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Introduction: The EORTC-Lung Cancer Group initiated a Delphi consensus process to establish a consensual definition of resectable stage III non-small cell lung cancer (NSCLC) for the use in clinical trials, including a systematic review, survey, and review of clinical cases. Here, the survey results are presented, aimed to identify areas of controversy., Methods: A survey was distributed among the members of six international organizations related to lung cancer. Respondents were interrogated on the resectability (not limited to the technical resectability) of all stage III NSCLC TNM-subsets (8th edition). Additionally, four N2-subdivisions were used. The threshold for agreement was 75%. Answers with "yes" were considered upfront resectable. "Yes" and "maybe" were grouped together and considered potentially resectable. Answers with "no" were considered unresectable., Results: 558 responses were collected from thoracic surgeons (38%), radiation oncologists (27%), medical oncologists (17%), pulmonologists (14%), and others (4%). Most worked in a specialized center (80%), had >5 years of experience (80%), were European (76%), male (73%), and treated >20 patients with stage III NSCLC annually (77%). Agreement was found in 26 (70%) out of 37 TNM-subsets: 9 (24%) were considered (potentially) resectable, and 17 (46%) unresectable. There was no agreement for 11 (30%) TNM-subsets: smaller tumors with N2-multistation, larger tumors with N2-single station, and invasive T4-tumors with maximum N2-single station involvement., Conclusions: This international and multidisciplinary survey showed agreement on the resectability for the majority of stage III NSCLC TNM-subsets, but also identified several TNM-subsets for which no agreement was found., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Abdominal aortic aneurysm (AAA) is characterized by weakening and dilatation of the aortic wall in the abdomen. The aim of this study was to gain insight into cell-specific mechanisms involved in AAA pathophysiology by analyzing the (phospho)proteome of vascular smooth muscle cells derived from patients with AAA compared with those of healthy donors., Methods: A (phospho)proteomics analysis based on tandem mass spectrometry was performed on vascular smooth muscle cells derived from patients with AAA (n=24) and healthy, control individuals (C-SMC, n=8). Following protein identification and quantification using MaxQuant, integrative inferred kinase activity analysis was used to calculate kinase activity scores., Results: Expression differences between vascular smooth muscle cells derived from patients with AAA and healthy, control individuals were predominantly found in proteins involved in ECM (extracellular matrix) remodeling (THSD4 [thrombospondin type-1 domain-containing protein 4] and ADAMTS1 [A disintegrin and metalloproteinase with thrombospondin motifs 1]), energy metabolism (GYS1 [glycogen synthase 1] and PCK2 [phosphoenolpyruvate carboxykinase 2, mitochondrial]), and contractility (CACNA2D1 [calcium voltage-dependent channel subunit α-2/δ-1] and TPM1 [tropomyosin α-1 chain]). Phosphorylation patterns on proteins related to actin cytoskeleton organization dominated the phosphoproteome of vascular smooth muscle cells derived from patients with AAA . Besides, phosphorylation changes on proteins related to energy metabolism (GYS1), contractility (PARVA [α-parvin], PPP1R12A [protein phosphatase 1 regulatory subunit 12A], and CALD1 [caldesmon 1]), and intracellular communication (GJA1 [gap junction α-1 protein]) were seen. Kinase activity of NUAK1 (NUAK family SNF1-like kinase 1), FYN (tyrosine-protein kinase Fyn), MAPK7 (mitogen-activated protein kinase 7), and STK10 (serine/threonine kinase 10) was different in vascular smooth muscle cells derived from patients with AAA compared with those from healthy, control individuals., Conclusions: This study revealed changes in expression and phosphorylation levels of proteins involved in various processes responsible for AAA progression and development (eg, energy metabolism, ECM remodeling, actin cytoskeleton organization, contractility, intracellular communication, and cell adhesion). These newly identified proteins, phosphosites, and related kinases provide further insight into the underlying mechanism of vascular smooth muscle cell dysfunction within the aneurysmal wall. Our omics data thereby offer the opportunity to study the relevance, either as drug target or biomarker, of these proteins in AAA development., Competing Interests: None.

The treatment landscape of resectable early-stage non-small cell lung cancer (NSCLC) is set to change significantly due to encouraging results from randomized trials evaluating neoadjuvant and adjuvant immunotherapy, as well as adjuvant targeted therapy. As of January 2024, marketing authorization has been granted for four new indications in Europe, and regulatory approvals for other study regimens are expected. Because cost-effectiveness and reimbursement criteria for novel treatments often differ between European countries, access to emerging developments may lead to inequalities due to variations in recommended and available lung cancer care throughout Europe. This Series paper (i) highlights the clinical studies reshaping the treatment landscape in resectable early-stage NSCLC, (ii) compares and contrasts approaches taken by the European Medicines Agency (EMA) for drug approval to that taken by the United States Food and Drug Administration (FDA), and (iii) evaluates the differences in access to emerging treatments from an availability perspective across European countries., Competing Interests: I.H., C.D., N.R., and I.B. declare no competing interests. C.A.G. has received grants or contracts from Boehringer Ingelheim, Astellas, Celgene, Sanofi, Janssen-Cilag, Bayer, Amgen, Genzyme, Merck, Gilead, Novartis, AstraZeneca, Roche, NIH, and ASCERTAIN, all payments were made to the institute, outside the submitted work. M.P. has received research funding from MSD, AstraZeneca, Roche, Boehringer Ingelheim, and Takeda, outside the submitted work; consulting fees from Bristol-Meyers, Roche, MSD, AstraZeneca, Takeda, Eli Lilly, F Hoffman-La Roche, Janssen, Pfizer, and Takeda, outside the submitted work; honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bristol-Meyers, Roche, MSD, AstraZeneca, Takeda, Eli Lilly, F Hoffman-La Roche, Janssen, and Pfizer, outside the submitted work; and support for attending meetings and/or travel from AstraZeneca, Boehringer Ingelheim, Bristol-Meyers Eli Lilly, F Hoffman-La Roche, Phierre Fabre Pharmaceuticals, and Takeda, outside the submitted work. A.L. has received grants for academic research from PharMamar, Beigene, Roche, AstraZeneca, and Amgen, outside the submitted work. R.D. has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, AstraZeneca, Takeda, Novartis, BMS, MSD, Pfizer, and Amgen, outside the submitted work; support for attending meetings and/or travel from Pfizer, outside the submitted work; drug samples from Novartis, outside the submitted work; and participated on a Data Safety Monitoring Board or Advisory Board of GlaxoSmithKline, outside the submitted work. C.P. has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, outside the submitted work. M.D.M. has received institutional research funding from Tesaro/GlaxoSmithKline and institutional funding for work in clinical trials/contracted research from Beigene, Exelixis, MSD, Pfizer and Roche, outside the submitted work; and personal fees for consultancy or participation to advisory boards from AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Roche, GlaxoSmithKline, Amgen, Merck, and Takeda, outside the submitted work. M.T. has received institutional research funding from AstraZeneca, BMS, MSD, Roche, and Takeda, outside the submitted work; payment or honoraria (personal) for speakers bureaus from Amgen, AstraZeneca, Beigene, BMS, Boehringer Ingelheim, Celgene, Chugai, Daiichi Sankyo, GlaxoSmithKline, Janssen Oncology, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, and Takeda, outside the submitted work; and support for attending meetings and/or travel from AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, and Takeda, outside the submitted work. A.B. has received consulting fees (personal) from AstraZeneca, BMS, MSD, and Roche, outside the submitted work; and payment or honoraria (personal) for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, BMS, MSD, and Roche, outside the submitted work. S.P. has received consulting fees (personal) from Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, GSK, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx, outside the submitted work; payment or honoraria (personal) for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche and Takeda, outside the submitted work; payment for expert testimony from Roche and Merck Serono, outside the submitted work; support for travel from Janssen and Roche, outside the submitted work; consulting fees for participation on an Advisory Board, outside the submitted work; unpaid leadership role in the British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETOP-IBCSG Partners Foundation Board, outside the submitted work. S.S. has received research grants (institution) from AstraZeneca and personal honoraria for participating in the trial steering committee for immunotherapy in small cell lung cancer from AstraZeneca, outside the submitted work; consulting fees from AstraZeneca and BMS, outside the submitted work; speaker honoraria (self) from AstraZeneca, outside the submitted work; participates on a Data Safety Monitoring Board as a review panel member for lung toxicity adjudication with immunotherapy (MSD), outside the submitted work; and has a leadership role as an ETOP member of the scientific committee for lung cancer, outside the submitted work., (© 2024 The Author(s).)

Background: Bereaved relatives of intensive care unit (ICU) patients are at increased risk of psychological complaints. Aftercare might help them cope with processing the ICU admission and their loved one's death. There is little (qualitative) evidence on how bereaved relatives experience aftercare. Also, the COVID-19 pandemic likely impacted aftercare provision. We aim to examine how many relatives in Dutch ICUs received aftercare before and during the pandemic and to qualitatively describe their experiences and needs regarding aftercare., Methods: A mixed-methods study among relatives of patients who died in an ICU before or during the COVID-19 pandemic. Bereaved relatives in six ICUs completed a questionnaire (n = 90), including two items on aftercare. These were analyzed using descriptive statistics and Chi-squared tests. Subsequently, both relatives that received and relatives that did not receive aftercare were interviewed about their experiences and needs regarding aftercare. The interviews were thematically analyzed., Results: After the passing of a loved one, 44% of the relatives were asked by a healthcare professional from the hospital how they were doing, and 26% had had a follow-up conversation. Both happened more often during the first wave of the pandemic than during the second wave or before the pandemic. The most common reason for not having had a follow-up conversation was not knowing about this option (44%), followed by not feeling a need (26%). Regarding the latter, interviewed relatives explained that this would not revive their loved one or that they had already discussed everything they wanted. Relatives who wanted a follow-up conversation, wanted this because this would help them realize the severity of their loved one's illness, to exchange personal experiences, and/or to thank the ICU team. Those with a follow-up conversation said that they had reviewed the medical course of the admission and/or discussed their (mental) well-being., Conclusions: ICU healthcare professionals may play a vital role in addressing aftercare needs by asking relatives how they are doing in the weeks following the death of their loved one and offering them a follow-up conversation with an ICU physician. We recommend to include aftercare for bereaved relatives in ICU guidelines., (© 2024. The Author(s).)

The treatment landscape of resectable early-stage non-small cell lung cancer (NSCLC) is transforming due to the approval of novel adjuvant and neoadjuvant systemic treatments. The European Medicines Agency (EMA) recently approved adjuvant osimertinib, adjuvant atezolizumab, adjuvant pembrolizumab, and neoadjuvant nivolumab combined with chemotherapy, and the approval of other agents or new indications may follow soon. Despite encouraging results, many unaddressed questions remain. Moreover, the transformed treatment paradigm in resectable NSCLC can pose major challenges to healthcare systems and magnify existing disparities in care as differences in reimbursement may vary across different European countries. This Viewpoint discusses the challenges and controversies in resectable early-stage NSCLC and how existing inequalities in access to these treatments could be addressed., Competing Interests: I.H., C.D., R.A.M.D., N.R., and I.B. declare no competing interests. C.A.G. has received grants or contracts from Boehringer Ingelheim, Astellas, Celgene, Sanofi, Janssen-Cilag, Bayer, Amgen, Genzyme, Merck, Gilead, Novartis, AstraZeneca, Roche, NIH, and ASCERTAIN, all payments were made to the institute, outside the submitted work. M.P. has received research funding from MSD, AstraZeneca, Roche, Boehringer Ingelheim, and Takeda, outside the submitted work; consulting fees from Bristol-Meyers, Roche, MSD, AstraZeneca, Takeda, Eli Lilly, F Hoffman-La Roche, Janssen, Pfizer, and Takeda, outside the submitted work; honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bristol-Meyers, Roche, MSD, AstraZeneca, Takeda, Eli Lilly, F Hoffman-La Roche, Janssen, and Pfizer, outside the submitted work; and support for attending meetings and/or travel from AstraZeneca, Boehringer Ingelheim, Bristol-Meyers Eli Lilly, F Hoffman-La Roche, Phierre Fabre Pharmaceuticals, and Takeda, outside the submitted work. A.L. has received grants for academic research from PharMamar, Beigene, Roche, AstraZeneca, and Amgen, outside the submitted work. R.D. has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, AstraZeneca, Takeda, Novartis, BMS, MSD, Pfizer, and Amgen, outside the submitted work; support for attending meetings and/or travel from Pfizer, outside the submitted work; drug samples from Novartis, outside the submitted work; and participated on a Data Safety Monitoring Board or Advisory Board of GlaxoSmithKline, outside the submitted work. C.P. has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, outside the submitted work. M.D.M. has received institutional research funding from Tesaro/GlaxoSmithKline and institutional funding for work in clinical trials/contracted research from Beigene, Exelixis, MSD, Pfizer and Roche, outside the submitted work; and personal fees for consultancy or participation to advisory boards from AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Roche, GlaxoSmithKline, Amgen, Merck, and Takeda, outside the submitted work. M.T. has received institutional research funding from AstraZeneca, BMS, MSD, Roche, and Takeda, outside the submitted work; payment or honoraria (personal) for speakers bureaus from Amgen, AstraZeneca, Beigene, BMS, Boehringer Ingelheim, Celgene, Chugai, Daiichi Sankyo, GlaxoSmithKline, Janssen Oncology, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, and Takeda, outside the submitted work; and support for attending meetings and/or travel from AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, and Takeda, outside the submitted work. A.B. has received consulting fees (personal) from AstraZeneca, BMS, MSD, and Roche, outside the submitted work; and payment or honoraria (personal) for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, BMS, MSD, and Roche, outside the submitted work. S.P. has received consulting fees (personal) from Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, GSK, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx, outside the submitted work; payment or honoraria (personal) for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche and Takeda, outside the submitted work; payment for expert testimony from Roche and Merck Serono, outside the submitted work; support for travel from Janssen and Roche, outside the submitted work; consulting fees for participation on an Advisory Board, outside the submitted work; unpaid leadership role in the British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETOP-IBCSG Partners Foundation Board, outside the submitted work. S.S. has received research grants (institution) from AstraZeneca and personal honoraria for participating in the trial steering committee for immunotherapy in small cell lung cancer from AstraZeneca, outside the submitted work; consulting fees from AstraZeneca and BMS, outside the submitted work; speaker honoraria (self) from AstraZeneca, outside the submitted work; participates on a Data Safety Monitoring Board as a review panel member for lung toxicity adjudication with immunotherapy (MSD), outside the submitted work; and has a leadership role as an ETOP member of the scientific committee for lung cancer, outside the submitted work., (© 2024 The Author(s).)

Background: In the intensive care unit (ICU) relatives play a crucial role as surrogate decision-makers, since most patients cannot communicate due to their illness and treatment. Their level of involvement in decision-making can affect their psychological well-being. During the COVID-19 pandemic, relatives' involvement probably changed. We aim to investigate relatives' involvement in decision-making in the ICU before and during the pandemic and their experiences and preferences in this regard., Methods: A mixed-methods study among relatives of ICU patients admitted to an ICU before or during the COVID-19 pandemic. Relatives in six ICUs completed a questionnaire (n = 329), including two items on decision-making. These were analysed using descriptive statistics and logistic regression analyses. Subsequently, relatives (n = 24) were interviewed about their experiences and preferences regarding decision-making. Thematic analysis was used for analysing the qualitative data., Results: Nearly 55% of the relatives indicated they were at least occasionally asked to be involved in important treatment decisions and of these relatives 97.1% reported to have had enough time to discuss questions and concerns when important decisions were to be made. During the first COVID-19 wave relatives were significantly less likely to be involved in decision-making compared to relatives from pre-COVID-19. The interviews showed that involvement varied from being informed about an already made decision to deliberation about the best treatment option. Preferences for involvement also varied, with some relatives preferring no involvement due to a perceived lack of expertise and others preferring an active role as the patient's advocate. Discussing a patient's quality of life was appreciated by relatives, and according to relatives healthcare professionals also found this valuable. In some cases the preferred and actual involvement was in discordance, preferring either a larger or a smaller role., Conclusions: As treatment alignment with a patient's values and preferences and accordance between preferred and actual involvement in decision-making is very important, we suggest that the treatment decision-making process should start with discussions about a patient's quality of life, followed by tailoring the process to relatives' preferences as much as possible. Healthcare professionals should be aware of relatives' heterogeneous and possibly changing preferences regarding the decision-making process., (© 2024. The Author(s).)

Surgeons have unique in situ access to tumors enabling them to apply immunotherapies to resection margins as a means to prevent local recurrence. Here, we developed a surgical approach to deliver stimulator of interferon genes (STING) ligands to the site of a purposeful partial tumor resection using a gel-based biomaterial. In a range of head and neck squamous cell carcinoma (HNSCC) murine tumor models, we demonstrate that although control-treated tumors recur locally, tumors treated with STING-loaded biomaterials are cured. The mechanism of tumor control required activation of STING and induction of type I IFN in host cells, not cancer cells, and resulted in CD8 T-cell-mediated cure of residual cancer cells. In addition, we used a novel tumor explant assay to screen individual murine and human HNSCC tumor responses to therapies ex vivo We then utilized this information to personalize the biomaterial and immunotherapy applied to previously unresponsive tumors in mice. These data demonstrate that explant assays identify the diversity of tumor-specific responses to STING ligands and establish the utility of the explant assay to personalize immunotherapies according to the local response. Significance: Delivery of immunotherapy directly to resection sites via a gel-based biomaterial prevents locoregional recurrence of head and neck squamous cell carcinoma. Cancer Res; 78(21); 6308-19. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Morphologic and cytogenetic assessments are required to characterize diagnostic and prognostic features of myelodysplastic syndromes (MDS). We assessed whether these assessments were performed among newly diagnosed MDS patients in the Netherlands., Methods: MDS cases were retrieved from the nationwide Netherlands Cancer Registry (N=9159; period 2001-2014) and the regional PHAROS MDS registry (N=676; period 2008-2011)., Results: The proportion of unclassified MDS decreased from 58% in 2001 to 13% in 2014. Data from the more detailed PHAROS registry revealed that the degree of bone marrow dysplasia was only reported in ∼30% of all evaluable bone marrow aspirates. Further, the International Prognostic Scoring System was undetermined in 55% of patients, primarily owing to unperformed cytogenetics in 46% of patients., Conclusion: The classification of MDS is improving in the Netherlands. Nevertheless, particular diagnostic and prognostic procedures that are essential for the diagnosis and subsequent treatment decision-making of MDS were not fully utilized in particular patient subsets., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Genetic and epigenetic alterations have been identified as to contribute directly or indirectly to the generation of transitional cell carcinoma of the urinary bladder (TCC-UB). We have previously found that amplification of chromosome 6p22 is significantly associated with the muscle-invasive rather than superficial TCC-UB. Here, we demonstrated that Sox4, one of the candidate oncogenes located within the chromosome 6p22 amplicon, confers bladder cancer stem cell (CSC) properties. Down-regulation of Sox4 led to the inhibition of cell migration, colony formation as well as mesenchymal-to-epithelial transition (MET). Interestingly, knockdown of Sox4 also reduced the sphere formation, enriched cell population with high levels of aldehyde dehydrogenase (ALDH (high)) and tumor formation potential. Using gene expression profiling, we further identified novel Sox4 target genes. Last, immunohistochemistry analysis of human bladder tumor tissue microarrays (TMAs) indicated that high Sox4 expression was correlated with advanced cancer stages and poor survival rate. In summary, our data show that Sox4 is an important regulator of the bladder CSC properties and it may serve as a biomarker of the aggressive phenotype in bladder cancer.