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Positron emission tomography (PET) is widely used to detect cancers. The usual isotope for PET imaging of cancer is

A New Plasmacytoid Dendritic Cell-Based Vaccine in Combination with Anti-PD-1 Expands the Tumor-Specific CD8 T Cells of Lung Cancer Patients.

The purpose of immune checkpoint inhibitor (ICI)-based therapies is to help the patients immune system to combat tumors by restoring the immune response mediated by CD8 cytotoxic T cells. Despite impressive clinical responses, most patients do not respond to ICIs. Therapeutic vaccines with autologous professional antigen-presenting cells, including dendritic cells, do not show yet significant clinical benefit. To improve these approaches, we have developed a new therapeutic vaccine based on an allogeneic plasmacytoid dendritic cell line (PDCline), which efficiently activates the CD8 T-cell response in the context of melanoma. The goal of the study is to demonstrate the potential of this platform to activate circulating tumor-specific CD8 T cells in patients with lung cancer, specifically non-small-cell lung cancer (NSCLC). PDCline cells loaded with peptides derived from tumor antigens are used to stimulate the peripheral blood mononuclear cells of NSCLC patients. Very interestingly, we demonstrate an efficient activation of specific T cells for at least two tumor antigens in 69% of patients irrespective of tumor antigen mRNA overexpression and NSCLC subtype. We also show, for the first time, that the antitumor CD8 T-cell expansion is considerably improved by clinical-grade anti-PD-1 antibodies. Using PDCline cells as an antigen presentation platform, we show that circulating antitumor CD8 T cells from lung cancer patients can be activated, and we demonstrate the synergistic effect of anti-PD-1 on this expansion. These results are encouraging for the development of a PDCline-based vaccine in NSCLC patients, especially in combination with ICIs.

Oligorecurrent Non-Small-Cell Lung Cancer Treated by Chemo-Radiation Followed by Immunotherapy and Intracranial Radiosurgery A Case Report and Mini Review of Literature.

Locally advanced non-small-cell lung cancer still represents a grey zone in terms of the best treatment choice and optimal clinical outcomes. Indeed, most patients may be suitable to receive different treatments with similar outcomes such as chemo-radiotherapy (CHT-RT) followed by immunotherapy (IO) or surgery followed by adjuvant localsystemic therapies. We report a clinical case of a patient submitted to primary thoracic surgery who developed a mediastinal nodal recurrence successfully treated by CHT-RT-IO. Subsequently, a single brain lesion was found to have been successfully treated by single fraction stereotactic ablative radiotherapy. The patient is still on follow-up and she is free from disease having a good quality of life. In this report, we also perform a mini review about the role of CHT-RT followed by IO in treating loco-regional relapse after surgery. The role of SABR after IO is also evaluated, finding that it is safe and well tolerated. More robust and larger clinical data are needed in this particular setting to better define the role of the combination of systemic and local treatments in the management of intrathoracic and intracranial relapse for patients already submitted to CHT-RT followed by immunotherapy.

Detectable Lipidomes and Metabolomes by Different Plasma Exosome Isolation Methods in Healthy Controls and Patients with Advanced Prostate and Lung Cancer.

Circulating exosomes in the blood are promising tools for biomarker discovery in cancer. Due to their heterogeneity, different isolation methods may enrich distinct exosome cargos generating different omic profiles. In this study, we evaluated the effects of plasma exosome isolation methods on detectable multi-omic profiles in patients with non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and healthy controls, and developed an algorithm to quantify exosome enrichment. Plasma exosomes were isolated from CRPC (n 10), NSCLC (n 14), and healthy controls (n 10) using three different methods size exclusion chromatography (SEC), lectin binding, and T-cell immunoglobulin domain and mucin domain-containing protein 4 (TIM4) binding. Molecular profiles were determined by mass spectrometry of extracted exosome fractions. Enrichment analysis of uniquely detected molecules was performed for each method with MetaboAnalyst. The exosome enrichment index (EEI) scores methods based on top differential molecules between patient groups. The lipidomic analysis detected 949 lipids using exosomes from SEC, followed by 246 from lectin binding and 226 from TIM4 binding. The detectable metabolites showed SEC identifying 191 while lectin binding and TIM4 binding identified 100 and 107, respectively. When comparing uniquely detected molecules, different methods showed preferential enrichment of different sets of molecules with SEC enriching the greatest diversity. Compared to controls, SEC identified 28 lipids showing significant difference in NSCLC, while only 1 metabolite in NSCLC and 5 metabolites in CRPC were considered statistically significant (FDR < 0.1). Neither lectin-binding- nor TIM4-binding-derived exosome lipids or metabolites demonstrated significant differences between patient groups. We observed the highest EEI from SEC in lipids (NSCLC 871.33) which was also noted in metabolites. These results support that the size exclusion method of exosome extraction implemented by SBI captures more heterogeneous exosome populations. In contrast, lectin-binding and TIM4-binding methods bind surface glycans or phosphatidylserine moieties of the exosomes. Overall, these findings suggest that specific isolation methods select subpopulations which may significantly impact cancer biomarker discovery.

E-Cigarette Quit Attempts and Experiences in a Convenience Sample of Adult Users.

Most e-cigarette users report planning to quit, but there is a paucity of evidence-based interventions for e-cigarette cessation. In the absence of interventions for e-cigarette cessation, we sought to understand how and why e-cigarette users attempt to quit on their own. Participants were recruited from Amazon Mechanical Turk, an online crowdsourcing platform. Those who reported they had ever used e-cigarettes regularly and had attempted to quit e-cigarette use were eligible for participation. Measures included demographic characteristics, other tobacco product use, e-cigarette device characteristics, barriers to quitting e-cigarettes, and facilitators to quitting e-cigarettes. A content analysis was conducted on twotwo open-ended questions that asked about advice respondents had for others trying to quit vaping and resources they wished they had during their quit attempt. Descriptive analyses were performed (meansstandard errors frequenciesproportions). A total of 89.0% reported using an e-cigarette with nicotine, 20.2% reported a nicotine concentration of 4-6 mgmL%, 32.8% reported using multiple flavors, and 77.7% reported using their e-cigarette every day or some days. The primary reason reported for wanting to quit e-cigarettes was health concerns (42.2%), and 56.7% reported trying to quit cold turkey. During quit attempts, 41.0% reported intense cravings and 53.1% reported stress as a trigger. From the content analysis, the most commonly cited suggestion for those wanting to quit e-cigarettes was distractionshobbies (19.9%), followed by reducingtapering down nicotine (16.9%). Descriptive information on demographics, e-cigarette use, device characteristics, barriers, facilitators, and quit methods provides a first step in identifying factors that contribute to successful interventions designed for e-cigarette cessation.

Radon Solubility in Different Tissues after Short Term Exposure.

Radon, a naturally occurring radioactive noble gas, contributes significantly to lung cancer when incorporated from our natural environment. However, despite having unknown underlying mechanisms, radon is also used for therapeutic purposes to treat inflammatory diseases such as rheumatoid arthritis. Data on the distribution and accumulation of radon in different tissues represent an important factor in dose determination for risk estimation, the explanation of potential therapeutic effects and the calculation of doses to different tissues using biokinetic dosimetry models. In this paper, radons solubility in bones, muscle tissue, adipose tissue, bone marrow, blood, a dissolved gelatin and oleic acid were determined. In analogy to current radon use in therapies, samples were exposed to radon gas for 1 h using two exposure protocols combined with established γ-spectroscopic measurements. Solubility data varied over two orders of magnitude, with the lowest values from the dissolved gelatin and muscle tissue radons solubility in flat bones, blood and adipose tissue was one order of magnitude higher. The highest values for radon solubility were measured in bone marrow and oleic acid. The data for long bones as well as bone marrow varied significantly. The radon solubility in the blood suggested a radon distribution within the body that occurred via blood flow, reaching organs and tissues that were not in direct contact with radon gas during therapy. Tissues with similar compositions were expected to reveal similar radon solubilities however, yellow bone marrow and adipose tissue showed differences in solubility even though their chemical composition is nearly the same-indicating that interactions on the microscopic scale between radon and the solvent might be important. We found high solubility in bone marrow-where sensitive hematopoietic cells are located-and in adipose tissue, where the biological impact needs to be further elucidated.

Quality of Life and Side Effects Management in Cancer Treatment-A Cross Sectional Study.

Cancer disease is a world problem which is increasing in its prevalence. Oncology patients have a multitude of symptoms derived from the treatments and from the disease itself that affect their quality of life to a greater or lesser extent. The aim of this study has been to discover the physical and psychological symptoms related to chemotherapy treatment in Spanish cancer patients in order to improve their quality of life. Symptoms from the previous week were taken into account and the Memorial Symptom Assessment Scale was used to measure the frequency, severity and associated distress of 32 symptoms. A total of 246 chemotherapy patients at the University Day Hospital in Salamanca completed the scale once while receiving chemotherapy treatment. A 95% confidence interval was considered. The most prevalent symptoms were a lack of energy (76.4%), anxiety (66.7%) and a dry mouth (60.6%). Lung cancer was the most prevalent cancer in men (26%) and breast cancer was the most prevalent cancer in women (72%). There is no consensus on which is the most prevalent symptom in this population and more studies will need to be carried out to determine the best treatment protocols. Symptoms prevalence knowledge could improve the patients care to prevent or avoid complications and to improve the cancer patients quality of life.

Development of Clinical Prediction Score for Chemotherapy Response in Advanced Non-Small Cell Lung Cancer Patients.

The outcomes of advanced non-small cell lung cancer (NSCLC) patients have been significantly improved with novel therapies, such as tyrosine kinase inhibitors and immune checkpoint inhibitors. However, in resource-limited countries, platinum-doublet chemotherapy is mainly used as a first-line treatment. We investigate clinical parameters to predict the response after chemotherapy, which may be useful for patient selection. A clinical prediction score (CPS) was developed, based on data from a retrospective cohort study of unresectable stage IIIB or IV NSCLC patients who were treated with platinum-doublet chemotherapy in the first-line setting with at least two cycles and an evaluated response by RECIST 1.1 at Surin Hospital Cancer Center, Thailand, between July 2014 and December 2018. The clinical parameters in the prediction model were derived by risk regression analysis. There were 117 responders (CR or PR) and 90 non-responders (SD or PD). The clinical prediction score was developed by six clinical parameters including gender, age, smoking status, ECOG, pre-treatment albumin, and histologic subtype. The AuROC of the model was 0.71 (95% CI 0.63-0.78). The internal validation was performed using a bootstrap technique and showed a consistent AuROC of 0.66 (95% CI 0.59-0.72). The prediction score ranged from 0-13, with a score of 0-8 meaning a low probability (PPV 50%) and a score of 8.5-13 meaning a high probability (PPV 83.7%) for chemotherapy response. Advanced NSCLC patients who cannot access novel therapies and have a CPS of 8.5-13 have a high probability for chemotherapy response in the first-line setting. This CPS could be used for risk communication and making decisions with patients, especially in regard to chemotherapy.

Does the Expression of Vascular Endothelial Growth Factor (VEGF) and Bcl-2 Have a Prognostic Significance in Advanced Non-Small Cell Lung Cancer

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 (

Endothelial Specific Deletion of Autotaxin Improves Stroke Outcomes.

Autotaxin (ATX) is an extracellular secretory enzyme (lysophospholipase D) that catalyzes the hydrolysis of lysophosphatidyl choline to lysophosphatidic acid (LPA). The ATX-LPA axis is a well-known pathological mediator of liver fibrosis, metastasis in cancer, pulmonary fibrosis, atherosclerosis, and neurodegenerative diseases. Additionally, it is believed that LPA may cause vascular permeability. In ischemic stroke, vascular permeability leading to hemorrhagic transformation is a major limitation for therapies and an obstacle to stroke management. Therefore, in this study, we generated an endothelial-specific ATX deletion in mice (ERT2 ATX

The Prognostic Long-Term Impact of Chronic Obstructive Pulmonary Disease and Postoperative Mucostasis in Patients with Curatively Resected Non-Small Cell Lung Cancer.

Chronic obstructive pulmonary disease (COPD) serves as risk factor for the development of lung cancer and seems to have a prognostic impact after surgery for non-small cell lung cancer (NSCLC). The aim was to investigate the impact of COPD and postoperative mucostasis on the long-term survival after resected NSCLC. We retrospectively reviewed the data from 342 patients with curatively resected NSCLC. The prognostic long-term impact of COPD and postoperative mucostasis on overall survival (OS), recurrence free survival (RFS) and cancer specific survival (CSS) was calculated using univariable and multivariable Cox regression analyses. We found that 52.3% suffered from COPD and 25.4% had postoperative mucostasis. COPD was significantly more common among smokers (59.9%) compared with non-smokers (21.3%), (

The Role of Aquaporin 5 (AQP5) in Lung Adenocarcinoma A Review Article.

Aquaporins (AQPs) are selective, transmembrane proteins, which are primarily responsible for the transport of water and small molecules. They have been demonstrated to play a key role in the development and progression of cancer. Lung adenocarcinoma is the most common primary lung cancer diagnosed in patients in Europe and the USA. The research done so far has provided firm evidence that some AQPs can be biomarkers for various diseases. The objective of this review article is to present a potential role of AQP5 in the development of lung adenocarcinoma. Original papers discussing the involvement of AQP5 in carcinogenesis and containing relevant clinical data were identified. In order to analyze the research material in accordance with PRISMA guidelines, a systematic search of the ScienceDirect, Web of Science, and Pubmed databases was conducted. Out of the total number of 199 papers identified, 14 original articles were subject to analysis. This article presents the pathophysiological role of AQP5 in the biology of lung adenocarcinoma as well as its prognostic value. The analysis substantiates the conclusion that the prognostic value of AQP5 in lung cancer requires further research. Another aim of this paper is to disseminate knowledge about AQPs among clinicians.

Voltage-Gated T-Type Calcium Channel Modulation by Kinases and Phosphatases The Old Ones, the New Ones, and the Missing Ones.

Calcium (Ca

Role of Annexin A1 Secreted by Neutrophils in Melanoma Metastasis.

Annexin A1 (AnxA1) is highly secreted by neutrophils and binds to formyl peptide receptors (FPRs) to trigger anti-inflammatory effects and efferocytosis. AnxA1 is also expressed in the tumor microenvironment, being mainly attributed to cancer cells. As recruited neutrophils are player cells at the tumor sites, the role of neutrophil-derived AnxA1 in lung melanoma metastasis was investigated here. Melanoma cells and neutrophils expressing AnxA1 were detected in biopsies from primary melanoma patients, which also presented higher levels of serum AnxA1 and augmented neutrophil-lymphocyte ratio (NLR) in the blood. Lung melanoma metastatic mice (C57BL6 i.v. injected B16F10 cells) showed neutrophilia, elevated AnxA1 serum levels, and higher labeling for AnxA1 in neutrophils than in tumor cells at the lungs with metastasis. Peritoneal neutrophils collected from naïve mice were co-cultured with B16F10 cells or employed to obtain neutrophil-conditioned medium (NCM 18 h incubation). B16F10 cells co-cultured with neutrophils or with NCM presented higher invasion, which was abolished if B16F10 cells were previously incubated with FPR antagonists or co-cultured with AnxA1 knockout (AnxA1

Phosphorylation of IGFBP-3 by Casein Kinase 2 Blocks Its Interaction with Hyaluronan, Enabling HA-CD44 Signaling Leading to Increased NSCLC Cell Survival and Cisplatin Resistance.

Cisplatin is a platinum agent used in the treatment of non-small cell lung cancer (NSCLC). Much remains unknown regarding the basic operative mechanisms underlying cisplatin resistance in NSCLC. In this study, we found that phosphorylation of IGFBP-3 by CK2 (P-IGFBP-3) decreased its binding to hyaluronan (HA) but not to IGF-1 and rendered the protein less effective at reducing cell viability or increasing apoptosis than the non-phosphorylated protein with or without cisplatin in the human NSCLC cell lines, A549 and H1299. Our data suggest that blocking CD44 signaling augmented the effects of cisplatin and that IGFBP-3 was more effective at inhibiting HA-CD44 signaling than P-IGFBP-3. Blocking CK2 activity and HA-CD44 signaling increased cisplatin sensitivity and more effectively blocked the PI3K and AKT activities and the phosphototal NFκB ratio and led to increased p53 activation in A549 cells. Increased cell sensitivity to cisplatin was observed upon co-treatment with inhibitors targeted against PI3K, AKT, and NFκB while blocking p53 activity decreased A549 cell sensitivity to cisplatin. Our findings shed light on a novel mechanism employed by CK2 in phosphorylating IGFBP-3 and increasing cisplatin resistance in NSCLC. Blocking phosphorylation of IGFBP-3 by CK2 may be an effective strategy to increase NSCLC sensitivity to cisplatin.

A Medical Image Segmentation Method Based on Improved UNet 3 Network.

In recent years, segmentation details and computing efficiency have become more important in medical image segmentation for clinical applications. In deep learning, UNet based on a convolutional neural network is one of the most commonly used models. UNet 3 was designed as a modified UNet by adopting the architecture of full-scale skip connections. However, full-scale feature fusion can result in excessively redundant computations. This study aimed to reduce the network parameters of UNet 3 while further improving the feature extraction capability. First, to eliminate redundancy and improve computational efficiency, we prune the full-scale skip connections of UNet 3. In addition, we use the attention module called Convolutional Block Attention Module (CBAM) to capture more essential features and thus improve the feature expression capabilities. The performance of the proposed model was validated by three different types of datasets skin cancer segmentation, breast cancer segmentation, and lung segmentation. The parameters are reduced by about 36% and 18% compared to UNet and UNet 3, respectively. The results show that the proposed method not only outperformed the comparison models in a variety of evaluation metrics but also achieved more accurate segmentation results. The proposed models have lower network parameters that enhance feature extraction and improve segmentation performance efficiently. Furthermore, the models have great potential for application in medical imaging computer-aided diagnosis.

Tumor Lung Visualization and Localization through Virtual Reality and Thermal Feedback Interface.

The World Health Organization estimates that there were around 10 million deaths due to cancer in 2020, and lung cancer was the most common type of cancer, with over 2.2 million new cases and 1.8 million deaths. While there have been advances in the diagnosis and prediction of lung cancer, there is still a need for new, intelligent methods or diagnostic tools to help medical professionals detect the disease. Since it is currently unable to detect at an early stage, speedy detection and identification are crucial because they can increase a patients chances of survival. This article focuses on developing a new tool for diagnosing lung tumors and providing thermal touch feedback using virtual reality visualization and thermal technology. This tool is intended to help identify and locate tumors and measure the size and temperature of the tumor surface. The tool uses data from CT scans to create a virtual reality visualization of the lung tissue and includes a thermal display incorporated into a haptic device. The tool is also tested by touching virtual tumors in a virtual reality application. On the other hand, thermal feedback could be used as a sensory substitute or adjunct for visual or tactile feedback. The experimental results are evaluated with the performance comparison of different algorithms and demonstrate that the proposed thermal model is effective. The results also show that the tool can estimate the characteristics of tumors accurately and that it has the potential to be used in a virtual reality application to touch virtual tumors. In other words, the results support the use of the tool for diagnosing lung tumors and providing thermal touch feedback using virtual reality visualization, force, and thermal technology.

Medical Images Segmentation for Lung Cancer Diagnosis Based on Deep Learning Architectures.

Lung cancer presents one of the leading causes of mortalities for people around the world. Lung image analysis and segmentation are one of the primary steps used for early diagnosis of cancer. Handcrafted medical imaging segmentation presents a very time-consuming task for radiation oncologists. To address this problem, we propose in this work to develop a full and entire system used for early diagnosis of lung cancer in CT scan imaging. The proposed lung cancer diagnosis system is composed of two main parts the first part is used for segmentation developed on top of the UNETR network, and the second part is a classification part used to classify the output segmentation part, either benign or malignant, developed on top of the self-supervised network. The proposed system presents a powerful tool for early diagnosing and combatting lung cancer using 3D-input CT scan data. Extensive experiments have been performed to contribute to better segmentation and classification results. Training and testing experiments have been performed using the Decathlon dataset. Experimental results have been conducted to new state-of-the-art performances segmentation accuracy of 97.83%, and 98.77% as classification accuracy. The proposed system presents a new powerful tool to use for early diagnosing and combatting lung cancer using 3D-input CT scan data.

Preoperative Hilar and Mediastinal Lymph Node Staging in Patients with Suspected or Diagnosed Lung Cancer Accuracy of 18F-FDG-PETCTA Retrospective Cohort Study of 138 Patients.

The aim of this study was to evaluate the diagnostic accuracy of integrated 18F-fluorodeoxyglucose positron emission computed tomography (18F-FDG-PETCT) in hilar and mediastinal lymph node (HMLN) staging of suspected or proven lung cancer, and to investigate potential risk factors for false negative and false positive HMLN metastases. We retrospectively analyzed 162 consecutive patients with suspected or pathologically proven non-small cell lung cancer (NSCLC). The receiver operating characteristic (ROC) curve was generated to determine the diagnostic efficacy of 18F-FDG-PETCT. Univariate and multivariate analyses were conducted to detect risk factors of false positives and false negatives. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of integrated 18F-FDG-PETCT in detecting HMLN metastases were 59.1% (2644), 69.1% (6594), 47.3% (2655), 78.3% (6583), and 65.9% (91138), respectively. The ROC curve showed an area under the curve (AUC) of 0.625 (95%-CI 0.468-0.782). The incidence of false negative and false positive HMLN metastases was 21.7% (1883) and 52.7% (2955), respectively. Our data shows that integrated 18F-FDG-PETCT staging provides lower specificity and sensitivity. This confirms the ESTS guideline on lymph node staging for PET-positive HMLN. Yet it advocates more invasive staging even for PET-negative HMLN.

Role of Cardiac Biomarkers in Non-Small Cell Lung Cancer Patients.

Treatment-induced cardiac toxicity represents an important issue in non-small cell lung cancer (NSCLC) patients, and no biomarkers are currently available in clinical practice. A novel and easy-to-calculate marker is the quantitative analysis of calcium plaque in the coronary, calculated on CT. It is called the Agatston score (or CAD score). At the same time, other potential predictors include cardiac ultrasonography and anamnesis of the patients. Our work aimed to correlate cardiac biomarkers with overall survival (OS) in NSCLC patients. We retrospectively analyzed patients with NSCLC discussed in the Multidisciplinary Tumor Board of our Institute for the present analysis between January 2018 and July 2022. Inclusion criteria were the availability of basal CT imaging of the thorax, cardiac ultrasonography with the calculation of ejection fraction (EF), and complete anamnesis, including assessment of co-pathologies and pharmacological drugs. The clinical data of the patients were retrospectively collected, and the CAD scores was calculated on a CT scan. All of these parameters were correlated with overall survival (OS) with univariate analysis (Kaplan-Meier analysis) and multivariate analysis (Cox regression analysis). Following the above-mentioned inclusion criteria, 173 patients were included in the present analysis. Of those, 120 patients died in the follow-up period (69.6%), and the median overall survival (OS) was 28 months (mean 47.2 months, 95% CI, 36-57 months). In univariate analysis, several parameters that significantly correlated with lower OS were the stage (

Clinicopathological Features and Significance of Epidermal Growth Factor Receptor Mutation in Surgically Resected Early-Stage Lung Adenocarcinoma.

The clinicopathological presentation of early-stage lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutations has been seldom studied. Our study enrolled patients with stage I and II lung adenocarcinoma between January 2014 and December 2017 at the National Taiwan University Hospital. Clinicopathological features and prognosis were retrospectively reviewed and analyzed depending on EGFR mutation status. EGFR mutations were detected in 622 (60%) out of 1034 patients. Compared to the group without EGFR mutations, the group with EGFR mutations had more patients above 65 years of age (

Radiomics and Artificial Intelligence Can Predict Malignancy of Solitary Pulmonary Nodules in the Elderly.

Solitary pulmonary nodules (SPNs) are a diagnostic and therapeutic challenge for thoracic surgeons. Although such lesions are usually benign, the risk of malignancy remains significant, particularly in elderly patients, who represent a large segment of the affected population. Surgical treatment in this subset, which usually presents several comorbidities, requires careful evaluation, especially when pre-operative biopsy is not feasible and comorbidities may jeopardize the outcome. Radiomics and artificial intelligence (AI) are progressively being applied in predicting malignancy in suspicious nodules and assisting the decision-making process. In this study, we analyzed features of the radiomic images of 71 patients with SPN aged more than 75 years (median 79, IQR 76-81) who had undergone upfront pulmonary resection based on CT and PET-CT findings. Three different machine learning algorithms were applied-functional tree, Rep Tree and J48. Histology was malignant in 64.8% of nodules and the best predictive value was achieved by the J48 model (AUC 0.9). The use of AI analysis of radiomic features may be applied to the decision-making process in elderly frail patients with suspicious SPNs to minimize the false positive rate and reduce the incidence of unnecessary surgery.

Antigene

Small-cell lung cancer (SCLC) is the most aggressive lung cancer type, and is associated with smoking, low survival rate due to high vascularization, metastasis and drug resistance. Alterations in

Enhancer Clusters Drive Type I Interferon-Induced TRAIL Overexpression in Cancer, and Its Intracellular Protein Accumulation Fails to Induce Apoptosis.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine produced and secreted by immune cells in response to an infection, often in response to interferon (IFN) stimulation. In cancer, it has also been shown that IFN stimulates the production of TRAIL, and it has been proposed that this TRAIL can induce apoptosis in an autocrine or paracrine manner in different cancer cells. Yet, the mechanism mediating TRAIL upregulation and the implications of TRAIL as an apoptotic molecule in cancer cells are still poorly understood. We show here that in certain cancer cells, TRAIL is upregulated by enhancer clusters, potent genomic regulatory regions containing densely packed enhancers that have combinatorial and additive activity and that are usually found to be associated with cancer-promoting genes. Moreover, we found that TRAIL upregulation by IFNα is mediated by these enhancer clusters in breast and lung cancer cells. Surprisingly, IFNα stimulation leads to the intracellular accumulation of TRAIL protein in these cancer cells. Consequently, this TRAIL is not capable of inducing apoptosis. Our study provides novel insights into the mechanism behind the interferon-mediated upregulation of TRAIL and its protein accumulation in cancer cells. Further investigation is required to understand the role of intracellular TRAIL or depict the mechanisms mediating its apoptosis impairment in cancer cells.

State of the Art MR Imaging for Lung Cancer TNM Stage Evaluation.

Since the Radiology Diagnostic Oncology Group (RDOG) report had been published in 1991, magnetic resonance (MR) imaging had limited clinical availability for thoracic malignancy, as well as pulmonary diseases. However, technical advancements in MR systems, such as sequence and reconstruction methods, and adjustments in the clinical protocol for gadolinium contrast media administration have provided fruitful results and validated the utility of MR imaging (MRI) for lung cancer evaluations. These techniques include (1) contrast-enhanced MR angiography for T-factor evaluation, (2) short-time inversion recovery turbo spin-echo sequences as well as diffusion-weighted imaging (DWI) for N-factor assessment, and (3) whole-body MRI with and without DWI and with positron emission tomography fused with MRI for M-factor or TNM stage evaluation as well as for postoperative recurrence assessment of lung cancer or other thoracic tumors using 1.5 tesla (T) or 3T systems. According to these fruitful results, the Fleischner Society has changed its position to approve of MRI for lung or thoracic diseases. The purpose of this review is to analyze recent advances in lung MRI with a particular focus on lung cancer evaluation, clinical staging, and recurrence assessment evaluation.

Labyrinthin Expression Is Associated with Poor Prognosis in Patients with Non-Small-Cell Lung Cancer.

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 208256 (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

Identifying Solitary Granulomatous Nodules from Solid Lung Adenocarcinoma Exploring Robust Image Features with Cross-Domain Transfer Learning.

This study aimed to find suitable source domain data in cross-domain transfer learning to extract robust image features. Then, a model was built to preoperatively distinguish lung granulomatous nodules (LGNs) from lung adenocarcinoma (LAC) in solitary pulmonary solid nodules (SPSNs). Data from 841 patients with SPSNs from five centres were collected retrospectively. First, adaptive cross-domain transfer learning was used to construct transfer learning signatures (TLS) under different source domain data and conduct a comparative analysis. The Wasserstein distance was used to assess the similarity between the source domain and target domain data in cross-domain transfer learning. Second, a cross-domain transfer learning radiomics model (TLRM) combining the best performing TLS, clinical factors and subjective CT findings was constructed. Finally, the performance of the model was validated through multicentre validation cohorts. Relative to other source domain data, TLS based on lung whole slide images as source domain data (TLS-LW) had the best performance in all validation cohorts (AUC range 0.8228-0.8984). Meanwhile, the Wasserstein distance of TLS-LW was 1.7108, which was minimal. Finally, TLS-LW, age, spiculated sign and lobulated shape were used to build the TLRM. In all validation cohorts, The AUC ranges were 0.9074-0.9442. Compared with other models, decision curve analysis and integrated discrimination improvement showed that TLRM had better performance. The TLRM could assist physicians in preoperatively differentiating LGN from LAC in SPSNs. Furthermore, compared with other images, cross-domain transfer learning can extract robust image features when using lung whole slide images as source domain data and has a better effect.

Comparison of Recurrence Patterns between Adenocarcinoma and Squamous Cell Carcinoma after Stereotactic Body Radiotherapy for Early-Stage Lung Cancer.

We compared recurrence patterns between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) after stereotactic body radiotherapy (SBRT) for early-stage lung cancer. Patients with ADC and SCC histology, who were treated with SBRT for clinical stage IA1-IIA lung cancer at our institution, were included in the analysis. The rates of disease-free survival (DFS), overall survival (OS), local recurrence (LR), lymph node metastasis (LNM), and distant metastasis (DM) were calculated using the Kaplan-Meier method or the cumulative incidence function. Among the 204 patients analyzed, 138 and 66 were in the ADC and SCC groups, respectively. The median follow-up period was 60 months. The five-year DFS and OS rates were 57% vs. 41% and 69% vs. 48% in the ADC and SCC groups, respectively (

Sodium Fluorescein-Guided Surgery for Resection of Brain Metastases from Lung Cancer A Consecutive Case Series Study and Literature Review.

(1) Introduction and objective Surgical resection plays an important role in the multidisciplinary treatment of lung cancer patients with brain metastases (BMs). Precisely distinguishing the tumor border intraoperatively to improve and maximize the extent of resection (EOR) without causing permanent neurological defects is crucial but still challenging. Therefore, we introduced our experience of utilizing sodium fluorescein (SF) in microneurosurgery of BMs from lung cancer. This study aims to evaluate whether the use of SF-guided surgery has a positive impact on postoperative outcomes. (2) Materials and methods A retrospective study was performed to collect data on a consecutive case series of patients with BMs from lung cancer who underwent surgical resection from January 2020 to December 2021 at the Department of Neuro-Oncology, Chongqing University Cancer Hospital. A total of 52 patients were enrolled, of which 23 received SF-guided surgery and 29 did not. EOR was assessed pre- and postoperatively on T1 contrast-enhanced MRI. Clinical and epidemiological data as well as follow-up were gathered and analyzed. (3) Results Compared with the non-SF-guided group, the SF-guided group revealed a significantly better EOR (87.0% vs. 62.1%) and a lower incidence of local recurrence (8.7% vs. 34.5%). Survival benefits were seen in patients with NSCLC, patients who were undergoing SF-guided surgery, and patients receiving postoperative systemic therapy. (4) Conclusions SF-guiding under the YELLOW 560 nm filter is a safe and feasible tool for improving the EOR in patients with BMs from lung cancer, leading to better local recurrence control and prolonged survival.

ITA-IMMUNO-PET The Role of 18FFDG PETCT for Assessing Response to Immunotherapy in Patients with Some Solid Tumors.

To examine the role of 18FFDG PETCT for assessing response to immunotherapy in patients with some solid tumors. Data recorded in a multicenter ( The study concerned 311 patients (median age 67 range 31-89 years) in all. The most common neoplasm was lung cancer (56.9%), followed by malignant melanoma (32.5%). Nivolumab was administered in 46.3%, and pembrolizumab in 40.5% of patients. Baseline PET and a first PET scan performed at a median 3 months after starting immunotherapy were available for all 311 patients, while subsequent PET scans were obtained after a median 6, 12, 16, and 21 months for 199 (64%), 102 (33%), 46 (15%), and 23 (7%) patients, respectively. Clinical response to therapy was recorded at around the same time points after starting immunotherapy for 252 (81%), 173 (56%), 85 (27%), 40 (13%), and 22 (7%) patients, respectively. After a median 18 (1-137) months, 113 (36.3%) patients had died. On Kaplan-Meier analysis, metabolic responders on the first two serial PET scans showed a better prognosis than non-responders, while clinical response became prognostically informative from the second assessment after starting immunotherapy onwards. 18FFDG PETCT could have a role in the assessment of response to immunotherapy in patients with some solid tumors. It can provide prognostic information and thus contribute to a patients appropriate treatment. Prospective randomized controlled trials are mandatory.

P38 Mediates Tumor Suppression through Reduced Autophagy and Actin Cytoskeleton Changes in NRAS-Mutant Melanoma.

Hotspot mutations in the NRAS gene are causative genetic events associated with the development of melanoma. Currently, there are no FDA-approved drugs directly targeting NRAS mutations. Previously, we showed that p38 acts as a tumor suppressor in vitro and in vivo with respect to NRAS-mutant melanoma. We observed that because of p38 activation through treatment with the protein synthesis inhibitor, anisomycin leads to a transient upregulation of several targets of the cAMP pathway, representing a stressed cancer cell state that is often observed by therapeutic doses of MAPK inhibitors in melanoma patients. Meanwhile, genetically induced p38 or its stable transduction leads to a distinct cellular transcriptional state. Contrary to previous work showing an association of invasiveness with high p38 levels in BRAF-mutated melanoma, there was no correlation of p38 expression with NRAS-mutant melanoma invasion, highlighting the difference in BRAF and NRAS-driven melanomas. Although the role of p38 has been reported to be that of both tumor suppressor and oncogene, we show here that p38 specifically plays the role of a tumor suppressor in NRAS-mutant melanoma. Both the transient and stable activation of p38 elicits phosphorylation of mTOR, reported to be a master switch in regulating autophagy. Indeed, we observed a correlation between elevated levels of phosphorylated mTOR and a reduction in LC3 conversion (LCIILCI), indicative of suppressed autophagy. Furthermore, a reduction in actin intensity in p38-high cells strongly suggests a role of mTOR in regulating actin and a remodeling in the NRAS-mutant melanoma cells. Therefore, p38 plays a tumor suppressive role in NRAS-mutant melanomas at least partially through the mechanism of mTOR upregulation, suppressed autophagy, and reduced actin polymerization. One or more combinations of MEK inhibitors with either anisomycin, rapamycin, chloroquinebafilomycin, and cytochalasin modulate p38 activation, mTOR phosphorylation, autophagy, and actin polymerization, respectively, and they may provide an alternate route to targeting NRAS-mutant melanoma.

Advances in the Management of Central Nervous System Metastases in Non-Small Cell Lung Cancer.

Central nervous system (CNS) metastases are common among patients with non-small cell lung cancer (NSCLC). While the presence of brain metastases has historically portended poor prognosis, recent advances in local and systemic therapies have greatly improved outcomes for NSCLC patients with CNS involvement. Stereotactic radiology surgery (SRS) has emerged as an effective radiotherapy technique with fewer toxicities compared to whole brain radiotherapy (WBRT). Furthermore, multi-generation tyrosine kinase inhibitors (TKIs) with CNS overall response rates (ORR) of up to 70-80% are now an accepted first-line approach for a subset of advanced NSCLC patients with targetable molecular alterations. In addition, while the CNS was once considered an immunologic sanctuary site, growing evidence shows that immune checkpoint inhibitors (ICIs) can induce durable responses in brain metastases as well. Ongoing efforts to optimize CNS metastases management are necessary to refine multimodal treatment approaches and develop new therapeutics with better CNS penetrance.

Osimertinib Resistance Molecular Mechanisms and Emerging Treatment Options.

The development of tyrosine kinase inhibitors (TKIs) targeting the mutant epidermal growth factor receptor (EGFR) protein initiated the success story of targeted therapies in non-small-cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR-TKI, is currently indicated as first-line therapy in patients with NSCLC with sensitizing EGFR mutations, as second-line therapy in patients who present the resistance-associated mutation T790M after treatment with previous EGFR-TKIs, and as adjuvant therapy for patients with early stage resected NSCLC, harboring EGFR mutations. Despite durable responses in patients with advanced NSCLC, resistance to osimertinib, similar to other targeted therapies, inevitably develops. Understanding the mechanisms of resistance, including both EGFR-dependent and -independent molecular pathways, as well as their therapeutic potential, represents an unmet need in thoracic oncology. Interestingly, differential resistance mechanisms develop when osimertinib is administered in a first-line versus second-line setting, indicating the importance of selection pressure and clonal evolution of tumor cells. Standard therapeutic approaches after progression to osimertinib include other targeted therapies, when a targetable genetic alteration is detected, and cytotoxic chemotherapy with or without antiangiogenic and immunotherapeutic agents. Deciphering the when and how to use immunotherapeutic agents in EGFR-positive NSCLC is a current challenge in clinical lung cancer research. Emerging treatment options after progression to osimertinib involve combinations of different therapeutic approaches and novel EGFR-TKI inhibitors. Research should also be focused on the standardization of liquid biopsies in order to facilitate the monitoring of molecular alterations after progression to osimertinib.

Kynureninase Upregulation Is a Prominent Feature of NFR2-Activated Cancers and Is Associated with Tumor Immunosuppression and Poor Prognosis.

The nuclear factor erythroid 2-related factor 2 (NRF2) pathway is frequently activated in various cancer types. Aberrant activation of NRF2 in cancer is attributed to gain-of-function mutations in the NRF2-encoding gene

CT-Derived Sarcopenia and Outcomes after Thoracoscopic Pulmonary Resection for Non-Small Cell Lung Cancer.

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 PETCT 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%

Development of

N-cadherin is considered a characteristic protein of EMT and has been found to be closely related to tumor resistance. In this study, a novel molecular imaging probe, ADH-1 was labeled indirectly with The

Advances in the Molecular Landscape of Lung Cancer Brain Metastasis.

Lung cancer is one of the most frequent tumors that metastasize to the brain. Brain metastasis (BM) is common in advanced cases, being the major cause of patient morbidity and mortality. BMs are thought to arise via the seeding of circulating tumor cells into the brain microvasculature. In brain tissue, the interaction with immune cells promotes a microenvironment favorable to the growth of cancer cells. Despite multimodal treatments and advances in systemic therapies, lung cancer patients still have poor prognoses. Therefore, there is an urgent need to identify the molecular drivers of BM and clinically applicable biomarkers in order to improve disease outcomes and patient survival. The goal of this review is to summarize the current state of knowledge on the mechanisms of the metastatic spread of lung cancer to the brain and how the metastatic spread is influenced by the brain microenvironment, and to elucidate the molecular determinants of brain metastasis regarding the role of genomic and transcriptomic changes, including coding and non-coding RNAs. We also present an overview of the current therapeutics and novel treatment strategies for patients diagnosed with BM from NSCLC.

MMP-9 as Prognostic Marker for Brain Tumours A Comparative Study on Serum-Derived Small Extracellular Vesicles.

Matrix metalloproteinase-9 (MMP-9) degrades the extracellular matrix, contributes to tumour cell invasion and metastasis, and its elevated level in brain tumour tissues indicates poor prognosis. High-risk tissue biopsy can be replaced by liquid biopsy however, the blood-brain barrier (BBB) prevents tumour-associated components from entering the peripheral blood, making the development of blood-based biomarkers challenging. Therefore, we examined the MMP-9 content of small extracellular vesicles (sEVs)-which can cross the BBB and are stable in body fluids-to characterise tumours with different invasion capacity. From four patient groups (glioblastoma multiforme, brain metastases of lung cancer, meningioma, and lumbar disc herniation as controls), 222 serum-derived sEV samples were evaluated. After isolating and characterising sEVs, their MMP-9 content was measured by ELISA and assessed statistically (correlation, paired

Duration of Immunotherapy in Non-Small Cell Lung Cancer Survivors A Lifelong Commitment

Lung cancer is one of the most common human malignancies and the leading cause of cancer-related death worldwide. Novel therapeutic approaches, like targeted therapies against specific molecular alterations and immunotherapy, have revolutionized in the last decade the oncological outcomes in patients affected by non-small cell lung cancer (NSCLC). The advent of immunotherapy for the treatment of NSCLC has significantly improved overall and progression-free survival, as well as the patients quality of life in comparison to traditional chemotherapy. Currently, it is estimated that long-term survival can be achieved in more than 15% of NSCLC patients treated with immunotherapy. Therefore, the optimal duration of immunotherapy in long survivors needs to be established to avoid overtreatment, side effects, and high costs and at the same time, protect them from potential disease relapse or progression. We performed a narrative review to discuss all the aspects related to the optimal duration of immunotherapy in long survivors with NSCLC. Data regarding the duration of immunotherapy in the most impacting clinical trials were collected, along with data regarding the impact of toxicities, side effects, and costs for healthcare providers. In addition, the two-year immunotherapy scheme in patients who benefit from first-line or subsequent treatment lines are examined, and the need for biomarkers that can predict outcomes during and after immunotherapy cessation in patients affected by NSCLC are discussed.

EGFR Pathway Expression Persists in Recurrent Glioblastoma Independent of Amplification Status.

Glioblastoma mortality is driven by tumour progression or recurrence despite administering a therapeutic arsenal consisting of surgical resection, radiation, and alkylating chemotherapy. The genetic changes underlying tumour progression and chemotherapy resistance are poorly understood. In this study, we sought to define the relationship between EGFR amplification status, EGFR mRNA expression, and EGFR pathway activity. We compared RNA-sequencing data from matched primary and recurrent tumour samples ( In the setting of glioblastoma recurrence, the EGFR pathway was overexpressed regardless of EGFR-amplification status, suggesting a common genomic endpoint in recurrent glioblastoma, although EGFR amplification did associate with higher EGFR mRNA expression. Three of forty patients in the study cohort had EGFR-amplified tumours and received targeted EGFR therapy. Their molecular subtypes and clinical outcomes did not significantly differ from patients who received conventional chemotherapy. Our findings suggest that while the EGFR amplification may confer a unique molecular profile in primary glioblastoma, pathway analysis reveals upregulation of the EGFR pathway in recurrence, regardless of amplification status. As such, the EGFR pathway may be a key mediator of glioblastoma progression.

Accuracy of p16 IHC in Classifying HPV-Driven OPSCC in Different Populations.

High-risk human papillomavirus (HPV) infection is a defined etiopathogenetic factor in oropharyngeal carcinogenesis with a clear prognostic value. The P16 IHC (immunohistochemistry) is a widely accepted marker for HPV-driven carcinogenesis in oropharyngeal squamous cell carcinoma (OPSCC) in the present paper, we discuss its reliability as a standalone marker in different populations. The literature suggests that rates of p16 IHC false positive results are inversely correlated with the prevalence of HPV-driven carcinogenesis in a population. We propose a formula that can calculate such a false positive rate while knowing the real prevalence of HPV-driven OPSCCs in a given population. As it has been demonstrated that p16 positiveHPV negative cases (i.e., false positives at p16 IHC) have the same prognosis as p16 negative OPSCC, we conclude that despite the valuable prognostic value of p16 IHC, relying only on a p16 IHC positive result to recommend treatment de-intensification could be risky. For this aim, confirmation with an HPV nucleic acid detection system, especially in areas with a low prevalence of HPV-related OPSCCs, should be pursued.

COVID and Cancer A Complete 3D Advanced Radiological CT-Based Analysis to Predict the Outcome.

Cancer patients infected with COVID-19 were shown in a multitude of studies to have poor outcomes on the basis of older age and weak immune systems from cancer as well as chemotherapy. In this study, the CT examinations of 22 confirmed COVID-19 cancer patients were analyzed. A retrospective analysis was conducted on 28 cancer patients, of which 22 patients were COVID positive. The CT scan changes before and after treatment and the extent of structural damage to the lungs after COVID-19 infection was analyzed. Structural damage to a lung was indicated by a change in density measured in Hounsfield units (HUs) and by lung volume reduction. A 3D radiometric analysis was also performed and lung and lesion histograms were compared. A total of 22 cancer patients were diagnosed with COVID-19 infection. A repeat CT scan were performed in 15 patients after they recovered from infection. Most of the study patients were diagnosed with leukemia. A secondary clinical analysis was performed to show the associations of COVID treatment on the study subjects, lab data, and outcome on mortality. It was found that post COVID there was a decrease of >50% in lung volume and a higher density in the form of HUs due to scar tissue formation post infection. It was concluded that COVID-19 infection may have further detrimental effects on the lungs of cancer patients, thereby, decreasing their lung volume and increasing their lung density due to scar formation.

Immune-Related Thyroiditis in Patients with Advanced Lung Cancer Treated with Immune Checkpoint Inhibitors Imaging Features and Clinical Implications.

Immune checkpoint inhibitors (ICI) are widely used in advanced nonsmall cell lung cancer (NSCLC) treatment, and the immune-related adverse events involving many organs have been recognized. This article investigated the incidence and imaging characteristics of immune-related thyroiditis in NSCLC patients and correlated the findings with clinical features. A total of 534 NSCLC patients treated with ICI were included. Imaging findings indicative of thyroiditis included changes in morphology and attenuation on restaging chest CT scans and FDG uptake on PETCT during ICI therapy. Fifty patients (9.4%) had imaging findings indicative of thyroiditis. The median time to onset was 9.5 weeks (range 0.9-87.4 weeks). The most common finding was diffuse hypoattenuation of the gland (72%), with enlargement in 15 and atrophy in 12 patients. Heterogeneous attenuation of the gland was noted in 12 patients (24%), with enlargement in 7 and atrophy in 1 patient. Two patients (4%) showed increased FDG uptake in the gland on PETCT without changes in the CT scan. Twenty-two patients who had both clinical and radiologic diagnoses of thyroiditis were more frequently managed with hormone replacement than those with thyroiditis without an imaging abnormality (

Increased Prevalence of EBV Infection in Nasopharyngeal Carcinoma Patients A Six-Year Cross-Sectional Study.

Epstein Barr Virus (EBV) is implicated in the carcinogenesis of nasopharyngeal carcinoma (NPC) and currently associated with at least 1% of global cancers. The differential prognosis analysis of NPC in EBV genotypes remains to be elucidated. Medical, radiological, pathological, and laboratory reports of 146 NPC patients were collected retrospectively over a 6-year period between 2015 and 2020. From the pathology archives, DNA was extracted from tumor blocks and used for EBV nuclear antigen 3C (EBNA-3C) genotyping by nested polymerase chain reaction (PCR). We found a high prevalence of 96% of EBV infection in NPC patients with a predominance of genotype I detected in 73% of NPC samples. Histopathological examination showed that most of the NPC patients were in the advanced stages of cancer stage III (38.4%) or stage IV-B (37.7%). Only keratinized squamous cell carcinoma was significantly higher in EBV negative NPC patients compared with those who were EBV positive (OR 0.01, 95%CI (0.004-0.32

Bevacizumab versus Ramucirumab in EGFR-Mutated Metastatic Non-Small-Cell Lung Cancer Patients A Real-World Observational Study.

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 studys 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,

The Relationship between Cancer and Dementia An Updated Review.

The risk of cancer and dementia increases with age, raising complex questions about whether it is appropriate to continue cancer treatment in older patients. There is emerging research suggesting the association between cancer and dementia. However, the mechanistic underpinnings are still under investigation. Progress has already been made toward understanding the cognitive effects associated with cancer therapy. Such associations raise awareness about the need to establish better prevention methods and early screening in clinical practice. Additionally, recent studies have suggested possible therapeutic strategies for better preserving cognitive function and reducing the risk for dementia before patients start cancer treatment. We review the current literature and summarize the incidence and mechanisms of cognitive impairment in patients with lung cancer, breast cancer, head and neck cancer, gastric cancer, prostate cancer, colorectal cancer, and brain tumorbrain metastasis following different kinds of therapies. Possible risk factors are suggested to identify the early onset of cognitive changes in cancer patients and provide more insight into the pathophysiological process of dementia.

Tumor Treating Fields (TTFields) Therapy Concomitant with Taxanes for Cancer Treatment.

Non-small cell lung cancer, ovarian cancer, and pancreatic cancer all present with high morbidity and mortality. Systemic chemotherapies have historically been the cornerstone of standard of care (SOC) regimens for many cancers, but are associated with systemic toxicity. Multimodal treatment combinations can help improve patient outcomes however, implementation is limited by additive toxicities and potential drug-drug interactions. As such, there is a high unmet need to develop additional therapies to enhance the efficacy of SOC treatments without increasing toxicity. Tumor Treating Fields (TTFields) are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. The therapy is locoregional and is delivered noninvasively to the tumor site via a portable medical device that consists of field generator and arrays that are placed on the patients skin. As a noninvasive treatment modality, TTFields therapy-related adverse events mainly consist of localized skin reactions, which are manageable with effective acute and prophylactic treatments. TTFields selectively target cancer cells through a multi-mechanistic approach without affecting healthy cells and tissues. Therefore, the application of TTFields therapy concomitant with other cancer treatments may lead to enhanced efficacy, with low risk of further systemic toxicity. In this review, we explore TTFields therapy concomitant with taxanes in both preclinical and clinical settings. The summarized data suggest that TTFields therapy concomitant with taxanes may be beneficial in the treatment of certain cancers.

Treatment Strategies for Non-Small Cell Lung Cancer with Common

The development of targeted therapies over the past two decades has led to a dramatic change in the management of

Associated Factors of Spontaneous Hemorrhage in Brain Metastases in Patients with Lung Adenocarcinoma.

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. 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. 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 ( 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.

MET Amplification as a Resistance Driver to TKI Therapies in Lung Cancer Clinical Challenges and Opportunities.

Targeted therapy has emerged as an important pillar for the standard of care in oncogene-driven non-small cell lung cancer (NSCLC), which significantly improved outcomes of patients whose tumors harbor oncogenic driver mutations. However, tumors eventually develop resistance to targeted drugs, and mechanisms of resistance can be diverse.

The β-Blocker Carvedilol Prevents Benzo(a)pyrene-Induced Lung Toxicity, Inflammation and Carcinogenesis.

The current study evaluated the effects of the β-blocker carvedilol on benzo(a)pyrene (B(a)P) and its active metabolite benzo(a)pyrene diol epoxide (BPDE)-induced lung toxicity, inflammation and carcinogenesis and explored the potential mechanisms. Carvedilol blocked the BPDE-induced malignant transformation of human bronchial epithelial cells BEAS-2B. In BEAS-2B cells, B(a)P strongly activated ELK-1, a transcription factor regulating serum response element (SRE) signaling, which was attenuated by carvedilol. Carvedilol also inhibited the B(a)P-induced AhRxenobiotic responsive element (XRE) and mRNA expression of

Clinical Analysis of Pulmonary Lymphoma.

To study the clinical, imaging, and pathological features of pulmonary lymphoma. Patients with pulmonary lymphoma diagnosed by lung biopsy in Zhongda Hospital Affiliated to Southeast University from November 2013 to December 2020 were collected and divided into secondary pulmonary lymphoma (SPL) group and primary pulmonary lymphoma (PPL) group according to the primary site of lymphoma. The clinical characteristics, stages, imaging features, diagnostic methods and pathological types of the two groups were analyzed. A total of 22 patients were included, 10 cases were PPL and 12 cases were SPL. The main symptoms of the two groups were cough, dyspnea and chest pain. The proportion of stage IIIIV patients and international prognostic index (IPI) in SPL group were significantly higher than those in PPL group ( The clinical symptoms of pulmonary lymphoma are nonspecific, but the chest HRCT has characteristic manifestations, which can also help to distinguish between SPL and PPL. 肺淋巴瘤患者的临床特征分析. 分析肺淋巴瘤患者的临床表现、影像学特征及病理类型. 收集东南大学附属中大医院2013年11月至2020年12月经肺部活检病理确诊为肺淋巴瘤的病例，按照淋巴瘤的原发部位分为原发性肺淋巴瘤（PPL）和继发性肺淋巴瘤（SPL）两组，分析两组患者临床表现、分期、影像学特征、诊断方法及病理类型. 共纳入22例，PPL 10例，SPL 12例。两组患者临床表现均以咳嗽、呼吸困难和胸痛为主，SPL组IIIIV期患者比例及国际预后指数显著高于PPL组（ 肺淋巴瘤的症状无特异性，胸部HRCT有特征性表现，且胸部HRCT可以协助鉴别SPL和PPL，

Feasibility analysis of combined surgery for esophageal cancer.

As the preoperative examination of esophageal cancer has improved, the likelihood of finding diseases in other organs that require surgical treatment has also increased. The purpose of this study was to explore the feasibility of combined surgery for esophageal cancer by analyzing the occurrence of postoperative complications in patients with esophageal cancer. The clinical characteristics of 1566 patients with esophageal cancer who underwent thoracic surgery in our hospital between January 2017 and September 2022 were analyzed retrospectively. The feasibility of combined surgery for esophageal cancer was analyzed by comparing postoperative complications in patients who underwent simple esophageal cancer surgery (SEC) with those in patients who underwent combined surgery for esophageal cancer (COEC). The tendency scores of patients in the COEC and SEC groups (12) were matched to balance the confounding clinical factors, and the difference in postoperative complications was further analyzed. Moreover, we performed a subgroup analysis of esophagectomy combined with lung resection (ECL). In addition, the independent risk factors for postoperative Clavien-Dindo ≥ grade III complications of esophageal cancer were analyzed by multivariate logistic regression. A total of 1566 patients (1147 (73.2%) males and 419 (26.8%) females), with an average age of 64.2 years, were analyzed. There was no significant difference in postoperative complications between the SEC and COEC groups according to the Clavien-Dindo classification (P0.713). An analysis of the complications revealed that those in the COEC group had a higher incidence of lung consolidation than those in the SEC group (P0.007). However, when we performed propensity score matching (PSM) on the SEC and COEC groups, there was still no significant difference in complications according to the Clavien-Dindo classification (P0.346) furthermore, when a detailed analysis of complications was performed, there was no significant difference between the two. In subgroup analysis, after we performed PSM in ECL patients and SEC patients, we also found no significant difference in postoperative complications between patients with ECL and patients with SEC. In addition, we found that a history of diabetes (OR1.604, P0.029, 95% CI1.049-2.454), a history of coronary heart disease (OR1.592, P0.046, 95% CI1.008-2.515), diffusing capacity of the lungs for carbon monoxide (DLCO) (OR0.916, P0.024, 95% CI0.849-0.988), and ALB level (OR0.955, P0.007, 95% CI0.924-0.987) were independent factors that influenced postoperative complications in esophageal cancer patients with grade III or higher complications. Combined surgery for esophageal cancer does not increase the incidence of postoperative complications. In addition, a history of diabetes mellitus or coronary heart disease, carbon monoxide dispersion, and preoperative ALB level are independent risk factors for grade III or higher postoperative complications of esophageal cancer.

Risks of second non-breast primaries following breast cancer in women a systematic review and meta-analysis.

Second primary cancer incidence is rising among breast cancer survivors. We examined the risks of non-breast second primaries, in combination and at specific cancer sites, through a systematic review and meta-analysis. We conducted a systematic search of PubMed, Embase, and Web of Science, seeking studies published by March 2022. We included studies that reported standardized incidence ratios (SIRs), with associated standard errors, assessing the combined risk of second non-breast primaries following breast cancer. We performed meta-analyses of combined second primary risks, stratifying by age, follow-up duration, and geographic region. We also assessed second primary risks at several specific sites, stratifying by age. The inverse variance method with DerSimonian-Laird estimators was used in all meta-analyses, assuming a random-effects model. Associated biases and study quality were evaluated using the Newcastle-Ottawa scale. One prospective and twenty-seven retrospective cohort studies were identified. SIRs for second non-breast primaries combined ranged from 0.84 to 1.84. The summary SIR estimate was 1.24 (95% CI 1.14-1.36, I Breast cancer survivors are at significantly increased risk of second primaries at many sites. Risks are higher for those diagnosed with breast cancer before age 50 and in Asian breast cancer survivors compared to European breast cancer survivors. This study is limited by a lack of data on potentially confounding variables. The conclusions may inform clinical management decisions following breast cancer, although specific clinical recommendations lie outside the scope of this review.

Efficacy of PD-1PD-L1 inhibitors in gastric or gastro-oesophageal junction cancer based on clinical characteristics a meta-analysis.

Programmed death-1 (PD-1) and its ligand (PD-L1) inhibitors have been reported in several clinical trials for gastric cancer and gastroesophageal junction cancer (GCGEJC). We presently carried out a meta analysis to evaluate the potency of PD-1PD-L1 inhibitors in advanced GCGEJC individuals with different clinical features and to determine patients more probably benefiting from the treatment. Randomized clinical trials (RCTs) in databases that compared PD-1PD-L1 inhibitors to chemotherapy in patients with GCGEJC published before May 2022 were retrieved. Basic characteristics were extracted from the included studies as well as hazard ratios (HR) and 95 percent confidence intervals (CI) for all individuals and subgroups. The inverse variance weighting method was used to evaluate pooled treatment data. Four RCTs involving 2,253 individuals were included. The results suggested that PD-1PD-L1 inhibitors substantially enhanced overall survival (OS) (HR, 0.91 CI 95%, 0.83-1.00 p 0.04) but not progression free survival (PFS) (HR, 1.17 CI 95%, 0.83-1.64 p 0.38) in GCGEJC individuals compared with chemotherapy. Significantly improved OS was observed in individuals aged < 65 years (HR, 0.84 p 0.003), and men (HR, 0.88 p 0.02), but not in individuals aged ≥ 65 years (HR, 0.97 p 0.62), and women (HR, 0.98 p 0.82). PD-1PD-L1 inhibitors improve OS but not PFS compared with chemotherapy in GCGEJC. Age and sex could be used to predict the treatment potency of PD-1PD-L1 inhibitors in GCGEJC.

In vitro antioxidant, anti-inflammatory, and anticancer activities of mixture Thai medicinal plants.

The phytochemical study of medicinal plants is rapidly gaining popularity with many pharmacologic effects. This study aims to determine the antioxidant capacity as well as anticancer and antimigration activities of Clear belongs Plus extract (CBL-P) which consisted of five medicinal plants namely, Alpinia galanga, Piper nigrum, Citrus aurantifolia, Tiliacora triandra, and Cannabis sativa on human colon cancer cells SW620 and HCT116 cell lines, and human non-small cell lung cancer cells A549 and NCI-H460 cell lines. In this study the dried-plant powder was extracted using 90% ethanol. Additionally, CBL-P was studied antioxidative activity via DPPH and ABTS assays and anti-inflammatory activities using nitric oxide assay using Griess reaction. Antiproliferation and antimigration of CBL-P were investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and scratch assay. The results showed that CBL-P had potent antiproliferative activity with IC In conclusion, the mixture extract possessed antioxidant and anti-inflammatory activity. Furthermore, the mixture plant extract significantly exhibited antiproliferative and antimigration activities on SW620, HCT116, A549, and NCI-H460 cells (P ≤ 0.05). Taken together, our results suggest that medicinal plants may have synergistic effects that could potentially enhance the effectiveness of cancer treatment when used as adjuvants. These findings provide a solid scientific foundation for future efforts to explore the mechanism of action.

The value of preoperative positron emission tomographycomputed tomography in differentiating the invasive degree of hypometabolic lung adenocarcinoma.

To investigate the value of preoperative positron emission tomographycomputed tomography (PETCT) in differentiating the invasive degree of hypometabolic lung adenocarcinoma. We retrospectively analyzed the data of patients who underwent PETCT examination, high-resolution computed tomography, and surgical resection for low-metabolism lung adenocarcinoma in our hospital between June 2016 and December 2021. We also investigated the relationship between the preoperative PETCT findings and the pathological subtype of hypometabolic lung adenocarcinoma. A total of 128 lesions were found in 113 patients who underwent resection for lung adenocarcinoma, including 20 minimally invasive adenocarcinomas (MIA) and 108 invasive adenocarcinomas (IAC), whose preoperative PETCT showed low metabolism. There were significant differences in the largest diameter (Dmax), lesion type, maximum standard uptake value (SUVmax), SUVindex (the ratio of SUVmax of lesion to SUVmax of contralateral normal lung paranchyma), fasting blood glucose, lobulation, spiculation, and pleura indentation between the MIA and IAC groups (p < 0.05). Multivariate logistic regression analysis showed that the Dmax (odds ratio (OR) 1.413, 95% confidence interval (CI 1.155-1.729, p 0.001)) and SUVmax (OR 12.137, 95% CI 1.068-137.900, p 0.044) were independent risk factors for predicting the hypometabolic IAC (p < 0.05). Receiver operating characteristic (ROC) curve analysis showed that the Dmax ≥ 10.5 mm and SUVmax ≥ 0.85 were the cut-off values for differentiating MIA from IAC, with high sensitivity (84.3% and 75.9%, respectively) and specificity (84.5% and 85.0%, respectively), the Combined Diagnosis showed higher sensitivity (91.7%) and specificity (85.0%). The PETCT findings correlated with the subtype of hypometabolic lung adenocarcinoma. The parameters Dmax and SUVmax were independent risk factors for predicting IAC, and the sensitivity of Combined Diagnosis prediction is better.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors and non-small cell lung cancer survival.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs with demonstrated renal and cardiovascular disease benefit. This study evaluates the role of SGLT2 inhibitors on the survival of non-small cell lung cancer (NSCLC) patients. We used National Surveillance, Epidemiology and End Results (SEER)-Medicare linked data. Twenty four thousand nine hundred fifteen NSCLC patients newly diagnosed between 2014 and 2017 with pre-exiting diabetes and aged 66 years or older were included and followed to the end of 2019. Information on SGLT2 inhibitors use was extracted from the Medicare Part D file. SGLT2 inhibitor use was associated with significantly reduced mortality risk after adjusting for potential confounders (HR 0.68, 95% CI 0.60-0.77) with stronger association for longer duration of use (HR 0.54, 85% CI 0.44-0.68). Further, we found that SGLT2 inhibitor use was associated with a significant reduced risk of mortality regardless of patients demographic, tumour characteristics and cancer treatments. Our large SEER-Medicare linked data study indicates that SGLT2 inhibitors use was associated with improved overall survival of NSCLC patients with pre-existing diabetes. Further studies are needed to confirm our findings and elucidate the possible mechanisms behind the association.

Prevalence and trends of perioperative major adverse cardiovascular and cerebrovascular events during cancer surgeries.

Major adverse cardiovascular and cerebrovascular events (MACCE) is an important cause of morbidity and mortality during perioperative period. In this study, we looked for national trends in perioperative MACCE and its components as well as cancer types associated with high rates of perioperative MACCE during major cancer surgeries. This study was a retrospective analysis of the National Inpatient Sample, 2005-2014. Hospitalizations for surgeries of prostate, bladder, esophagus, pancreas, lung, liver, colorectal, and breast among patients 40 years and greater were included in the analysis. MACCE was defined as a composite measure that included in-hospital all-cause mortality, acute myocardial infarction (AMI), and ischemic stroke. A total of 2,854,810 hospitalizations for major surgeries were included in this study. Of these, 67,316 (2.4%) had perioperative MACCE. Trends of perioperative MACCE showed that it decreased significantly for AMI, death and any MACCE, while stroke did not significantly change during the study period. Logistic regression analysis for perioperative MACCE by cancer types showed that surgeries for esophagus, pancreas, lung, liver, and colorectal cancers had significantly greater odds for perioperative MACCE. The surgeries identified to have greater risks for MACCE in this study could be risk stratified for better informed decision-making and management.

Integration of single sample and population analysis for understanding immune evasion mechanisms of lung cancer.

A deep understanding of the complex interaction mechanism between the various cellular components in tumor microenvironment (TME) of lung adenocarcinoma (LUAD) is a prerequisite for understanding its drug resistance, recurrence, and metastasis. In this study, we proposed two complementary computational frameworks for integrating multi-source and multi-omics data, namely ImmuCycReg framework (single sample level) and L0Reg framework (population or subtype level), to carry out difference analysis between the normal population and different LUAD subtypes. Then, we aimed to identify the possible immune escape pathways adopted by patients with different LUAD subtypes, resulting in immune deficiency which may occur at different stages of the immune cycle. More importantly, combining the research results of the single sample level and population level can improve the credibility of the regulatory network analysis results. In addition, we also established a prognostic scoring model based on the risk factors identified by Lasso-Cox method to predict survival of LUAD patients. The experimental results showed that our frameworks could reliably identify transcription factor (TF) regulating immune-related genes and could analyze the dominant immune escape pathways adopted by each LUAD subtype or even a single sample. Note that the proposed computational framework may be also applicable to the immune escape mechanism analysis of pan-cancer.

How has the COVID-19 pandemic affected the utilisation of online consultation and face-to-face medical treatment An interrupted time-series study in Beijing, China.

The COVID-19 pandemic has had a major impact on healthcare utilisation. This study aimed to quantify how the online and face-to-face utilisation of healthcare services changed during this time and thus gain insights into the planning of future healthcare resources during the outbreak of infectious diseases. This work is an interrupted time-series study. Monthly hospital-grade healthcare-service data from 22 tertiary first-class public hospitals managed by the Beijing Hospital Authority and online-consultation data from GoodDoctor were used in this study. This is an interrupted time-series study about the change in face-to-face and online healthcare utilisation before and after the COVID-19 outbreak. We compared the impact of COVID-19 on the primary outcomes of both face-to-face healthcare utilisation (outpatient and emergency visits, discharge volume) and online healthcare utilisation (online consultation volume). And we also analysed the impact of COVID-19 on the healthcare utilisation of different types of diseases. The monthly average outpatient visits and discharges decreased by 36.33% and 35.75%, respectively, compared with those in 2019 in 22 public hospitals in Beijing. Moreover, the monthly average online consultations increased by 90.06%. A highly significant reduction occurred in the mean outpatients and inpatients, which dropped by 1 755 930 cases (p<0.01) and 5 920 000 cases (p<0.01), respectively. Online consultations rose by 3650 cases (p<0.05). We identified an immediate and significant drop in healthcare services for four major diseases, that is, acute myocardial infarction (-174, p<0.1), lung cancer (-2502, p<0.01), disk disease (-3756, p<0.01) and Parkinsons disease (-205, p<0.01). Otherwise, online consultations for disk disease (63, p<0.01) and Parkinsons disease (25, p<0.05) significantly increased. More than 1300 unique physicians provided online-consultation services per month in 2020, which was 35.3% higher than in 2019. Obvious complementary trends in online and face-to-face healthcare services existed during the COVID-19 pandemic. Different changes in healthcare utilisation were shown for different diseases. Non-critically ill patients chose online consultation immediately after the COVID-19 lockdown, but critically ill patients chose hospital healthcare services first. Additionally, the volume of online physician services significantly rose as a result of COVID-19.

Protocol for the derivation and external validation of a 30-day postoperative pulmonary complications (PPCs) risk prediction model for elderly patients undergoing thoracic surgery a cohort study in southern China.

Postoperative pulmonary complications (PPCs) occur after up to 60% of non-cardiac thoracic surgery (NCTS), especially for multimorbid elderly patients. Nevertheless, current risk prediction models for PPCs have major limitations regarding derivation and validation, and do not account for the specific risks of NCTS patients. Well-founded and externally validated models specific to elderly NCTS patients are warranted to inform consent and treatment decisions. We will develop, internally and externally validate a multivariable risk model to predict 30-day PPCs in elderly NCTS patients. Our cohort will be generated in three study sites in southern China with a target population of approximately 1400 between October 2021 and December 2023. Candidate predictors have been selected based on published data, clinical expertise and epidemiological knowledge. Our model will be derived using the combination of multivariable logistic regression and bootstrapping technique to lessen predictors. The final model will be internally validated using bootstrapping validation technique and externally validated using data from different study sites. A parsimonious risk score will then be developed on the basis of beta estimates derived from the logistic model. Model performance will be evaluated using area under the receiver operating characteristic curve, max-rescaled Brier score and calibration slope. In exploratory analysis, we will also assess the net benefit of Probability of PPCs Associated with THoracic surgery in elderly patients score in the complete cohort using decision curve analysis. Ethical approval has been obtained from the Institutional Review Board of the Affiliated Cancer Hospital and Institute of Guangzhou Medical University, the Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine and the University of Hongkong-Shenzhen Hospital, respectively. The final risk prediction model will be published in an appropriate journal and further disseminated as an online calculator or nomogram for clinical application. Approved and anonymised data will be shared. ChiCTR2100051170.

Feasibility of omitting the clinical target volume under PET-CT guidance in unresectable stage III non-small-cell lung cancer a phase II clinical trial.

This clinical trial aims at investigate the feasibility of CTV-omitted, positron-emission tomography computed tomography (PET-CT) combined with intensity-modulated radiation therapy (IMRT) for unresectable stage III NSCLC. This was a single-center, phase II clinical trial initiated in July 2016. Patients with unresectable stage III NSCLC undergoing routine IMRT were randomly enrolled into the study group (CTV-omitted under PET-CT guidance) and the control group (CTV-delineated). Patients received platinum-based dual-drug concurrent chemoradio therapy. In the study group, the PGTV dose was 60 Gy given in 30 daily 2 Gy fractions in the control group, the PCTV dose was 54 Gy given in 30 daily 1.8 Gy fractions, and the PGTV dose was 60 Gy given in 30 daily 2 Gy fractions. The primary endpoint was the incidence of radiation respiratory events or esophagitis with grade 3 or higher. The secondary endpoints included objective response rate (ORR), locate control rate, progression-free survival (PFS), failure pattern and overall survival (OS). A total of 90 patients were enrolled between July 2016 and March 2019. The incidence of radiation respiratory events or esophagitis with grade 3 or higher was 11.1 % in the study group, significantly lower than the rate of 28.9 % in the control group (P 0.035), basically due to the reduced irradiated volumes of the lungs and esophagus in the study group. The median PFS was 9.0 months versus 10.0 months (P 0.597), and the median OS 31.0 months versus 26.0 months (P 0.489) in the study group and the control group, respectively. The failure pattern was not significantly different between the two groups (P 0.826). Omitting the CTV under PET-CT guidance has high feasibility to reduce severe radiation associated toxicity in IMRT for unresectable stage III NSCLC, without compromising the efficacy.

Contemporary Treatment Outcome of Metastases to the Pituitary Gland.

Metastasis to the pituitary gland is uncommon. With life expectancy after cancer diagnosis improving, we sought to understand the impact of treating pituitary metastasis in the modern era of advanced cancer treatment. Patients diagnosed and treated as pituitary metastasis from 2000 to 2021 were retrospectively analyzed. Forty-eight patients were identified. Twenty-three (48%) were women. The common primary cancer origins were the lung (23 patients 48%) and the breast (9 patients). Twenty-nine patients (60%) had hypopituitarism and 12 (25%) had visual field deficits. Twenty-seven patients (56%) had solitary pituitary metastasis (no evidence of other intracranial metastatic lesions). Fourteen patients (29%) had surgery, and 20 (42%) had standalone radiation (biopsy was preceded in three). After surgery andor radiation, visual field deficits improved in six patients, hypopituitarism improved in four patients, and hypopituitarism occurred in three patients. The median overall survival (OS) was 12 months (interquartile range, 3.0-28). Multivariate analysis showed non-solitary pituitary metastasis (hazard ratio HR, 2.8 95% confidence interval CI, 1.5-5.5 P0.0021) and no surgery or radiation (HR, 2.08 95% CI, 1.04-4.15 P0.038) to be associated with OS. For solitary pituitary metastasis, patients who had surgery and radiation had better 1-year OS than patients who had neither (P0.03), whereas, for non-solitary pituitary metastasis, patients who had standalone radiation had better 1-year OS than patients who had neither (P0.03). In the selected population, metastasis-directed therapy was associated with improved OS. Either correct patient selection for additional therapy or surgeryradiation directly benefited the patient in OS.

Preparation of PEGylated nedaplatin liposomes with sustained release behavior for enhancing the antitumor efficacy of non-small cell lung cancer.

Nedaplatin (NDP) plays an important role in the chemotherapies of non-small cell lung cancer (NSCLC). However, dose-limiting toxicities such as myelosuppression and drug resistance restrict its clinical application. Herein, we intended to overcome these defects by developing a PEGylated liposomal formulation encapsulated NDP (NDP-LPs). For the first time, we found the incompatibility between NDP and natural phospholipids such as egg phosphatidylcholine (EPC) using the high-performance liquid chromatography (HPLC) method. The orthogonal experimental design was applied to optimize the conditions for preparing NDP-LPs, with encapsulation efficiency (EE) as the evaluation indicator. The physicochemical properties of optimized NDP-LPs were further characterized, including particle size, zeta potential, EE, drug release profiles, and so on. Results showed that a significantly sustained-release profile of NDP-LPs was observed and the releasing time of NDP could reach as long as 8 days. At the cellular level, NDP encapsulated in the PEGylated liposomes enhanced its cellular uptake and possessed potent cytotoxic activity. After intravenous injection, NDP-LPs could accumulate at tumor sites and effectivelyinhibit tumor growth of mice without obvious adverse effects. In conclusion, our results demonstrated that PEGylated liposomes could serve as a promising carrier to enhance the therapeutic effects of NDP.

Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS

Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRAS We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRAS Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n171 50%) or docetaxel (n174 50%). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4-20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months 95% CI 4·3-7·8 vs 4·5 months 3·0-5·7 hazard ratio 0·66 0·51-0·86 p0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n56 33% vs n61 40%) and serious treatment-related adverse events compared with docetaxel (n18 11% vs n34 23%). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n 20 12%), alanine aminotransferase increase (n13 8%), and aspartate aminotransferase increase (n9 5%). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n13 9%), fatigue (n9 6%), and febrile neutropenia (n8 5%). Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRAS Amgen.

Dexamethasone activates c-Jun NH2-terminal kinase (JNK) which interacts with GR and protects it from ubiquitin-mediated degradation in NSCLC cells.

Dexamethasone-mediated pharmacological activation of the glucocorticoid receptor (GR) is widely used in the treatment regimen of hematological malignancies and solid cancers. However, DEX sensitivity towards patients primarily depends on the endogenous protein levels of GR. We observed that DEX treatment leads to an increase in GR protein levels despite inhibition of neo-protein synthesis in non-small cell lung cancer (NSCLC) cells. Mechanistically, DEX-stimulation concomitantly increased the JNK phosphorylation and GR protein levels, however the JNK stimulation preceds GR upregulation. Moreover, we also observed that DEX-mediated phosphorylation is partially mediated by upregulation in MEKK1 phosphorylation. Further, GR protein levels were significantly decreased in JNK inhibitor (JNKi, SP600125) treated cells whereas MG132 treatment restored GR levels indicating that DEX induced JNK activity regulated the GR protein levels through proteasomal-degradation pathway. Next, we showed that DEX led to JNK activation which physically interacts with GR and protects it from ubiquitination-mediated degradation. Furthermore, at basal level GR interacts with JNK in cytoplasm whereas upon DEX stimulation GR and pJNK both localized to nucleus and interact with each other. Next, we show that JNK-mediated GR stabilization affects its nuclear transcriptional functional activity in NSCLC cells. In line with these in vitro data, patient dataset analysis also shows that increased levels of both JNK and GR contributes towards better prognosis of NSCLC patients. Taken together, our data shows that DEX treatment may lead to positive feedback regulation of GR by activating JNK and thus highlights importance of GR-JNK crosstalk in NSCLC.

Utility of

Reliable predictive markers are lacking for resectable non-small cell lung cancer (NSCLC) patients treated with neoadjuvant chemoimmunotherapy. The present study investigated the utility of SUV SUV A total of 129 cases with an MPR rate of 46.5 % was identified. In neoadjuvant chemoimmunotherapy, ΔSUV These findings highlighted that the ΔSUV

Targeting HER3 for cancer treatment a new horizon for an old target.

Human epidermal growth factor receptor 3 (HER3) is a member of the human epidermal growth factor receptors family, having as its main ligands neuregulins 1 and 2. Although its poor tyrosine kinase activity entails a weak oncogenic power on its own, HER3 can heterodimerize with HER2 andor epidermal growth factor receptor (EGFR), leading to a drastic enhancement of transphosphorylation and activation of downstream signaling pathways, ultimately promoting oncogenesis, metastatic dissemination, and drug resistance. Given its ubiquitous expression across solid tumors, multiple efforts have been done to therapeutically target HER3 by blocking either the ligand binding domain or its dimerization with other receptors. Treatment with anti-HER3 monoclonal antibodies or bispecific antibodies, both as single agents and in combination with other compounds, unfortunately led to unsatisfactory results across several tumor types. The HER3-directed delivery of cytotoxic payloads through antibody-drug conjugates has recently demonstrated encouraging activity in several tumor types, however, suggesting a potential role for the therapeutic targeting of HER3 in cancer treatment.

Trends in keratinocyte skin cancer incidence, mortality and burden of disease in 33 countries between 1990 and 2017.

Keratinocyte cancers (KCs) are the most common type of cancer in the White population worldwide, with associated high healthcare costs. Understanding the epidemiological trends for KCs, namely basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (SCCs), is required to assess burden of disease, project future trends and identify strategies for addressing this pressing global health issue. To report trends in BCC and SCC incidence, and SCC mortality and disability-adjusted life-years (DALYs). An observational study of the Global Burden of Disease (GBD) database between 1990 and 2017 was performed. European Union countries and other selected high-income countries, including the UK and the USA, classified as having high-quality mortality data, were included. Annual age-standardized incidence rates (ASIRs), age-standardized death rates (ASDRs) and DALYs for each country were obtained from the GBD database. Trends were described using joinpoint regression analysis. Overall, 33 countries were included. For both BCC and SCC in 2015-2017, the highest ASIRs were observed in the USA and Australia. Males had higher ASIRs than females at the end of the observation period in all countries for SCC, and in all countries but two for BCC. In contrast, the highest ASDRs for SCC were observed in Australia and Latvia for males, and in Romania and Croatia for females. The highest DALYs for SCC for both sexes were seen in Australia and Romania. Over the observation period, there were more countries demonstrating decreasing trends in mortality than in incidence, and disparities were observed between which countries had comparatively high mortality rates and which had high incidence rates. Overall reductions in SCC DALYs were observed in 24 of 33 countries for males, and 25 countries for females. Over the past 27 years, although trends in SCC incidence have risen in most countries, there is evidence that mortality rates have been decreasing. Burden of disease as assessed using DALYs has decreased in the majority of countries. Future work will explore potential explanatory factors for the observed disparity in trends in SCC incidence and mortality.

Na, K-ATPase α1 cooperates with its endogenous ligand to reprogram immune microenvironment of lung carcinoma and promotes immune escape.

Dysregulated endocrine hormones (EHs) contribute to tumorigenesis, but how EHs affect the tumor immune microenvironment (TIM) and the immunotherapy of non-small cell lung cancer (NSCLC) is still unclear. Here, endogenous ouabain (EO), an adrenergic hormone, is elevated in patients with NSCLC and closely related to tumor pathological stage, metastasis, and survival. EO promotes the suppression of TIM in vivo by modulating the expression of immune checkpoint proteins, in which programmed cell death protein ligand 1 (PD-L1) plays a major role. EO increases PD-L1 transcription however, the EO receptor Na- and K-dependent adenosine triphosphatase (Na, K-ATPase) α1 interacts with PD-L1 to trigger the endocytic degradation of PD-L1. This seemingly contradictory result led us to discover the mechanism whereby EO cooperates with Na, K-ATPase α1 to finely control PD-L1 expression and dampen tumoral immunity. In conclusion, the Na, K-ATPase α1EO signaling facilitates immune escape in lung cancer, and manipulation of this signaling shows great promise in improving immunotherapy for lung adenocarcinoma.

Effect of body tissue composition on the outcome of patients with metastatic non-small cell lung cancer treated with PD-1PD-L1 inhibitors.

Obesity and sarcopenia have been reported to affect outcomes in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). We analyzed prospective data from 52 patients with non-oncogene driven metastatic NSCLC treated with ICIs. Body tissue composition was calculated by measuring the fat and muscle densities at the level of 3rd lumbar vertebra in each patient computed tomography scan before ICI initiation using sliceOmatic tomovision. We converted the densities to indices Intramuscular Fat Index (IMFI), Visceral Fat Index (VFI), Subcutaneous Fat Index (SFI), Lumbar Skeletal Muscle Index (LSMI) by dividing them by height in meters squared. Patients were dichotomized based on their baseline IMFI, VFI and SFI according to their gender-specific median value. The cut-offs that were set for LMSI values were 55 cm2m2 for males and 39 cm2m2 for females. SFI distribution was significantly higher (p 0.040) in responders compared to non-responders. None of the other variables affected response rates. Low LSMI HR 2.90 (95% CI 1.261-6.667, p 0.012) and low SFI 2.20 (95% CI 1.114-4.333, p 0.023) values predicted for inferior OS. VFI and IMFI values did not affect survival. Subcutaneous adipose and skeletal muscle tissue composition significantly affected immunotherapy outcomes in our cohort.

Real-world utilization of SARS-CoV-2 serological testing in RNA positive patients across the United States.

As diagnostic tests for COVID-19 were broadly deployed under Emergency Use Authorization, there emerged a need to understand the real-world utilization and performance of serological testing across the United States. Six health systems contributed electronic health records andor claims data, jointly developed a master protocol, and used it to execute the analysis in parallel. We used descriptive statistics to examine demographic, clinical, and geographic characteristics of serology testing among patients with RNA positive for SARS-CoV-2. Across datasets, we observed 930,669 individuals with positive RNA for SARS-CoV-2. Of these, 35,806 (4%) were serotested within 90 days 15% of which occurred <14 days from the RNA positive test. The proportion of people with a history of cardiovascular disease, obesity, chronic lung, or kidney disease or presenting with shortness of breath or pneumonia appeared higher among those serotested compared to those who were not. Even in a population of people with active infection, raceethnicity data were largely missing (>30%) in some datasets-limiting our ability to examine differences in serological testing by race. In datasets where raceethnicity information was available, we observed a greater distribution of White individuals among those serotested however, the time between RNA and serology tests appeared shorter in Black compared to White individuals. Test manufacturer data was available in half of the datasets contributing to the analysis. Our results inform the underlying context of serotesting during the first year of the COVID-19 pandemic and differences observed between claims and EHR data sources-a critical first step to understanding the real-world accuracy of serological tests. Incomplete reporting of raceethnicity data and a limited ability to link test manufacturer data, lab results, and clinical data challenge the ability to assess the real-world performance of SARS-CoV-2 tests in different contexts and the overall U.S. response to current and future disease pandemics.

Adagrasib First Approval.

Adagrasib (KRAZATI™) is an orally available, potent, irreversible, small molecule inhibitor of KRAS G12C mutant isoform being developed by Mirati Therapeutics for the treatment of solid tumours harbouring KRAS G12C oncogenic driver mutation, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Adagrasib covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactive state, thereby preventing downstream signalling without affecting wild-type KRAS protein. In December 2022, adagrasib received its first approval in the USA for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic NSCLC (as determined by an FDA approved test) who have received ≥ 1 prior systemic therapy. It was approved under accelerated approval based on objective response rate and duration of response, and its continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s). The drug is under regulatory review for NSCLC in the European Union and is in development for CRC in the US. Clinical studies of adagrasib in solid tumours, including CRC, are underway in several countries. This article summarizes the milestones in the development of adagrasib leading to this first approval for KRAS G12C-mutated locally advanced or metastatic NSCLC.

Hsacirc0017956 Acts as miR-758-3p Sponge to Facilitate the Progression of Non-small-Cell Lung Cancer by Regulating FOXP4 Expression.

Accumulating studies have demonstrated the important role of circular RNAs (circRNAs) in the progression of different human tumors, including non-small-cell lung cancer (NSCLC). The purpose of this study was to deeply study the function and mechanism of circ0017956 in NSCLC. Real-time quantitative polymerase chain reaction (RT-qPCR) was applied to detect the expression of circ0017956, microRNA-758-3p (miR-758-3p), and Forkhead Box P4 (FOXP4). Western blot was performed to determine the protein levels. Cell proliferation was examined by cell counting kit-8 (CCK-8) assay and 5-ethynyl-2-deoxyuridine (EdU) assay. Flow cytometry was used to evaluate the apoptosis of NSCLC cells. Transwell assay was applied to detect cell migratory and invasive capacities. The angiogenesis ability was evaluated by tube formation experiment. The target relationship between miR-758-3p and circ0017956 or FOXP4 was confirmed by dual-luciferase reporter assay. Animal experiment was conducted to assess the effect of circ0017956 in vivo. Circ0017956 and FOXP4 were upregulated, while miR-758-3p was downregulated in NSCLC tissues and cells. Silencing of circ0017956 significantly suppressed cell proliferation, migration, invasion, and angiogenesis, but promoted cell apoptosis in NSCLC cells. Mechanically, circ0017956 functioned as a sponge for miR-758-3p and miR-758-3p could directly interact with FOXP4. Moreover, silencing of miR-758-3p or overexpression of FOXP4 could overturn the anticancer influence of circ0017956 interference on NSCLC cells. Besides that, circ0017956 knockdown hindered tumor growth in vivo. Altogether, circ0017956 promoted the progression of NSCLC by regulating FOXP4 through sponging miR-758-3p.

Targeting Mesothelin in Solid Tumours Anti-mesothelin Antibody and Drug Conjugates.

This review aims to summarise the pathobiological role of mesothelin and the current data on therapeutic antibodies targeting mesothelin in solid tumours. High mesothelin expression is restricted to the pericardium, pleura, peritoneum and tunica vaginalis. Mesothelin does not seem to have any normal biological function in adult normal tissues. Mesothelin is highly expressed in mesothelioma, serous ovarian cancer, pancreatic cancer and some gastric cancer and adenocarcinoma of the lung and is responsible for tumour proliferation, metastasis, resistance to chemotherapy or radiation and evasion of immune system. To date, antibody, antibody drug conjugates and bispecific antibodies with immune checkpoints have been investigated in mesothelin expressing malignancies. After a couple of decades of clinical investigation in antibody targeting mesothelin, the therapeutic benefit is relatively modest. Novel delivery of mesothelin targeting agents, more potent payload in antibody drug conjugates and immune checkpoint inhibitor, may improve therapeutic benefit.

Ion-Pair-Enhanced Double-Click Driven Cell Adhesion and Altered Expression of Related Genes.

Bio-orthogonal ligations that crosslink living cells with a substrate or other cells require high stability and rapid kinetics to maintain the nature of target cells. In this study, we report water-soluble cyclooctadiyne (WS-CODY) derivatives that undergo an ion-pair enhanced double-click reaction. The cationic side chain of WS-CODY accelerated the kinetics on the azide-modified cell surface due to proximity effect. Cationic WS-CODY was able to crosslink azide-modified, poorly adherent human lung cancer PC-9 cells not only to azide-grafted glass substrates but also to other cells within 5-30 min. We discovered that cell-substrate crosslinking induced the ITGA5 gene expression, whereas cell-cell crosslinking induced the CTNNA1 gene, according to the adhesion partner. Ion-pair-enhanced WS-CODY can be applied to a wide range of cells with established azide modifications and is expected to provide a powerful tool to regulate cell-substrate and cell-cell interactions.

Occupational exposure to diesel engine exhaust and serum levels of microRNAs in a cross-sectional molecular epidemiology study in China.

Diesel engine exhaust (DEE) is an established lung carcinogen, but the biological mechanisms of diesel-induced lung carcinogenesis are not well understood. MicroRNAs (miRNAs) are small noncoding RNAs that play a potentially important role in regulating gene expression related to lung cancer. We conducted a cross-sectional molecular epidemiology study to evaluate whether serum levels of miRNAs are altered in healthy workers occupationally exposed to DEE compared to unexposed controls. We conducted a two-stage study, first measuring 405 miRNAs in a pilot study of 6 DEE-exposed workers exposed and 6 controls. In the second stage, 44 selected miRNAs were measured using the Fireplex circulating miRNA assay that profiles miRNAs directly from biofluids of 45 workers exposed to a range of DEE (Elemental Carbon (EC), median, range 47.7, 6.1-79.7 μgm Serum levels of four miRNAs were significantly lower (miR-191-5p, miR-93-5p, miR-423-3p, miR-122-5p) and one miRNA was significantly higher (miR-92a-3p) in DEE exposed workers compared to controls. Of these miRNAs, miR-191-5p (P Our findings suggest that occupational exposure to DEE may affect circulating miRNAs implicated in biological processes related to carcinogenesis, including immune function. This article is protected by copyright. All rights reserved.

Molecular Biology of Brain Metastases.

Brain metastases (BMs) often occur in patients with lung cancer, breast cancer, and melanoma and are the leading cause of morbidity and mortality. The incidence of BM has increased with advanced neuroimaging and prolonged overall survival of cancer patients. With the advancement of local treatment modalities, including stereotactic radiosurgery and navigation-guided microsurgery, BM can be controlled long-term, even in cases with multiple lesions. However, radiationchemotherapeutic agents are also toxic to the brain, usually irreversibly and cumulatively, and it remains difficult to completely cure BM. Thus, we must understand the molecular events that begin and sustain BM to develop effective targeted therapies and tools to prevent local and distant treatment failure. BM most often spreads hematogenously, and the blood-brain barrier (BBB) presents the first hurdle for disseminated tumor cells (DTCs) entering the brain parenchyma. Nevertheless, how the DTCs cross the BBB and settle on relatively infertile central nervous system tissue remains unknown. Even after successfully taking up residence in the brain, the unique tumor microenvironment is marked by restricted aerobic glycolysis metabolism and limited lymphocyte infiltration. Brain organotropism, certain phenotype of primary cancers that favors brain metastasis, may result from somatic mutation or epigenetic modulation. Recent studies revealed that exosome secretion from primary cancer or over-expression of proteolytic enzymes can pre-condition brain vasculoendothelial cells. The concept of the metastatic niche, where resident DTCs remain dormant and protected from systemic chemotherapy and antigen exposure before proliferation, is supported by clinical observation of BM in patients clearing systemic cancer and experimental evidence of the interaction between cancer cells and tumor-infiltrating lymphocytes. This review examines extant research on the metastatic cascade of BM through the molecular events that create and sustain BM to reveal clues that can assist the development of effective targeted therapies that treat established BMs and prevent BM recurrence.

AKR1C2 Promotes Metastasis and Regulates the Molecular Features of Luminal Androgen Receptor Subtype in Triple Negative Breast Cancer Cells.

Patients with triple-negative breast cancer (TNBC) have an increased risk of distant metastasis compared to those with other subtypes. In this study, we aimed to identify the genes associated with distant metastasis in TNBC and their underlying mechanisms. We established patient-derived xenograft (PDX) models using surgically resected breast cancer tissues from 31 patients with TNBC. Among these, 15 patients subsequently developed distant metastases. Candidate metastasis-associated genes were identified using RNA sequencing. RNA sequencing of primary and PDX tumors showed that genes involved in steroid hormone biosynthesis, including AKR1C2, were significantly upregulated in patients who subsequently developed metastasis. Our data indicate that AKR1C2 is an important regulator of cancer growth and metastasis in TNBC and may be a critical determinant of LAR subtype features.

Metformin attenuates multiple myeloma cell proliferation and encourages apoptosis by suppressing METTL3-mediated m6A methylation of THRAP3, RBM25, and USP4.

Based on the results of epidemiological and preclinical studies, metformin can improve the prognosis of patients with malignant tumors. Studies have confirmed that metformin inhibits multiple myeloma (MM) cell proliferation and promotes apoptosis. Nevertheless, the specific mechanism remains to be elucidated. MM cells were intervened with different doses of metformin to detect cell proliferation and apoptosis. Western blotting and RT-qPCR were employed to assess the expression of METTL3, METTL14, WTAP, FTO, and ALKBH5 after metformin intervention. The microarray dataset GSE29023 was retrieved from the Gene Expression Omnibus (GEO) database and calculated using the R language (limma package) to authenticate differentially expressed genes (DEGs). The database for annotation, visualization, and integrated discovery (David) was applied for GO annotation analysis of DEGs. Subsequently, the string database and Cytoscape software were applied to construct protein-protein interaction (PPI) and DEM hub gene networks. Bioinformatics analysis and MeRIP were applied to predict and test METTL3-mediated m6A levels on mRNA of THRAP3, RBM25, and USP4 in METTL3 knocked-down cells. Then rescue experiments were performed to explore effects of METTL3 and THRAP3, RBM25, or USP4 on cell proliferation and apoptosis. The effect on MM cell xenograft tumor growth was observed by injection of metformin orand overexpression of METTL3 in in vivo experiments. Metformin decreased cell proliferation and encouraged cell apoptosis in a dose-dependent manner. Global m6A modification was elevated in MM cells compared to normal cells, which was counteracted by metformin treatment. Furthermore, THRAP3, RBM25, and USP4 were identified as possible candidate genes for metformin treatment by GSE29023 data mining. METTL3 interference impaired m6A modification on mRNA of THRAP3, RBM25, and USP4 as well as expression levels. The mRNA stability and expression of THRAP3, RBM25, and USP4 was decreased after metformin treatment, which was reversed by METTL3 overexpression. THRAP3, RBM25 or USP4 knockdown reversed the assistance of METTL3 overexpression on the malignant behavior of MM cells. Finally, upregulation of METTL3 was shown to exert facilitative effects on xenograft tumor growth by blocking metformin injection. The present study demonstrates that metformin can repress the expression of THRAP3, RBM25, and USP4 by inhibiting METTL3-mediated m6A modification, which in turn hamper cell proliferation and promotes cell apoptosis.

Anti-ThTo antibodies in systemic sclerosis analysis of long-term follow-up of pulmonary involvement, organ damage accrual and mortality in an Italian cohort with a case-control study.

In systemic sclerosis (SSc) American patients, anti-ThTo antibodies were reported to be associated with interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). Few data in European patients are available, so we aimed at describing the clinical associations of anti-ThTo antibodies, focusing on ILD outcome, organ damage and mortality in an Italian single-centre cohort. Case-control study anti-ThTo SSc patients vs. anti-topoisomerase (anti-topo)1, anticentromere (ACA) and quadruple-negative (anti-topo 1-, ACA-, anti-RNAP3-, anti-ThTo-) SSc patients (13 matched for sex and age at SSc onset). Organ damage was assessed with the SCTC-Damage Index. Thirteen anti-ThTo patients were evaluated 100% had limited cutaneous involvement 46% digital ulcers none had PAH, synovitis, joint contractures. As compared to anti-topo 1 and quadruple-negative patients, anti-ThTo patients developed less frequently ILD (40% vs. 85% and 84%), that required less immunosuppression (8% vs. 41% and 44%), and rarely had functional worsening (15.4% at 5 years), without development of long-term complications (no need for O2, pulmonary hypertension, death). In anti-ThTo patients, the Damage Index was lower than in anti-topo 1 and quadruple-negative patients at various timepoints, and remained low during the long-term follow-up (median 16 years). The 5- and 10-year survival of anti-ThTo patients was 92% and 72%, respectively, and did not differ from those of the SSc matched patients none of the anti-ThTo patients died due to SSc, while mortality was mainly related to cancer. In this study, anti-ThTo patients showed a mild SSc phenotype, characterised by low organ damage, favourable ILD outcome and good survival.

Pulmonary Open, Robotic and Thoracoscopic Lobectomy (PORTaL) Study Survival Analysis of 6,646 Cases.

The aim of this study was to analyze overall survival of robotic-assisted lobectomy (RL), video-assisted thoracoscopic lobectomy (VATS) and open lobectomy (OL) performed by experienced thoracic surgeons across multiple institutions. Surgeons have increasingly adopted RL for resection of early-stage lung cancer. Comparative survival data following these approaches is largely from single-institution case series or administrative datasets. Retrospective data was collected from 21 institutions from 2013-2019. Consecutive cases performed for clinical stage IA-IIIA lung cancer were included. Induction therapy patients were excluded. The propensity-score method of inverse-probability of treatment weighting (IPTW) was used to balance baseline characteristics. Overall survival (OS) was estimated using the Kaplan-Meier method. Multivariable Cox proportional hazard models were used to evaluate association among OS and relevant risk factors. A total of 2,789 RL, 2,661 VATS, and 1,196 OL cases were included. The unadjusted 5-year overall survival rate was highest for OL (84%) followed by RL (81%) and VATS (74%) P0.008. Similar trends were also observed after IPTW adjustment (RL 81% VATS 73%, OL 85%, P0.001). Multivariable Cox regression analyses revealed that OL and RL were associated with significantly higher overall survival compared to VATS (OL vs. VATS HR 0.64, P<0.001 and RL vs. VATS HR 0.79 P0.007). Our finding from this large multicenter study suggests that patients undergoing RL and OL have statistically similar OS, while the VATS group was associated with shorter OS. Further studies with longer follow-up are necessary to help evaluate these observations.

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Clinical Utility and Application of Liquid Biopsy Genotyping in Lung Cancer A Comprehensive Review.

Precision medicine has revolutionized the therapeutic management of cancer patients with a major impact on non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma, where advances have been remarkable. Tissue biopsy, required for tumor molecular testing, has significant limitations due to the difficulty of the biopsy site or the inadequacy of the histological specimen. In this context, liquid biopsy, consisting of the analysis of tumor-released materials circulating in body fluids, such as blood, is increasingly emerging as a valuable and non-invasive biomarker for detecting circulating tumor DNA (ctDNA) carrying molecular tumor signatures. In advancedmetastatic NSCLC, liquid biopsy drives target therapy by monitoring response to treatment and identifying eventual genomic mechanisms of resistance. In addition, recent data have shown a significant ability to detect minimal residual disease in early-stage lung cancer, underlying the potential application of liquid biopsy in the adjuvant setting, in early detection of recurrence, and also in the screening field. In this article, we present a review of the currently available data about the utility and application of liquid biopsy in lung cancer, with a particular focus on the approach to different techniques of analysis for liquid biopsy and a comparison with tissue samples as well as the potential practical uses in early and advancedmetastatic NSCLC.

Metal-polyphenol polymer modified polydopamine for chemo-photothermal therapy.

Chemotherapy combined with photothermal therapy (PTT) is a new way to improve the curative effect of cancer treatment. Here, we developed a multifunctional nanoparticle, namely PTXmPDAFe-GA with the loading of a chemotherapeutic drug paclitaxel (PTX) for targeted and synergistic chemotherapyphotothermal therapy in lung cancer. Fe-gallic acid (Fe-GA) was coated on the surface of mesoporous polydopamine (mPDA) nanoparticles, and then the PTX was placed in the mesopores. The drug release of the loaded PTX exhibited pH- and thermal-dual responsive manner. Both mPDA and Fe-GA have high photothermal conversion ability and play a role in photothermal therapy. In addition, the results revealed that mPDAFe-GA had excellent biocompatibility and low hemolysis rate. The PTX-loaded mPDAFe-GA not only has excellent killing effect on lung cancer cells (A549)

Efficacy and safety of immune checkpoint inhibitors with or without radiotherapy in metastatic non-small cell lung cancer A systematic review and meta-analysis.

Circulating immune response proteins predict the outcome following disease progression of osimertinib treated epidermal growth factor receptor-positive non-small cell lung cancer patients.

Lung cancer patients with sensitizing epidermal growth factor receptor (EGFR) mutations treated with osimertinib will eventually develop progressive disease (PD). The survival following PD varies greatly between patients, and no effective treatment strategy has been established. Furthermore, at the moment, no easily accessible and precise biomarker exists that can predict the survival after PD. We analyzed blood samples drawn from non-small cell lung cancer patients harboring EGFR mutations that were treated with osimertinib. The levels of 92 circulating proteins were analyzed from plasma samples using a proximity extension assay (PEA). The results were evaluated with Gene Ontology (GO) enrichment analysis to reveal patterns of protein expression at progression while on osimertinib treatment. We found that the expression of 7 proteins were significantly altered at PD, compared to a sample taken at osimertinib response. GO enrichment analysis demonstrated that most of the significant proteins were related to the immune system, specifically the adaptive immune response. Defining two groups of patients, based on the levels of circulating immune response proteins at PD, revealed significant differences in the overall survival (OS) after PD hazard ratio (HR) 3.04 95% confidence interval (CI) 1.24-7.45 P0.0046. In this study, we discover novel circulating biomarkers that can predict the OS after PD on osimertinib. These findings support the recent acknowledgement of the immune systems importance in osimertinib resistance.

Narrative review blood and tumor biomarker testing in non-small cell lung cancer without an oncogenic driver.

For patients with metastatic non-small cell lung cancer (NSCLC) without an oncogenic driver, systemic therapy with immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy have significantly improved the outcomes. However, the majority of patients do not have a durable response, and there is a need for additional predictive biomarkers. The objective of this narrative review is to describe potential biomarkers for immunotherapy. Narrative overview of the literature synthesizing the findings of literature reporting retrospective, prospective, and subset analyses of studies investigating potential predictive biomarkers for ICI. Tumor expression of programmed death ligand-1 (PD-L1) is the only clinically available biomarker for patients receiving ICI-based therapy. However, PD-L1 has significant limitations and studies have investigated the predictive value of higher PD-L1 expression levels. There has been interest in tumor mutation burden (TMB) based on the premise that a higher TMB would be associated with a more neoantigens, which would increase the likelihood of an immune response. The studies to date have not revealed a consistent association with TMB level and survival benefit. Kelch-like ECH Associated Protein 1 ( None of the current biomarkers in development are validated for use in routine clinical care. Given the complexity of NSCLC biology and immune response to ICI most likely a composite biomarker using multiple biomarkers will need to be develop.

BRAF RNA is prognostic and widely expressed in lung adenocarcinoma.

BRAF is a critical member of proliferation pathways in cancer, and a mutation is present in only 2-4% of lung adenocarcinomas (LADC). There is no data available on the expression pattern of BRAF RNA that might result in enhanced signalling and drug resistance. LADC tissue samples (n64) were fixed and processed into paraffin blocks. Tissue microarrays (TMA) were constructed, and RNAScope WT BRAF RNA is expressed in LADC, with no significant expressional difference between early-stage (I-II) and advanced-stage (III-IV) patients (P0.317). Never smokers exhibited significantly increased BRAF expression (compared to current and ex-smokers, P<0.01) and tumor necrosis correlated significantly with BRAF expression (P0.014). PD-L1 expression was assessed on tumor cells and immune cells, PD-1 expression was evaluated on immune cells. There was no significant difference in BRAF RNA expression between tumor cell PD-L1-high We found an increased expression of BRAF RNA in all stages in LADC. High BRAF expression was associated with tumor necrosis, distinct immune checkpoint biology and outcomes. We recommend further evaluating the potential of targeting overexpressed BRAF pathways in LADC.

Genome-wide epigenetic and mRNA-expression profiling followed by CRISPRCas9-mediated gene-disruptions corroborate the

Epithelial-mesenchymal-transition (EMT) is an epigenetic-based mechanism contributing to the acquired treatment resistance against receptor tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) cells harboring epidermal growth factor receptor ( We characterized genome-wide changes in mRNA-expression, DNA-methylation and the histone-modification H3K36me3 in Acquired EMT-E-TKI-R was analyzed with three omics approaches. RNA-sequencing identified 2,233 and 1,972 up- and down-regulated genes, respectively, and among these were established EMT-markers. DNA-methylation EPIC array analyses identified 14,163 and 7,999 hyper- and hypo-methylated, respectively, differential methylated positions of which several were present in EMT-markers. Finally, H3K36me3 chromatin immunoprecipitation (ChIP)-sequencing detected 2,873 and 3,836 genes with enrichment and depletion, respectively, and among these were established EMT-markers. Correlation analyses showed that EMT-E-TKI-R mRNA-expression changes correlated better with H3K36me3 changes than with DNA-methylation changes. Moreover, the omics data supported the involvement of the The current study describes the synchronous genome-wide changes in mRNA-expression, DNA-methylation, and H3K36me3 in NSCLC EMT-E-TKI-R. The omics approaches revealed potential novel diagnostic markers and treatment targets. Besides, the study consolidates the functional impact of the

The association between clinical parameters and resectability in stage III non-small cell lung cancer, and a combination of N2 lymph node burden and lung immune prognostic index score as a potential biomarker.

Surgery is important treatment option for stage III non-small cell lung cancer (NSCLC) because of its curative potential. We investigated the characteristics of resectable patients, and compared the outcomes according to treatment modalities. Among 1,092 patients with NSCLC diagnosed between 2008 to 2020 from 7 university hospitals of Catholic Medical Center, we retrospectively analyzed 252 patients with clinical or pathological stage III. We compared survival outcomes among the groups according to resectability, first-line treatments, and the lung immune prognostic index (LIPI) score. Clinical N2 subgroup was analyzed using multi-parameter scoring system. The resectable group consisted of less smokers, showed better pulmonary function and lower inflammatory markers, and tended to be diagnosed as earlier cancer stage than the unresectable group. The resectable group showed better progression-free survival (PFS) and overall survival (OS) than the unresectable group (P<0.001 and P<0.001, respectively). Regarding the first-line treatment, surgery showed the longest median PFS (33.70 months) and the highest 12-month OS rate (91.6%) than the other treatment modalities. OS was significantly different depending on the LIPI score in whole population, as well as in the unresectable group (P0.004 and P0.003, respectively). LIPI 0 group exhibited better OS than LIPI 1 and 2 in both populations. Eastern Cooperative Oncology Group (ECOG) 2-4, LIPI 1-2, and first-line treatment were independent prognostic factors for OS. Smoking, forced expiratory volume in the first second (FEV1) and more advanced cancer stage were associated with unresectability. In subgroup analysis of N2 disease, we attempted to create new scoring system combining lymph node (LN) status and LIPI score. This scoring system showed significant association with OS. The patients with resectable stage III NSCLC showed better PFS and OS than the patients with unresectable tumor. LIPI score exhibited possibility to be used as potential biomarker in stage III NSCLC. The multi-parameter scoring system using LN status and LIPI score was predictive of OS in the N2 subgroup.

A new preoperative localization of pulmonary nodules guided by mixed reality a pilot study of an animal model.

With the popularity of high-resolution computed tomography (HRCT), more and more pulmonary nodules are being discovered. Video-assisted thoracoscopic surgery (VATS) has become the first choice for surgical treatment of pulmonary nodules. The use of accurate preoperative localization is crucial for successful resection in VATS. At present, there are many kinds of preoperative localization methods, but there are certain disadvantages. This study aimed to evaluate the feasibility and safety of mixed reality (MR)-guided pulmonary nodules localization, which is a new method that can benefit patients to a greater extent. By constructing an animal model of pulmonary nodules localization, 28 cases of pulmonary nodules were located by MR-guided localization. We recorded the localization accuracy, localization time, insertion attempts, and incidence of complications related to localization under MR-guidance. All 28 nodules were successfully located the deviation of MR-guided localization was 5.71±2.59 mm, localization time was 8.07±1.44 min, and insertion attempts was 1. A pneumothorax and localizer dislodgement occurred in 1 case, respectively. Since preoperative localization is critical for VATS resection of pulmonary nodules, we investigated a new localization method. As indicated by our study, MR-guided localization of pulmonary nodules is feasible and safe, which is worthy of further research and promotion. We have also registered corresponding clinical trials to further investigate and help to improve our understanding of this technique.

Effect of histology on stereotactic body radiotherapy for non-small cell lung cancer oligometastatic pulmonary lesions.

Stereotactic body radiotherapy (SBRT) is commonly used to provide targeted treatment to metastatic lung disease. Investigation is needed to understand the influence of histology on treatment outcomes. We report how tumor histology affects local control (LC) in a cohort of patients with non-small cell lung cancer (NSCLC) receiving SBRT for oligometastatic and recurrent pulmonary lesions. Patients who received SBRT to recurrent or oligometastatic NSCLC pulmonary lesions from 2015-2019 at our institution were included in this retrospective cohort study. Minimum follow-up was 2 months. Kaplan-Meier (KM) analysis was performed to assess local progression-free survival (LPFS). Local failure cumulative incidence curves using death as a competing risk factor were also generated. A total of 147 treated lesions from 83 patients were included 95 lesions from 51 patients with lung adenocarcinoma and 52 lesions from 32 patients with lung squamous cell carcinoma (SqCC). Median follow-up was 23 interquartile range (IQR) 9.5-44.5 months for adenocarcinoma, and 11.5 (6-32.25) months for SqCC. Two-year LC was 89% for adenocarcinoma and 77% for SqCC (P0.04). Median overall survival (OS) was 24.5 (10-46.25) months for adenocarcinoma and 14.5 (7.75-23.25) months for SqCC. Adenocarcinoma had improved LPFS over SqCC (P0.014). SqCC was associated with increased local failure risk that approached statistical significance (P0.061) with death as a competing risk. Overall toxicity incidence was 8.2% with no G3 toxicities. For SBRT-treated oligometastatic or recurrent NSCLC pulmonary lesions, adenocarcinoma histology is associated with improved 2-year LC and LPFS compared to SqCC and reduced incidence of local recurrence (LR) with death as a competing risk.

Gene expression profiling of circulating tumor cells captured by MicroCavity Array is superior to enumeration in demonstrating therapy response in patients with newly diagnosed advanced and locally advanced non-small cell lung cancer.

Circulating tumor cells (CTCs) are a promising non-invasive tool for monitoring therapy response. The only Food and Drug Administration (FDA)-approved test is limited to enumeration of epithelial CTC without further characterization and is not approved for the management of non-small cell lung cancer (NSCLC). Here we use a MicroCavity Array (MCA) system to capture CTC agnostic of epithelial markers for further molecular testing in NSCLC. CTCs were enumerated by fluorescent microscopy as longitudinal sampling throughout disease management from 213 NSCLC patients. CTC-enriched samples from a subset of 127 patients were interrogated for gene expression by reverse transcription polymerase chain reaction (RT-PCR) using a customized pre-selected panel of 20 genes. At least 1 CTC was detected by enumeration in 53.8% of samples. Most patients had fewer than 5 CTCs (91%) and the highest observed count was 35 CTCs. Enumeration of single CTCs was not prognostic, although detection of CTC clusters at any time point was associated with increased risk of progression hazard ratio (HR) 3.00, 95% confidence interval (CI) 1.1-8.2, P0.0318. In contrast, 124 (97.6%) patients with samples interrogated for gene expression had at least 1 gene detectable in at least 1 sample, and 101 (79.5%) had at least one elevated epithelial gene in at least one timepoint. High expression of BCL2, CD274 programmed death-ligand 1 (PD-L1), CDH1, EPCAM, FGFR1, FN1, KRT18, MET and MUC1 were associated with poor prognosis. Patients with CTCs positive for at least 3 epithelial genes at baseline all progressed within 10 months (HR 8.2, P<0.001, 95% CI 3.2-21.1). BCL2, CD274 (PD-L1), EPCAM and MUC1 remained significant independent prognostic factors in multivariate, time-dependent analyses of progression and death. The selective profile of CTC genes and identification of CTC clusters better correlated with prognosis than enumeration of enriched CTC in NSCLC patients in this study.

The landscape of cancer cachexia in advanced non-small cell lung cancer a narrative review.

Cancer cachexia presents with weight loss, anorexia, and fatigue and worsens the prognosis and quality of life of cancer patients. We aimed to summarize the current relevant discourse in the literature about cancer cachexia in the setting of non-small cell lung carcinoma and the possible current and future treatments. We conduct a narrative review of the literature on the landscape of cancer cachexia in the context of non-small cell lung cancer, multimodality therapy, markers, imaging, tumor biology, pathology, chemoprevention, and technical advances. The need for appropriate intervention for cancer cachexia is increasing as the prognosis of patients with advanced non-small cell lung cancer is improving with advances in treatment. Tumor cells play a role in the pathogenesis of cachexia, where they release factors that elicit the production of inflammatory cytokines by the immune system resulting in decreased appetite, abnormal energy metabolism, and skeletal muscle degeneration. Comorbid chronic lung diseases are associated with pulmonary cachexia and sarcopenia and commonly occur in the context of lung cancer, further contributing to the increased incidence of cachexia in patients with lung cancer. Currently, a ghrelin-like agonist, anamorelin, is approved for the treatment of cancer cachexia and is used in clinical practice in Japan. The role that nutritional and exercise therapies can play as added treatments must be further explored. Cancer cachexia remains a poorly understood phenomenon, and awareness must be raised through educational activities for health care providers and patient family members. In addition, new therapeutics targeting cancer cachexia, such as GDF-15 antibodies, are in development, and further progress is expected.

Effectiveness and safety of camrelizumab in inoperable or advanced non-small cell lung cancer patients a multicenter real-world retrospective observational study (CTONG2004-ADV).

Camrelizumab plus chemotherapy have been approved as standards for the treatment of advanced non-small cell lung cancer (NSCLC) patients based on two phase III trials. However, clinical trial results may not be representative of the general population, as clinical trials often have specific inclusion and exclusion criteria. Our research aims to investigate the real-world effectiveness and safety of camrelizumab in inoperable or advanced NSCLC patients. This multicenter retrospective observational study included inoperable or advanced pathologically confirmed NSCLC patients who received at least one dose of camrelizumab at 22 hospitals. Clinical and follow-up data of camrelizumab were collected retrospectively from the medical records. The primary outcome was the objective response rate (ORR) and secondary outcomes were disease control rate (DCR), 6-month progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Multivariate logistic and Cox regression analyses were applied to identify potential predictive factors of ORR and PFS, respectively. Between July 2019 and March 2021, 336 patients were included. Adenocarcinoma was seen in 58.4% and stage IV disease in 69.3%. Twenty-nine (8.6%) had liver metastasis at baseline. Most patients received camrelizumab in the first-line setting (74.1%) and in combination with chemotherapy (60.7%). The ORR was 40.2% 95% confidence interval (CI) 34.9-45.6% and DCR was 85.1% (95% CI 81.3-88.9%), while the 6-month PFS and OS rates were 73.0% (95% CI 67.1-78.0%) and 93.1% (95% CI 89.8-95.4%), respectively. In multivariate analyses, liver metastasis odds ratio (OR), 0.324 95% CI 0.115-0.915 P0.033 and increasing lines of camrelizumab treatment ( We conducted a comprehensive overview of the effectiveness and safety profile of camrelizumab in a broader NSCLC population in real world NSCLC patients, and subgroup analysis indicated the presence of liver metastasis was associated with worse outcomes.

Neoadjuvant pembrolizumab and chemotherapy in resectable clinical stage III non-small-cell lung cancer a retrospective cohort study.

Pembrolizumab has been shown to be effective and safe in improving the survival of patients with advanced non-small-cell lung cancer (NSCLC). However, the effectiveness and safty of pembrolizumab in the induction treatment of patients with potential resectable clinical stage III NSCLC remains undetermined. A total of 25 patients who received neoadjuvant pembrolizumab plus chemotherapy for preoperative stage III NSCLC between August 2020 and November 2021 in Zhongshan Hospital were retrospectively evaluated, and 21 of them were followed by pulmonary resection. The neoadjuvant treatment was as follows intravenous pembrolizumab (200 mg) on day 1, carboplatin target area under the curve (AUC) 5 mgmL or cisplatin (75 mgm The mean age of all 25 patients was 65 years, of whom 22 were men and 3 were women. Seventeen were diagnosed before treatment as clinical stage IIIA, seven as IIIB, and one as IIB. All received neoadjuvant immunotherapy plus chemotherapy. Following induction therapy, 21 patients with stable disease or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) underwent surgical resection without delay. Among the patients who underwent operation, major pathological response (MPR) was achieved in 13 patients, including 6 (28.6%) patients achieved a complete pathological response (CPR). Two patients with partial radiologic remission refused operative treatment, one had progressive disease (PD), and another developed a grade immune pneumonia and could not tolerate surgery. However, none of the adverse events caused surgery delays or deaths. Neoadjuvant pembrolizumab plus chemotherapy could be considered reliable for clinical stage III NSCLC, but needs to be validated with more robust clinical trials.

Efficacy and safety of gemcitabine and capecitabine combination for patients with previously treated advanced primary pulmonary lymphoepithelioma-like carcinoma a retrospective single-arm cohort study.

Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare and unique subtype of non-small cell lung cancer (NSCLC). Studies reporting on salvage treatment for pretreated PLELC are limited. Positive interactions between gemcitabine (GEM) and capecitabine (CAP) have been demonstrated in preclinical studies. In addition, the clinical benefit of the combination has been reported for other malignancies. However, the efficacy and safety of the combination for pretreated PLELC remain unclear. Therefore, we conducted this retrospective study to examine the activity and safety of gemcitabine plus capecitabine (GEMCAP) combination for previously treated PLELC. Patients with PLELC at Sun Yat-sen University Cancer Center who received GEM combined with CAP between May 2013 and January 2021 as the second-line therapy or beyond were retrospectively enrolled. Treatment consisted of intravenous GEM (1,000 mgm A total of 16 patients were enrolled in this study. There were 5, 4, 4, and 3 patients treated with GEMCAP combination as the second-, third-, fourth-, and fifth-line settings, respectively. There were 8 patients with partial response (PR) (50.00%), 6 with stable disease (SD) (37.50%), 2 with progressive disease (PD) (12.50%), and none with complete response (CR). The objective response rate and disease control rate (DCR) were 50.00% and 87.50%, respectively. The most common hematological and nonhematological adverse events (AEs) at any grade were neutropenia (31.25%) and hand-foot syndrome (43.75%). At a median follow-up of 29.3 months with 95% confidence interval (CI) of 20.3 to 38.3 months, the median progression-free survival (PFS) was 9.3 months (95% CI 6.5-12.1 months). The median overall survival (OS) was 41.5 months (95% CI 3.1-79.8 months). This retrospective study demonstrated the potential clinical benefit of GEM in combination with CAP for pretreated PLELC. Future multicenter large-scale, prospective studies are warranted.

Case report A rare case of sintilimab-induced gastric stenosis and literature review.

Sintilimab is a fully human IgG4 monoclonal antibody against programmed death-1 (PD-1) used to treat classical Hodgkins lymphoma and various solid tumors. With increasing use of sintilimab, some rare adverse reactions have been reported. Here, we report a case of a 50-year-old woman with squamous non-small cell lung cancer (NSCLC) (metastasis to pericardium and pleura) who received two cycles of 200 mg sintilimab immunotherapy combined with albumin-bound paclitaxel and carboplatin chemotherapy and one cycle of sintilimab monotherapy. She was diagnosed with Sjogrens syndrome (with symptoms of fever, dry mouth, dysphagia, and eating difficulty) after three cycles treatment and received standard steroidal therapy. Prior to admission, the patient experienced severe stomach discomfort with vomiting and was hospitalized. Upper gastrointestinal iodine angiography showed significant gastric stenosis as well as lower esophageal stenosis. Subsequent ultrafine gastroscopy revealed ulceration at the stenotic site and an absence of normal peristalsis of the gastric wall. Pathological examination of the lesions showed reactive changes, including ulceration, fibrosis, and inflammatory cell infiltration. After multidisciplinary consultation, it was considered that the patients gastric stenosis with inflammatory fibrosis changes was due to a sintilimab-induced immune hyperinflammatory reaction. The patient had been treated with standard steroidal therapy since suffering from Sjogrens syndrome, but the gastric stenotic changes were not relieved. The patient then received regular bouginage of esophago-cardiac stenosis under gastroscopy to physically reexpand the fibrous hyperplasia and stenotic site, enabling normal eating function. To our knowledge, this is the first case of gastric stenosis in a patient with squamous NSCLC after using sintilimab and may help clinicians better understand potential immune-related adverse events due to sintilimab and improve assessment and management.