Search

In epithelial tissues, intercellular adhesion structures are formed between adjacent cells via intercellular adhesion factors, such as zonula occludens (ZO-1), to maintain the structure and function of tissues and organs, thereby contributing to homeostasis. Epithelial cells are polarized into apical and basal regions by tight junctions (TJs), a type of intercellular adhesion structure, and thus, their intracellular organelles are asymmetrically distributed. Normal epithelial cells maintain their cellular function by controlling cytoskeletal reorganization, motility, and division by maintaining asymmetry in their intracellular organelles. Among the features common to many cancer tissues are abnormalities in cell polarity and intercellular adhesion. Lung adenocarcinoma consists of a mixture of five different histologic types that can be distinguished in the same section: lepidic, papillary, acinar, micropapillary, and solid patterns. Therefore, it is often difficult to accurately assess histological images because the staining differs according to the histological types. In the present study, we evaluated ZO-1 staining based on histological features observed in a single section and examined its relationship to clinicopathological features. In non-tumor areas, ZO-1 was expressed on the plasma membrane and in the cytoplasm of normal alveolar epithelial cells. However, in tumor areas, ZO-1 staining was mainly localized in the cytoplasm and on the plasma membrane only in a few cells. ZO-1-negative cases tended to have poorer prognoses in all histological types, with a poorer prognosis in the solid pattern. These results suggest that ZO-1 expression in solid-pattern lung adenocarcinoma may be a useful prognostic marker. [ABSTRACT FROM AUTHOR]

Metastatic lung cancer classically portends a poor prognosis. The management of metastatic lung cancer has dramatically changed with the emergence of immune checkpoint inhibitors, targeted therapy and due to a better understanding of the oligometastatic process. In metastatic lung cancers, radiation therapy which was only used with palliative intent for decades, represents today a promising way to treat primary and oligometastatic sites with a curative intent. Herein we present through a literature review the role of radiotherapy in the management of synchronous metastatic lung cancers. [ABSTRACT FROM AUTHOR]

Aim: The overall survival (OS) of operable lung cancer patients is directly related to clinicopathological features and some laboratory parameters. In this study, we aimed to examine the factors affecting the survival of the operated patients. Materials and Methods: In our study, we retrospectively analyzed 202 operated-on patients diagnosed with lung carcinoma who were in stages I-IIIA at the time of diagnosis. The clinico-pathological features and some laboratory parameters of the patients included in our study were retrospectively analyzed. The effects of those parameters on the overall survival of the patients and their disease-free survival (DFS) have been investigated. Results: The age of the patient at the time of diagnosis and the presence of lymphovascular invasion (LVI) were found to be statistically significant in terms of OS (p<0.05). Pathological tumor size, LVI, and peri-neural invasion (PNI) parameters were statistically significant for DFS. In addition, neutrophil-lymphocyte ratio (NLR), which is an inflammatory indicator, is an important parameter with statistical significance in terms of both OS and DFS (p<0.05). Conclusion: Our study yielded that LVI and PNI parameters would be beneficial to estimate patients' survival and prognosis. In addition, NLR was observed to have a statistically significant effect on OS and DFS. [ABSTRACT FROM AUTHOR]

Ramucirumab plus docetaxel (RD) is a promising treatment for previously treated advanced non-small cell lung cancer (NSCLC). However, its clinical significance after platinum-based chemotherapy plus programmed death-1 (PD-1) blockade remains unclear. What is the clinical significance of RD as a second-line treatment after the failure of chemo-immunotherapy in NSCLC? In this multicentre retrospective study, 288 patients with advanced NSCLC who received RDas second-line therapy after platinum-based chemotherapy plus PD-1 blockade, at 62 Japanese institutions from January 2017 to August 2020, were included. Prognostic analyses were performed using the log-rank test. Prognostic factor analyses were performed using a Cox regression analysis. A total of 288 patients were enrolled: 222 were men (77.1%), 262 were aged <75 years (91.0%), 237 (82.3%) had smoking history and 269 (93.4%) had a performance status (PS) of 0–1. One hundred ninety-nine patients (69.1%) were classified as adenocarcinoma (AC) and 89 (30.9%) as non-AC. The types of PD-1 blockade used in the first-line treatment were anti-PD-1 antibody and anti-programmed death-ligand 1 antibody in 236 (81.9%) and 52 (18.1%) patients, respectively. The objective response rate for RD was 28.8% (95% confidence interval [CI], 23.7–34.4). The disease control rate was 69.8% (95% CI, 64.1–75.0).The median progression free survival and overall survival were 4.1 months (95% CI, 3.5–4.6) and 11.6 months (95% CI, 9.9–13.9), respectively. In a multivariate analysis, non-AC and PS 2–3 were independent prognostic factors for worse progression free survival , while bone metastasis on diagnosis, PS 2–3 and non-AC were identified as independent prognostic factors for poor overall survival. RD is a feasible second-line treatment in patients with advanced NSCLC who had received combined chemo-immunotherapy with PD-1 blockade. UMIN000042333. • The response rate for docetaxel plus ramucirumab (RD) after chemo-immunotherapy was 28.8%. • Progression free survivaland overall survival for RD after chemo-immunotherapy were 4.1 months and 11.6 months, respectively. • The frequency of pneumonitis due to RD after chemo-immunotherapy was 10.8%. • Bone metastasis, poor performance status and non-adenocarcinoma were prognostic factors for poor overall survival. [ABSTRACT FROM AUTHOR]

Background. Non-small-cell lung cancer (NSCLC) is a major health problem that endangers human health. The prognosis of radiotherapy or chemotherapy is still unsatisfactory. This study is aimed at investigating the predictive value of glycolysis-related genes (GRGs) on the prognosis of NSCLC patients with radiotherapy or chemotherapy. Methods. Download the clinical information and RNA data of NSCLC patients receiving radiotherapy or chemotherapy from TCGA and geo databases and obtain GRGs from MsigDB. The two clusters were identified by consistent cluster analysis, the potential mechanism was explored by KEGG and GO enrichment analyses, and the immune status was evaluated by estimate, TIMER, and quanTIseq algorithms. Lasso algorithm is used to build the corresponding prognostic risk model. Results. Two clusters with different GRG expression were identified. The high-expression subgroup had poor overall survival. The results of KEGG and GO enrichment analyses suggest that the differential genes of the two clusters are mainly reflected in metabolic and immune-related pathways. The risk model constructed with GRGs can effectively predict the prognosis. The nomogram combined with the model and clinical characteristics has good clinical application potential. Conclusion. In this study, we found that GRGs are associated with tumor immune status and can assess the prognosis of NSCLC patients receiving radiotherapy or chemotherapy. [ABSTRACT FROM AUTHOR]

Objectives: Ramucirumab (RAM) and docetaxel (DOC) are commonly used after first-line therapy for advanced non-small cell lung cancer (NSCLC). Therefore, we aimed to elucidate sequencing strategies of RAM and DOC following prior treatments, including immune checkpoint inhibitor (ICI), cytotoxic agent (CTx) alone, bevacizumab (BEV), and tyrosine kinase inhibitor (TKI). Methods: We recruited patients with NSCLC who received RAM and DOC and compared the groups with and without prior ICI, CTx alone, BEV, and TKI, respectively. By tumor response to such treatments, the patients were further classified into "complete response (CR) + partial response (PR)," "stable disease," and "progressive disease" groups, respectively. We compared RAM and DOC efficacy among these groups. Results: In total, 237 patients were registered. In the group with prior ICI, the objective response rate and disease control rate were significantly higher than those without prior ICI (p = 0.012 and 0.028, respectively), and the median progression-free survival (PFS) was also significantly longer (p = 0.027). There were no significant differences in PFS between the groups with and without CTx alone, BEV, and TKI. Multivariate analysis revealed that prior ICI was an independent factor associated with better PFS. Furthermore, the prior ICI group with CR + PR significantly prolonged PFS compared to the group without prior ICI (p = 0.013). Conclusion: RAM and DOC may be preferably administered after ICI, rather than after CTx alone, BEV, or TKI, and, furthermore, enhanced if the prior ICI has a favorable tumor response. [ABSTRACT FROM AUTHOR]

Background: The budding uninhibited by benzimidazoles (BUB) family is involved in the cell cycle process as mitotic checkpoint components. Abnormal proliferation is a vital process in the development of lung adenocarcinoma (LUAD). Nevertheless, the roles of BUB1 in LUAD remain unclear. In this study, we evaluated the prognostic value and biological functions of BUB1 in LUAD using data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), clinical LUAD samples, and in vitro experiments. Methods: The expression, prognostic significance, functions, immune infiltration, and methylation of BUB1 in LUAD were comprehensively analyzed using TCGA, GEO, Gene Expression Profiling Interactive Analysis, Metascape, cBioPortal, MethSurv, and cancerSEA databases. Furthermore, we performed a battery of in vitro experiments and immunohistochemistry (IHC) to verify the bioinformatics results. Results: Multivariate analysis revealed that BUB1 overexpression was an independent prognostic factor (hazard ratio = 1.499, p = 0.013). Functional enrichment analysis showed that BUB1 was correlated with cell cycle, proliferation, DNA repair, DNA damage, and invasion (p < 0.05). Finally, in vitro experiments showed that downregulation of BUB1 inhibited the proliferation, migration, and invasion of LUAD cells and promoted LUAD cell apoptosis. IHC also showed that BUB1 was overexpressed in LUAD (p < 0.001) and was significantly associated with poor prognosis (p < 0.001). Conclusions: Our bioinformatics and IHC analyses revealed that BUB1 overexpression was an adverse prognostic factor in LUAD. In vitro experiments demonstrated that BUB1 promoted tumor cell proliferation, migration, and invasion in LUAD. These results indicated that BUB1 was a promising biomarker and potential therapeutic target in LUAD. [ABSTRACT FROM AUTHOR]

Background: Sleeve lobectomy is recommended to avoid pneumonectomy and preserve pulmonary function in patients with central lung cancer. However, the relationship between postoperative pulmonary functional loss and resected lung parenchyma volume has not been fully characterized. The aim of this study was to evaluate the relationship between pulmonary function and lung volume in patients undergoing sleeve lobectomy or pneumonectomy. Methods: A total of 61 lung cancer patients who had undergone pneumonectomy or sleeve lobectomy were analyzed retrospectively. Among them, 20 patients performed pulmonary function tests, including vital capacity (VC) and forced expiratory volume in 1 s (FEV1) tests, preoperatively and then about 6 months after surgery. VC and FEV1 ratios were calculated (measured postoperative respiratory function/predicted postoperative respiratory function) as the standardized pulmonary functional loss ratio. Results: Thirty‐day operation‐related mortality was significantly lower after sleeve lobectomy (3.2%) than pneumonectomy (9.6%). The 5‐year relapse‐free survival rate was 46.67% versus 29.03%, and the 5‐year overall survival rate was 63.33% versus 38.71% in patients receiving sleeve lobectomy versus pneumonectomy. The VC ratio in the pneumonectomy group was better than in the sleeve lobectomy group (1.003 ± 0.117 vs. 0.779 ± 0.12; p = 0.0008), as was the FEV1 ratio (1.132 ± 0.226 vs. 0.851 ± 0.063; p = 0.0038). Conclusions: Both short‐term and long‐term outcomes were better with sleeve lobectomy than pneumonectomy. However, actual postoperative pulmonary function after pneumonectomy may be better than clinicians expect, and pneumonectomy should still be considered a treatment option for patients with sufficient pulmonary reserve and in whom sleeve lobectomy is less likely to be curative. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is one of the biggest public health issues due to its high prevalence and mortality. Currently, increasing consideration is given to the incidence of lung cancer in the individuals with no lifetime history of tobacco smoking. However, up-to-date data on the characteristics of a group of non-smokers with lung cancer are limited. The current literature also contains gaps in the differences in the clinical course of lung cancer in smokers and non-smokers. This study aimed to investigate the differences in tumor characteristics, survival rates, and comorbidities between a group of smokers and a group of non-smokers with lung cancer. The presented results may be used in clinical practice and in shaping future lung cancer prevention programs. Changes in smoking trends and changes in lifestyle, together with worldwide data regarding the incidence of lung cancer in the group of patients with no previous history of smoking, leads to consideration of the differences in the course of the disease, the time of cancer diagnosis, the survival rate, and the occurrence of comorbidities in this group of patients. This study aimed to determine the occurrence of non-smokers among patients undergoing anatomical resection of the lung tissue due to lung carcinoma and to investigate the differences between the course of lung cancer, survival, and the comorbidities in the groups of patients with lung cancer depending on the history of tobacco smoking. The study included a cohort of 923 patients who underwent radical anatomical resection of the lung tissue with lung primary adenocarcinoma or squamous cell carcinoma. The Chi2 Pearson's test, the t-test, the Mann–Whitney U test, the Kaplan–Meier method, the Log-rank test with Mantel correction, and the Cox proportional hazard model were used for data analysis. We observed a significantly higher mean age of smoking patients compared to the mean age of non-smoking patients. The coexistence of former neoplastic diseases was significantly more frequent in the group of non-smokers compared to the group of smoking patients. We did not observe differences depending on smoking status in the tumor stage, grade, vascular and pleural involvement status in the diagnostic reports. We did not observe differences in the survival between smokers vs. non-smokers, however, we revealed better survival in the non-smoker women group compared to the non-smoker men group. In conclusion, 22.11% of the patients undergoing radical anatomical resection of the lung tissue due to lung cancers were non-smokers. More research on survival depending on genetic differences and postoperative treatment between smokers and non-smokers is necessary. [ABSTRACT FROM AUTHOR]

Simple Summary: Limited studies have focused specifically on early-stage NSCLC patients, although there is a particular clinical need for risk stratification in these patients because there are very few therapeutic options in the adjuvant setting. In this prospective study, we compared ddPCR data of hotspot mutations for four therapeutically relevant genes (BRAF, EGFR, KRAS, PIK3CA) from three different patient-matched sample types (FFPE, CTC-derived DNA and plasma-ctDNA) from early-stage NSCLC patients before surgery. We demonstrated that simultaneous analyses of plasma-cfDNA and CTC-derived DNA provided complementary molecular information from the same blood sample and greater diversity in genomic information for cancer treatment and prognosis. Purpose: We assessed whether preoperativemutational analyses of circulating tumor cells (CTCs) and plasma-cfDNA could be used as minimally invasive biomarkers and as complimentary tools for early prediction of relapse in early-stage non-small -cell lung cancer (NSCLC). Experimental Design: Using ddPCR assays, hotspot mutations of BRAF, KRAS, EGFR and PIK3CA were identified in plasma-cfDNA samples and size-based enriched CTCs isolated from the same blood samples of 49 early-stage NSCLC patients before surgery and in a control group of healthy blood donors (n= 22). Direct concordance of the mutational spectrum was further evaluated in 27 patient-matched plasma-cfDNA and CTC-derived DNA in comparison to tissue-derived DNA. Results: The prevalence of detectable mutations of the four tested genes was higher in CTC-derived DNA than in the corresponding plasma-cfDNA (38.8% and 24.5%, respectively).The most commonly mutated gene was PIK3CA, in both CTCs and plasma-cfDNA at baseline and at the time of relapse. Direct comparison of the mutation status of selected drug-responsive genes in CTC-derived DNA, corresponding plasma-cfDNA and paired primary FFPE tissues clearly showed the impact of heterogeneity both within a sample type, as well as between different sample components. The incidence of relapse was higher when at least one mutation was detected in CTC-derived DNA or plasma-cfDNA compared with patients in whom no mutation was detected (p =0.023). Univariate analysis showed a significantly higher risk of progression (HR: 2.716; 95% CI, 1.030–7.165; p =0.043) in patients with detectable mutations in plasma-cfDNA compared with patients with undetectable mutations, whereas the hazard ratio was higher when at least one mutation was detected in CTC-derived DNA or plasma-cfDNA (HR: 3.375; 95% CI, 1.098–10.375; p =0.034). Conclusions: Simultaneous mutational analyses of plasma-cfDNA and CTC-derived DNA provided complementary molecular information from the same blood sample and greater diversity in genomic information for cancer treatment and prognosis. The detection of specific mutations in ctDNA and CTCs in patients with early-stage NSCLC before surgery was independently associated with disease recurrence, which represents an important stratification factor for future trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Systemic inflammation and changes in the inflammatory status are frequent features of lung cancer. There is a close interconnection between cancer development and the clinical, general, and inflammatory status of patients. In this paper, we evaluate a large panel of inflammatory indexes in patients who underwent lung resection for NSCLC lung cancer; we show that pre-operative inflammatory status strongly influences long-term prognosis in patients affected by NSCLC and undergoing surgery. Background (1): Our goal was to investigate if and how pre-operative inflammatory status can influence the long-term prognosis of patients undergoing lung surgery for cancer. Materials and Methods (2): This prospective observational study includes the agreement of all operable patients to the study, who were referred to our department between 1 January 2017 and 30 December 2018. The inflammatory pre-operative status of the patients was investigated by calculating albumin, CPR (c-protein reactive), complete blood count (neutrophils, lymphocytes, platelets, hemoglobin), and some other indexes referring to inflammatory status, namely the HALP amalgamated index, platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocytes ratio (NLR), systemic immune-inflammation index (SII), and advanced lung cancer inflammation Index (ALI). The follow-up ended in November 2021. Patient overall survival was assessed using the Kaplan–Meier method. The log-rank test was used to compare survival rates. Variables significantly associated with survival at univariate analysis were entered int Cox multivariate analysis (stepwise mode) to assess their independent character. Hazard ratios and their 95% confidence intervals were calculated. Variables associated with p < 0.05 were considered significative. Results (3): We enrolled 257 patients in our study. The overall survival of the cohort was as follows: 1 year, 96.1%; 3 year, 81.3%; and 4 year, 74.2%. Univariate analysis showed risk factors for overall survival as follows: Thoracoscore ≥ 2 (p = 0.002); histology (p = 0.002); HALP < 32.2 (p = 0.0002); SII ≥ 808.9 (p = 0.0004); ALI < 34.86 (p = 0.0005); NLr ≥ 2.29 (p = 0.01); hemoglobin < 13 g/dl (p = 0.01); PLR ≥ 196.1 (p = 0.005); pN+ (p < 0.0001); pleural invasion (p = 0.0002); and presence of vascular or lymphatic tumor emboli (p = 0.0002). Multivariate Cox analysis (stepwise model) identified Thoracoscore ≥ 2 (p = 0.02); histology, HALP < 32.2 (p = 0.004), and pN (p < 0.0001) as independent predictors of death. Conclusion (4): Pre-operative inflammatory status strongly influences long-term prognosis in patients affected by NSCLC and undergoing surgery. [ABSTRACT FROM AUTHOR]

Simple Summary: A retrospective study was performed on 955 eligible patients with stage I lung adenocarcinoma (LUAD) after surgery. The systematic oxidative stress score (SOS) was established based on three biochemical indicators, including serum creatinine (CRE), lactate dehydrogenase (LDH), and uric acid (UA). SOS is an independent prognostic indicator for stage I LUAD. In addition, the constructed nomogram based on SOS could accurately predict the survival of those patients. This study aimed to construct an effective nomogram based on the clinical and oxidative stress-related characteristics to predict the prognosis of stage I lung adenocarcinoma (LUAD). A retrospective study was performed on 955 eligible patients with stage I LUAD after surgery at our hospital. The relationship between systematic-oxidative-stress biomarkers and the prognosis was analyzed. The systematic oxidative stress score (SOS) was established based on three biochemical indicators, including serum creatinine (CRE), lactate dehydrogenase (LDH), and uric acid (UA). SOS was an independent prognostic factor for stage I LUADs, and the nomogram based on SOS and clinical characteristics could accurately predict the prognosis of these patients. The nomogram had a high concordance index (C-index) (0.684, 95% CI, 0.656–0.712), and the calibration curves for recurrence-free survival (RFS) probabilities showed a strong agreement between the nomogram prediction and actual observation. Additionally, the patients were divided into two groups according to the cut-off value of risk points based on the nomogram, and a significant difference in RFS was observed between the high-risk and low-risk groups (p < 0.0001). SOS is an independent prognostic indicator for stage I LUAD. These things considered, the constructed nomogram based on SOS could accurately predict the survival of those patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with early-stage non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT) often receive different treatment regimens based on the location of the tumor to minimize the risk of severe side effects. The aim of our study was to examine survival outcomes of patients treated with single-fraction SBRT for peripheral tumors and five-fraction SBRT for central tumors. In a cohort of 265 patients with NSCLC, we found no differences in patients treated for peripheral versus central tumors in progression-free survival, overall survival, local failure, nodal failure, or distant failure. These findings were confirmed upon propensity score matching. Our study demonstrated survival outcomes of patients treated with SBRT for early-stage NSCLC were equivalent for central and peripheral tumors. Background: The treatment of early-stage non-small cell lung cancer (NSCLC) with stereotactic body radiation therapy (SBRT) frequently involves different fractionation schemes for peripheral and central tumors due to concerns with toxicity. We performed an observational cohort study to determine survival outcomes for patients with peripheral and central NSCLC treated with SBRT. Methods: A single-institutional database of patients with early-stage NSCLC treated with SBRT from September 2008 to December 2018 was evaluated. Outcomes were progression-free survival (PFS), overall survival (OS), local failure (LF), nodal failure (NF), and distant failure (DF). Cox multivariable analysis (MVA), Kaplan–Meier plotting, Fine–Gray competing risk MVA, and propensity score matching were performed. Results: A total of 265 patients were included with a median follow-up of 44.2 months. There were 191 (72%) and 74 (28%) patients with peripheral and central tumors treated with single-fraction SBRT to a dose of 27 Gy and five-fraction SBRT to a dose of 50 Gy, respectively. On Cox MVA, there was no difference in OS (adjusted hazards ratio (aHR) of 1.04, 95% CI of 0.74–1.46) or PFS (aHR of 1.05, 95% CI of 0.76–1.45). On Fine–Gray competing risk MVA, there were no differences in LF, NF, or DF. Propensity matching confirmed these findings. Conclusion: The survival outcomes of patients treated with SBRT for early-stage NSCLC were equivalent for central and peripheral tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: Circulating tumor DNA (ctDNA) samples reflect the total tumor burden and allow longitudinal monitoring of mutational sensitizing alterations in routine use for advanced non-small cell lung cancer (NSCLC). Various assays are developed at high sensitivity and specificity. To drive the choice of the best assay at diagnosis, we compared the clinical performance of an ultra-sensitive Plasma-SeqSensei™ SOLID CANCER IVD kit with the Plasma OncoBEAMTM EGFR V2 assay, or with our custom validated NGS routine assay. Global clinical concordances rates of 75% and 68% were found between the Plasma-SeqSensei™ SOLID CANCER IVD assay with the Plasma OncoBEAMTM EGFR V2 assay, and our custom validated NGS assays. The Plasma-SeqSensei™ SOLID CANCER IVD tool enables the identification of the maximum number of patients bearing sensitizing alterations for a tyrosine kinase inhibitor indication at diagnosis, while the custom NGS assay, with weaker clinical sensitivity, is dedicated to the exploration of resistance mechanisms and co-mutations during clinical progression. Introduction: Progressive advanced non-small cell lung cancer (NSCLC) accounts for about 80–85% of all lung cancers. Approximately 10–50% of patients with NSCLC harbor targetable activating mutations, such as in-frame deletions in Exon 19 (Ex19del) of EGFR. Currently, for patients with advanced NSCLC, testing for sensitizing mutations in EGFR is mandatory prior to the administration of tyrosine kinase inhibitors. Patients and Methods: Plasma was collected from patients with NSCLC. We carried out targeted NGS using the Plasma-SeqSensei™ SOLID CANCER IVD kit on cfDNA (circulating free DNA). Clinical concordance for plasma detection of known oncogenic drivers was reported. In a subset of cases, validation was carried out using an orthogonal OncoBEAMTM EGFR V2 assay, as well as with our custom validated NGS assay. Somatic alterations were filtered, removing somatic mutations attributable to clonal hematopoiesis for our custom validated NGS assay. Results: In the plasma samples, driver targetable mutations were studied, with a mutant allele frequency (MAF) ranging from 0.00% (negative detection) to 82.25%, using the targeted next-generation sequencing Plasma-SeqSensei™ SOLID CANCER IVD Kit. In comparison with the OncoBEAMTM EGFR V2 kit, the EGFR concordance is 89.16% (based on the common genomic regions). The sensitivity and specificity rates based on the genomic regions (EGFR exons 18, 19, 20, and 21) were 84.62% and 94.67%. Furthermore, the observed clinical genomic discordances were present in 25% of the samples: 5% in those linked to the lower of coverage of the OncoBEAMTM EGFR V2 kit, 7% in those induced by the sensitivity limit on the EGFR with the Plasma-SeqSensei™ SOLID CANCER IVD Kit, and 13% in the samples linked to the larger KRAS, PIK3CA, BRAF coverage of the Plasma-SeqSensei™ SOLID CANCER IVD kit. Most of these somatic alterations were cross validated in our orthogonal custom validated NGS assay, used in the routine management of patients. The concordance is 82.19% in the common genomic regions (EGFR exons 18, 19, 20, 21; KRAS exons 2, 3, 4; BRAF exons 11, 15; and PIK3CA exons 10, 21). The sensitivity and specificity rates were 89.38% and 76.12%, respectively. The 32% of genomic discordances were composed of 5% caused by the limit of coverage of the Plasma-SeqSensei™ SOLID CANCER IVD kit, 11% induced by the sensitivity limit of our custom validated NGS assay, and 16% linked to the additional oncodriver analysis, which is only covered by our custom validated NGS assay. Conclusions: The Plasma-SeqSensei™ SOLID CANCER IVD kit resulted in de novo detection of targetable oncogenic drivers and resistance alterations, with a high sensitivity and accuracy for low and high cfDNA inputs. Thus, this assay is a sensitive, robust, and accurate test. [ABSTRACT FROM AUTHOR]

Simple Summary: The improved survival rates of lung cancer patients have led to an increased number of patients experiencing multiple primary malignancies during the course of their life. Therefore, a tool that can evaluate the risk of multiple primary cancers and detect them as early as possible could be of great clinical relevance. [18F]fluoro-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) has been widely used and recommended as standard care for clinical staging in lung cancer by international guidelines. However, only very limited data on the detection of additional primary malignancies on FDG-PET/CT at initial staging in non-small cell lung cancer (NSCLC) patients have been published in recent years. Therefore, we aimed to assess the frequency of additional primary malignancies detected incidentally on FDG-PET/CT at staging in patients with the initial diagnosis of NSCLC. Moreover, their impact on patient management and survival was assessed. FDG-PET/CT performed for staging might be a valuable tool to identify additional primary tumors in NSCLC patients. In our study, FDG-PET/CT identified a significant number of additional primary malignancies. Upon validation, additional primary tumors might have substantial implications for patient management clinicians that they should be aware of. Early detection of additional primary tumors together with interdisciplinary patient management may lead to similar survival rates as compared to patients with NSCLC only. We aimed to assess the frequency of additional primary malignancies detected incidentally on [18F]fluoro-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) at staging in NSCLC patients. Moreover, their impact on patient management and survival was assessed. Consecutive NSCLC patients with available staging FDG-PET/CT between 2020 and 2021 were retrospectively enrolled. We reported whether further investigations of suspicious findings presumably not related to NSCLC were recommended and performed after FDG-PET/CT. Any additional imaging, surgery or multimodal management was considered as an impact on patient management. Patient survival was defined using overall survival OS and progression-free survival PFS. A total of 125 NSCLC patients were included, while 26 findings in 26 different patients were suspicious for an additional malignancy on FDG-PET/CT at staging. The most frequent anatomical site was the colon. A total of 54.2% of all additional suspicious lesions turned out to be malignant. Almost every malignant finding had an impact on patient management. No significant differences were found between NSCLC patients with suspicious findings versus no suspicious findings with regards to their survival. FDG-PET/CT performed for staging might be a valuable tool to identify additional primary tumors in NSCLC patients. Identification of additional primary tumors might have substantial implications for patient management. An early detection together with interdisciplinary patient management could prevent a worsening of survival compared to patients with NSCLC only. [ABSTRACT FROM AUTHOR]

Simple Summary: Aberrations in DNA methylation profiles may alter the expression of key miRNAs in non-small cell lung cancer. In this study, we focus on the analysis of the imprinted C19MC and MIR371-3 miRNA clusters due to their oncogenic role. We identified the DNA methylation status and discovered its deregulated target genes in this disease. Additionally, we found five downstream target genes that were correlated with worse overall survival in non-small cell lung cancer. We conclude that C19MC and MIR371-3 are key players in lung cancer because their polycistronic epigenetic regulation leads to differential tumor expression, affecting downstream targets with prognostic value. Epigenetic mechanisms have emerged as an important contributor to tumor development through the modulation of gene expression. Our objective was to identify the methylation profile of the imprinted C19MC and MIR371-3 clusters in patients with non-small cell lung cancer (NSCLC) and to find their potential target genes, as well as to study their prognostic role. DNA methylation status was analyzed in a NSCLC patient cohort (n = 47) and compared with a control cohort including COPD patients and non-COPD subjects (n = 23) using the Illumina Infinium Human Methylation 450 BeadChip. Hypomethylation of miRNAs located on chromosome 19q13.42 was found to be specific for tumor tissue. We then identified the target mRNA–miRNA regulatory network for the components of the C19MC and MIR371-3 clusters using the miRTargetLink 2.0 Human tool. The correlations of miRNA-target mRNA expression from primary lung tumors were analyzed using the CancerMIRNome tool. From those negative correlations identified, we found that a lower expression of 5 of the target genes (FOXF2, KLF13, MICA, TCEAL1 and TGFBR2) was significantly associated with poor overall survival. Taken together, this study demonstrates that the imprinted C19MC and MIR371-3 miRNA clusters undergo polycistronic epigenetic regulation leading to deregulation of important and common target genes with potential prognostic value in lung cancer. [ABSTRACT FROM AUTHOR]

Background: Stereotactic ablative radiotherapy (SABR) is now the standard of care for patients with inoperable early‐stage lung cancer. Many of these patients are elderly. EGFR (epidermal growth factor receptor) mutation is also common in the Asian population. Methods: To evaluate the effects of old age and EGFR mutation on treatment outcomes and toxicity, we reviewed the medical records of 71 consecutive patients with inoperable early‐stage non‐small cell lung cancer (NSCLC) who received SABR at Taipei Veterans General Hospital between 2015 and 2021. Results: The study revealed that median age, follow‐up, Charlson comorbidity index, and ECOG score were 80 years, 2.48 years, 3, and 1, respectively. Of these patients, 37 (52.1%) were 80 years or older, and 50 (70.4%) and 21 (29.6%) had T1 and T2 diseases, respectively. EGFR mutation status was available for 33 (46.5%) patients, of whom 16 (51.5%) had a mutation. The overall survival rates at 1, 3, and 5 years were 97.2, 74.9, and 58.3%, respectively. The local control rate at 1, 3, and 5 years was 97.1, 92.5, and 92.5%, respectively. Using Cox proportional hazards regression we found that male sex was a risk factor for overall survival (p = 0.036, 95% CI: 1.118–26.188). Two patients had grade 2 pneumonitis, but no other grade 2 or higher toxicity was observed. We did not find any significant differences in treatment outcomes or toxicity between patients aged 80 or older and those with EGFR mutations in this cohort. Conclusion: These findings indicate that age and EGFR mutation status do not significantly affect the effectiveness or toxicity of SABR for patients with inoperable early‐stage NSCLC. [ABSTRACT FROM AUTHOR]

This study aims to identify potential core genes of lung adenocarcinoma (LUAD). Three datasets (GSE32863, GSE43458, and GSE116959) were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between LUAD and normal tissues were filtrated by GEO2R tool. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed via Metascape database. The protein–protein interaction (PPI) network was constructed and core genes were identified using STRING and Cytoscape. Core genes expressions and their relevant clinical characteristics were performed via Oncomine and UALCAN databases respectively. The correlation between core genes and immune infiltrates was investigated by TIMER database. Kaplan–Meier plotter was performed for survival analysis. The signal pathway network of core genes was mapped by KEGG Mapper analysis tool. In this study, ten core genes were significantly related to overall survival (OS) of LUAD patients, which can provide clues for prognosis of LUAD. [ABSTRACT FROM AUTHOR]

Summary: Background: To evaluate whether circulating proteins are associated with survival after lung cancer diagnosis, and whether they can improve prediction of prognosis. Methods: We measured up to 1159 proteins in blood samples from 708 participants in 6 cohorts. Samples were collected within 3 years prior to lung cancer diagnosis. We used Cox proportional hazards models to identify proteins associated with overall mortality after lung cancer diagnosis. To evaluate model performance, we used a round-robin approach in which models were fit in 5 cohorts and evaluated in the 6th cohort. Specifically, we fit a model including 5 proteins and clinical parameters and compared its performance with clinical parameters only. Findings: There were 86 proteins nominally associated with mortality (p

Background: Combination immunotherapy (immune checkpoint inhibitors and cytotoxic anticancer agents) is widely used as first‐line treatment for advanced non‐small cell lung cancer (NSCLC). However, the therapeutic effect of combination immunotherapy has not been fully investigated. C‐reactive protein, performance status, lactate dehydrogenase, albumin, and derived neutrophil‐to‐lymphocyte ratio (C‐PLAN) are useful biomarkers for predicting the prognosis of NSCLC; however, there are no reports examining the C‐PLAN index, which combines these five factors in a single prognostic factor. Methods: We retrospectively collected data from 178 patients with previously untreated advanced NSCLC who received combination immunotherapy at multicenter institutions in Nagano Prefecture between December 2018 and April 2022. We investigated the utility of the C‐PLAN index as a prognostic factor using Cox regression analysis and correlated it with survival. Results: The good and poor C‐PLAN index groups included 85 and 93 patients, respectively. The good C‐PLAN index group had a longer median progression‐free survival (PFS) (10.7 vs. 6.0 months; p = 0.022) and overall survival (OS) (25.3 vs. 16.5 months; p = 0.003) than the poor C‐PLAN index group. The C‐PLAN index was an independent favorable prognostic factor that correlated with PFS and OS in multivariate analysis. The good C‐PLAN index group had a higher proportion of never‐smokers (16.5 vs. 4.3%; p = 0.007) and stage III disease/postoperative recurrence (32.9 vs. 15.1%; p = 0.005) than the poor C‐PLAN index group. Conclusion: The C‐PLAN index is a useful prognostic factor for patients with previously untreated advanced NSCLC undergoing combination immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Tumor size and consolidation‐to‐tumor ratio (CTR) are crucial for non–small cell lung cancer (NSCLC) prognosis. However, the optimal CTR cutoff remains unclear. Whether tumor size and CTR are independent prognostic factors for part‐solid NSCLC is under debate. Here, we aimed to evaluate the prognostic impacts of CTR and tumor size on NSCLC, especially on part‐solid NSCLC. Methods: We reviewed 1366 clinical T1 NSCLC patients who underwent surgical treatment. Log‐rank test and Cox regression analyses were adopted for prognostic evaluation. The "surv_cutpoint" function was used to identify the optimal CTR and tumor size cutoff values. Results: There were 416, 510, and 440 subjects with pure ground‐glass opacity (pGGO), part‐solid, and pure solid nodules. The 5‐year overall survival (disease‐free survival) for patients with pGGO, part‐solid, and pure solid nodules were 99.5% (99.5%), 97.3% (95.8%), and 90.4% (78.9%), respectively. Multivariate Cox regression analysis indicated that CTR was an independent prognostic factor for the whole patients, and the optimal CTR cutoff was 0.99. However, for part‐solid NSCLC, CTR was not independently associated with survival, even if categorized by the optimal cutoffs. The predicted optimal cutoffs of total tumor size and solid component size were 2.4 and 1.4 cm for part‐solid NSCLC. Total tumor size (HR = 6.21, 95% CI: 1.58–24.34, p = 0.009) and solid component size (HR = 2.27, 95% CI: 1.04–5.92, p = 0.045) grouped by the cutoffs were significantly associated with part‐solid NSCLC prognosis. Conclusions: CTR was an independent prognostic factor for the whole NSCLC, but not for the part‐solid NSCLC. Tumor size was still meaningful for part‐solid NSCLC. [ABSTRACT FROM AUTHOR]

Background: The eighth edition of the American Joint Committee on Cancer (AJCC) staging system for lung cancer adopts new criteria for tumor size, and for determining pTis, pT1a(mi), and pT1a. The latter is based on the size of stromal invasion. It is quite challenging for lung pathologists. Methods: All patients who had undergone surgical resection for pulmonary adenocarcinoma (ADC) at Chung Shan Medical University Hospital between January 2014 and April 2018 were reviewed, and restaged according to the eighth AJCC staging system. The clinical characteristics and survival of patients with tumor stage 0 (pTis), I or II were analyzed. Results: In total, 376 patients were analyzed. None of the pTis, pT1a(mi), or pT1a tumors recurred during the follow‐up period up to 5 years, but pT1b, pT1c, pT2a, and pT2b tumors all had a few tumor recurrences (p < 0.0001). In addition, 95.2%, 100%, and 77.5% of pTis, pT1a(mi), and pT1a tumors, respectively, had tumor sizes ≤1.0 cm by gross examination. All pTis, pT1a(mi), and pT1a tumors exhibited only lepidic, acinar, or papillary patterns histologically. Conclusions: This study demonstrated excellent survival for lung ADC patients with pTis, pT1a(mi), and pT1a tumors when completely excised. To reduce the inconsistencies between pathologists, staging lung ADC with tumors of ≤1 cm in size grossly as pTis, pT1a(mi), or pT1a may not be necessary when the tumors exhibit only lepidic, acinar, or papillary histological patterns. A larger cohort study with sufficient follow‐up data is necessary to support this proposal. [ABSTRACT FROM AUTHOR]

Background: This study focused on the relationship between the neutrophil‐to‐lymphocyte ratio (NLR) and the dose of organs at risk in patients with stage II–III non‐small cell lung cancer (NSCLC) receiving intensity‐modulated radiotherapy. Methods: The clinical characteristics and dosimetric parameters of 372 patients were collected retrospectively. A high NLR was defined as that ≥1.525. Survival analysis was conducted using the Kaplan–Meier and Cox regression analysis. Least absolute shrinkage and selection operator (LASSO) analysis was conducted to select appropriate dosimetric parameters. The risk factors of NLR were evaluated using univariate and multivariate logistic regression analyses. Results: Patients with a high NLR had poorer progression‐free survival (PFS) (p = 0.011) and overall survival (OS) (p = 0.061). A low NLR (<1.525) predicted better PFS (hazard ratio [HR] 0.676, 95% confidence interval [CI]: 0.508–0.900, p = 0.007) and OS (HR 0.664, 95% CI: 0.490–0.901, p = 0.009). The aorta dose differed between the low and high NLR groups (all <0.1) in the univariate analysis. An aorta V10 was confirmed as a significant risk factor for a high NLR (odds ratio [OR] 1.029, 95% CI: 1.011–1.048, p = 0.002). Receiving chemotherapy before (OR 0.428, 95% CI: 0.225–0.813, p = 0.010) and during (OR 0.491, 95% CI: 0.296–0.815, p = 0.006) radiotherapy were predictive factors of a low NLR. Conclusion: The aorta dose was significantly associated with a high NLR. Patients with stage II–III NSCLC with a high NLR had poorer prognosis. Receiving chemotherapy before and/or during radiotherapy predicted a low NLR. [ABSTRACT FROM AUTHOR]

To improve prognosis of cancer patients and determine the integrative value for analysis of disease-free survival prediction, a clinic investigation was performed involving with 146 non-small cell lung cancer (NSCLC) patients (83 men and 73 women; mean age: 60.24 years ± 8.637) with a history of surgery. Their computed tomography (CT) radiomics, clinical records, and tumor immune features were firstly obtained and analyzed in this study. Histology and immunohistochemistry were also performed to establish a multimodal nomogram through the fitting model and cross-validation. Finally, Z test and decision curve analysis (DCA) were performed to evaluate and compare the accuracy and difference of each model. In all, seven radiomics features were selected to construct the radiomics score model. The clinicopathological and immunological factors model, including T stage, N stage, microvascular invasion, smoking quantity, family history of cancer, and immunophenotyping. The C-index of the comprehensive nomogram model on the training set and test set was 0.8766 and 0.8426 respectively, which was better than that of the clinicopathological-radiomics model (Z test, P =0.041<0.05), radiomics model and clinicopathological model (Z test, P =0.013<0.05 and P =0.0097<0.05). Integrative nomogram based on computed tomography radiomics, clinical and immunophenotyping can be served as effective imaging biomarker to predict DFS of hepatocellular carcinoma after surgical resection. [ABSTRACT FROM AUTHOR]

Background. Lung cancer is one of the malignant tumors with the highest morbidity and mortality in my country and the world. Among them, non-small-cell lung cancer (NSCLC) accounts for about 80%. For patients who are diagnosed with NSCLC and have epidermal growth factor receptor, EGFR gene-sensitive mutations The treatment is particularly important. Aims. To investigate the efficacy and prognosis of 3DCRT combined with local SBRT in patients with EGFR mutation oligometastatic NSCLC. Materials and Methods. Eighty patients with EGFR mutation oligometastatic NSCLC were selected by random remainder grouping method. 3DCRT combined with SBRT is effective and safer in patients with EGFR-mutant oligometastatic NSCLC, and significantly improves the patient's immune and tumor marker levels. It has a certain reference value in the clinical treatment of EGFR-mutant oligometastatic NSCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitor (ICI)-based immunotherapy has dramatically improved the survival of patients with advanced non-small cell lung cancer (NSCLC); however, a significant percentage of these patients do not benefit from this approach. Therefore, predictive biomarkers are needed. Increasing evidence demonstrates that cancer cachexia, which is often reported in patients with NSCLC, with associated chronic inflammation and related changes in body composition, metabolism, and nutritional status, may affect the immune response and impair immunotherapy efficacy. However, few prospective studies have explored the association between cachexia and the response to immunotherapy in NSCLC. We designed a prospective observational study to evaluate the prognostic and predictive role of cachexia, with its related changes in inflammatory, immunological, and nutritional parameters, on the survival and clinical response (i.e., disease control rate) to ICI in patients with advanced NSCLC. Our results suggest that cachexia can be an independent unfavorable prognostic and predictive factor. Then, the evaluation of cachexia should be strongly considered as a key parameter in the design of immunotherapy-based trials. Immune checkpoint inhibitor (ICI)-based immunotherapy has significantly improved the survival of patients with advanced non-small cell lung cancer (NSCLC); however, a significant percentage of patients do not benefit from this approach, and predictive biomarkers are needed. Increasing evidence demonstrates that cachexia, a complex syndrome driven by cancer-related chronic inflammation often encountered in patients with NSCLC, may impair the immune response and ICI efficacy. Herein, we carried out a prospective study aimed at evaluating the prognostic and predictive role of cachexia with the related changes in nutritional, metabolic, and inflammatory parameters (assessed by the multidimensional miniCASCO tool) on the survival and clinical response (i.e., disease control rate) to ICI-based immunotherapy in patients with advanced NSCLC. We included 74 consecutive patients. Upon multivariate regression analysis, we found a negative association between IL-6 levels (odds ratio (OR) = 0.9036; 95%CI = 0.8408–0.9711; p = 0.0025) and the miniCASCO score (OR = 0.9768; 95%CI = 0.9102–0.9999; p = 0.0310) with the clinical response. As for survival outcomes, multivariate COX regression analysis found that IL-6 levels and miniCASCO-based cachexia severity significantly affected PFS (hazard ratio (HR) = 1.0388; 95%CI = 1.0230–1.0548; p < 0.001 and HR = 1.2587; 95%CI = 1.0850–1.4602; p = 0.0024, respectively) and OS (HR = 1.0404; 95%CI = 1.0221–1.0589; p < 0.0001 and HR = 2.3834; 95%CI = 1.1504–4.9378; p = 0.0194, respectively). A comparison of the survival curves by Kaplan–Meier analysis showed a significantly lower OS in patients with cachexia versus those without cachexia (p = 0.0323), as well as higher miniCASCO-based cachexia severity (p = 0.0428), an mGPS of 2 versus those with a lower mGPS (p = 0.0074), and higher IL-6 levels (>6 ng/mL) versus those with lower IL-6 levels (≤6 ng/mL) (p = 0.0120). In conclusion, our study supports the evidence that cachexia, with its related changes in inflammatory, body composition, and nutritional parameters, is a key prognostic and predictive factor for ICIs. Further larger studies are needed to confirm these findings and to explore the potential benefit of counteracting cachexia to improve immunotherapy efficacy. [ABSTRACT FROM AUTHOR]

Objective. To investigate the effect of garlic extract (GE) on the proliferation and apoptosis of cell lines A549 and H1299 in lung cancer (LC). Methods. A549 and H1299 cells with well-developed logarithmic growth were added with GE at a concentration of 0 μg/ml, 25 μg/ml, 50 μg/M, 75 μg/ml, and 100 μg/ml, respectively. The inhibition of A549 cell proliferation was detected using CCK-8 after cultured for 24 h, 48 h, and 72 h. The apoptosis of A549 cells was analyzed via flow cytometry (FCM) after 24 h of cultivation. In vitro migration of A549 and H1299 cells was determined by cell wound scratch assay after 0 h and 24 h culture. The caspase-3 and caspase-9 protein expression levels in A549 and H1299 cells were evaluated through western blot after 24 h of cultivation. Results. Colony formation and EdU assays revealed that Z-ajoene could inhibit cell viability and cell proliferation in NSCLC cells. After 24 h culture, there was no significant difference in the proliferation rate of A549 and H1299 cells with different GE concentrations (P > 0.05). A remarkable proliferation rate difference emerged between A549 and H1299 cells with different GE concentrations after 48 and 72 hours of cultivation. The proliferation rate of A549 and H1299 cells in the experiment group was significantly lower than that in the control group. With an elevated level of GE concentration, the proliferation rate of A549 and H1299 cells decreased (P < 0.05) while the apoptotic rate increased continuously. Conclusion. GE could exert toxic effects on A549 and H1299 cells, inhibit cell proliferation, promote apoptosis, and attenuate cell migration. Meanwhile, it might induce apoptosis of A549 and H1299 cells through the caspase signal pathway, which is positively correlated with the mass action concentration and is expected to be a new drug for LC treatment. [ABSTRACT FROM AUTHOR]

Objective: This study was conducted to investigate the association between genetic variants in histone modification regions and clinical outcomes of PEM chemotherapy in patients with lung adenocarcinoma. Methods: Potentially functional SNPs were selected using integrated analysis of ChIP-seq and RNA-seq. The associations of 279 SNPs with chemotherapy response and overall survival (OS) were analyzed in 314 lung adenocarcinoma patients who underwent PEM chemotherapy. Results: Among the SNPs investigated, 18 were significantly associated with response to chemotherapy, while 28 with OS. Of these SNPs, rs549794A>G in an enhancer which is expected to regulate the expression of ribosomal protein S3 (RPS3) gene was significantly associated with both worse response to chemotherapy and worse OS (adjusted odds ratio = 0.59, 95% CI = 0.36–0.97, p = 0.04; adjusted hazard ratio = 1.44, 95% CI = 1.09–1.91, p = 0.01, respectively). Previous studies suggested that RPS3, a multi-functional protein with various extraribosomal activities, may play a role in chemotherapy resistance. Therefore, it is postulated that rs549794-induced change in the expression level of RPS3 may affect the response to PEM chemotherapy and consequently the survival outcomes in lung adenocarcinoma patients. Conclusion: This study suggests that genetic variants in the histone modification regions may be useful for the prediction of clinical outcomes of PEM chemotherapy in advanced lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Introduction: The differences in biological characteristics among different genotypes of classical EGFR mutations have not been clarified. This study aimed to clarify the clinical and biological differences between L858R and 19 deletion in NSCLC. Methods: We analyzed a cohort of 191 consecutive cases of surgically resected NSCLC harboring EGFR driver mutations (L858R or 19 deletion) in which curative resection was performed in Aichi Cancer Center Hospital, Nagoya, Japan, from January 2006 to September 2021 and in which recurrence subsequently developed. We also subjected 61 surgically resected NSCLC specimens harboring EGFR driver mutations (L858R or 19 deletion) to an RNA sequencing analysis. Results: In patients with stage I disease, the median time to recurrence did not differ to a statistically significant extent between the types of EGFR mutations; however, among those with stage II and III disease, the median time to recurrence in patients with the L858R genotype tended to be shorter in comparison to those with 19 deletion (log-rank test, p = 0.47 and 0.46, respectively). In comparison to 19 deletion tumors, L858R tumors had higher cytological malignancy (e.g., mitotic ability) and showed stronger immunogenicity. Conclusion: L858R and 19 deletion tumors are likely to have a slight difference in the time to recurrence. They suggest that even in EGFR driver tumors, which are treated as the same disease category, the biological characteristics of the tumors are different, which may leave room for innovations in postoperative treatment and treatment at recurrence. [ABSTRACT FROM AUTHOR]

Simple Summary: Adenocarcinomas represent nearly 40% of all cancer types, and account for more than 70% of cancer-related deaths. Labyrinthin (LAB) is a novel cancer neoantigen expressed on the surface of adenocarcinoma cells of various cancer types. Several treatment strategies are being developed for targeting LAB as a pan-adenocarcinoma target. This study aimed to develop an immunohistochemistry (IHC) assay to detect LAB expression on archival tumor specimens of non-small-cell lung cancer (NSCLC) and characterize the clinical significance of LAB expression. We also explored LAB mRNA expression by RNA sequencing using NSCLC data in The Cancer Genome Atlas (TCGA), and correlated with clinical phenotype and outcome. Further study is warranted to validate LAB IHC and LAB RNA expression as independent biomarkers for selecting patients for cancer therapy targeting LAB. To determine Labyrinthin (LAB) expression in non-small-cell lung cancer (NSCLC), we immunostained and scored for LAB immunohistochemistry (IHC) expression on sections of tissue microarrays (TMAs) prepared from 256 archival tissue blocks of NSCLC. Propensity-score-weighted Kaplan–Meier curves and weighted Cox models were used to associate LAB expression with overall survival. LAB mRNA expression was assessed in The Cancer Genome Atlas (TCGA) and correlated with clinical phenotype and outcome. Positive LAB IHC expression (>5% of tumor cells) was detected in 208/256 (81.3%) of NSCLC samples, and found in both lung adenocarcinomas (LUAD) and lung squamous cell cancer (LUSC). LAB positivity was associated with poor overall survival (HR = 3.56, 95% CI: 2.3–5.4; p < 0.0001) and high tumor differentiation grade or metastasis compared with negative LAB expression. Univariant and multivariate survival analyses demonstrated LAB expression as an independent prognostic factor for NSCLC patients. LAB RNA expression in TCGA-LUAD was higher in primary and advanced-stage tumors than in normal tissue, and was associated with poorer overall survival. No significant differences or associations were found with LAB RNA expression in TCGA-LUSC. The LAB IHC assay is being used to identify candidate cancer patients for the first-in-human phase I trial evaluating the LAB vaccines (UCDCC#296, NCT051013560). [ABSTRACT FROM AUTHOR]

Simple Summary: Sarcopenia is defined as a progressive loss of skeletal muscle strength, mass, and function. Lung cancer patients frequently present with sarcopenia, which may be associated with poorer postoperative outcomes. This study aimed to evaluate the impact of CT-derived preoperative sarcopenia on postoperative outcomes and survival in patients that underwent thoracoscopic anatomical pulmonary resection for non-small cell lung cancer. Sarcopenia was observed in almost one-quarter of patients. Our results showed that CT-derived sarcopenia seems to have a small impact on early postoperative outcomes but no effect on overall survival. Preoperative sarcopenia screening may be a useful tool to include in the surgical risk assessment. We aimed to evaluate whether computed tomography (CT)-derived preoperative sarcopenia measures were associated with postoperative outcomes and survival after video-assisted thoracoscopic (VATS) anatomical pulmonary resection in patients with early-stage non-small cell lung cancer (NSCLC). We retrospectively reviewed all consecutive patients that underwent VATS anatomical pulmonary resection for NSCLC between 2012 and 2019. Skeletal muscle mass was measured at L3 vertebral level on preoperative CT or PET/CT scans to identify sarcopenic patients according to established threshold values. We compared postoperative outcomes and survival of sarcopenic vs. non-sarcopenic patients. A total of 401 patients underwent VATS anatomical pulmonary resection for NSCLC. Sarcopenia was identified in 92 patients (23%). Sarcopenic patients were predominantly males (75% vs. 25%; p < 0.001) and had a lower BMI (21.4 vs. 26.5 kg/m2; p < 0.001). The overall postoperative complication rate was significantly higher (53.2% vs. 39.2%; p = 0.017) in sarcopenic patients and the length of hospital stay was prolonged (8 vs. 6 days; p = 0.032). Two factors were associated with postoperative morbidity in multivariate analysis: BMI and American Society of Anesthesiologists score >2. Median overall survival was comparable between groups (41 vs. 46 months; p = 0.240). CT-derived sarcopenia appeared to have a small impact on early postoperative clinical outcomes, but no effect on overall survival after VATS anatomical lung resection for NSCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: The addition of bevacizumab or ramucirumab to systemic therapy for EGFR-mutated non-small-cell lung cancer (NSCLC) patients provides survival benefits. No study to date has compared the efficacy and safety of these two antiangiogenic therapies (AATs). This study enrolled patients with stage IIIB to IV EGFR-mutated NSCLC who were treated with first-line EGFR-TKIs between January 2014 and May 2022. The progression-free survival (PFS) of patients who received front-line AATs combined with EGFR-TKI therapy was longer than that of patients receiving later-line AATs combined with other therapies (19.6 vs. 10.0 months, p < 0.001). Bevacizumab and ramucirumab did not differ in PFS (24.1 vs. 15.7 months, p = 0.454). No difference in overall survival (OS) was observed between front-line and later-line therapy (non-reach vs. 44.0 months, p = 0.261) or between the two AATs (48.6 vs. 43.0 months, p = 0.924). The incidence of some adverse events such as bleeding and hepatitis was higher for bevacizumab than for ramucirumab but it was not significant. The effectiveness and safety of the two AATs were similar. The combination of bevacizumab or ramucirumab with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy, chemotherapy, or immunotherapy for non-small-cell lung cancer (NSCLC) patients with EGFR mutations could have survival benefits. However, no study, to date, has been conducted to compare the efficacy and safety of these two antiangiogenic therapies (AATs). Stage IIIB to IV EGFR-mutated NSCLC patients who received first-line EGFR-TKIs between January 2014 and May 2022 were enrolled. These patients were divided into two groups: those receiving bevacizumab and those receiving ramucirumab as a combination therapy in any line of treatment. Ninety-six patients were enrolled in this study's final analysis. The progression-free survival (PFS) of patients who received front-line AATs combined with EGFR-TKI therapy was longer than that of patients receiving later-line AATs combined with other therapies (19.6 vs. 10.0 months, p < 0.001). No difference in overall survival (OS) was observed between front-line and later-line therapy (non-reach vs. 44.0 months, p = 0.261). Patients who received these two different AATs did not differ in PFS (24.1 vs. 15.7 months, p = 0.454) and OS (48.6 vs. 43.0 months, p = 0.924). In addition, these two AATs showed similar frequencies of the T790M mutation (43.6% vs. 38.2%; p = 0.645). Multivariate Cox regression analysis indicated several AAT cycles as an independent good prognostic factor in OS. The incidence of some adverse events such as bleeding and hepatitis was higher for bevacizumab than for ramucirumab but it was not significant. Front-line AAT and EGFR-TKI combination therapy improved the PFS of stage IV EGFR-mutated NSCLC patients. The effectiveness and safety of the two AATs were similar. [ABSTRACT FROM AUTHOR]

Simple Summary: Risk factors of hemorrhage in brain metastases from lung adenocarcinoma has been unknown and how hemorrhage in brain metastases affects patients' prognosis has not been clarified. We performed a retrospective analysis on 159 BMs and found that hemorrhage in BMs from lung adenocarcinomas may be associated with BM tumor size and a combination of TKI and intracranial radiotherapy. However, BM hemorrhage did not affect OSBM. Background: Hemorrhage in brain metastases (BMs) from lung cancer is common and associated with a poor prognosis. Research on associated factors of spontaneous hemorrhage in patients with BMs is limited. This study aimed to investigate the predictive risk factors for BM hemorrhage and assess whether hemorrhage affects patient survival. Methods: We retrospectively evaluated 159 BMs from 80 patients with lung adenocarcinoma from January 2017 to May 2022. Patients were classified into hemorrhagic and non-hemorrhagic groups. Patient demographics, lung cancer molecular subtype, treatment type, and tumor–node–metastasis stage were compared between the groups. Multivariate generalized estimating equation (GEE) analysis and gradient boosting were performed. To determine whether BM hemorrhage can stratify overall survival after BM (OSBM), univariate survival analysis was performed. Results: In the univariate analysis, hemorrhagic BMs were significantly larger and had a history of receiving combination therapy with tyrosine kinase inhibitor (TKI) and intracranial radiation (p < 0.05). Multivariate GEE showed that tumor size and combination therapy were independent risk factors for BM hemorrhage (p < 0.05). Gradient boosting demonstrated that the strongest predictor of BM hemorrhage was tumor size (variable importance: 49.83), followed by age (16.65) and TKI combined with intracranial radiation (13.81). There was no significant difference in OSBM between the two groups (p = 0.33). Conclusions: Hemorrhage in BMs from lung adenocarcinomas may be associated with BM tumor size and a combination of TKI and intracranial radiotherapy. BM hemorrhage did not affect OSBM. [ABSTRACT FROM AUTHOR]

The impact of pre-immunotherapy sarcopenia in patients with non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs) is elusive. We performed a meta-analysis to investigate the association between sarcopenia and clinical outcomes of ICIs. PubMed, EMBASE, and the Cochrane Library were searched. Thirteen clinical trials were selected. The 1,2-year overall survival rate was lower in the sarcopenia group (odds ratio (OR) = 2.44, 95% confidence interval (CI), 1.78–3.35, P < 0.00001; OR = 1.60, 95% CI, 1.08–2.37, P = 0.02), with I2 = 34%, P = 0.15, and I2 = 41%, P = 0.12. The 1,2-year progression-free survival (PFS) was the same (OR = 3.43, 95% CI, 1.86–6.33, P < 0.0001; OR = 2.06, 95% CI, 1.19–3.58, P < 0.0001), with I2 = 31%, P = 0.17 and I2=31%, P = 0.17. Sarcopenia reduced the overall response rate (OR = 2.22, 95% CI, 1.01–4.84, P = 0.02), with I2= 56%, P = 0.02, and disease control rate (OR = 3.15, 95% CI, 2.10–4.72, P < 0.0001) with I2 = 33%, P = 0.18. Pre-immunotherapy sarcopenia was associated with poor clinical outcomes in patients with advanced NSCLC who received ICIs. [ABSTRACT FROM AUTHOR]

Purpose: Accumulating evidence has highlighted the critical roles of circular RNAs (circRNAs) in non‐small‐cell lung cancer (NSCLC). This study aims to unveil the roles of circRARS (circular RARS) (hsa_circ_0001551) in NSCLC. Methods: Quantitative real‐time PCR was used to determine the expression of circRARS in NSCLC tissues and cells. Kaplan–Meier analysis was used to determine the prognostic value of circRARS expression. CCK8, transwell, and wound healing assays were used to assess the proliferation, invasion, and migration abilities of NSCLC cells. RNA pull‐down, cell fraction, glucose consumption, lactate production, and lactate dehydrogenase activity assays were conducted to explore the potential mechanisms of circRARS in NSCLC. Results: circRARS is upregulated in NSCLC tissues and positively correlated with smoking status, lymph node metastasis, and higher tumor stages. NSCLC patients with high expression of circRARS have poor overall survival. Functional assays demonstrated that circRARS accelerated the proliferation, invasion, and migration of NSCLC cells in vitro. The cell fraction suggested that circRARS mainly accumulated in cytoplasm and the RNA pull‐down assay showed lactate dehydrogenase (LDHA) could bind with circRARS. Furthermore, circRARS positively regulates LDHA activity and LDHA expression at the transcription level. Moreover, downregulated circRARS decreases glucose consumption and lactate production and compromises aerobic glycolysis in NSCLC cells. Finally, rescue assays showed circRARS could promote NSCLC cell proliferation by regulating LDHA activity. Conclusion: This study shows that circRARS can promote glycolysis and tumor progression in NSCLC by regulating LDHA. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) are standard treatments for advanced non–small cell lung cancer (NSCLC) patients harboring the EGFR mutation. Patients experiencing intolerable adverse events (AEs) would discontinue EGFR‐TKIs. This study aimed to evaluate the impact of intolerable AEs and subsequent treatment on the survival of patients who discontinued EGFR‐TKIs. Patients: The data of advanced NSCLC patients treated with EGFR‐TKIs as frontline treatment at Chang Gung Memorial Hospitals from June 2014 to March 2018 were retrospectively reviewed. Results: A total of 2190 patients were enrolled and treated with frontline EGFR‐TKIs. In August 2021, 114 (5.2%) patients experienced intolerable AEs requiring discontinuation of EGFR‐TKIs. The time median of EGFR‐TKIs discontinuation was 2.56 months. Age >65 years, females, body weight, and body surface area were associated with the occurrence of intolerable AEs for patients treated with afatinib. Patients experiencing skin/paronychia/mucositis and abnormal liver function test had favorable survivals results. Patients who received subsequent EGFR‐TKIs treatment, experienced better progression‐free survival (PFS), total PFS (from frontline line EGFR‐TKIs), and overall survival (OS) compared to patients receiving chemotherapy or no treatment. Patients undergoing subsequent EGFR‐TKIs had better total PFS (median, 14.9 vs. 11.3 months, p = 0.013) and OS (median, 31.3 vs. 20.1 months, p = 0.001) than patients who did not discontinue because of AEs. Favorable OS was validated by propensity score matching. Conclusion: Patients experiencing intolerable AEs during EGFR‐TKI treatment should consider switching to an alternative EGFR‐TKI, which increase the survival results as compared to those patients who did not experience intolerable AEs. [ABSTRACT FROM AUTHOR]

Accelerated hypofractionated radiotherapy is used at our institution for non-small cell lung cancer (NSCLC) patients not eligible for stereotactic body radiotherapy or chemoradiotherapy. The purpose of this study was to report clinical outcomes of delivering 60 Gy in 15 fractions for these patients. All NSCLC patients who received 60 Gy in 15 fractions were reviewed. Outcomes of interest were local failure, regional failure, distant progression, overall survival and treatment-associated toxicities. In total, 111 patients were included. The median age was 78.8 years and most tumours were adenocarcinoma (n = 55, 49.6%). Sixty-five patients (58.6%) were N0. The cumulative incidence of local failure at 12 and 24 months in the N0 cohort was 5.2% and 14.2%, respectively, compared with 11.5% and 14.8% for N+ patients. Tumour size >35 mm predicted for local failure (hazard ratio 2.706, 95% confidence interval 1.002–7.307, P = 0.0494). Distant progression at 12 and 24 months in N0 patients was 13.7% and 24.3% compared with 24.6% and 33.5% in N+ patients. In N0 patients, larger tumour size was associated with increased risk of distant progression. The median overall survival was 38.1 months in N0 patients versus 31.7 months in N+ patients. The most common toxicity was radiation pneumonitis (n = 6, 6.4%). The incidence of any grade 3 toxicity was 10.3% at ≥1 year. There were no deaths or hospitalisations attributed to treatment. Accelerated hypofractionated radiotherapy is well tolerated and resulted in favourable clinical outcomes in various stages of NSCLC patients. • Patients with NSCLC ineligible for SBRT or chemoradiotherapy can be considered for accelerated hypofractionated radiotherapy. • Local control and survival in non-metastatic patients were favourable with this strategy. • Grade ≥3 toxicity was uncommon. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant and adjuvant immune checkpoint inhibitor treatments for non-small cell lung cancer (NSCLC) patients with resectable disease have presented promising results. This is a phase I study to evaluate the safety and efficacy of neoadjuvant toripalimab in combination with chemotherapy for NSCLC. Methods: Treatment-naive patients with resectable NSCLC (stage II–IIIB) received two to four cycles of toripalimab (240 mg, intravenously, q3w) combined with platinum-paclitaxel chemotherapy. Surgical operation was performed approximately 4 weeks after the last cycle. The primary end point was safety. The efficacy endpoints included radiographic and pathological response rates, expression of programmed death ligand 1 (PD-L1) and molecular targets. Results: A total of 11 patients were enrolled, consisting of 2 patients (18%) with adenocarcinoma and 9 patients (82%) with squamous cell carcinoma. All patients received two to four cycles of toripalimab plus chemotherapy and underwent radical resection. Regarding safety, 5 of 11 patients (45%) had neoadjuvant treatment-related adverse events, and 1 patient (9%) experienced grade 3 or worse treatment-related adverse events. Radiographic partial response was achieved in 10 patients, with an objective response rate of 91%. Among 11 patients, 6 (55%) achieved pathological complete response, including 1 PD-L1-negative patient. Conclusion: Neoadjuvant toripalimab plus platinum-paclitaxel chemotherapy was tolerable and induced a pathological complete response in 55% of resectable NSCLC patients. [ABSTRACT FROM AUTHOR]

Summary: The survival benefit of icotinib (an oral epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor) in patients with advanced lung cancer has been confirmed in several studies. This study (ICAPE) evaluated the efficacy of icotinib as adjuvant therapy for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma. Patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma were enrolled in the multicenter, open-label, single-arm, phase II study. Eligible patients received oral icotinib 125 mg thrice daily for 1.5 years after complete surgical resection. The primary endpoint was disease-free survival (DFS). Between March 2014 and January 2018, 79 patients were enrolled. The median follow-up time was 39.7 months with a median DFS and overall survival (OS) of 41.4 months (95% CI: 33.6–51.8) and 67.0 months (95% CI: 21.2-not reached [NR]), respectively. The 1-year, 3-year, and 5-year OS rates were 100%, 83.3%, and 61.7%, respectively. No significant difference was found in the median DFS between patients with Bcl-2 interacting mediator of cell death (BIM) mutant-type and wild-type (NR vs. 41.7 months; p = 0.75). No significant difference was found in the median DFS according to EGFR mutation types. Icotinib as adjuvant therapy demonstrated a favorable survival benefit in patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma, indicating that icotinib might be a promising treatment option for this patient population. The optimal adjuvant duration of icotinib is still not clear and needs more incoming data to answer. [ABSTRACT FROM AUTHOR]

Background: Wide variation exists globally in the treatment and outcomes of stage III patients with non–small cell lung cancer (NSCLC). We conducted an up-to-date patterns of care analysis in the state of Victoria, Australia, with a particular focus on the proportion of patients receiving treatment with radical intent, treatment trends over time, and survival. Materials and Methods: Stage III patients with NSCLC were identified in the Victorian Lung Cancer Registry and categorized by treatment received and treatment intent. Logistic regression was used to explore factors predictive of receipt of radical treatment and the treatment trends over time. Cox regression was used to explore variables associated with overall survival (OS). Covariates evaluated included age, sex, ECOG performance status, smoking status, year of diagnosis, Australian born, Aboriginal or Torres Strait Islander status, socioeconomic status, rurality, public/private status of notifying institution, and multidisciplinary meeting discussion. Results: A total of 1396 patients were diagnosed between 2012 and 2019 and received treatment with radical intent 67%, palliative intent 23%, unknown intent 5% and no treatment 5%. Radical intent treatment was less likely if patients were >75 years, ECOG ≥1, had T3-4 or N3 disease or resided rurally. Surgery use decreased over time, while concurrent chemoradiotherapy and immunotherapy use increased. Median OS was 38.0, 11.1, and 4.4 months following radical treatment, palliative treatment or no treatment, respectively. Conclusion: Almost a third of stage III patients with NSCLC still do not receive radical treatment. Strategies to facilitate radical treatment and better support decision making between increasing multimodality options are required. Variations exist in the treatment and outcomes for patients with stage III non–small cell lung cancer. This article reports an up-to-date patterns of care analysis focusing on the proportion of patients receiving treatment with radical intent, treatment trends over time, and survival. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common cause of mortality from malignant tumors worldwide. The five-year survival rate for people with advanced stages varies considerably, from 35.4% to 6.9%. The angiogenic potential of bcl2 is not well known, nor is the way in which tumor cells with excessive bcl2 expression affect VEGF production. Hypothetically, given that tumor growth, progression and metastasis are dependent on angiogenesis, the antiapoptotic effect is expected to form a link between these two molecules. The aim of this study was to evaluate the relationship between bcl-2 and VEGF expression, clinicopathological features and survival in 216 patients with advanced NSCLC. Archival tumor tissues were examined by immunohistochemistry for the expression of bcl-2 and VEGF. Immunoreactivity for bcl-2 was observed in 41.4% of NSCLCs, 51% of squamous and 34.8% of adenocarcinomas-expressed Bcl-2. There was an inverse correlation of mononuclear stromal reaction and bcl-2 expression in adenocarcinoma (p < 0.0005). A total of 71.8% NSCLCs were VEGF positive, 56% of squamous and 82.2% of adenocarcinomas. High level of VEGF expression was significantly associated with histology type (p = 0.043), low histology grade (p = 0.014), clinical stage IV (p = 0.018), smoking history (p = 0.008) and EGFR mutations (p = 0.026). There was an inverse correlation in the expression of Bcl-2 and VEGF in NSCLC patients (p = 0.039, r = −0.163). Two-year survival of patients with unresectable NSCLC was 39.3%, and 50% of patients were alive at 17 months. Our results demonstrated no difference in survival for patients in advanced NSCLC grouped by bcl-2 and VEGF status. Additionally, we observed an inverse correlation in the expression of Bcl-2 and VEGF in NSCLC and mononuclear reaction and bcl-2 expression in adenocarcinomas. [ABSTRACT FROM AUTHOR]

Due to the absence of accurate tools for early detection and successful treatment, lung adenocarcinoma (LUAD) is one of the most aggressive tumors with high morbidity and mortality globally. It is absolutely necessary to investigate the process behind its development and search for new biomarkers that could aid in the early detection of LUAD. There is a correlation between the immune microenvironment of the tumor and the prognosis of lung cancer as well as the efficacy of immunotherapy. Long noncoding RNAs (lncRNAs) have been identified as potential prognostic biomarkers linked to immunological activities. In this study, we identified 1 downregulated lncRNA and 76 upregulated lncRNAs in LUAD samples from TCGA datasets. Among the 77 dysregulated lncRNAs, our attention focused on lncRNA LINC01833 (LINC01833). When compared with nontumor specimens, the level of expression of LINC01833 was shown to be significantly elevated in LUAD samples. In addition, the data of the ROC study revealed that LUAD patients with high LINC01833 expression had an AUC value of 0.840 (95% confidence interval: 0.804 to 0.876). There was a correlation between high LINC01833 expression and an advanced clinical stage. Patients who had a high expression of LINC01833 were shown to have a lower overall survival rate p < 0.001 and a lower disease-specific survival rate (p = 0.004) in comparison to patients who were in the low LINC01833 group, according to the data on survival. In addition, the results of the multivariate analysis revealed that high LINC01833 expression was an independent predictor of poor survival in LUAD. Moreover, the immune analysis revealed that we found that the expression of LINC01833 was positively associated with Th2 cells, aDC, and Tgd, while negatively associated with Mast cells, Tcm, Eosinophils, iDC, DC, Tem, Th17 cells, and pDC. Overall, our data point to the possibility that the unique lncRNA LINC01833 might be employed as a diagnostic and prognostic marker, and as a result, it has a significant impact on clinical practice. [ABSTRACT FROM AUTHOR]

Purpose. To screen the main active components of Citrus aurantium through a network pharmacology approach, construct a component-disease target network, explore its molecular mechanism for the treatment of non-small-cell lung cancer (NSCLC), and validate it experimentally. Methods. The active ingredients in Citrus aurantium and the targets of Citrus aurantium and NSCLC were collected through the Traditional Chinese Medicine Systematic Pharmacology Database and Analysis Platform (TCMSP), GeneCards, and OMIM databases. The protein interaction network was constructed using the STRING database, and the component-disease relationship network graph was analyzed using Cytoscape 3.9.1. The Metascape database can be used for GO and KEGG enrichment analyses. The Kaplan-Meier plotter was applied for overall survival analysis of key targets of Citrus aurantium in the treatment of NSCLC. Real-time PCR (RT-PCR) and Western blotting were used to determine the mRNA and protein levels of key targets of Citrus aurantium for the treatment of NSCLC. Results. Five active ingredients of Citrus aurantium were screened, and 54 potential targets for the treatment of NSCLC were found, of which the key ingredient was nobiletin and the key targets are TP53, CXCL8, ESR1, PPAR-α, and MMP9. GO and KEGG enrichment analyses indicated that the mechanism of nobiletin in treating NSCLC may be related to the regulation of cancer signaling pathway, phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt) signaling pathway, lipid and atherosclerosis signaling pathway, and neurodegenerative signaling pathway. The experimental results showed that nobiletin could inhibit the proliferation of NSCLC cells and upregulate the levels of P53 and PPAR-α and suppress the expression of MMP9 (P < 0.05). Conclusion. Citrus aurantium can participate in the treatment of NSCLC through multiple targets and pathways. [ABSTRACT FROM AUTHOR]

Background: In this retrospective study, based on recent studies reporting the superiority of sublobar resection to lobectomy for peripheral small size non‐small cell lung cancer (NSCLC), we investigated the optimal pathological factors for predicting noninvasive cancer and the selection of operative procedure. Methods: Patients with peripheral NSCLC of ≤2 cm who underwent surgery at our hospital between January 2010 and June 2020 were included in this study. We evaluated the relationship between pathologically noninvasive cancer and predictive factors according to the area under the curve (AUC) and accuracy, and the cutoff value was set to investigate indications for sublobar resection. Results: The comparison of the AUCs revealed that the maximum standardized uptake value and consolidation to tumor (C/T) volume ratio were better predictors than the C/T ratio. Among the three factors, the C/T volume ratio showed the best accuracy. The patients were divided into two groups (low and high) using the cutoff value of the C/T volume ratio and compared according to the surgical procedure (lobectomy vs. segmentectomy). In the low‐group, there was no significant difference in the prognosis. In the high‐group, the 5‐year recurrence‐free survival rate of the patients who received lobectomy was 87.8%, while that of patients who received segmentectomy was 75.8% (p = 0.08). Conclusions: The C/T volume ratio was the best preoperative pathologically noninvasive predictive factor. Sublobar resection should be performed with caution in cases with significant solid components on three‐dimensional images. [ABSTRACT FROM AUTHOR]

Background: Atezolizumab has recently been approved for first-line treatment of high PD-L1 expression metastatic Non-Small-Cell Lung Cancer (NSCLC) patients with no EGFR or ALK mutations, on the basis of the IMpower110 trial. This study aims to estimate the cost-effectiveness of atezolizumab compared with pembrolizumab among these patients in Spanish settings, based on the results of the two cut-offs of the IMpower110 study. Methods: A three-state partitioned-survival model was adapted to Spanish settings to calculate health outcomes and costs over a lifetime horizon. Clinical data for atezolizumab were collected from the interim and the exploratory results (data cut-off: Sept'18 and Feb'20, respectively) of the IMpower110 trial while a network meta-analysis was used to model pembrolizumab treatment. Utility data were collected from the trial. Direct medical costs were considered based on resources identified by experts. Costs and outcomes were discounted at 3% per year. Health outcomes were expressed as cost per Life Year (LY) and cost per Quality-Adjusted Life Year (QALY). Both deterministic and probabilistic sensitivity analyses were performed to assess the robustness of results. Results: Over a lifetime horizon, the incremental results showed that atezolizumab generated similar health outcomes (LYs and QALYs) to pembrolizumab, with minimal differences depending on the cut-off used (+ 0.70 and + 0.42 LYs and QALYs with Sept'18 cut-off and − 0.80 and − 0.72 LYs and QALYs with Feb'20 cut-off). However, for both cut-offs, atezolizumab produced meaningfully less costs than pembrolizumab (€ − 54,261 with Sept'18 cut-off and € − 81,907 with Feb'20 cut-off). The sensitivity analyses carried out confirmed the robustness of the base-case results. Conclusions: The cost-effectiveness analysis, comparing the two cut-off of IMpower110, shows that atezolizumab provides similar health gains to pembrolizumab but at a lower cost for the first-line treatment of metastasic NSCLC patients in Spain. [ABSTRACT FROM AUTHOR]

Simple Summary: Although video-assisted thoracoscopy surgery is now considered the standard treatment for early-stage lung cancer, the relevance of VATS in locally advanced lung cancer remains unknown. Several studies have been conducted to assess the feasibility and safety of VATS lobectomy for locally advanced NSCLC. However, only a handful have used propensity score matching to compare the operative and oncologic outcomes of VATS versus open lobectomy. Furthermore, these studies included a mixture of stages (II, III, and IV) and did not particularly evaluate the significance of VATS in the treatment of stage III disease. In this study, we compared the perioperative and oncologic outcomes of VATS with open lobectomy for stage III NSCLC and used propensity score matching to produce a well-balanced cohort of patients undergoing VATS and open lobectomy in order to minimize selection bias and achieve convincing statistical results. Objectives: This study aims to evaluate the perioperative and oncologic outcomes of thoracoscopic lobectomy for advanced stage III NSCLC. Methods: We retrospectively reviewed 205 consecutive patients who underwent VATS or open lobectomy for clinical stage III lung cancer between January 2013 and December 2020. The perioperative and oncologic outcomes of the two approaches were compared. Long-term survival was assessed using the Kaplan–Meier estimator. Propensity score-matched (PSM) comparisons were used to obtain a well-balanced cohort of patients undergoing VATS and open lobectomy. Results: VATS lobectomy was performed in 77 (37.6%) patients and open lobectomy in 128 (62.4%) patients. Twelve patients (15.6%) converted from VATS to the open approach. PSM resulted in 64 cases in each group, which were well matched according to twelve potential prognostic factors, including tumor size, histology, and pTNM stage. Between the VATS and the open group, there were no significant differences in unmatched and matched analyses, respectively, of the overall postoperative complications (p = 0.138 vs. p = 0.109), chest tube duration (p = 0.311 vs. p = 0.106), or 30-day mortality (p = 1 vs. p = 1). However, VATS was associated with shorter hospital stays (p < 0.0001). The five-year overall survival (OS) and five-year Recurrence-free survival (RFS) were comparable between the VATS and the open groups. There was no significant difference in the recurrence pattern between the two groups in both the unmatched and matched analyses. Conclusion: For the advanced stage III NSCLC, VATS lobectomy achieved equivalent postoperative and oncologic outcomes when compared with open lobectomy without increasing the risk of procedure-related locoregional recurrence. [ABSTRACT FROM AUTHOR]

Background and Aims. Histone deacetylase 1 (HDAC1) codes a protein that is a component of the histone deacetylase complex. The abnormal expression of HDAC1 is strongly correlated with cell proliferation, differentiation, transcription, and translation. Through continuous screening of genes associated with changes in lung adenocarcinoma (LUAD), gene networks are formed to explore tumor pathogenesis and new therapeutic targets. Methods. We evaluated HDAC1 gene survival analysis and its expression of LUAD using relevant websites and databases (TCGA and GEO databases). Through data mining, we determined the frequency and type of HDAC1 mutation, obtained the relevant heat map of the gene interaction network, completed the analysis of gene ontology and function enrichment, and understood the pharmaceutic of HDAC1. Results. We found that HDAC1 expression was associated with the prognosis of patients with LUAD. In gene expression analysis, HDAC1 was highly expressed in LUAD, and the HDAC1 interaction gene network (MARCKSL, eIF3I) was closely related to cellular gene expression. Functional network analysis shows that the expression of HDAC1 is related to the monitoring point of the G1-S phase of the cell cycle and the activation of the Notch signaling pathway (CSL transcription factor), which is involved in the process of cell proliferation and differentiation and gene expression associated with new therapeutic targets. Conclusion. Our data revealed the expression and potential regulatory factors of HDAC1 in LUAD of data mining, which laid a foundation for the study of the occurrence, development, and treatment of HDAC1 in LUAD. [ABSTRACT FROM AUTHOR]

Introduction: Predictors of the effectiveness of immune checkpoint inhibitor (ICI) monotherapy in previously treated patients with non-small cell lung cancer (NSCLC) remain ill-defined. We investigated whether the Glasgow prognostic score (GPS) could serve as such predictors. Methods: Eighty patients treated with pembrolizumab or atezolizumab monotherapy as second- or subsequent-line therapy for NSCLC were retrospectively reviewed, and the associations between GPS, body mass index (BMI), and each of progression-free survival (PFS) and overall survival (OS) were assessed. Results: The median follow-up period was 11.1 months. Patients with a BMI ≥20.4 kg/m2 had significantly longer PFS and OS (3.7 and 22.2 month, respectively) than did those with a BMI <20.4 kg/m2 (2.2 and 11.5 months, respectively). Patients with a GPS of 0 had a significantly longer PFS (6.6 months) than did those with a GPS of 1 (2.2 months, p = 0.002) and 2 (1.8 months, p = 0.029). Patients with a GPS of 0 also had a significantly longer OS (22.2 month) than did those with a GPS of 1 (9.2 months, p = 0.002) and 2 (4.7 months, p = 0.002). Notably, the GPS, BMI, and clinical stage were independent predictors of PFS, while the GPS and performance status were independent predictors of OS. The response rate of patients with a GPS of 0 was significantly higher than that of patients with a GPS of 1–2 (26.2% vs. 7.9%, p = 0.03). Conclusion: The GPS is an independent predictor of PFS and OS in patients with NSCLC who received second- or subsequent-line pembrolizumab or atezolizumab monotherapy. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the leading cause of cancer deaths worldwide. Pharmacogenomics plays an important role in tailoring cancer patients' treatment. Pemetrexed is widely used in first- and second-line chemotherapy of non-small cell lung cancer (NSCLC); however, there is no available predictive biomarker for pemetrexed treatment. The present study aimed to investigate the role of polymorphisms in thymidylate synthase and SLC19A1 polymorphisms with clinical outcome in patients with advanced NSCLC treated in first-line with pemetrexed or pemetrexed plus cisplatin. Method: This cohort study included 40 metastatic lung cancer patients treated with pemetrexed plus cisplatin. We utilized the tetra-primer amplification refractory mutation system-polymerase chain (ARMS-PCR) reaction for genotyping of rs3788189 and rs1051298. TYMS 28-VNTR and rs16430 were genotyped in the patients via PCR amplification and PCR-RFLP, respectively. Fisher's exact test and Kaplan-Meier curve were used for statistical analysis. Results: We recruited 40 patients in this research with a median age of 58.9 years. The median survival of all the 40 patients was 11.6 months. The overall survival of the patients, as well as their gender, age, and metastatic sites were not found to be statistically associated with rs1051298, rs3788189, TYMS VNTR, and rs16430. Conclusion: Our study did not identify any associations between the SLC19A1 and TYMS VNTR and rs16430 and clinical outcomes in advanced NSCLC patients. However, further investigation will be conducive to finding effective clinical biomarkers for the treatment of patients with NSCLC. [ABSTRACT FROM AUTHOR]

We assessed the presence of 'tertiary lymphoid structures' (TLS) in a series of surgically treated non-small cell lung carcinomas (NSCLC). The TLS-density in the tumor periphery (pTLS) ranged from 0 to 1.8 (median 0.45), while in inner tumor areas (iTLS) ranged from 0 to 1.0 (median 0); (p < 0.0001). High pTLS-density was linked with early stage of the disease. Glycolysis-related enzyme expression (MCT1, Hexokinase 2) was linked with high pTLS-density (p < 0.05). High pTLS and iTLS densities were linked with better postoperative prognosis (p = 0.02 and p = 0.01, respectively). Assessment of TLS is a useful prognostic marker in NSCLC. [ABSTRACT FROM AUTHOR]