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Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher's exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher's exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Neoplasia Residual , Humanos , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/terapia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , Prognóstico , Masculino , Feminino , Resultado do Tratamento , Biomarcadores Tumorais , Pessoa de Meia-Idade , DNA Tumoral CirculanteRESUMO
Neoadjuvant immunotherapy has significantly changed the therapeutic approach for treating patients with surgically resectable non-small cell lung cancer (NSCLC). Here, peripheral blood inflammation-based biomarkers as well as previously less focused eosinophil fraction, modified Glasgow prognostic score (mGPS), and prognostic nutritional index (PNI) were systematically included to comprehensively analyze their potential in predicting neoadjuvant immunotherapy efficacy and prognosis. We enrolled 189 patients (94 in training and 95 in validation cohorts) with stage I-III B surgically resectable NSCLC treated with neoadjuvant immunotherapy from the National Cancer Center of China. Baseline and post-treatment eosinophils fraction, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), monocyte-to-lymphocyte ratio (MLR), PNI, mGPS, and their changes were calculated and analyzed for correlation with neoadjuvant immunotherapy efficacy and prognosis. In patients in the major pathological response (MPR) group, the post-treatment eosinophil fraction was significantly high, and NLR, PLR, SII, and MLR were significantly lower compared to the non-MPR group in both the training and validation cohorts. The receiver operating characteristic curve showed that post-treatment, eosinophil fraction and SII and their changing were two of the most important factors. Univariate and multivariate logistic regression analyses showed that post-treatment eosinophil fraction, SII, mGPS, and ΔSII could independently predict MPR in patients treated with neoadjuvant immunotherapy. Survival analysis showed a significant correlation between high post-treatment NLR, PLR, SII, mGPS, and their changes in ΔNLR and ΔSII elevation with poor overall survival and event-free survival of patients. Our results suggest that inflammatory biomarkers could predict the patient's response to neoadjuvant immunotherapy and prognosis.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia Neoadjuvante , Estudos Retrospectivos , Prognóstico , Biomarcadores , Linfócitos , Neutrófilos/patologia , Inflamação/patologia , ImunoterapiaRESUMO
BACKGROUND: A Phase II study was undertaken to evaluate the safety and efficacy of the neoadjuvant socazolimab, a novel PD-L1 inhibitor, in combination with nab-paclitaxel and cisplatin for locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Sixty-four patients were randomly divided between the Socazolimab + nab-paclitaxel + cisplatin (TP) arm (n = 32) and the control arm (n = 32), receiving either socazolimab (5 mg/kg intravenously (IV), day 1) or a placebo with nab-paclitaxel (125 mg/m2 IV, day 1/8) and cisplatin (75 mg/m2 IV, day 1) repeated every 21 days for four cycles before surgery. The primary endpoint was major pathological response (MPR), and the secondary endpoints were pathological complete response (pCR), R0 resection rate, event-free survival (EFS), overall survival (OS), and safety. RESULTS: A total of 29 (90.6%) patients in each arm underwent surgery, and 29 (100%) and 28 (98.6%) patients underwent R0 resection in the Socazolimab + TP and Placebo + TP arms, respectively. The MPR rates were 69.0 and 62.1% (95% Confidence Interval (CI): 49.1-84.0% vs. 42.4-78.7%, P = 0.509), and the pCR rates were 41.4 and 27.6% (95% CI: 24.1-60.9% vs. 13.5-47.5%, P = 0.311) in the Socazolimab + TP and Placebo + TP arms, respectively. Significantly higher incidence rates of ypT0 (37.9% vs. 3.5%; P = 0.001) and T downstaging were observed in the Socazolimab + TP arm than in the Placebo + TP arm. The EFS and OS outcomes were not mature. CONCLUSIONS: The neoadjuvant socazolimab combined with chemotherapy demonstrated promising MPR and pCR rates and significant T downstaging in locally advanced ESCC without increasing surgical complication rates. TRIAL REGISTRATION: Registration name (on clinicaltrials.gov): A Study of Anti-PD-L1 Antibody in Neoadjuvant Chemotherapy of Esophageal Squamous Cell Carcinoma. REGISTRATION NUMBER: NCT04460066.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Cisplatino , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Inibidores de Checkpoint Imunológico , Terapia NeoadjuvanteRESUMO
BACKGROUND: The most common form of treatment for non-metastatic lung cancer is surgery-based combination therapy, which may also include adjuvant radiotherapy or chemotherapy. Second primary malignancies (SPMs) are uncommon but significant radiation side effects in patients with resectable lung cancer, and SPMs have not been adequately investigated. Our study aims to assess the correlations of radiotherapy with the development of SPMs in patients with resectable lung cancer. METHODS: We screened for any primary malignancy that occurred more than five years after the diagnosis of resectable lung cancer. Based on the large cohort of the Surveillance, Epidemiology and End Results database, radiotherapy-correlated risks were estimated using the Poisson regression analysis and the cumulative incidence of SPMs was calculated using Fine-Gray competing risk regression analysis. RESULTS: Among the 62,435 patients with non-metastatic lung cancer undergoing surgery, a total of 11,341 (18.16%) patients have received radiotherapy. Our findings indicated that radiotherapy was substantially related to a high risk of main second solid malignancies (RR = 1.21; 95%CI, 1.08 to 1.35) and a negligible risk of main second hematologic malignancies (RR = 1.08; 95%CI, 0.84 to 1.37). With the greatest number of patients, the risk of acquiring a second primary gastrointestinal cancer was the highest overall (RR = 1.77; 95 percent CI, 1.44 to 2.15). The cumulative incidence and standardized incidence ratios of SPMs revealed similar findings. Furthermore, the young and the elderly may be more vulnerable, and the highest risk of acquiring most SPMs was seen more than ten years after lung cancer diagnosis. Additionally, more attention should be paid to the second primary gastrointestinal cancer in young individuals with resectable lung cancer. CONCLUSION: After receiving radiotherapy, an increased risk of developing second primary solid and gastrointestinal cancers was observed for patients with resectable lung cancer. The prevention of SPMs associated with radiotherapy requires further attention.
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Neoplasias Pulmonares , Segunda Neoplasia Primária , Humanos , Idoso , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Medição de Risco , Incidência , Terapia Combinada , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/radioterapia , Fatores de Risco , Programa de SEERRESUMO
Pulmonary sarcomatoid carcinoma (PSC) is a unique form of poorly differentiated nonsmall cell lung cancer (NSCLC) and is notorious for its highly malignant nature and dismal prognosis. To introduce effective treatment for PSC patients, precise subtyping of PSC is demanding. In our study, TTF-1 and P40 immunohistochemistry (IHC) staining were applied to 56 PSC patients with multiomics data. According to IHC results, we categorized these patients into three subgroups and profiled their molecular contexture using bioinformatic skills. IHC results classified these patients into three subgroups: TTF-1 positive subgroup (n = 27), P40 positive subgroup (n = 15) and double-negative subgroup (n = 14). Spindle cell samples accounted for 35.71% (5/14) of double-negative patients, higher than others (P = .034). The three subgroups were heterogeneous in the genomic alteration spectrum, showing significant differences in the RTK/RAS pathway (P = .004) and the cell cycle pathway (P = .030). The methylation profile of the double-negative subgroup was between the other two subgroups. In similarity analysis, the TTF-1 and p40 subgroups were closely related to LUAD and LUSC, respectively. The TTF-1 positive subgroup had the highest leukocyte fraction (LF) among several cancer types, and the tumor mutation burden (TMB) of the p40 positive subgroup ranked third in the TMB list, suggesting the applicability of immunotherapy for PSC. The study established a new subtyping method of PSC based on IHC results and reveals three subgroups with distinct molecular features, providing evidence for refined stratification in the treatment of PSC.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma , Neoplasias Pulmonares , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/patologiaRESUMO
Aim: To comprehensively analyze the expression profiles of ubiquitin-related genes (URGs) and determine potential biomarkers in KRAS-driven lung adenocarcinoma (LUAD). Materials & methods: Differential expression analyses were performed between KRAS-wild and KRAS-mutant LUAD samples from The Cancer Genome Atlas database, and 34 URGs were screened out. ESTIMATE and CIBERSORT methods were used to calculate the ratio of immune and stromal components. Results & conclusion: TRIM58 was positively correlated with abundances of M2 macrophages and resting mast cells and negatively correlated with follicular helper T-cell abundances in KRAS-driven LUAD. TRIM58 was a potential prognosis-associated indicator for tumor microenvironment modulation and played a key role in TME-specific AS landscapes alterations in KRAS-driven LUAD.
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Adenocarcinoma de Pulmão/diagnóstico , Biomarcadores Tumorais/genética , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Pulmonares/diagnóstico , Proteínas com Motivo Tripartido/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Estimativa de Kaplan-Meier , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Mastócitos/imunologia , Mutação , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Células T Auxiliares Foliculares/imunologia , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologiaRESUMO
Aim: Predicting the prognostic outcome of a single case among postoperative non-small-cell lung cancer (NSCLC) patients is difficult. We created a precise prognostic model to assess the condition and prognosis of postoperative NSCLC patients. Methods: We combined eight prognostic indicators (age, prothrombin time, international normalized ratio, globulin, albumin-to-globulin ratio, tumor diameter, number of positive lymph nodes and number of dissected lymph nodes) to construct a new risk index (RI) model. Results: The best cut-off value was -1.86 (area under the curve: 0.719). The overall survival of postoperative NSCLC patients decreased as the RI increased (p < 0.001). Conclusion: This RI model can assist clinicians in screening high-risk groups and developing treatment and follow-up plans for postoperative NSCLC patients.
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Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Feminino , Humanos , Linfonodos/patologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Prognóstico , Estudos RetrospectivosRESUMO
Aim: Prognosis of patients with metastatic non-small-cell lung cancer differ widely. Methods: All patients were randomly divided into training or validation cohort. Cox-regression analyses were conducted to select independent predictors. We built a nomogram by R code and evaluated the accuracy and the reliability of the model using C-index, calibration curves and decision curve analyses. We made a risk classification system based on the nomogram. Results: In the validation cohort, C-index was 0.729 and 0.738 for 1- and 2-year overall survival. Calibration plots and decision curve analyses presented great prognostic accuracy and clinical applicability. Its prognostic accuracy preceded the American Joint Committee on Cancer staging with evaluated integrated discrimination improvement. Conclusion: The model can be a practical tool in treatment decision and individual counseling.
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Adenocarcinoma de Pulmão/mortalidade , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/mortalidade , Quimiorradioterapia/mortalidade , Neoplasias Pulmonares/mortalidade , Nomogramas , Medição de Risco/métodos , Adenocarcinoma de Pulmão/secundário , Adenocarcinoma de Pulmão/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/terapia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Programa de SEER , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: In China, real-world data on surgical challenges and postoperative complications after neoadjuvant immunotherapy of lung cancer are limited. METHODS: Patients were retrospectively enrolled from January 2018 to January 2023, and their clinical and pathological characters were subsequently analyzed. Surgical difficulty was categorized into a binary classification according to surgical duration: challenging or routine. Postoperative complications were graded using Clavien-Dindo grades. Logistic regression was used to identify risk factors affecting the duration of surgery and postoperative complications greater than Clavien-Dindo grade 2. RESULTS: In total, 261 patients were included. Of these, stage III patients accounted for 62.5% (163/261) at initial diagnosis, with 25.3% (66/261) at stage IIIB. Central-type non-small-cell lung cancer accounted for 61.7% (161/261). One hundred and forty patients underwent video-assisted thoracoscopic surgery and lobectomy accounted for 53.3% (139/261) of patients. Surgical time over average duration was defined as challenging surgeries, accounting for 43.7%. The postoperative complications rate of 261 patients was only 22.2%. Smoking history (odds ratio [OR] = 9.96, 95% [CI] 1.15-86.01, p = 0.03), chemoimmunotherapy (OR = 2.89, 95% CI 1.22-6.86, p = 0.02), and conversion to open surgery (OR = 11.3, 95% CI 1.38-92.9, p = 0.02) were identified as independent risk factors for challenging surgeries, while pneumonectomy (OR = 0.36, 95% CI 0.15-0.86, p= 0.02) was a protective factor. Meanwhile, pneumonectomy (OR = 7.51, 95% CI 2.40-23.51, p < 0.01) and challenging surgeries (OR = 5.53, 95% CI 1.50-20.62, p = 0.01) were found to be risk factors for postoperative complications greater than Clavien-Dindo grade 2. CONCLUSIONS: Compared to immunotherapy alone or in combination with apatinib, neoadjuvant chemoimmunotherapy could increase the difficulty of surgery while the incidence of postoperative complications remained acceptable. The conversion to open surgery and pneumonectomy after neoadjuvant immunotherapy should be reduced.
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Imunoterapia , Neoplasias Pulmonares , Terapia Neoadjuvante , Complicações Pós-Operatórias , Humanos , Masculino , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/patologia , Feminino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Imunoterapia/métodos , Imunoterapia/efeitos adversos , Estudos Retrospectivos , Idoso , Pneumonectomia/efeitos adversos , Pneumonectomia/métodos , AdultoRESUMO
BACKGROUND: Neoadjuvant immunotherapy has evolved as an effective option to treat non-small cell lung cancer (NSCLC). B cells play essential roles in the immune system as well as cancer progression. However, the repertoire of B cells and its association with clinical outcomes remains unclear in NSCLC patients receiving neoadjuvant immunotherapy. METHODS: Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data for LUAD samples were accessed from the TCGA and GEO databases. LUAD-related B cell marker genes were confirmed based on comprehensive analysis of scRNA-seq data. We then constructed the B cell marker gene signature (BCMGS) and validated it. In addition, we evaluated the association of BCGMS with tumor immune microenvironment (TIME) characteristics. Furthermore, we validated the efficacy of BCGMS in a cohort of NSCLC patients receiving neoadjuvant immunotherapy. RESULTS: A BCMGS was constructed based on the TCGA cohort and further validated in three independent GSE cohorts. In addition, the BCMGS was proven to be significantly associated with TIME characteristics. Moreover, a relatively higher risk score indicated poor clinical outcomes and a worse immune response among NSCLC patients receiving neoadjuvant immunotherapy. CONCLUSIONS: We constructed an 18-gene prognostic signature derived from B cell marker genes based on scRNA-seq data, which had the potential to predict the prognosis and immune response of NSCLC patients receiving neoadjuvant immunotherapy.
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Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Terapia Neoadjuvante , Análise de Sequência de RNA , Análise de Célula Única , Microambiente Tumoral , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Prognóstico , Imunoterapia/métodos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Feminino , Masculino , Biomarcadores Tumorais/genética , Linfócitos B/imunologia , Pessoa de Meia-Idade , IdosoRESUMO
Suppressor of cytokine signaling 2 (SOCS2) plays an essential role in a number of physiological phenomena and functions as a tumor suppressor. Understanding the predictive effects of SOCS2 on non-small cell lung cancer (NSCLC) is urgently needed. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to assess SOCS2 gene expression levels in NSCLC. The clinical significance of SOCS2 was evaluated through Kaplan-Meier curve analysis and the analysis of related clinical factors. Gene Set Enrichment Analysis (GSEA) was used to identify the biological functions of SOCS2. Subsequently proliferation, wound-healing, colony formation and Transwell assays, and carboplatin drug experiments were used for verification. The results revealed that SOCS2 expression was low in the NSCLC tissues of patients in TCGA and GEO database analyses. Downregulated SOCS2 was associated with poor prognosis, as determined by Kaplan-Meier survival analysis (HR 0.61, 95% CI 0.52-0.73; P<0.001). GSEA showed that SOCS2 was involved in intracellular reactions, including epithelial-mesenchymal transition (EMT). Cell experiments indicated that knockdown of SOCS2 caused the malignant progression of NSCLC cell lines. Furthermore, the drug experiment showed that silencing of SOCS2 promoted the resistance of NSCLC cells to carboplatin. In conclusion, low expression of SOCS2 was associated with poor clinical prognosis by effecting EMT and causing drug resistance in NSCLC cell lines. Furthermore, SOCS2 could act as a predictive indicator for NSCLC.
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INTRODUCTION: Oesophageal cancer is a prevalent and deadly cancer around the world. OBJECTIVES: We aimed to present a comprehensive analysis of the global geographic patterns and temporal trends in the mortality and incidence of oesophageal cancer. METHODS: The mortality and incidence data of oesophageal cancer in 2020 were obtained from the GLOBOCAN database. Based on World Health Organization (WHO) mortality database and the Cancer Incidence in Five Continents (CI5), we also retrieved the mortality and incidence age-standardized rates (ASRs) of oesophageal cancer. The average annual percentage changes (AAPCs) of mortality and incidence were calculated using the joinpoint regression analysis. RESULTS: Globally, 0.54 million deaths and 0.6 million new cases were identified in 2020. In the majority of countries of South America and Asia, the mortality and incidence trends have substantially decreased, but trends in European countries have varied. The prevalence in European nations varied, but the incidence in most other continents decreased dramatically. In terms of mortality, the global average rate was 5.6 per 100000, ranging from 16.7 (Malawi) to 0.28 (Belize). European countries varied in mortality, such as Norway (AAPC, male: 0.68; female: 0.89) and Ireland (AAPC, male: -0.96; female: -1.52). Most non-European countries saw large decreases in mortality, such as Singapore (AAPC, male: -4.78; female: -6.89). The elderly had more noticeable trends in mortality and incidence in most countries. CONCLUSIONS: We have identified different trends in mortality and incidence among European countries, whereas declining trends were identified in most non-European countries. However, increasing trends were identified in specific subgroups of some countries, such as men in Thailand. For populations with rising mortality and incidence trends, more preventative efforts are required.
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Neoplasias Esofágicas , Saúde Global , Humanos , Masculino , Feminino , Idoso , Incidência , Organização Mundial da Saúde , Neoplasias Esofágicas/epidemiologia , TailândiaRESUMO
INTRODUCTION: With the advancements in early diagnosis, more and more patients with multiple primary lung cancer (MPLC) have been identified. However, the progression of MPLC involves complex changes in cell composition and metabolic function, which remains largely controversial. OBJECTIVE: Our study aims to comprehensively reveal the cellular characteristics and inter-cellular connections of MPLC. METHODS: We performed scRNA-seq from 23 samples of six MPLC patients, combined with bulk whole-exome sequencing. We performed trajectory analysis to investigate the transition of different cell types during the development of MPLC. RESULTS: A total of 1 67 397 cells were sequenced derived from tumour and adjacent tissues of MPLC patients, and tumour, normal, immune and stromal cells were identified. Two states of epithelial cells were identified, which were associated with immune response and cell death, respectively. Furthermore, both CD8+ naïve and memory T cells participated in the differentiation of CD8+ T cells. The terminal states of CD8+ T cells were exhausted T cells and cytotoxic T cells, which positively regulated cell death and were implicated in the regulation of cytokine production, respectively. Two main subpopulations of B cells with distinct functions were identified, which participate in the regulation of the immune response and antigen presentation, respectively. In addition, we found a specific type of endothelial cells that were abundant in tumour samples, with an increasing trend from normal to tumour samples. CONCLUSIONS: Our study showed the comprehensive landscape of different cells of MPLC, which might reveal the key cellular mechanisms and, therefore, may provide new insights into the early diagnosis and treatment of MPLC.
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Neoplasias Pulmonares , Neoplasias Primárias Múltiplas , Humanos , Linfócitos T CD8-Positivos , Células Endoteliais , Sequenciamento do Exoma , Análise de Sequência de RNA , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genéticaRESUMO
PURPOSE: The aim of present study was to investigate the efficiency of 18F-FDG uptake in predicting major pathological response (MPR) in resectable non-small cell lung cancer (NSCLC) patients with neoadjuvant immunotherapy. METHODS: A total of 104 patients with stage I-IIIB NSCLC were retrospectively derived from National Cancer Center of China, of which 36 cases received immune checkpoint inhibitors (ICIs) monotherapy (I-M) and 68 cases with ICI combination therapy (I-C). 18F-FDG PET-CT scans were performed at baseline and after neoadjuvant therapy (NAT). Receiver-operating characteristic (ROC) curve analyses were conducted and area under ROC curve (AUC) was calculated for biomarkers including maximum standardized uptake value (SUVmax), inflammatory biomarkers, tumor mutation burden (TMB), PD-L1 tumor proportion score (TPS) and iRECIST. RESULTS: Fifty-four resected NSCLC tumors achieved MPR (51.9%, 54/104). In both neoadjuvant I-M and I-C cohorts, post-NAT SUVmax and the percentage changes of SUVmax (ΔSUVmax%) were significantly lower in the patients with MPR versus non-MPR (p < 0.01), and were also negatively correlated with the degree of pathological regression (p < 0.01). The AUC of ΔSUVmax% for predicting MPR was respectively 1.00 (95% CI: 1.00-1.00) in neoadjuvant I-M cohort and 0.94 (95% CI: 0.86-1.00) in I-C cohort. Baseline SUVmax had a statistical prediction value for MPR only in I-M cohort, with an AUC up to 0.76 at the threshold of 17.0. ΔSUVmax% showed an obvious advantage in MPR prediction over inflammatory biomarkers, TMB, PD-L1 TPS and iRECIST. CONCLUSION: 18F-FDG uptake can predict MPR in NSCLC patients with neoadjuvant immunotherapy.
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Multimodal epigenetic characterization of cell-free DNA (cfDNA) could improve the performance of blood-based early cancer detection. However, integrative profiling of cfDNA methylome and fragmentome has been technologically challenging. Here, we adapt an enzyme-mediated methylation sequencing method for comprehensive analysis of genome-wide cfDNA methylation, fragmentation, and copy number alteration (CNA) characteristics for enhanced cancer detection. We apply this method to plasma samples of 497 healthy controls and 780 patients of seven cancer types and develop an ensemble classifier by incorporating methylation, fragmentation, and CNA features. In the test cohort, our approach achieves an area under the curve value of 0.966 for overall cancer detection. Detection sensitivity for early-stage patients achieves 73% at 99% specificity. Finally, we demonstrate the feasibility to accurately localize the origin of cancer signals with combined methylation and fragmentation profiling of tissue-specific accessible chromatin regions. Overall, this proof-of-concept study provides a technical platform to utilize multimodal cfDNA features for improved cancer detection.
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Ácidos Nucleicos Livres , Neoplasias , Humanos , Ácidos Nucleicos Livres/genética , Epigenoma , Neoplasias/diagnóstico , Neoplasias/genética , Epigenômica/métodos , Metilação de DNA/genética , Biomarcadores Tumorais/genéticaRESUMO
Programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) is an important pair of immune checkpoints (IC), which play an essential role in the immune escaping process of tumors. Anti-PD-1/PD-L1 immunotherapy can block the suppression effect of the immune system produced by tumor cells through the PD-1/PD-L1 axis and restore the pernicious effect of the immune system on tumor cells. The specific mechanism of anti-PD-1/PD-L1 immunotherapy is closely related to PI3K (phosphatidylinositol 3-kinase)/AKT (AKT serine/threonine kinase 1), JNK (c-Jun N-terminal kinase), NF-kB (nuclear factor-kappa B subunit 1), and other complex signaling pathways. Patients receiving anti-PD-1/PD-L1 immunotherapy are prone to drug resistance. The mechanisms of drug resistance mainly include weakening recognition of tumor antigens by immune cells, inhibiting activation of immune cells, and promoting the production of suppressive immune cells and molecules. Anti-PD-1/PD-L1 immunotherapy plays a vital role in non-small cell lung cancer (NSCLC). It is essential to find better efficacy prediction-related biomarkers and screen patients suitable for immunotherapy. At present, common biomarkers related to predicting immune efficacy mainly include PD-L1 expression level in tumors, tumor mutation burden (TMB), microsatellite instability (MSI)/mismatch repair (MMR), mutations of driver gene, etc. However, the screening efficacy of each indicator is not ideal, and the combined application of multiple indicators is currently used. This article comprehensively reviews anti-PD-1/PD-L1 immunotherapy-related mechanisms, drug resistance-related mechanisms, and therapeutic efficacy-related predictive biomarkers.
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BACKGROUND: RNA modifications, including adenosine-to-inosine RNA editing, alternative polyadenylation, m1A and m6A, play a significant role in tumorigenesis and tumor immunity. However, the functions of RNA modification enzymes (writers) in immunotherapy and tumor microenvironment (TME) remain unknown. METHODS: Nonnegative matrix factorization clustering was applied to identify RNA modification clusters in lung adenocarcinoma, one of the most prevalent subtypes of non-small cell lung cancer (NSCLC). CIBERSORT and ESTIMATE algorithms were performed to depict TME characteristics. Additionally, a scoring system called Writer-Score was established to quantify RNA modification patterns and subsequently predict clinical outcomes. We subsequently used RNA sequencing, targeted DNA sequencing and multiplex immunofluorescence to further evaluate the efficacy of Writer-Score in NSCLC patients receiving neoadjuvant immunotherapy. FINDINGS: We identified three distinct RNA modification clusters and two DEGclusters, which were shown to be strongly associated with a variety of TME features and biological processes. Additionally, the Writer-Score served as an important factor in post-transcriptional events and immunotherapy. The Writer-Score was capable of properly predicting the prognosis of NSCLC patients receiving neoadjuvant PD-1 inhibitor therapy. INTERPRETATION: Our work systematically analyzed four types of RNA modifications and constructed a scoring system to guide neoadjuvant immunotherapy in NSCLC, which highlighted the writers' roles in post-transcriptional events, TME and neoadjuvant immunotherapy. FUNDING: A full list of funding bodies that supported this study can be found in the Acknowledgements section.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenosina/genética , Adenosina/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Humanos , Inibidores de Checkpoint Imunológico , Fatores Imunológicos , Imunoterapia , Inosina , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Terapia Neoadjuvante , Prognóstico , RNA , Microambiente Tumoral/genéticaRESUMO
The mRNA vaccines have been a novel strategy of immunotherapies for multiple cancers. Although several types of mRNA vaccines have been investigated and validated in some studies, their efficacy among patients with lung adenocarcinoma (LUAD) remains largely unknown. The number of tumor-associated antigens is not enough and no study focuses on stratifying the subgroup of LUAD patients suitable for vaccination. Based on the expression profiles of immune-related genes, consensus clustering was performed to identify the most appropriate phenotype for vaccination. The immune landscape of LUAD was shown via the graph learning-based dimensionality reduction analysis. We screened for five mutated and upregulated LUAD-related antigens (CCNB1, KIAA0101, PBK, OIP5 and PLEK2) that were highly correlated with immune infiltrating cells and unfavorable clinical outcomes. And three distinct immune phenotypes were identified in the TCGA and GSE72094 cohorts. Group S1 was an immunological "hot" cluster and related to a better prognosis, whereas Group S2&S3 was an immunological "cold" cluster and associated with a poorer prognosis. At last, the results revealed heterogeneity of LUAD patients in the immune landscape. We identified five potential cancer-related antigens for mRNA vaccines, and Group S2&S3 were the most suitable phenotypes for vaccination.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/terapia , Antígenos de Neoplasias/genética , Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Fenótipo , Prognóstico , Vacinas Sintéticas , Vacinas de mRNARESUMO
BACKGROUND: We comprehensively analyzed the global burdens and trends in incidence and mortality of tracheal, bronchus, and lung (TBL) cancer among subgroups of distinctive ages and genders. METHODS: We retrieved incidence and mortality rates of lung cancer in 2020 from the GLOBOCAN database among 185 countries. The incidence and mortality age-standardized rates (ASRs) were mostly obtained from Cancer Incidence in Five Continents and World Health Organization mortality database, respectively. The joinpoint regression analysis has been conducted to evaluate the average annual percentage change of incidence and mortality in recent years. FINDINGS: Trends in the incidence and mortality were decreasing among men in most countries, whereas the trends were increasing among women in some regions. As for mortality, most countries had a decreasing trend in mortality among males, but increasing trends were observed in more than half of countries among females. Furthermore, the majority of countries showed a significant decrease in incidence among males (AAPCs, -0·34 to -6·53), whereas most countries had a significant increase among females (AAPCs, 9·39 to 0·6), especially in European countries. In addition, a more drastic decrease was identified in the trends of the incidence among young people. 33 countries had a drastic decrease among males, especially in countries in Europe (AAPCs, -0·93 to -11·71). And 15 countries showed a significant decrease in incidence among young women (AAPCs, -0·94 to -9·35). INTERPRETATION: Decreasing incidence and mortality trends were identified in TBL cancer, particularly among all-age men and women younger than 50 years old. But some other groups of individuals showed an opposite trend, such as women in European countries. More preventive interventions are required for the specific populations. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
Assuntos
Neoplasias Pulmonares , Adolescente , Brônquios , Feminino , Humanos , Incidência , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Organização Mundial da SaúdeRESUMO
Background: The current N classification, which is determined by the anatomical location of positive lymph nodes, does not effectively stratify N1 and N2 non-small cell lung cancer (NSCLC) patients into prognostically significant subgroups. Methods: We acquired the clinical data of 3,234 N1 and N2 NSCLC patients from the Surveillance, Epidemiology, and End Results (SEER) database (2004-2015). We eliminated patients undergoing chemotherapy or radiation because chemotherapy and radiotherapy might lower lymph node stage, and the SEER database does not distinguish between therapy administered before and after surgery. We developed the N-new classification based on the former N stage, the number and ratio of lymph nodes. Patients were finally classified into four categories (N1a, N1b, N2a, N2b). Then, the N-new classification was validated in subgroups based on a variety of clinical characteristics, such as tumor size. The multivariable Cox regression analysis, the decision curve analysis (DCA) and the time-dependent receiver operating characteristic (ROC) analysis were conducted to compare the performance of the N-new classification and the current N classification. Results: The cancer-specific survival (CSS) and overall survival were significantly different among each pair of N-new classification. And the same results were shown in the majority of the subgroups determined by various clinical characteristics. Compared with the current N classification (C-index, 0.639), the N-new classification (C-index, 0.652) performed better in classifying N1 and N2 NSCLC patients into subgroups with distinctive clinical outcomes. The 5-year CSS rates were 49.7%, 41.4%, 30.4% and 20.4% for N1a, N1b, N2a and N2b, respectively. Conclusions: When compared to the current N classification, the N-new classification could be a more reliable and accurate prognostic determinant, which is worth considering in the revision of the 9th edition of the tumor, node, metastasis (TNM) staging system.