Search

Background: In non-small cell lung cancer (NSCLC) patients off erlotinib therapy, positron emission tomography (PET) using [C]erlotinib distinguished epidermal growth factor receptor (EGFR) mutations from wild-type EGFR. However, tumor uptake of [C]erlotinib during erlotinib therapy is unknown. Therefore, the aims of this study were to evaluate tumor [C]erlotinib uptake in NSCLC patients both on and off erlotinib therapy, to evaluate the effect of erlotinib therapy on tumor perfusion and its correlation to tumor [C]erlotinib uptake, and also, to investigate simplified uptake parameters using arterial and venous blood samples. Methods: Ten patients were to be scanned twice with a 1-2-week interval, i.e., on (E+) and off (E−) erlotinib therapy. Each procedure consisted of a low-dose CT scan, a 10-min dynamic [O]HO PET scan, and a 60-min dynamic [C]erlotinib PET scan with arterial and venous sampling at six time points. In patients(E+), the optimal compartment model was analyzed using Akaike information criterion. In patients(E−), the uptake parameter was the volume of distribution ( V), estimated by using metabolite-corrected plasma input curves based on image-derived input functions and discrete arterial and venous blood samples. Tumor blood flow (TBF) was determined by rate constant of influx (K1) of [O]HO using the 1T2k model and correlated with V and K1 values of [C]erlotinib. The investigated simplified parameters were standardized uptake value (SUV) and tumor-to-blood ratio (TBR) at 40-60 min pi interval. Results: Of the 13 patients included, ten were scanned twice. In patients(E+), [C]erlotinib best fitted the 2T4k model with V. In all patients, tumor V(E+) was lower than V(E−) (median V(E−) = 1.61, range 0.77-3.01; median V(E+) = 1.17, range 0.53-1.74; P = 0.004). Using [O]HO, five patients were scanned twice. TBF did not change with erlotinib therapy, TBF showed a positive trend towards correlation with [C]erlotinib K1, but not with V. TBR and TBR, using both arterial and venous sampling, correlated with V(E−) (all r >0.9, P < 0.001), while SUV did not. In patients off and on therapy, venous TBR underestimated arterial TBR by 26 ± 12 and 9 ± 9 %, respectively. Conclusions: In patients on erlotinib in therapeutic dose, tumor V decreases with high variability, independent of tumor perfusion. For simplification of [C]erlotinib PET scanning protocols, both arterial and venous TBR 40-60 min post injection can be used; however, arterial and venous TBR values should not be interchanged as venous values underestimate arterial values. Trial registration: Registered at the Netherlands Trial Registry: . [ABSTRACT FROM AUTHOR]

Purpose: [F]Fluoroazomycin arabinoside (FAZA) is a positron emission tomography (PET) tracer developed to enable identification of hypoxic regions within a tumour. The aims of this study were to determine the optimal kinetic model along with validation of using alternatives to arterial blood sampling for analysing [F]FAZA studies and to assess the validity of simplified analytical methods. Methods: Dynamic 70-min [F]FAZA PET/CT scans were obtained from nine non-small cell lung cancer patients. Continuous arterial blood sampling, together with manual arterial and venous sampling, was performed to derive metabolite-corrected plasma input functions. Volumes of interest (VOIs) were defined for tumour, healthy lung muscle and adipose tissue generating [F]FAZA time-activity curves (TACs). TACs were analysed using one- and two-tissue compartment models using both metabolite-corrected blood sampler plasma input functions (BSIF) and image-derived plasma input functions (IDIF). Results: The reversible two-tissue compartment model with blood volume parameter (2T4k+V) best described kinetics of [F]FAZA in tumours. Volumes of distribution (V) obtained using IDIF correlated well with those derived using BSIF ( R = 0.82). Venous samples yielded the same radioactivity concentrations as arterial samples for times >50 min post-injection (p.i.). In addition, both plasma to whole blood ratios and parent fractions were essentially the same for venous and arterial samples. Both standardised uptake value (SUV), normalised to lean body mass, and tumour to blood ratio correlated well with V ( R = 0.77 and R = 0.87, respectively, at 50-60 min p.i.), although a bias was observed at low V. Conclusion: The 2T4k+V model provided the best fit to the dynamic [F]FAZA data. IDIF with venous blood samples can be used as input function. Further data are needed to validate the use of simplified methods. [ABSTRACT FROM AUTHOR]

Simple Summary: Interaction between blood platelets and cancer cells play an important role in various steps of cancer development and progression. These interactions lead to changes in the platelets' RNA content, resulting in tumor-mediated "education" of platelets. Tumor-educated platelets (TEPs) can be used as a non-invasive biomarker source for cancer detection and progression monitoring. Our lab has previously identified that spliced mRNA TEP signatures provide specific information on the presence, location, and molecular features of cancers. Next to mRNA, other RNA types are present in platelets, and their repertoire can potentially be subjected to cancer-mediated alterations. Despite the evidence that circRNA could be a promising cancer biomarker, they have not yet been analyzed in blood platelets of cancer patients. In this proof-of-concept study, we aim to evaluate whether platelets' circRNA signature could be used as a biomarker for cancer detection and progression. Tumor-educated Platelets (TEPs) have emerged as rich biosources of cancer-related RNA profiles in liquid biopsies applicable for cancer detection. Although human blood platelets have been found to be enriched in circular RNA (circRNA), no studies have investigated the potential of circRNA as platelet-derived biomarkers for cancer. In this proof-of-concept study, we examine whether the circRNA signature of blood platelets can be used as a liquid biopsy biomarker for the detection of non-small cell lung cancer (NSCLC). We analyzed the total RNA, extracted from the platelet samples collected from NSCLC patients and asymptomatic individuals, using RNA sequencing (RNA-Seq). Identification and quantification of known and novel circRNAs were performed using the accurate CircRNA finder suite (ACFS), followed by the differential transcript expression analysis using a modified version of our thromboSeq software. Out of 4732 detected circRNAs, we identified 411 circRNAs that are significantly (p-value < 0.05) differentially expressed between asymptomatic individuals and NSCLC patients. Using the false discovery rate (FDR) of 0.05 as cutoff, we selected the nuclear receptor-interacting protein 1 (NRIP1) circRNA (circNRIP1) as a potential biomarker candidate for further validation by reverse transcription–quantitative PCR (RT-qPCR). This analysis was performed on an independent cohort of platelet samples. The RT-qPCR results confirmed the RNA-Seq data analysis, with significant downregulation of circNRIP1 in platelets derived from NSCLC patients. Our findings suggest that circRNAs found in blood platelets may hold diagnostic biomarkers potential for the detection of NSCLC using liquid biopsies. [ABSTRACT FROM AUTHOR]

Introduction: The novel positron emission tomography (PET) imaging tracer, [18F]F-AraG, targets activated T-cells, offering a potential means to improve our understanding of immune-oncological processes. The aim of this study was to determine the optimal pharmacokinetic model to quantify tumour lesion [18F]F-AraG uptake in patients with non-small cell lung cancer (NSCLC), and to validate simplified measures at different time intervals against the pharmacokinetic uptake parameter.Ten patients with early-stage NSCLC and three patients with advanced NSCLC underwent a dynamic PET scan of minimal 60 min. Venous and/or arterial blood sampling was obtained at maximum seven time points. Tumour lesion time activity curves and metabolite-corrected input functions were analysed using single-tissue reversible (1T2k), two-tissue irreversible (2T3k) and two-tissue reversible (2T4k) plasma input models. Simplified uptake measures, such as standardised uptake value (SUV) and tumour-to-blood (TBR) or tumour-to-plasma ratio (TPR), were evaluated for different time intervals.Whole-blood and plasma radioactivity concentrations showed rapid clearance of [18F]F-AraG. Metabolite analysis revealed a low rate of metabolism, at 70 min p.i., on average, 79% (SD = 9.8%) of the total radioactivity found in blood corresponded to intact [18F]F-AraG. The time activity curves were best fitted by the 2T3k model. Strong positive correlations were found for SUV (body weight (BW), lean body mass (LBM) or body surface area (BSA) corrected), TBR and TPR for any time interval between 20 and 70 min p.i. against the 2T3k-derived Ki. The correlation of TBR at 60–70 min p.i. with 2T3K-derived Ki (r (df = 20) = 0.87, p < 0.01), was stronger than for SUVBW (r (df = 20) = 0.80, p < 0.01).Tumour lesion [18F]F-AraG uptake in patients with NSCLC is characterised by a 2T3k model. TBR and TPR show most potential for simplified quantification of tumour lesion [18F]F-AraG uptake in patients with NSCLC.Methods: The novel positron emission tomography (PET) imaging tracer, [18F]F-AraG, targets activated T-cells, offering a potential means to improve our understanding of immune-oncological processes. The aim of this study was to determine the optimal pharmacokinetic model to quantify tumour lesion [18F]F-AraG uptake in patients with non-small cell lung cancer (NSCLC), and to validate simplified measures at different time intervals against the pharmacokinetic uptake parameter.Ten patients with early-stage NSCLC and three patients with advanced NSCLC underwent a dynamic PET scan of minimal 60 min. Venous and/or arterial blood sampling was obtained at maximum seven time points. Tumour lesion time activity curves and metabolite-corrected input functions were analysed using single-tissue reversible (1T2k), two-tissue irreversible (2T3k) and two-tissue reversible (2T4k) plasma input models. Simplified uptake measures, such as standardised uptake value (SUV) and tumour-to-blood (TBR) or tumour-to-plasma ratio (TPR), were evaluated for different time intervals.Whole-blood and plasma radioactivity concentrations showed rapid clearance of [18F]F-AraG. Metabolite analysis revealed a low rate of metabolism, at 70 min p.i., on average, 79% (SD = 9.8%) of the total radioactivity found in blood corresponded to intact [18F]F-AraG. The time activity curves were best fitted by the 2T3k model. Strong positive correlations were found for SUV (body weight (BW), lean body mass (LBM) or body surface area (BSA) corrected), TBR and TPR for any time interval between 20 and 70 min p.i. against the 2T3k-derived Ki. The correlation of TBR at 60–70 min p.i. with 2T3K-derived Ki (r (df = 20) = 0.87, p < 0.01), was stronger than for SUVBW (r (df = 20) = 0.80, p < 0.01).Tumour lesion [18F]F-AraG uptake in patients with NSCLC is characterised by a 2T3k model. TBR and TPR show most potential for simplified quantification of tumour lesion [18F]F-AraG uptake in patients with NSCLC.Results: The novel positron emission tomography (PET) imaging tracer, [18F]F-AraG, targets activated T-cells, offering a potential means to improve our understanding of immune-oncological processes. The aim of this study was to determine the optimal pharmacokinetic model to quantify tumour lesion [18F]F-AraG uptake in patients with non-small cell lung cancer (NSCLC), and to validate simplified measures at different time intervals against the pharmacokinetic uptake parameter.Ten patients with early-stage NSCLC and three patients with advanced NSCLC underwent a dynamic PET scan of minimal 60 min. Venous and/or arterial blood sampling was obtained at maximum seven time points. Tumour lesion time activity curves and metabolite-corrected input functions were analysed using single-tissue reversible (1T2k), two-tissue irreversible (2T3k) and two-tissue reversible (2T4k) plasma input models. Simplified uptake measures, such as standardised uptake value (SUV) and tumour-to-blood (TBR) or tumour-to-plasma ratio (TPR), were evaluated for different time intervals.Whole-blood and plasma radioactivity concentrations showed rapid clearance of [18F]F-AraG. Metabolite analysis revealed a low rate of metabolism, at 70 min p.i., on average, 79% (SD = 9.8%) of the total radioactivity found in blood corresponded to intact [18F]F-AraG. The time activity curves were best fitted by the 2T3k model. Strong positive correlations were found for SUV (body weight (BW), lean body mass (LBM) or body surface area (BSA) corrected), TBR and TPR for any time interval between 20 and 70 min p.i. against the 2T3k-derived Ki. The correlation of TBR at 60–70 min p.i. with 2T3K-derived Ki (r (df = 20) = 0.87, p < 0.01), was stronger than for SUVBW (r (df = 20) = 0.80, p < 0.01).Tumour lesion [18F]F-AraG uptake in patients with NSCLC is characterised by a 2T3k model. TBR and TPR show most potential for simplified quantification of tumour lesion [18F]F-AraG uptake in patients with NSCLC.Conclusion: The novel positron emission tomography (PET) imaging tracer, [18F]F-AraG, targets activated T-cells, offering a potential means to improve our understanding of immune-oncological processes. The aim of this study was to determine the optimal pharmacokinetic model to quantify tumour lesion [18F]F-AraG uptake in patients with non-small cell lung cancer (NSCLC), and to validate simplified measures at different time intervals against the pharmacokinetic uptake parameter.Ten patients with early-stage NSCLC and three patients with advanced NSCLC underwent a dynamic PET scan of minimal 60 min. Venous and/or arterial blood sampling was obtained at maximum seven time points. Tumour lesion time activity curves and metabolite-corrected input functions were analysed using single-tissue reversible (1T2k), two-tissue irreversible (2T3k) and two-tissue reversible (2T4k) plasma input models. Simplified uptake measures, such as standardised uptake value (SUV) and tumour-to-blood (TBR) or tumour-to-plasma ratio (TPR), were evaluated for different time intervals.Whole-blood and plasma radioactivity concentrations showed rapid clearance of [18F]F-AraG. Metabolite analysis revealed a low rate of metabolism, at 70 min p.i., on average, 79% (SD = 9.8%) of the total radioactivity found in blood corresponded to intact [18F]F-AraG. The time activity curves were best fitted by the 2T3k model. Strong positive correlations were found for SUV (body weight (BW), lean body mass (LBM) or body surface area (BSA) corrected), TBR and TPR for any time interval between 20 and 70 min p.i. against the 2T3k-derived Ki. The correlation of TBR at 60–70 min p.i. with 2T3K-derived Ki (r (df = 20) = 0.87, p < 0.01), was stronger than for SUVBW (r (df = 20) = 0.80, p < 0.01).Tumour lesion [18F]F-AraG uptake in patients with NSCLC is characterised by a 2T3k model. TBR and TPR show most potential for simplified quantification of tumour lesion [18F]F-AraG uptake in patients with NSCLC. [ABSTRACT FROM AUTHOR]

Introduction: The novel positron emission tomography (PET) imaging tracer, [ 18 F]F-AraG, targets activated T-cells, offering a potential means to improve our understanding of immune-oncological processes. The aim of this study was to determine the optimal pharmacokinetic model to quantify tumour lesion [ 18 F]F-AraG uptake in patients with non-small cell lung cancer (NSCLC), and to validate simplified measures at different time intervals against the pharmacokinetic uptake parameter., Methods: Ten patients with early-stage NSCLC and three patients with advanced NSCLC underwent a dynamic PET scan of minimal 60 min. Venous and/or arterial blood sampling was obtained at maximum seven time points. Tumour lesion time activity curves and metabolite-corrected input functions were analysed using single-tissue reversible (1T2k), two-tissue irreversible (2T3k) and two-tissue reversible (2T4k) plasma input models. Simplified uptake measures, such as standardised uptake value (SUV) and tumour-to-blood (TBR) or tumour-to-plasma ratio (TPR), were evaluated for different time intervals., Results: Whole-blood and plasma radioactivity concentrations showed rapid clearance of [ 18 F]F-AraG. Metabolite analysis revealed a low rate of metabolism, at 70 min p.i., on average, 79% (SD = 9.8%) of the total radioactivity found in blood corresponded to intact [ 18 F]F-AraG. The time activity curves were best fitted by the 2T3k model. Strong positive correlations were found for SUV (body weight (BW), lean body mass (LBM) or body surface area (BSA) corrected), TBR and TPR for any time interval between 20 and 70 min p.i. against the 2T3k-derived K i . The correlation of TBR at 60-70 min p.i. with 2T3K-derived K i (r (df = 20) = 0.87, p < 0.01), was stronger than for SUV BW (r (df = 20) = 0.80, p < 0.01)., Conclusion: Tumour lesion [ 18 F]F-AraG uptake in patients with NSCLC is characterised by a 2T3k model. TBR and TPR show most potential for simplified quantification of tumour lesion [ 18 F]F-AraG uptake in patients with NSCLC., (© 2024. The Author(s).)

Recognizing non-invasive growth patterns is necessary for correct diagnosis, invasive size determination and pT-stage in resected non-small cell lung carcinoma. Due to iatrogenic collapse after resection, the distinction between adenocarcinoma in-situ (AIS) and invasive adenocarcinoma may be difficult. The aim of this study is to investigate the complex morphology of non-mucinous non-invasive patterns of AIS in resection specimen with iatrogenic collapse, and to relate this to follow-up. The effects of iatrogenic collapse on the morphology of collapsed AIS were simulated in a mathematical model. Three dimensional related criteria applied in a modified classification, using also cytokeratin 7 and elastin as additional stains, in two independent retrospective cohorts of primary pulmonary adenocarcinomas ≤3 cm resection specimen with available follow-up information. The model demonstrated that infolding of alveolar walls occurs during iatrogenic collapse and lead to a significant increase in tumor cell heights in maximal collapse areas, compared to less collapsed areas. The morphology of infolded AIS overlaps with patterns described as papillary and acinar adenocarcinoma according to the WHO classification, necessitating an adaptation. The modified classification incorporates recognition of iatrogenic and biologic collapse, tangential cutting effect true invasion and surrogate markers of invasion i.e. grey zone, covering a multilayering falling short of micropapillary, cribriform and solid alveolar filling growth. The use of elastin and CK7 staining aids in the morphologic recognition of iatrogenic collapsed AIS and the distinction from invasive adenocarcinoma. Out of a total of 70 resection specimens 1 case was originally classified as AIS and 9 were reclassified as iatrogenic collapsed AIS. Patients with collapsed AIS showed a 100 % recurrence-free survival after a mean follow-up time of 69.5 months. With the current WHO classification, AIS is overdiagnosed as invasive adenocarcinoma due to infolding. The modified classification facilitates the diagnosis of AIS., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andreas schonau is developer of the pathogate website. None of the other authors declares a conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: In non-small cell lung cancer (NSCLC), chemoradiotherapy (CRT) yields pathological complete response (pCR) rates of approximately 30%. We investigated using ipilimumab plus nivolumab (IPI-NIVO) with neoadjuvant CRT in resectable, and borderline resectable NSCLC., Methods: This single-arm, phase-II trial enrolled operable T3-4N0-2 patients with NSCLC without oncogenic drivers. Primary study endpoints were safety, major pathological response (MPR) and pCR. Treatment encompassed platinum-doublet concurrent CRT, IPI 1 mg/kg intravenous and NIVO 360 mg intravenous on day-1, followed by chemotherapy plus NIVO 360 mg 3 weeks later. Thoracic radiotherapy was 50 or 60 Gy, in once-daily doses of 2 Gy. Resections were 6 weeks post-radiotherapy., Results: In a total of 30 patients in the intention-to-treat (ITT) population, grades 3-4 treatment-related adverse events (TRAEs) occurred in 70%, one TRAE grade 5 late-onset pneumonitis on day 96 post-surgery (1/30, 3.3%) occurred, and one non-TRAE COVID-19 death (1/30, 3.3%). pCR and MPR were achieved in 50% (15/30) and 63% (19/30) of the ITT; and in 58% (15/26) and 73% (19/26) of the 26 patients who underwent surgery, respectively. Postoperative melanoma was seen in one non-pCR patient. The R0 rate was 100% (26/26), and no patient failed surgery due to TRAEs. In peripheral blood, proliferative CD8 + T cells were increased, while proliferative regulatory T cells (Tregs) were not. On-treatment, pCR-positives had higher CD8 + CD39 + T cells and lower HLA-DR + Tregs., Conclusions: Neoadjuvant IPI-NIVO-CRT in T3-4N0-2 NSCLC showed acceptable safety with pCR and MPR in 58% and 73% of operated patients, respectively. No patient failed surgery due to TRAEs., Trial Registration Number: NCT04245514., Competing Interests: Competing interests: The authors have disclosed the following conflicts of interest: DEO-L received grants from Janssen and Curium, honoraria from EANM, EAU, ESMO, and Curium, travel support from EANM, ESMO, EAU, and Bayer, and serves on a Bayer advisory board. CD received institutional fees for advisory roles with BMS, AstraZeneca, and MSD. SMSH has research contracts with several pharmaceutical companies and received honoraria from Janssen. IB’s institution received support from BMS, AstraZeneca, and Boehringer Ingelheim, and he received honoraria from AstraZeneca, MSD, and BMS. FLS received a research grant from ViewRay and honoraria from AstraZeneca. SS’s institution received grants from Varian, ViewRay, and AstraZeneca; he received consulting fees and honoraria from AstraZeneca and MSD, and serves on advisory boards for AstraZeneca and MSD. TDdG’s institution received grants from Idera Pharmaceuticals, consulting fees from LAVA Therapeutics and Mendus, and she holds stock in LAVA Therapeutics. All other authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Blood contains multiple analytes that can be used as liquid biopsy to analyze cancer. Mutations have been detected in DNA associated with small extracellular vesicles (sEVs). The genome-wide composition and structure of sEV DNA remains poorly characterized, and whether sEVs are enriched in tumor signal compared to cell-free DNA (cfDNA) is unclear. Here, using whole-genome sequencing from lung cancer patients we determined that the tumor fraction and heterogeneity are comparable between DNA associated with sEV (<200 nm) and matched plasma cfDNA. sEV DNA, obtained with size-exclusion chromatography, is composed of short ∼150-180 bp fragments and long >1000 bp fragments poor in tumor signal. The structural patterns of sEV DNA are related to plasma cfDNA. Mitochondrial DNA is relatively enriched in the sEV fractions. Our results suggest that DNA associated to sEV (including exosomes) is not preferentially enriched in tumor signal and is less abundant than cfDNA., Competing Interests: F.M. is coinventor on patents related to cfDNA fragmentation analysis. F.M. has consulted for Roche Dx. D.M.P. is co-founder and CSO of ExBiome BV. Other coauthors have no relevant conflict of interests., (© 2024 The Author(s).)

Background: The Pacific trial reported improved outcomes when durvalumab was administered following concurrent chemoradiotherapy (CRT) for stage III NSCLC. Post-hoc subgroup analysis did not show favorable results for PD-L1 negative cases. We compared nationwide survival data with the trial outcomes, and evaluated the influence of PD-L1., Patients and Methods: Data from the Netherlands Cancer Registry were queried regarding patients with clinical stage III who underwent CRT, either by concurrent or sequential administration. Predictors for the use of consolidation treatment with durvalumab were evaluated by tabulations and logistic regression analysis. Overall survival (OS) was calculated from start of radiation or start of durvalumab and was stratified by PD-L1 score., Results: Between 2017 and 2021, application of consolidation durvalumab increased from 2% to 21%, 40%, 57%, 62%, respectively. In the period 2020-2021, durvalumab use was more frequent among patients with younger age, concurrent CRT, better performance score and proton radiation, but was irrespective of PD-L1 score. For patients receiving durvalumab (n = 1639), the 4-year OS was 53% overall (95%CI 50-57), and it was 56% (95%CI 52-60) after concurrent CRT. Four-year OS was considerably better for the PD-L1 subgroup ≧50% at 67% (95%CI 59-73), and it was similar for PD-L1 subgroups 0 and 1-49, at 51% (95%CI 42-58) and 46% (95%CI 39-54), respectively., Conclusion: In real-world clinical practice, survival outcomes were equivalent to results from trial series. Overall survival in patients with negative PD-L1 was similar to the survival in patients with PD-L1 1-49, questioning the restrictions imposed by the European Medicines Agency., Competing Interests: Disclosure IB reports research grants from AstraZeneca, Bristol-Myers Squibb and Boehringer Ingelheim, consulting fees from AstraZeneca, Bristol-Myers Squibb and Boehringer Ingelheim. SS reports participating on advisory boards for AstraZeneca, Merck Sharp & Dohme, and Varian Medical Systems; and institutional research grants from AstraZeneca, Varian Medical Systems, and ViewRay. RD declares no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The majority of patients with resected stage II-IIIA non-small cell lung cancer (NSCLC) are treated with platinum-based adjuvant chemotherapy (ACT) in a one-size-fits-all approach. However, a significant number of patients do not derive clinical benefit, and no predictive patient selection biomarker is currently available. Using mass spectrometry-based proteomics, we have profiled tumour resection material of 2 independent, multi-centre cohorts of in total 67 patients with NSCLC who underwent ACT. Unsupervised cluster analysis of both cohorts revealed a poor response/survival sub-cluster composed of ~ 25% of the patients, that displayed a strong epithelial-mesenchymal transition signature and stromal phenotype. Beyond this stromal sub-population, we identified and validated platinum response prediction biomarker candidates involved in pathways relevant to the mechanism of action of platinum drugs, such as DNA damage repair, as well as less anticipated processes such as those related to the regulation of actin cytoskeleton. Integration with pre-clinical proteomics data supported a role for several of these candidate proteins in platinum response prediction. Validation of one of the candidates (HMGB1) in a third independent patient cohort using immunohistochemistry highlights the potential of translating these proteomics results to clinical practice., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Immune-based treatment approaches are successfully used for the treatment of patients with cancer. While such therapies can be highly effective, many patients fail to benefit. To provide optimal therapy choices and to predict treatment responses, reliable biomarkers for the assessment of immune features in patients with cancer are of significant importance. Biomarkers (BM) that enable a comprehensive and repeatable assessment of the tumor microenvironment (TME), the lymphoid system, and the dynamics induced by drug treatment can fill this gap. Medical imaging, notably positron emission tomography (PET) and magnetic resonance imaging (MRI), providing whole-body imaging BMs, might deliver such BMs. However, those imaging BMs must be well characterized as being 'fit for purpose' for the intended use. This review provides an overview of the key steps involved in the development of 'fit-for-purpose' imaging BMs applicable in drug development, with a specific focus on pharmacodynamic biomarkers for assessing the TME and its modulation by immunotherapy. The importance of the qualification of imaging BMs according to their context of use (COU) as defined by the Food and Drug Administration ( FDA ) and National Institutes of Health Biomarkers, EndpointS, and other Tools ( BEST ) glossary is highlighted. We elaborate on how an imaging BM qualification for a specific COU can be achieved., Competing Interests: AT and AW were employees of Boehringer Ingelheim. JW holds stock in Quantitative Imaging Ltd. and is a Director of, and has received compensation from, Bioxydyn Ltd., a for-profit company engaged in the discovery and development of MR biomarkers and the provision of imaging biomarker services. CM reports research funding from Bristol-Myers Squibb, Boehringer Ingelheim, GSK, Pfizer, and AstraZeneca. Consultancy: GE Health Care, Novartis, Eli Lilly. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Eertink, Bahce, Waterton, Huisman, Boellaard, Wunder, Thiele and Menke-van der Houven van Oordt.)

Context: Loose tumor cells and tumor cell clusters can be recognized in the lumen of intratumoral pulmonary arteries of resected non-small cell lung cancer specimens. It is unclear whether these should be considered tumor-emboli, and as such could predict a worsened prognosis., Objective: To investigate the nature and prognostic impact of pulmonary artery intraluminal tumor cells., Design: This multicenter study involved an exploratory pilot study and a validation study from 3 institutions. For the exploratory pilot study, a retrospective pulmonary resection cohort of primary adenocarcinomas, diagnosed between November 2007 and November 2010, were scored for the presence of tumor cells, as well as potentially other cells in the intravascular spaces, using hematoxylin-eosin and cytokeratin 7 (CK7) stains. In the validation part, 2 retrospective cohorts of resected pulmonary adenocarcinomas, between January 2011 and December 2016, were included. Recurrence-free survival (RFS) and overall survival (OS) data were collected., Results: In the pilot study, CK7+ intravascular cells, mainly tumor cells, were present in 23 of 33 patients (69.7%). The 5-year OS for patients with intravascular tumor cells was 61%, compared with 40% for patients without intravascular tumor cells (P = .19). In the validation study, CK7+ intravascular tumor cells were present in 41 of 70 patients (58.6%). The 5-year RFS for patients with intravascular tumor cells was 80.0%, compared with 80.6% in patients without intravascular tumor cells (P = .52). The 5-year OS rates were, respectively, 82.8% and 71.6% (P = .16)., Conclusions: Loose tumor cells in pulmonary arterial lumina were found in most non-small cell lung cancer resection specimens and were not associated with a worse RFS or OS. Therefore, most probably they represent an artifact., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

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).)

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: PET scans using zirconium-89 labelled monoclonal antibodies ( 89 Zr-mAbs), known as 89 Zr-immuno-PET, are made to measure uptake in tumour and organ tissue. Uptake is related to the supply of 89 Zr-mAbs in the blood. Measuring activity concentrations in blood, however, requires invasive blood sampling. This study aims to identify the best delineation strategy to obtain the image-derived blood concentration (IDBC) from 89 Zr-immuno-PET scans., Methods: PET imaging and blood sampling of two 89 Zr-mAbs were included, 89 Zr-cetuximab and 89 Zr-durvalumab. For seven patients receiving 89 Zr-cetuximab, PET scans on 1-2 h, 2 and 6 days post-injection (p.i.) were analysed. Five patients received three injections of 89 Zr-durvalumab. The scanning protocol for the first two injections consisted of PET scanning on 2, 5 and 7 days p.i. and for the third injection only on 7 days p.i. Blood samples were drawn with every PET scan and the sample-derived blood concentration (SDBC) was used as gold standard for the IDBC. According to an in-house developed standard operating procedure, the aortic arch, ascending aorta, descending aorta and left ventricle were delineated. Bland-Altman analyses were performed to assess the bias (mean difference) and variability (1.96 times the standard deviation of the differences) between IDBC and SDBC., Results: Overall, the activity concentration obtained from the IDBC was lower than from the SDBC. When comparing IDBC with SDBC, variability was smallest for the ascending aorta (20.3% and 17.0% for 89 Zr-cetuximab and 89 Zr-durvalumab, respectively). Variability for the other regions ranged between 17.9 and 30.8%. Bias for the ascending aorta was - 10.9% and - 11.4% for 89 Zr-cetuximab and 89 Zr-durvalumab, respectively., Conclusions: Image-derived blood concentrations should be obtained from delineating the ascending aorta in 89 Zr-immuno-PET scans, as this results in the lowest variability with respect to sample-derived blood concentrations., (© 2024. The Author(s).)

Background: In patients with locally advanced unresectable non-small cell lung cancer (NSCLC), durvalumab, an anti-programmed cell death ligand-1 (PD-L1) antibody, has shown improved overall survival when used as consolidation therapy following concurrent chemoradiotherapy (CRT). However, it is unclear whether CRT itself upregulates PD-L1 expression. Therefore, this study aimed to explore the changes in the uptake of the anti PD-L1 antibody [ 89 Zr]Zr-durvalumab in tumors and healthy organs during CRT in patients with NSCLC., Methods: Patients with NSCLC scheduled to undergo CRT were scanned 7±1 days after administration of 37±1 MBq [ 89 Zr]Zr-durvalumab at baseline, 1-week on-treatment and 1 week after finishing 6 weeks of CRT. First, [ 89 Zr]Zr-durvalumab uptake was visually assessed in a low dose cohort with a mass dose of 2 mg durvalumab (0.13% of therapeutic dose) and subsequently, quantification was done in a high dose cohort with a mass dose of 22.5 mg durvalumab (1.5% of therapeutic dose). Tracer pharmacokinetics between injections were compared using venous blood samples drawn in the 22.5 mg cohort. Visual assessment included suspected lesion detectability. Positron emission tomography (PET) uptake in tumoral and healthy tissues was quantified using tumor to plasma ratio (TPR) and organ to plasma ratio, respectively., Results: In the 2 mg dose cohort, 88% of the 17 identified tumor lesions were positive at baseline, compared with 69% (9/13) for the 22.5 mg cohort. Although the absolute plasma concentrations between patients varied, the intrapatient variability was low. The ten quantitatively assessed lesions in the 22.5 mg cohort had a median TPR at baseline of 1.3 (IQR 0.7-1.5), on-treatment of 1.0 (IQR 0.7-1.4) and at the end of treatment of 0.7 (IQR 0.6-0.7). On-treatment, an increased uptake in bone marrow was seen in three out of five patients together with a decreased uptake in the spleen in four out of five patients., Conclusions: This study successfully imaged patients with NSCLC with [ 89 Zr]Zr-durvalumab PET before and during CRT. Our data did not show any increase in [ 89 Zr]Zr-durvalumab uptake in the tumor 1-week on-treatment and at the end of treatment. The changes observed in bone marrow and spleen may be due to an CRT-induced effect on immune cells., Trial Registration Number: EudraCT number: 2019-004284-51., Competing Interests: Competing interests: SMSH is on the advisory board and/or received institutional research support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche and Takeda. DV received institutional research support from Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Boehringer Ingelheim, Roche and Aplagon. SS is on the advisory board of AstraZeneca, receives institutional research support and a speakers fee from AstraZeneca. SS is on the advisory board of Bristol-Myers Squibb and receives institutional research support from Bristol-Myers Squibb. CWM-vdHvO is advisor for GEHealthcare and Eli Lilly and received institutional research support from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, G1 Therapeutics and Bristol-Myers Squibb., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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

Cell-free DNA (cfDNA) can be isolated and sequenced from blood and/or urine of cancer patients. Conventional short-read sequencing lacks deployability and speed and can be biased for short cfDNA fragments. Here, we demonstrate that with Oxford Nanopore Technologies (ONT) sequencing we can achieve delivery of genomic and fragmentomic data from liquid biopsies. Copy number aberrations and cfDNA fragmentation patterns can be determined in less than 24 h from sample collection. The tumor-derived cfDNA fraction calculated from plasma of lung cancer patients and urine of bladder cancer patients was highly correlated (R = 0.98) with the tumor fraction calculated from short-read sequencing of the same samples. cfDNA size profile, fragmentation patterns, fragment-end composition, and nucleosome profiling near transcription start sites in plasma and urine exhibited the typical cfDNA features. Additionally, a high proportion of long tumor-derived cfDNA fragments (> 300 bp) are recovered in plasma and urine using ONT sequencing. ONT sequencing is a cost-effective, fast, and deployable approach for obtaining genomic and fragmentomic results from liquid biopsies, allowing the analysis of previously understudied cfDNA populations., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Existing methods to detect tumor signal in liquid biopsy have focused on the analysis of nuclear cell-free DNA (cfDNA). However, non-nuclear cfDNA and in particular mitochondrial DNA (mtDNA) has been understudied. We hypothesize that an increase in mtDNA in plasma could reflect the presence of cancer, and that leveraging cell-free mtDNA could enhance cancer detection., Results: We survey 203 healthy and 664 cancer plasma samples from three collection centers covering 12 cancer types with whole genome sequencing to catalogue the plasma mtDNA fraction. The mtDNA fraction is increased in individuals with cholangiocarcinoma, colorectal, liver, pancreatic, or prostate cancer, in comparison to that in healthy individuals. We detect almost no increase of mtDNA fraction in individuals with other cancer types. The mtDNA fraction in plasma correlates with the cfDNA tumor fraction as determined by somatic mutations and/or copy number aberrations. However, the mtDNA fraction is also elevated in a fraction of patients without an apparent increase in tumor-derived cfDNA. A predictive model integrating mtDNA and copy number analysis increases the area under the curve (AUC) from 0.73 when using copy number alterations alone to an AUC of 0.81., Conclusions: The mtDNA signal retrieved by whole genome sequencing has the potential to boost the detection of cancer when combined with other tumor-derived signals in liquid biopsies., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Curative-intent treatment of superior sulcus tumors (SSTs) of the lung invading the spine presents considerable challenges. We retrospectively studied outcomes in a single center, uniformly staged patient cohort treated with induction concurrent chemoradiotherapy followed by surgical resection (trimodality therapy)., Methods: An institutional surgical database from the period between 2002 and 2021 was accessed to identify SSTs in which the resection included removal of at least part of the vertebral body. All patients were staged using fluorodeoxyglucose positron emission tomography (/computed tomography), computed tomography scan of the chest/upper abdomen, and brain imaging. Surgical morbidity was assessed using the Clavien-Dindo classification. Overall and disease-free survival were calculated using the Kaplan-Meier method., Results: A total of 18 patients were included: 8 complete and 10 partial vertebrectomies were performed, with six of the eight complete vertebrectomies involving two vertebral levels, resulting in Complete surgical resection (R0) in 94%. Nine patients had a 1-day procedure, and nine were staged over 2 days. The median follow-up was 30 months (interquartile range 11-57). The 90-day postoperative morbidity was 44% (grade III/IV), with no 90-day surgery-related mortality. There were 83% who had a major pathologic response, associated with improved survival ( p  = 0.044). The 5-year overall and disease-free survival were 55% and 40%, respectively. Disease progression occurred in 10 patients, comprising locoregional recurrences in two and distant metastases in eight patients., Conclusions: Multimodality treatment in selected patients with a superior sulcus tumor invading the spine is safe and results in good survival. Such patients should be referred to expert centers. Future research should focus on improving distant control (e.g. [neo]adjuvant immunotherapy)., (© 2023 The Authors.)

Liquid biopsy approaches offer a promising technology for early and minimally invasive cancer detection. Tumor-educated platelets (TEPs) have emerged as a promising liquid biopsy biosource for the detection of various cancer types. In this study, we processed and analyzed the TEPs collected from 466 Non-small Cell Lung Carcinoma (NSCLC) patients and 410 asymptomatic individuals (controls) using the previously established thromboSeq protocol. We developed a novel particle-swarm optimization machine learning algorithm which enabled the selection of an 881 RNA biomarker panel (AUC 0.88). Herein we propose and validate in an independent cohort of samples (n = 558) two approaches for blood samples testing: one with high sensitivity (95% NSCLC detected) and another with high specificity (94% controls detected). Our data explain how TEP-derived spliced RNAs may serve as a biomarker for minimally-invasive clinical blood tests, complement existing imaging tests, and assist the detection and management of lung cancer patients., (© 2023. The Author(s).)