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Objective: Harmonized European NSCLC incidence, treatment approach, and survival based on national tumor registries are unclear., Summary Background Data: Surgery has the potential to cure NSCLC and significantly prolong survival. This large-scale international study aimed to investigate treatment variations in Europe and the USA, as well as the determinants for its utilization., Methods: The retrospective cohort study analyzed data from six European national population-based cancer registries (Belgium, Denmark, Estonia, Germany, the Netherlands, and Slovenia) and the US SEER database from 2010-2015., Results: The study computed cancer incidence, survival, and age-standardized proportions of the use of various therapies. Multivariable logistic regression models were used to assess associations between resection and demographic and clinical parameters. A total of 428,107 records were analyzed. Among all countries, Estonia had the highest surgical resection rate (79.3 %) and the lowest radiation rate (7.3 %) for stage I patients. The Netherlands had the highest rate of radiotherapy across all years of investigation and the lowest surgery rate between 2012 and 2015. The primary treatment for early-stage NSCLC showed significant international variation, with the USA having a decrease in surgical rates from 67.6 % to 59.5 %. Resection was less frequently performed as tumor stage increased, patients aged, other lung cancer besides adenocarcinoma was present, and when the tumor site overlapped multiple lobes., Conclusions: Resection rates have declined in some studied European countries and the USA and resection rates vary substantially among countries. Interpretation of current scientific lung cancer evidence and international guidelines results in wide variations in patient treatment., Competing Interests: Declaration of Competing Interest A.F.T.M. Verhagen reports institutional payments from Johnson & Johnson and Bristol Myers Squibb. Kersti Oselin declares research grants from Pfizer to study the role of artificial intelligence and genomic factors in lung cancer recurrence 2021 and an ongoing research collaboration with Optellum to develop an artificial intelligence tool to assess lung cancer prognosis. She reports travel support from MSD, Roche and Astra Zeneca. H. Winter reports consultancy fees, travel support and data safety monitoring honoraria from Astra Zeneca, Roche and Intuitive Surgical. All other authors declare no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Arcagen (NCT02834884) is a European prospective study aiming at defining the molecular landscape of rare cancers for treatment guidance. We present data from the cohort of rare thoracic tumors. Patients with advanced pleural mesothelioma (PM) or thymic epithelial tumors (TET) underwent genomic profiling with large targeted assay [>300 genes, tumor mutational burden (TMB), microsatellite instability (MSI) status] on formalin-fixed paraffin-embedded (FFPE) or plasma samples. EORTC molecular tumor board (MTB) advised for biomarker-guided treatments. 102 patients recruited from 8 countries between July 2019 and May 2022 were evaluable: 56 with PM, 46 with TET (23 thymomas, 23 thymic carcinomas). Molecular profiling was performed on 70 FFPE samples (42 PM, 28 TET), and 32 cases on ctDNA (14 PM, 18 TET), within a median turnaround time of 8 days from sample reception. We detected relevant molecular alterations in 66 out of 102 patients (65%; 79% PM, 48% TET), 51 of 70 FFPE samples (73%; 90% PM, 46% TET), and 15 of 32 plasma samples (47%; 43% PM, 50% TET). The most frequently altered genes were CDKN2A/B, BAP1, MTAP in PM and TP53, CDKN2A/B, SETD2 in TET. The TMB was low (mean 3.2 Muts/MB), 2 PM had MSI-high status. MTB advised molecular-guided treatment options in 32 situations, for 17 PM and 15 TET patients (75% clinical trial option, 22% off-label drug or compassionate use, 3% early access program). Molecular testing and MTB discussion were feasible for patients with rare thoracic cancers and allowed the broadening of treatment options for 30% of the cases., (© 2024. The Author(s).)

Purpose: Spironolactone is a potassium sparing diuretic used for decades. Until now, pharmacokinetic (PK) studies of spironolactone have not been conducted in infants and therefore pediatric dosing is based on expert opinion. We aimed to describe the PK profiles of spironolactone and its main metabolites (7alpha-thiomethylspironolactone (TMS) and canrenone (CAN)) in infants up to two years of age., Methods: The PK of spironolactone and its main metabolites were evaluated following an oral administration of spironolactone (1 mg/kg/dose) to pediatric patients with chronic heart failure, ascites, and/or oedema. The plasma concentration of spironolactone and metabolites (TMS and CAN) was determined using an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Based on rich sampling PK data, the estimation of population PK parameters was performed using nonlinear mixed-effects modelling software Monolix 2018R2., Results: A total of 150 spironolactone, 158 TMS, and 158 CAN concentrations from 23 patients (ages: 3 days-21 months; median weight 4.3 kg (2.2-12.6)) were available for PK analysis. A one-compartment model for spironolactone, TMS, and CAN best fitted the data. The median (range) of individual estimated apparent clearance values were 47.7 (11.9-138.1) L/h for spironolactone, 9.7 (1.5-66.9) L/h for TMS, and 1.0 (0.2-5.9) L/h for CAN. The disposition of spironolactone and metabolites was mainly affected by size of the patient: body weight explained 22% of inter-individual variability of spironolactone clearance. None of the undesirable effects of spironolactone was documented during the study period., Conclusion: The pharmacokinetics of spironolactone and its metabolites was highly variable between patients below 2 years of age. Body weight explained a significant part of this variability; this highlights the need to take it into account for dosing prescription in this population. (Clinical trial Registration Number 2013-001189-40)., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Lung cancer remains the leading cause of cancer-related deaths in Europe, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. NSCLC is a heterogeneous disease encompassing various oncogenic alterations. Among them, EGFR exon 20 insertion mutations, constituting 0.3-2.2% of NSCLC cases, rank as the third most common EGFR alteration after exon 19 deletions and the L858R point mutation in exon 21, also known as "typical" EGFR alterations. Recent advancements in understanding the molecular pathogenesis of NSCLC have led to significant breakthroughs in targeted therapies, revolutionizing treatment options for patients with specific genetic alterations.This article presents the outcomes of a Virtual Meeting conducted on the online platform (provided Within3©) from September 19 to October 30, 2022. The meeting focused on addressing the challenges in the diagnosis and treatment of NSCLC patients with EGFR exon 20 insertion mutations. The participants consisted of healthcare professionals from ten Central and Eastern European countries who shared their experiences and opinions on various aspects, including epidemiology, treatment options, and diagnostic approaches employed in their respective healthcare institutions. The discussions were facilitated through open-ended and multiple-choice questions.The primary objective of this article is to provide an overview of the identified challenges associated with the diagnosis and treatment of this heterogeneous disease, based on the assessments of the meeting participants. Among the major emerging challenges discussed, the reimbursement issues concerning next-generation sequencing (NGS), a recommended method in NSCLC molecular diagnosis, and the availability of approved targeted treatments to enhance patient outcomes were of paramount importance. Furthermore, fostering community awareness of lung cancer and promoting harmonized lung cancer care were identified as areas deserving greater attention. Notably, the rapidly evolving treatment landscape, particularly with NGS for NSCLC patients with genomic alterations like EGFR, ALK, RET, MET, NTRK, and ROS1, necessitates prioritizing the development of new drugs, even for the relatively smaller subgroup with exon 20 insertion mutations., (© 2023. The Author(s).)

Introduction: 33-70% of lung cancer (LC) patients develop recurrence after radical treatment. Previous studies have shown the importance of clinical-pathological characteristics for the risk of recurrence. The role of molecular mechanisms remains unclear. The aim was analyzing genomic features in LC patients with local (LR) versus distant recurrence (DR) to predict the risk and type of recurrence., Materials and Methods: Patients previously curatively treated with LC recurrences from 2015 to 2017 were retrospectively enrolled. Histological specimens collected at the time of LC diagnosis were sent for whole exome sequencing (WES). Genomic data was analyzed for single nucleotide polymorphisms (SNPs) and insertion-deletion mutations (INDELs)., Results: 191 patients were included. 33% of patients had LR and 67% DR, with median recurrence-free survival (RFS) 15.4 versus 11.2 months (p = 0.20) and overall survival (OS) after recurrence 12.9 versus 8.5 months (p = 0.007), respectively. Of various laboratory parameters studied, lymphocytes were significantly decreased at recurrence (p < 0.0001) in the DR group. In genetic analysis, significantly enriched INDEL mutations were found in 38 and 98 genes and SNP mutations in 63 and 179 genes in DR and LR groups, respectively. DMXL2 and ABCC9 gene mutations caused by INDELs appeared exclusively in the DR group. Enrichment analysis detected genes, like KNTC1, CLASP1, CLASP2 and CENPE, responsible of microtubule disturbance in the DR group. Furthermore, genes related to cytosolic Ca2+ such as STIM1, ITPR3 and RYR3, were significantly enriched in DR group whereas in LR group enrichment of pathways related to endoplasmic/sarcoplasmic reticulum Ca2+ was observed., Conclusion: Our findings indicate distinct genomic signatures in the LR and DR cohorts, with microtubule disturbance and calcium regulation playing a crucial role in invasiveness in DR of LC. Understanding molecular mechanisms of LC recurrence may lead to the discovery of novel drug targets that could potentially stop spread of cancer cells., 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Pembrolizumab is a standard-of-care for advanced non-small-cell lung cancer (NSCLC). We assessed pembrolizumab as adjuvant therapy for completely resected stage IB-IIIA NSCLC., Methods: In this randomised, triple-blind, phase 3 trial (PEARLS/KEYNOTE-091), patients were recruited from 196 medical centres in 29 countries. Eligible patients were aged 18 years or older, with completely resected, pathologically confirmed stage IB (tumours of ≥4 cm in diameter), II, or IIIA NSCLC per the American Joint Committee on Cancer staging system (7th edition) of any histology or PD-L1 expression level, and an Eastern Cooperative Oncology Group performance status of 0 or 1; adjuvant chemotherapy was to be considered for stage IB disease and was strongly recommended for stage II and IIIA disease, according to national and local guidelines. Using a central interactive voice-response system, eligible participants were randomly assigned (1:1), using a minimisation technique and stratified by disease stage, previous adjuvant chemotherapy, PD-L1 expression, and geographical region, to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks for up to 18 cycles. Participants, investigators, and analysts were masked to treatment assignment. Dual primary endpoints were disease-free survival in the overall population and in the population with PD-L1 tumour proportion score (TPS) of 50% or greater. Efficacy was assessed in the intention-to-treat (ITT) population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants randomly assigned to treatment who received at least one dose of study treatment. Here we report results of the second interim analysis, prespecified to occur when approximately 118 disease-free survival events had occurred in the PD-L1 TPS of 50% or greater population. This study is registered with ClinicalTrials.gov, NCT02504372, and is active but not recruiting., Findings: Between Jan 20, 2016, and May 6, 2020, 1177 (60%) of 1955 screened participants were randomly assigned to pembrolizumab (n=590, including n=168 with PD-L1 TPS of ≥50%) or placebo (n=587; including n=165 with PD-L1 TPS of ≥50%) and included in the ITT population. Median follow-up as of data cutoff (Sept 20, 2021) for this interim analysis was 35·6 months (IQR 27·1-45·5). In the overall population, median disease-free survival was 53·6 months (95% CI 39·2 to not reached) in the pembrolizumab group versus 42·0 months (31·3 to not reached) in the placebo group (HR 0·76 [95% CI 0·63-0·91], p=0·0014). In the PD-L1 TPS of 50% or greater population, median disease-free survival was not reached in either the pembrolizumab group (95% CI 44·3 to not reached) or the placebo group (95% CI 35·8 to not reached; HR 0·82 [95% CI 0·57-1·18]; p=0·14). Grade 3 or worse adverse events occurred in 198 (34%) of 580 participants who received pembrolizumab and 150 (26%) of 581 participants who received placebo. Grade 3 or worse events that occurred in at least ten participants in either treatment group were hypertension (35 [6%]) and pneumonia (12 [2%]) with pembrolizumab and hypertension (32 [6%]) with placebo. Serious adverse events occurred in 142 (24%) participants in the pembrolizumab group and 90 (15%) in the placebo group; serious adverse events that occurred in more than 1% of participants were pneumonia (13 [2%]), pneumonitis (12 [2%]), and diarrhoea (seven [1%]) with pembrolizumab and pneumonia (nine [2%]) with placebo. Treatment-related adverse events led to death in four (1%) participants treated with pembrolizumab (one due to both cardiogenic shock and myocarditis, one due to both septic shock and myocarditis, one due to pneumonia, and one due to sudden death) and in no participants treated with placebo., Interpretation: Pembrolizumab significantly improved disease-free survival compared with placebo and was not associated with new safety signals in completely resected, PD-L1-unselected, stage IB-IIIA NSCLC. Pembrolizumab is potentially a new treatment option for stage IB-IIIA NSCLC after complete resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1 expression., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co., Competing Interests: Declaration of interests MO, LP-A, SM, UD, KO, LH, EE, DI, AM-M, MF, MT, J-SL, KN, MM, NJ, RS, BB, and SP report funding to their institutions from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co (Rahway, NJ, USA; MSD) to support conduct of this study. All authors received medical writing support for the preparation of this manuscript from MSD. MO additionally reports consulting fees for serving on advisory boards for MSD, Merck, Pierre Fabre, Amgen, Puma, Iteos, and PharmaMar; honoraria from Roche and Lilly in China; travel support from MSD; payment for serving as a member of an independent data monitoring committee for PharmaMar; and payment from ALPI (Sweden) for an academic review. LP-A additionally reports institutional grants or contracts from MSD, AstraZeneca, Pfizer, and Bristol Myers Squibb (BMS); consulting fees from Lilly, MSD, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, and Takeda; honoraria from AstraZeneca, Janssen, Merck, and Mirati; participation on a data safety monitoring board for Altum Sequencing and Genomica; and serving as a principal investigator on trials for Alkermes, Amgen, AstraZeneca, BMS, Daiichi Sankyo, IO Biotech, Janssen-Cilag, Lilly, MSD, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Takeda, and Tesaro. UD additionally reports consulting fees from Roche. KO additionally reports institutional grants or contracts from Pfizer and Takeda; consulting fees from Amgen, Takeda, MSD, Janssen, Roche, and AstraZeneca; and travel support from MSD. DI additionally reports consulting fees from MSD, Roche, AstraZeneca, Amgen, Pfizer, Sanofi, Bayer, BMS, GSK, Janssen, and Takeda; honoraria from MSD, Roche, AstraZeneca, Amgen, Pfizer, Sanofi, Bayer, BMS, and Takeda; and travel support from AstraZeneca. AM-M additionally reports consulting fees for advisory board membership from AstraZeneca/MedImmune, BMS, F Hoffmann-La Roche AG, MSD, and Pfizer; honoraria from AstraZeneca/MedImmune, BMS, F Hoffmann-La Roche AG, MSD, and Pfizer; serving as a steering committee member for AstraZeneca/MedImmune; and travel support from AstraZeneca/MedImmune, BMS, F Hoffmann-La Roche AG, MSD, Pfizer, and Lilly. MF additionally reports honoraria from Roche and Sanofi; travel support from AstraZeneca; and serving as an advisory board member for MSD, Roche, and AstraZeneca. MT additionally reports institutional grants or contracts from Boehringer-Ingelheim Japan, MSD, AstraZeneca KK, Ono Pharmaceutical, and Novartis; consulting fees from AstraZeneca KK, Chugai Pharmaceutical, and MSD KK; honoraria from Johnson & Johnson Japan, AstraZeneca KK, Eli Lilly Japan, Chugai Pharmaceutical, Taiho Pharma, Medtronic Japan, Ono Pharmaceutical, MSD KK, BMS KK, Daiichi Sankyo KK, and Teijin Pharma; serving as a data safety monitoring committee member for Chugai Pharmaceutical; and serving as an advisory board member for AstraZeneca KK, MSD, Novartis, and Eli Lilly. KN additionally reports institutional grants or contracts from AstraZeneca KK, MSD KK, Ono Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma KK, Pfizer Japan, BMS, Eli Lilly Japan KK, Chugai Pharmaceutical, Daiichi Sankyo, Merck Biopharma, Parexel International, PRA Health Sciences, EPS Corporation, Kissei Pharmaceutical, Taiho Pharmaceutical, PPD-SNBL KK, SymBio Pharmaceutical, IQVIA Services Japan KK, Syneos Health Clinical KK, Nippon Kayaku, EP-CRSU, Mebix, Janssen Pharmaceutical KK, AbbVie, Bayer Yakuhin, Eiasi, Mochida Pharmaceutical, Covance Japan, Japan Clinical Research Operations, Takeda Pharmaceutical, GSK KK, Sanofi KK, Sysmex Corporation, Medical Research Support, Otsuka Pharmaceutical, SRL, Pfizer R&D Japan GK, and Amgen; consulting fees from Eli Lilly Japan KK, Kyorin Pharmaceutical, Ono Pharmaceutical, and Pfizer Japan; honoraria from Ono Pharmaceutical, Amgen, Nippon Kayaku, AstraZeneca KK, Chugai Pharmaceutical, Eli Lilly Japan KK, MSD KK, Pfizer Japan, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Bayer Yakuhin, CMIC ShiftZero KK, Life Technologies Japan, Neo Communication, Roche Diagnostics KK, AbbVie, Merck Biopharma, Kyowa Kirin, Takeda Pharmaceutical, 3H Clinical Trial, CareNet, Medical Review, Yodosha, Nikkei Business Publications, Japan Clinical Research Operations, CMIC, Novartis Pharma KK, Taiyo Pharma, Kyorin Pharmaceutical, BMS KK; and patents with Daiichi Sankyo. RS additionally reports institutional grants or contracts from AstraZeneca, BMS, Daiichi Sankyo, Celgene, Ipsen, Janssen, Mirati, MSD, Novartis, Pfizer, Pierre Fabre, and Roche; consulting fees from AstraZeneca, BMS, Boehringer Ingelheim, GSK, Janssen, MSD, Pfizer, Roche, Sandoz, Seagen, and Takeda; honoraria from Amgen, AstraZeneca, Blueprint Medicines, BMS, Boehringer Ingelheim, GSK, MSD, Novartis, and Roche; data safety monitoring or advisory board participation with Roche and Takeda; and a leadership role with the European Thoracic Oncology Platform International Breast Cancer Study Group (ETOP IBCSG) Partners Foundation. BB additionally reports institutional grants or contracts from 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Chugai Pharmaceutical, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, Eisai, Genzyme Corporation, GSK, Inivata, Ipsen, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals, and Turning Point Therapeutics. SP additionally reports institutional grants or contracts from Amgen, AstraZeneca, BeiGene, BMS, GSK, MSD, and Roche/Genentech; consulting fees paid to their institution from AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Imedex, IQVIA, Incyte, iTeos, Janssen, Medscape, MSD, Merck Serono, Merrimack, Novartis, Novocure, Oncology Education, PharmaMar, PeerView, PER, Phosplatin Therapeutics, Pfizer, Prime, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seagen, Takeda, and Vaccibody; honoraria paid to their institution from AiCME, AstraZeneca, Boehringer Ingelheim, BMS, ecancer, Eli Lilly, Foundation Medicine, Illumina, Imedex, Medscape, MSD, Mirati, Novartis, PeerView, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, and Takeda; travel support from AstraZeneca, BMS, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pfizer, Roche/Genentech, and Takeda; and participation on a data safety monitoring or advisory board, with all fees paid to their institution, from AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Incyte, iTeos, Janssen, MSD, Merck Serono, Merrimack, Novartis, Novocure, PharmaMar, Phosplatin Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seagen, Takeda, and Vaccibody. JY, AS, and SMK report salary for full-time employment from MSD; AS and SMK also own stock in Merck & Co, Rahway, NJ, USA., (Copyright © 2022 Elsevier Ltd. All rights reserved.)