scholarly journals Tumor Transcriptome in Patients with Lower Pectoralis Muscle Area Reveals IL-8 as a Prognostic Biomarker in Non-Small Cell Lung Cancer

2019 ◽  
Author(s):  
Sarah Santiloni Cury ◽  
Diogo de Moraes ◽  
Paula Paccielli Freire ◽  
Grasieli de Oliveira ◽  
Douglas Venâncio Pereira Marques ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
In Vitro Assays ◽  
C2c12 Myotubes ◽  
Pectoralis Muscle ◽  
Small Cell Lung ◽  
Nsclc Patients ◽  
Worse Prognosis

Cachexia is a syndrome characterized by an ongoing loss of skeletal muscle mass associated with poor patient prognosis in non-small cell lung cancer (NSCLC). However, prognostic cachexia biomarkers in NSCLC are unknown. Here, we analyzed computed tomography (CT) images and tumor transcriptome data to identify potentially secreted cachexia biomarkers (PSCB) in NSCLC patients with low-muscularity. We integrated radiomics features (pectoralis muscle, sternum, and T10 vertebra) from CT of 89 NSCLC patients, which allowed us to identify an index for screening muscularity. Next, a tumor transcriptomic-based secretome analysis from these patients (discovery set) was evaluated to identify potential cachexia biomarkers in patients with low-muscularity. The prognostic value of these biomarkers for predicting recurrence and survival outcome was confirmed using expression data from eight lung cancer datasets (validation set). Finally, C2C12 myoblasts differentiated into myotubes were used to evaluate the ability of the selected biomarker, IL-8, in inducing muscle cell atrophy. We identified 75 over-expressed transcripts in patients with low-muscularity, which included IL6, CSF3, and IL8. Also, we identified NCAM1, CNTN1, SCG2, CADM1, IL8, NPTX1, and APOD as PSCB in the tumor secretome. These PSCB were capable of distinguishing worse and better prognosis (recurrence and survival) in NSCLC patients. IL8 was confirmed as a predictor of worse prognosis in all validation sets. In vitro assays revealed that IL-8 promoted C2C12 myotube atrophy. Tumors from low-muscularity patients presented a set of upregulated genes encoding for secreted proteins, including pro-inflammatory cytokines that predict worse overall survival in NSCLC. Among these up-regulated genes, IL8 expression in NSCLC tissues was associated with worse prognosis and the recombinant IL-8 was capable of triggering atrophy in C2C12 myotubes.

scholarly journals Tumor Transcriptome Reveals High Expression of IL-8 in Non-Small Cell Lung Cancer Patients with Low Pectoralis Muscle Area and Reduced Survival

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1251 ◽  
Author(s):  
Sarah Santiloni Cury ◽  
Diogo de Moraes ◽  
Paula Paccielli Freire ◽  
Grasieli de Oliveira ◽  
Douglas Venâncio Pereira Marques ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
C2c12 Myotubes ◽  
Pectoralis Muscle ◽  
Small Cell Lung ◽  
Nsclc Patients ◽  
Upregulated Genes ◽  
Worse Prognosis

Cachexia is a syndrome characterized by an ongoing loss of skeletal muscle mass associated with poor patient prognosis in non-small cell lung cancer (NSCLC). However, prognostic cachexia biomarkers in NSCLC are unknown. Here, we analyzed computed tomography (CT) images and tumor transcriptome data to identify potentially secreted cachexia biomarkers (PSCB) in NSCLC patients with low-muscularity. We integrated radiomics features (pectoralis muscle, sternum, and tenth thoracic (T10) vertebra) from CT of 89 NSCLC patients, which allowed us to identify an index for screening muscularity. Next, a tumor transcriptomic-based secretome analysis from these patients (discovery set) was evaluated to identify potential cachexia biomarkers in patients with low-muscularity. The prognostic value of these biomarkers for predicting recurrence and survival outcome was confirmed using expression data from eight lung cancer datasets (validation set). Finally, C2C12 myoblasts differentiated into myotubes were used to evaluate the ability of the selected biomarker, interleukin (IL)-8, in inducing muscle cell atrophy. We identified 75 over-expressed transcripts in patients with low-muscularity, which included IL-6, CSF3, and IL-8. Also, we identified NCAM1, CNTN1, SCG2, CADM1, IL-8, NPTX1, and APOD as PSCB in the tumor secretome. These PSCB were capable of distinguishing worse and better prognosis (recurrence and survival) in NSCLC patients. IL-8 was confirmed as a predictor of worse prognosis in all validation sets. In vitro assays revealed that IL-8 promoted C2C12 myotube atrophy. Tumors from low-muscularity patients presented a set of upregulated genes encoding for secreted proteins, including pro-inflammatory cytokines that predict worse overall survival in NSCLC. Among these upregulated genes, IL-8 expression in NSCLC tissues was associated with worse prognosis, and the recombinant IL-8 was capable of triggering atrophy in C2C12 myotubes.

scholarly journals The Prognostic Value of LDH And ADA in Serum and Pleural Fluid of Non-Small Cell Lung Cancer

2021 ◽  
Author(s):  
Shuang Zhao ◽  
Jun Zeng ◽  
Juanli Wu
Keyword(s):  
Lung Cancer ◽  
Pleural Effusion ◽  
Small Cell Lung Cancer ◽  
Pleural Fluid ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Diagnosis Method ◽  
Nsclc Patients ◽  
Worse Prognosis

Abstract Objective: To explore the value of dehydrogenase (LDH) and adenosine deaminase (ADA) in serum and pleural fluid in predicting the prognosis of non-small cell lung cancer.Methods: A total of 134 patients with non-small cell lung cancer (NSCLC) with pleural effusion were enrolled. LDH in Serum and LDH and ADA in pleural fluid were detected, and the cancer ratio (serum LDH/pleural fluid ADA ratio) was calculated. Patients were followed until death. To analyze the correlation between the above indicators and the clinical pathological characteristics of the patients, and the predictive value for the prognosis of the patients.Results: Among the included NSCLC patients with pleural effusion, the average age was 61.76 years old, mainly male (66.7%), the right lung was more common (47.2%), adenocarcinoma was the main (82.1%), and smoking patients accounted for 48.0%. In the diagnosis method, there were 94 cases were diagnosed by pleural fluid exfoliated cells or pleural biopsy. In terms of clinical features, serum LDH is only related to adrenal metastasis (p = 0.000), and pleural fluid LDH is related to the patient's pathological type (p = 0.001). There was no correlation between pleural fluid ADA or cancer ratio and patient gender, lesion location, pathological type, diagnosis method, smoking history, and metastatic location. In terms of prognostic value, patients with ADA < 20U/L and cancer ratio >20 have shorter overall survival and worse prognosis (​​p < 0.0001 and p = 0.0178, respectively). The multivariate Cox regression analysis suggested that the cancer ratio (HR = 1.699, 95%CI: 1.097–2.630, p = 0.017) was an independent risk factor for the poor prognosis of patients.Conclusion: The NSCLC patients with pleural fluid ADA < 20U/L and cancer ratio > 20 combined with pleural effusion had a shorter overall survival and worse prognosis.

scholarly journals miR-34c-3p targets CDK1 a synthetic lethality partner of KRAS in non-small cell lung cancer

2020 ◽  
Author(s):  
Francesco Palma ◽  
Alessandra Affinito ◽  
Silvia Nuzzo ◽  
Giuseppina Roscigno ◽  
Iolanda Scognamiglio ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Synthetic Lethality ◽  
Small Cell ◽  
In Vitro Assays ◽  
Prognostic Impact ◽  
Small Cell Lung ◽  
Nsclc Patients

Abstract Lung cancer is still the leading cause of death by cancer worldwide despite advances both in its detection and therapy. Multiple oncogenic driver alterations have been discovered, opening the prospective for new potential therapeutic targets. Among them, KRAS mutations represent the most frequent oncogene aberrations in non-small cell lung cancer (NSCLC) patients with a negative prognostic impact, but effective therapies targeting KRAS are not well characterized yet. Here, we demonstrate that the microRNA miR-34c-3p is a positive prognostic factor in KRAS-mutated NSCLC patients. Firstly, looking at the TGCA dataset, we found that high miR-34c-3p expression correlated with longer survival of KRAS-mutated NSCLC patients. In vitro assays on immortalized and patient-derived primary NSCLC cells revealed that miR-34c-3p overexpression increased apoptosis and lowered proliferation rate in KRASmut cells. Computational analysis and in vitro assays identified CDK1, one of the most promising lethal targets for KRAS-mutant cancer, as a target of miR-34c-3p. Moreover, the combination of CDK1 inhibition (mediated by RO3306) and miR-34c-3p overexpression resulted in an additive effect on the viability of KRASmut-expressing cells. Altogether, our findings demonstrate that miR-34c-3p is a novel biomarker that may allow tailored treatment for KRAS-mutated NSCLC patients.

Surrogates of response to treatment of non-small cell lung cancer with immunotherapy: Toxicity and leukocyte ratios—Experience of a center.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21052-e21052
Author(s):  
Alba Moratiel Pellitero ◽  
Ines Ruiz Moreno ◽  
Mara Cruellas ◽  
Natalia Alonso Marin ◽  
Maitane Ocáriz ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune System ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Neutrophil To Lymphocyte Ratio ◽  
Small Cell Lung ◽  
Lymphocyte Ratio ◽  
Nsclc Patients ◽  
Worse Prognosis

e21052 Background: Immunotherapy is proposed as a therapeutic novelty in metastatic non-small cell lung cancer (NSCLC), in many cases already in front line. It presents different adverse effects than traditional schemes, due to the stimulation of the immune system. There is a possible relationship between toxicity and response. Neutrophil-to-lymphocyte ratio (NLR) as a possible predictive factor of response. Objectives: Evaluating the response according to the toxicity degree in NSCLC patients in real clinical practice. Analyze whether pretreatment NLR high patients have a worse prognosis. Methods: Observational, retrospective, analytical, single-center study. HCULB stage IV NSCLC patients with inmunotherapy treatment during 2016-2018. Descriptive and multivariate analysis. Toxicity grade: CTCAE version 4.0. Response assessment: RECIST 2.0 and immunorelated criteria. Toxicity degree and response (global and individualized results according to treatment and histology). Neutrophil-to-lymphocyte ratio and response. Results: N = 43 patients (35 men, 8 women). Average age 64 years. Response: 3 complete response (CR) (toxicity ≥2), 13 partial response (PR) (toxicity ≥1), 13 stable disease (SD), 12 progression (P) (only 4 toxicity and ≤2), 2 not evaluated. Hypothyroidism as the most common irAE. Relationship between toxicity and response: the absence of irAEs conditions worse prognosis p < 0.05. Histology: 25 adenocarcinoma [18 with irAES (1 CR, 7 PR, 8 SD,) and 7 without (1 SD, 5 P, 1 no ev.)]; 17 squamous [13 with irAES (1 CR, 6 PR, 4 SD) and 4 without (3 P, 1 no ev.)]; 1 adenosquamous with irAES and CR. Drug: Atezolizumab N = 8 [6 with irAES (2 PR, 3 SD, 1 P) and 2 without (both P)], Nivolumab N = 16 [9 with irAES (1 CR, 3 PR, 3 SD, 2 P) and 7 without (1 SD, 4 P, 2 no ev.)], Pembrolizumab N = 19 [17 with irAEs (2 CR, 8 PR, 6 SD, 1 P) and 2 without (both P)]. Significant positive correlation between toxicity and response (p < 0.001) R = 0.067, (CI 99% 0.378-0.837), regardless of histology and drug. It is observed a better response in those patients who presented a NRL close to 3 or less at the beginning of treatment. On the contrary, it is observed that subjects with NRL greater than 4 obtained worse results when they were treated with immunotherapy. Conclusions: The appearance of irAES like a response indicator of immune system, seem to conditione better evolution. In contrast, the absence of toxicity predicts a worse prognosis. Further studies with a larger sample are needed to confirm our findings about the predictive value of NLR and optimize therapeutic regimens if necessary.

scholarly journals A Radioresponse-Related lncRNA Biomarker Signature for Risk Classification and Prognosis Prediction in Non-Small-Cell Lung Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Jiahang Song ◽  
Shuming Zhang ◽  
Yuanyuan Sun ◽  
Junjie Gu ◽  
Ziqi Ye ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Risk Model ◽  
Differential Expression Analysis ◽  
Small Cell ◽  
In Vitro Assays ◽  
Small Cell Lung ◽  
Nsclc Patients

Purpose. Radiotherapy resistance is now recognized as the major obstacle to the effective therapeutic management of non-small-cell lung cancer (NSCLC). As a single biomarker has limited effect in stratifying NSCLC patients, this research aimed to identify long non-coding RNAs (lncRNAs) correlated with radiotherapy response to ameliorate forecast of NSCLC prognosis. Methods. In a cohort of NSCLC patients with radiotherapy history (n = 96) from TCGA, genetic data of lncRNA expression profiling were performed. To identify radioresponse-related lncRNA sets which dysregulated significantly between radiosensitive (RS) and radioresistant (RR) groups, differential expression analysis was carried out. Cox relative regression was implemented to set up a radioresponse-related risk model. Moreover, we adopted survival analysis to measure the predictive potentiality of the prognosis model. Results. Four radioresponse-related lncRNAs (CASC19, LINC01977, LINC02471, and MAGI2-AS3) were screened to create a prognostic signature. Then, we described a lncRNA signature-based regulatory network and explored the correlation of the immune microenvironment and the signature. Additionally, in vitro assays uncovered inhibition of LINC01977 weakened radioresistance of NSCLC cells. Conclusion. We provided a novel radioresponse-related lncRNAs signature with excellent clinical potency for an effective prognostic forecast of patients.

scholarly journals Biomarkers and Gene Signatures to Predict Durable Response to Pembrolizumab in Non-Small Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3828
Author(s):  
Anello Marcello Poma ◽  
Rossella Bruno ◽  
Iacopo Pietrini ◽  
Greta Alì ◽  
Giulia Pasquini ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Cell ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Durable Response ◽  
Nsclc Patients

Pembrolizumab has been approved as first-line treatment for advanced Non-small cell lung cancer (NSCLC) patients with tumors expressing PD-L1 and in the absence of other targetable alterations. However, not all patients that meet these criteria have a durable benefit. In this monocentric study, we aimed at refining the selection of patients based on the expression of immune genes. Forty-six consecutive advanced NSCLC patients treated with pembrolizumab in first-line setting were enrolled. The expression levels of 770 genes involved in the regulation of the immune system was analysed by the nanoString system. PD-L1 expression was evaluated by immunohistochemistry. Patients with durable clinical benefit had a greater infiltration of cytotoxic cells, exhausted CD8, B-cells, CD45, T-cells, CD8 T-cells and NK cells. Immune cell scores such as CD8 T-cell and NK cell were good predictors of durable response with an AUC of 0.82. Among the immune cell markers, XCL1/2 showed the better performance in predicting durable benefit to pembrolizumab, with an AUC of 0.85. Additionally, CD8A, CD8B and EOMES showed a high specificity (>0.86) in identifying patients with a good response to treatment. In the same series, PD-L1 expression levels had an AUC of 0.61. The characterization of tumor microenvironment, even with the use of single markers, can improve patients’ selection for pembrolizumab treatment.

scholarly journals Circulating Biomarkers of Response and Toxicity of Immunotherapy in Advanced Non-Small Cell Lung Cancer (NSCLC): A Comprehensive Review

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1794
Author(s):  
Alice Indini ◽  
Erika Rijavec ◽  
Francesco Grossi
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Liquid Biopsy ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Circulating Biomarkers ◽  
Small Cell Lung ◽  
Nsclc Patients

Immune checkpoint inhibitors (ICIs) targeting the programmed cell death (PD)-1 protein and its ligand, PD-L1, and cytotoxic T-lymphocyte-associated antigen (CTLA)-4, have revolutionized the management of patients with advanced non-small cell lung cancer (NSCLC). Unfortunately, only a small portion of NSCLC patients respond to these agents. Furthermore, although immunotherapy is usually well tolerated, some patients experience severe immune-related adverse events (irAEs). Liquid biopsy is a non-invasive diagnostic procedure involving the isolation of circulating biomarkers, such as circulating tumor cells (CTC), cell-free DNA (cfDNA), and microRNAs (miRNAs). Thanks to recent advances in technologies, such as next-generation sequencing (NGS) and digital polymerase chain reaction (dPCR), liquid biopsy has become a useful tool to provide baseline information on the tumor, and to monitor response to treatments. This review highlights the potential role of liquid biomarkers in the selection of NSCLC patients who could respond to immunotherapy, and in the identification of patients who are most likely to experience irAEs, in order to guide improvements in care.

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