Search

Simple Summary: The metabolism of carbohydrates and lipids is essential to meet the diverse needs of cells. The autophagy cellular pathway is crucial for normal cellular function through its ability to target and degrade damaged organelles and misfolded proteins. Autophagy also provides cells with necessary energy as an end product. Cancer cells have a high rate of proliferation and, thus, require more energy compared to normal cells. Not surprisingly, cancer cells are highly dependent on these metabolic pathways. This review provides an in-depth review of recent research findings on how carbohydrate and lipid metabolism regulate autophagy and how this impacts cancer cells. Metabolic changes are an important component of tumor cell progression. Tumor cells adapt to environmental stresses via changes to carbohydrate and lipid metabolism. Autophagy, a physiological process in mammalian cells that digests damaged organelles and misfolded proteins via lysosomal degradation, is closely associated with metabolism in mammalian cells, acting as a meter of cellular ATP levels. In this review, we discuss the changes in glycolytic and lipid biosynthetic pathways in mammalian cells and their impact on carcinogenesis via the autophagy pathway. In addition, we discuss the impact of these metabolic pathways on autophagy in lung cancer. [ABSTRACT FROM AUTHOR]

The recent increase in the number of molecular targeted agents for lung cancer has led to the demand for the simultaneous testing of multiple genes. Although gene panels using next-generation sequencing (NGS) are ideal, conventional panels require a high tumor content, and biopsy samples often do not meet this requirement. We developed a new NGS panel, called compact panel, characterized by high sensitivity, with detection limits for mutations of 0.14%, 0.20%, 0.48%, 0.24%, and 0.20% for EGFR exon 19 deletion, L858R, T790M, BRAF V600E, and KRAS G12C, respectively. Mutation detection also had a high quantitative ability, with correlation coefficients ranging from 0.966 to 0.992. The threshold for fusion detection was 1%. The panel exhibited good concordance with the approved tests. The identity rates were as follows: EGFR positive, 100% (95% confidence interval, 95.5–100); EGFR negative, 90.9 (82.2–96.3); BRAF positive, 100 (59.0–100); BRAF negative, 100 (94.9–100); KRAS G12C positive, 100 (92.7–100); KRAS G12C negative, 100 (93.0–100); ALK positive, 96.7 (83.8–99.9); ALK negative, 98.4 (97.2–99.2); ROS1 positive, 100 (66.4–100); ROS1 negative, 99.0 (94.6–100); MET positive, 98.0 (89.0–99.9); MET negative 100 (92.8–100); RET positive, 93.8 (69.8–100); RET negative, 100 (94.9–100). The analytical performance showed that the panel could handle various types of biopsy samples obtained by routine clinical practice without requiring strict pathological monitoring, as in the case of conventional NGS panels. [ABSTRACT FROM AUTHOR]

Purpose We aimed to investigate the feasibility of four criteria on oligometastasis (OM) concerning clear survival benefits of local therapy (LT) during tyrosine kinase inhibitor (TKI) treatment in non-small cell lung cancer (NSCLC). Materials and Methods This single-center, retrospective study included patients with advanced NSCLC who received LT because of OM during TKI treatment at Asan Medical Center from January 2011 to December 2020. At the application of LT OM was classified according to four criteria: TNM, European Organization for Research and Treatment of Cancer Lung Cancer Group (EORTC-LCG), National Comprehensive Network (NCCN), and ORGAN. We compared survival outcomes between patients with and without OM. Results The median overall survival of the 117 patients included in the analysis was 70.8 months (95% confidence interval [CI], 56.6 to 85.1). The patients with OM meeting all four criteria (hazard ratio [HR] with 95% CI of TNM criteria 0.24 with 0.10-0.57; p=0.001, EORTC-LCG criteria 0.34 with 0.17-0.67; p=0.002, NCCN criteria 0.41 with 0.20-0.86; p=0.018 and ORGAN criteria 0.33 with 0.18-0.60; p < 0.001) had significantly longer survival compared with patients who did not after adjusting for confounding factors. Furthermore, increasing the number of extra-thoracic metastatic organs to two or more were independent predictive factors for worse survival outcomes (2 organs: HR, 3.51; 95% CI, 1.01 to 12.14; p=0.048; 3 organs: HR, 4.31; 95% CI, 0.94 to 19.73; p=0.060; 4 organs: HR, 24.47; 95% CI, 5.08 to 117.80; p < 0.001). Conclusion Patients with OM defined by all four criteria showed prognostic benefits from LT during TKI therapy. [ABSTRACT FROM AUTHOR]

A 68-year-old man with a previous history of lung cancer presented with deteriorating appetite and weight loss. Imaging revealed significant retroperitoneal lymphadenopathy, as well as liver and bone lesions consistent with widespread metastatic carcinoma. Biopsy results from the liver lesions confirmed the diagnosis of metastatic non-small cell lung carcinoma. A PDL-1 immunostain, performed on the initial lung resection specimen, showed a combined positive score (CPS) of 15 and pembrolizumab treatment was initiated. The patient presented with diarrhea three weeks after starting therapy and duodenal biopsies obtained at this time displayed intact villous architecture with an increase in intraepithelial lymphocytes (IELs). The colon biopsies exhibited lymphocytic colitis, characterized by significant thinning of the surface epithelium, a higher mixed inflammatory infiltrate within the lamina propria, and diffuse increase of IELs (greater than 30 per 100 epithelial cells). These findings collectively raised the differential diagnosis of celiac disease with lymphocytic colitis or immunotherapy-associated enterocolitis. Further serological testing for celiac disease, including anti-tissue transglutaminase antibodies, yielded negative results. Consequently, a final diagnosis of immune adverse event associated with immunotherapy was established. Cases reported in literature as celiac disease occurring soon after immunotherapy are likely misdiagnosed cases of immunotherapy enteritis. [ABSTRACT FROM AUTHOR]

Aims: Durvalumab (Durva) administration after chemoradiation therapy (CRT) in locally advanced non‐small‐cell lung cancer (NSCLC) is the standard of care, associated with relatively prolonged progression‐free (PFS) and overall survival. However, pneumonitis occurs in 73.6% of Japanese patients. This retrospective study aimed to identify factors associated with Durva efficacy and safety, specifically, the risk of pneumonitis. Methods: This study included data from 26 consecutive patients with locally advanced NSCLC who underwent CRT followed by Durva. The rates of adverse events and PFS were examined. Results: The median PFS time was 15.6 months (95% confidence interval [CI]: 8.7‐not available). Patients developed pneumonitis of grade 1, 2, 3, and 4 at the rate of 62%, 27%, 12%, and 0%, respectively. The median PFS time was 6.4 months for patients with programmed death ligand 1 (PD‐L1) expression level of <50% and not reached for patients with PD‐L1 expression level of ≥50% (hazard ratio [HR], 0.19; 95% CI: 0.04–0.89), which was significantly prolonged. The cumulative incidence of pneumonitis grade 2 or above was significantly higher when the time between the last day of thoracic radiotherapy (TRT) and the start of Durva therapy was within 14 days compared to >14 days (HR: 0.19; 95% CI: 0.06–0.59). This association was statistically significant in multivariate analysis. Conclusions: The initiation of Durva therapy within 14 days after TRT may increase the risk of pneumonitis grade 2 or above. Careful observation and suitable treatment are recommended. [ABSTRACT FROM AUTHOR]

Purpose: C-type lectin domain family 4 member M (CLEC4M) has been found to be involved in the occurrence and development of cancer, but its role in NSCLC remains to be fully explored. Our work aims to evaluate the diagnostic and prognostic value of CLEC4M in NSCLC and to investigate the underlying mechanisms of CLEC4M in the immune microenvironment of NSCLC. Methods: Integrating publicly accessible data and clinical tissue samples to verify the expression of CLEC4M in NSCLC. The diagnostic value of CLEC4M was determined by receiver operating characteristic (ROC) curve. Kaplan–Meier survival analysis, nomogram plot, univariate and multivariate Cox regression models were performed to evaluate the prognostic impact of CLEC4M on NSCLC patients. The correlation between CLEC4M and tumor immune infiltration was estimated using TIMER and UALCAN databases. Functional assessments including GO, KEGG pathway and GSEA analyses were implemented to illustrate the potential mechanisms of CLEC4M in NSCLC. Results: CLEC4M was significantly downregulated in NSCLC tissue, as confirmed by immunohistochemistry of clinical tissues. The high AUC value of ROC curves demonstrated the diagnostic accuracy of CLEC4M in NSCLC. Additionally, low CLEC4M expression was associated with poor survival in NSCLC patients. Furthermore, CLEC4M was found to be significantly associated with tumor immune infiltration, and CLEC4M may be involved in immune activation and proliferation inhibition through the functional assessment, suggesting that CLEC4M may be a therapeutic target for NSCLC patients. Conclusion: Our findings reveal CLEC4M is significantly downregulated in NSCLC tissues, and illustrate the diagnostic and prognostic value of CLEC4M in NSCLC, as well as its potential serve as an immune-related therapeutic target. [ABSTRACT FROM AUTHOR]

SMARCA4-deficient non-small cell carcinoma is an aggressive neoplasm with poor outcome. Several studies have highlighted its immunochemistry, pathophysiology, and underlying mechanisms, but studies of its definite treatment are few. Here, we report on a 69-year-old male with heterogenous pathological presentations of SMARCA4-deficient non-small cell carcinoma. He initially presented with neck lymphadenopathies. Immunohistochemistry staining and genomic profiling confirmed the diagnosis of SMARCA4-deficient non-small cell carcinoma. The patient responded well to immune checkpoint inhibitors with nivolumab. However, new lesions with various pathological presentations and various responses to nivolumab appeared during the treatment course. The patient survived more than 3 years from the initial diagnosis. This case shows the efficacy of nivolumab to treat SMARCA4-deficient non-small cell lung carcinoma. [ABSTRACT FROM AUTHOR]

Objectives: This study examines the role of tumor texture on computed tomography(CT) images as a complement to clinical prognostic factors in predicting survival in patients of non‑small cell lung carcinoma (NSCLC) treated with radical chemo‑radiation (CRT). Methods: A total of 93 patients with confirmed NSCLC treated with CRT accrued in a study approved by the institutional ethics committee were analyzed for CT‑based radiomic features. Pretreatment CT images were used to contour the primary tumor and texture features were computed by the image filtration method to differentially highlight fine to coarse textures. Texture parameters included mean intensity, entropy, kurtosis, standard deviation, and mean positive pixel and skewness. Optimal threshold cut‑off values of the above tumor texture features were analyzed. These features were explored as imaging biomarkers to predict survival using Kaplan–Meier and Cox proportional hazard model. Results: Median follow‑up of the entire cohort was 23.5 months [Interquartile range, IQR: 14–37] while for alive patients, median follow‑up was 31 months (IQR: 23–49), 47 (50.6%) patients had died at the last follow‑up. Univariate analysis revealed certain features like age, gender, response to therapy, and texture features like mean and kurtosis in CT images to be significant predictors of survival. In multivariate analysis, age (P = 0.006), gender (P = 0.004), treatment response (P < 0.0001), and two CT texture parameters: mean (P = 0.027) and kurtosis (P = 0.002) were independent prognostic factors of survival. Interpretation and Conclusion: CT‑derived tumor heterogeneity (mean and kurtosis) complements clinical factors for predicting survival in NSCLC patients treated with CRT. Tumor radiomics warrants further validation as potential prognostic biomarkers for these patients. [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]

Hepatocyte growth factor receptor (HGFR or Met) upregulation has been proven to play important roles in non‐small cell lung carcinoma (NSCLC). Interestingly, chemoresistance against epidermal growth factor receptor (EGFR) inhibitors including erlotinib and gefitinib was also related to Met. Targeting bromodomain and extra terminal domain (BET) proteins, especially BRD4, has shown inhibitory effects on lung cancer, but the mechanism is unclear. Herein, we found that JQ1 (BET inhibitor) suppressed NSCLC cell growth, reduced the Met expression, and contributed to inactivation of PI3K/Akt and MAPK/ERK pathways. Moreover, another BET protein inhibitor I‐BET151, or BRD4 depletion, also inhibited NSCLC cell growth and downregulated Met. JQ1 inhibited HGF‐induced cell growth and Met/PI3K/Akt activation, also inhibited A549 tumor growth in xenograft mouse models, in parallel with Met downregulation. Moreover, JQ1 inhibited the growth of paired erlotinib‐sensitive and resistant HCC827 cells in parallel with Met downregulation and PI3K/Akt signaling inactivation. JQ1 also exerted inhibitory influences on the growth of erlotinib‐sensitive and resistant HCC827 tumors in xenograft mouse models. These results suggested that targeting BET proteins inhibited NSCLC via downregulating Met and inactivating PI3K/AKT pathway. Our findings reveal a novel mechanism of BET proteins implicated in NSCLC progression with Met taken into consideration. [ABSTRACT FROM AUTHOR]

In the last ten years, liquid biopsy has been slowly joining the traditional invasive techniques for the diagnosis and monitoring of tumors. Liquid biopsies allow easy repeated sampling of blood, reflect the tumor scenario, and make personalized therapy real for the patient. Liquid biopsies isolate and utilize different substrates present in patients' body fluids such as circulating tumor cells, circulating tumor DNA, tumor extracellular vesicles, etc. One of the most-used solid cancers in the development of the non-invasive liquid biopsy approach that has benefited from scientific advances is non-small cell lung cancer (NSCLC). Using liquid biopsy, it is possible to have more details on NSCLC staging, progression, heterogeneity, gene mutations and clonal evolution, etc., basing the treatment on precision medicine as well as on the screening of markers for therapeutic resistance. With this review, the authors propose a complete and current overview of all different liquid biopsies available to date, to understand how much has been carried out and how much remains to be completed for a better characterization of NSCLC. [ABSTRACT FROM AUTHOR]

Abstract Background Fibroblast‐activating protein (FAP) is expressed in cancer‐associated fibroblasts (CAFs) in many human carcinomas and in some types of carcinoma cells. Here, we examined the proportion of FAP protein expression in non‐small cell lung carcinoma (NSCLC) and investigated the correlation of FAP expression with clinicopathological background. Methods In total, 344 NSCLC tissues were examined. Tissue microarrays were constructed, and FAP expression was analyzed using immunohistochemistry. The status of FAP expression in tumor cells and CAFs was correlated with clinicopathological background, molecular features, and patient outcomes. Results A total of 280 patients (81.4%) had low FAP expression, and 64 patients (18.6%) had high FAP expression in tumor cells. In CAFs, 230 patients (66.9%) had low FAP expression, and 114 patients (33.1%) had high FAP expression. In multivariate analyses, high FAP expression in tumor cells was an independent predictive factor of both overall survival (OS; hazard ratio [HR] = 2.57, 95% confidence interval [CI]: 1.49–4.42, p

Abstract Background There are no guidelines for straightforwardly managing advanced lung cancer (T3 or T4). Although surgery has traditionally been regarded as the mainstay treatment and the only curative modality, it has limited relevance for patients with locally advanced non-small cell lung cancer (NSCLC). Photodynamic therapy (PDT) is a clinically approved cancer therapy; it is an established treatment modality with curative intent for early-stage and superficial endobronchial lesions. However, the efficacy of PDT in advanced lung cancer is controversial, and it has primarily been used in palliative care. Case presentation This case report describes a 70-year-old male who had right upper lung cancer and an endobronchial lesion that extended into the distal trachea. A biopsy specimen was obtained upon bronchoscopy, and the result confirmed squamous cell carcinoma. We performed a definitive sleeve lobectomy and intraoperative PDT. Gross total resection of the tumor was achieved, but the presence of microscopic residual tumors was inevitable. Complete anatomical resection of the primary tumor by pneumonectomy was not possible due to poor lung function and endobronchial extension to the distal trachea. We decided to apply intraoperative PDT to the lumen and outer wall of the bronchi and distal trachea for local tumor control. The patient is alive with no evidence of disease after 13 months of follow-up. Conclusions This is the first report to describe the feasibility and efficacy of intraoperative PDT as part of multimodal therapy for locally advanced NSCLC.

Abstract Background We aim to develop and test performance of a semi-automated method (computerized query combined with manual review) for chart abstraction in the identification and characterization of surveillance radiology imaging for post-treatment non-small cell lung cancer patients. Methods A gold standard dataset consisting of 3011 radiology reports from 361 lung cancer patients treated at the Veterans Health Administration from 2008 to 2016 was manually created by an abstractor coding image type, image indication, and image findings. Computerized queries using a text search tool were performed to code reports. The primary endpoint of query performance was evaluated by sensitivity, positive predictive value (PPV), and F1 score. The secondary endpoint of efficiency compared semi-automated abstraction time to manual abstraction time using a separate dataset and the Wilcoxon rank-sum test. Results Query for image type demonstrated the highest sensitivity of 85%, PPV 95%, and F1 score 0.90. Query for image indication demonstrated sensitivity 72%, PPV 70%, and F1 score 0.71. The image findings queries ranged from sensitivity 75–85%, PPV 23–25%, and F1 score 0.36–0.37. Semi-automated abstraction with our best performing query (image type) improved abstraction times by 68% per patient compared to manual abstraction alone (from median 21.5 min (interquartile range 16.0) to 6.9 min (interquartile range 9.5), p

Liquid biopsy is a non-invasive method of detecting cancer-related mutations from circulating cell-free DNA (cfDNA) and has emerged as a promising alternative to traditional tissue biopsies. However, its utility has so far been limited to the detection of somatic mutations in cancer cells. Our study examined germline mutations that are associated with pharmacogenetics in 19 patients diagnosed with colorectal cancer and 12 patients with non-small cell lung carcinoma, utilizing the highly advanced and non-invasive technique of liquid biopsy, followed by subsequent next-generation sequencing for comprehensive analysis. Despite the relatively modest sample size of patients under consideration, our results indicated a noteworthy correlation between the presence of adverse effects and the identified germline mutations. We have identified the following mutations with significant implications for pharmacogenetics: MTHFR c.1286A > C, MTHFR c.665C > T, DPYD c.2194G > A, DPYD c.85C > T, XPC c.2815C > A, UMPS c.638G > C, SLC22A2 c.808T > G, EGFR c.1562G > A, ABCB1 2677 T > G, GSTP1 c.313A > G, ERCC2 c.2251A > C, and SLC19A1 c.80A > G. In addition, we observed various adverse drug reactions in our patient cohort, encompassing myelosuppression, hepatotoxicity, neurotoxicity and gastrointestinal toxicity. Liquid biopsy has the potential to revolutionize cancer diagnosis and treatment by detecting both somatic and germline mutations. The preliminary results of studies on germline mutations are promising, but further research is needed to address the remaining challenges and to establish the utility of liquid biopsy as a reliable diagnostic tool for germline mutations.

Background: Renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC) are representative malignancies that respond well to immune checkpoint inhibitors (ICIs). Research has been conducted to identify biomarkers, such as programmed death ligand-1 (PD-L1), that would allow the response to ICI therapy to be predicted; however, the complex tumor immune system consisting of both host and tumor factors may also exert an influence. Case presentation: Computed tomographic imaging (CT) incidentally revealed a left renal mass, and a left pulmonary nodule with multiple lymph node metastases (LNMs). Firstly, video-assisted thoracic surgery revealed a lung tumor invading the chest wall. Histologically, the findings of the tumor were consistent with squamous cell carcinoma (SCC), and immunohistochemistry (IHC) showed positive PD-L1 expression. The renal tumor was excised by robotic-assisted partial nephrectomy (RAPN). Histologically, the renal tumor showed the features of clear cell carcinoma (CCC). Four months after the RAPN, CT revealed left hydronephrosis caused by an enhancing ureteral tumor. Then, multiple right lung metastases appeared, and the left lung tumor increased. Following treatment including atezolizumab, the primary lung SCC and the multiple LNMs almost disappeared completely, while the ureteral and right lung metastases showed progression. The ureteral metastasis was resected by left open nephroureterectomy. Histology of the ureteral tumor revealed features consistent with CCC. Histological examination of the multiple right lung metastases that were resected by partial lobectomy via a small thoracic incision also revealed features consistent with CCC. Two months after nephroureterectomy, a solitary left lung metastasis was treated by nivolumab and ipilimumab. Six months after nephroureterectomy, the patient died of RCC. Further studies of specimens revealed that the tumor cells in the primary RCC and the ureteral and lung metastases showed negative results of IHC for PD-L1. Conclusions: The responses to ICI therapy of concomitant RCC and NSCLC were quite different. The PD-L1 expression status in individual tumors in cases of multiple primary malignancies (MPMs) may directly predict the response of each malignancy to ICI therapy, because the host immune system, which may affect the response to ICI therapy, could be the same in MPMs. [ABSTRACT FROM AUTHOR]

Aim: Lung cancer has opened a new era in cancer treatment by elucidating the tumor's molecular structure and identifying the targetable mutations. Identifying the targeted mutations in lung cancer constitutes one of the main steps of treatment planning. The frequency of EGFR (epidermal growth factor receptor gene) and ALK (anaplastic lymphoma kinase gene) mutations in non-small cell lung cancer (NSCLC) also varies in populations depending on ethnicity, gender, smoking, and histopathological subtype. In general, limited data are available regarding the frequency and regional distribution of these mutations in the Turkish population. Our study aimed to determine the frequency of EGFR and ALK mutations in patients with advanced-stage NSCLC and compare the clinical characteristics, treatment, and survival results of cases with mutations with the group without mutations. Materials and Methods: In our study, 593 patients with advanced-stage NSCLC diagnosis and mutational analyses were evaluated retrospectively. Demographic characteristics, tumor stages (tumor, node, metastasis, TNM), EGFR and ALK analysis results, treatments applied, and survival of the cases were recorded. EGFR analysis, exon 18, 19, 20, and 21 mutations were studied with real-time PCR (RT-PCR) Rotor-Gene system from patients' samples. For ALK analysis, the ALK Break Apart kit (Zytovision GmbH; Germany) was used with the fluorescent in situ hybridization (FISH) method. Results: In our study, EGFR mutation was detected in 63 patients (10.6%) and ALK mutation in 19 patients (3.2%) out of 593 patients. EGFR mutation was observed more frequently in women and non-smokers (P = 0.001, P = 0.003). No correlation was found between the presence of EGFR mutation and metastases regions and recurrence (P > 0.05). ALK mutation was observed more frequently in non-smokers and females (P = 0.001, P = 0.003). Patients with ALK mutations were younger than other groups (P = 0.003). There was also no significant relationship between ALK mutation and metastates regions and recurrence after treatment (P > 0.05). Patients with EGFR or ALK mutations had a longer life span than other cases (P = 0.474). Those who had ALK mutations and received targeted therapy had a longer average life expectancy (P < 0.05). No difference was observed in those who had EGFR mutations and received targeted treatment in terms of survival (P > 0.05). Conclusion: In our study, conducted in the Aegean region of Turkey, the positivity rates of EGFR and ALK mutations were found to be at similar rates with the Caucasian race across the world. EGFR mutation was more common in women, non-smokers, and patients with adenocarcinoma histology. ALK mutation was also detected more frequently in younger patients, women, and non-smokers. Patients with EGFR and ALK mutations had a longer life expectancy than those without the mutation. It was observed that testing patients diagnosed with advanced-stage NSCLC for genetic mutations of the tumor in the first step of the treatment and initiating treatment in patients with mutations provided a significant survival advantage. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is the most frequent form of lung cancer and represents a set of histological entities that have an ominous long-term prognosis, for example, adenocarcinoma, squamous carcinoma and large cell carcinoma. Both small cell and non-small cell lung cancer are the main causes of oncological death and the oncological diseases with the highest incidence worldwide. With regard to clinical approaches for NSCLC, several advances have been achieved in diagnosis and treatment; the analysis of different molecular markers has led to the development of new targeted therapies that have improved the prognosis for selected patients. Despite this, most patients are diagnosed in an advanced stage, presenting a limited life expectancy with an ominous short-term prognosis. Numerous molecular alterations have been described in recent years, allowing for the development of therapies directed against specific therapeutic targets. The correct identification of the expression of different molecular markers has allowed for the individualization of treatment throughout the disease course, expanding the available therapeutic arsenal. The purpose of this article is to summarize the main characteristics of NSCLC and the advances that have occurred in the use of targeted therapies, thus explaining the limitations that have been observed in the management of this disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is the leading cause of cancer-related deaths, with a low overall survival rate. Anaemia is one of the most common cancer side effects, reducing the patient's survival time among other things. Lung cancer patients have the highest incidence of anaemia, with 50–70% of patients experiencing anaemia during the course of their disease. In clinical practice, however, anaemia is not a problem in cancer patients until it becomes severe or life-threatening, at which point therapeutic actions are taken. We choose to change this perception by first investigating the characteristics of proteins involved in the pathogenesis of anaemia, as well as their diagnostic capabilities. We assume that predicting anaemia using diagnostic biomarkers, and thus preventing and treating anaemia in lung cancer patients, is beneficial to both the patient and the economy. We aim to describe the characteristics of hepcidin, IL-6, and TNF-α levels in anaemia of lung cancer patients with operative tumour as well as to investigate the potential diagnostic capabilities of hepcidin in combination with IL-6, TNF-α, and acute phase proteins. We present a retrospective study of 112 lung cancer patients (41 women and 71 men) who were surgically treated at the Lower Silesian Centre for Lung Diseases in Wroclaw, Poland. Serum blood samples were collected from all these patients prior to any surgical treatment and used to determine hepcidin, IL-6, TNF-α, SAA1, and CRP concentrations. Patients were also examined with a complete blood count several times during their hospitalization. The female and male groups were divided based on the occurrence of anaemia during their hospitalization. Patients who developed anaemia post-operatively had significantly lower hepcidin concentrations than non-anaemic patients (p = 0.000694 in females with ≥3 complete blood count examinations and p = 0.007905 in males with 2 complete blood count examinations), whereas patients with anaemia since hospital admission had higher hepcidin concentrations. We observed two hepcidin roles related to two cancer anaemia pathogeneses: (1) higher hepcidin concentrations in patients with anaemia since hospital admission (anaemia of inflammation) and (2) lower hepcidin concentrations in patients who developed anaemia after surgery (anaemia of iron deficiency). Our data support the role of hepcidin, IL-6, and TNF-α in cancer-related anaemia and provide diagnostic values for predicting post-operative anaemia in lung cancer patients. [ABSTRACT FROM AUTHOR]

• NSCLC small biopsy exfoliates tumour cells of good cellularity in fixative media. • Cell pellet collection is encouraged while TBLB samples are being processed. • Residual cell pellet retention post a thoracic small biopsy aids ancillary testing. • Combining cell pellets with traditional sampling is beneficial in advanced NSCLC. Lung cancer tissue obtained using small biopsies are relatively fragile, leaving behind some tiny tissue fragments or cell clusters in the fixative medium that are difficult to collect for processing as a paraffin-embedded tissue block. Usually, the cellular component of the residual fixative medium is discarded as medical waste as per routine laboratory protocol. No protocol exists for utilizing the cellular component of the residual fixative medium after processing the tissue blocks to improve lung cancer ancillary testing. This study aimed to undercover the potential value of these samples for lung cancer diagnosis and targeted therapy development. A protocol was developed for cell pellet sample collection from the residual fixative medium of a transbronchial forceps lung biopsy sample. Tumour cell number and fraction in a paired cell pellet and matching formalin-fixed paraffin-embedded tissue section were evaluated from 324 non-smallcell lung carcinoma (NSCLC) cases. We defined the adequacy of the cell pellet for molecular analysis as ≥ 200 tumour cells and ≥ 10 % tumour cells. Real-time polymerase chain reaction and next-generation sequencing were performed on adequate cell pellet samples. We discovered that the fixative medium of most transbronchial forceps lung biopsy samples was enriched in tumour cells. Among 324 biopsy samples, 70 (21.6%) exhibited inadequate formalin-fixed paraffin-embedded tissue sections, whereas 53 (75.7%) yielded adequate cell pellet samples. Somatic mutations detected in the formalin-fixed paraffin-embedded tissue section samples were also detected in the matching cell pellets. Cell pellets collected from the fixative medium of thoracic small biopsies are a beneficial supplemental material for ancillary testing. Combined use of cell pellets with traditional tissue-based samples can enhance the detection rate of informative mutations in patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

In this report, we present a patient with metastatic non-small cell lung cancer who developed Sjögren's syndrome secondary to immune checkpoint inhibition. This patient had a typical clinical presentation as well as biochemical signature, developing only 18 months after the start of treatment with PD-1 inhibition (pembrolizumab). [ABSTRACT FROM AUTHOR]

Liquid biopsy is a non-invasive method of detecting cancer-related mutations from circulating cell-free DNA (cfDNA) and has emerged as a promising alternative to traditional tissue biopsies. However, its utility has so far been limited to the detection of somatic mutations in cancer cells. Our study examined germline mutations that are associated with pharmacogenetics in 19 patients diagnosed with colorectal cancer and 12 patients with non-small cell lung carcinoma, utilizing the highly advanced and non-invasive technique of liquid biopsy, followed by subsequent next-generation sequencing for comprehensive analysis. Despite the relatively modest sample size of patients under consideration, our results indicated a noteworthy correlation between the presence of adverse effects and the identified germline mutations. We have identified the following mutations with significant implications for pharmacogenetics: MTHFR c.1286A > C, MTHFR c.665C > T, DPYD c.2194G > A, DPYD c.85C > T, XPC c.2815C > A, UMPS c.638G > C, SLC22A2 c.808T > G, EGFR c.1562G > A, ABCB1 2677 T > G, GSTP1 c.313A > G, ERCC2 c.2251A > C, and SLC19A1 c.80A > G. In addition, we observed various adverse drug reactions in our patient cohort, encompassing myelosuppression, hepatotoxicity, neurotoxicity and gastrointestinal toxicity. Liquid biopsy has the potential to revolutionize cancer diagnosis and treatment by detecting both somatic and germline mutations. The preliminary results of studies on germline mutations are promising, but further research is needed to address the remaining challenges and to establish the utility of liquid biopsy as a reliable diagnostic tool for germline mutations. [ABSTRACT FROM AUTHOR]

Background: Non–small cell lung carcinoma (NSCLC) patients with BRAF V600E–mutated tumors respond to targeted therapy. Testing for BRAF V600E is commonly performed with molecular methods; however, a mutation‐specific VE1 antibody clone can provide an alternative testing option using immunohistochemistry (IHC) for practices using single‐gene testing and in situations when the specimen is inadequate for molecular testing. This study evaluates the usefulness of VE1 IHC in screening for BRAF V600E mutations in NSCLC cytology specimens. Methods: The authors retrospectively identified cytology cases with a diagnosis of NSCLC that had BRAF V600E IHC performed on cell block sections with the monoclonal VE1 antibody clone. The BRAF V600E IHC results were compared with those of molecular testing performed with an amplicon‐based next‐generation sequencing assay. Results: There were 201 NSCLC cases evaluated. The VE1 IHC was positive in seven of seven BRAF V600E–mutated tumors (100%) and was negative in 158 of 158 nonmutated BRAF V600E tumors (100%). Thirty cases did not undergo molecular testing, primarily because of insufficient tissue or because molecular testing was performed on an alternative specimen. Six cases showed equivocal weak/focal staining: Two cases demonstrated BRAF V600E mutations, and four cases were negative by molecular testing. Conclusions: This study suggests that BRAF V600E IHC can be used reliably to screen NSCLC cytology specimens, and negative results strongly indicate the absence of a BRAF V600E mutation. Having a low threshold for equivocal staining is recommended with molecular confirmation of BRAF V600E for any cases demonstrating weak and/or focal cytoplasmic staining. BRAF V600E immunohistochemistry can be used reliably to screen cytologic specimens of non–small cell lung carcinoma, and negative results strongly indicate the absence of a BRAF V600E mutation. Having a low threshold for equivocal staining is recommended with molecular confirmation of BRAF V600E for any cases demonstrating weak and/or focal cytoplasmic staining. [ABSTRACT FROM AUTHOR]

Mediastinal lymph node assessment is a crucial step in non-small cell lung cancer staging. Positron emission tomography (PET) has been the gold standard for the assessment of mediastinal lymphadenopathy, though it has limited specificity. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is quick, accurate, and a less invasive method for obtaining a diagnostic sample in contrast to mediastinoscopy. We performed a retrospective chart analysis of 171 patients to assess the adequacy of tissue obtained by EBUS for diagnosis and molecular profiling as well as the assessment of staging and lymph node (LN) stations diagnostic yield, in correlation to PET scan and the operator's level of experience. A significantly increased tissue adequacy was observed based on the operators' experience, with the highest adequacy noted in trained Interventional Pulmonologist (IP) (100%), followed by >5 years of experience (93.33%), and 88.89% adequacy with <5 years of experience (p = 0.0019). PET-CT scan 18F-fluorodeoxyglucose (FDG) uptake in levels 1, 2, and 3 LN had a tissue adequacy of 76.67%, 54.64%, and 35.56%, respectively (p = 0.0009). EBUS bronchoscopy method could be used to achieve an accurate diagnosis, with IP-trained operators yielding the best results. There is no correlation with PET scan positivity, indicating that both PET and EBUS are complementary methods needed for staging. [ABSTRACT FROM AUTHOR]

Purpose: The optimal extent of lymph node dissection (LND) during segmentectomy is unclear. During segmentectomy, it is more challenging to dissect the non-adjacent interlobar lymph node (non-aiLN) away from the primary tumor than to dissect the adjacent interlobar lymph node (aiLN), as injury to the preserved parenchyma and bronchus may occur. We examined whether dissection of non-aiLNs was required during intentional segmentectomy. Methods: This retrospective cohort study included 310 patients who underwent lobectomy and mediastinal LND for non-small cell lung cancer of ≤ 2 cm at the Osaka International Cancer Institute during January 2006 to December 2015. We investigated LN metastasis distribution and evaluated metastases in non-aiLNs distant from the primary lesion. Results: Six (1.9%) patients had iLN metastasis. Patients with iLN metastasis did not have primary lesions in the right upper lobe or left upper segment. Of the six patients with iLN metastasis, three had non-aiLN metastasis with a tumor diameter of ≥ 15 mm, with high positron emission tomography standard uptake values (> 3.5). Two patients had multiple LN metastases, and one had solitary LN metastasis. Conclusion: Non-aiLN dissection may be unnecessary during segmentectomy of the right upper lobe or left upper segment; however, it should be considered during lower-lobe segmentectomy. [ABSTRACT FROM AUTHOR]

Abstract Background Programmed death ligand-1 (PD-L1), anaplastic lymphoma kinase (ALK), and c-ros oncogene1 (ROS1) expression may influence the prognosis of non-small cell lung carcinoma (NSCLC). We aimed to investigate the prognostic and predictive significance of PD-1/PD-L1 along with c-ros ROS1 and ALK in NSCLC patients. Methods Immunohistochemistry used to identify ALK, ROS1, PD-1, and PD-L1 proteins expression as well as ROS1 rearrangement via fluorescence in situ hybridization, in 70 NSCLC patients. Results were related to clinicopathological feature, survival, and treatment response. Results Expression of ROS1, ALK, PD-1, and PD-L1 and ROS1-rearrangement were detected in 18.57%, 54.29%, 84.29%, 87.14%, and 15.71% of the cases, respectively. No association was found between ROS1, PD-1, and PD-L1 and any clinicopathological features, survival, or treatment outcome. ALK expression significantly associated with stage-IV and left-sided tumors. Epidermal growth factor receptor (EGFR) mutation and ALK-positive patients had significantly reduced progression-free survival than patients with wild type EGFR [HR: 1.99, 95% CI: 1.37–2.93, p

Background The remarkable efficacy of osimertinib in non‒small cell lung cancer (NSCLC) with acquired T790M mutation has been widely documented in clinical trials and real-world practice. However, some patients show primary resistance to this drug. Even patients who initially show a favorable response have inconsistent clinical outcomes later. Therefore, the aim of this study was to identify additional clinical predictive factors for osimertinib efficacy. Methods A prospective cohort of patients with acquired T790M positive stage IV lung adenocarcinoma treated with osimertinib salvage therapy in Hallym University Medical Center were analyzed. Results Sixty-one eligible patients were analyzed, including 38 (62%) women and 39 (64%) who never smoked. Their mean age was 63.3 years. The median follow-up after treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) was 36.0 months (interquartile range, 24.7–50.2 months). The majority (n=45, 74%) of patients were deceased. Based on univariate analysis, low baseline neutrophil-to-lymphocyte ratios (NLR), age ≥50 years, never-smoking history, stage IVA at osimertinib initiation, and prolonged response to previous TKIs (≥10 months) were associated with a significantly longer progression-free survival (PFS). Multivariate analysis showed that never-smoking status (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.30–0.98; p=0.041) and a baseline NLR less than or equal to 3.5 (HR, 0.23; 95% CI, 0.12–0.45; p

Brain metastasis (BM) is one of the main causes of death in patients with non-small cell lung carcinoma. The specific pathological processes of BM, which are inextricably linked to the brain tumor microenvironment, such as the abundance of astrocytes, lead to limited treatment options and poor prognosis. Reactive astrocytes are acquired in the BM; however, the underlying mechanisms remain unclear. This study aimed to explore the mechanisms by which astrocytes promote BM development. We determined the crucial role of reactive astrocytes in promoting the proliferation and migration of brain metastatic lung tumor cells by upregulating protocadherin 1 (PCDH1) expression in an in vitro co-culture model. The overexpression of PCDH1 was confirmed in clinical BM samples using immunohistochemical staining. Survival analysis indicated that high- PCDH1 expression was associated with poor survival in patients with lung adenocarcinoma. In vivo assays further showed that silence of PCDH1 effectively inhibited the tumor progression of brain metastases and prolonged the survival of animals. RNA sequencing has revealed that PCDH1 plays an important role in cell proliferation and adhesion. In conclusion, the present study revealed the promoting role of astrocytes in enhancing the aggressive phenotype of brain metastatic tumor cells by regulating the expression of PCDH1, which might be a biomarker for BM diagnosis and prognosis, suggesting the potential efficacy of targeting important astrocyte-tumor interactions in the treatment of patients with non-small cell lung carcinoma with BM. [Display omitted] • Reactive astrocytes increase the proliferation and migration abilities of LCBM cells. • PCDH1 is up-regulated by reactive astrocytes and promotes malignant phenotypes. • Overexpressed PCDH1 induces the growth of brain metastasis in viv o. [ABSTRACT FROM AUTHOR]

• Alternative pembrolizumab dosing reduced median daily dose per patient by 22%. • We reported real-world data including overall survival in NSCLC patients. • Alternative dosing was non-inferior to standard dosing for overall survival. • Alternative dosing can significantly reduce treatment costs. High and increasing expenses on pembrolizumab ask for more cost-effective and sustainable treatment strategies to improve affordability of healthcare. Therefore, a part of the Dutch hospitals implemented an alternative, partially lower, weight-based dosing protocol for pembrolizumab. This provided the unique opportunity to compare the overall survival (OS) of the alternative pembrolizumab dosing protocol to standard dosing using a nationwide registry in non-small cell lung cancer (NSCLC) patients. This is a retrospective cohort study with a non-inferiority primary objective. Forty hospitals in the Dutch Medication Audit and Dutch Lung Cancer Audit treated 1966 patients with NSCLC with first line pembrolizumab (mono- or combination therapy) between Jan 1st 2021, and Mar 31st, 2023. Alternative weight-based pembrolizumab dosing (100/150/200 mg Q3W or 200/300/400 mg Q6W) was administered to 604 patients, and 1362 patients received standard pembrolizumab dosing (200 mg Q3W or 400 mg Q6W). A Cox proportional hazard model with selected covariates was used to compare the OS between alternative and standard dosing protocols. The non-inferiority margin was set at a hazard ratio (HR) of 1.2 for OS. Non-inferiority is established by showing that the upper limit of the 95 % confidence interval (CI) of the HR of OS is smaller or equal to 1.2. Distribution of age (66.7 years +/-9.4), sex (45 % female) and treatment combinations were similar for both groups, comorbidity score was higher in the standard group. Median daily dose in the alternative dosing group was 22 % lower compared to the standard dosing group, 7.14 mg/day (interquartile range (IQR):5.48–8.04 mg/day) vs. 9.15 mg/day (IQR:8.33–9.52 mg/day), respectively. Alternative dosing was non-inferior to standard dosing regarding overall survival (adjusted HR 0.83, 95 %CI:0.69–1.003). This large, retrospective real-world analysis supports the hypothesis that the alternative, partially lower pembrolizumab dosing protocol in NSCLC maintains treatment effectiveness while reducing treatment costs. [ABSTRACT FROM AUTHOR]

The prevalence of lung cancer as one of the most common cancers with the highest mortality rate is one of the most important health problems in humans across the world. Molecular research can provide valuable information about genetic changes associated with the pathogenesis of the disease that may be used to improve prognosis and treatment. The current study aimed to examine the genotyping utility of the Il12p40 (IL-12B) gene (rs3212227, A>C) polymorphisms and detect its relationship with the concentration levels of HGH and IGF-1 for the non-small cell lung carcinoma (NSCLC). This study investigated 67 cases with NSCLC (60 males and 7 females) and 28 healthy individuals as controls. The serum level of HGH and IGF-1 was determined using an enzyme-linked immunosorbent assay. Genotyping of the IL-12B gene polymorphisms (rs3212227, A>C) was carried out by polymerase chain reaction-restriction fragment length polymorphism. The serum levels of the HGH and IGF-1 were estimated, and the results of the IL-12B genotyping showed an increased risk of NSCLC. The homozygous wild (AA) genotype of the IL-12 gene showed that the risk of NSCLC was higher than that of the heterozygous (AC) and homozygous genotypes (CC). Moreover, a significant elevation was found in the serum levels of the HGH in the NSCLC patients, compared to the control group. The result showed that the IL-12 gene polymorphism was implicated in the pathogenesis of the NSCLC and directed several metabolic changes.

Abstract Background We aimed to investigate the characteristics and pretreatment risk factors for postoperative pulmonary complications (PPCs) after neoadjuvant concurrent chemoradiotherapy (CRTx) in patients with non‐small cell lung cancer (NSCLC). Methods We retrospectively reviewed data of 122 patients who underwent curative resection after neoadjuvant CRTx for NSCLC between 2007 and December 2019. Clinical data, including pulmonary function and body mass index (BMI) at the time of concurrent CRTx initiation, were analyzed. We performed logistic regression analyses to identify the risk factors for PPCs and built a nomogram with significant factors. Results Of the 122 patients included (mean age, 60.1 ± 9.7 years; 69.7% male), 27 experienced PPCs (severity grade ≥ 2). The most common PPCs were pneumonia (n = 17). Patients with PPCs had a significantly longer hospital stay (median 6.0 vs. 17 days, p

Xiaochuan Zhang,1,2,&ast; Fajin Lv,1,&ast; Binjie Fu,1 Wangjia Li,1 Ruiyu Lin,1 Zhigang Chu1 1Department of Radiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2Department of Radiology, Chonggang General Hospital, Chongqing, 400080, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhigang Chu, Tel +86 18723032809, Fax +86 23 68811487, Email chuzg0815@163.comPurpose: To investigate the clinical and computed tomography (CT) characteristics of peripheral small-cell lung cancer (pSCLC) to improve its early diagnosis.Patients and Methods: In total, 70, 132, 69, and 95 patients with pathological confirmed nodular (≤ 3 cm) pSCLC, peripheral non-small cell lung cancer (pNSCLC), benign lung tumor (pBLT), and inflammatory lesion (pIL) were enrolled in this study retrospectively. The clinical and CT data of studied patients with different lesions were analyzed and compared by univariate analysis. Multivariate analysis was used to reveal the key features to distinguish pSCLC from pNSCLC, pBLT, and pIL, respectively.Results: Univariate and multivariate analysis of the clinical and CT characteristics of studied patients indicated that 1) compared with pNSCLC and pIL, vessel convergence, spiculation, and peripheral ground-glass opacity were less common in pSCLC; 2) density homogeneity (OR = 38.84– 120.21, P < 0.05), bronchial cutoff sign (OR = 10.00– 60.13, P = 0.001), hilar lymph node enlargement (OR = 22.81– 95.08, P < 0.0001) (pSCLC vs pNSCLC, pBLT, and pIL), male sex (OR = 5.53– 10.92, P < 0.05) (pSCLC vs pNSCLC and pBLT), and emphysema (OR = 36.57– 56.63, P < 0.05) (pSCLC vs pBLT and pIL) were significantly and independently associated with pSCLC. Type I and II bronchial cutoff sign, especially type I, were closely related to pSCLC.Conclusion: Peripheral solid nodules with homogeneous density, bronchial cutoff sign, hilar lymph node enlargement, but without spiculation or vessel convergence in male patients with emphysema should be highly suspected of pSCLC.Keywords: small-cell lung carcinoma, non-small cell lung carcinoma, tomography, X-ray computed

SMARCA4/BRG1-deficient lung adenocarcinoma (SD-LUAD) is being recognized as a distinct subtype based on subtle differences in its clinical, morphological, and immunophenotypic attributes compared to other non–small cell lung carcinomas. We present here a case of SD-LUAD with curious thyroid transcription factor 1 (TTF1) expression in a morphologically heterogenous lung adenocarcinoma. The better differentiated area showed preservation of TTF1 expression, and a poorly differentiated tumor had loss of TTF1 expression with universal BRG1 loss.

Objective: Determination of the molecular status is mandatory for personalized treatment of patients with non-small cell lung carcinoma. The present study was performed to detect anaplastic lymphoma kinase (ALK) rearrangements in pulmonary adenocarcinoma on cytology samples, using immunocytochemistry (ICC) and fluorescence in situ hybridization (FISH) on cell-blocks to assess the diagnostic reliability of these two techniques. Material and Method: A total of 50 confirmed lung adenocarcinoma cases were included. In all the 50 cases, ICC was performed for ALK protein expression by using the D5F3 clone on Ventana platform. On the basis of ALK protein expression on ICC, the cases were categorized as ALK positive (2+ or 3+ strong cytoplasmic granular positivity) or negative (negative or 1+ cytoplasmic granular positivity). FISH for detection of ALK gene rearrangement was performed in 7 ALK ICC positive cases and 7 ALK ICC negative cases using the Vysis ALK break apart FISH probe kit. Results: Based on ICC, 7(14%) cases were ALK positive and 43(86%) were ALK negative. ALK gene rearrangements in lung adenocarcinoma were more commonly seen in non-smokers (31.25%) as compared to smokers (6.25%). Among the ALK-ICC positive cases, FISH demonstrated break apart signal in 5 cases (ALK- ICC positive); however, no break-apart signals were seen in 2 ALK-ICC positive and all the seven ALK-ICC negative cases. Conclusion: Immunocytochemistry on cell- blocks using DF53 clone is a highly sensitive and specific method for the detection of ALK gene rearrangements in lung adenocarcinoma with a greater number of ALK positive cases being detected on ICC as compared to the ALK-FISH.

Introduction: Gene fusion testing of ALK, ROS1, RET, NTRK, and MET exon 14 skipping mutations is guideline recommended in nonsquamous NSCLC (NS-NSCLC). Nevertheless, assessment is often hindered by the limited availability of tissue and prolonged next-generation sequencing (NGS) testing, which can protract the initiation of a targeted therapy. Therefore, the development of faster gene fusion assessment is critical for optimal clinical decision-making. Here, we compared two ultrafast gene fusion assays (UFGFAs) using NGS (Genexus, Oncomine Precision Assay, Thermo Fisher Scientific) and a multiplex reverse-transcriptase polymerase chain reaction (Idylla, GeneFusion Assay, Biocartis) approach at diagnosis in a retrospective series of 195 NS-NSCLC cases and five extrapulmonary tumors with a known NTRK fusion. Methods: A total of 195 NS-NSCLC cases (113 known gene fusions and 82 wild-type tumors) were included retrospectively. To validate the detection of a NTRK fusion, we added five NTRK-positive extrathoracic tumors. The diagnostic performance of the two UFGFAs and standard procedures was compared. Results: The accuracy was 92.3% and 93.1% for Idylla and Genexus, respectively. Both systems improved the sensitivity for detection by including a 5′-3′ imbalance analysis. Although detection of ROS1, MET exon 14 skipping, and RET was excellent with both systems, ALK fusion detection was reduced with sensitivities of 87% and 88%, respectively. Idylla had a limited sensitivity of 67% for NTRK fusions, in which only an imbalance assessment was used. Conclusions: UFGFA using NGS and reverse-transcriptase polymerase chain reaction approaches had an equal level of detection of gene fusion but with some technique-specific limitations. Nevertheless, UFGFA detection in routine clinical care is feasible with both systems allowing faster initiation of therapy and a broad degree of screening.

Background: At present, lung cancer is a leading cause of cancer death in the world. Most of the patients are asymptomatic at the early stages of the disease and manifest at the advanced stage. It is broadly classified into two types based on histopathology, Non-small cell lung cancer (NSCLC), the predominant type, and Small cell lung cancer (SCLC). Â Our study aimed to evaluate the enhancement pattern of malignant lung lesion during contrast-enhanced computed tomography. Methodology: A cross-sectional study was conducted on 34 patients with lung cancer after clearance from the Institutional Ethical Committee. Contrast enhanced computed tomography (CECT) Thorax was performed by 16 slice Multi-Detector computed tomography (MDCT )machine, and the tumor's pre and post-contrast Hounsfield Unit (HU) value was measured in the area of highest density. Results: Out of the 34 patients, Squamous cell carcinoma and adenocarcinoma were seen in 15 patients in each group, whereas small cell carcinoma was found in 4 patients. Pre and post-contrast mean HU value was 39.5 (SD= 2.95) HU and 72.13 (SD= 4.21) HU for adenocarcinoma, 34.6 (SD=2.61) HU and 63.8(SD=2.88) HU for squamous cell carcinoma and 31.00 (SD=1.41) HU and 55.7 (SD=2.75) HU for small cell carcinoma. The significant of density difference was measured using paired t-test (p20HU) during the CECT study. Evaluation of enhancement pattern of lung mass by measuring pre and post-contrast HU value will help the radiologist to predict the histopathological type of lung cancer.

Long-term recurrences or metastases occur in some patients with non-small cell lung carcinoma after complete remission in the early stages. This phenomenon may be related to the presence of tumor lesions undetectable by radiographic or laboratory methods, which are called minimal residual disease. Poor prognosis of patients is closely associated with these potential sources of tumor recurrences, so it is essential to supervise these lesions during the treatment of non-small cell lung carcinoma. Currently, the detection of minimal residual disease mainly relies on liquid biopsy, including circulating tumor DNA detection, circulating tumor cell detection and other approaches. Through non-invasive detection methods, remaining tumor lesions provide us with the progression of the tumor and specific molecular information, predict the prognosis of patients, and further guide the follow-up treatment regimen. In this review, we will explore the mechanism and impact of the occurrence and development of minimal residual disease, and focus on its potential application value in the clinical treatment process.

IntroductionChemoradiotherapy (CRT) has been associated with increased incidence of cardiovascular (CV) adverse events (CVAE). Coronary artery calcium scoring (CAC) has shown to predict coronary events beyond the traditional CV risk factors. This study examines whether CAC, measured on standard of care, non-contrast chest CT (NCCT) imaging, predicts the development of CVAE in patients with non-small cell lung cancer (NSCLC) treated with CRT.MethodsPatients with NSCLC treated with CRT at MD Anderson Cancer Center from 7/2009 until 4/2014 and who had at least one NCCT scan within 6 months from their first CRT were identified. CAC scoring was performed on NCCT scans by an expert cardiologist and a cardiac radiologist following the 2016 SCCT/STR guidelines. CVAE were graded based on the most recent Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. CVAE were also grouped into (i) coronary/vascular events, (ii) arrhythmias, or (iii) heart failure. All CVAE were adjudicated by a board-certified cardiologist.ResultsOut of a total of 193 patients, 45% were female and 91% Caucasian. Mean age was 64 ± 9 years and mean BMI 28 ± 6 kg/m2. Of 193 patients, 74% had CAC >0 Agatston units (AU), 49% CAC ≥100 AU and 36% CAC ≥300 AU. Twenty-nine patients (15%) developed a grade ≥2 CVAE during a median follow-up of 24.3 months (IQR: 10.9–51.7). Of those, 11 (38%) were coronary/vascular events. In the multivariate cox regression analysis, controlling for mean heart dose and pre-existing CV disease, higher CAC score was independently associated with development of a grade ≥2 CVAE [HR: 1.04 (per 100 AU), 95% CI: 1.01–1.08, p = 0.022] and with worse overall survival (OS; CAC ≥100 vs.

Dendritic cells (DCs) have received considerable attention as potential targets for the development of novel cancer immunotherapies. However, the clinical efficacy of DC-based vaccines remains suboptimal, largely reflecting local and systemic immunosuppression at baseline. An autologous DC-based vaccine (DCVAC) has recently been shown to improve progression-free survival and overall survival in randomized clinical trials enrolling patients with lung cancer (SLU01, NCT02470468) or ovarian carcinoma (SOV01, NCT02107937), but not metastatic castration-resistant prostate cancer (SP005, NCT02111577), despite a good safety profile across all cohorts. We performed biomolecular and cytofluorometric analyses on peripheral blood samples collected prior to immunotherapy from 1000 patients enrolled in these trials, with the objective of identifying immunological biomarkers that may improve the clinical management of DCVAC-treated patients. Gene signatures reflecting adaptive immunity and T cell activation were associated with favorable disease outcomes and responses to DCVAC in patients with prostate and lung cancer, but not ovarian carcinoma. By contrast, the clinical benefits of DCVAC were more pronounced among patients with ovarian carcinoma exhibiting reduced expression of T cell-associated genes, especially those linked to TH2-like signature and immunosuppressive regulatory T (TREG) cells. Clinical responses to DCVAC were accompanied by signs of antitumor immunity in the peripheral blood. Our findings suggest that circulating signatures of antitumor immunity may provide a useful tool for monitoring the potency of autologous DC-based immunotherapy.

Molecular diagnosis of lung cancer is a constantly evolving field thanks to major advances in precision oncology. The wide range of actionable molecular alterations in non-squamous non-small cell lung carcinoma (NS-NSCLC) and the multiplicity of mechanisms of resistance to treatment resulted in the need for repeated testing to establish an accurate molecular diagnosis, as well as to track disease evolution over time. While assessing the increasing complexity of the molecular composition of tumors at baseline, as well as over time, has become increasingly challenging, the emergence and implementation of next-generation sequencing (NGS) testing has extensively facilitated molecular profiling in NS-NSCLC. In this review, we discuss recent developments in the molecular profiling of NS-NSCLC and how NGS addresses current needs, as well as how it can be implemented to address future challenges in the management of NS-NSCLC. [ABSTRACT FROM AUTHOR]

• Non-small cell lung cancer patients with different genetic mutations may have different risks of thrombosis. • The presence of ALK/ROS rearrangements is significantly associated with an increase in thrombosis risk in NSCLC patients, compared to other common gene mutation status. • Based on the result of our study, for patients who are treated with ALK/ROS TKI, the risk of TE might increase additionally. • Identifying patients at high risk of TE will allow a more personalized approach and benefit more from the use of pharmacologic thromboprophylaxis. This retrospective study aimed to estimate the incidence, risk factors of thromboembolism events (TEs) in non-small cell lung cancer patients harboring common gene mutation, and evaluate a genetic link between oncogenes and the risk of TEs in Asian patients with NSCLC. Univariate and multivariate Cox's proportional hazards regression models were used to identify the strongest predictors of TE development and evaluate the risk of TE in patients with different gene statuses of NSCLC patients. In univariate and multivariate COX analysis, patient with squamous cell carcinoma (HR 3.01, 95% CI: [1.06,8.56]; p = 0.039), multi-site metastases (HR: 2.72; 95% CI: [1.08,6.92]; p = 0.032) or high white blood cell (WBC) (HR 3.24, 95% CI: [1.46,7.22]; p = 0.004), less hemoglobin (HGB) (HR 4.89, 95% CI: [1.90,12.64]; p = 0.001), are at higher risk of thrombosis. At the molecular level, ROS and ALK rearrangement is highly associated with TE development, with HR of 4.04 (95%CI: [1.54,10.58]; p = 0.005) and HR of 3.57 (95% CI: [1.01,12.66]; p = 0.049) in univariate analysis, and even higher in multivariate analysis. EGFR mutations seem to be a protective factor against TE in univariate analyses (HR:0.28, 95%CI [0.12,0.65], p = 0.003) but are not statistically significant in the multivariate model. No correlation between KRAS mutations and TE events in both models. Besides, a numerically higher cumulative incidence of thrombosis event was observed in patients who used TKI (HR 1.473; 95% CI: [0.682, 3.181]; p = 0.32). Our study demonstrated that driver gene mutation may increase the risk of thrombosis in non-small cell lung cancer patients. The presence of ALK/ROS rearrangements in our study is associated with an approximately threefold to fourfold increase in thrombosis risk in NSCLC patients. For advanced-stage patients who used TKI, an increased incidence of thrombosis risk and shorter follow-up were observed. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study is to evaluate the safety and efficacy of ex vivo activated and expanded natural killer (NK) cell therapy (SNK01) plus pembrolizumab in a randomized phase I/IIa clinical trial. Materials and Methods Overall, 18 patients with advanced non-small cell lung cancer (NSCLC) and a programmed death ligand 1 tumor proportion score of 1% or greater who had a history of failed frontline platinum-based therapy were randomized (2:1) to receive pembrolizumab every 3 weeks +/- 6 weekly infusions of SNK01 at either 2x109 or 4x109 cells per infusion (pembrolizumab monotherapy vs. SNK01 combination). The primary endpoint was safety, whereas the secondary endpoints were the objective response rate (ORR), progression-free survival (PFS), overall survival, and quality of life. Results Since no dose-limiting toxicity was observed, the maximum tolerated dose was determined as SNK01 4x109 cells/dose. The safety data did not show any new safety signals when SNK01 was combined with pembrolizumab. The ORR and the 1-year survival rate in the NK combination group were higher than those in patients who underwent pembrolizumab monotherapy (ORR, 41.7% vs. 0%; 1-year survival rate, 66.7% vs. 50.0%). Furthermore, the median PFS was higher in the SNK01 combination group (6.2 months vs. 1.6 months, p=0.001). Conclusion Based on the findings of this study, the NK cell combination therapy may consider as a safe treatment method for stage IV NSCLC patients who had a history of failed platinum-based therapy without an increase in adverse events. [ABSTRACT FROM AUTHOR]

Purpose The illness-death model (IDM) is a comprehensive approach to evaluate the relationship between relapse and death. This study aimed to illustrate the value of the IDM for identifying risk factors and evaluating predictive probabilities for relapse and death in patients with non-small cell lung cancer (NSCLC) in comparison with the disease-free survival (DFS) model. Materials and Methods We retrospectively analyzed 612 NSCLC patients who underwent a curative operation. Using the IDM, the risk factors and predictive probabilities for relapse, death without relapse, and death after relapse were simultaneously evaluated and compared to those obtained from a DFS model. Results The IDM provided more detailed risk factors according to the patient's disease course, including relapse, death without relapse, and death after relapse, in patients with resected lung cancer. In the IDM, history of malignancy (other than lung cancer) was related to relapse and smoking history was associated with death without relapse; both were indistinguishable in the DFS model. In addition, the IDM was able to evaluate the predictive probability and risk factors for death after relapse; this information could not be obtained from the DFS model. Conclusion Compared to the DFS model, we found that the IDM provides more comprehensive information on transitions between states and disease stages and provides deeper insights with respect to understanding the disease process among lung cancer patients. [ABSTRACT FROM AUTHOR]

Purpose This study was to evaluate anti-tumor efficacy of osimertinib in patients positive for acquired epidermal growth factor receptor (EGFR) T790M mutation in liquid biopsy using plasma, bronchoalveolar lavage fluid (BALF) or bronchial washing fluid (BWF), and pleural effusion. Materials and Methods Among patients benefited from previous EGFR-tyrosine kinase inhibitor (TKI) treatment followed by treatment failure, patients in whom T790M mutations are detected in at least one of the samples including tumor tissues, BALF/BWF, plasma, and pleural effusion were enrolled. T790M mutation was detected by extracting cell free DNA from liquid biopsy samples, using PANA Mutyper. Objective response rate (ORR) and progression-free survival (PFS) with osimertinib treatment were evaluated. Results Between January 2018 and December 2019, 63 patients were enrolled and received osimertinib. Mean age was 63 years, and 38 (60.3%) were female. Twenty-six patients had T790M mutation in both liquid and tissue samples (group A), 19 patients had only in tissue biopsy samples (group B), and 18 patients had T790M mutation only in liquid biopsy samples (group C). ORR in overall population was 63.5%, and was 61.5% in group A, 68.4% in group B, and 61.1% in group C, respectively. Median PFS in overall patients was 15.6 months (95% confidence interval, 10.7 to 24.2). There was no significant difference in ORR or PFS between groups. Conclusion Osimertinib showed favorable efficacy in lung cancer patients with acquired resistance to prior EGFR-TKI therapies, who screened positive for harboring T790M mutation detected from cell free DNA extracted from plasma, BALF/BWF, and pleural effusion. [ABSTRACT FROM AUTHOR]

Metastasis is crucial for the mortality of non-small cell lung carcinoma (NSCLC) patients. The epithelial–mesenchymal transition (EMT) plays a critical role in regulating tumor metastasis. Glioma-associated oncogene 1 (Gli1) is aberrantly active in a series of tumor tissues. However, the molecular regulatory relationships between Gli1 and NSCLC metastasis have not yet been identified. Herein, we reported Gli1 promoted NSCLC metastasis. High Gli1 expression was associated with poor survival of NSCLC patients. Ectopic expression of Gli1 in low metastatic A549 and NCI-H460 cells enhanced their migration, invasion abilities and facilitated EMT process, whereas knock-down of Gli1 in high metastatic NCI-H1299 and NCI-H1703 cells showed an opposite effect. Notably, Gli1 overexpression accelerated the lung and liver metastasis of NSCLC in the intravenously injected metastasis model. Further research showed that Gli1 positively regulated Snail expression by binding to its promoter and enhancing its protein stability, thereby facilitating the migration, invasion and EMT of NSCLC. In addition, administration of GANT-61, a Gli1 inhibitor, obviously suppressed the metastasis of NSCLC. Collectively, our study reveals that Gli1 is a critical regulator for NSCLC metastasis and suggests that targeting Gli1 is a prospective therapy strategy for metastatic NSCLC. Gli1 promotes Snail transcription and enhances its protein stability, and then facilitates EMT process and metastasis of NSCLC. Targeting Gli1 is a prospective therapy strategy for metastatic NSCLC. [Display omitted] [ABSTRACT FROM AUTHOR]

Tumor necrosis factor receptor‐associated factor 4 (TRAF4) is overexpressed in a variety of carcinomas of different origins, but its role in tumorigenesis remains incompletely understood. Previous studies suggest that TRAF4 promotes epidermal growth factor receptor (EGFR) activation in non‐small cell lung cancer (NSCLC). However, the downstream signaling pathway of TRAF4‐mediated EGFR activation, as well as its effects on tumor cells, have not been fully elucidated. Here we report that TRAF4 overexpression is associated with increased activity of extracellular signal‐regulated kinase 5 (ERK5) in NSCLC tissues. Activation of ERK5 was dependent on TRAF4‐mediated EGFR activation, since inhibition of either TRAF4 or EGFR dramatically abolished phosphorylation of ERK5. Mechanistically, EGFR recruited mitogen‐activated protein kinase kinase kinase 3 (MEKK3), an upstream kinase of ERK5, in a TRAF4‐dependent manner. Thus, our data suggest that an EGFR‐TRAF4‐MEKK3‐ERK5 axis promotes the proliferation of tumor cells, and this may be a potential target for therapeutic intervention of NSCLC. [ABSTRACT FROM AUTHOR]

Background: At present, lung cancer is a leading cause of cancer death in the world. Most of the patients are asymptomatic at the early stages of the disease and manifest at the advanced stage. It is broadly classified into two types based on histopathology, Non-small cell lung cancer (NSCLC), the predominant type, and Small cell lung cancer (SCLC). Our study aimed to evaluate the enhancement pattern of malignant lung lesion during contrast-enhanced computed tomography. Methodology: A cross-sectional study was conducted on 34 patients with lung cancer after clearance from the Institutional Ethical Committee. Contrast enhanced computed tomography (CECT) Thorax was performed by 16 slice Multi-Detector computed tomography (MDCT) machine, and the tumor's pre and post-contrast Hounsfield Unit (HU) value was measured in the area of highest density. Results: Out of the 34 patients, Squamous cell carcinoma and adenocarcinoma were seen in 15 patients in each group, whereas small cell carcinoma was found in 4 patients. Pre and post-contrast mean HU value was 39.5 (SD= 2.95) HU and 72.13 (SD= 4.21) HU for adenocarcinoma, 34.6 (SD=2.61) HU and 63.8(SD=2.88) HU for squamous cell carcinoma and 31.00 (SD=1.41) HU and 55.7 (SD=2.75) HU for small cell carcinoma. The significant of density difference was measured using paired t-test (p<0.05). Conclusion: All histopathological subtypes of lung cancer showed significant post-contrast enhancement (>20HU) during the CECT study. Evaluation of enhancement pattern of lung mass by measuring pre and post-contrast HU value will help the radiologist to predict the histopathological type of lung cancer. [ABSTRACT FROM AUTHOR]

Astragali Radix (AR) and Schisandrae chinensis Fructus (SCF) have been used individually and in traditional Chinese medicine (TCM) formulas for treating non-small cell lung carcinoma (NSCLC). Qi Wei Wan (QWW), a 2-herb TCM formula composed of AR and SCF, is used to treat blood deficiency, fatigue, and metabolic abnormalities. We speculate that QWW may be more effective in treating NSCLC than AR or SCF alone. We identified 28 bioactive compounds in QWW and 322 targets of these compounds from databases. Network pharmacology analysis was used to identify 248 putative NSCLC-related gene targets of the bioactive compounds in QWW. Common target genes were analyzed to build protein–protein interaction networks. Implicated biological functions and pathways (p53, PI3K-Akt, etc) were identified by Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses. Molecular docking of core target proteins with the key active compounds was also performed. This study identified the potential gene targets and mechanisms involved in the anti-NSCLC effects of QWW. [ABSTRACT FROM AUTHOR]