific recurrence-free survival patterns (CMS4 versus CMS2: hazard ratio 1.75, 95% CI 1.24-2.46). Key molecular and clinical associations of the CMSs were confirmed. In particular, we demonstrated the predictive value of CMS2 and CMS3 for anti-EGFR therapy response (CMS2&3: odds ratio 5.48, 95% CI 1.10-27.27). The CMSFFPE classifier is an optimized FFPE-curated research tool for CMS classification of clinical CRC samples., (© 2024 de Back et al.)

Peritoneal metastases (PMs) from colorectal cancer (CRC) respond poorly to treatment and are associated with unfavorable prognosis. For example, the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery in resectable patients shows limited benefit, and novel treatments are urgently needed. The majority of CRC-PMs represent the CMS4 molecular subtype of CRC, and here we queried the vulnerabilities of this subtype in pharmacogenomic databases to identify novel therapies. This reveals the copper ionophore elesclomol (ES) as highly effective against CRC-PMs. ES exhibits rapid cytotoxicity against CMS4 cells by targeting mitochondria. We find that a markedly reduced mitochondrial content in CMS4 cells explains their vulnerability to ES. ES demonstrates efficacy in preclinical models of PMs, including CRC-PMs and ovarian cancer organoids, mouse models, and a HIPEC rat model of PMs. The above proposes ES as a promising candidate for the local treatment of CRC-PMs, with broader implications for other PM-prone cancers., Competing Interests: Declaration of interests L.V. is an employee and shareholder of Genentech-Roche. M.F.B. has received research funding from Celgene, Frame Therapeutics, and Lead Pharma and has acted as a consultant to Servier and Olympus., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Due to the impact respiratory viruses have on human health, a lot of data has been collected and visualised in tools such as dashboards that provide retrospective insights into the course of an epidemic or pandemic. Two well-known respiratory viruses, influenza virus and SARS-CoV-2, are the causative agents of influenza and COVID-19, respectively. A scoping review was performed using Embase including data from January 2000 until April 2021 to identify individual and environmental health parameters that affect transmission of influenza virus and SARS-CoV-2, as well as disease severity (morbidity (hospitalisation) and mortality) of influenza and COVID-19. Summary data was extracted from published articles. A total of 2280 unique articles were identified by the search, 484 articles were analysed, and 149 articles were included. The information of included articles was combined with data from Dutch databases to create prospective interactive maps that visualise risk areas in the Netherlands on health region, municipality, and neighbourhood-level. Included health parameters are contacts per day, mixing patterns, household composition, presence of certain indoor public spaces, urbanity, meteorological values, average income, age, ethnicity, comorbidity, sex, and smoking habits. The impact and input of these parameters are adjustable by users allowing a fit-for-purpose approach. These maps can be used to corroborate local policy decisions in times of health crisis, or in pandemic preparedness plans, serving as an instant visualisation tool of risk areas in the country. Despite limitations caused by data unavailability, simplification steps, and lack of validation, these interactive maps provide an important basis that can be elaborated on by further research that integrates both individual and environmental parameters., Competing Interests: The authors declare no competing interests. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report., (© 2024 The Authors. Published by Elsevier B.V.)

The structure of cell-free DNA (cfDNA) is altered in the blood of patients with cancer. From whole-genome sequencing, we retrieve the cfDNA fragment-end composition using a new software (FrEIA [fragment end integrated analysis]), as well as the cfDNA size and tumor fraction in three independent cohorts (n = 925 cancer from >10 types and 321 control samples). At 95% specificity, we detect 72% cancer samples using at least one cfDNA measure, including 64% early-stage cancer (n = 220). cfDNA detection correlates with a shorter overall (p = 0.0086) and recurrence-free (p = 0.017) survival in patients with resectable esophageal adenocarcinoma. Integrating cfDNA measures with machine learning in an independent test set (n = 396 cancer, 90 controls) achieve a detection accuracy of 82% and area under the receiver operating characteristic curve of 0.96. In conclusion, harnessing the biological features of cfDNA can improve, at no extra cost, the diagnostic performance of liquid biopsies., Competing Interests: Declaration of interests F.M. is co-inventor on multiple patents related to cfDNA analysis. Other co-authors have no relevant conflict of interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)