Invasive Non-small Cell Lung Cancer Research Articles

ASO Author Reflections: Long-Term Follow-Up Results of Stage IA Invasive Non-Small Cell Lung Cancer Patients.

ASO Author Reflections: Long-Term Follow-Up Results of Stage IA Invasive Non-Small Cell Lung Cancer Patients.

Ten-Year Follow-Up of Lung Cancer Patients with Resected Stage IA Invasive Non-Small Cell Lung Cancer.

The purpose of this study was to assess 10-year follow-up outcomes after surgical resection in patients with stage IA invasive non-small cell lung cancer (NSCLC) based on postoperative pathological diagnosis. Patients with stage IA invasive NSCLC who underwent resection between December 2008 and December 2013 were reviewed. Patients were categorized into the pure-ground glass opacity (pGGO), mixed-ground glass opacity (mGGO), and solid groups based on consolidation to tumor ratio (CTR). Postoperative survival and risk of recurrence and developing secondary primary lung cancer were analyzed in each group. Among the 645 stage IA invasive NSCLC, the 10-year overall survival and recurrence-free survival rate was 79.38% and 77.44%, respectively. The 10-year overall survival for pGGO, mGGO, and solid group of patients was 95.08%, 86.21%, and 72.39%, respectively. The respective recurrence-free survival rate was 100%, 89.82%, and 65.83%. Multivariable Cox regression analysis associated tumor size and GGO components with recurrence and younger age, and tumors with GGO components were associated with longer overall survival. The cumulative incidence curve indicated no recurrence of GGO lung cancer ≥ 5 years postoperatively. Our cohort indicated that the number and stations of dissected lymph node did not influence long-term prognosis of IA invasive NSCLC. Recurrence of invasive stage IA NSCLC with GGO was more prevalent in patients with tumor size >1cm and CTR > 0.5, occurring within 5 years after surgery. This will provide important evidence for follow-up strategies in these patients.

Abstract 2889: Cartilage oligomeric matrix protein as a potential biomarker and therapeutic target of radiation resistance in NSCLC

Abstract Despite recent advances in lung cancer treatment, the survival rate of non-small cell lung cancer (NSCLC) is ~57% largely due to treatment resistance. Cartilage Oligomeric Matrix Protein (COMP) has previously been implicated in promoting metastasis and is associated with poor survival outcomes in breast, prostate and colorectal cancers. Patients with prostate cancer and osteoarthritis (a condition characterized by elevated circulating COMP) had both increased tumor COMP expression and rate of metastasis. Additionally, elevated COMP expression, among others, was observed in a study that investigated the gene expression of invasive NSCLC cell lines, though association with COMP was not further studied. Therefore, COMP could potentially increase the metastatic potential for NSCLC and thus serve as a therapeutic target to reduce tumor aggressiveness. We performed proliferation and migration assays on NSCLC cell lines, A549 and NCI-H1975, treated with 2 µg/mL COMP to identify COMP’s role in NSCLC progression. Plated cells in monolayer were treated with either COMP (2µg/mL) or PBS (control), and then within each group received either: 1] one of two different inhibitors of COMP signaling (either the αᵥ integrin antagonist cilengitide (1µM), or the Src inhibitor PP2 (1µM)), or 2] no additional treatment. Replicates from each group then received 2Gy Cs137 γ-radiation, or no irradiation. Proliferation and migration were monitored via the IncuCyte ZOOM live-cell imaging system over a 48hr interval. Radiation alone reduced both proliferation (-22%, p<0.0001) and migration (-40%, p<0.01) of A549 cells. However, exogenous COMP treatment attenuated the effects of radiation, maintaining both A549 proliferation (19% vs irradiated control, p<0.05) and migration (91% vs irradiated control, p<0.0001). While the overall pattern for NCI-H1975 cells with/without COMP treatment was similar, the magnitude of the responses was reduced vs A549 cells and non-significant. In contrast, radiation resistance with COMP treatment was abrogated by exogenous treatment of both COMP inhibitors. Cilengitide treatment resulted in lower proliferation rates of the COMP treated, irradiated A549 (-16%, p<0.05) and NCI-H1975 cell lines (-58%, p<0.0001) vs COMP treatment alone, while PP2 reduced proliferation and migration rates for both irradiated and non-irradiated COMP treated cell lines (p<0.0001). PP2 treatment alone did not reduce migration rates of either irradiated control cell lines. In conclusion, COMP serves to radioprotect NSCLC in an undetermined manner, and could serve as both a prognostic biomarker for and therapeutic target against radiation resistance in patients with NSCLC. Support: Milton Raben Foundation Citation Format: Kaitlyn E. Reno, Sun H. Park, Michael K. Farris, Ryan T. Hughes, Joseph E. Moore, Chirayu M. Patel, Jeffrey S. Willey. Cartilage oligomeric matrix protein as a potential biomarker and therapeutic target of radiation resistance in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2889.

Factors associated with incomplete resection for large, locally invasive non-small cell lung cancer.

Large, node-negative but locally invasive non-small cell lung cancer (NSCLC) is associated with increased perioperative risk but improved survival if a complete resection is obtained. Factors associated with positive margins in this population are not well-studied. We performed a retrospective cohort study using National Cancer Database (NCDB) for adult patients with >5 cm, clinically node-negative NSCLC with evidence of invasion of nearby structures [2006-2015]. Patients were classified as having major structure involvement (azygous vein, pulmonary artery/vein, vena cava, carina/trachea, esophagus, recurrent laryngeal/vagus nerve, heart, aorta, vertebrae) or chest wall invasion (rib pleura, chest wall, diaphragm). Our primary outcome was to evaluate factors associated with incomplete resection (microscopic: R1, macroscopic: R2). Kaplan-Meier analysis and cox multivariable regression models were used to evaluate overall survival (OS), 90-day mortality, and factors associated with positive margins. Among 2,368 patients identified, the median follow-up was 33.8 months [interquartile range (IQR), 12.6-66.5 months]. Most patients were white (86.9%) with squamous cell histology (47.3%). Major structures were involved in 26.4% of patients and chest wall invasion was seen in 73.6%. Four hundred and seventy-eight patients (20.2%) had an incomplete resection. Multivariable analysis revealed that black race [hazard ratio (HR) 1.568, 95% confidence interval (CI): 1.109-2.218] and major structure involvement (HR 1.412, 95% CI: 1.091-1.827) was associated with increased risk of incomplete resection and surgery at an academic hospitals (HR 0.773, 95% CI: 0.607-0.984), adenocarcinoma histology (HR 0.672, 95% CI: 0.514-0.878), and neoadjuvant chemotherapy (HR 0.431, 95% CI: 0.316-0.587) were associated with decreased risk of incomplete resection. The 5-year OS was 43.7% in the entire cohort and 28.8% in patients with positive margins and 47.5% in patients with an R0 resection. Positive margin was also associated with a significantly higher 90-day mortality rate (9.9% versus 6.7%). For patients with large, node-negative NSCLC invading nearby structures, R0 resection portends better survival. Treatment at academic centers, adenocarcinoma histology, and receipt of neoadjuvant chemotherapy are associated with R0 resection in this high-risk cohort.

Country of birth and non-small cell lung cancer incidence, treatment, and outcomes in New South Wales, Australia: a population-based linkage study.

ObjectiveTo compare treatment within 12 months of diagnosis, and survival by country of birth for people diagnosed with invasive non-small cell lung cancer (NSCLC) in New South Wales (NSW), Australia. Design, patients, and settingA population-based cohort study of NSW residents diagnosed with NSCLC in 2003–2016 using de-identified linked data from the NSW Cancer Registry, NSW Admitted Patient Data collection, Emergency Departments, Medicare Benefits and Pharmaceutical Benefits Scheme, and National Death Index.Main outcome measuresOdds of receiving any treatment, surgery, systemic therapy, or radiotherapy respectively, in the 12 months following diagnosis were calculated using multivariable logistic regression. The hazard of death (all-cause) at one- and five-years following diagnosis was calculated using multivariable proportional hazards regression.Results27,114 People were recorded with NSCLC in the 14-year study period. Higher percentages of older males from European countries applied in the earlier years, with a shift to younger people from South East Asia, New Zealand, and the Middle East. Adjusted analyses indicated that, compared with the Australian born, people from European countries were more likely to receive treatment, and, specifically surgery. Also, people from Asian countries were more likely to receive systemic therapy but less likely to receive radiotherapy. Survival at one- and five-years following diagnosis was higher for people born in countries other than Australia, New Zealand the United Kingdom and Germany.ConclusionsVariations exist in treatment and survival by country of birth in NSW. This may be affected by differences in factors not recorded in the NSW Registry, including use of general health services, family histories, underlying health conditions, other intrinsic factors, and cultural, social, and behavioural influences.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12890-022-02163-z.

Structure-based classification of EGFR mutations in operable pre-invasive and invasive non-small cell lung cancer: a cross-sectional study.

BackgroundIt has been reported that the structure-based approach for defining functional groups of epidermal growth factor receptor (EGFR) mutations predicts the efficacy of EGFR inhibitors better than the traditional exon-based approach in the advanced stage. However, less is known about this structure-based classification of EGFR mutations in operable early-stage lung adenocarcinoma.MethodsNon-small cell lung cancer (NSCLC) patients with pathological stage I–III or adenocarcinoma in situ (AIS) who had EGFR mutations identified in next-generation sequencing (NGS) testing were recruited. Both exon-based and structure-based groupings of EGFR mutations were compared between the AIS and stage I–III patients using Fisher’s exact test.ResultsIn total 1,012 patients including 66 AIS and 946 stage I–III patients were analyzed in the study. A total of 1185 EGFR mutations were identified in the 1,012 NSCLC patients, of whom 84.39% harbored a single EGFR mutation and 15.61% harbored complex EGFR mutations. As expected, L858R was more common than 19del in our population (39.33% vs. 35.67%). Interestingly, concurrent L858R and 19del mutations were identified in 9 patients (0.89%), and all these patients were diagnosed with multiple primary lung cancer. A higher percentage of atypical EGFR mutations was identified in the AIS cohort than in the stage I–III NSCLC cohort (33.33% vs. 21.66%, P=0.03). According to the structure-based classification of EGFR mutations, 86.07%, 7.11%, 5.04%, and 1.78% of the EGFR mutations were classified as classical-like, P-loop and α C-helix compressing (PACC), exon 20 insertions (Ex20ins), and T790M-like mutations, respectively. The composition of EGFR mutations was different between patients <65 and ≥65 years (P=0.0267) but similar between patients with AIS and stage I–III NSCLC (P=0.1436). However, a higher percentage of Ex20ins occurred in younger (<65 years) patients, nonsmoking patients, and patients with AIS (6.7% vs. 2.5%, P=0.003; 5.8% vs. 0.8%, P=0.0107; and 10.6% vs. 4.7%, P=0.0423, respectively).ConclusionsThis large cross-sectional study delineated the structure-based classification of EGFR mutations in patients with operable NSCLC. While the traditional exon-based EGFR grouping showed difference between AIS and stage I–III NSCLC cohort, no difference was identified in the structural approach. Which approach had better prediction of targeted therapy efficacy in adjuvant settings warrants further investigation.

Soluble Immune Checkpoint-Related Proteins in Blood Are Associated With Invasion and Progression in Non-Small Cell Lung Cancer.

BackgroundImmune checkpoint inhibition therapy has been achieved significant success in the treatment of non-small cell lung cancer (NSCLC). However, the role of soluble immune checkpoint- related proteins in NSCLC remains obscure.MethodsWe evaluated the circulating levels of 14 immune checkpoint-related proteins panel (BTLA, LAG-3, GITR, IDO, PD-L2, PD-L1, PD-1, HVEM, Tim-3, CD28, CD27, CD80, CD137 and CTLA-4) and their associations with the risk of invasive disease and the risk of NSCLC in 43 pre-invasive (AIS), 81 invasive NSCLC (IAC) patients and matched 35 healthy donors using a multiplex Luminex assay. Gene expression in tumors from TCGA were analyzed to elucidate potential mechanisms. The multivariate logistic regression model was applied in the study. ROC(receiver operator characteristic) curve and calibration curve were used in the performance evaluation.ResultsWe found that sCD27, sCD80, CD137 and sPDL2 levels were significantly increased in IAC cases compared to AIS cases (P= 1.05E-06, 4.44E-05, 2.30E-05 and 1.16E-06, respectively), whereas sPDL1 and sPDL2 levels were significantly increased in NSCLC cases compared to healthy controls (P=3.25E-05 and 1.49E-05, respectively). Unconditional univariate logistic regression analysis indicated that increased sCD27, sCD80, sCD137, and sPDL2 were significantly correlated with the risk of invasive diseases. The model with clinical variables, sCD27 and sPDL2 demonstrated the best performance (AUC=0.845) in predicting the risk of IAC. CD27 and PDCD1LG2 (PDL2) showed significant association with cancer invasion signature in TCGA dataset.ConclusionOur study provides evidence that soluble immune checkpoint-related proteins may associate with the risk of IAC, and we further established an optimized multivariate predictive model, which highlights their potential application in the treatment of NSCLC patients. Future studies may apply these biomarkers to test their predictive value of survival and treatment outcome during immunotherapy in NSCLC patients.

Reconstruction of post-resection chest wall defects in surgical treatment of invasive non-small cell lung cancer

To present the results of reconstruction of post-resection chest wall defects with nickel-titanium (TiNi) implants in patients with invasive NSCLC and to analyze the features of perioperative management. We enrolled 9 patients with NSCLC involving the ribs after lobectomy or pneumonectomy with chest wall reconstruction. Defects were closed used TiNi mesh and rib prostheses. We selected the shape and dimensions of artificial ribs individually before surgery according to CT data and 3D models of reinforcing elements. There were male smokers aged 64.6±4.6 years among patients (range 58-73). T3N0M0 was diagnosed in 6 patients, T3N1M0 - 2, T3N2M0 - 1. Squamous cell carcinoma was verified in 4 (44.4%) patients, adenocarcinoma - in 5 (55.6%) patients. All patients had comorbidities. Mean Charlson's comorbidity index was 6.56±4.6. Dimension of chest wall defect varied from 78 to 100 cm2. Postoperative period was uneventful without signs of respiratory failure. There were no lethal outcomes. Complications occurred in 33.3% of patients (prolonged air discharge through the drains, pleuritis and atrial fibrillation). Surgical treatment of NSCLC spreading to the chest wall is a complex task requiring further improvement. Bioadaptive TiNi implants are a promising reinforcing material that allows successful reconstruction of post-resection chest wall defects with good anatomical, functional and cosmetic results. «Sandwich» technology is advisable for extensive defects. This approach includes 2 layers of knitted mesh and rib prostheses between these layers.

Abstract PO-072: Care coordination for older cancer patients with multi-morbidities: Implications for addressing cancer health disparities

Abstract Purpose: Newly diagnosed cancer patients with multi-morbidities require a clinical care team of higher complexity due to greater care coordination demands to simultaneously coordinate cancer care and chronic disease management. Whereas teams of lower complexity may streamline care needs by using one clinician or discipline type to manage all care needs. However, this requires clinicians to understand that they are assuming other clinical roles and responsibilities or else care needs go unmanaged leading to poor health outcomes. Given that chronic disease management drops off following the cancer diagnosis, we examined whether cancer patients identifying as non-Hispanic Black, with dual Medicaid coverage, more chronic diseases, and later cancer stage were more likely to have a clinical care team of higher complexity in the 4-months post cancer diagnosis. Methods: Surveillance, Epidemiology and End Results (SEER)-Medicare data were used to identify patients with invasive breast, colorectal, or non-small cell lung cancer with a co-diagnosis of cardiopulmonary disease or diabetes (n=85,876). The data were linked with American Medical Association files to identify clinician's discipline (e.g., oncology, primary care, cardiology) from encounter claims. Using Zaccaro's classification of multi-team systems, we categorized the degree of complexity of the clinical care team: lower (1-2 disciplines and 1-3 clinicians) versus higher (2+ disciplines and 4+ clinicians). We used multivariable logistic regression to examine patient factors associated with having a clinical care team of higher complexity (compared with lower). Results: Among older cancer patients with multi-morbidities, the most common clinical care team composition was oncology with primary care (37%) followed by oncology, primary care, and medical subspecialty (34%). In the adjusted model, cancer patients were less likely to have a clinical care team of higher complexity if they were non-Hispanic Black compared to non-Hispanic White (OR: 0.88; 95% CI: 0.83, 0.93), dual Medicaid-Medicare covered compared with Medicare only (OR: 0.63; 95% CI: 0.61, 0.65), and diagnosed with stage III cancer compared to stage I (OR: 0.87; 95% CI: 0.84, 0.90). Cancer patients were more likely to have a clinical care team of higher complexity if they had cardiopulmonary disease (OR: 1.74; 95% CI: 1.68, 1.81) or diabetes (OR: 1.69; 95% CI: 1.63,1.75) compared with hypertension only. Conclusion: Clinical care teams of lower complexity were associated with identifying as Black, Medicaid coverage, and later stage, which are known factors associated with poorer care outcomes. This warrants further investigation to examine whether clinicians are assuming other clinicians' roles and responsibilities for patient care or if cancer care is taking precedence over other chronic diseases. Future research to address cancer care disparities need to focus on clinical care teams and the healthcare organizational context that provide and optimize care coordination for newly diagnosed cancer patients with multi-morbidities. Citation Format: Michelle Doose, Dana Verhoeven, Janeth I. Sanchez, Veronica Chollette, Sallie J. Weaver. Care coordination for older cancer patients with multi-morbidities: Implications for addressing cancer health disparities [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-072.

Perioperative and long-term outcomes of spontaneous ventilation video-assisted thoracoscopic surgery for non-small cell lung cancer.

BackgroundSpontaneous ventilation video-assisted thoracoscopic surgery (SV-VATS) exhibits dual intraoperative and postoperative advantages for patients with non-small cell lung cancer (NSCLC). However, there is a lack of data regarding its long-term survival superiority over the double-lumen intubated mechanical ventilation video-assisted thoracoscopic surgery (MV-VATS) or thoracotomy.MethodsA retrospective study was conducted from 2011 to 2018 in the First Affiliated Hospital of Guangzhou Medical University among patients with NSCLC who underwent the SV-VATS or the MV-VATS. Patients receiving the SV-VATS were the study group, and patients receiving the MV-VATS were the control group. Propensity score matching (PSM) was performed to establish 1:1 SV-VATS versus MV-VATS group matching to balance potential baseline confounding factors. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Secondary endpoints were perioperative outcomes. The baseline information of these patients was recorded. The perioperative data and survival data were collected using a combination of electronic data record system and telephone interview. A 1:1:1 SPM was also used to compare the OS in the SV-VATS, the MV-VATS and thoracotomy group by using another database, including patients undergoing thoracotomy and the MV-VATS.ResultsFor the two-group comparison, after 1:1 PSM, a matched cohort with 400 (200:200) patients was generated. The median follow-up time in this cohort was 4.78 years (IQR, 3.78–6.62 years). The OS (HR =0.567, 95% CI, 0.330 to 0.974, P=0.0498) and the DFS (HR =0.546, 95% CI, 0.346 to 0.863, P=0.013) of the SV-VATS group were significantly better than the MV-VATS group. There were no statistically differences between the SV-VATS and the MV-VATS group on the operative time (158.56±40.09 vs. 172.06±61.75, P=0.200) anesthesia time (247.4±62.49 vs. 256.7±58.52, P=0.528), and intraoperative bleeding volume (78.88±80.25 vs. 109.932±180.86, P=0.092). For the three-group comparison, after 1:1:1 PSM, 582 (194:194:194) patients were included for the comparison of SV-VATS, MV-VATS and thoracotomy. The OS of the SV-VATS group was significantly better than the thoracotomy group (HR =0.379, 95% CI, 0.233 to 0.617, P<0.001).ConclusionsInvasive NSCLC patients undergoing SV-VATS lobectomy demonstrated better long-term outcomes compared with MV-VATS.

Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution.

APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when APOBEC3 expression is induced during cancer development remains to be defined. Here we show that specific APOBEC3 genes are upregulated in breast ductal carcinoma in situ, and in preinvasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx preinvasive to invasive non-small cell lung cancer (NSCLC) lesions. We find that APOBEC3B exacerbates DNA replication stress and chromosomal instability through incomplete replication of genomic DNA, manifested by accumulation of mitotic ultrafine bridges and 53BP1 nuclear bodies in the G1 phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models revealed APOBEC3B expression driving replication stress and chromosome missegregation. We propose that APOBEC3 is functionally implicated in the onset of chromosomal instability and somatic mutational heterogeneity in preinvasive disease, providing fuel for selection early in cancer evolution. SIGNIFICANCE: This study reveals the dynamics and drivers of APOBEC3 gene expression in preinvasive disease and the exacerbation of cellular diversity by APOBEC3B through DNA replication stress to promote chromosomal instability early in cancer evolution.This article is highlighted in the In This Issue feature, p. 2355.

Detection of the mesenchymal-to-epithelial transition of invasive non-small cell lung cancer cells by their membrane undulation spectra.

A cancer cell changes its state from being epithelial- to mesenchymal-like in a dynamic manner during tumor progression. For example, it is well known that mesenchymal-to-epithelial transition (MET) is essential for cancer cells to regain the capability of seeding on and then invading secondary/tertiary regions. However, there is no fast yet reliable method for detecting this transition. Here, we showed that membrane undulation of invasive cancer cells could be used as a novel marker for MET detection, both in invasive model cell lines and repopulated circulating tumor cells (rCTCs) from non-small cell lung cancer (NSCLC) patients. Specifically, using atomic force microscopy (AFM), it was found that the surface oscillation spectra of different cancer cells, after undergoing MET, all exhibited two distinct peaks from 0.001 to 0.007 Hz that are absent in the spectra before MET. In addition, by adopting the long short-term memory (LSTM) based recurrent neural network learning algorithm, we showed that the positions of recorded membrane undulation peaks can be used to predict the occurrence of MET in invasive NSCLC cells with high accuracy (>90% for model cell lines and >80% for rCTCs when benchmarking against the conventional bio-marker vimentin). These findings demonstrate the potential of our approach in achieving rapid MET detection with a much reduced cell sample size as well as quantifying changes in the mesenchymal level of tumor cells.

Segment Location and Ground Glass Opacity Ratio Reliably Predict Node-Negative Status in Lung Cancer

Although selective mediastinal lymph node dissection based on lobe-specific nodal metastasis has been proposed for non-small cell lung cancer, controversy remains over its validity. We hypothesized that different segments within the same lobe might have different patterns of lymph node metastasis. Data on 2749 invasive non-small cell lung cancer patients who underwent pulmonary resection with systematic lymph node dissection from April 2008 to December 2015 were retrospectively analyzed. The segment location and consolidation tumor ratio were identified using preoperative computed tomography scans. None of the 151 tumors with consolidation tumor ratio ≤ 0.5 had lymph node involvement. None of the 333 tumors located in apical segments had inferior mediastinal lymph node metastasis. When the analysis was limited to patients without hilar nodes involvement, only 7 out of 740 (0.9%) peripheral upper lobe tumors had inferior mediastinal lymph node metastasis. Interestingly, all these 7 tumors showed visceral pleural invasion. If hilar nodes were negative, superior mediastinal lymph node metastasis was not present for lower lobe ground glass opacity lesions. Among patients with left lower lobe tumors, if hilar nodes were negative, station 4L lymph node metastasis was not found in superior-segment or basal-segment tumors, and station 5/6 lymph node involvement was always absent in basal-segment tumors. Segment location, ground glass opacity proportion, and absence of hilar lymph nodes involvement are reliable predictors of node-negative status in specific mediastinal regions. Based on these findings, we propose a new selective mediastinal lymph node dissection strategy for non-small cell lung cancer.

&lt;p&gt;Ultra-late recurrence of non-small cell lung cancer over 10 years after curative resection&lt;/p&gt;

PurposeMost postoperative recurrences of non-small cell lung cancer (NSCLC) develop within 5 years after curative resection, with ultra-late recurrences developing over 10 years after the resection being rare. This study aimed to analyze the features of ultra-late recurrence in cases with NSCLC who had undergone curative resection.Patients and methodsAmong 1458 consecutive cases with NSCLC who underwent curative resection with systematic lymph node dissection during 1990–2006, 12 cases developed recurrence over 10 years after the resection. We defined the recurrence developing over 10 years after the resection as ultra-late recurrence and analyzed the factors related to it.ResultsAmong the 1458 cases, recurrence developed in 476 (32.6%) cases. Of them, ultra-late recurrence developed in 12 (2.5%) cases. The ultra-late recurrence was histopathologically classified as adenocarcinoma in 11 cases and atypical carcinoid in 1 case. All cases were of invasive carcinoma. We compared ultra-late recurrence cases with non-recurrence cases and showed that none of the examined factors significantly influenced ultra-late recurrence; however, lymphatic invasion was close to significantly influencing it. There were two cases in which recurrence developed over 15 years after the resection; both cases were of adenocarcinoma with anaplastic lymphoma kinase (ALK) rearrangement.ConclusionThere is a possibility of ultra-late recurrence developing over 10 years after the resection of any invasive NSCLC. Lymphatic invasion is close to significantly influencing ultra-late recurrence. Furthermore, a long follow-up period may be required in cases with adenocarcinoma with ALK rearrangement because it has the possibility of recurrence over 15 years after the resection.

Nck-associated protein 1 associates with HSP90 to drive metastasis in human non-small-cell lung cancer

BackgroundMetastatic lung cancer is a life-threatening condition that develops when cancer in another area of the body metastasizes, or spreads, to the lung. Despite advances in our understanding of primary lung oncogenesis, the biological basis driving the progression from primary to metastatic lung cancer remains poorly characterized.MethodsGenetic knockdown of the particular genes in cancer cells were achieved by lentiviral-mediated interference. Invasion potential was determined by Matrigel and three-dimensional invasion. The secretion of matrix metalloproteinase 2 (MMP2) and MMP9 were measured by ELISA. Protein levels were assessed by Western blotting and immunohistochemistry. Protein-protein interactions were determined by immunoprecipitation. An experimental mouse model was generated to investigate the gene regulation in tumor growth and metastasis.ResultsNck-associated protein 1 (NAP1/NCKAP1) is highly expressed in primary non-small-cell lung cancer (NSCLC) when compared with adjacent normal lung tissues, and its expression levels are strongly associated with the histologic tumor grade, metastasis and poor survival rate of NSCLC patients. Overexpression of NAP1 in lowly invasive NSCLC cells enhances MMP9 secretion and invasion potential, whereas NAP1 silencing in highly invasive NSCLC cells produces opposing effects in comparison. Mechanistic studies further reveal that the binding of NAP1 to the cellular chaperone heat shock protein 90 (HSP90) is required for its protein stabilization, and NAP1 plays an essential role in HSP90-mediated invasion and metastasis by provoking MMP9 activation and the epithelial-to-mesenchymal transition in NSCLC cells.ConclusionsOur insights demonstrate the importance and functional regulation of the HSP90-NAP1 protein complex in cancer metastatic signaling, which spur new avenues to target this interaction as a novel approach to block NSCLC metastasis.

Retracted: miR-145 modulates epithelial-mesenchymal transition and invasion by targeting ZEB2 in non-small cell lung cancer cell lines.

Lung cancer is the leading cause of cancer-related deaths worldwide. Epithelial-mesenchymal transition (EMT) is a major event that drives cancer progression. Here we aim to investigate the role of microRNA, miR-145, in regulating EMT of the highly invasive non-small cell lung cancer (NSCLC). Quantitative real-time polymerase chain reaction analysis indicated that miR-145 was downregulated in cancer tissue compared with that in adjacent normal tissue. NSCLC cell lines, namely H1299, PC7, and SPCA-1, also demonstrated miR-145 downregulation, which is correlated well with their invasive ability, assessed by the Matrigel invasion assay. miR-145 overexpression resulted in downregulation of N-cadherin, and downregulation of vimentin and E-cadherin, suggesting a decreased EMT activity. TargetScan analysis predicted that a binding site exists between miR-145 and an oncogene, ZEB2, which was verified using the dual-luciferase assay. Alteration of miR-145 expression also induced inverse effects on ZEB2 expression, and a negative correlation exists between ZEB2 and miR-145 in human tissues. ZEB2 and miR-145 also exerted antagonizing effects on the invasion of NSCLC cells. Therefore, miR-145 is an important molecule in NSCLC that regulates cancer EMT through targeting ZEB2.

Treatment and outcomes of non-small-cell lung cancer patients with high comorbidity.

BackgroundThe life expectancy of untreated non-small-cell lung cancer (NSCLC) is dismal, while treatment for NSCLC improves survival. The presence of comorbidities is thought to play a significant role in the decision to treat or not treat a given patient. We aim to evaluate the association of comorbidities with the survival of patients treated for NSCLC.MethodsWe performed a retrospective study of patients aged ≥66 years with invasive NSCLC between the years 2007 and 2011 in the Surveillance, Epidemiology, and End Results Kentucky Cancer Registry. Comorbidity was measured using the Klabunde Comorbidity Index (KCI), and univariate and multivariate logistic regression models were used to measure association between receiving treatment and comorbidity. Kaplan–Meier plots were constructed to estimate time-to-event outcomes.ResultsA total of 4014 patients were identified; of this, 94.9% were white and 55.7% were male. The proportion of patients who did not receive any treatment was 8.7%, 3.9%, 19.1%, and 23.5% for stages I, II, III, and IV, respectively (p<0.0001). In multivariate analysis, older age, higher stage, and higher comorbidity (KCI ≥3) were associated with a lower likelihood of receiving any treatment. The median overall survival (OS) for untreated and KCI=0 was 17.7 months for stages I and II, 2.3 months for stage III, and 1.3 months for stage IV. The median OS for treated and KCI=0 was 58.9 months for stages I and II, 16.8 months for stage III, and 5.8 months for stage IV (p<0.01). Treatment was an independent predictor of OS in multivariate analysis that included KCI scores.ConclusionOur data suggest that lung cancer patients may derive a survival benefit from therapies, regardless of the presence of comorbidities, although the degree of benefit seems to decrease with higher KCI scores.

Video-assisted thoracoscopic surgery en bloc chest wall resection.

In the latest two decades, the video-assisted thoracoscopic surgery (VATS) technique has gained recognition as an effective alternative to conventional open surgery, and the field of its application has gradually extended to more complex diseases, such as locally invasive non-small cell lung cancer (NSCLC) requiring combined lung and chest wall resection. The en bloc chest wall resection can be accomplished by using a typical VATS port placement, each time adjusted to allow a better thoracoscopic guidance and a correct resection of the tumour to achieve negative margins. Different approaches have been described by experienced surgeons, with a remarkable variability in the number and disposition of the ports, in the surgical tools used and in the strategy of sparing the covering tissues. The common denominator of these experiences is the aim of extending the criteria of functional and oncological operability to high-risk patients who are not suitable for a conventional thoracotomy. Indeed, the VATS approach has shown effectiveness in reaching unchanged oncological outcomes in comparison with the thoracotomic technique but involving significantly less postoperative pain, faster recovery, shorter hospitalisation and lower overall complications.

Importance of Ground Glass Opacity Component in Clinical Stage IA Radiologic Invasive Lung Cancer

We evaluated the clinical significance of the presence of a ground glass opacity (GGO) component in clinical stage IA radiologic invasive non-small cell lung cancer (NSCLC). We reviewed 497 surgically resected clinical stage IA radiologic invasive NSCLCs, which were then classified into two groups based on consolidation tumor ratio (CTR), that is part-solid (0.5 ≤ CTR < 1.0, n= 177) and pure-solid (CTR= 1.0, n= 320). The part-solid tumors were subdivided into GGO-predominant (0.5 ≤ CTR < 0.75, n= 115) and solid-predominant (0.75 ≤ CTR < 1.0, n= 62) groups. Impact of tumor size was assessed based on CTR using Cox proportional hazards model. Among the radiologic invasive NSCLCs, multivariate analyses revealed that the presence of the carcinoembryonic antigen and a radiologic pure-solid appearance were independent significant prognostic variables (p= 0.019 and 0.034). The 5-year overall survival (OS) revealed significant differences between pure-solid and part-solid tumors (82.7% versus 95.3%, p < 0.0001) and differed significantly among radiologic pure-solid NSCLCs in terms of maximum tumor size (≤20 mm: 86.1%, 21 to 30 mm: 78.1%, p= 0.0274). However, oncologic characteristics between GGO-predominant andsolid-predominant types are clinicopathologically similar. The 5-year OS was equivalent in the GGO-predominant and solid-predominant arms (5-year OS: 95.3% versus 96.8%, p= 0.703). Furthermore, it was identical despite the maximum tumor size (≤20 mm: 96.6%, 21 to 30 mm: 94.9%, p= 0.4810) or the solid component size (≤20 mm: 96.0%, 21 to 30 mm: 93.8%, p=0.6119). Presence of a GGO component might have a notable impact on a favorable prognosis even in clinical stage IA radiologic invasive NSCLCs. Therefore, a clear distinction between part-solid and pure-solid findings on thin-section computed tomography is extremely important when evaluating the oncologic outcomes of radiologically solid NSCLCs.

Surgical resection for clinical-Stage I radiological pure-solid lung cancer that met the current high risk criteria.

We assessed whether surgical resection is acceptable for radiological invasive non-small cell lung cancer (NSCLC) that met the current high-risk criteria. We reviewed 500 clinical-Stage I NSCLCs with a radiological pure-solid appearance. High-risk criterion was defined as follows: (1) preoperative FEV1% ≤ 50% or DLco% ≤ 50%, (2) age> 75y with 50% < FEV1% < 60% or 50% < DLco% < 60%, and (3) three or more severe general comorbidities. The high-risk group comprised 184 (37%) patients. The percentages for elderly, male, smoker, non-adenocarcinoma histology were significantly higher than those of the normal-risk group (P < 0.001). Lobectomy was performed in 148 (80%) patients. Overall survival (OS) was significantly worse in the high-risk group (59.4% vs 73.1%, P = 0.004), however, a multivariate analysis revealed that high-risk was not associated with poor survival (P = 0.519). Furthermore, there were no significant differences between the high-risk and normal-risk groups regarding cancer-specific survival (74.5% vs 79.2%, P = 0.569). Postoperative morbidity rates were significantly different between the two study arms (45% vs 25%, P < 0.001), however, the 30-day and 90-day mortality rates for the high-risk group were 1.6% and 3.8%, respectively. In the high-risk patients, the difference in survival between lobectomy and sublobar resection was not significant (69.4% vs 78.6%, P = 0.716), and was also proven in the propensity-score matched patients (82.1% vs 76.0%, P = 0.623). Conventional high-risk criteria are not always appropriate prognostic variables, and lung cancer specific survival or short-term mortalities for high-risk patients were fully acceptable. Surgical therapy including lobectomy should not be readily excluded from radical local management even when a patient meets the high-risk criteria.