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Competing Interests: We declare no competing interests.

Leadership as a key building block of a health system plays a crucial role in achieving high performance and helps deliver change and shape the policy agenda and its implementation. Echoing the emerging need for effective leaders in Oncology, the "Improving Cancer Outcomes and Leadership Course" was developed jointly by the European School of Oncology (ESO), the European Cancer Organization (ECO) and Sharing Progress in Cancer Care (SPCC). The course was offered as a hybrid event online and in Warsaw in June 2022. It aimed to introduce early and mid-career cancer healthcare professionals of all disciplines and professions to the expertise required to develop strategic plans, support and collaborate in relevant applied health research, develop implementation approaches and acquire the skill sets required to support leadership and change management within their countries and regions. A total of 47 participants, mainly from Europe, participated and prepared 'case discussions' of organisational challenges or projects aiming to improve health care in their regions. These were deliberated and further developed in 3 break out groups. A qualitative evaluation of the course impact performed 2 years after the course showed that most participants remained in contact with each other, the majority had implemented learnings from the course to help improve cancer outcomes, 87% had further developed their projects that were presented during the breakout sessions and of those 89% felt that the discussions that were held during course had actively helped them to develop and potentially apply these projects. Finally, 77% have thought of or initiated a different project than the one they discussed during the course, based on ideas coming from the discussions during or after the course. Here we describe the course, give three examples of topics discussed in Warsaw and present plans for the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024. Published by Elsevier Ltd.)

The term 'precancer' typically refers to an early stage of neoplastic development that is distinguishable from normal tissue owing to molecular and phenotypic alterations, resulting in abnormal cells that are at least partially self-sustaining and function outside of normal cellular cues that constrain cell proliferation and survival. Although such cells are often histologically distinct from both the corresponding normal and invasive cancer cells of the same tissue origin, defining precancer remains a challenge for both the research and clinical communities. Once sufficient molecular and phenotypic changes have occurred in the precancer, the tissue is identified as a 'cancer' by a histopathologist. While even diagnosing cancer can at times be challenging, the determination of invasive cancer is generally less ambiguous and suggests a high likelihood of and potential for metastatic disease. The 'hallmarks of cancer' set out the fundamental organizing principles of malignant transformation but exactly how many of these hallmarks and in what configuration they define precancer has not been clearly and consistently determined. In this Expert Recommendation, we provide a starting point for a conceptual framework for defining precancer, which is based on molecular, pathological, clinical and epidemiological criteria, with the goal of advancing our understanding of the initial changes that occur and opportunities to intervene at the earliest possible time point., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Medication safety is an important health priority that focuses on preventing harm from medication-related events. Unsafe medication administration practices can lead to errors, which can cause avoidable injury (or harm) to patients., Objectives: This paper reports on an evidence implementation project conducted in a large tertiary hospital in Australia to improve nursing compliance with best practice recommendations for medication administration., Methods: The project was guided by JBI's seven-phase approach to evidence implementation, using audit and feedback and a structured framework to identify barriers, enablers, and implementation strategies., Results: The project resulted in improved compliance with best practice recommendations. This was achieved through multimodal strategies, including education, improved access to resources, and targeted feedback and discussion sessions to encourage culture and behavior change., Conclusions: The project improved nurses' medication administration practices, specifically in performing independent second checks. Collaborative efforts of the project leads facilitated the review of medication administration policy and the development of staff education resources. Patient engagement remains an area for improvement, along with the potential need for further ongoing medication education., Spanish Abstract: http://links.lww.com/IJEBH/A237., (Copyright © 2024 JBI. Unauthorized reproduction of this article is prohibited.)

Competing Interests: We declare no competing interests.

Vulnerable children from poor communities with high HIV and Tuberculosis(TB) burdens were impacted by COVID-19 lockdowns. Concern was raised about the extent of this impact and anticipated post-pandemic surges in mortality. Interrupted time series segmented regression analyses were done using routinely collected facility-level data of children admitted for medical conditions at four South African referral hospitals. Monthly admission and mortality data over 60 months from 01 April 2018 to 31 January 2023 was analysed using models which included dummy lockdown level variables, a dummy post-COVID period variable, Fourier terms to account for seasonality, and excess mortality as a proxy for healthcare burden. Of the 45 015 admissions analysed, 1237(2·75%) demised with significant decreases in admissions during all the lockdown levels, with the most significant mean monthly decrease of 450(95%, CI = 657·3, -244·3) p<0·001 in level 5 (the most severe) lockdown. There was evidence of loss of seasonality on a six-month scale during the COVID periods for all admissions (p = 0·002), including under-one-year-olds (p = 0·034) and under-five-year-olds (p = 0·004). No decreases in mortality accompanied decreased admissions. Post-pandemic surges in admissions or mortality were not identified in children with acute gastroenteritis, acute pneumonia and severe acute malnutrition.During the COVID-19 pandemic, paediatric admissions in 4 hospitals serving communities with high levels of HIV, TB and poverty decreased, similar to global experiences; however, there was no change in in-hospital mortality. No post-pandemic surge in admissions or mortality was documented. Differences in the impact of pandemic control measures on the transmission of childhood infections and access to health care may account for differing outcomes seen in our setting compared to the global experiences. Further studies are needed to understand the impact of pandemic control measures on healthcare provision and transmission dynamics and to better inform future responses amongst vulnerable child populations., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Naidoo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: The Ending Discrimination against Cancer Survivors research project is grateful for the support received from FOCA (Fonds Cancer, ASBL, Belgium). ML is supported by funding from Health Data Research UK. ML has received honoraria from Bayer, Novartis, and Roche, unrelated to this work. GS and FM declare no competing interests.

Precision oncology has a significant role to play in delivering optimal patient care. Biomarkers are critical enablers for precision oncology across the continuum of cancer diagnosis, in defining patient prognosis, and in predicting the response to treatments and their potential toxicities, as well as delineating the risk of hereditary cancer syndromes. Biomarkers also potentiate cancer drug development, accelerating patient access to safe and effective therapies. However, despite an accurate and timely diagnosis being critical to patient survival, advances in genomic testing are not being fully exploited in daily clinical practice, leading to missed opportunities to deliver the most effective treatments for patients. Biomarker testing availability and implementation often lag behind approvals of respective biomarker-informed therapies, limiting prompt patient access to these life-saving drugs. Multiple factors currently impede the routine adoption of biomarker testing including, but not limited to, cost, lack of test reimbursement, limited access, regulatory hurdles, lack of knowledge, insufficient cooperation on assay development, and the urgent need to harmonize and validate testing assays, all leading to inefficient diagnostic pathways. Clinical guidelines increasingly include genomic profiling, and recent evidence suggests that precision oncology can be delivered in a cost-effective way for financially-challenged health systems. Therefore, precision genomic testing for cancer biomarkers must be embedded into the clinical practice of oncology care delivery going forward. We articulate a series of recommendations and a call to action to underpin the mainstreaming of a biomarker-informed precision oncology approach to enhance patient outcomes and deliver cost effective 21st century cancer care., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024. Published by Elsevier Ltd.)

Background: Financial toxicity, defined as both the objective financial burden and subjective financial distress from a cancer diagnosis and its treatment, is a topic of interest in the assessment of the quality of life of patients with cancer and their families. Current evidence implicates financial toxicity in psychosocial, economic and other harms, leading to suboptimal cancer outcomes along the entire trajectory of diagnosis, treatment, supportive care, survivorship and palliation. This paper presents the results of a virtual consensus, based on the evidence base to date, on the screening and management of financial toxicity in patients with and beyond cancer organized by the European Society for Medical Oncology (ESMO) in 2022., Methods: A Delphi panel of 19 experts from 11 countries was convened taking into account multidisciplinarity, diversity in health system contexts and research relevance. The international panel of experts was divided into four working groups (WGs) to address questions relating to distinct thematic areas: patients with cancer at risk of financial toxicity; management of financial toxicity during the initial phase of treatment at the hospital/ambulatory settings; financial toxicity during the continuing phase and at end of life; and financial risk protection for survivors of cancer, and in cancer recurrence. After comprehensively reviewing the literature, statements were developed by the WGs and then presented to the entire panel for further discussion and amendment, and voting., Results and Discussion: A total of 25 evidence-informed consensus statements were developed, which answer 13 questions on financial toxicity. They cover evidence summaries, practice recommendations/guiding statements and policy recommendations relevant across health systems. These consensus statements aim to provide a more comprehensive understanding of financial toxicity and guide clinicians globally in mitigating its impact, emphasizing the importance of further research, best practices and guidelines., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Existing evidence often indicates higher cancer incidence and mortality rates, later diagnosis, lower screening uptake and poorer long-term survival for people living in rural compared to more urbanised areas. Despite wide inequities and variation in cancer care and outcomes across Europe, much of the scientific literature explicitly exploring the impact of rurality on cancer continues to come from Australia and North America. The European Code of Cancer Practice or "The Code" is a citizen and patient-centred statement of the most salient requirements for good clinical cancer practice and has been extensively co-produced by cancer patients, cancer professionals and patient advocates. It contains 10 key overarching Rights that a cancer patient should expect from their healthcare system, regardless of where they live and has been strongly endorsed by professional and patient cancer organisations as well as the European Commission. In this article, we use these 10 fundamental Rights as a framework to argue that (i) the issues and needs identified in The Code are generally more profound for rural people with cancer; (ii) addressing these issues is also more challenging in rural contexts; (iii) interventions and support must explicitly account for the unique needs of rural residents living with and affected by cancer and (iv) new innovative approaches are urgently required to successfully overcome the challenges faced by rural people with cancer and their caregivers. Despite equitable healthcare being a key European policy focus, the needs of rural people living with cancer have largely been neglected., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Molecular stratification using gene-level transcriptional data has identified subtypes with distinctive genotypic and phenotypic traits, as exemplified by the consensus molecular subtypes (CMS) in colorectal cancer (CRC). Here, rather than gene-level data, we make use of gene ontology and biological activation state information for initial molecular class discovery. In doing so, we defined three pathway-derived subtypes (PDS) in CRC: PDS1 tumors, which are canonical/LGR5 + stem-rich, highly proliferative and display good prognosis; PDS2 tumors, which are regenerative/ANXA1 + stem-rich, with elevated stromal and immune tumor microenvironmental lineages; and PDS3 tumors, which represent a previously overlooked slow-cycling subset of tumors within CMS2 with reduced stem populations and increased differentiated lineages, particularly enterocytes and enteroendocrine cells, yet display the worst prognosis in locally advanced disease. These PDS3 phenotypic traits are evident across numerous bulk and single-cell datasets, and demark a series of subtle biological states that are currently under-represented in pre-clinical models and are not identified using existing subtyping classifiers., (© 2024. The Author(s).)

Background: Skin cancer is a prevalent cancer in the UK. Its rising incidence and mortality rates are expected to result in substantial financial implications, particularly on diagnostic and treatment services for skin cancer management in Northern Ireland (NI). Such anticipated disease increases underscore the need for prevention and control measures that should help guide policymaking and planning efforts., Methods: We conducted a cost of illness study to assess the economic impact of skin cancer in NI from the healthcare system's perspective, using a bottom-up method, employing NHS reference costs (UK£) for skin cancer diagnosis and treatment patient pathways in 2021/22. Sensitivity analyses varied diagnostic volumes by applying multipliers for benign cases, assuming a diagnostic conversion rate of 6.8%, and examined an alternative chemotherapy regimen compliance rate of 75%. Additionally, proportional cost increases were projected based on future estimated increases of 9% and 28% to malignant melanoma (MM) cases for diagnostic, treatment, and follow-up volumes., Results: Significant numbers of non-melanoma skin cancers (NMSC) and MM cases were recorded, 4289 NMSCs and 439 MM cases. The total cost for managing NMSC was £ 3,365,350. Total costs for MM skin cancer were £ 13,740,681, including £ 8,753,494 for procurement, administration, and chemotherapy drug use. Overall healthcare spending on skin cancer care totalled £ 21,167,651. Sensitivity analysis suggested diagnostic cost may increase significantly to £ 12,374,478 based on referral volume assumptions. If base case rates rise by 9 or 28% estimated total costs of treating skin cancer will increase to £ 22.3 million and £ 24.9 million, respectively., Conclusions: Skin cancer management costs in NI totalled ∼£ 21.1 million to £ 32.1 million, depending on diagnostic referral assumptions. Costs have risen ∼10-fold over the past decade for MM due largely to chemotherapy costs. A predicted 28% increase in MM cases by 2040 would lead to ∼£ 3.8 million of additional expenditures, providing a significant challenge for cancer health systems., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Human genetic evidence shows that PDE3B is associated with metabolic and dyslipidemia phenotypes. A number of PDE3 family selective inhibitors have been approved by the FDA for various indications; however, given the undesirable proarrhythmic effects in the heart, selectivity for PDE3B inhibition over closely related family members (such as PDE3A; 48% identity) is a critical consideration for development of PDE3B therapeutics. Selectivity for PDE3B over PDE3A may be achieved in a variety of ways, including properties intrinsic to the compound or tissue-selective targeting. The high (>95%) active site homology between PDE3A and B represents a massive obstacle for obtaining selectivity at the active site; however, utilization of libraries with high molecular diversity in high throughput screens may uncover selective chemical matter. Herein, we employed a DNA-encoded library screen to identify PDE3B-selective inhibitors and identified potent and selective boronic acid compounds bound at the active site.

National health services in Ireland and the UK fund the majority of social prescribing services and have issued recommendations for evaluation. However, it is not known what outcomes are prioritised for evaluation within individual services and what evaluation methods are used to capture recommended outcomes. A survey was carried out to examine evaluation practices of social prescribing services on the island of Ireland. This study used a cross-sectional observational design. The sample was all the staff involved in delivering and/or managing SP services on the island of Ireland. Questionnaires were distributed at a national SP conference and online. Closed-response questions were analysed using descriptive statistics. Content analysis was used for open-ended questions. Eighty-four usable surveys were returned (50% from the Republic of Ireland and 50% from Northern Ireland). All respondents (100%) agreed on the importance of measuring SP outcomes. The most frequently measured outcomes were health and well-being (89.2%) and loneliness (84%). The least frequently measured outcome was the satisfaction of healthcare professionals referring to SP: 78.4% of respondents never measured this outcome. The most frequently used measurement tool was the Short Warwick Edinburgh Mental Well-Being Scale, with 38/76 (50%) respondents using this measure. There was a lack of standardised measures identified for some outcomes. For example, 70% of respondents reported always measuring physical activity (PA), but only four respondents identified a specific PA measure. In open-ended questions, respondents recommended flexibility in evaluation methods to reflect the complexity and individualised focus of SP. They also identified the need for protected time to complete evaluations and recommended a national strategy to inform priorities in evaluations. This study demonstrates a wide variation on the island of Ireland on how SP services are measuring outcomes, with many outcomes rarely or never measured using standardised measures. Agreement is needed on a core outcome set for social prescribing in order to guide service delivery and evaluations.

Cancer affects one in two people in the UK and the incidence is set to increase. The UK National Health Service is facing major workforce deficits and cancer services have struggled to recover after the COVID-19 pandemic, with waiting times for cancer care becoming the worst on record. There are severe and widening disparities across the country and survival rates remain unacceptably poor for many cancers. This is at a time when cancer care has become increasingly complex, specialised, and expensive. The current crisis has deep historic roots, and to be reversed, the scale of the challenge must be acknowledged and a fundamental reset is required. The loss of a dedicated National Cancer Control Plan in England and Wales, poor operationalisation of plans elsewhere in the UK, and the closure of the National Cancer Research Institute have all added to a sense of strategic misdirection. The UK finds itself at a crossroads, where the political decisions of governments, the cancer community, and research funders will determine whether we can, together, achieve equitable, affordable, and high-quality cancer care for patients that is commensurate with our wealth, and position our outcomes among the best in the world. In this Policy Review, we describe the challenges and opportunities that are needed to develop radical, yet sustainable plans, which are comprehensive, evidence-based, integrated, patient-outcome focused, and deliver value for money., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Kaplan-Meier (KM) survival analyses based on complex patient categorization due to the burgeoning volumes of genomic, molecular and phenotypic data, are an increasingly important aspect of the biomedical researcher's toolkit. Commercial statistics and graphing packages for such analyses are functionally limited, whereas open-source tools have a high barrier-to-entry in terms of understanding of methodologies and computational expertise. We developed surviveR to address this unmet need for a survival analysis tool that can enable users with limited computational expertise to conduct routine but complex analyses. surviveR is a cloud-based Shiny application, that addresses our identified unmet need for an easy-to-use web-based tool that can plot and analyse survival based datasets. Integrated customization options allows a user with limited computational expertise to easily filter patients to enable custom cohort generation, automatically calculate log-rank test and Cox hazard ratios. Continuous datasets can be integrated, such as RNA or protein expression measurements which can be then used as categories for survival plotting. We further demonstrate the utility through exemplifying its application to a clinically relevant colorectal cancer patient dataset. surviveR is a cloud-based web application available at https://generatr.qub.ac.uk/app/surviveR , that can be used by non-experts users to perform complex custom survival analysis., (© 2023. The Author(s).)

2023 marks the 25th anniversary of the Good Friday Agreement, which led peace in Northern Ireland. As well as its impact on peace and reconciliation, the Good Friday Agreement has also had a lasting positive impact on cancer research and cancer care across the island of Ireland. Pursuant to the Good Friday Agreement, a Memorandum of Understanding (MOU) was signed between the respective Departments of Health in Ireland, Northern Ireland and the US National Cancer Institute (NCI), giving rise to the Ireland - Northern Ireland - National Cancer Institute Cancer Consortium, an unparalleled tripartite agreement designed to nurture and develop linkages between cancer researchers, physicians and allied healthcare professionals across Ireland, Northern Ireland and the US, delivering world class research and better care for cancer patients on the island of Ireland and driving research and innovation in the US., Competing Interests: Declaration of Competing Interest ML declares honoraria from Bayer, Carnall Farrar, Novartis, Pfizer and Roche unrelated to this work, GKA declares research support from Agenus, Arcus, Astra Zeneca, BioNtech, BMS, Elicio, Genentech/Roche, Helsinn, Parker Institute, Pertzye, Puma, QED, Yiviva, and consulting support from Astellas, Astra Zeneca, Autem, Berry Genomics, BioNtech, Boehringer Ingelheim, BMS, Eisai, Exelixis, Fibriogen, Genentech/Roche, Incyte, Ipsen, Merck, Merus, Neogene, Novartis, Servier, Tempus, Thetis, Vector, Yiviva unrelated to this work RDL declares interests as Founder of CV6 Therapeutics (NI) Ltd, Belfast, UK unrelated to this work MAG declares interests as Founder of Aviceda Therapeutics and Aviceda Glycotech and as an equity shareholder of Aviceda Glycotech Ltd and Aviceda Therapeutics Inc unrelated to this work MLo declares advisory roles with AstraZeneca, Roche/Genentech, Servier and research funding from Astellas Pharma, Basilea, Exelixis and MSD unrelated to this work WMG declares interests as Co-Founder and Chief Scientific Officer, OncoAssure and Scientific Advisory Board member, Carrick Therapeutics unrelated to this work RS, KDMcC, DK, JF, WD, EM, JLG, CJS, DBL, ACC, NO, SJC, SG declare no competing interests, The opinions expressed in this article are the authors own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States Government., (Copyright © 2023. Published by Elsevier Ltd.)

Aim: Cancer is one of Europe's key research missions, with gender equity a major policy pillar. To benchmark how well European countries perform for gender balance in cancer research, high quality intelligence is required., Methods: For cancer research papers in Europe (EUR31; the 28 EU Member States plus Iceland, Norway and Switzerland) from two specific years (2009 and 2019), we evaluated the numbers of female authors overall and then the female last-author presence, as a proxy of female cancer research leadership., Results: Overall, female authorship increased from 42% to 49%. In 2009, females represented 50% or more of cancer research authors in only five EUR31 countries. By 2019, that number had risen to 17. In Eastern European (EE) countries, females were more likely to be in the majority. The presence of female cancer research authors in the last (senior) author position increased from 24% to 34%. Five of the top six countries for female authorship in 2019 were from EE, whereas disappointingly four central European countries (Austria (AT), Czechia (CZ), Germany (DE) and Switzerland (CH)) were below the 25th percentile. A number of European powerhouses of cancer research (UK, DE, CH) underperformed in terms of female cancer research leadership. However, when cancer researchers from these countries worked abroad (e.g. Scandinavia, USA) the percentage of females was similar to that of their host countries. A factor potentially influencing female cancer research participation was availability and relative cost of child-care, which is more favourable in Scandinavia and EE than in central/western Europe., Conclusion: Our data show that Horizon Europe's Cancer Mission must ensure gender equity in its future research programmes and support the enhancement of female cancer research leadership opportunities., Competing Interests: Declaration of Competing Interest ML declares honoraria for presentations unrelated to this work from Bayer, Carnall Farrar, EMD Serono, Novartis, Pfizer and Roche. No other authors declare DOI., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

DNA-encoded libraries (DELs) provide the means to make and screen millions of diverse compounds against a target of interest in a single experiment. However, despite producing large volumes of binding data at a relatively low cost, the DEL selection process is susceptible to noise, necessitating computational follow-up to increase signal-to-noise ratios. In this work, we present a set of informatics tools to employ data from prior DEL screen(s) to gain information about which building blocks are most likely to be productive when designing new DELs for the same target. We demonstrate that similar building blocks have similar probabilities of forming compounds that bind. We then build a model from the inference that the combined behavior of individual building blocks is predictive of whether an overall compound binds. We illustrate our approach on a set of three-cycle OpenDEL libraries screened against soluble epoxide hydrolase (sEH) and report performance of more than an order of magnitude greater than random guessing on a holdout set, demonstrating that our model can serve as a baseline for comparison against other machine learning models on DEL data. Lastly, we provide a discussion on how we believe this informatics workflow could be applied to benefit researchers in their specific DEL campaigns.

Purpose: Public health measures instituted at the onset of the COVID-19 pandemic in the UK in 2020 had profound effects on the cancer patient pathway. We hypothesise that this may have affected analgesic prescriptions for cancer patients in primary care., Methods: A whole-nation retrospective, observational study of opioid and antineuropathic analgesics prescribed in primary care for two cohorts of cancer patients in Wales, using linked anonymised data to evaluate the impact of the pandemic and variation between different demographic backgrounds., Results: We found a significant increase in strong opioid prescriptions during the pandemic for patients within their first 12 months of diagnosis with a common cancer (incidence rate ratio (IRR) 1.15, 95% CI: 1.12-1.18, p < 0.001 for strong opioids) and significant increases in strong opioid and antineuropathic prescriptions for patients in the last 3 months prior to a cancer-related death (IRR = 1.06, 95% CI: 1.04-1.07, p < 0.001 for strong opioids; IRR = 1.11, 95% CI: 1.08-1.14, p < 0.001 for antineuropathics). A spike in opioid prescriptions for patients diagnosed in Q2 2020 and those who died in Q2 2020 was observed and interpreted as stockpiling. More analgesics were prescribed in more deprived quintiles. This differential was less pronounced in patients towards the end of life, which we attribute to closer professional supervision., Conclusions: We demonstrate significant changes to community analgesic prescriptions for cancer patients related to the UK pandemic and illustrate prescription patterns linked to patients' demographic background., (© 2023. The Author(s).)

Background: Precision oncology medicines represent a paradigm shift compared to non-precision oncology medicines in cancer therapy, in some situations delivering more clinical benefit, and potentially lowering healthcare costs. We determined whether employing a companion diagnostic (CDx) approach during oncology medicines development delivers effective therapies that are within the cost constraints of current health systems. R&D costs of developing a medicine are subject to debate, with average estimates ranging from $765 million (m) to $4.6 billion (b). Our aim was to determine whether precision oncology medicines are cheaper to bring from R&D to market; a secondary goal was to determine whether precision oncology medicines have a greater return on investment (ROI)., Method: Data on oncology medicines approved between 1997 and 2020 by the US Food and Drug Administration (FDA) were analysed from the Securities and Exchange Commission (SEC) filings. Data were compiled from 10-K, 10-Q, and 20-F financial performance filings on medicines' development costs through their R&D lifetime. Clinical trial data were split into clinical trial phases 1-3 and probability of success (POS) of trials was calculated, along with preclinical costs. Cost-of-capital (CoC) approach was applied and, if appropriate, a tax rebate was subtracted from the total., Results: Data on 42 precision and 29 non-precision oncology medicines from 56 companies listed by the National Cancer Institute which had complete data available were analysed. Estimated mean cost to deliver a new oncology medicine was $4.4b (95% CI, $3.6-5.2b). Costs to bring a precision oncology medicine to market were $1.1b less ($3.5b; 95% CI, $2.7-4.5b) compared to non-precision oncology medicines ($4.6b; 95% CI, $3.5-6.1b). The key driver of costs was POS of clinical trials, accounting for a difference of $591.3 m. Additional data analysis illustrated that there was a 27% increase in return on investment (ROI) of precision oncology medicines over non-precision oncology medicines., Conclusion: Our results provide an accurate estimate of the R&D spend required to bring an oncology medicine to market. Deployment of a CDx at the earliest stage substantially lowers the cost associated with oncology medicines development, potentially making them available to more patients, while staying within the cost constraints of cancer health systems., (© 2023. The Author(s).)

Purpose: Immune checkpoint blockade (ICB) has become a standard of care in the treatment of recurrent/metastatic head and neck squamous cell cancer (R/M HNSCC). However, only a subset of patients benefit from treatment. Quantification of plasma circulating tumour DNA (ctDNA) levels and on-treatment kinetics may permit real-time assessment of disease burden under selective pressures of treatment., Patients and Methods: R/M HNSCC patients treated with systemic therapy, platinum-based chemotherapy (CT) or ICB, underwent serial liquid biopsy sampling. Biomarkers tested included ctDNA measured by CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) and markers of host inflammation measured by neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR)., Results: Among 53 eligible patients, 16 (30%) received CT, 30 (57%) ICB [anti-PD1/L1] monotherapy and 7 (13%) combination immunotherapy (IO). Median progression-free survival (PFS) and overall survival (OS) were 2.8 months (95% CI, 1.3-4.3) and 8.2 months (95% CI, 5.6-10.8), respectively. Seven (13%) patients experienced a partial response and 21 (40%) derived clinical benefit. At baseline, median ctDNA variant allele frequency (VAF) was 4.3%. Baseline ctDNA abundance was not associated with OS (p = 0.56) nor PFS (p = 0.54). However, a change in ctDNA VAF after one cycle of treatment (ΔVAF (T1-2)) was predictive of both PFS (p< 0.01) and OS (p< 0.01). Additionally, decrease in ΔVAF identified patients with longer OS despite early radiological progression, 8.2 vs 4.6 months, hazard ratio 0.44 (95% CI, 0.19-0.87) p = 0.03. After incorporating NLR and PLR into multivariable Cox models, ctDNA ∆VAF retained an association with OS., Conclusions: Early dynamic changes in ctDNA abundance, after one cycle of treatment, compared to baseline predicted both OS and PFS in R/M HNSCC patients on systemic therapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: KT – Nothing to declare. JZ – Nothing to declare. MM – Nothing to declare. MO reports consultant/advisory role for: Merck, EMD Serono, Transgene; Grant/Research support from (Clinical Trials): Merck, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Bayer, Abbvie, EMD Serono, ALX Oncology, ISA Therapeutics, Ayala Therapeutics, Debiopharm; Honoraria: Merck, EMD Serono, BMS outside the submitted work. AS reports grants and personal fees from Novartis, Merck, BMS, JNJ, and Oncorus and grants from Symphogen, Roche, Northern Biologics, Regeneron, AstraZeneca MedImmune, ArrayBiopharma/Pfizer, GSK, Bayer, Surface Oncology, and Treadwell outside the submitted work. AH reports grants and other support from GSK, Merck, Eisai, and Novartis, as well as grants from MedImmune, Roche, Boehringer Ingelheim, Pfizer, Janssen, and BMS outside the submitted work. SMcD reports Co-founder/shareholder: AilseVax outside of submitted work. VC reports research grants: Astex Pharmaceuticals, Cancer Research UK, NIHR and honoraria: Servier, outside of submitted work. ML reports educational grant from Pfizer and honoraria: Pfizer, EMD Serono, Roche, Carnall Farrar outside the submitted work. EE reports receiving research funding from Bristol Myers Squibb and Zymeworks; serving as a consultant or in an advisory role for Bristol Myers Squibb, Zymeworks, and Adaptimmune; and having an immediate family member employed by Merck, outside the submitted work. SVB is inventor on patents related to cell-free DNA mutation and methylation analysis technologies that have been licensed to Roche Molecular Diagnostics and Adela, respectively. SVB is a cofounder of, has ownership in, and serves in a leadership role at Adela. LLS reports personal fees from Merck, Pfizer, Celgene, AstraZeneca, Morphosys, Roche, Loxo, Oncorus, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi, Treadwell Therapeutics, Arvinas, Tessa, Navire, Relay Therapeutics, Rubius, Janpix, Agios, and Treadwell Therapeutics and grants from Merck, Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca, Astellas, Bayer, AbbVie, Amgen, Symphogen, Intensity Therapeutics, Mirati, Shattucks, and Avid outside the submitted work., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

European cancer research stakeholders met in October 2022 in Heidelberg, Germany, at the 5 th Gago conference on European Cancer Policy, to discuss the current cancer research and cancer care policy landscape in Europe. Meeting participants highlighted gaps in the existing European programmes focusing on cancer research, including Europe's Beating Cancer Plan (EBCP), the Mission on Cancer (MoC), Understanding Cancer (UNCAN.eu), and the joint action CRANE, and put forward the next priorities, in the form of the Heidelberg Manifesto for cancer research. This meeting report presents all discussions that shed light on how infrastructures can be effectively shaped for translational, prevention, clinical and outcomes cancer research, with a focus on implementation and sustainability and while engaging patients and the public. In addition, we summarize recommendations on how to introduce frameworks for the digitalization of European cancer research. Finally, we discuss what structures, commitment, and resources are needed to establish a collaborative cancer research environment in Europe to achieve the scale required for innovation., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Introduction: The COVID-19 epidemic interrupted normal cancer diagnosis procedures. Population-based cancer registries report incidence at least 18 months after it happens. Our goal was to make more timely estimates by using pathologically confirmed cancers (PDC) as a proxy for incidence. We compared the 2020 and 2021 PDC with the 2019 pre-pandemic baseline in Scotland, Wales, and Northern Ireland (NI)., Methods: Numbers of female breast (ICD-10 C50), lung (C33-34), colorectal (C18-20), gynaecological (C51-58), prostate (C61), head and neck (C00-C14, C30-32), upper gastro-intestinal (C15-16), urological (C64-68), malignant melanoma (C43), and non-melanoma skin (NMSC) (C44) cancers were counted. Multiple pairwise comparisons generated incidence rate ratios (IRR)., Results: Data were accessible within 5 months of the pathological diagnosis date. Between 2019 and 2020, the number of pathologically confirmed malignancies (excluding NMSC) decreased by 7315 (14.1 %). Scotland experienced early monthly declines of up to 64 % (colorectal cancers, April 2020 versus April 2019). Wales experienced the greatest overall change in 2020, but Northern Ireland experienced the quickest recovery. The pandemic's effects varied by cancer type, with no significant change in lung cancer diagnoses in Wales in 2020 (IRR 0.97 (95 % CI 0.90-1.05)), followed by an increase in 2021 (IRR 1.11 (1.03-1.20)., Conclusion: PDC are useful in reporting cancer incidence quicker than cancer registrations. Temporal and geographical differences between participating countries mirrored differences in responses to the COVID-19 pandemic, indicating face validity and the potential for quick cancer diagnosis assessment. To verify their sensitivity and specificity against the gold standard of cancer registrations, however, additional research is required., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mark Lawler has received an unrestricted educational grant from Pfizer for research unrelated to this work. ML has received honoraria from Pfizer, EMF Serono, Roche, Bayer, Novartis and Carnall Farrar unrelated to this work. Dyfed Wyn Huws has received research consultancy fees from Pfizer for research unrelated to this work and his department (Welsh Cancer Intelligence and Surveillance Unit, Public Health Wales) has received analysis partnership funding from Macmillan Cancer Support for unrelated work. All other authors have declared no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Upon the COVID-19 pandemic onset in Ireland, cancer service disruptions occurred due to prioritisation of COVID-19 related care, redeployment of staff, initial pausing of screening, diagnostic, medical and surgical oncology procedures, staff shortages due to COVID-19 infection and impacts on the physical and mental health of cancer healthcare workers. This was coupled with reluctance among people with symptoms suspicious for cancer to attend for clinical evaluation, due to concerns of contracting the virus. This was further compounded by a cyber-attack on national health service IT systems on May 14th 2021. The Irish Cancer Society, a national cancer charity with a role in advocacy, research and patient supports, convened a multi-disciplinary stakeholder group (COVID-19 and Cancer Working Group) to reflect on and understand the impact of the pandemic on cancer patients and services in Ireland, and discuss potential mitigation strategies. Perspectives on experiences were gathered across domains including timeliness of data acquisition and its conversion into intelligence, and the resourcing of cancer care to address cancer service impacts. The group highlighted aspects for future research to understand the long-term pandemic impact on cancer outcomes, while also highlighting potential strategies to support cancer services, build resilience and address delayed diagnosis. Additional measures include the need for cancer workforce recruitment and retention, increased mental health supports for both patients and oncology professionals, improvements to public health messaging, a near real-time multimodal national cancer database, and robust digital and physical infrastructure to mitigate impacts of the current pandemic and future challenges to cancer care systems., Competing Interests: Disclosure/conflict of interest statement All authors have declared that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: MPL and GL contributed equally. ML has received honoraria from Pfizer, EMG Serono, Carnall Farrar, Roche, Novartis, and Bayer for presentations unrelated to this work. AA has received funding from the National Institute for Health and Care Research through an advanced fellowship. All other authors declare no competing interests.

Introduction: Two valid group and saves are commonly required for patients undergoing laparoscopic appendicectomy and laparoscopic hernia repairs preoperatively; however, perioperative blood transfusions are seldom required. This is financially burdensome and frequently leads to delays in theatre lists. We performed a retrospective analysis to investigate blood transfusions performed perioperatively and within 28 days of these procedures., Method: We used our electronic records to collect data of all laparoscopic appendectomies and laparoscopic hernia repairs between March 2017 and March 2021. Patients of any age undergoing these operations were included. Patients requiring concomitant intra-abdominal surgery or who had incomplete medical records were excluded., Results: A total of 1891 patients were included, of which 1462 (77.3%) had a laparoscopic appendicectomy versus 429 (22.7%) who had a laparoscopic hernia repair. In all, 3507 group and saves were taken costing £47,398.50. One patient (0.068%) required emergency blood transfusion (4 units of red cells) secondary to major haemorrhage., Conclusion: Our findings demonstrate that the incidence of perioperative blood transfusions for laparoscopic appendicectomy and laparoscopic hernia repairs is low, challenging the indication for routine preoperative group and saves.

Clinical research is crucial for national cancer control plans. Prior to the Russian invasion on 24th Feb 2022 both Russia and Ukraine were significant contributors to global clinical trials and cancer research. In this short analysis we describe this and the impact that the conflict has had with wider consideration for the global cancer research ecosystems., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Multiple myeloma is characterized by clonal proliferation of plasma cells that accumulate preferentially in the bone marrow (BM). The tumor microenvironment is one of the leading factors that promote tumor progression. Neutrophils and monocytes are a major part of the BM tumor microenvironment, but the mechanism of their contribution to multiple myeloma progression remains unclear. Here, we describe a novel mechanism by which S100A8/S100A9 proteins produced by BM neutrophils and monocytes promote the expansion of megakaryocytes supporting multiple myeloma progression. S100A8/S100A9 alone was not sufficient to drive megakaryopoiesis but markedly enhanced the effect of thrombopoietin, an effect that was mediated by Toll-like receptor 4 and activation of the STAT5 transcription factor. Targeting S100A9 with tasquinimod as a single agent and in combination with lenalidomide and with proteasome inhibitors has potent antimyeloma effect that is at least partly independent of the adaptive immune system. This newly identified axis of signaling involving myeloid cells and megakaryocytes may provide a new avenue for therapeutic targeting in multiple myeloma., Significance: We identified a novel mechanism by which myeloid cells promote myeloma progression independently of the adaptive immune system. Specifically, we discovered a novel role of S100A8/S100A9, the most abundant proteins produced by neutrophils and monocytes, in regulation of myeloma progression via promotion of the megakaryocyte expansion and angiogenesis. Tasquinimod, an inhibitor of S100A9, has potent antimyeloma effects as a single agent and in combination with lenalidomide and with proteasome inhibitors., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Objectives: Cancer is a leading cause of death. This paper examines the utilisation of unscheduled emergency end-of-life healthcare and estimates expenditure in this domain. We explore care patterns and quantify the likely benefits from service reconfigurations which may influence rates of hospital admission and deaths., Methods: Using prevalence-based retrospective data from the Northern Ireland General Registrar's Office linked by cancer diagnosis to Patient Administration episode data for unscheduled emergency care (1st January 2014 to 31st December 2015), we estimate unscheduled-emergency-care costs in the last year of life. We model potential resources released by reductions in length-of-stay for cancer patients. Linear regression examined patient characteristics affecting length of stay., Results: A total of 3134 cancer patients used 60,746 days of unscheduled emergency care (average 19.5 days). Of these, 48.9% had ≥1 admission during their last 28 days of life. Total estimated cost was £28,684,261, averaging £9200 per person. Lung cancer patients had the highest proportion of admissions (23.2%, mean length of stay = 17.9 days, mean cost=£7224). The highest service use and total cost was in those diagnosed at stage IV (38.4%), who required 22,099 days of care, costing £9,629,014. Palliative care support, identified in 25.5% of patients, contributed £1,322,328. A 3-day reduction in the mean length of stay with a 10% reduction in admissions, could reduce costs by £7.37 million. Regression analyses explained 41% of length-of-stay variability., Conclusions: The cost burden from unscheduled care use in the last year of life of cancer patients is significant. Opportunities to prioritise service reconfiguration for high-costing users emphasized lung and colorectal cancers as offering the greatest potential to influence outcomes., (© 2023. The Author(s).)

Background: Colorectal cancer (CRC) primary tumours are molecularly classified into four consensus molecular subtypes (CMS1-4). Genetically engineered mouse models aim to faithfully mimic the complexity of human cancers and, when appropriately aligned, represent ideal pre-clinical systems to test new drug treatments. Despite its importance, dual-species classification has been limited by the lack of a reliable approach. Here we utilise, develop and test a set of options for human-to-mouse CMS classifications of CRC tissue., Methods: Using transcriptional data from established collections of CRC tumours, including human (TCGA cohort; n = 577) and mouse (n = 57 across n = 8 genotypes) tumours with combinations of random forest and nearest template prediction algorithms, alongside gene ontology collections, we comprehensively assess the performance of a suite of new dual-species classifiers., Results: We developed three approaches: MmCMS-A; a gene-level classifier, MmCMS-B; an ontology-level approach and MmCMS-C; a combined pathway system encompassing multiple biological and histological signalling cascades. Although all options could identify tumours associated with stromal-rich CMS4-like biology, MmCMS-A was unable to accurately classify the biology underpinning epithelial-like subtypes (CMS2/3) in mouse tumours., Conclusions: When applying human-based transcriptional classifiers to mouse tumour data, a pathway-level classifier, rather than an individual gene-level system, is optimal. Our R package enables researchers to select suitable mouse models of human CRC subtype for their experimental testing., (© 2023. The Author(s).)

In order to tailor treatment to their needs, cancer patients are encouraged to be more active and engaged in their care decisions and to be autonomous yet collaborative with their healthcare professionals when it comes to aspects of their treatment in order to get better results. However, this can only happen after providing them with accurate information about cancer and the different treatment alternatives and their potential side effects. However, sharing robust data-based information is often hindered by exposure to misleading information through different media and online platform, where patients might come across unscientifically founded health practices. Increasing health literacy and cancer-specific literacy is essential to fight this negative trend. The idea is that more knowledgeable patients will be able to debunk more easily misinformation they encounter. This is also related to inequalities among cancer patients. Not only levels of cancer literacy within Europe are uneven across and within countries, but there are social groups that, due to specific social determinants, are systematically less informed and skilled regarding cancer care. In this paper an overview of gaps in addressing literacy issues, and the importance of health literacy to empower patients in their journey through treatment is delineated, concluding with some recommendations to improve cancer literacy in Europe., (Copyright © 2022. Published by Elsevier Ltd.)

Competing Interests: We declare no competing interests. The authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/WHO.

The purpose of this study was to provide an evidence base for colorectal cancer research activity that might influence policy, mainly at the national level. Improvements in healthcare delivery have lengthened life expectancy, but within a situation of increased cancer incidence. The disease burden of CRC has risen significantly, particularly in Africa, Asia and Latin America. Research is key to its control and reduction, but few studies have delineated the volume and funding of global research on CRC. We identified research papers in the Web of Science (WoS) from 2007 to 2021, and determined the contributions of the leading countries, the research domains studied, and their sources of funding. We identified 62 716 papers, representing 5.7% of all cancer papers. This percentage was somewhat disproportionate to the disease burden (7.7% in 2015), especially in Eastern Europe. International collaboration increased over the time period in almost all countries except in China. Genetics, surgery and prognosis were the leading research domains. However, research on palliative care and quality-of-life in CRC was lacking. In Western Europe, the main funding source was the charity sector, particularly in the UK, but in most other countries government played the leading role, especially in China and the USA. There was little support from industry. Several Asian countries provided minimal contestable funding, which may have reduced the impact of their CRC research. Certain countries must perform more CRC research overall, especially in domains such as screening, palliative care and quality-of-life. The private-non-profit sector should be an alternative source of support., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Colorectal cancer (CRC) is becoming an increasing health problem worldwide. However, with the help of screening, early diagnosis can reduce incidence and mortality rates. To elevate the economic burden that CRC can cause, cost-effectiveness analysis (CEA) can assist healthcare systems to make screening programmes more cost-effective and prolong survival for early-stage CRC patients. This review aims to identify different CEA modelling methods used internationally to evaluate health economics of CRC screening., Methods: This review will systematically search electronic databases which include MEDLINE, EMBASE, Web of Science and Scopus. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidance recommendations will design the review, and the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement will be used to extract relevant data from studies retrieved. Two reviewers will screen through the evidence using the PICOS (Participant, Intervention, Comparators, Outcomes, Study Design) framework, with a third reviewer to settle any disagreements. Once data extraction and quality assessment are complete, the results will be presented qualitatively and tabulated using the CHEERS checklist., Discussion: The results obtained from the systematic review will highlight how different CRC screening programmes around the world utilise and incorporate health economic modelling methods to be more cost-effective. This information can help modellers develop CEA models which can be adapted to suit the specific screening programmes that they are evaluating., Systematic Review Registration: PROSPERO CRD42022296113., (© 2023. The Author(s).)

Background: Multisystem inflammatory syndrome in children (MIS-C) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been infrequently described in Africa., Objective: To describe the clinical characteristics, outcomes and associations of severe disease in children hospitalized with MIS-C in KwaZulu-Natal., Methods: Retrospective multicenter study of children (0-13 years) who met the Centers for Disease Control and Prevention criteria for MIS-C. Children with shock were compared with children without shock to determine the characteristics of severe MIS-C., Results: Twenty-nine children with MIS-C were identified, the mean age was 55 (SD ±45) months, 25 (86%) were Black-African, and 8 (28%) had pre-existing comorbidities. The predominant presenting symptoms included fever 29 (100%), gastrointestinal symptoms 25 (83%), skin rash 19 (65%), and shock 17 (59%). Children with shock had significantly increased CRP (P = 0.01), ferritin (P < 0.001), troponin-T (P = 0.02), B-type natriuretic peptide (BNP) (P = 0.01), and lower platelets (P = 0.01). Acute kidney injury (P = 0.01), cardiac involvement (P = 0.02), and altered levels of consciousness (P = 0.03) were more common in children with shock. The median length of hospital stay was 11 (IQR 7-19) days, with a mortality of 20.6%. Children who did not survive had significantly higher ferritin levels 1593 (IQR 1069-1650) ng/mL versus 540 (IQR 181-1156) ng/mL; P = 0.03) and significantly more required mechanical ventilation (OR 18; confidence interval 1.7-191.5; P = 0.005)., Conclusions: Hospitalized children with MIS-C in KwaZulu-Natal had more aggressive disease and higher mortality than children in better-resourced settings. Markedly elevated biomarkers and critical organ involvement were associated with severe disease. Risk factors for poor outcomes include higher ferritin levels and the need for mechanical ventilation., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Cancer research is a crucial pillar for countries to deliver more affordable, higher quality, and more equitable cancer care. Patients treated in research-active hospitals have better outcomes than patients who are not treated in these settings. However, cancer in Europe is at a crossroads. Cancer was already a leading cause of premature death before the COVID-19 pandemic, and the disastrous effects of the pandemic on early diagnosis and treatment will probably set back cancer outcomes in Europe by almost a decade. Recognising the pivotal importance of research not just to mitigate the pandemic today, but to build better European cancer services and systems for patients tomorrow, the Lancet Oncology European Groundshot Commission on cancer research brings together a wide range of experts, together with detailed new data on cancer research activity across Europe during the past 12 years. We have deployed this knowledge to help inform Europe's Beating Cancer Plan and the EU Cancer Mission, and to set out an evidence-driven, patient-centred cancer research roadmap for Europe. The high-resolution cancer research data we have generated show current activities, captured through different metrics, including by region, disease burden, research domain, and effect on outcomes. We have also included granular data on research collaboration, gender of researchers, and research funding. The inclusion of granular data has facilitated the identification of areas that are perhaps overemphasised in current cancer research in Europe, while also highlighting domains that are underserved. Our detailed data emphasise the need for more information-driven and data-driven cancer research strategies and planning going forward. A particular focus must be on central and eastern Europe, because our findings emphasise the widening gap in cancer research activity, and capacity and outcomes, compared with the rest of Europe. Citizens and patients, no matter where they are, must benefit from advances in cancer research. This Commission also highlights that the narrow focus on discovery science and biopharmaceutical research in Europe needs to be widened to include such areas as prevention and early diagnosis; treatment modalities such as radiotherapy and surgery; and a larger concentration on developing a research and innovation strategy for the 20 million Europeans living beyond a cancer diagnosis. Our data highlight the important role of comprehensive cancer centres in driving the European cancer research agenda. Crucial to a functioning cancer research strategy and its translation into patient benefit is the need for a greater emphasis on health policy and systems research, including implementation science, so that the innovative technological outputs from cancer research have a clear pathway to delivery. This European cancer research Commission has identified 12 key recommendations within a call to action to reimagine cancer research and its implementation in Europe. We hope this call to action will help to achieve our ambitious 70:35 target: 70% average 10-year survival for all European cancer patients by 2035., Competing Interests: Declaration of interests ML declares honoraria from Bayer, Carnall Farrar, EMD Serono, Novartis, Pfizer, and Roche unrelated to this work and membership of the board of the European Cancer Organisation (ECO). AA declares Advanced NIH Fellowship unrelated to this work. AMB declares honorarium from Roche unrelated to this work and Presidency of Lung Cancer Europe. MC declares membership of the board of ECO and the European Society of Oncology Pharmacy. FC declares consultancy and advisory board membership of Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, Gilead, GlaxoSmithKline, Iqvia, Macrogenics, Medscape, Merck-Sharp, Merus, Mylan, Mundipharma, Novartis, Pfizer, PierreFabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva, and Touchime unrelated to this work. TC declares honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Roche, Merck Sharpe & Dohme, Pfizer, and Takeda unrelated to this work. LD declares consultancy from the International Cancer Research Partnership unrelated to this work. FDN declares grants from the AIRC Foundation for Cancer Research, Associazione Italiana per la Ricerca sul Cancro, and Fondazione Piemontese per la Ricerca sul Cancro-ONLUS, and consultancy from Pierre Fabre unrelated to this work. JJ declares consultancy from AstraZeneca, Exact Sciences, and Merck Sharpe & Dohme unrelated to this work. DK declares honoraria from Merck Sharpe & Dohme unrelated to this work. TKo declares grants from Ipsen, AAA Pharma, Novartis, Isotope Technologies Munich, Victory Net Foundation, and Camulus, and honoraria or support from Cor2Ed, Ipsen, ECO, International Cancer Genome Consortium unrelated to this work. CLV received support from AIRC Foundation. YL is chair of the HERO VBHC and member of the European Society for Radiotherapy and Oncology (ESTRO) Scientific Committee, the Belgian College of Oncology, and a personal investigator on the European Organization for Research and Treatment of Cancer/ESTRO E2-RADIATE project. PS declares support from ECO and the European School of Oncology. SO, KO, AS, CA, PN, KA, MA, AC, MPC, ACo, CLD, AE, SE, MG, BJo, OK, TKu, GL, FM, JP, TP, RP, BR, ITR, MJS, GSB, JVH, EV, WW, UW, and RS declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The pro-tumourigenic role of epithelial TGFβ signalling in colorectal cancer (CRC) is controversial. Here, we identify a cohort of born to be bad early-stage (T1) colorectal tumours, with aggressive features and a propensity to disseminate early, that are characterised by high epithelial cell-intrinsic TGFβ signalling. In the presence of concurrent Apc and Kras mutations, activation of epithelial TGFβ signalling rampantly accelerates tumourigenesis and share transcriptional signatures with those of the born to be bad T1 human tumours and predicts recurrence in stage II CRC. Mechanistically, epithelial TGFβ signalling induces a growth-promoting EGFR-signalling module that synergises with mutant APC and KRAS to drive MAPK signalling that re-sensitise tumour cells to MEK and/or EGFR inhibitors. Together, we identify epithelial TGFβ signalling both as a determinant of early dissemination and a potential therapeutic vulnerability of CRC's with born to be bad traits., (© 2022. The Author(s).)

Objective: Stroma-rich tumours represent a poor prognostic subtype in stage II/III colon cancer (CC), with high relapse rates and limited response to standard adjuvant chemotherapy., Design: To address the lack of efficacious therapeutic options for patients with stroma-rich CC, we stratified our human tumour cohorts according to stromal content, enabling identification of the biology underpinning relapse and potential therapeutic vulnerabilities specifically within stroma-rich tumours that could be exploited clinically. Following human tumour-based discovery and independent clinical validation, we use a series of in vitro and stroma-rich in vivo models to test and validate the therapeutic potential of elevating the biology associated with reduced relapse in human tumours., Results: By performing our analyses specifically within the stroma-rich/high-fibroblast (HiFi) subtype of CC, we identify and validate the clinical value of a HiFi-specific prognostic signature (HPS), which stratifies tumours based on STAT1-related signalling (High-HPS v Low-HPS=HR 0.093, CI 0.019 to 0.466). Using in silico, in vitro and in vivo models, we demonstrate that the HPS is associated with antigen processing and presentation within discrete immune lineages in stroma-rich CC, downstream of double-stranded RNA and viral response signalling. Treatment with the TLR3 agonist poly(I:C) elevated the HPS signalling and antigen processing phenotype across in vitro and in vivo models. In an in vivo model of stroma-rich CC, poly(I:C) treatment significantly increased systemic cytotoxic T cell activity (p<0.05) and reduced liver metastases (p<0.0002)., Conclusion: This study reveals new biological insight that offers a novel therapeutic option to reduce relapse rates in patients with the worst prognosis CC., Competing Interests: Competing interests: ML has received honoraria from Pfizer, EMF Serono and Roche for presentations unrelated to this work; ML has received an unrestricted educational grant from Pfizer for research unrelated to this work. PT has received honoraria and travel expenses from BMS, Merck, Roche, Lilly and Sanofi-Aventis for contributions that are not related to the present work. The authors declare no other potential conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: The invasion of Ukraine by Russia in February 2022 has resulted in destruction of healthcare infrastructure and triggered the largest wave of internally displaced populations and refugees since World War Two. Conflicts in transitioned countries such as Ukraine create new non-communicable disease (NCD) challenges, especially for cancer care for refugees and humanitarian assistance in host countries. In the early days, rapid attempts were made to model possible impacts., Methods: By evaluating open source intelligence used in the first three months of the conflict through snowball search methods, we aimed to address: (i) burden of cancer in Ukrainian population, specifically considering translating to the refugees population, and its cancer care capacity; ii) baseline capacity/strengths of cancer systems in initial host countries. Moreover, using a baseline scenario based on crude cancer incidence in Ukraine, and considering data from UNHCR, we estimated how cancer cases would be distributed across host countries. Finally, a surveillance assessment instrument was created, intersecting health system's capacity and influx of internally displaced populations and refugees., Findings and Conclusions: The total new cancer patients per month in pre-conflict Ukraine was estimated as 13,106, of which < 1 % are paediatric cases. The estimated cancer cases in the refugee population (combining prevalent and incident), assuming 7.5 million refugees by July 2022 and a female:male ratio of 9:1, was 33,121 individuals (Poland: 19284; Hungary: 3484; Moldova: 2651; Slovakia: 2421; Romania: 5281). According to our assessments, Poland is the only neighbouring country classified as green/yellow for cancer capacity, i.e. sufficient ablility to absorb additional burden into national health system; Slovakia we graded as yellow, Hungary and Romania as yellow/red and Moldova as red., Competing Interests: Conflicts of interest None to be declared., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cancer policy differences might help to explain international variation in cancer survival, but empirical evidence is scarce. We reviewed cancer policies in 20 International Cancer Benchmarking Partnership jurisdictions in seven countries and did exploratory analyses linking an index of cancer policy consistency over time, with monitoring and implementation mechanisms, to survival from seven cancers in a subset of ten jurisdictions from 1995 to 2014. All ten jurisdictions had structures in place to oversee or deliver cancer control policies and had published at least one major cancer plan. Few cancer plans had explicit budgets for implementation or mandated external evaluation. Cancer policy consistency was positively correlated with improvements in survival over time for six of the seven cancer sites. Jurisdictions that scored the highest on policy consistency had large improvements in survival for most sites. Our analysis provides an important first step to systematically capture and evaluate what are inherently complex policy processes. The findings can help guide policy makers seeking approaches and frameworks to improve cancer services and, ultimately, cancer outcomes., Competing Interests: Decleration of interests ML reports having received honoraria unrelated to to this work from Bayer, Carnall Farrar, Novartis, Pfizer, and Roche. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Competing Interests: Nicolo Matteo Luca BattistiConsulting or Advisory Role: Pfizer, Sanofi, Abbott NutritionSpeakers' Bureau: Pfizer, AbbVie, SanofiTravel, Accommodations, Expenses: Pfizer, Genomic Health, Lilly Mark LawlerHonoraria: Pfizer, Roche, Bayer Health, NovartisTravel, Accommodations, Expenses: Pfizer, Roche Katie RizviHonoraria: Roche Robert GreeneConsulting or Advisory Role: GlaxoSmithKline Kathy OliverConsulting or Advisory Role: Bristol Myers Squibb (Inst), Seattle Genetics (Inst), Novartis Italy (Inst), Sanofi/Regeneron (Inst), Novocure (Inst), Eisai (Inst)Other Relationship: Bristol Myers Squibb (Inst), Novocure (Inst), Photonamic (Inst), Bayer (Inst), Northwest Biotherapeutics (Inst), Novartis (Inst), Elekta (Inst), Medac (Inst), GW Pharmaceuticals (Inst), Pfizer (Inst), Karyopharm Therapeutics (Inst), Apogenix (Inst)No other potential conflicts of interest were reported.

Purpose: Precise mechanism-based gene expression signatures (GES) have been developed in appropriate in vitro and in vivo model systems, to identify important cancer-related signaling processes. However, some GESs originally developed to represent specific disease processes, primarily with an epithelial cell focus, are being applied to heterogeneous tumor samples where the expression of the genes in the signature may no longer be epithelial-specific. Therefore, unknowingly, even small changes in tumor stroma percentage can directly influence GESs, undermining the intended mechanistic signaling., Experimental Design: Using colorectal cancer as an exemplar, we deployed numerous orthogonal profiling methodologies, including laser capture microdissection, flow cytometry, bulk and multiregional biopsy clinical samples, single-cell RNA sequencing and finally spatial transcriptomics, to perform a comprehensive assessment of the potential for the most widely used GESs to be influenced, or confounded, by stromal content in tumor tissue. To complement this work, we generated a freely-available resource, ConfoundR; https://confoundr.qub.ac.uk/, that enables users to test the extent of stromal influence on an unlimited number of the genes/signatures simultaneously across colorectal, breast, pancreatic, ovarian and prostate cancer datasets., Results: Findings presented here demonstrate the clear potential for misinterpretation of the meaning of GESs, due to widespread stromal influences, which in-turn can undermine faithful alignment between clinical samples and preclinical data/models, particularly cell lines and organoids, or tumor models not fully recapitulating the stromal and immune microenvironment., Conclusions: Efforts to faithfully align preclinical models of disease using phenotypically-designed GESs must ensure that the signatures themselves remain representative of the same biology when applied to clinical samples., (©2022 The Authors; Published by the American Association for Cancer Research.)