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Non-Small Cell Lung Cancer

There are many different types of lung cancer. Non-Small Cell Lung Cancers (NSCLC) are grouped together because they tend to be treated in the same way, which is different to Small Cell Lung Cancer. NSCLCs account for abour 85% of all lung cancer cases. The most common types of NSCLC are Adenocarcinoma, Squamous cell (epidermoid) carcinoma, and large cell carcinoma. Less common types of NSCLC include: pleomorphic, carcinoid tumor, salivary gland carcinoma, and unclassified carcinoma of the lung.

Note: most of the resources on the general Lung Cancer page are relevant to NSCLC.

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Lung Cancer

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  • PubMed search for publications about Lung Cancer, Non-Small Cell - Limit search to: [Reviews]

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    MeSH term: Carcinoma, Non-Small-Cell Lung
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Lin CY, Chang CC, Su PL, et al.
Brain MRI imaging characteristics predict treatment response and outcome in patients with de novo brain metastasis of EGFR-mutated NSCLC.
Medicine (Baltimore). 2019; 98(33):e16766 [PubMed] Related Publications
Patients with non-small cell lung cancer (NSCLC) and de novo brain metastasis (BM) have poor prognosis. We aim to investigate the characteristic of brain magnetic resonance (MR) imaging and the association with the treatment response of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for lung cancer with BM.EGFR-mutated NSCLC patients with BM from October 2013 to December 2017 in a tertiary referral center were retrospectively analyzed. Patient's age, sex, cell type, EGFR mutation status, treatment, and characteristics of BM were collected. Survival analysis was performed using Kaplan-Meier method. The efficacy of different EGFR-TKIs were also analyzed.Among the 257 eligible patients, 144 patients with Exon 19 deletion or Exon 21 L858R were included for analysis. The erlotinib group had the best progression free survival (PFS) (median PFS 13 months, P = .04). The overall survival (OS) revealed no significant difference between three EGFR-TKI groups. Brain MR imaging features including tumor necrosis, rim enhancement and specific tumor locations (frontal lobe, putamen or cerebellum) were factors associated with poor prognosis. Patients with poor prognostic imaging features, the high-risk group, who received erlotinib had the best PFS (median PFS 12 months, P < .001). However, the OS revealed no significant difference between 3 EGFR-TKI groups. The low risk group patients had similar PFS and OS treated with three different EGFR-TKIs.In NSCLC patients with common EGFR mutation and de novo BM, those with poor prognostic brain MR characteristics, erlotinib provided better PFS than afatinib or gefitinib.

Shang X, Zi H, Li Y, et al.
Combined use of salivary biomarkers and carcinoembryonic antigen for lung cancer detection in a Chinese population.
Medicine (Baltimore). 2019; 98(31):e16511 [PubMed] Related Publications
Blood-based biomarkers, such as carcinoembryonic antigen (CEA), and saliva-based biomarkers, such as mRNA, have emerged as potential liquid biopsies for non-invasive detection of many cancers. However, current tests typically use single type of biomarkers, and their sensitivity and specificity is often unsatisfactory.In this study, we developed a novel biomarker panel that measures both CEA level in blood and GREB1 and FRS2 levels in saliva to achieve high sensitivity and high specificity in detecting Non-Small Cell Lung Cancer (NSCLC).In the discovery phase, we achieved sensitivity of 96.67% and specificity of 93.33% for 30 NSCLC patients and 30 healthy controls. To further evaluate the prediction performance of our biomarker panel, we applied it to an independent set of 15 NSCLC cancer patients and 25 healthy controls. The sensitivity and specificity of our test reached 93.33% and 80.00% respectively.Our study discovered that the combined analysis of CEA and mRNA can be a novel liquid-biopsy technology for non-invasive detection of NSCLC.

Hötzel J, Melling N, Müller J, et al.
Protein expression of close homologue of L1 (CHL1) is a marker for overall survival in non-small cell lung cancer (NSCLC).
J Cancer Res Clin Oncol. 2019; 145(9):2285-2292 [PubMed] Related Publications
BACKGROUND: The cell adhesion molecule close homologue of L1 (CHL1) is a potential tumour suppressor and was recently detected in non-small cell lung cancer (NSCLC) specimens. The expression pattern, prognostic, and functional role of CHL1 in NSCLCs is unknown.
METHODS: We evaluated the protein expression of CHL1 by immunohistochemistry in 2161 NSCLC patients based on a tissue microarray. The results were correlated with clinical, histopathological, and patient survival data (Chi square test, t test, and log-rank test, respectively). A multivariate analysis (Cox regression) was performed to validate its impact on patients' survival.
RESULTS: CHL1 was expressed in NSCLC patients and was significantly overexpressed in lung adenocarcinomas and squamous cell carcinomas compared to neuroendocrine and large cell carcinomas of the lung (p < 0.001). CHL1 expression was associated with the T stage in adenocarcinomas (p = 0.011) and with metastatic lymph node status and UICC stage in squamous cell carcinomas (p = 0.034 and p = 0.035, respectively). Increased CHL1 expression was associated with improved survival in univariate (p = 0.031) and multivariate analyses (odds ratio 0.797, 95% confidence interval 0.677-0.939, p = 0.007).
CONCLUSION: The prognostic significance of CHL1 makes it a potential prognostic and therapeutic target and underlines its role as a tumour suppressor. Further validation studies and functional analyses are needed to investigate its potential role in tumourigenesis and dissemination.

Cortinovis D, Chiari R, Catino A, et al.
Italian Cohort of the Nivolumab EAP in Squamous NSCLC: Efficacy and Safety in Patients With CNS Metastases.
Anticancer Res. 2019; 39(8):4265-4271 [PubMed] Related Publications
BACKGROUND/AIM: Brain metastases are an additional challenge in patients with non-small-cell lung cancer (NSCLC) because most chemotherapy agents cannot cross the blood-brain barrier. Nivolumab has demonstrated efficacy in patients with advanced squamous NSCLC, but because patients with central nervous system (CNS) metastases are typically excluded from registration trials, 'field-practice' data are needed.
PATIENTS AND METHODS: Patients in the Italian cohort of the Expanded Access Program (EAP) who had CNS metastases at baseline were analyzed.
RESULTS: Thirty-seven patients with CNS metastases received a median of six doses of nivolumab. Three patients (8%) had grade 3-4 adverse events and one patient discontinued due to an adverse event. The objective response rate was 19%. Median overall survival was 5.8 (95% confidence interval=1.9-9.8) months and median progression-free survival was 4.9 (95% confidence interval=2.7-7.1) months.
CONCLUSION: The safety and efficacy of nivolumab in patients with CNS metastases appear to be similar to those seen in the overall EAP cohort in Italy.

Kotsantis I, Economopoulou P, Psyrri A, et al.
Prognostic Significance of IGF-1 Signalling Pathway in Patients With Advanced Non-small Cell Lung Cancer.
Anticancer Res. 2019; 39(8):4185-4190 [PubMed] Related Publications
BACKGROUND/AIM: Insulin-like growth factor 1 (IGF-1)-mediated molecular pathway has been implicated in non-small cell lung cancer (NSCLC) pathogenesis and progression. We aimed to evaluate serum levels of IGF-1, IGF-2 and IGF-binding protein 3 (IGF-BP3) before and after standard treatment in patients with advanced NSCLC and their prognostic and predictive correlations.
PATIENTS AND METHODS: Seventy-three patients were prospectively included. Analysis and quantification of circulating levels of IGF1, IGF2, IGFBP3 were performed by total ELISA in peripheral blood samples at baseline and 3 months post-treatment.
RESULTS: The median values of IGF-1 and IGF-1/IGF-BP3 ratios (125.82 vs. 133.4 ng/ml, p=0.087 and 0.01006 vs. 0.01252, p=0.011) were both decreased after treatment. Importantly, the post-treatment value of the ratio was significantly reduced only among responders to treatment (0.01044 from 0.01255, p=0.02).
CONCLUSION: Reduction of IGF-1/IGF-BP3 ratio was statistically significant only among patients with NSCLC who responded to first-line treatment. If validated in larger cohorts, IGF-1/IGFBP3 might be a useful predictive tool for response to chemotherapy in NSCLC.

Xu L, Wu Q, Zhou X, et al.
TRIM13 inhibited cell proliferation and induced cell apoptosis by regulating NF-κB pathway in non-small-cell lung carcinoma cells.
Gene. 2019; 715:144015 [PubMed] Related Publications
Tripartite Motif Containing 13 (TRIM13), a member of TRIM proteins, is deleted in multiple tumor types, especially in B-cell chronic lymphocytic leukemia and multiple myeloma. The present study explored the expression and potential role of TRIM13 in non-small-cell lung carcinoma (NSCLC). We found that TRIM13 mRNA and protein expression was reduced in NSCLC tissues and cell lines in comparison to paired non-cancerous tissues and a human normal bronchial epithelial cell line, respectively. Overexpression of TRIM13 in NCI-H1975 and SPC-A-1 cells hampered cell proliferation. Additionally, TRIM13 overexpression increased the levels of cleaved caspase-3. TRIM13-induced NSCLC cell apoptosis was attenuated by a caspase-3 inhibitor Ac-DEVD-CHO, suggesting that TRIM13 induced cell apoptosis partially through a caspase-3-dependent pathway. Moreover, it has been reported that TRIM13 can regulate nuclear factor kappaB (NF-κB) activity. Our data showed that TRIM13 overexpression inactivated NF-κB as indicated by the increased cytosolic NF-κB and decreased nuclear NF-κB. Exposure to an NF-κB inhibitor PDTC significantly blocked the impact of TRIM13 knockdown on cell proliferation and apoptosis, indicating the functions of TRIM13 in NSCLC cells were mediated by the NF-κB pathway. Finally, we demonstrated that TRIM13 overexpression suppressed tumor growth and induced cell apoptosis in vivo by using a xenograft mouse model. Collectively, our results indicate that TRIM13 behaves as a tumor suppressor in NSCLC through regulating NF-κB pathway. Our findings may offer a promising therapeutic target for NSCLC.

Chai T, Zhang P, Lin Y, et al.
Postoperative adjuvant therapy for resectable early non-small cell lung cancer: A protocol for a systematic review and meta-analysis.
Medicine (Baltimore). 2019; 98(30):e16468 [PubMed] Related Publications
BACKGROUND: Lung cancer is one of the most common malignant tumors, and non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancer diagnosed. For patients with resectable early stage non-small cell lung cancer, routine postoperative adjuvant therapy can significantly prolong overall patient survival and reduce the risk of cancer recurrence. With the emergence and maturity of molecular targeted therapy and immunotherapy, the postoperative chemotherapy strategy of lung cancer patients has changed a lot. To evaluate the efficacy of postoperative adjuvant therapy (platinum-based chemotherapy, platinum-based chemotherapy plus molecular targeted therapy, platinum-based chemotherapy plus anti-angiogenic agents, or platinum-based chemotherapy plus immunotherapy) with or without radiotherapy for patients with NSCLC, we will conduct a systematic review and meta-analysis of the published or unpublished relevant randomized controlled trials.
METHODS: We will search PubMed (Medline), Embase, Google Scholar, Cancerlit, and the Cochrane Central Register of Controlled Trials for related studies published without language restrictions before June 20, 2019. Two review authors will search and assess relevant studies independently. Randomized controlled trials (RCTs) and quasi-RCTs studies will be included. We will perform subgroup analysis in different methods of postoperative adjuvant therapy for patients with resectable early NSCLC. Because this study will be based on published or unpublished records and studies, there is no need for ethics approval.
RESULTS: The results of this study will be published in a peer-reviewed journal.
CONCLUSION: This study will comprehensively compare the efficacy of platinum-based chemotherapy with that of molecular targeted therapy and immunotherapy for patients after surgery with resectable early NSCLC. Since large-sample randomized trials meeting the inclusion criteria of this study may be insufficient, we will consider incorporating some high-quality small-sample-related trials, which may lead to high heterogeneity and affect the reliability of the results.

Sun Y, Ling C
Analysis of the long non-coding RNA LINC01614 in non-small cell lung cancer.
Medicine (Baltimore). 2019; 98(30):e16437 [PubMed] Related Publications
The aim of this study was toexplore the long non-coding RNA (lncRNA) expression pattern of non-small cell lung cancer (NSCLC) on a genome-wide scale and investigate their potential biological function in NSCLC.LncRNAs were investigated in 6 pairs of NSCLC and matched adjacent non-tumor lung tissues (NTL) by microarray. A validation cohort was obtained from The Cancer Genome Atlas (TCGA) database and the effect of LINC01614 on diagnosis and prognosis in NSCLC was analyzed. Gene set enrichment analysis (GSEA) was used to predict the potential molecular mechanism of LINC01614, one identified lncRNA.A total of 1392 differentially expressed lncRNAs were identified. LINC01614 was the most aberrantly expressed lncRNA in NSCLC compared with NTL. We confirmed the significantly upregulated LINC01614 in NSCLC patients from TCGA database. Furthermore, in TCGA database, LINC01614 was significantly upregulated in both adenocarcinoma and squamous cell carcinoma. And high expression of LINC01614 indicated poor overall survival of NSCLC patients. A sensitivity of 93% was calculated conditional on a high specificity of 95% for the discrimination of NSCLC tissues from normal tissues. Furthermore, the expression levels of LINC01614 were associated with the stage of tumor, but had no relationship with age and sex. Additionally, GSEA found that LINC01614 might be involved in TGF-β-, P53-, IGF-IR-mediated, Wnt and RTK/Ras/MAPK signaling pathways.lncRNAs may play key roles in the development of NSCLC. LINC01614 is the most aberrantly expressed lncRNA in NSCLC tissues in our experiment and is also significantly differentially expressed in NSCLC patients from TCGA database. LINC01614 could be a prognostic indicator and has the potential to be a diagnostic biomarker of NSCLC.

Liu R, Wei S, Zhang Q, et al.
Epidermal growth factor receptor tyrosine kinase inhibitors combined with thoracic radiotherapy or chemoradiotherapy for advanced or metastatic non-small cell lung cancer: A systematic review and meta-analysis of single-arm trials.
Medicine (Baltimore). 2019; 98(29):e16427 [PubMed] Related Publications
BACKGROUND: Preclinical in vitro experiments demonstrated that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) might have synergistic effect in combination with radiotherapy on Non-small cell lung cancer (NSCLC), but the clinical trials showed inconsistence results in NSCLC patients with EGFR status unknow or mutations. This study aimed to determine if added TKIs to Thoracic radiotherapy (TRT) improve primary disease response rate (RR) and survival outcomes in advanced or metastatic NSCLC.
METHODS: We searched MEDLINE, EMBASE, and Cochrane Library from January 2000 to December 2017 for eligible studies where patients received concurrent EGFR TKIs and TRT or CRT. Concerned outcomes were primary tumor RR, overall survival (OS), and adverse events (AEs). The meta-analysis was performed using Stata software (version 12.0). Random effects models were used to pool outcomes across studies. Sensitivity analysis was performed to determine if the results would be different.
RESULTS: We found 16 prospective clinical trials with mature results for meta-analyses. Twelve studies including 446 patients reported the RR and survival outcomes of TRT combined TKIs. The CR, PR, SD, and PD, respectively, were 0.06 (95% CI 0.03-0.09, I = 0%), 0.44 (95% CI 0.38-0.49, I = 64.9%), 0.29 (95% CI 0.24-0.34, I = 78.4%), and 0.15 (95% CI 0.11-0.19, I = 84.2%). One- and 2-year OS, respectively, were 0.52 (95% CI 0.44-0.60, I = 38.8%) and 0.26 (95% CI 0.18-0.33, I = 0%). Four studies including 182 patients reported the RR and survival outcomes of CRT combined TKIs. The pooled CR, PR, SD, and PD, respectively, were 0.12 (95% CI 0.02-0.22, I = 69.1%), 0.41 (95% CI 0.27-0.55, I71.6%), 0.31 (95% CI 0.16-0.46, I = 79%), and 0.14 (95% CI -0.01-0.30, I = 87.8%). Only 1 study reported the survival event rate, 1- and 2-year OS, respectively, were 0.83 (95% CI 0.71-0.94) and 0.67 (95% CI 0.54-0.81). There were not severe adverse events (SAEs) reported either TRT combined TKIs or CRT combined TKIs.
CONCLUSION: There is evidence, albeit of low quality, that added the TKIs to TRT or CRT may improve RR and survival outcomes in patients with EGFR mutant status unknown advanced or metastatic NSCLC relative to other studies of TKIs alone, TRT alone or CRT.

Bonaventura A, Grossi F, Carbone F, et al.
Serum PCSK9 levels at the second nivolumab cycle predict overall survival in elderly patients with NSCLC: a pilot study.
Cancer Immunol Immunother. 2019; 68(8):1351-1358 [PubMed] Related Publications
Monoclonal antibodies targeting PD-1 are used for treating NSCLC. To date, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been poorly investigated in the oncologic field. Here, we aimed at evaluating whether serum PCSK9 might represent a predictive factor for OS in older patients with advanced NSCLC under nivolumab treatment. Among 78 patients with advanced, pre-treated NSCLC previously enrolled in a prospective study at Ospedale Policlinico San Martino in Genoa (Italy), 44 patients have been included in this sub-analysis due to the availability of serum samples for the measurement of PCSK9. Before each nivolumab administration, clinical information and blood samples were collected. Median age was 71, with a prevalence of the male sex. The most represented histological type of lung cancer was adenocarcinoma. The majority of patients were former smokers (72.1%). Median PCSK9 levels were 123.59 (86.32-169.89) ng/mL and 117.17 (80.46-147.79) ng/mL at cycle 1 and 2, respectively. Based on a receiver operating characteristic curve analysis, a PCSK9 value at cycle 2 of 95 ng/mL was found as the best cutoff point for OS. Kaplan-Meier analysis demonstrated that patients below the PCSK9 cutoff (< 95 ng/mL) experienced a better OS, as confirmed by Cox proportional hazard regression analysis. In this pilot study, circulating levels of PCSK9 < 95 ng/mL at the time of the second cycle of nivolumab treatment could independently predict a better OS in elderly patients with advanced, pre-treated NSCLC. However, further studies are warranted to validate these preliminary results.

Zhao R, Shi Z, Cheng S
Uniport video assisted thoracoscopic surgery (U-VATS) exhibits increased feasibility, non-inferior tolerance, and equal efficiency compared with multiport VATS and open thoracotomy in the elderly non-small cell lung cancer patients at early stage.
Medicine (Baltimore). 2019; 98(28):e16137 [PubMed] Free Access to Full Article Related Publications
This study aimed to compare the feasibility, efficacy and safety among uniport video assisted thoracoscopic surgery (U-VATS), multiport VATS (M-TATS), and open thoracotomy in elderly non-small cell lung cancer (NSCLC) patients at early stage.One hundred ninety-one elderly NSCLC patients at early stage underwent U-VATS (N = 73), M-VATS (N = 56) or open thoracotomy (N = 62) were included. Perioperative parameters, short-term outcomes, postoperative complications, and overall survival (OS) were assessed.Three-group analysis disclosed that operational duration, blood loss, drainage duration, hospital stay, pain score on the first day (D1) and D3, patients' global assessment (PGA), lasing air leak, infection, arrhythmia, and cardio-cerebrovascular events incidences were different among U-VATS, M-VATS, and open thoracotomy groups. Subsequently, 2-group analysis revealed that:In addition, there was no difference of OS among 3 groups, nor between any of the 2 groups.U-VATS presents with elevated feasibility, non-inferior tolerance, and similar efficacy compared with M-VATS and open thoracotomy in the elderly NSCLC patients at early stage.

Jiang Y, Luo F, Zhou W, et al.
Association between cancer concealment and the survival of the patients with non-small cell lung carcinoma.
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2019; 44(6):657-663 [PubMed] Related Publications
OBJECTIVE: To explore the relationship between cancer awareness and the survival of the patients with non-small cell lung carcinoma (NSCLC).
 Methods: A total of 865 NSCLC patients were screened for the risk factors, including age, gender, address, tumor/lymph nodes/metastasis (TNM) stage, and cancer awareness. Survival of the patients was calculated by Kaplan-Meier method and Cox regression analysis.
 Results: After an average observation time of 304 d (ranging from 0 to 4 718 d), 62 of the 394 patients in the cancer awareness group survived, whereas 26 of the 471 patients in the cancer concealment group survived. Cancer-specific and all-cause survival was poorer in the cancer concealment group (P<0.001 for each, log-rank test). Cox multivariate regression analysis showed that cancer concealment displayed significantly lower cancer-specific survival [hazard ratio (HR)=1.534, 95% confidence interval (CI) 1.320 to 1.784, P<0.001] and all-cause survival (HR=1.558, 95% CI 1.346 to 1.803, P<0.001).
 Conclusion: Cancer concealment is associated with a poor survival of NSCLC patients, which may prohibit the patients from obtaining the real "right to survival".

Makarov M, Peled N, Shochat T, et al.
Circulating Tumor DNA T790M Testing as a Predictor of Osimertinib Efficacy in Epidermal Growth Factor Receptor Mutant Non-small Cell Lung Cancer: A Single Center Experience.
Isr Med Assoc J. 2019; 21(6):394-398 [PubMed] Related Publications
BACKGROUND: The main acquired resistance mechanism to first- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR mutant non-small cell lung cancer (NSCLC) is the propagation of T790M clones, which can be detected in circulating tumor DNA (ctDNA).
OBJECTIVES: To analyze osimertinib outcomes according to T790M testing method.
METHODS: The study comprised 33 consecutive patients with advanced EGFR mutant NSCLC who were diagnosed with a T790M mutation after progression on first- or second-generation EGFR TKIs and treated with osimertinib. The patients were divided into groups A (diagnosed by tumor testing) and B (by ctDNA testing). Osimertinib outcomes were compared between the groups.
RESULTS: Objective response rate with osimertinib comprised 54% and 62% in groups A and B, respectively (P = 0.58). Median progression-free survival (PFS) with osimertinib was 8.9 months (95% confidence interval [95%CI] 1.8-17.5) and 9.1 months (95%Cl 5.3-12.6) in groups A and B, respectively (log-rank test 0.12, P = 0.73). Median overall survival (OS) was 13.8 months (95%CI 4.9-25.5) and 13.8 months (95%Cl 7.7-27.7) in groups A and B, respectively (log-rank test 0.09, P = 0.75). T790M testing technique did not affect PFS (hazard ratio [HR] 1.16, 95%CI 0.50-2.69, P = 0.73) or OS (HR = 1.16, 95%CI 0.45-3.01, P = 0.76). The proportion of patients diagnosed by ctDNA grew from 56% in 2015 to 67% in 2016-2017.
CONCLUSIONS: Our study provides a ctDNA validation for the purpose of T790M testing in EGFR mutant NSCLC.

Tsunezuka H, Inoue M
Treatment rationale and design of the induction chemotherapy and adjuvant thoracic radiation in resectable N2-3A/3B non-small cell lung cancer (ICAT) study.
Medicine (Baltimore). 2019; 98(27):e16298 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The optimal treatment strategy for stage N2-3A/3B non-small cell lung cancer (NSCLC) remains controversial owing to its heterogeneity. Although multimodal therapy is considered the standard therapeutic approach for stage N2-3A/3B resectable NSCLC patients, the optimal combination strategy still needs to be clarified.
PATIENTS AND METHODS: In total, 25 male and female patients aged between 20 and 75 years with stage N2-3A/3B resectable NSCLC will be included. Eligible patients will undergo tri-modality therapy comprising induction chemotherapy (3 cycles of combination therapy with carboplatin and nab-paclitaxel), followed by surgery and postoperative radiotherapy. Recruitment was commenced in April 2017, with a planned last follow-up in March 2024. As of May 2019, 1 subject has been enrolled. The primary endpoint is the treatment completion rate. The secondary endpoints are objective response rate (ORR) of induction chemotherapy, treatment-related adverse event, recurrence-free survival (RFS) time, and overall survival (OS) time. RFS and OS time will be calculated as the time from this study registration to first recurrence and all-cause death, respectively.
ETHICS AND DISSEMINATION: The protocol was approved by the institutional review boards of Kyoto Prefectural University of Medicine and all the participating hospitals. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. The study results will be disseminated via publication in peer-reviewed journals.
TRIAL REGISTRATION: Trial registration number UMIN000025010 and jRCT1051180028.

Hung MS, Wu YF, Chen YC
Efficacy of chemoradiotherapy versus radiation alone in patients with inoperable locally advanced non-small-cell lung cancer: A meta-analysis and systematic review.
Medicine (Baltimore). 2019; 98(27):e16167 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This meta-analysis compared radiotherapy (RT) versus concurrent chemoradiotherapy (RT+CT) in treating patients with inoperable stage III non-small-cell lung cancer (NSCLC).
METHODS: Medline, Cochrane, EMBASE, Google Scholar databases were searched until July 28, 2015 using the following keywords non-small cell lung cancer, advanced cancer, incurable/inoperable/unresectable, chemotherapy, radiotherapy, chemoradiotherapy/chemoradiation. Randomized controlled trials (RCTs) and two-armed prospective studies that compared combined RT+CT with RT alone in patients with locally advanced (stage III) nonresectable NSCLC were eligible for inclusion. Treatment effect on overall survival, progression-free survival (PFS), and objective response rate (ORR) were evaluated.
RESULTS: Ultimately, 13 RCT studies were included in the systematic review and meta-analysis. The 13 studies included a total of 1936 patients with incurable/inoperable stage III NSCLC, of which 975 received RT alone and 961 received RT+CT combination therapy. The average age ranged from 54 to 77 years. At 1 and 2 years after treatment, the pooled data reveal that patients receiving CT+RT combination therapy had higher overall survival (pooled hazard ratio (HR), 0.72; 95% CI, 0.62-0.84; P < .001; 1-yr: HR, 0.67; 95% CI, 0.54-0.84; P < .001; 2-year: HR, 0.57; 95% CI, 0.45-0.73; P < .001), higher PFS (pooled HR, 0.73, 95% CI, 0.60-0.89; P = .002; 1-year: HR, 0.36; 95% CI, 0.24-0.53; P < .001; 2-year: HR, 0.38; 95% CI, 0.23-0.63; P < .001).
CONCLUSION: Our findings show higher efficacy for concurrent CT+RT over RT alone in treating locally-advanced, unresectable stage III NSCLC.

Facchinetti F, Pilotto S, Metro G, et al.
Treatment of metastatic non-small cell lung cancer: 2018 guidelines of the Italian Association of Medical Oncology (AIOM).
Tumori. 2019; 105(5_suppl):3-14 [PubMed] Related Publications
The treatment landscape of metastatic non-small cell lung cancer (NSCLC) has dramatically evolved in recent years, since the recognition of several clinical-biological entities requiring personalized treatment approaches, leading to significant improvements in patients' survival outcomes. In particular, targeted therapies acting against

van Seijen M, Brcic L, Gonzales AN, et al.
Impact of delayed and prolonged fixation on the evaluation of immunohistochemical staining on lung carcinoma resection specimen.
Virchows Arch. 2019; 475(2):191-199 [PubMed] Free Access to Full Article Related Publications
Pre-analytical factors, such as fixation time, influence morphology of diagnostic and predictive immunohistochemical staining, which are increasingly used in the evaluation of lung cancer. Our aim was to investigate if variations in fixation time influence the outcome of immunohistochemical staining in lung cancer. From lung resections, specimen with tumor size bigger than 4 cm, 10 samples were obtained: 2 were put through the standard fixation protocol, 5 through the delayed, and 3 through the prolonged fixation protocol. After paraffin embedding, tissue microarrays (TMAs) were made. They were stained with 20 antibodies and scored for quality and intensity of staining. Samples with delay in fixation showed loss of TMA cores on glass slides and deterioration of tissue quality leading to reduction in the expression of CK 7, Keratin MNF116, CAM 5.2, CK 5/6, TTF-1, C-MET, Napsin A, D2-40, and PD-L1. Prolonged fixation had no influence on the performance of immunohistochemical stains. Delay of fixation negatively affects the expression of different immunohistochemical markers, influencing diagnostic (cytokeratins) and predictive (PD-L1) testing. These results emphasize the need for adequate fixation of resection specimen.

Giuliani J, Bonetti A
Financial Toxicity and Non-small Cell Lung Cancer Treatment: The Optimization in the Choice of Immune Check Point Inhibitors.
Anticancer Res. 2019; 39(7):3961-3965 [PubMed] Related Publications
BACKGROUND/AIM: Immune check point inhibitors (ICIs) are changing cancer treatment in several malignancies, including non-small cell lung cancer (NSCLC). The introduction of these active new agents is associated with a relevant increase of costs and it is, therefore, important to create a balance between the costs of treatment and the added value represented by the improvement of the clinical parameters of interest such as overall survival (OS). This analysis was conducted to assess the pharmacological costs of first- and second-line treatments with ICIs (pembrolizumab, nivolumab and atezolizumab) for metastatic NSCLC.
MATERIALS AND METHODS: The present evaluation was restricted to phase III randomized controlled trials (RCTs). We calculated the pharmacological costs necessary to get the benefit in OS.
RESULTS: Six phase III RCTs were evaluated. Concerning first-line, the lowest cost per month of OS-gain was associated with the use of pembrolizumab at 2,734 €. Concerning second-line, the lowest cost per month of OS-gain was associated with the use of atezolizumab at 3,724 €.
CONCLUSION: Pembrolizumab and atezolizumab are cost-effective in both first and second-line treatment for metastatic NSCLC, respectively.

Tamiya M, Tamiya A, Suzuki H, et al.
Which Is Better EGFR-TKI Followed by Osimertinib: Afatinib or Gefitinib/Erlotinib?
Anticancer Res. 2019; 39(7):3923-3929 [PubMed] Related Publications
BACKGROUND/AIM: Treatment with EGFR-tyrosine kinase inhibitor (TKI) shows a durable response against NSCLC harboring EGFR mutation; however, treatment resistance occurs within 1-1.5 years following first-line EGFR-TKIs [first- and second-generation (G) TKIs]. When resistant NSCLC exhibits T790M mutations, osimertinib is the standard therapy. However, intratumoral heterogeneity and clonal evolution may occur in NSCLC. Afatinib may overcome tumor heterogeneity, leading to T790M colonal purity. We aimed to determine whether NSCLC treatment with afatinib followed by osimertinib (afatinib group) provides higher therapeutic efficacy than other 1st-G EFGR-TKIs followed by osimertinib (1st-G group).
MATERIALS AND METHODS: This multicenter retrospective study evaluated outcomes between afatinib group and 1st-G group. We analyzed clinical data from NSCLC patients receiving osimertinib after progression following 1st- or 2nd-G EGFR-TKIs between March 28, 2016 and March 31, 2018. Patients with performance status (PS) 0-2 were enrolled to reduce bias of patients' conditions.
RESULTS: We enrolled 111 patients treated with osimertinib. The median age was 69 (range: 39-88) years. Out of 111 patients, 33 (29.7%) were men, 100 (90%) had PS 0-1, and 35 (31.5%) were in the afatinib group. The objective RR and DCR were significantly higher in the afatinib group than in the 1st-G group [82.9% vs. 53.9% (p=0.0065); 91.4% vs. 71.1% (p=0.032)]. The median PFS tended higher in the afatinib group than in the 1st-G group (15.6 vs. 8.9 months, p=0.195).
CONCLUSION: Afatinib followed by osimertinib may provide better outcomes for T790M-positive NSCLC than 1st-G EGFR-TKIs. Afatinib followed by osimertinib may be a therapeutic option for NSCLC harboring EGFR mutation.

Fujita K, Uchida N, Yamamoto Y, et al.
Retreatment With Anti-PD-L1 Antibody in Advanced Non-small Cell Lung Cancer Previously Treated With Anti-PD-1 Antibodies.
Anticancer Res. 2019; 39(7):3917-3921 [PubMed] Related Publications
AIM: To evaluate the efficacy and safety of re-treatment with anti-programmed death (PD)-L1 antibody (atezolizumab) after anti-PD-1 antibody (nivolumab/pembrolizumab) treatment in advanced non-small cell lung cancer (NSCLC) patients.
PATIENTS AND METHODS: We retrospectively reviewed 18 NSCLC patients who received atezolizumab after anti-PD-1 antibody treatment. Data on patient characteristics, number of cycles of anti-PD-1 antibody and atezolizumab, regimens between anti-PD-1 antibody and atezolizumab, best response, and immune-related adverse events (irAEs) were collected and analyzed.
RESULTS: Nine patients a had high (≥50%) PD-L1 expression. The median number of cycles of atezolizumab was 3 (range=2-7). The median progression-free survival was 2.9±1.8 months. Seven (38.9%) and 11 (61.1%) patients had stable and progressive disease, respectively. No patient achieved partial or complete response. There were no significant differences in the occurrence of irAEs between anti-PD-1 antibodies and atezolizumab.
CONCLUSION: Preliminary results showed that patients previously treated with anti PD-1 antibodies received only limited benefit from subsequent atezolizumab.

Xiao X, Wang S, Long G
C-reactive protein is a significant predictor of improved survival in patients with advanced non-small cell lung cancer.
Medicine (Baltimore). 2019; 98(26):e16238 [PubMed] Free Access to Full Article Related Publications
This study tries to evaluate the associations between circulating C-reactive protein (CRP) and the overall survival of patients with non-small cell lung cancer (NSCLC).One hundred ninety-two patients with advanced NSCLC who treated with chemotherapy were enrolled in this study. The cut-off value of CRP concentration was 5.0 mg/L. The patients were divided into low, intermediate and high 3 groups respectively according to the baseline level of CRP before the treatment. Kaplan-Meier analysis and Cox proportional-hazard models were used to evaluate the relationship between the CRP and overall survival time of patients.After adjusting for age, gender, smoking history, pathologic type, CRP was a significant independent impact which predicts the survival prognosis of patients with NSCLC. For all patients, the hazard ratio with high CRP levels for NSCLC-specific survival was 1.83 [95%confidenceinterval (CI) = 0.96, 3.48] compared with low CRP levels. The level of CRP was significantly correlated with survival time (hazard ratio = 1.77; 95% CI = 0.73, 4.26) for the patient with first-line chemotherapy. Patients with high level of circulating CRP also responded poorly to chemotherapy.A high level of circulating CRP was associated with a poor response and worse survival in patients with NSCLC.

Jiang Q, Zhang NL, Ma DY, et al.
Efficacy and safety of apatinib plus docetaxel as the second or above line treatment in advanced nonsquamous NSCLC: A multi center prospective study.
Medicine (Baltimore). 2019; 98(26):e16065 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Apatinib is an oral small-molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR-2). Some clinical trials have demonstrated that apatinib is efficacious against advanced nonsquamous NSCLC.
OBJECTIVE: This study aimed to probe efficacy and safety of apatinib plus docetaxel, as the second or above line treatment, in advanced nonsquamous NSCLC.
DESIGN: Multicenter, prospective, single arm study.
SETTING: Three teaching hospitals centers in the Sichuan.
PARTICIPANTS: Fourteen patients with stage IVA/B nonsquamous NSCLC had previously received at least 1 platinum-based chemotherapy regimen.
INTERVENTION: Patients who were enrolled between November 2016 and January 2018 were given docetaxel (75 mg/m, i.v., d1) plus oral apatinib (250 mg/d), 4 weeks as one cycle, until disease progression or intolerance to adverse events (AE).
MAIN OUTCOME MEASURES: The primary endpoint was progression-free survival (PFS). The secondary endpoints comprised objective response rate (ORR), disease control rate (DCR), overall survival (OS), and AE incidence rate.
RESULTS: All patients carried adenocarcinoma by pathological type. The median follow-up duration was 9.76 months. Out of 14 cases, 12 were evaluable, showing ORR of 33.33%, DCR of 66.67%, DCR of 50% in cases with brain metastasis, median PFS of 2.92 months (95% CI: 1.38-4.48), and 6-month OS of 80%. Primary AEs encompassed: leukopenia in 7 cases (58.33%), hand-foot skin reaction in 5 cases (41.67%), and diarrhea in 4 cases (33.33%). Among them, grade 3 AEs were: leukopenia in 4 cases (33.33%), and hand-foot skin reaction in 1 case (8.33%). No grade 4/5 AEs were reported. Univariate and multivariate analysis were conducted respectively for PFS and OS. These factors encompassed: gender, age, gene mutations, clinical stage, ECOG scores, quantity of metastatic foci, brain metastasis, and hand-foot skin reaction. Results demonstrated zero risk factors for PFS or OS.
CONCLUSION: Apatinib plus docetaxel, as the second or above line treatment, is effective and safe against advanced nonsquamous NSCLC, with good tolerance profile.

Alvur O, Tokgun O, Baygu Y, et al.
The triazole linked galactose substituted dicyano compound can induce autophagy in NSCLC cell lines.
Gene. 2019; 712:143935 [PubMed] Related Publications
As seen in other types of cancer, development of drug resistance in NSCLC treatment causes adverse effects on disease fighting process. Recent studies have shown that one of the drug resistance development mechanisms is that cancer cells may acquire the ability to escape from cell death. Therefore, development of anticancer drugs which have the strategy to redirect cancer cells to any cell death pathways may provide positive results for cancer treatments. Autophagy may be a target mechanism of alternative cancer treatment strategy in cases of blocked apoptosis. There is also a complex molecular link between autophagy and apoptosis, has not been fully understood yet. The dicyano compound which we used in our study caused cell death in NSCLC cell lines. When we analyzed the cells which were treated with dicyano compound by transmission electron microscope, we observed autophagosome structures. Upon this result, we investigated expression levels of autophagic proteins in the dicyano compound-treated cells by immunoblotting and observed that expression levels of autophagic proteins were increased significantly. The TUNEL assay and qRT-PCR for pro-apoptotic and anti-apoptotic gene expression, which we performed to assess apoptosis in the dicyano compound-treated cells, showed that the cell death does not occur through apoptotic pathway. We showed that the dicyano compound, which was developed in our laboratories, may play a role in molecular link between apoptosis and autophagy and may shed light on development of new anticancer treatment strategies.

Qian Z, Yang J, Liu H, et al.
The miR-1204 regulates apoptosis in NSCLC cells by targeting DEK.
Folia Histochem Cytobiol. 2019; 57(2):64-73 [PubMed] Related Publications
INTRODUCTION: This study endeavors to analyze the effects of miR-1204 on the expression of DEK oncogene in non-small cell lung cancer (NSCLC) cell lines and to study the molecular mechanisms of these effects.
MATERIAL AND METHODS: The miR-1204 mimics and inhibitors were transfected into the (A549 and SPC) NSCLC cells. Then the mRNA levels, cell viability, apoptosis rate, morphology and caspase activity were determined. The expression of apoptosis-related proteins Bcl-2 and Bax was also analyzed.
RESULTS: In NSCLC cell lines (A549 and SPC), DEK mRNA levels were down-regulated in miR-1204 overex-pression group. In miR-1204 inhibition group, the expression of DEK mRNA showed an opposite trend. The overexpression of miR-1204 increases the apoptosis rate in NSCLC cells. The Bcl-2 levels in the miR-1204 over-expression group were decreased, while the Bax level was increased. In the miR-1204 inhibition group, expression of Bcl-2 and Bax showed opposite trends. Cell staining revealed cell's morphological changes; the apoptosis in the miR-1204 overexpression group revealed significant morphological features, such as brighter nuclei and nu-clear condensation. Results indicated a typical characteristic of apoptosis in the miR-1204 overexpression group. Caspase-9 and Caspase-3 were involved in the apoptosis pathway, which was mediated by miR-1204 and DEK.
CONCLUSIONS: The miR-1204 induces apoptosis of NSCLC cells by inhibiting the expression of DEK. The mech-anism of apoptosis involves down-regulation of Bcl-2 and up-regulation of Bax expression. Moreover, the apoptosis was mediated by mitochondria-related caspase 9/3 pathway.

Wang Y, Fu M, Liu J, et al.
Inhibition of tumor metastasis by targeted daunorubicin and dioscin codelivery liposomes modified with PFV for the treatment of non-small-cell lung cancer.
Int J Nanomedicine. 2019; 14:4071-4090 [PubMed] Free Access to Full Article Related Publications

Jiang XN, Dang YF, Gong FL, Guo XL
Role and regulation mechanism of Gal-3 in non-small cell lung cancer and its potential clinical therapeutic significance.
Chem Biol Interact. 2019; 309:108724 [PubMed] Related Publications
Galectin-3 (Gal-3), the only chimeric lectin of the galectin family, affects numerous biological processes and seems to be involved in different physiological and pathophysiological conditions, such as tumor development, invasion and metastasis as well as immune reactions. There is growing evidence to show that Gal-3 participates in the tumorigenesis, invasion and metastasis as well as tumor immunity in non-small cell lung cancer (NSCLC). A better understanding of the molecular mechanisms of Gal-3 involved in NSCLC development is avidly needed as the basis to identify novel therapeutic targets and develop new strategies for the treatment of NSCLC. In this review, we summarized the distribution and expression of Gal-3 in NSCLC which is highly expressed in NSCLC than in normal lung tissues, and the molecular regulation mechanism of Gal-3 in the development of NSCLC, including upregulation of Wnt/β-catenin pathway and EGFR expression, involvement in Notch signaling pathway, etc. Moreover, Gal-3 promoted the invasion and metastasis of NSCLC through induction of MMPs secretion, cooperation with integrins, and interaction with mucin 1 to promote cancer-endothelial adhesion. Furthermore, Gal-3 binded to Poly-N-acetyl-lactosamine on N-glycans to promote NSCLC metastasis as well as contributing to tumor microenvironment immunosuppression, which might provide potential therapeutic implications for the clinical treatment of NSCLC.

Chen H, Chong W, Teng C, et al.
The immune response-related mutational signatures and driver genes in non-small-cell lung cancer.
Cancer Sci. 2019; 110(8):2348-2356 [PubMed] Free Access to Full Article Related Publications
Immune checkpoint blockade (ICB) therapy has achieved remarkable clinical benefit in non-small-cell lung cancer (NSCLC), but our understanding of biomarkers that predict the response to ICB remain obscure. Here we integrated somatic mutational profile and clinicopathologic information from 113 NSCLC patients treated by ICB (CTLA-4/PD-1). High tumor mutation burden (TMB) and neoantigen burden were identified significantly associated with improved efficacy in NSCLC immunotherapy. Furthermore, we identified apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) mutational signature was markedly associated with responding of ICB therapy (log-rank test, P = .001; odds ratio (OR), 0.18 [95% CI, 0.06-0.50], P < .001). The association with progression-free survival remained statistically significant after controlling for age, sex, histological type, smoking, PD-L1 expression, hypermutation, smoking signature and mismatch repair (MMR) (HR, 0.30 [95% CI, 0.12-0.75], P = .010). Combined high TMB with APOBEC signature preferably predict immunotherapy responders in NSCLC cohort. The CIBERSORT algorithm revealed that high APOBEC mutational activity samples were associated with increased infiltration of CD4 memory activated T cells, CD8

Hill A, Gupta R, Zhao D, et al.
Targeted Therapies in Non-small-Cell Lung Cancer.
Cancer Treat Res. 2019; 178:3-43 [PubMed] Related Publications
The treatment landscape for non-small-cell lung cancer (NSCLC) has dramatically shifted over the past two decades. Targeted or precision medicine has primarily been responsible for this shift. Older paradigms of treating metastatic NSCLC with cytotoxic chemotherapy, while still important, have given way to evaluating tumor tissues for specific driver mutations that can be treated with targeted agents. Patients treated with targeted agents frequently have improved progression-free survival and overall survival compared to patients without a targetable driver mutation, highlighting the clinical benefit of precision medicine. In this chapter, we explore the historic landmark trials, the current state of the field, and potential future targets under investigation, in this exciting, rapidly evolving discipline of precision medicine in lung cancer.

Jones GG, Del Río IB, Sari S, et al.
SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers.
Nat Commun. 2019; 10(1):2532 [PubMed] Free Access to Full Article Related Publications
Targeted inhibition of the ERK-MAPK pathway, upregulated in a majority of human cancers, has been hindered in the clinic by drug resistance and toxicity. The MRAS-SHOC2-PP1 (SHOC2 phosphatase) complex plays a key role in RAF-ERK pathway activation by dephosphorylating a critical inhibitory site on RAF kinases. Here we show that genetic inhibition of SHOC2 suppresses tumorigenic growth in a subset of KRAS-mutant NSCLC cell lines and prominently inhibits tumour development in autochthonous murine KRAS-driven lung cancer models. On the other hand, systemic SHOC2 ablation in adult mice is relatively well tolerated. Furthermore, we show that SHOC2 deletion selectively sensitizes KRAS- and EGFR-mutant NSCLC cells to MEK inhibitors. Mechanistically, SHOC2 deletion prevents MEKi-induced RAF dimerization, leading to more potent and durable ERK pathway suppression that promotes BIM-dependent apoptosis. These results present a rationale for the generation of SHOC2 phosphatase targeted therapies, both as a monotherapy and to widen the therapeutic index of MEK inhibitors.

Chaszczewska-Markowska M, Kosacka M, Chryplewicz A, et al.
Anticancer Res. 2019; 39(6):3269-3272 [PubMed] Related Publications
BACKGROUND/AIM: Although genetic factors are presumed to account only for a part of the inter-individual variation in lung cancer susceptibility, the results are conflicting and there are no data available regarding the Polish population. We, therefore, performed a case-control study to investigate the association of seven selected single nucleotide polymorphisms (SNPs), in genes coding for excision repair cross-complimentary group 1 (ERCC1: rs11615, rs3212986, rs2298881), nuclear factor ĸB (NFKB2: rs7897947, rs12769316), bone morphogenetic protein 4 (BMP4: rs1957860), complement receptor 1 (CR1: rs7525160) and del/ins polymorphism in the family hypoxia inducible factor 2 gene (EGLN2: rs10680577), with non-small cell lung cancer (NSCLC) risk.
MATERIALS AND METHODS: Real-time PCR with melting curve analysis was used for genotyping of NSCLC patients and healthy individuals of Polish origin.
RESULTS: The ERCC1 rs11615 T allele and rs3212986 GG homozygosity were found to be associated with a higher risk of developing NSCLC. In addition, NFKB2 rs12769316 GG homozygosity was more frequently detected among male patients than controls, while no significant differences were found between the five polymorphisms.
CONCLUSION: ERCC1 polymorphisms may affect NSCLC risk in the Polish population, while the NFKB2 variant may be a possible marker of the disease in males.

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