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The growing scale and dimensionality of multiplexed imaging require reproducible and comprehensive yet user-friendly computational pipelines. TRACERx-PHLEX performs deep learning-based cell segmentation (deep-imcyto), automated cell-type annotation (TYPEx) and interpretable spatial analysis (Spatial-PHLEX) as three independent but interoperable modules. PHLEX generates single-cell identities, cell densities within tissue compartments, marker positivity calls and spatial metrics such as cellular barrier scores, along with summary graphs and spatial visualisations. PHLEX was developed using imaging mass cytometry (IMC) in the TRACERx study, validated using published Co-detection by indexing (CODEX), IMC and orthogonal data and benchmarked against state-of-the-art approaches. We evaluated its use on different tissue types, tissue fixation conditions, image sizes and antibody panels. As PHLEX is an automated and containerised Nextflow pipeline, manual assessment, programming skills or pathology expertise are not essential. PHLEX offers an end-to-end solution in a growing field of highly multiplexed data and provides clinically relevant insights.
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Aprendizaje Profundo , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Animales , Programas Informáticos , Análisis Espacial , Análisis de la Célula Individual/métodos , Fenotipo , Ratones , Citometría de Imagen/métodosRESUMEN
The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.
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Inestabilidad Cromosómica , Receptores ErbB , Neoplasias Pulmonares , Mutación , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Animales , Ratones , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Receptores ErbB/genética , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inhibidores , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Terapia Molecular Dirigida/métodos , Femenino , Variaciones en el Número de Copia de ADN , MasculinoRESUMEN
The cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a pivotal role in innate immune responses to viral infection and inhibition of autoimmunity. Recent studies have suggested that micronuclei formed by genotoxic stress can activate innate immune signaling via the cGAS-STING pathway. Here, we investigated cGAS localization, activation, and downstream signaling from micronuclei induced by ionizing radiation, replication stress, and chromosome segregation errors. Although cGAS localized to ruptured micronuclei via binding to self-DNA, we failed to observe cGAS activation; cGAMP production; downstream phosphorylation of STING, TBK1, or IRF3; nuclear accumulation of IRF3; or expression of interferon-stimulated genes. Failure to activate the cGAS-STING pathway was observed across primary and immortalized cell lines, which retained the ability to activate the cGAS-STING pathway in response to dsDNA or modified vaccinia virus infection. We provide evidence that micronuclei formed by genotoxic insults contain histone-bound self-DNA, which we show is inhibitory to cGAS activation in cells.
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Segregación Cromosómica , Proteínas de la Membrana , Micronúcleos con Defecto Cromosómico , Nucleótidos Cíclicos , Nucleotidiltransferasas , Transducción de Señal , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/genética , Humanos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Micronúcleos con Defecto Cromosómico/efectos de la radiación , Nucleótidos Cíclicos/metabolismo , Fosforilación , Replicación del ADN/efectos de la radiación , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Factor 3 Regulador del Interferón/metabolismo , Factor 3 Regulador del Interferón/genética , Inmunidad Innata/efectos de la radiación , Daño del ADN , Células HEK293 , Animales , Radiación Ionizante , Células HeLaRESUMEN
Understanding the role of the tumor microenvironment (TME) in lung cancer is critical to improving patient outcomes. We identified four histology-independent archetype TMEs in treatment-naïve early-stage lung cancer using imaging mass cytometry in the TRACERx study (n = 81 patients/198 samples/2.3 million cells). In immune-hot adenocarcinomas, spatial niches of T cells and macrophages increased with clonal neoantigen burden, whereas such an increase was observed for niches of plasma and B cells in immune-excluded squamous cell carcinomas (LUSC). Immune-low TMEs were associated with fibroblast barriers to immune infiltration. The fourth archetype, characterized by sparse lymphocytes and high tumor-associated neutrophil (TAN) infiltration, had tumor cells spatially separated from vasculature and exhibited low spatial intratumor heterogeneity. TAN-high LUSC had frequent PIK3CA mutations. TAN-high tumors harbored recently expanded and metastasis-seeding subclones and had a shorter disease-free survival independent of stage. These findings delineate genomic, immune, and physical barriers to immune surveillance and implicate neutrophil-rich TMEs in metastasis. SIGNIFICANCE: This study provides novel insights into the spatial organization of the lung cancer TME in the context of tumor immunogenicity, tumor heterogeneity, and cancer evolution. Pairing the tumor evolutionary history with the spatially resolved TME suggests mechanistic hypotheses for tumor progression and metastasis with implications for patient outcome and treatment. This article is featured in Selected Articles from This Issue, p. 897.
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Neoplasias Pulmonares , Microambiente Tumoral , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Microambiente Tumoral/inmunología , Linfocitos T/inmunología , Células Mieloides/inmunología , Femenino , Masculino , Evasión InmuneRESUMEN
BACKGROUND: Checkpoint inhibitor (CPI) immunotherapies have provided durable clinical responses across a range of solid tumor types for some patients with cancer. Nonetheless, response rates to CPI vary greatly between cancer types. Resolving intratumor transcriptomic changes induced by CPI may improve our understanding of the mechanisms of sensitivity and resistance. METHODS: We assembled a cohort of longitudinal pre-therapy and on-therapy samples from 174 patients treated with CPI across six cancer types by leveraging transcriptomic sequencing data from five studies. RESULTS: Meta-analyses of published RNA markers revealed an on-therapy pattern of immune reinvigoration in patients with breast cancer, which was not discernible pre-therapy, providing biological insight into the impact of CPI on the breast cancer immune microenvironment. We identified 98 breast cancer-specific correlates of CPI response, including 13 genes which are known IO targets, such as toll-like receptors TLR1, TLR4, and TLR8, that could hold potential as combination targets for patients with breast cancer receiving CPI treatment. Furthermore, we demonstrate that a subset of response genes identified in breast cancer are already highly expressed pre-therapy in melanoma, and additionally we establish divergent RNA dynamics between breast cancer and melanoma following CPI treatment, which may suggest distinct immune microenvironments between the two cancer types. CONCLUSIONS: Overall, delineating longitudinal RNA dynamics following CPI therapy sheds light on the mechanisms underlying diverging response trajectories, and identifies putative targets for combination therapy.
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Neoplasias de la Mama , Melanoma , Humanos , Femenino , Melanoma/tratamiento farmacológico , Inmunoterapia/efectos adversos , Terapia Combinada , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Microambiente Tumoral/genéticaRESUMEN
Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and 'tumor spread through air spaces' were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk.
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Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Adenocarcinoma/genética , Adenocarcinoma/patología , Recurrencia Local de Neoplasia/patología , Adenocarcinoma del Pulmón/genética , Progresión de la Enfermedad , ADN Helicasas , Proteínas Nucleares , Factores de TranscripciónRESUMEN
Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.
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Carcinoma de Pulmón de Células no Pequeñas , Evolución Clonal , Células Clonales , Evolución Molecular , Neoplasias Pulmonares , Metástasis de la Neoplasia , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Células Clonales/patología , Estudios de Cohortes , Progresión de la Enfermedad , Neoplasias Pulmonares/patología , Metástasis de la Neoplasia/diagnóstico , Metástasis de la Neoplasia/patología , Recurrencia Local de NeoplasiaRESUMEN
B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.
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Retrovirus Endógenos , Inmunoterapia , Neoplasias Pulmonares , Animales , Humanos , Ratones , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/terapia , Adenocarcinoma del Pulmón/virología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/virología , Modelos Animales de Enfermedad , Retrovirus Endógenos/inmunología , Inmunoterapia/métodos , Pulmón/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/virología , Microambiente Tumoral , Linfocitos B/inmunología , Estudios de Cohortes , Anticuerpos/inmunología , Anticuerpos/uso terapéuticoRESUMEN
Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.
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Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Mutación , Metástasis de la Neoplasia , Carcinoma Pulmonar de Células Pequeñas , Humanos , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Estudios de Cohortes , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Metástasis de la Neoplasia/diagnóstico , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Filogenia , Carcinoma Pulmonar de Células Pequeñas/patología , Biopsia LíquidaAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Cardiopatías , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Dosificación RadioterapéuticaRESUMEN
(1) Purpose: We analysed overall survival (OS) rates following radiotherapy (RT) and chemo-RT of locally-advanced non-small cell lung cancer (LA-NSCLC) to investigate whether tumour repopulation varies with treatment-type, and to further characterise the low α/ß ratio found in a previous study. (2) Materials and methods: Our dataset comprised 2-year OS rates for 4866 NSCLC patients (90.5% stage IIIA/B) belonging to 51 cohorts treated with definitive RT, sequential chemo-RT (sCRT) or concurrent chemo-RT (cCRT) given in doses-per-fraction ≤3 Gy over 16-60 days. Progressively more detailed dose-response models were fitted, beginning with a probit model, adding chemotherapy effects and survival-limiting toxicity, and allowing tumour repopulation and α/ß to vary with treatment-type and stage. Models were fitted using the maximum-likelihood technique, then assessed via the Akaike information criterion and cross-validation. (3) Results: The most detailed model performed best, with repopulation offsetting 1.47 Gy/day (95% confidence interval, CI: 0.36, 2.57 Gy/day) for cCRT but only 0.30 Gy/day (95% CI: 0.18, 0.47 Gy/day) for RT/sCRT. The overall fitted tumour α/ß ratio was 3.0 Gy (95% CI: 1.6, 5.6 Gy). (4) Conclusion: The fitted repopulation rates indicate that cCRT schedule durations should be shortened to the minimum in which prescribed doses can be tolerated. The low α/ß ratio suggests hypofractionation should be efficacious.
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Radiation-induced lung damage (RILD) is a common side effect of radiotherapy (RT). The ability to automatically segment, classify, and quantify different types of lung parenchymal change is essential to uncover underlying patterns of RILD and their evolution over time. A RILD dedicated tissue classification system was developed to describe lung parenchymal tissue changes on a voxel-wise level. The classification system was automated for segmentation of five lung tissue classes on computed tomography (CT) scans that described incrementally increasing tissue density, ranging from normal lung (Class 1) to consolidation (Class 5). For ground truth data generation, we employed a two-stage data annotation approach, akin to active learning. Manual segmentation was used to train a stage one auto-segmentation method. These results were manually refined and used to train the stage two auto-segmentation algorithm. The stage two auto-segmentation algorithm was an ensemble of six 2D Unets using different loss functions and numbers of input channels. The development dataset used in this study consisted of 40 cases, each with a pre-radiotherapy, 3-, 6-, 12-, and 24-month follow-up CT scans (n = 200 CT scans). The method was assessed on a hold-out test dataset of 6 cases (n = 30 CT scans). The global Dice score coefficients (DSC) achieved for each tissue class were: Class (1) 99% and 98%, Class (2) 71% and 44%, Class (3) 56% and 26%, Class (4) 79% and 47%, and Class (5) 96% and 92%, for development and test subsets, respectively. The lowest values for the test subsets were caused by imaging artefacts or reflected subgroups that occurred infrequently and with smaller overall parenchymal volumes. We performed qualitative evaluation on the test dataset presenting manual and auto-segmentation to a blinded independent radiologist to rate them as 'acceptable', 'minor disagreement' or 'major disagreement'. The auto-segmentation ratings were similar to the manual segmentation, both having approximately 90% of cases rated as acceptable. The proposed framework for auto-segmentation of different lung tissue classes produces acceptable results in the majority of cases and has the potential to facilitate future large studies of RILD.
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We present a novel classification system of the parenchymal features of radiation-induced lung damage (RILD). We developed a deep learning network to automate the delineation of five classes of parenchymal textures. We quantify the volumetric change in classes after radiotherapy in order to allow detailed, quantitative descriptions of the evolution of lung parenchyma up to 24 months after RT, and correlate these with radiotherapy dose and respiratory outcomes. Diagnostic CTs were available pre-RT, and at 3, 6, 12 and 24 months post-RT, for 46 subjects enrolled in a clinical trial of chemoradiotherapy for non-small cell lung cancer. All 230 CT scans were segmented using our network. The five parenchymal classes showed distinct temporal patterns. Moderate correlation was seen between change in tissue class volume and clinical and dosimetric parameters, e.g., the Pearson correlation coefficient was ≤0.49 between V30 and change in Class 2, and was 0.39 between change in Class 1 and decline in FVC. The effect of the local dose on tissue class revealed a strong dose-dependent relationship. Respiratory function measured by spirometry and MRC dyspnoea scores after radiotherapy correlated with the measured radiological RILD. We demonstrate the potential of using our approach to analyse and understand the morphological and functional evolution of RILD in greater detail than previously possible.
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Magnetic resonance imaging (MRI) has enabled non-invasive cancer diagnosis, monitoring, and management in common clinical settings. However, inadequate quantitative analyses in MRI continue to limit its full potential and these often have an impact on clinicians' judgments. Magnetic resonance fingerprinting (MRF) has recently been introduced to acquire multiple quantitative parameters simultaneously in a reasonable timeframe. Initial retrospective studies have demonstrated the feasibility of using MRF for various cancer characterizations. Further trials with larger cohorts are still needed to explore the repeatability and reproducibility of the data acquired by MRF. At the moment, technical difficulties such as undesirable processing time or lack of motion robustness are limiting further implementations of MRF in clinical oncology. This review summarises the latest findings and technology developments for the use of MRF in cancer management and suggests possible future implications of MRF in characterizing tumour heterogeneity and response assessment.
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The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy1,2. However, measurements of tumour infiltrating lymphocytes (TILs) are limited by a shortage of appropriate data. Whole-exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify actionable mutations. Here we develop T cell exome TREC tool (T cell ExTRECT), a method for estimation of T cell fraction from WES samples using a signal from T cell receptor excision circle (TREC) loss during V(D)J recombination of the T cell receptor-α gene (TCRA (also known as TRA)). TCRA T cell fraction correlates with orthogonal TIL estimates and is agnostic to sample type. Blood TCRA T cell fraction is higher in females than in males and correlates with both tumour immune infiltrate and presence of bacterial sequencing reads. Tumour TCRA T cell fraction is prognostic in lung adenocarcinoma. Using a meta-analysis of tumours treated with immunotherapy, we show that tumour TCRA T cell fraction predicts immunotherapy response, providing value beyond measuring tumour mutational burden. Applying T cell ExTRECT to a multi-sample pan-cancer cohort reveals a high diversity of the degree of immune infiltration within tumours. Subclonal loss of 12q24.31-32, encompassing SPPL3, is associated with reduced TCRA T cell fraction. T cell ExTRECT provides a cost-effective technique to characterize immune infiltrate alongside somatic changes.
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Inmunoterapia , Neoplasias/inmunología , Neoplasias/terapia , Linfocitos T/citología , Linfocitos T/metabolismo , Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/terapia , Ácido Aspártico Endopeptidasas/genética , Estudios de Cohortes , Exoma/genética , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Mutación , Neoplasias/diagnóstico , Neoplasias/genética , Pronóstico , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Secuenciación del Exoma/economíaRESUMEN
Background: Timing for intervention of small indeterminate pulmonary nodules has long been a topic of debate given the low incidence of malignancy and difficulty in obtaining a definite preoperative diagnosis. We sought to determine survival outcomes of surgical and non-surgical managements in non-small cell lung cancer (NSCLC) ≤8 mm, which may provide a reference for prospective decision-making for patients with suspected NSCLC. Method: A total of 1,652 patients with Stage IA NSCLC ≤8 mm were identified from the Surveillance, Epidemiology, and End Results (SEER) database and categorized into surgery and non-surgery groups. Chi-square test, t-test and Mann-Whitney U test were used to compare the baseline characteristics between groups. Survival curves were depicted using Kaplan-Meier method and compared by log-rank test. Cox proportional hazard model was used for univariate and multivariate analyses. Adjustment of confounding factors between groups was performed by propensity score matching. Results: The surgery and non-surgery groups included 1,438 and 208 patients, respectively. Patients in surgery group demonstrated superior survival outcome than patients in non-surgery group both before [overall survival (OS): HR, 16.22; 95% CI, 11.48-22.91, p < 0.001; cancer-specific survival (CSS): HR, 49.6; 95% CI, 31.09-79.11, p < 0.001] and after (OS: HR, 3.12; 95% CI, 2.40-4.05, p < 0.001; CSS: HR, 3.85; 95% CI, 2.74-5.40, p < 0.001) propensity score matching. The 30-day mortality rates were 3.1 and 12.0% in surgery and non-surgery groups, respectively. Multivariate analysis suggested age, sex, race, tumor size, grade, pathological stage were all independent prognostic factors in patients with ≤8 mm NSCLC. A comparison of surgical resections revealed a survival superiority of lobectomy over sub-lobectomy. In terms of CSS, no statistically significant difference was found between segmentectomy and wedge resection. Conclusion: The current SEER database showed better prognosis of surgical resection than non-surgical treatment in patients with ≤8 mm NSCLC. However, the factors that should be essentially included in the proper propensity-matched analysis, such as comorbidity, cardiopulmonary function and performance status were unavailable and the true superiority or inferiority should be examined further by ongoing randomized trial, especially comparing surgery and stereotactic body irradiation.
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Delivering lung cancer care during the COVID-19 pandemic has posed significant and ongoing challenges. There is a lack of published COVID-19 and lung cancer evidence-based reviews, including for the whole patient pathway. We searched for COVID-19 and lung cancer publications and brought together a multidisciplinary group of stakeholders to review and comment on the evidence and challenges. A rapid review of the literature was undertaken up to 28 October 2020, producing 144 papers, with 113 full texts screened. We focused on new primary data collection (qualitative or quantitative evidence) and excluded case reports, editorials and commentaries. Following exclusions, 15 published papers were included in the review and are summarised. They included one qualitative paper and 14 quantitative studies (surveys or cohort studies), with a total of 2295 lung cancer patients data included (mean study size 153 patients; range 7-803). Review of current evidence and commentary included awareness and help-seeking; lung cancer screening; primary care assessment and referral; diagnosis and treatment in secondary care, including oncology and surgery; patient experience and palliative care. Cross-cutting themes and challenges were identified using qualitative methods for patients, healthcare professionals and service delivery, with a clear need for continued studies to guide evidence-based decision-making.
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COVID-19/epidemiología , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Detección Precoz del Cáncer , Humanos , Pandemias , SARS-CoV-2/aislamiento & purificaciónRESUMEN
Locoregional recurrence occurs in 10%-30% of non-small cell lung cancer (NSCLC) after treatment with definitive (chemo)radiotherapy. Re-irradiation is the main curative-intent treatment option for these patients; however, it represents a therapeutic challenge for thoracic radiation oncologists. Re-irradiation practices are variable worldwide with lack of agreement on the optimal dose or the cumulative maximum dose acceptable for critical organs. The role of re-irradiation in NSCLC is also not clearly defined in the era of immunotherapy. In this review, we will present published and on-going re-irradiation studies for recurrent NSCLC. We will appraise available evidence for critical organ dose constraints and provide a framework for future therapeutic approaches and trials.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Reirradiación , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Humanos , Neoplasias Pulmonares/radioterapia , Recurrencia Local de Neoplasia/radioterapiaRESUMEN
Lung cancer is the leading cause of cancer mortality worldwide and most patients are unsuitable for 'gold standard' treatment, which is concurrent chemoradiotherapy. CONCORDE is a platform study seeking to establish the toxicity profiles of multiple novel radiosensitisers targeting DNA repair proteins in patients treated with sequential chemoradiotherapy. Time-to-event continual reassessment will facilitate efficient dose-finding.