Recurrence Of Non-small Cell Lung Cancer Research Articles

Survival benefit of immune checkpoint inhibitor monotherapy in patients with non-small cell lung cancer recurrence after completely pulmonary resection.

BackgroundSelected patients in non-small cell lung cancer (NSCLC) responded to the treatment of immune checkpoint inhibitors (ICIs) have the survival benefit for advanced stages or metastatic status.MethodsWe investigated whether a response to ICI monotherapy since 2016 influences the survival of NSCLC patients with recurrence after completely pulmonary resection between 2009 and 2017. Disease control rate (DCR) was calculated as complete plus partial response plus stable disease during more than 6 months.ResultsThirty-five patients (mean age 67 years, range 46–79 years, 60% male) were included in the study. The most frequent histology and pathological stage were adenocarcinoma (60%) and IIB (45.7%), respectively. ICI was used at a median of second-line treatment. The DCR and median progression-free survival were 42.8% and 2.5 (95% CI: 1.6–3.4) months, respectively. The therapeutic outcome from recurrence was 47.5%. Multivariate analysis revealed a significant impact of DCR on favorable therapeutic outcome (P=0.04). A serial increase (pre- to post-surgery to ICI initiation) of C-reactive protein (CRP) and prognostic nutritional index (PNI) was associated with treatment response (both P=0.01).ConclusionsThese results suggest that a response to ICI monotherapy significantly contributes to a survival benefit regardless of therapeutic lines in NSCLC patients with recurrence after completely pulmonary resection, and the therapeutic response is strongly associated with a serial increase in CRP or decrease in prognostic nutritional index.

Recurrence and disease-free survival outcomes after computed tomography-guided needle biopsy in stage IA non-small cell lung cancer patients in China: a propensity score matching analysis.

Whether preoperative biopsy before radical resection can lead to recurrence and impact patient survival in non-small cell lung cancer (NSCLC) remains controversial. In this study, we carried out a retrospective analysis to determine whether preoperative biopsy can cause disease recurrence and influence disease-free survival (DFS) in patients with stage IA NSCLC. Patients diagnosed with stage IA NSCLC (solid nodule) between January 2010 and December 2014 were identified from the databases of 7 Chinese medical centers and divided into two groups: a preoperative computed tomography (CT)-guided needle biopsy (CTNB) plus radical resection group, and a non-CTNB group. The propensity score matching (PSM) method was adopted to balance the observed covariates, and Kaplan-Meier estimates were used for survival analysis. Cox regression was used in a single-factor analysis to identify the factors affecting DFS in stage IA NSCLC. After initial screening, 730 patients were enrolled in this study, with 186 and 544 patients in the CTNB group and the non-CTNB group, respectively. After PSM, 186 patients were eventually included in each group. No significant differences in basic clinical features were identified between the two groups (P>0.05). The rates of recurrence were 17.2% and 14.0% in the CTNB and non-CTNB groups (χ2=0.735, P=0.391), respectively. No notable differences in DFS (χ2=1.895, P=0.173) or overall survival (OS, χ2=1.785, P=0.182) were observed. Lung adenocarcinoma [hazard ratio (HR), 0.167, P=0.001] and lesion size (>2 cm) (HR, 2.712, P=0.000) were identified as risk factors for DFS in stage IA NSCLC. CTNB does not increase the incidence of recurrence in stage IA NSCLC or affect patient survival; therefore, it is not a risk factor for DFS. Lung adenocarcinoma and lesion size are risk factors for DFS.

Effects of Vasculogenic Mimicry on Postoperative Recurrence and Progression of Non-Small Cell Lung Cancer

Vasculogenic mimicry (VM) in lung cancer shortens overall survival (OS) but its’ associations with postoperative recurrence and progression of early non-small cell lung cancer (NSCLC) remain unclear. The purpose of this study was to analyze the association of VM with postoperative recurrence and progression of NSCLC as well as the effect of VM on postoperative recurrence-free survival (RFS). This study included NSCLC patients and detected VM in surgical specimens. The associations of VM with the recurrence and progression were analyzed to assess the effect of VM on postoperative RFS in NSCLC. A total of 80 NSCLC cases were followed up for 3 years. During follow-up, 35 cases showed recurrence and progression where 5 (6.25%) cases had simple local recurrence and the other 30 (37.5%) cases had distant metastasis. The recurrence and progression rates in the first, second, and third years were 12.50%, 23.75%, and 7.50%, respectively. The median RFS was 14.2 months. VM was detected in 30 out of 80 cases and was significantly correlated with tumor differentiation (r = 0.365) and clinical stage (r = 0.374) (both, P = 0.001). Local recurrence of NSCLC was not correlated with VM, unlike distant metastasis (r = 0.598, P < 0.001). Average RFS was significantly longer in NSCLC patients without VM compared with the VM group 3 years post-operation (32 months versus 18 months, log-rank test P < 0.001). Considering these, VM is significantly correlated with postoperative distant metastasis of NSCLC in which it is of a certain value for predicting poor prognosis in NSCLC.

Abstract 67: Paralleled convergence of antigen load, disease progression and systemic T cell exhaustion in lung cancer and HIV-1 infection

Abstract Fatal immune failure in untreated HIV-1 infection is co-defined by evolution of viral escape mutants, increasing antigen diversity and concomitant T cell exhaustion. We have recently described mutational heterogeneity as a negative prognostic factor in primary non-small cell lung cancer (NSCLC), highlighted pathways of neoantigen-driven immune escape and reported a program of TMB-associated T cell exhaustion. Here we present interim analysis from a direct comparison of antigen evolution, peripheral T cell exhaustion and disease progression in 279 longitudinal samples from 64 HIV-1 infected volunteers in the retrospective IAVI protocol C cohort and 85 longitudinal samples from 35 NSCLC patients in the TRACERx study. Systemic PD1hi TOX+TCF7- Tex cell subsets were associated with virus load and CD4 loss in HIV-1 infection and tumour burden and disease progression in NSCLC. Levels of systemic Tex cells in NSCLC tracked with the extent of compartment-wide intra-tumoral CD4 and CD8 T cell dysfunction. Tex populations contracted upon antigen loss via ART in HIV-1, a process paralleled during surgical resection in NSCLC. Resurrection of systemic Tex populations was observed at disease recurrence in NSCLC, mediated in-part by post-operative persistence and re-expansion of minor circulating Tex subsets. These data highlight a common convergence of T cell exhaustion, antigen load and disease progression in distinct clinical conditions of impaired immune surveillance and chronic antigen stimulation. Citation Format: James L. Reading, Rachel Rosenthal, Lucas Black, Seng Kuong Ung, Claire Streatfield, Dominic Wooding, Joakim Esbjornsson, Eric Hunter, Sergio A. Quezada, Jonathan Hare, Charles Swanton. Paralleled convergence of antigen load, disease progression and systemic T cell exhaustion in lung cancer and HIV-1 infection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 67.

Immunotherapy and Vaccination in Surgically Resectable Non-Small Cell Lung Cancer (NSCLC).

Early-stage NSCLC (stages I and II, and some IIIA diseases) accounts for approximately 30% of non-small cell lung cancer (NSCLC) cases, with surgery being its main treatment modality. The risk of disease recurrence and cancer-related death, however, remains high among NSCLC patients after complete surgical resection. In previous studies on the long-term follow-up of post-operative NSCLC, the results showed that the five-year survival rate was about 65% for stage IB and about 35% for stage IIIA diseases. Platinum-based chemotherapy with or without radiation therapy has been used as a neoadjuvant therapy or post-operative adjuvant therapy in NSCLC, but the improvement of survival is limited. Immune checkpoint inhibitors (ICIs) have effectively improved the 5-year survival of advanced NSCLC patients. Cancer vaccination has also been explored and used in the prevention of cancer or reducing disease recurrence in resected NSCLC. Here, we review studies that have focused on the use of immunotherapies (i.e., ICIs and vaccination) in surgically resectable NSCLC. We present the results of completed clinical trials that have used ICIs as neoadjuvant therapies in pre-operative NSCLC. Ongoing clinical trials investigating ICIs as neoadjuvant and adjuvant therapies are also summarized.

A Model-free Approach for Testing Association.

The question of association between outcome and feature is generally framed in the context of a model based on functional and distributional forms. Our motivating application is that of identifying serum biomarkers of angiogenesis, energy metabolism, apoptosis, and inflammation, predictive of recurrence after lung resection in node-negative non-small cell lung cancer patients with tumor stage T2a or less. We propose an omnibus approach for testing association that is free of assumptions on functional forms and distributions and can be used as a general method. This proposed maximal permutation test is based on the idea of thresholding, is readily implementable and is computationally efficient. We demonstrate that the proposed omnibus tests maintain their levels and have strong power for detecting linear, nonlinear and quantile-based associations, even with outlier-prone and heavy-tailed error distributions and under nonparametric setting. We additionally illustrate the use of this approach in model-free feature screening and further examine the level and power of these tests for binary outcome. We compare the performance of the proposed omnibus tests with comparator methods in our motivating application to identify preoperative serum biomarkers associated with non-small cell lung cancer recurrence in early stage patients.

Multiomics analysis reveals high-immune infiltration in tumor-adjacent lung tissues affects the prognosis of stage I NSCLC.

8540 Background: Along with the wide application of low-dose spiral CT in lung cancer screening, a large number of resectable patients with lung cancer are identified, especially stage I Non-Small Cell Lung Cancer (NSCLC). However, their prognosis varies greatly and 5-year recurrence rate of stage I NSCLC is around 30%. Therefore, it is crucial to explore the potential mechanism of recurrence of early NSCLC. Methods: Eighty-seven patients with stage I NSCLC were enrolled from April 2008 to July 2015, including 79 squamous carcinoma and 28 adenocarcinoma. Frozen tumor tissues and paired tumor-adjacent lung tissues were collected to employ targeted panel sequencing, RNA sequencing and TCR repertoire sequencing. Results: Ninety-five non-silent mutations were detected in tumor-adjacent lung tissues with a median tumor mutation burden of 1.5/Mb, significantly lower than that in tumor tissues (11/Mb), p < 0.05. 42 mutations were specifically detected in the adjacent normal tissues, enriching in the immune response pathways. Comparing with paired tumors, tumor-adjacent lung tissues were found more favorable immune infiltration including higher immune cell activity like CD8+ T cell (0.50 vs 0.43, p < 0.0001), up-regulated immune-associated pathways, higher TCR clonality (0.19 vs 0.18, p < 0.05), less loss of heterozygosity (LOH) of human leukocyte antigen (HLA) (6.25% vs 50%, p < 0.0001) and observed predicted neoantigens expression (1 vs 128, p < 0.01). However, more shared viral-associated TCRs in tumor and tumor-adjacent tissues were found using the GLIPH algorithm. Prognostic analysis showed patients with higher overlap of TCR in tumors and tumor-adjacent lung tissues were prone to recur in five years. Furthermore, patients with higher immune infiltration in tumor-adjacent lung tissues had favorable outcomes than those with lower immune infiltration (HR: 0.37 for DFS, p < 0.05, HR: 0.31 for OS, p < 0.05), irrelevant of the infiltration level in tumor tissues. Conclusions: Immune microenvironment in tumor-adjacent lung tissues plays important roles in progress of stage I NSCLC.

Residual ctDNA after treatment predicts early relapse in patients with early-stage NSCLC.

8517 Background: Liquid biopsies based on circulating tumor DNA (ctDNA) analysis are being investigated for detection of residual disease and recurrence. Conclusive evidence for utility of ctDNA in early-stage non-small cell lung cancer (NSCLC) is awaited. Due to low ctDNA levels in early-stage disease or post-treatment, effective methods require high analytical sensitivity to detect mutant allele fractions (MAF) below 0.01%. Methods: We analysed 363 plasma samples from 88 patients with NSCLC recruited to the LUng cancer CIrculating tumour DNA (LUCID) study, with disease stage I (49%), II (28%) and III (23%). 62% were adenocarcinomas. Plasma was collected before and after treatment, and at 3, 6 and 9 months after surgery (N = 69) or chemoradiotherapy (N = 19). Additional plasma was collected at disease relapse for 17 patients. Median follow-up was 3 years, and 40 patients progressed or died of any cause. We employed the RaDaR™ assay, a highly sensitive personalized assay using deep sequencing of up to 48 tumor-specific variants. Variants identified by tumor exome analysis were tested by deep sequencing of tumor tissue and buffy coat DNA to verify somatic mutations and exclude clonal hematopoiesis. The RaDaR assay demonstrated 90% sensitivity at 0.001% MAF in analytical validation studies. Results: ctDNA was detected in 26% of samples, at median MAF of 0.047% (range: 0.0007% to > 2%), and prior to treatment in 87%, 77% and 24% for disease stage III, II and I respectively. For 62 patients, plasma was collected at a landmark timepoint, between 2 weeks and 4 months after initial treatment. ctDNA detection at the landmark timepoint was strongly predictive of clinical disease relapse, with Hazard Ratio of 20.7 (CI: 7.7-55.5, p-value < 0.0001). All 11 cases with ctDNA detected at landmark had disease progression, a median of 121 days after detection, and these included all 8 patients that relapsed within 300 days of treatment. Across 27 patients whose disease progressed during the study, ctDNA was detected at any timepoint post-treatment in 17 cases, with a median lead time of 203 days, and up to 741 days prior to clinical progression. ctDNA was detected post-treatment, in 13 of the 15 patients that progressed and had ctDNA detected prior to treatment. Conclusions: Our results support an emerging paradigm shift, by demonstrating that liquid biopsies can reliably detect recurrence of NSCLC at a preclinical stage, many months before clinical progression, thereby offering the opportunity for earlier therapeutic intervention. Clinical trial information: NCT04153526.

Circulating CD15+ LOX-1+ PMN-MDSCs are a potential biomarker for the early diagnosis of non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is the most common clinical lung cancer. Polymorphonuclear-myeloid derived suppressor cells (PMN-MDSCs), which are the major population of MDSCs, are involved in NSCLC progression. Recently, it was found that lectin-type oxidized LDL receptor 1 (LOX-1) could identify human PMN-MDSCs. However, the role of CD15+ LOX-1+ PMN-MDSCs in NSCLC early diagnosis has not been revealed. Here, we tried to confirm the application of the newly identified CD15+ LOX-1+ PMN-MDSCs in the early diagnosis of NSCLC. Flow cytometry (FCM) was used to detect the proportion of CD15+ LOX-1+ PMN-MDSCs in the peripheral blood (PB) of healthy controls (HC) and NSCLC patients. The correlation of CD15+ LOX-1+ PMN-MDSC frequency with levels of cytokeratin 19-fragments (CYFRA21-1), carcinoembryonic antigen (CEA), and carbohydrate antigen 125 (CA125) was analysed. Receiver operating characteristic (ROC) curve was used to estimate the diagnostic efficacy of CD15+ LOX-1+ PMN-MDSCs for NSCLC. Additionally, the association of CD15+ LOX-1+ PMN-MDSC frequency with NSCLC prognosis/recurrence after surgery was explored. The proportion of CD15+ LOX-1+ PMN-MDSCs increased in PB of NSCLC patients. CD15+ LOX-1+ PMN-MDSC proportion was positively correlated with levels of CEA, CA125 and CYFRA21-1. Detection of PMN-MDSC percentage in PB owed high sensitivity and specificity for NSCLC diagnosis. The proportion of CD15+ LOX-1+ PMN-MDSCs decreased in patients after surgery. The frequency of CD15+ LOX-1+ PMN-MDSCs was lower in NSCLC patients without recurrence compared to those with recurrence after surgery. Circulating CD15+ LOX-1+ PMN-MDSCs are a potential diagnostic marker for NSCLC, and are associated with NSCLC prognosis and recurrence after surgery.

Preoperative inflammation-based scores predict early recurrence after lung cancer resection.

BackgroundInflammation in the tumor microenvironment is hypothesized to have a major role in cancer invasiveness, progression, and metastases. The purpose of this study was to evaluate the prognostic value of preoperative inflammation-based scores in terms of estimating the timing of recurrence by hazard curves in a cohort of operable, early-stage non-small cell lung cancer (NSCLC) patients.MethodsA total of 387 patients with NSCLC who underwent complete pulmonary resection from 2010 to 2019 had their C-reactive protein-to-albumin ratio (CAR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), Glasgow prognostic score (GPS), modified GPS, systemic immune-inflammation index (SII), and advance lung cancer inflammation index (ALI) measurements taken before surgery. Hazard curves indicating changes in hazards over time were evaluated.ResultsMedian follow-up was 39.2 months. In total, 105 patients (27.1%) experienced recurrence. The resulting hazard curve with elevated CAR, SII, GPS, and mGPS, values displayed an initial high peak during the first year. Multivariate analyses showed that an elevated CAR [hazard ratio (HR), 1.987; 95% confidence interval (CI), 1.202–3.284] independently predicted the recurrence-free survival. Even in stage I disease, patients with elevated CAR and SII values showed an earlier peak of recurrence, which was about 12 to 16 months earlier than those with low values.ConclusionsEven after complete resection of stage I NSCLC, patients with elevated CAR and SII values retain a high risk of early recurrence. Preoperative inflammation-based scores can be an objective, simple, and cost-effective measurement for predicting early recurrence of NSCLC.

Quantification of BIM mRNA in circulating tumor cells of osimertinib-treated patients with EGFR mutation-positive lung cancer

The response rate for osimertinib is high among patients with untreated epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, there exist no biomarkers to predict the efficacy of the same. This study investigated whether BIM-γ mRNA expression in circulating tumor cells (CTCs) predicts poor outcomes for osimertinib treatment in patients with EGFR mutation-positive NSCLC. Patients with advanced EGFR-tyrosine kinase inhibitor-untreated NSCLC or post-operative recurrence with EGFR-sensitive mutations (exon 19 deletion or L858R mutation) were included. Informed consent was obtained from all participants. The candidate biomarker BIM-γ was measured in CTCs after blood collection (10mL of whole blood) at baseline. CTCs were collected with the ClearCell FX system, and quantitative real-time PCR was performed. Relative expression of BIM-γ mRNA from CTCs, as normalized to the reference gene (GAPDH mRNA), was calculated using the KCL22cell line for calibration. We enrolled 30 EGFR mutation-positive NSCLC patients treated with osimertinib during the period from April 2018 through December 2019. All the patients had an EGFR mutation at the primary site: exon 19 deletion in 15 cases and L858R in 15 cases. Median CTC count at baseline was 12 (range 3-127)/7.5mL, and median BIM-γ mRNA expression was 0.073 (range 0-1.37). Furthermore, the response rate to osimertinib was worse in patients with high than in those with low BIM-γ mRNA expression (n=15 each) (26.6% vs. 73.3%, respectively; p=0.011). Progression-free survival did not significantly differ between groups (p=0.13). BIM-γ mRNA overexpression in CTCs from EGFR mutation-positive NSCLC patients is a potential a biomarker for poor response to osimertinib. UMIN:00032055.

GOLM1 predicts poor prognosis of patients with NSCLC and is associated with the proliferation and chemo-sensitivity of cisplatin in NSCLC cells: bioinformatics analysis and laboratory validation.

Lung cancer is one of the deadliest malignant tumors with non-small cell lung cancer (NSCLC) being the most prevalent type. Patients with NSCLC usually were diagnosed at the advance clinical stages, and these patients often had high rate of tumor-recurrence, thus leading to poor prognosis. Yet, the molecular mechanisms underlying NSCLC progression and recurrence are largely unknown. This study aimed to identify potential hub genes associated with the pathophysiology of NSCLC by bioinformatics analysis and laboratory validation. The GSE51852, GSE52248 and GSE75037 datasets were downloaded from the Gene Expression Omnibus database. The overlapping differentially expressed genes (DEGs) were analyzed by GEO2R tool. Gene Ontology (GO) and KEGG pathway enrichment analysis were performed on these overlapping DEGs. The protein-protein interaction network was constructed to identify hub genes from DEGs. The expression and survival analysis of these hub genes were performed by using the integrated bioinformatics tools. Finally, the effects of GOLM1 on the proliferation and chemo-sensitivity of NSCLC cells were determined by in vitro functional assays. A total of 197 overlapping DEGs (37 up-regulated and 160 down-regulated) were identified from the microarray datasets. Furthermore, the PPI network with 89 nodes and 768 edges was constructed and 17 hub genes were identified from PPI network by using MCODE analysis. The survival analysis revealed that the expression of 5 hub genes (FGF2, GOLM1, GPC3, IL6 and SPP1) were significantly correlated with overall survival of patients with lung cancer. Furthermore, the in vitro functional studies showed that GOLM1 overexpression promoted the NSCLC cell proliferation and colony formation; while GOLM1 knockdown exerted the opposite effects. Importantly, GOLM1 overexpression reduced the chemo-sensitivity of cisplatin in NSCLC cells by attenuating the inhibitory effects of cisplatin on the cell proliferation and colony formation. In conclusion, the present study showed that 5 hub genes including FGF2, GOLM1, GPC3, IL6 and SPP1 were deregulated in NSCLC tissues and may predict the prognosis of patients with NSCLC. GOLM1 may play an important role in regulating the cell proliferation and chemo-sensitivity of cisplatin in NSCLC.

Mechanisms of resistance to chemotherapy in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), which represents 80-85% of lung cancer cases, is one of the leading causes of human death worldwide. The majority of patients undergo an intensive and invasive treatment regimen, which may include radiotherapy, chemotherapy, targeted therapy, immunotherapy, or a combination of these, depending on disease stage and performance status. Despite advances in therapeutic regimens, the 5-year survival of NSCLC is approximately 20-30%, largely due to diagnosis at advanced stages. Conventional chemotherapy is still the standard treatment option for patients with NSCLC, especially those with advanced disease. However, the emergence of resistance to chemotherapeutic agents (chemoresistance) poses a significant obstacle to the management of patients with NSCLC. Therefore, to develop efficacious chemotherapeutic approaches for NSCLC, it is necessary to understand the mechanisms underlying chemoresistance. Several mechanisms are known to mediate chemoresistance. These include altered cellular targets for chemotherapy, decreased cellular drug concentrations, blockade of chemotherapy-induced cell cycle arrest and apoptosis, acquisition of epithelial-mesenchymal transition and cancer stem cell-like phenotypes, deregulated expression of microRNAs, epigenetic modulation, and the interaction with tumor microenvironments. In this review, we summarize the mechanisms underlying chemoresistance and tumor recurrence in NSCLC and discuss potential strategies to avoid or overcome chemoresistance.

Circulating tumor cells can predict the prognosis of patients with non-small cell lung cancer after resection: a retrospective study.

BackgroundThe development of metastasis is the primary cause of death in patients with non-small cell lung cancer (NSCLC). However, identifying those NSCLC patients who will have loco-regional or distant disease recurrence after surgery is still challenging. Circulating tumor cells (CTCs) can accurately reflect the impact of micro-metastasis of tumor cells in circulating blood on patients’ treatment and prognosis. The aim of the present study was to explore the value of preoperative CTC concentration in predicting postoperative metastasis and recurrence risk in patients with NSCLC.MethodsThis study enrolled 347 patients with stage I–IIIA NSCLC. The CTCs were isolated using folate receptor (FR) positivity from peripheral blood samples before surgery, and then enriched and analyzed. Patients were divided into two groups for retrospective survival analysis based on the geometric mean of CTC concentration. The primary study endpoint was recurrence-free survival. Spearman’s correlation was used to evaluate the relationship between CTC concentration and clinical characteristics of NSCLC patients. A nomogram based on the multivariate Cox regression model was developed to predict recurrence and metastasis in the NSCLC patients. The performance of the nomogram was evaluated using the concordance index, calibration curve, and Hosmer-Lemeshow test.ResultsThe median follow-up time was 38 months. Preoperative CTC concentration was not significantly related to tumor-node-metastasis staging (P>0.05) and was an independent prognostic factor for NSCLC patients [hazard ratio (HR), 5.489; 95% confidence interval (CI): 2.660–11.326, P<0.001]. The nomogram based on preoperative CTC concentration had a concordance index value of 0.82. Validation revealed that the nomogram possessed excellent predictive ability and calibration.ConclusionsPreoperative CTC concentration is an independent and sensitive biomarker of prognosis in patients with NSCLC. Our nomogram based on preoperative CTC concentration is an effective and non-invasive tool for predicting the recurrence and metastasis of NSCLC.

Can the Japanese National Clinical Database risk calculator predict long-term survival of patients who undergo palliative segmentectomy for primary lung cancer?

ObjectivesSelection criteria for palliative limited surgery in patients with non-small cell lung cancer (NSCLC) can vary by institution or surgeon. We retrospectively reviewed outcomes of poor-risk patients who underwent palliative segmentectomy (PS), using the National Clinical Database Risk Calculator (RC).MethodsWe retrospectively analyzed medical records of patients with NSCLC tumors ≥ 20 mm and consolidation/tumor ratios ≥ 0.5 on computed tomography, who underwent PS from January 2009 to March 2016. Median follow-up time was 47 months (range 2–102 months).ResultsWe enrolled 67 patients (median age: 73.0 years), of whom 54 received thoracoscopic surgery and 28 received medial lymph-node dissection. The RC’s mean predictive probability rate for perioperative mortality or severe complications was 7.1%. Of the 67 patients, 24 patients (43.0%) suffered post-surgical complications, including 2 (3%) who died in hospital; 17 eventually suffered NSCLC recurrences and/or metastases, 11 eventually died from NSCLC, and 17 died from other diseases. Five-year overall survival (OS) was 59.4%. When the patients were divided into high-risk (HR) and low-risk (LR) groups based on the RC, 5-year OS was significantly less in the HR group (43.9%) than in the LR group (82.2%; P < 0.05).ConclusionThe RC, which was developed primarily to determine perioperative risk, can predict long-term prognosis for compromised patients who undergo PS.

Combined prognostic value of the SUVmax derived from FDG-PET and the lymphocyte-monocyte ratio in patients with stage IIIB-IV non-small cell lung cancer receiving chemotherapy

BackgroundWe evaluated the prognostic potential of tumor 18F-fluorodeoxyglucose (FDG) uptake derived from positron emission tomography (PET) and known inflammatory hematological markers, both individually and in combination, for chemosensitivity and survival in patients with stage IIIB-IV non-small cell lung cancer (NSCLC) receiving first-line chemotherapy.MethodsA total of 149 patients with stage IIIB and IV NSCLC (based on TNM 7th edition) were retrospectively reviewed. Maximum standardized uptake value (SUVmax) were used to quantitatively assess FDG uptake. The lymphocyte-monocyte ratio (LMR), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were selected as hematological markers. Receiver operating characteristic (ROC) curves were constructed for the determination of optimal cut-off values to predict chemotherapeutic response.ResultsPatients with SUVmax > 11.6 or LMR ≤3.73 exhibited a significantly lower objective response rate (ORR) to chemotherapy (p < 0.001 and p < 0.001). Through multivariable logistic regression analysis, both the SUVmax and LMR were identified as independent predictive factors for chemotherapeutic response (p = 0.001 and p < 0.001). Furthermore, a multivariable Cox proportional hazard model identified a high SUVmax (> 11.6) and low LMR (≤3.73) as independent predictors of poor PFS (p < 0.001 and p = 0.025) and OS (p < 0.001 and p = 0.032). A novel score system was constructed based on the SUVmax and LMR (SUV_LMR score), and patients were stratified into three subgroups. The patients with a score of 0 had a significantly higher ORR (88.9%) than did those with a score of 1 (59.6%) and score of 2 (25.0%) (p < 0.001). Moreover, multivariable Cox analysis further identified the SUV_LMR score as an independent prognostic factor for PFS (p < 0.001) and OS (p < 0.001).ConclusionsPre-treatment SUVmax and LMR were not only predictive factors for chemotherapeutic response but also independent prognostic factors of survival in stage IIIB-IV NSCLC. Moreover, the SUV_LMR score, which is based on primary tumor metabolic activity and the systemic inflammatory response, might provide a promising tool to predict chemosensitivity, recurrence and survival of advanced NSCLC.

Clinical utility of the C-reactive protein:albumin ratio in non-small cell lung cancer patients treated with nivolumab.

BackgroundNivolumab is a second‐line chemotherapy for non‐small cell lung cancer (NSCLC). This study explored the impact of clinical biomarkers such as neutrophil:lymphocyte ratio (NLR), C‐reactive protein:albumin ratio (CAR), and modified Glasgow prognostic score on the efficacy and outcome of nivolumab monotherapy in previously treated NSCLC patients.MethodsWe retrospectively analyzed advanced or postoperative recurrence of NSCLC in 113 patients in two Japanese facilities from January 2015 to December 2019. Optimal cutoff values of NLR and CAR were assessed by the area under the receiver operating characteristic curves predicting death events to conduct regression analysis. Baseline values and values collected eight weeks after nivolumab treatment were measured to investigate time‐series changes of these markers.ResultsThe patients showed median overall survival (OS) and progression‐free survival (PFS) of 14.0 months and 2.3 months, respectively, with both being significantly longer in patients with partial response (PR) than in patients with progressive disease (PD). Optimal cutoff levels for NLR and CAR were 5.8 and 0.83, with significant decrease in CAR (P = 0.002) from baseline levels in PR patients and significant increase in PD patients. Baseline CAR ≥0.83 was significantly associated with one‐year mortality events and overall survival (OS), and multivariate analysis showed significant association of age ≤70 years, an Eastern Cooperative Oncology Group performance status score of 2 or 3, and a baseline CAR ≥0.83 with inferior OS.ConclusionsFor second‐line nivolumab therapy, evaluation of baseline CAR and subsequent changes in CAR may be predictive of therapeutic response to nivolumab and long‐term survival in NSCLC patients.Key points Significant findings of the study The baseline value of C‐reactive protein:albumin ratio was significantly associated with one‐year mortality and overall survival in non‐small cell lung cancer patients treated with nivolumab. What this study adds Time‐series change of C‐reactive protein:albumin ratio may be useful for predicting the treatment efficacy in patients treated with nivolumab.

Thermal treatment decreases resistance to osimertinib in non-small cell lung cancer through the EGFR/PI3K/AKT pathway.

Osimertinib (OSI) resistance commonly occurs during the treatment of non-small-cell lung cancer (NSCLC). This study aims to investigate whether the thermal effects of radiofrequency ablation (RFA) can increase the sensitivity of OSI-resistant NSCLC to OSI treatment and whether OSI effectively inhibits the recurrence of OSI-resistant NSCLC following RFA treatment and improve survival of NSCLC patients. In vitro, OSI-resistant NCI-H1975 (NCI-H1975/OSIR) cells and thermotolerant NCI-H1975/OSIR (NCI-H1975/OSIR-a-h) cells were established using human NSCLC cell line NCI-H1975. Cell viability, apoptosis, sensitivity to OSI, threonine-methionine amino acid substitution at position 790 (T790M) mutation levels, and protein expression of epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), hypoxia-inducible factor-1 alpha (HIF-1a) were detected using different methods. In vivo, a nude mouse model of metastatic human lung cancer was developed and subjected to RFA treatment. The tumor growth, apoptosis, sensitivity to OSI, expression of EGFR/PI3K/AKT/HIF-1a, and CD34 levels were detected in the micrometastases of the transition zone (TZ) around the central ablation zone, and the reference zone (RZ) far from central ablation zone. NCI-H1975/OSIR and thermotolerant NCI-H1975/OSIR cell models were successfully established. Thermotolerant NCI-H1975/OSIR cells show higher sensitivity to OSI than NCI-H1975/OSIR cells and NCI-H1975 cells. OSI treatment can inhibit the EGFR/PI3K/AKT pathway and induce apoptosis in both NCI-H1975 cells and thermotolerant NCI-H1975/OSIR cells, but not in NCI-H1975/OSIR cells. In vivo, RFA treatment increases sensitivity to OSI in NCI-H1975/OSIR cell micrometastases in the TZ but not in the RZ. OSI intervention effectively inhibits the over-proliferation of micrometastases and activation of the EGFR/PI3K/AKT pathway, and induces apoptosis of micrometastases in the TZ, but shows little effects on the micrometastases in the RZ. The thermal effects can increase the sensitivity of OSI-resistant NSCLC cells to OSI through the EGFR/PI3K/AKT/HIF-1a signaling pathway, indicating that RFA combined with OSI might be a clinically effective and comprehensive therapy for the treatment of OSI-resistant NSCLC.

Tie2-expressing monocytes as a novel angiogenesis-related cellular biomarker for non-small cell lung cancer.

To investigate the clinical value of Tie2-expressing monocytes (TEMs) in the early diagnosis of lung cancer and assess its correlation with angiogenesis, a total of 184 patients with non-small cell lung cancer (NSCLC), 101 patients with benign pulmonary disease (BPD), and 77 healthy controls were enrolled in our study. The distribution of TEMs in lung tissue was determined by immunofluorescence staining. Lung microvascular density was assessed by immunohistochemical staining. Receiver-operating characteristic (ROC) curve analysis was performed to assess the diagnostic value of TEM frequency. Patients with NSCLC were followed up for 26 months. We found that the TEM frequency in peripheral blood monocytes of patients with NSCLC was significantly greater than that in patients with BPD and healthy controls. TEM frequency showed a correlation with NSCLC recurrence. The majority of TEMs in tumor tissues were localized around blood vessels; tumoral TEM frequency showed a positive correlation with microvascular density. High percentage of TEMs in the peripheral blood was associated with poor overall survival. ROC curve analysis revealed the potential diagnostic value of circulating TEM frequency in NSCLC. Thus, we believe that TEM frequency is related to angiogenesis in tumor tissues and may serve as a diagnostic marker for NSCLC.

Caspase-3 knockout attenuates radiation-induced tumor repopulation via impairing the ATM/p53/Cox-2/PGE2 pathway in non-small cell lung cancer.

Radiotherapy is an effective treatment for non-small cell lung cancer (NSCLC). However, irradiated, dying tumor cells generate potent growth stimulatory signals during radiotherapy that promote the repopulation of adjacent surviving tumor cells to cause tumor recurrence. We investigated the function of caspase-3 in NSCLC repopulation after radiotherapy. We found that radiotherapy induced a DNA damage response (DDR), activated caspase-3, and promoted tumor repopulation in NSCLC cells. Unexpectedly, caspase-3 knockout attenuated the ataxia-telangiectasia mutated (ATM)/p53-initiated DDR by decreasing nuclear migration of endonuclease G (EndoG), thereby reducing the growth-promoting effect of irradiated, dying tumor cells. We also identified p53 as a regulator of the Cox-2/PGE2 axis and its involvement in caspase-3-induced tumor repopulation after radiotherapy. In addition, injection of caspase-3 knockout NSCLC cells impaired tumor growth in a nude mouse model. Our findings reveal that caspase-3 promotes tumor repopulation in NSCLC cells by activating DDR and the downstream Cox-2/PGE2 axis. Thus, caspase-3-induced ATM/p53/Cox-2/PGE2 signaling pathway could provide potential therapeutic targets to reduce NSCLC recurrence after radiotherapy.