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OBJECTIVES: This study aims to externally validate a commercially available Computer-Aided Detection (CAD)-system for the automatic detection and characterization of solid, part-solid, and ground-glass lung nodules (LN) on CT scans. METHODS: This retrospective study encompasses 263 chest CT scans performed between January 2020 and December 2021 at a Dutch university hospital. All scans were read by a radiologist (R1) and compared with the initial radiology report. Conflicting scans were assessed by an adjudicating radiologist (R2). All scans were also processed by CAD. The standalone performance of CAD in terms of sensitivity and false-positive (FP)-rate for detection was calculated together with the sensitivity for characterization, including texture, calcification, speculation, and location. The R1's detection sensitivity was also assessed. RESULTS: A total of 183 true nodules were identified in 121 nodule-containing scans (142 non-nodule-containing scans), of which R1 identified 165/183 (90.2%). CAD detected 149 nodules, of which 12 were not identified by R1, achieving a sensitivity of 149/183 (81.4%) with an FP-rate of 49/121 (0.405). CAD's detection sensitivity for solid, part-solid, and ground-glass LNs was 82/94 (87.2%), 42/47 (89.4%), and 25/42 (59.5%), respectively. The classification accuracy for solid, part-solid, and ground-glass LNs was 81/82 (98.8%), 16/42 (38.1%), and 18/25 (72.0%), respectively. Additionally, CAD demonstrated overall classification accuracies of 137/149 (91.9%), 123/149 (82.6%), and 141/149 (94.6%) for calcification, spiculation, and location, respectively. CONCLUSIONS: Although the overall detection rate of this system slightly lags behind that of a radiologist, CAD is capable of detecting different LNs and thereby has the potential to enhance a reader's detection rate. While promising characterization performances are obtained, the tool's performance in terms of texture classification remains a subject of concern. CLINICAL RELEVANCE STATEMENT: Numerous lung nodule computer-aided detection-systems are commercially available, with some of them solely being externally validated based on their detection performance on solid nodules. We encourage researchers to assess performances by incorporating all relevant characteristics, including part-solid and ground-glass nodules. KEY POINTS: Few computer-aided detection (CAD) systems are externally validated for automatic detection and characterization of lung nodules. A detection sensitivity of 81.4% and an overall texture classification sensitivity of 77.2% were measured utilizing CAD. CAD has the potential to increase single reader detection rate, however, improvement in texture classification is required.
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PURPOSE: Immunotherapies have shown limited responses in patients with advanced pancreatic cancer. Recently, we reported that dendritic cell (DC)-based immunotherapy induced T-cell responses against pancreatic cancer antigens. The primary objective of this study was to determine the efficacy of DC-based immunotherapy to prevent recurrence of disease. METHODS: This was a single-center, open-label, single-arm, combined phase I/II trial. The primary end point was the 2-year recurrence-free survival (RFS) rate. A 2-year RFS rate of ≥60% was defined as a clinically meaningful improvement. We included patients with pancreatic cancer after resection and completion of standard-of-care (SOC) treatment without recurrent disease on cross-sectional imaging. Patients were treated with autologous DCs pulsed with an allogeneic mesothelioma tumor cell lysate, comprising antigens also expressed in pancreatic ductal adenocarcinoma. RESULTS: Thirty-eight patients were included in the analysis of the primary end point (47% male, 53% female). The median age was 62 years (IQR, 55-68). Twenty-eight patients (74%) received five DC vaccinations and completed the study protocol. Three patients (8%) received four vaccinations, and seven patients (16%) received three vaccinations. After a median follow-up of 25.5 months, 26 patients (68%) had not developed recurrence of disease. The estimated 2-year RFS was 64%. Vaccination led to the enrichment of circulating activated CD4+ T cells and the detection of treatment-induced immune responses in vitro. T-cell receptor-sequencing analyses of a resected solitary lung metastasis showed influx of vaccine-specific T cells. CONCLUSION: This study reached its primary end point of a 2-year RFS rate of ≥60% following pancreatectomy after SOC treatment and adjuvant DC-based immunotherapy in patients with pancreatic cancer. These results warrant a future randomized trial.
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Peritoneal mesothelioma (PeM) is an aggressive tumor with limited treatment options. The current study aimed to evaluate the value of next generation sequencing (NGS) of PeM samples in current practice. Foundation Medicine F1CDx NGS was performed on 20 tumor samples. This platform assesses 360 commonly somatically mutated genes in solid tumors and provides a genomic signature. Based on the detected mutations, potentially effective targeted therapies were identified. NGS was successful in 19 cases. Tumor mutational burden (TMB) was low in 10 cases, and 11 cases were microsatellite stable. In the other cases, TMB and microsatellite status could not be determined. BRCA1 associated protein 1 (BAP1) mutations were found in 32% of cases, cyclin dependent kinase inhibitor 2A/B (CDKN2A/B) and neurofibromin 2 (NF2) mutations in 16%, and ataxia-telangiectasia mutated serine/threonine kinase (ATM) in 11%. Based on mutations in the latter two genes, potential targeted therapies are available for approximately a quarter of cases (i.e., protein kinase inhibitors for three NF2 mutated tumors, and polyADP-ribose polymerase inhibitors for two ATM mutated tumors). Extensive NGS analysis of PeM samples resulted in the identification of potentially effective targeted therapies for about one in four patients. Although these therapies are currently not available for patients with PeM, ongoing developments might result in new treatment options in the future.
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Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Peritoneais , Humanos , Mesotelioma/diagnóstico , Mesotelioma/tratamento farmacológico , Mesotelioma/genética , Neoplasias Pulmonares/genética , Mutação , Genômica , Biomarcadores Tumorais/genética , Neoplasias Peritoneais/diagnóstico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/genéticaRESUMO
Identification of immunogenic cancer neoantigens as targets for therapy is challenging. Here, we integrate the whole-genome and long-read transcript sequencing of cancers to identify the collection of neo-open reading frame peptides (NOP) expressed in tumors. We termed this collection of NOPs the tumor framome. NOPs represent tumor-specific peptides that are different from wild-type proteins and may be strongly immunogenic. We describe a class of hidden NOPs that derive from structural genomic variants involving an upstream protein coding gene driving expression and translation of noncoding regions of the genome downstream of a rearrangement breakpoint, i.e., where no gene annotation or evidence for transcription exists. The entire collection of NOPs represents a vast number of possible neoantigens particularly in tumors with many structural genomic variants and a low number of missense mutations. We show that NOPs are immunogenic and epitopes derived from NOPs can bind to MHC class I molecules. Finally, we provide evidence for the presence of memory T cells specific for hidden NOPs in peripheral blood from a patient with lung cancer. This work highlights NOPs as a major source of possible neoantigens for personalized cancer immunotherapy and provides a rationale for analyzing the complete cancer genome and transcriptome as a basis for the detection of NOPs.
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Antígenos de Neoplasias , Imunoterapia , Neoplasias , Fases de Leitura Aberta , Humanos , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/genética , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Peptídeos/imunologiaRESUMO
INTRODUCTION: For patients with KRASG12C-mutated NSCLC who are treated with sotorasib, there is a lack of biomarkers to guide treatment decisions. We therefore investigated the clinical utility of pretreatment and on-treatment circulating tumor DNA (ctDNA) and treatment-emergent alterations on disease progression. METHODS: Patients with KRASG12C-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker study (NCT05221372). Plasma samples were collected before sotorasib treatment, at first-response evaluation and at disease progression. The TruSight Oncology 500 panel was used for ctDNA and variant allele frequency analysis. Tumor response and progression-free survival were assessed per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Pretreatment KRASG12C ctDNA was detected in 50 of 66 patients (76%). Patients with detectable KRASG12C had inferior progression-free survival (hazard ratio [HR] 2.13 [95% confidence interval [CI]: 1.06-4.30], p = 0.031) and overall survival (HR 2.61 [95% CI: 1.16-5.91], p = 0.017). At first-response evaluation (n = 40), 29 patients (73%) had a molecular response. Molecular nonresponders had inferior overall survival (HR 3.58 [95% CI: 1.65-7.74], p = 0.00059). The disease control rate was significantly higher in those with a molecular response (97% versus 64%, p = 0.015). KRAS amplifications were identified as recurrent treatment-emergent alterations. CONCLUSIONS: Our data suggest detectable pretreatment KRASG12C ctDNA as a marker for poor prognosis and on-treatment ctDNA clearance as a marker for treatment response. We identified KRAS amplifications as a potential recurring resistance mechanism to sotorasib. Identifying patients with superior prognosis could aid in optimizing time of treatment initiation, and identifying patients at risk of early progression could allow for earlier treatment decisions.
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Carcinoma Pulmonar de Células não Pequenas , DNA Tumoral Circulante , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas p21(ras) , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/sangue , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/sangue , Mutação , Piperazinas/uso terapêutico , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridinas/uso terapêutico , Pirimidinas/uso terapêuticoRESUMO
BACKGROUND: Sotorasib given after immunotherapy could put patients at increased risk of hepatotoxicity. Therefore, there is a need to gain insight into the potential correlation between anti-PD-(L)1 treatment, anti-PD-(L)1 concentrations, sotorasib concentrations, and the incidence of hepatotoxicity during sotorasib. METHODS: Patients with KRASG12C-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker cohort study (NCT05221372). Plasma samples were collected prior and during sotorasib treatment for anti-PD-1 and sotorasib concentrations. ALT/AST/ALP/GGT increases were collected prospectively and graded according to CTCAEv5.0. Severe hepatotoxicity was defined as grade ≥3 ALT/AST/ALP/GGT increase. FINDINGS: Of the 91 included patients, 80 (88%) received prior anti-PD-(L)1. Prior anti-PD-(L)1 and prior immune-related hepatotoxicity were associated with a higher incidence of severe hepatotoxicity (35% versus 0%, p = 0.016 and 75% versus 31%, p = 0.019, respectively). Patients with an interval of ≤6 weeks between anti-PD-(L)1 and sotorasib (n = 18) had a significantly higher incidence of severe hepatotoxicity than those with a 6-12 week (n = 24) and ≥12 week (n = 38) interval (83% versus 33% versus 13%, respectively, p < 0.0001). Sotorasib trough concentrations did not differ significantly between those with or without severe hepatotoxicity (106 versus 126 ng/mL, p = 0.16). Pembrolizumab concentrations were higher in those with severe hepatotoxicity versus those without (25.6 versus 6.1 µg/mL, p < 0.0001). INTERPRETATION: In this preliminary prospective study, sotorasib after PD-(L)1 blockade was associated with severe hepatotoxicity, especially in patients with a short interval between treatments, prior immune-related hepatitis and higher anti-PD-1 plasma concentrations. Our results suggest a minimum interval of 6 weeks between anti-PD-(L)1 and sotorasib to minimize the risk of hepatotoxicity. FUNDING: None.
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Carcinoma Pulmonar de Células não Pequenas , Doença Hepática Induzida por Substâncias e Drogas , Neoplasias Pulmonares , Piperazinas , Piridinas , Pirimidinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos de Coortes , Neoplasias Pulmonares/tratamento farmacológico , Estudos Prospectivos , Imunoterapia/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Proteínas Proto-Oncogênicas p21(ras) , MutaçãoAssuntos
Anticorpos Biespecíficos , Neoplasias Pulmonares , Humanos , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/metabolismo , Fatores de Crescimento Endotelial , Receptor de Morte Celular Programada 1 , Fator A de Crescimento do Endotélio VascularRESUMO
PURPOSE: Amid the need for new approaches to improve survival in pancreatic ductal adenocarcinoma (PDAC), immune-based therapies have garnered interest. Rintatolimod, a Toll-like receptor 3 (TLR-3) agonist, is a potential candidate due to its dual impact on restraining PDAC cell functions and boosting the antitumor immune response. This study investigates the effect of TLR-3 activation through rintatolimod on the peripheral immune landscape of patients with advanced PDAC. EXPERIMENTAL DESIGN: Paired blood samples of 30 patients with advanced PDAC, collected at baseline and after 12 rintatolimod intravenous infusions, underwent comprehensive transcriptomic NanoString and proteomic flow cytometry profiling. The impact of rintatolimod and immunologic factors on survival outcomes was assessed through univariate Cox proportional hazards models. RESULTS: Rintatolimod treatment enhances peripheral immune activity at the transcriptomic and proteomic levels, particularly involving type 1 conventional dendritic cells (cDC1) and T cells. Post-rintatolimod, the increased peripheral abundance of BTLA+ XCR1+ cDC1s and CD4+SELL+ T cells correlated with improved clinical outcomes. Patients with stable disease exhibited pronouncedDCand T-cell activation gene overexpression. Notably, the expression of immune checkpoints PD-L1 and PD-L2 decreased post-rintatolimod across all patients. However, those with progressive disease showed increased expression of genes encoding IDO1 and PD-1. CONCLUSIONS: This study presents compelling evidence of the immune-stimulatory properties linked to TLR-3 activation through rintatolimod. Rintatolimod may break immunologic tolerance by enhancing antitumor immunity through DC-mediated Th-cell responses. Furthermore, our findings lay the groundwork for investigating the potential synergy between TLR-3 activation and immune checkpoint inhibitor therapy to improve therapeutic outcomes. See related commentary by Martínez-Riaño et al., p. 3355.
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Células Dendríticas , Neoplasias Pancreáticas , Humanos , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Feminino , Masculino , Receptor 3 Toll-Like/agonistas , Pessoa de Meia-Idade , Idoso , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologiaRESUMO
BACKGROUND: Patient experiences with COVID-19 aftercare remain largely unknown. We evaluated COVID-19 aftercare from a patient perspective one year after hospitalization, assessing satisfaction and its associated factors, and unmet needs. METHODS: The Satisfaction with COVID-19 Aftercare Questionnaire (SCAQ) was developed as part of a multicenter prospective cohort study and administered one year after hospital discharge. The SCAQ assesses (1) patient satisfaction, comprising information provision, rehabilitation, follow-up by hospitals and general practitioners (GPs), the most important aftercare topics, and overall satisfaction, and (2) unmet needs. RESULTS: 487/561 (87%) COVID-19 patients completed the SCAQ, all had been discharged from the hospital between March 2020 and May 2021. Among responders, the median age of patients was 60 (IQR 54-67) years, 338 (69%) were male, and the median length of stay in the hospital was 13 (6-27) days. Patients were least satisfied with information on who could be contacted with questions when health problems arise (59% satisfied or very satisfied). Many patients (75%) received rehabilitation, most frequently community-based (70%). Across the different community-based therapies, ≥ 60% of patients were satisfied with shared-decision making and ≥ 70% with the received therapy; a majority (≥ 79%) indicated a preference for receiving the same therapy again if needed. Regarding follow-up by hospitals, 86% of patients received this follow-up, most frequently visiting a pulmonologist (96%), being generally satisfied with the received aftercare. Aftercare from GPs was received by 39% of patients, with 88% being satisfied with the GP's availability and 79% with referral to appropriate aftercare providers. Patients (> 50%) considered information-related items most important in aftercare. Overall, patients rated their satisfaction with aftercare 8/10 (7-9) points. Those who received medical rehabilitation (versus no rehabilitation, adjusted beta 0.61 [95%CI 0.11 to 1.11], p = 0.02) or aftercare by a hospital medical specialist (1.1 [0.46 to 1.64], p < 0.001) or GP (0.39 [0.053 to 0.72], p = 0.023) reported significantly higher satisfaction than those without such aftercare. Unmet needs were reported by 35% of patients, with lack of information (20%) and lack of additional aftercare and/or involvement of their GP (19%) being the most frequently reported. CONCLUSION: Despite the forced quick development of COVID-19 aftercare, patients were generally satisfied. Follow-up by healthcare professionals and information provision is important to meet patients' aftercare needs.
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Assistência ao Convalescente , COVID-19 , Feminino , Humanos , Masculino , COVID-19/terapia , Hospitalização , Satisfação do Paciente , Estudos Prospectivos , Pessoa de Meia-Idade , IdosoRESUMO
OBJECTIVES: Various mechanisms, such as immune dysregulation, viral reservoir, and auto-immunity, are hypothesized to underlie the pathogenesis of long-term health problems after hospitalization for COVID-19. We aimed to assess the effect of in-hospital COVID-19 treatments on prominent long-term health problems. METHODS: In this prospective multicenter cohort study, we enrolled patients (age ≥18 years) who had been hospitalized for COVID-19 in the Netherlands between July 2020 and October 2021. We retrospectively collected data on in-hospital COVID-19 treatments, including steroid, anti-inflammatory, and antiviral treatments. Patients completed questionnaires on self-reported recovery, dyspnea, fatigue, cognitive failures, and health-related quality of life and performed the 6-minute walk test at the 2-year follow-up visit. RESULTS: Five hundred two patients with COVID-19 were included, all were discharged from the hospital between March 2020 and June 2021. The median age at admission was 60.0 (IQR 53.0-68.0) years and 350 (69.7%) patients were male. At hospital admission, 5/405 (1.2%) of the patients had been vaccinated against SARS-CoV-2. Among all 502 patients, the majority (248 [49.4%]) received steroids only, 57 (11.4%) anti-inflammatory treatment, 78 (15.5%) antiviral treatment, and 119 (23.7%) none during hospitalization. Long-term health problems were common in all groups. We found that in-hospital treatments were not significantly associated with health problems at 2 years after hospital discharge, nor after adjusting for confounders. CONCLUSION: Many patients with COVID-19 suffer from long-term health problems 2 years after hospital discharge. Acute treatment for COVID-19 is not associated with long-term health problems.
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COVID-19 , Feminino , Humanos , Masculino , Anti-Inflamatórios , Antivirais/uso terapêutico , Estudos de Coortes , Tratamento Farmacológico da COVID-19 , Hospitalização , Estudos Prospectivos , Qualidade de Vida , Estudos Retrospectivos , SARS-CoV-2 , Pessoa de Meia-Idade , IdosoRESUMO
PURPOSE: The clinical value of STK11, KEAP1, and EGFR alterations for guiding immune checkpoint blockade (ICB) therapy in non-small cell lung cancer (NSCLC) remains controversial, as some patients with these proposed resistance biomarkers show durable ICB responses. More specific combinatorial biomarker approaches are urgently needed for this disease. EXPERIMENTAL DESIGN: To develop a combinatorial biomarker strategy with increased specificity for ICB unresponsiveness in NSCLC, we performed a comprehensive analysis of 254 patients with NSCLC treated with ligand programmed death-ligand 1 (PD-L1) blockade monotherapy, including a discovery cohort of 75 patients subjected to whole-genome sequencing (WGS), and an independent validation cohort of 169 patients subjected to tumor-normal large panel sequencing. The specificity of STK11/KEAP1/EGFR alterations for ICB unresponsiveness was assessed in the contexts of a low (<10 muts/Mb) or high (≥10 muts/Mb) tumor mutational burden (TMB). RESULTS: In low TMB cases, STK11/KEAP1/EGFR alterations were highly specific biomarkers for ICB resistance, with 0/15 (0.0%) and 1/34 (2.9%) biomarker-positive patients showing treatment benefit in the discovery and validation cohorts, respectively. This contrasted with high TMB cases, where 11/13 (85%) and 15/34 (44%) patients with at least one STK11/KEAP1/EGFR alteration showed durable treatment benefit in the discovery and validation cohorts, respectively. These findings were supported by analyses of progression-free survival and overall survival. CONCLUSIONS: The unexpected ICB responses in patients carrying resistance biomarkers in STK11, KEAP1, and EGFR were almost exclusively observed in patients with a high TMB. Considering these alterations in context, the TMB offered a highly specific combinatorial biomarker strategy for limiting overtreatment in NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Ligantes , Mutação , Fator 2 Relacionado a NF-E2/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/uso terapêutico , Imunoterapia , Genômica , Receptores ErbB/genética , Antígeno B7-H1/genéticaRESUMO
OBJECTIVE: We aimed to perform an early cost-effectiveness analysis of using a whole-genome sequencing-based tumor mutation burden (WGS-TMB), instead of programmed death-ligand 1 (PD-L1), for immunotherapy treatment selection in patients with non-squamous advanced/metastatic non-small cell lung cancer ineligible for targeted therapy, from a Dutch healthcare perspective. METHODS: A decision-model simulating individual patients with metastatic non-small cell lung cancer was used to evaluate diagnostic strategies to select first-line immunotherapy only or the immunotherapy plus chemotherapy combination. Treatment was selected using PD-L1 [A, current practice], WGS-TMB [B], and both PD-L1 and WGS-TMB [C]. Strategies D, E, and F take into account a patient's disease burden, in addition to PD-L1, WGS-TMB, and both PD-L1 and WGS-TMB, respectively. Disease burden was defined as a fast-growing tumor, a high number of metastases, and/or weight loss. A threshold of 10 mutations per mega-base was used to classify patients into TMB-high and TMB-low groups. Outcomes were discounted quality-adjusted life-years (QALYs) and healthcare costs measured from the start of first-line treatment to death. Healthcare costs includes drug acquisition, follow-up costs, and molecular diagnostic tests (i.e., standard diagnostic techniques and/or WGS for strategies involving TMB). Results were reported using the net monetary benefit at a willingness-to-pay threshold of 80,000/QALY. Additional scenario and threshold analyses were performed. RESULTS: Strategy B had the lowest QALYs (1.84) and lowest healthcare costs (120,800). The highest QALYs and healthcare costs were 2.00 and 140,400 in strategy F. In the base-case analysis, strategy A was cost effective with the highest net monetary benefit (27,300), followed by strategy B (26,700). Strategy B was cost effective when the cost of WGS testing was decreased by at least 24% or when immunotherapy results in an additional 0.5 year of life gained or more for TMB high compared with TMB low. Strategies C and F, which combined TMB and PD-L1 had the highest net monetary benefit (≥ 76,900) when the cost of WGS testing, immunotherapy, and chemotherapy acquisition were simultaneously reduced by at least 47%, 39%, and 43%, respectively. Furthermore, strategy C resulted in the highest net monetary benefit (≥ 39,900) in a scenario where patients with both PD-L1 low and TMB low were treated with chemotherapy instead of immunotherapy plus chemotherapy. CONCLUSIONS: The use of WGS-TMB is not cost effective compared to PD-L1 for immunotherapy treatment selection in non-squamous metastatic non-small cell lung cancer in the Netherlands. WGS-TMB could become cost effective provided there is a reduction in the cost of WGS testing or there is an increase in the predictive value of WGS-TMB for immunotherapy effectiveness. Alternatively, a combination strategy of PD-L1 testing with WGS-TMB would be cost effective if used to support the choice to withhold immunotherapy in patients with a low expected benefit of immunotherapy.
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Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Análise de Custo-Efetividade , Antígeno B7-H1 , Biomarcadores Tumorais , Análise Custo-BenefícioRESUMO
BACKGROUND: FOLFIRINOX chemotherapy has improved outcomes for pancreatic cancer patients, but poor long-term survival outcomes and high toxicity remain challenges. This study investigates the impact of FOLFIRINOX on plasma proteins and peripheral immune cells to guide immune-based combination therapies and, ideally, to identify a potential biomarker to predict early disease progression during FOLFIRINOX. METHODS: Blood samples were collected from 86 pancreatic cancer patients before and two weeks after the first FOLFIRINOX cycle and subjected to comprehensive immune cell and proteome profiling. Principal Component Analysis and Linear Mixed Effect Regression models were used for data analysis. FOLFIRINOX efficacy was radiologically evaluated after the fourth cycle. RESULTS: One cycle of FOLFIRINOX diminished tumour-cell-related pathways and enhanced pathways related to immune activation, illustrated by an increase in pro-inflammatory IL-18, IL-15, and TNFRSF4. Similarly, FOLFIRINOX promoted the activation of CD4 + and CD8 + T cells, the proliferation of NK(T), and the activation of antigen-presenting cells. Furthermore, high pre-treatment levels of VEGFA and PRDX3 and an elevation in FCRL3 levels after one cycle predicted early progression under FOLFIRINOX. Finally, patients with progressive disease exhibited high levels of inhibitory markers on B cells and CD8 + T cells, while responding patients exhibited high levels of activation markers on CD4 + and CD8 + T cell subsets. CONCLUSION: FOLFIRINOX has immunomodulatory effects, providing a foundation for clinical trials exploring immune-based combination therapies that harness the immune system to treat pancreatic cancer. In addition, several plasma proteins hold potential as circulating predictive biomarkers for early prediction of FOLFIRINOX response in patients with pancreatic cancer.
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Neoplasias Pancreáticas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Irinotecano/uso terapêutico , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Proteínas SanguíneasRESUMO
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and is resistant to immunotherapy. B cells play an essential role in PDAC progression and immune responses, both locally and systemically. Moreover, increasing evidence suggests that microbial compositions inside the tumor, as well as in the oral cavity and the gut, are important factors in shaping the PDAC immune landscape. However, the gut-associated lymphoid tissue (GALT) has not previously been explored in PDAC patients. In this study, we analyzed healthy vermiform appendix (VA) from 20 patients with PDAC and 32 patients with colon diseases by gene expression immune profiling, flow cytometry analysis, and microbiome sequencing. We show that the VA GALT of PDAC patients exhibits markers of increased inflammation and cytotoxic cell activity. In contrast, B cell function is decreased in PDAC VA GALT based on gene expression profiling; B cells express significantly fewer MHC class II surface receptors, whereas plasma cells express the immune checkpoint molecule HLA-G. Additionally, the vermiform appendix microbiome of PDAC patients is enriched with Klebsiella pneumoniae, Bifidobacterium animalis, and Adlercreutzia equolifaciens, while certain commensals are depleted. Our findings may suggest impaired B cell function within the GALT of PDAC patients, which could potentially be linked to microbial dysbiosis. Additional investigations are imperative to validate our observations and explore these potential targets of future therapies.
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Apêndice , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Apêndice/microbiologia , Apêndice/patologia , Disbiose , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Antígenos HLA-GRESUMO
BACKGROUND AND OBJECTIVE: Bronchiectasis is a frequent incidental finding on chest computed tomography (CT), but its relevance in lung cancer screening is not fully understood. We investigated the association between bronchiectasis and respiratory symptoms, pulmonary function, and emphysema in lung cancer screening participants with and without chronic obstructive pulmonary disease (COPD). METHODS: We included 3260 (ex-)smokers from the Dutch-Belgian lung cancer screening trial (NELSON). Bronchiectasis was scored by chest radiologists. The relationship with pulmonary function (FEV1%predicted, FEV1/FVC), respiratory complaints (cough, dyspnea, wheezing, mucus hypersecretion), and CT-quantified emphysema (15th percentile) was examined with independent t-tests and multivariate regression. RESULTS: Bronchiectasis was present in 5.4% (n = 175/3260). There was no difference in prevalence between subjects with and without COPD (68/1121 [5.9%] vs. 109/2139 [5.1%]; p = .368). COPD subjects with bronchiectasis had a lower FEV1%predicted (76.2% vs. 85.0%; p < .001), lower FEV1/FVC (0.58 vs. 0.62; p < .001), and more emphysema (- 938 HU vs. - 930 HU; p = .001) than COPD subjects without bronchiectasis. In COPD subjects, bronchiectasis was independently associated with a lower FEV1%predicted (B = - 7.7; CI [- 12.3, - 3.3]), lower FEV1/FVC (B = - 2.5; CI [- 4.3, - 0.8]), more cough (OR 2.4; CI [1.3, 4.3]), more mucus hypersecretion (OR 1.8; CI [1.0, 3.1]) and more dyspnea (OR 2.3; CI [1.3, 3.9]). In those without COPD (n = 2139), bronchiectasis was associated with more cough, mucus hypersecretion, and wheezing, but not with deteriorating lung function. CONCLUSION: Bronchiectasis was present in 5.4% of our lung cancer screening participants and was associated with more respiratory symptoms and, in those with COPD, with lower lung function and more emphysema. CLINICAL RELEVANCE STATEMENT: In a lung cancer screening population, bronchiectasis has a prevalence of 5.4% with a mainly mild severity. This finding is of little clinical relevance unless mild COPD is also present. In those subjects, bronchiectasis was associated with a lower lung function, more respiratory symptoms, and more emphysema. KEY POINTS: ⢠Bronchiectasis was found in 5.4% of lung cancer screening participants, consisting of (ex-)smokers with and without mild COPD. ⢠In those with mild COPD, bronchiectasis was associated with a lower lung function, more respiratory symptoms, and more emphysema. ⢠Incidental findings of mild bronchiectasis are not very relevant in a lung cancer screening population, unless COPD is also present.
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Background: Many patients with SARS-CoV-2 infection develop long COVID with fatigue as one of the most disabling symptoms. We performed clinical and immune profiling of fatigued and non-fatigued long COVID patients and age- and sex-matched healthy controls (HCs). Methods: Long COVID symptoms were assessed using patient-reported outcome measures, including the fatigue assessment scale (FAS, scores ≥22 denote fatigue), and followed up to one year after hospital discharge. We assessed inflammation-related genes in circulating monocytes, serum levels of inflammation-regulating cytokines, and leukocyte and lymphocyte subsets, including major monocyte subsets and senescent T-lymphocytes, at 3-6 months post-discharge. Results: We included 37 fatigued and 36 non-fatigued long COVID patients and 42 HCs. Fatigued long COVID patients represented a more severe clinical profile than non-fatigued patients, with many concurrent symptoms (median 9 [IQR 5.0-10.0] vs 3 [1.0-5.0] symptoms, p<0.001), and signs of cognitive failure (41%) and depression (>24%). Immune abnormalities that were found in the entire group of long COVID patients were low grade inflammation (increased inflammatory gene expression in monocytes, increased serum pro-inflammatory cytokines) and signs of T-lymphocyte senescence (increased exhausted CD8+ TEMRA-lymphocytes). Immune profiles did not significantly differ between fatigued and non-fatigued long COVID groups. However, the severity of fatigue (total FAS score) significantly correlated with increases of intermediate and non-classical monocytes, upregulated gene levels of CCL2, CCL7, and SERPINB2 in monocytes, increases in serum Galectin-9, and higher CD8+ T-lymphocyte counts. Conclusion: Long COVID with fatigue is associated with many concurrent and persistent symptoms lasting up to one year after hospitalization. Increased fatigue severity associated with stronger signs of monocyte activation in long COVID patients and potentially point in the direction of monocyte-endothelial interaction. These abnormalities were present against a background of immune abnormalities common to the entire group of long COVID patients.
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COVID-19 , Linfócitos T , Humanos , Monócitos , COVID-19/complicações , Síndrome de COVID-19 Pós-Aguda , Assistência ao Convalescente , SARS-CoV-2 , Alta do Paciente , Fadiga , Citocinas , Inflamação/complicaçõesRESUMO
Background: Bacterial colonization (BC) of the lower airways is common in lung transplant recipients (LTRs) and increases the risk of chronic lung allograft dysfunction. Diagnosis often requires bronchoscopy. Exhaled breath analysis using electronic nose (eNose) technology may noninvasively detect BC in LTRs. Therefore, we aimed to assess the diagnostic accuracy of an eNose to detect BC in LTRs. Methods: We performed a cross-sectional analysis within a prospective, single-center cohort study assessing the diagnostic accuracy of detecting BC using eNose technology in LTRs. In the outpatient clinic, consecutive LTR eNose measurements were collected. We assessed and classified the eNose measurements for the presence of BC. Using supervised machine learning, the diagnostic accuracy of eNose for BC was assessed in a random training and validation set. Model performance was evaluated using receiver operating characteristic analysis. Results: In total, 161 LTRs were included with 80 exclusions because of various reasons. Of the remaining 81 patients, 16 (20%) were classified as BC and 65 (80%) as non-BC. eNose-based classification of patients with and without BC provided an area under the curve of 0.82 in the training set and 0.97 in the validation set. Conclusions: Exhaled breath analysis using eNose technology has the potential to noninvasively detect BC.
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In order to prevent long-term immunity-related complications after lung transplantation, close monitoring of immunosuppressant levels using therapeutic drug monitoring (TDM) is paramount. Novel electronic nose (eNose) technology may be a non-invasive alternative to the current invasive procedures for TDM. We investigated the diagnostic and categorization capacity of eNose breathprints for Tacrolimus trough blood plasma levels (TACtrough) in lung transplant recipients (LTRs). We performed eNose measurements in stable LTR attending the outpatient clinic. We evaluated (1) the correlation between eNose measurements and TACtrough, (2) the diagnostic capacity of eNose technology for TACtrough, and (3) the accuracy of eNose technology for categorization of TACtroughinto three clinically relevant categories (low: <7µg ml-1, medium: 7-10µg ml-1, and high: >10µg ml-1). A total of 186 measurements from 86 LTR were included. There was a weak but statistically significant correlation (r= 0.21,p= 0.004) between the eNose measurements and TACtrough. The root mean squared error of prediction for the diagnostic capacity was 3.186 in the training and 3.131 in the validation set. The accuracy of categorization ranged between 45%-63% for the training set and 52%-69% in the validation set. There is a weak correlation between eNose breathprints and TACtroughin LTR. However, the diagnostic as well as categorization capacity for TACtroughusing eNose breathprints is too inaccurate to be applicable in TDM.
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Transplante de Pulmão , Tacrolimo , Humanos , Monitoramento de Medicamentos , Testes Respiratórios/métodos , Nariz EletrônicoRESUMO
BACKGROUND: Malignant peritoneal mesothelioma (MPM) is an aggressive malignancy with a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival outcomes, but recurrence rates remain high. Dendritic cell-based immunotherapy (DCBI) showed promising results in patients with pleural mesothelioma. The primary aim of this trial was to determine feasibility of adjuvant DCBI after CRS-HIPEC. METHODS: This open-label, single-center, phase II clinical trial, performed in the Erasmus MC Cancer Institute Rotterdam, the Netherlands, included patients with epithelioid MPM. 4-6 weeks before CRS-HIPEC leukapheresis was performed. 8-10 weeks after surgery, DCBI was administered three times biweekly. Feasibility was defined as administration of at least three adjuvant vaccinations in 75% of patients. Comprehensive immune cell profiling was performed on peripheral blood samples prior to and during treatment. RESULTS: All patients who received CRS-HIPEC (n=16) were successfully treated with adjuvant DCBI. No severe toxicity related to DCBI was observed. Median progression-free survival (PFS) was 12 months (IQR 5-23) and median overall survival was not reached. DCBI was associated with increased proliferation of circulating natural killer cells and CD4+ T-helper (Th) cells. Co-stimulatory molecules, including ICOS, HLA-DR, and CD28 were upregulated predominantly on memory or proliferating Th-cells and minimally on CD8+ cytotoxic T-lymphocytes (CTLs) after treatment. However, an increase in CD8+ terminally differentiated effector memory (Temra) cells positively correlated with PFS, whereas co-expression of ICOS and Ki67 on CTLs trended towards a positive correlation. CONCLUSIONS: Adjuvant DCBI after CRS-HIPEC in patients with MPM was feasible and safe, and showed promising survival outcomes. DCBI had an immune modulatory effect on lymphoid cells and induced memory T-cell activation. Moreover, an increase of CD8+ Temra cells was more pronounced in patients with longer PFS. These data provide rationale for future combination treatment strategies. TRIAL REGISTRATION NUMBER: NTR7060; Dutch Trial Register (NTR).