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Although tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have a favorable and durable treatment response, almost all patients will eventually acquire resistance and develop disease progression. Re-administration of first and second-generation EGFR TKIs has been successfully executed in advanced non-small cell lung cancer (NSCLC) subsequent to EGFR-TKI resistance. However, osimertinib rechallenge following osimertinib resistance in EGFR T790M-negative patient is less explored. Herein, we describe a metastatic adenocarcinoma NSCLC patient with exon 19 deletion in EGFR (19del) who acquired resistance to initial gefitinib and second-line osimertinib but was successfully rechallenged with osimertinib following treatment failure with chemotherapy. The osimertinib rechallenge, despite the absence of EGFR T790M, was considered after the development of multiple small pulmonary lesions and an increase in EGFR exon 19 deletion. After a month of osimertinib rechallenge, pulmonary and brain lesions significantly reduced achieving partial response. The success of osimertinib rechallenge following previous osimertinib resistance in a metastatic NSCLC patient with EGFR 19del in the absence of T790M suggests that re-administration of osimertinib can be a treatment option in similar situations. In addition, this case also highlights the importance of mutational profiling for treatment monitoring to understand the mutational landscape of the patient and guide subsequent treatment including treatment rechallenge.

BACKGROUND Rearrangements of the anaplastic lymphoma kinase (ALK) gene (ALK-positive) represent an oncogenic driver in approximately 3%-5% of non-small-lung cancer (NSCLC) patients. Sarcoidosis is a multisystem disease, and its reported incidence in Asia is 1 or less per 100000 people per year. The co-occurrence of sarcoidosis and ALK-positive NSCLC is rare, and ALK-positive lung cancer is likely to spread quickly. Therefore, the co-occurrence of sarcoidosis is more easily misdiagnosed as metastatic lung cancer by radiological examination. CASE SUMMARY A 50-year-old man had a nodule in the left superior lobe, many small nodules in left superior and right lungs, and enlarged bilateral hilar, mediastinal, and right supraclavicular lymph nodes. Computed tomography-guided pulmonary biopsy of the nodule in the left superior lobe revealed echinoderm microtubule-associated protein-like 4 gene-ALK positive NSCLC with concomitant noncaseating granuloma. This patient was treated with crizotinib. Thirty days later, a chest computed tomography scan revealed a dramatic decrease in the size of the left superior lobe nodule; however, the lesions in the right lung progressed. The right supraclavicular lymph nodes showed granulomas, and no tumor cells were identified in the specimens. The angiotensin-converting enzyme level was high. After 1 wk of methylprednisolone treatment, a significant response of all lesions was revealed. Following radical resection of the lung cancer, noncaseating granulomas were observed in both lung tissues and lymph nodes, which resulted in a diagnosis of echinoderm microtubule-associated protein-like 4-ALK positive NSCLC accompanied with sarcoidosis. CONCLUSION Our experience illustrates that pathological evidence is needed to confirm metastatic disease, especially when some suspected metastatic lesions are negative for malignancy.

Since accelerated metabolism produces much higher levels of reactive oxygen species (ROS) in cancer cells compared to ROS levels found in normal cells, human MutT homolog 1 (MTH1), which sanitizes oxidized nucleotide pools, was recently demonstrated to be crucial for the survival of cancer cells, but not required for the proliferation of normal cells. Therefore, dozens of MTH1 inhibitors have been developed with the aim of suppressing cancer growth by accumulating oxidative damage in cancer cells. While several inhibitors were indeed confirmed to be effective, some inhibitors failed to kill cancer cells, complicating MTH1 as a viable target for cancer eradication. In this review, we summarize the current status of developing MTH1 inhibitors as drug candidates, classify the MTH1 inhibitors based on their structures, and offer our perspectives toward the therapeutic potential against cancer through the targeting of MTH1., Graphical abstract As an essential enzyme for the survival of cancer cells, human MutT homolog 1 (MTH1), was recently demonstrated as a promising target for cancer eradication. This review summarizes the current progress of developing MTH1 inhibitors with various structures as drug candidates and presents our perspectives toward the therapeutic potential.Image 1

Our study examined for the inhibitory effect of ethanolic extract of Eleagnus Conferta Roxb leaves on TNF –α induced NF- kB nuclear translocation in lung cancer A549 cell line using flow cytometry. Apoptosis also studied to know about the antiproliferative and anticancer effects. However, our results revealed in apoptosis, Elaeagnus conferta Roxb leaves showed (33.54%) increased in proportion of cells. In the study of pre-treatment of A549 cells with Elaeagnus conferta Roxb leaves followed by TNF- α caused the increased proportion of cells (20.78%) at apoptosis induced cell death, which was statistically significant (p< 0.001). The untreated A549 cells had minimal NF-kB expression (0.25± 0.01%). However, the approach of A549 cells with Elaeagnus conferta Roxb had induced NF-kB production many fold (11.50± 1.05%). Therefore, we conclude our study was proved the impact of Elaeagnus conferta Roxb leaves inhibit the cellular growth of NSCLC-A549 cell line and induces apoptosis. Hence, from our findings, we proved this plant has anticancer activity, further feasibly taken for drug formulation.

To report a case of isolated optic neuritis associated with pembrolizumab immunotherapy for metastatic non-small cell lung carcinoma.A 76-year-old man, with a history of metastatic non-small cell lung carcinoma, presented with vision loss in his left eye for the past week. He had been treated with pembrolizumab for the underlying disease for 2 months. On presentation, best corrected visual acuity was 20/30 in the right eye and 20/200 in the left eye. Fundoscopy revealed optic nerve edema in the left eye. Visual fields examination in right eye revealed an enlarged blind spot and an extended defect in the inferior nasal quadrant. In the left eye a partial superior arcuate defect and an extended defect in the inferior hemisphere was observed. The mean deviation was -12.15 dB in the right eye and -13.70 dB in left eye. Pembrolizumab was withheld and corticosteroids were administered for a total of nine weeks, first intravenously and then slowly tapered orally, resulting in resolution of optic neuritis, restoration of visual acuity and in relative improvement in the visual field defects after 3 months. Calculated Naranjo Nomogram score was 7, indicating a 'highly probable' correlation.Optic neuritis is a relatively rare immune-related adverse event after exposure to checkpoint inhibitors cancer immunotherapy. Prompt discontinuation of the offending agent and early initiation of corticosteroid therapy is the mainstay of the treatment.

Despite new therapeutic perspectives, the presence of central airways occlusion (CAO) in patients with locally advanced non-small cell lung cancer (NSCLC) is associated with poor survival. There is no clear evidence on the clinical impact of interventional bronchoscopy as a part of an integrated treatment to cure these patients.This retrospective cohort study was conducted in two teaching hospitals over a 10 years period (January 2010-January 2020) comparing patients with NSCLC at stage IIIB and CAO at disease onset treated with chemotherapy/radiotherapy (standard therapy-ST) with those receiving interventional bronchoscopy plus ST (integrated treatment-IT). Primary outcome was 1-year survival. The onset of respiratory events, symptoms-free interval, hospitalization, need for palliation, and overall mortality served as secondary outcomes.A total of 100 patients were included, 60 in the IT and 40 in the ST group. Unadjusted Kaplan-Meier estimates showed greater effect of IT compared to ST on 1-year survival (HR = 2.1 95%CI[1.1-4.8], p = 0.003). IT showed a significantly higher survival gain over ST in those patients showing KRAS mutation (7.6 VS 0.8 months,0.0001), a lumen occlusion65% (6.6 VS 2.9 months,0.001), and lacking the involvement of left bronchus (7 VS 2.3 months,0.0001). Compared to ST, IT also showed a favorable difference in terms of new hospitalizations (p = 0.03), symptom-free interval (p = 0.02), and onset of atelectasis (p = 0.01).In patients with NSCLC stage IIIB and CAO, additional interventional bronchoscopy might impact on 1-year survival. Genetic and anatomic phenotyping might allow identifying those patients who may gain life expectancy from the endoscopic intervention.

Immune checkpoint inhibitors (ICIs) can induce immunity-related adverse events. We demonstrate the clinical use of cardiac magnetic resonance and endomyocardial biopsy in the diagnosis and subsequent monitoring of ICI-associated myocarditis, suggesting the need to establish and evaluate a cardiac monitoring protocol for patients under ICI therapy. (Level of Difficulty: Intermediate.), Graphical abstract, Immune checkpoint inhibitors (ICIs) can induce immunity-related adverse events. We demonstrate the clinical use of cardiac magnetic resonance…

Background The involvement of lncRNA FEZF1-AS1 has been analyzed in many types of cancers, while its roles in non-small cell lung cancer (NSCLC) remains unclear. We then explored the role of FEZF1-AS1 in NSCLC. Methods qPCR and western blot were performed to measure gene expression. FEZF1-AS1, miR-34a, and NOTCH-1 were overexpressed to analyze the relationship between them. Transwell assays were performed to analyze the effects of transfections on cell invasion and migration. Results FEZF1-AS1 was up-regulated in NSCLC patients. Increased expression levels of FEZF1-AS1 were observed with the increase in clinical stages. Bioinformatics analysis showed that miR-34a can bind with FEZF1-AS1. In NSCLC tissues, NOTCH-1 and FEZF1-AS1 were positively correlated. In NSCLC cells, over-expression of FEZF1-AS1 resulted in up-regulated expressions of NOTCH-1, while miR-34a over-expression mediated down-regulated expressions of NOTCH-1. In addition, FEZF1-AS1 and miR-34a did not alter each other, while bioinformatics analysis showed that miR-34a can bind FEZF1-AS1. Analysis of cell migration and invasion showed increased cell invasion and migration rates after FEZF1-AS1 and NOTCH-1 over-expression. MiR-34a played the opposite role and reduced the effects of FEZF1-AS1 over-expression. Conclusions FEZF1-AS1 promoted NSCLC cell migration and invasion through the up-regulation of NOTCH1 by serving as a sponge of miR-34a.

SummaryThis article intends to summarize personal non-small cell lung cancer (NSCLC) highlights of the ESMO 2019 meeting. Again, immunotherapy in the first-line setting of wildtype NSCLC was a major aspect and the search of the optimal biomarker for therapy stratification continues. Moreover, important data on the use of osimertinib, a third-generation epidermal growth factor receptor (EGFR) inhibitor in the first-line setting of EGFR-mutated NSCLC were presented, emerging as the preferred therapeutic strategy in these patients. The ideal treatment sequence, however, remains discussed controversially. The treatment of rare genetic alterations was another important topic, covering updated data on effective NTRK and ROS1 inhibition. In conclusion, ESMO 2019 fueled the lung cancer community with inspiring new data, contributing to a more individualized, hopefully improved lung cancer treatment and continuing to decrease lung cancer mortality.

Incorporation of molecular targeted therapies into the care of patients with sensitizing mutations has driven significant improvements in outcomes in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor ( EGFR )-mutant lung cancer includes the greatest percentage of these cases, and

Das Ziel dieser Arbeit ist die Bestimmung der Wertigkeit von Heterogenit��tsanalysen der[18F]-FDG PET/CT (18-F-Fluor-desoxy-glucose; Positronen-Emissions-Tomo-graphie/Computer-Tomographie) zur pr��therapeutischen Evaluation der Prognose von Patienten mit nicht-kleinzelligem Bronchialkarzinom. Hierf��r wurden retrospektiv die Daten von 81Patienten mit histologisch gesichertem, nicht-kleinzelligem Bronchialkarzinom in den UICC-Stadien(Union International Contre Cancer)I und II analysiert, die sich im Zeitraum 1999-2019dem Staging an der Universit��tsklinik Ulm unterzogen und pr��operativ ein [18F]-FDG PET/CT erhielten. Anhand dieser Daten wurde die prognostische Aussagekraft von Heterogenit��tsanalysen evaluiert. Im Rahmen dieser Doktorarbeit konnte erfolgreich ein neuer Algorithmus zur Festlegung eines optimalen Schwellenwertes zur Abgrenzung zweier prognostisch unterschiedlicher Gruppenetabliert werden. Mit Hilfe dieses Algorithmus konnte gezeigt werden, dass selbst in einer homogenen Gruppe von nicht kleinzelligen-Bronchialkarzinom-Patienten mit niedrigem Risiko durch Texturanalysen der CT und PET starke prognostische Heterogenit��ts-Parameter definiert werden k��nnen. Dabei zeigten sich der SUVmax(Standardized Uptake Value; Maximum),die Solidity, die Circularity und die SUVstd(Standardized Uptake Value; Standard deviation)in der PET und das Tumorvolumen der CT als prognostisch relevante Parameter. So zeigte bspw. die PET-SUVstd(Standartabweichung der SUV Werte)bei einer Kohortentrennung bei einem Schwellenwert von 2,33ein signifikant besseres ��berleben der Patienten mit einer geringeren SUVstd. (p= 0,0065; n1(SUVstd 2,33)=43Patienten;Medianes ��berleben n1=110 Monate,n2=82 Monate; 5-Jahres��berleben n1=90,1%,n2=66,5%; Hazard Rate A/B: 0,3620; Hazard Rate B/A:2,763; Konfidenzintervall 0,1655 bis 0,7918). Au��erdem weisen die Ergebnisse auf synergistische Information durch Kombination von SUVmax undPET-Solidity, SUVmax und CT-Volumen, sowie PET-Solidity und CT-Volumenhin. Besonders Patienten, deren Histologie einen G2-Tumor ergab, k��nnten von den hier gezeigten Heterogenit��tsanalysen profitieren. Diese k��nnen helfen eine Gruppe von Patienten mit einer signifikant schlechteren Prognose zu definieren, die von einer adjuvanten Therapie profitieren k��nnten.

Background: Lung cancer (LC) is one of the most common types of cancer with a high mortality rate. Depending on molecular and histological properties, LC is divided into non–small-cell and small-cell lung cancer. Not only surgery but also radiotherapy, chemotherapy, or combination treatment are used for patients. However, the survival rate of LC is still very low. Erufosine (ErPC3) is a novel promising antineoplastic agent and inhibits the translocation of AKT to the plasma membrane by dephosphorylating AKT. Methods and Results: In the current study, the cell-type dependent effects of ErPC3 on cell viability, apoptotic situation, cell cycle distribution, related gene expression, and migration capacities of A549 and DMS 114 were investigated. As results, ErPC3 exhibited cytotoxic and pro-apoptotic properties against both cells, while DMS 114 was more affected. ErPC3 accumulated the cells in G2/M phase and blocked cell cycle. Proliferation markers were downregulated, while pro-apoptotic markers were upregulated in ErPC3 treated cells. Besides, ErPC3 displayed anti-migratory effect on A549 and DMS 114 compared to the control group according to scratch assay. Conclusion: These findings promise a treatment approach and drug development against LC. The obtained results from the recent study lead it necessary to carry out more detailed studies about ErPC3.

The safety of anti-programmed cell death 1 (PD-1) antibody for patients with preexisting interstitial lung disease (ILD) remains unknown. The aim of this study was to evaluate the dependence of preexisting ILD on anti-PD-1 antibody-induced pneumonitis in non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed the association of preexisting ILD with the incidence, radiographic pattern, and outcome of pneumonitis in NSCLC patients receiving anti-PD-1 antibody. A total of 331 patients were included in this study. Of these patients, 17 had preexisting ILD. The incidence of pneumonitis was higher among the patients with preexisting ILD than among those without preexisting ILD (29% vs. 10%, P = 0.027). The distributions of the CT appearances at the onset of anti-PD-1 antibody-induced pneumonitis were as follows: for the patients with preexisting ILD, two patients (40%) had diffuse alveolar damage (DAD), one patient each with organizing pneumonia-like (OP), hypersensitivity pneumonitis (HP), and other patterns (20% each); for the patients without preexisting ILD, 19 patients (61%) had OP, 8 (26%) had HP, 3 (10%) had DAD, and 1 (3.2%) had other patterns. The median onset time from the initiation of anti-PD-1 antibody treatment until the development of pneumonitis was 1.3 months (range 0.3-2.1 months) for the patients with preexisting ILD and 2.3 months (range 0.2-14.6 months) for the patients without preexisting ILD. Careful attention to the development of pneumonitis is needed, especially within the first 3 months after the start of anti-PD-1 antibody treatment, when using anti-PD-1 antibody to treat patients with preexisting ILD.

Amaç: Akciğer kanseri için en etkili tedavi cerrahidir. Morbidite oranları, yıllar içinde mortalite dışında hemen hemen aynı kalmıştır. Morbidite oranları da perioperatif ve postoperatif prosedürlerin iyi yönetimi ile azalmaya başlamıştır. Rezeksiyon cerrahisinden sonra, yıllara göre postoperatif morbidite ve mortalite nedenlerini ve sonuçlarını incelemektir. Yöntemler: Ocak 2013’ten Aralık 2017’ye kadar, anatomik akciğer rezeksiyonları retrospektif olarak gözden geçirildi. Bilateral akciğer rezeksiyonu uygulanan, apse ve tüberküloz gibi enfeksiyonlara eşlik eden hastalar çalışmaya dahil edilmedi. Bulgular: Çalışmaya 907 hasta dahil edildi. Hastaların %79’u erkek ve yaş ortanca değeri 56 olarak bulundu. Malign pulmoner rezeksiyon oranlarındaki artış istatistiksel olarak anlamlıydı (p

Lung cancer continues to be the leading cause for cancer-related deaths in men and women worldwide. Sufficient screening tools enabling early diagnosis are essential to improve patient outcomes. The aim of this study was to evaluate serum midkine (S-MK) both as a diagnostic and prognostic biomarker in non-small cell lung cancer (NSCLC). This single-center analysis included 59 NSCLC patients counting 30 squamous cell cancers and 29 adenocarcinomas. Preoperative S-MK concentration was determined using ELISA. Patients were followed up to five years. S-MK was found to be significantly overexpressed in patients with NSCLC compared to healthy controls (p < 0.001). The discriminative power of S-MK to differentiate NSCLC subjects from controls was fairly high with an area under the receiver operating characteristic curve of 0.83 (p < 0.001). Optimal sensitivity of 92 % and reasonable specificity of 68% was reached at a threshold of 416 pg/ml S-MK. Patients with high S-MK concentration showed a significantly shorter overall survival compared to patients with low S-MK expression (p < 0.05). In conclusion, S-MK is overexpressed in patients with NSCLC and serves as an independent prognostic factor for overall survival. S-MK may thus be considered as an additional non-invasive biomarker not only for NSCLC screening but also for outcome prediction.

The possibility of using three-dimensional reconstructions as an intraoperative aid to thoracic surgeons has not yet been fully explored. With this in mind, we developed a technology based on a three-dimensional virtual model of lungs obtained from lung computed tomography scans, the Hyper-Accuracy Three-Dimensional reconstruction (HA3D™), which aids the surgeon during surgery. We tested this technology while performing a uniportal video-assisted thoracic surgery right upper lobectomy for lung cancer.

Objectives: Few studies investigated whether the types of histology had an influence on the postsurgical prognosis for patients 70 years and older with Ⅰ A stage non-small lung cancer (NSCLC). Methods: The study population in our study were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program.Results: A total of 10,376 eligible patients were included in our study. In both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LSQCC) patients with TS ≤10 mm, sublobar resection (SR) achieved similar overall survival (OS) (LUAD: HR=0.843, 95% CI (0.673, 1.062), P=0.149; LSQCC: HR=0.799, 95 %CI (0.615, 0.036), P=0.091) and LCSS (LUAD: HR=1.074, 95% CI (0.626, 1.843), P=0.795; LSQCC: HR=0.987, 95 % CI (0.532, 1.833), P=0.967) to lobectomy (LT). For LUAD patients with TS >10 mm &≤20 mm, LT was associated with better OS (HR=0.785, 95% CI (0.703, 878), P20 mm &≤30 mm received SR were at a significant risk of reduction of OS (HR=0.816, 95% CI (0.709, 0.938), P=0.004) but not LCSS (HR=0.954, 95% CI (0.732, 1.244), P=0.729); while for LSQCC, patients received LT had a better OS (HR=0.742, 95% CI (0.624, 0.883), PConclusion: The postsurgical prognosis differed in patients with different histology, and SR maybe acceptable for elderly LUAD patients with TS ≤10 mm and LSQCC patients with TS ≤20 mm.

Background: Cancer-derived exosomes are considered to be the main driving force for cancer-induced metastasis niche formation at foreign sites, but the mechanism is unclear.Methods: Identification of differentially expressed miRNAs in exosomes by miRNA sequencing. Through a series of in vitro and in vivo experiments, it was studied that the tumor-derived exosome miR-3157-3p can be taken up by the endothelium and exert biological functions. The molecular mechanism of miR-3157-3p was confirmed by Western blot, luciferase test and rescue experiment. Finally, real-time fluorescence quantitative PCR and RNA in situ hybridization were used to evaluate the clinical relevance of miR-3157-3p expression.Result: In metastatic NSCLC patients, the expression level of miR-3157-3p in circulating exosomes was significantly higher than that of non-metastatic NSCLC patients. Here, we found that miR-3157-3p can be transferred from NSCLC cells to vascular endothelial cells through exosomes. Exosome miR-3157-3p has regulated the expression of VEGF / MMP2 / MMP9 and occludin in endothelial cells by targeting TIMP / KLF2, thereby promoted angiogenesis and increased vascular permeability. In addition, exosome miR-3157-3p from NSCLC cells enhances NSCLC metastasis in mouse lungs.Conclusion: Our work indicates that exosome miR-3157-3p is involved in the formation of pre-metastatic niche and may be used as a blood-based biomarker for NSCLC metastasis.

Erlotinib inhibits epithelial growth factor receptor (EGFR) kinase activity and is used to treat non-small cell lung cancer (NSCLC). Despite its high efficacy, recurrence can occur in patients who become resistant to the drug. To address the underlying mechanism of Erlotinib resistance, we investigated additional mechanisms related to mode-of-drug-action, by multiple protein-binding interactions, besides EGFR by using drug affinity responsive target stability (DARTS) and liquid chromatography-mass spectrometry (LC-MS/MS) methods with non-labeled Erlotinib. DNA polymerase alpha subunit B (POLA2) was identified as a new Erlotinib binding protein that was validated by the DARTS platform, complemented with cellular thermal shift assays. Genetic knock-down of POLA2 promoted the anti-proliferative effect of the drug in the Erlotinib-resistant cell line H1299 with high POLA2 expression, whereas overexpression of POLA2 restored anti-proliferative effects in the Erlotinib-sensitive cell line HCC827 with low POLA2 expression. Importantly, POLA2 expression levels in four NSCLC cell lines were positively correlated with anti-proliferative Erlotinib efficacy, verified by bio-statistical analysis (Pearson correlation coefficient, R=0.9886). These results suggest that POLA2 is a novel complementary target protein of Erlotinib, and could clinically provide validity as a surrogate marker for drug resistance in patients with NSCLC.

Background The treatment efficacy remains unsatisfactory due to the rapid progress, high rate of metastasis, and drug-resistance of NSCLS. It has been demonstrated that aberrant expression of long non coding RNA colon cancer-associated transcript 2 (CCAT2) in cells was closely related to tumorigenesis, tumor metastasis, and development of drug-resistance. The present study was aimed to thoroughly investigate the effect of CCAT2 in the growth of NSCLC and the underlying mechanisms, so that provide valuable theoretical basis for efficient treatment of NSCLC. Methods The expressions of CCAT2 and its target genes and downstream signals were respectively determined by Western-blot assay and RT-qPCR experiment. Cell growth of NSCLC cells was investigated using the CCK-8 kit while the proliferation assay was performed with the help of EDU staining. The NSCLC-bearing mice mode was established to evaluate the effect of PYCR1 on the progress of NSCLC and the underlying mechanisms in vivo. Results The CCAT2 was highly expressed in NSCLC tumor tissues and cells while not the corresponding normal ones. Further studies revealed that aberrant expression of CCAT2 in lung cancer signally contributed to proliferation, invasion, and migration of cancer cells and the progress of tumor tissues. Moreover, high level of CCAT2 dramatically down-regulated the cytotoxicity of cisplatin (DDP) to NSCLC cells and tissues by upregulation of the drug-resistance related proteins. Mechanisms studies displayed that upregulation of CCAT2 markedly decreased the miR-204-3p while contrary result was obtained when down-regulated the CCAT2 level. We further demonstrated that down-regulation of miR-204-3p level signally enhanced the activity of the insulin-like growth factor (IGF) signaling pathway. Conclusions The CCAT2 promoted the progress and drug-resistance of NSCLC thorough activation of the miR-204-3p suppressed IGFBP2/AKT/Bcl2 pathway, and may provide theoretical basis for improvement of therapy of NSCLC.

Background To evaluate the efficacy of the nodal descriptors and subgroups proposed by International Association for the Study of Lung Cancer (IASLC) in the 8th edition of the TNM classification system and to provide references for future editions. Methods A total of 3,177 patients with non-small cell lung cancer at the Beijing Cancer Hospital were classified based on the following three methods: (I) the N descriptors in the 8th edition of the TNM classification system: N0, N1, N2, and N3; (II) the IASLC-proposed N subgroups: N1a, N1b, N2a1, N2a2, and N2b; (III) our more extensive division method: N1a, N1b, N1c, N2a1, N2a2, N2b1, N2b2, N2c, N3a, and N3b. Five-year survival analysis was performed using the Kaplan-Meier method, and differences between subgroups were evaluated using the log-rank test. Results (I) A significant survival difference was found between each adjacent N descriptor; (II) the difference between each adjacent subgroup N descriptor was significant, but the difference between N1b and N2a1 was not; (III) in our proposed method, a significant difference was found between all the subgroups apart from N2a2 and N2b1, N2b1 and N2b2, N2c and N3a, and N3a and N3b. Conclusions The N descriptors in the 8th edition of the tumor, node, and metastasis (TNM) classification system are consistent with our data. Although our more extensive division method could distinguish between patients at different stages, its implementation is complicated; thus, we recommend the implementation of the IASLC-proposed subgroups with the addition of the N1b and N2a1 groups.

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Single gene assays for variants in Epidermal Growth Factor Receptor (EGFR) demonstrate actionable and sensitising mutations in majority of the cases. However, the emergence of next generation sequencing platforms has facilitated the detection of newer variants in the already known drivers of lung carcinomas, which may be clinically actionable. Mutations in exons 18 to 21 of EGFR are widely characterised in literature, and rare unusual mutations in these regions are constantly being demonstrated recently. This report describes a rare exon 18 insertion variant in EGFR gene in a 61-year-old patient of non-small cell lung carcinoma, which is potentially actionable, thus highlighting the need of next generation sequencing based platforms in this era of precision medicine.

Gemcitabine and pemetrexed are clinically approved antimetabolites for the therapy of mesothelioma diseases. These drugs are often applied in combination with platinum complexes and other drugs. The activity of antimetabolites depended on the expression levels of certain non-coding RNAs, in particular, of small microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The development of tumor resistance towards antimetabolites was regulated by non-coding RNAs. An overview of the interplay between gemcitabine/pemetrexed antimetabolites and non-coding RNAs in mesothelioma is provided. Further to this, various non-coding RNA-modulating agents are discussed which displayed positive effects on gemcitabine or pemetrexed treatment of mesothelioma diseases. A detailed knowledge of the connections of non-coding RNAs with antimetabolites will be constructive for the design of improved therapies in future. Keywords: MicroRNA, Long non-coding RNA, Mesothelioma, Gemcitabine, Pemetrexed, Anticancer drugs

Natural biomacromolecules have attracted increased attention as carriers in biomedicine in recent years because of their inherent biochemical and biophysical properties including renewability, nontoxicity, biocompatibility, biodegradability, long blood circulation time and targeting ability. Recent advances in our understanding of the biological functions of natural-origin biomacromolecules and the progress in the study of biological drug carriers indicate that such carriers may have advantages over synthetic material-based carriers in terms of half-life, stability, safety and ease of manufacture. In this review, we give a brief introduction to the biochemical properties of the widely used biomacromolecule-based carriers such as albumin, lipoproteins and polysaccharides. Then examples from the clinic and in recent laboratory development are summarized. Finally the current challenges and future prospects of present biological carriers are discussed., Graphical abstract This review will give an introduction of properties and applications of biomacromolecule-based carriers including proteins and polysaccharides in drug delivery systems and tissue engineering, and current challenges and prospects will be also discussed in the end.fx1

Background: Tumor-related leukocytosis is a paraneoplastic syndrome that is encountered occasionally in the clinical course of patients with lung carcinoma. The aim of this study is to evaluate the prognostic significance of leucocytosis in patients with metastatic non small cell lung carcinoma. Methods: We retrospectively reviewed 205 cases of metastatic non small cell lung carcinoma diagnosed between January 2007 and December 2012 at the department of medical oncology, Hassan II University Hospital of Fez, Morocco. Clinical and laboratory data were collected including white blood cells at baseline. Leucocytosis was studied in relation to overall survival and progression free survival. Results: The frequency of leucocytosis was of 57.5%. Patients with leucocytosis had shorter overall survival (OS, p = 0.015) and disease-free survival (DFS, p 0.0001) than those without leucocytosis. In multivariable analysis, patients with leucocytosis had a significantly greater risk of death and recurrence than those without leucocytosis. Conclusion: Leucocytosis was valuable for predicting the prognosis of patients with metastatic non small cell lung carcinoma.

Aim This study aims to evaluate the role of the EPHA5 mutation in the migration and invasion of non-small cell lung cancer (NSCLC) cells and in modulating the killing effect of natural killer (NK) cells to NSCLC cells. Methods EPHA5-wt (wild type) and EPHA5-mut (mutation) plasmids were constructed. EPHA5 was silenced using si-EPHA5. NSCLC cell migration and invasion were determined using Transwell assays. NK cell proliferation and apoptosis were determined using CCK-8 assay and flow cytometry, respectively. The killing effect of NK cells to NSCLC cells was also examined. Results EPHA5 mutation significantly promoted migration and invasion in NSCLC cells. Furthermore, EPHA5 mutation notably impaired the cytotoxicity of NK cells against NSCLC cells. In contrast, EPHA5-wt overexpression and EPHA5 silencing exerted the opposite effect. Conclusion EPHA5 mutation impairs the NK cell-mediated cytotoxicity against NSCLC cells and promotes migration and invasion in NSCLC cells.

e21050 Background: Five-year overall survival (OS) was reported in 20% of patients treated by Pembrolizumab (Pembro) in 1st-line advanced/metastatic (a/m)-non-small lung cancer (nsLC). Costs of the immune check point inhibitors (ICI) are relatively high and bound to increase with extended use. We purposed to weigh and compare costs of ICI vs outcome. Methods: OS, hazard ratio (HR) and survival ratio (SR) defined as (1.0-HR) were used. Chemo-drug excluded; costs were calculated in US$. Results: Adjuvant Durv one-year costs in unresectable stage III were $130,956, OS gain 363 days and SR 0.47. Pembro one-year costs were $134,778. OS were 474 and SR 0.37 in programmed death receptor-ligand-1 > 50%. At 5 years, costs were $673,890. Costs of 35-cycle Pembro combination were $336,945, OS 339 and SR 0.51. Costs increased with extended use. Atezolizumab/Bevacizumab-combination (Atezo/Bev) costs x 2-years were $492,114, OS 135 and SR 0.22. Using Biosimilar Bev costs dropped to $429,744. Ipilimumab/Nivolumab (Ipi/Nivo) costs x 2 were $544,696, OS 141 and SR 0.34. Costs of both Atezo/Bev and Ipi/Nivo increased by 50% with one year of extended use. Costs of Pembro-combination were 0.78 lower than Atezo/Bev and 0.62 than Ipi/Nivo. Pembro SR were 2.32 higher than Atezo/Bev and 1.65 than Ipi/Nivo. Absence of direct comparison, however, cast doubts on Pembro advantage. Conclusions: Costs of one-year adjuvant Durv, 3-year Pembro and 35-cycle Pembro-combination were considered fair and equitable with their corresponding SR. Pembro-combination costs were cheaper than Atezo/Bev and Nivo/Ipi. Costs of all drugs and combinations multiplied with extended use.

e21034 Background: Pembrolizumab (Pembro) demonstrated marked prolongation of 5-year overall survival (OS) in 1st-line advanced/metastatic (a/m)-non-small lung cancer (nsLC). Adjuvant Durvalumab (Durv), Atezolizumab/Bevacizumab (Atezo/Bev), Ipilimumab/Nivolumab (Ipi/Nivo) and Pembro-combination have since improved the outcome. Progress, however, came at high costs of the immune check point inhibitors (ICI). There is unmet need for cost-constraining policies. We purposed 1- Weigh costs of ICI vs outcome 2- Propose cost bundling at negotiable $450,000 - $550,000 thresholds, depending on the number of companies and drugs involved. Methods: OS, hazard ratio (HR) and survival ratio (SR), defined as (1.0-HR) were used. Chemo-drugs excluded, costs of ICI doses were calculated in US$. Results: Durv one-year costs in unresectable stage III were $130,956, OS gain 363 days and SR 0.47. Pembro one-year costs were $134,778, OS 474 and SR 0.37 in PD-L1 > 50%. At 5 years, costs were $673,890. Bundling negotiated at $450,000-$550,000 would save $123,112-$223,890. Costs of 35 cycles of Pembro-combination were $336,945, OS 339 and SR 0.51. Costs of Atezo/Biosimilar-Bev-comnination supplied by > one company, were $429,744, OS 135 and SR 0.22. Ipi/Nivo costs were $544,696, OS 141 and SR 0.34. Costs of Atezo/Bev and Nivo/Ipi used beyond 2 years exceeded $550,000 and multiplied by one more of use. Costs of Pembro-combination were 0.78 lower than Atezo/Bev and 0.62 than Ipi/Nivo. Pembro SR were 2.32 higher than Atezo/Bev and 1.65 than Ipi/Nivo. Lack of direct comparison undermined Pembro SR advantage. Conclusions: Costs of one-year adjuvant Durv, 3-year Pembro and 35-cycle Pembro-combination seemed equitable with their corresponding SR and below the $450,000 threshold. Pembro-combination costs were cheaper than Atezo/Bev and Nivo/Ipi. ICI costs of extended use tend to support the bundling proposal.

e20513 Background: Lung cancer is the leading cause of cancer death in Taiwan. The poor prognosis of lung cancer patients with advanced disease and recent development of precision medicine motivates the investigation of molecular targets. The purpose of the study is to estimate the prevalence of KRAS gene mutations and 15 other gene targets among non-small cell lung cancer (NSCLC) patients in Taiwan. Methods: This retrospective study included 933 NSCLC patients diagnosed between January 1992 and July 2018 at six medical centers in Taiwan, including Taichung Veteran’s General Hospital, Chung San Medical University Hospital, China Medical University Hospital, Kaohsiung Veteran’s General Hospital, Tri-Service General Hospital and National Taiwan University Hospital. Patients ≥18 years, had primary histologically confirmed NSCLC diagnosis at time before any treatment, and availability of archival tumor tissue with >30% tumor cellularity. Mutational Analysis: The Formalin-Fixed Paraffin-Embedded (FFPE) tumor blocks were analyzed for the prevalence of somatic mutations. The entire coding sequence of 16 genes was analyzed by next generation sequencing of macrodissected DNA from FFPE recut slides at a depth of greater than 300x and interrogated for somatic pathogenic variants. RNA was not available; hence this limits sensitivity to detect fusions. Results: The mean age at diagnosis was 62 years, 498/933 (53%) were women, 411/843 (49%) were smokers or former smokers, and 829/933 (89%) of adenocarcinoma histopathology. Stage was available for 723 patients with a distribution of 328/723 (45%) Stage I, 120/723 (17%) Stage II, 210/723 (29%) Stage III, and 65/723 (9%) Stage IV. EGFR mutations were identified in 327/933 (35.1%) and TP53 mutations in 179/933 (19.2%). KRAS mutations were identified in 72/933 (7.7%) patients, with KRAS G12C mutations observed in 23/933 (2.5%), KRAS G12D in 16/933 (1.7%), and KRAS G12V in 14/933 (1.5%) (Table). In addition, co-occurring mutations with KRAS were observed and are highlighted, including 14 TP53, 4 PIK3CA, 2 EGFR, 2 CTNNB1, 1 STK11, 1 BRAF and 1 PTEN. Conclusions: EGFR and TP53 were the most frequent mutations identified among all stage NSCLC in Taiwanese populations, followed by KRAS. KRAS G12C and KRAS G12D, the two most frequent KRAS mutations, were identified in 32% and 22% of the KRAS-mutant tumors. Although the prevalence of any KRAS mutation or KRAS G12C mutation is lower than typically seen in Western countries, it is similar to observations among Asian populations. These findings broaden the understanding of the mutational landscape of NSCLC patients in Taiwan to inform development of new therapeutic approaches. [Table: see text]

9046 Background: Eftilagimod alpha (efti) is a soluble LAG-3 protein that binds to a subset of MHC class II molecules to mediate antigen presenting cell (APC) activation and CD8 T-cell activation. The stimulation of the dendritic cell network and subsequent T cell recruitment with efti may lead to stronger anti-tumor responses in combination than observed with pembrolizumab alone. We hereby report results of the 1st line non-small cell lung carcinoma (NSCLC) part of the phase II trial (NCT03625323). Methods: Patients (pts) with untreated, immunotherapy naïve, advanced NSCLC unselected for PD-L1 expression were recruited into part A. The study used a Simon's 2-stage design (17 pts planned for stage 1 and 19 pts for stage 2), with objective response rate (ORR) by iRECIST as the primary endpoint (EP). Secondary EPs include tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS), PK, PD and immunogenicity. Efti is administered as 30 mg subcutaneous injection every 2 wks for 8 cycles and then every 3 wks for 9 cycles with pembrolizumab (200 mg intravenous infusion every 3 wks for up to 2 yrs). Imaging was performed every 8 weeks locally and with blinded independent central review (BICR) retrospectively. The study was approved by ethic committees and institutional review boards. Results: In total 36 pts were enrolled. At data cut-off (Jan 2021; median FU of 14 months), the median age was 69 yrs (range 53-84) and 69 % were male. The ECOG PS 0 and 1 was 42% and 58% respectively. Patients had squamous (42%) and non-squamous (58%) NSCLC and 95% presented with metastatic disease. All PD-L1 subgroups (TPS < 1 %, ≥ 1 % to ≤49 %; ≥50 %) were represented with 36% pts having ≥50% TPS. Pts received a median of 7.0 (range 1 – 31) pembrolizumab and 11.5 (range 1-22) efti administrations. Responses as per BICR and local read are shown in the table. ORR (local, iRECIST) by different PD-L1 subgroups was 27% for pts with TPS 20 %) treatment emergent adverse events (AEs) were asthenia (47 %), cough (36 %), decreased appetite (36 %), dyspnea (32 %), pruritus (31 %), fatigue (28 %), diarrhea (25 %), anemia (25 %), constipation (25 %) and back pain (22%). Two patients discontinued treatment due to adverse reactions (Grade 4 immune-mediated hepatitis, Grade 3 AST+ALT increase). Conclusions: Efti in combination with pembrolizumab is safe and shows encouraging antitumor activity in 1st line advanced NSCLC patients across all PD-L1 (TPS) levels. Clinical trial information: NCT03625323. [Table: see text]

As one member of Forkhead box transcription factors, Forkhead box J2 (FOXJ2) has been found to be involved in epithelial-mesenchymal transition (EMT) process. However, the role and mechanism of FOXJ2 in non-small cell lung cancer (NSCLC) and EMT regulation have not been fully revealed. In this paper, it was revealed that the expression of FOXJ2 was lower in NSCLC samples compared with matched peritumoral lung tissue. We demonstrated that FOXJ2 expression was down-regulated by transforming growth factor-β1 (TGF-β1) treated, and overexpression of FOXJ2 inhibited TGF-β1-induced EMT. Mechanistically, knocking out the expression of FOXJ2 promoted EMT by increasing the expression of Notch1 and NICD. This study implicates the potential value of FOXJ2 as a molecular marker for NSCLC.

In 1960, Cahan reported the first patients to successfully undergo lobectomy with regional lymph node dissection, which was called radical lobectomy (1). Since then, this procedure has been broadly accepted and has remained as a standard surgery for non-small cell lung cancer (NSCLC). Systematic nodal dissection (SND) has been reported to be important for survival as well as accurate disease staging (2,3). However, the effect of SND on the prognosis remains controversial.

Background: The human YTH domain family protein (YTHDF) family is RNA binding protein which specifically recognizes N6-methyladenosine (m6A), and exerts distinct roles in eukaryocytes; YTHDF1 promotes the translation of m6A modified mRNAs collaborating with initiation factors, and YTHDF2 reduces the stability of the m6A-modified transcripts. The previous reports showed YTHDF1/2 are associated with cancer progressiveness in colorectal cancers and prostate cancers. In contrast, YTHDF2 is reported to act as an anti-tumoral function in hematologic malignancies. Further, a recent investigation showed that YTHDF1 interacted with the tumor immune microenvironment and modulate an anti-tumor immune response. However, the clinical relevance of YTHDF1/2 in non-small cell lung cancers (NSCLCs) has yet to be elucidated fully. Method: We evaluated the protein expression levels of YTHDF1/2 in the 603 resected NSCLCs, including 392 adenocarcinomas and 170 squamous cell carcinomas by immunohistochemistry. The tumor expression levels were assessed by H-scores that ranged from 0 to 300. We also assessed the four subsets of lymphocytes, PD-1+, CD8+, Foxp3+, and CD45RO+ as tumor-infiltrating lymphocytes (TILs), in tumor nest and surrounding stroma separately. TILs were counted under high-power fields (× 200). Their associations with patients' characteristics and survival were retrospectively explored. We additionally validated the prognostic association of YTHDF1/2 using the mRNA expression data derived from the TCGA dataset. Result: The median age was 68 years old (range, 23-88) and 414 (68.7%) patients were male. Significantly higher expressions of YTHDF1/2 was observed in tumors with a lower grade of the pathological stage. They were also significantly associated with adenocarcinoma histology. Multivariate Cox regression analyses demonstrated that YTHDF2 were independent favorable prognostic factors for overall survivals (HR, 0.674; 95% CI, 0.455-0.998) and YTHDF1/2 were independent favorable prognostic factors recurrence-free survivals (HR, 0.755; 95%CI, 0.572-0.998 for YTHDF1, and HR, 0.679; 95%CI, 0.500-0.921 for YTHDF2). Regarding stromal TILs, the numbers of individual TILs significantly increased in high YTHDF2 tumors. All subsets of TILs except CD8+ were also significantly greater in high YTHDF1 tumors. In tumor nest, the numbers of Foxp3+ were also significantly prominent in high YTHDF2 tumors, but neither kind of TILs was associated with YTHDF1 expression. TCGA dataset showed that YTHDF1/2 expressions were significantly higher in tumor tissue than in corresponding non-tumor tissues. High YTHDF2 mRNA expression was also a favorable prognostic indicator, but YTHDF1 was not. Conclusion: High YTHDF1/2 expressions were favorable prognostic factors in patients with NSCLC. They were also significantly associated with several kinds of TILs. YTHDF2 and part of YTHDF1 might not only exhibit anti-tumor activity but also relate to the inflamed tumor microenvironment. Citation Format: Kazuo Tsuchiya, Katsuhiro Yoshimura, Yusuke Inoue, Yuji Iwashita, Hidetaka Yamada, Akikazu Kawase, Masayuki Tanahashi, Hiroshi Ogawa, Kazuhito Funai, Kazuya Shinmura, Takafumi Suda, Haruhiko Sugimura. m6A reader proteins, YTHDF1 and YTHDF2, are associated with better patients' survival and inflamed tumor immune microenvironment in non-small lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 414A.