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Tissue- and cell-specific properties of enterochromaffin cells affect the fate of tumorigenesis toward nonendocrine adenocarcinoma of the small intestine.

Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting well-differentiated neuroendocrine tumors of putative enterochromaffin (EC) cell origin. However, EC cell-derived tumorigenesis remains poorly understood. Here, we examined whether the gain of Myc and the loss of RB1 and Trp53 function in EC cells result in SI-NET using tryptophan hydroxylase 1 (TPH1) Cre-ERT2-driven RB1

New Niflumic Acid Derivatives as EGFR Inhibitors Design, Synthesis, In Silico Studies, and Anti-proliferative Assessment.

1,3,4-oxadizole and pyrazole derivatives, are very important scaffold for medicinal chemistry. Literature survey revealed that they possess wide spectrum of biological activities among which are anti-inflammatory and antitumor. To describe the synthesis and evaluation of two classes of new niflumic acid (NF) derivatives, the 1,3,4-oxadizole derivatives (compounds 4AE) and pyrazole derivatives (compounds 5 and 6) as EGFR tyrosine kinase inhibitors in silico and in vitro. The designed compounds were synthesized using conventional organic synthesis methods. The antitumor activities of the new NF derivatives against HepG2 hepatocellular carcinoma and A549 non-small cell lung cancer cell lines were assessed in vitro via MTT assay, flow cytometry, RT-PCR, as well as via molecular docking studies. The cytotoxicity results indicated that the newly synthesized NF derivatives were cytotoxic against the two cancer cell lines, with compound 6 being the most cytotoxic, achieving the lowest IC50 concentration. Furthermore, compound 6 targeted EGFR tyrosine kinase leading to cell cycle arrest at the G2M cell cycle phase, and induction of apoptosis. The in vitro biological investigation results matched those of the molecular docking analysis. In conclusion, the new NF derivatives, specifically compound 6, exhibited favorable pharmacokinetic features and are promising EGFR tyrosine kinase inhibitors. A series of niflumic acid derivatives (3, 4A-E, 5 and 6) were successfully created and FT-IR, 1H, 13CNMR, and HRMS were used to confirm their chemical structures. According to molecular docking studies, compounds 3, 5, and 6 have the highest docking scores (ΔG) and the majority of the tested compounds have a good pharmacokinetic profile. Results of compound 6 in vitro antitumor activities show that it is a promising EGFR tyrosine kinase inhibitor.

A temporo-spatial description of moving tumor and organs by the probability of presence time proportion concept and implementation for 4D dose calculation and optimization.

Lorlatinib beyond progression plus platinumpemetrexed for ALK-positive non-small cell lung cancer patients report of two cases.

Lorlatinib is an active treatment for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) pretreated with ALK-tyrosine kinase inhibitors (-TKIs). However, there is paucity of data on the activity of platinumpemetrexed chemotherapy administered at the time of progression on lorlatinib. In addition, it is uncertain whether continuation of lorlatinib beyond progression (LBP) would provide any additional clinical benefit. Here, we describe two cases experiencing an exceptional response to platinumpemetrexed chemotherapy plus LBP and make an attempt to identify which patients characteristics and biologic profiles of the tumor could predict benefit from such an approach. In this report, presence of controlled brain metastases, rapidly progressing extracranial disease, and presence of ALK-dependent mechanisms of resistance were associated with benefit from platinumpemetrexed chemotherapy plus lorlatinib beyond progression.

Raising the Dead Limits of CPR and Harms of Defensive Practices.

We describe the case of an eighty-four-year-old man with disseminated lung cancer who had been receiving palliative care in the hospital and was found by nursing staff unresponsive, with clinically obvious signs of death, including rigor mortis. Because there was no documentation to the contrary, the nurses commenced cardiopulmonary resuscitation and called a code blue, resulting in resuscitative efforts that continued for around twenty minutes. In discussion with the hospital ethicist, senior nurses justified these actions, mainly citing disciplinary and medicolegal concerns. We argue that moral harms arise from CPR performed on a corpse and that legal concerns about failing to perform it are unfounded. We contend that such efforts are an unintended consequence of managerialist policies mandating do-not-resuscitate orders and advance care plans and of defensive practices that can value the interests of institutions and practitioners over those of patients. Health management teaching should include managerialism and its pitfalls, while clinician training should prioritize ethical reasoning and legal knowledge over defensive practice.

An abscopal effect in a gastric cancer patient treated with combined chemoimmunotherapy and palliative radiotherapy.

The prognosis of advanced gastric cancer remains poor. Palliative radiotherapy has been utilized to palliate bleeding in unresectable gastric cancer. Recent studies have described that a systemic immune response may be induced by local radiotherapy to the primary tumor lesion. Here we report a rare case of an abscopal effect in a patient with inoperable gastric cancer combined with tumor hemorrhage. A short course of radiotherapy was performed to palliate bleeding additionally, the patient was treated with chemotherapy and immunotherapy. Complete response was achieved in the lung metastasis lesion. The observed abscopal effect suggests that there may be a synergistic effect between immunotherapy and radiotherapy. This case report supports the combination of immunotherapy and radiotherapy in patients with advanced gastric cancer. Our case report suggests the potential benefits of immunotherapy combined with palliative radiotherapy in advanced gastric cancer. Metastatic lesions of cancer patients could obtain a treatment response by local radiotherapy to the primary tumor and systemic immunotherapy. The results indicate a synergistic effect of immunotherapy and radiotherapy in activating an antitumor immune response.

Characterization and management of adverse events observed with mobocertinib (TAK-788) treatment for

Mobocertinib has demonstrated durable clinical benefit in platinum-pretreated patients (PPP) with epidermal growth factor receptor exon 20 insertion-positive non-small cell lung cancer (NSCLC). Pooled safety analysis of two studies included patients with NSCLC (N 257) treated with the recommended phase 2 dose (RP2D) of mobocertinib (160 mg once daily). We report overall safety (treatment-emergent adverse events TEAEs) in the RP2D population characterization of GI and skin-related events in 114 PPP from a phase 12 study (NCT02716116) and clinical activity in PPP with and without dose reductions due to TEAEs. In the RP2D population (N 257), the most common TEAEs were diarrhea (93%), nausea (47%), rash (38%), and vomiting (37%). In PPP (N 114), median times to diarrhea onset and resolution were 5 and 2 days, respectively. Median times to onset and resolution of skin-related events were 9 and 78 days, respectively. Among PPP with (n 29) or without (n 85) dose reductions due to TEAEs, overall response rates were 21% and 31% and median durations of response were 5.7 and 17.5 months, respectively. GI and skin-related events are common with mobocertinib minimizing dose reductions with proactive management may improve clinical outcomes. NCT02716116 NCT03807778. Mobocertinib is a treatment for patients with a certain type of lung cancer. We analyzed the safety of mobocertinib in 257 patients with lung cancer. The most common side effects with mobocertinib were diarrhea, nausea, vomiting, and skin rash. In 114 patients with lung cancer who were treated in the past with chemotherapy that included platinum-based drugs, diarrhea started after about 5 days of mobocertinib treatment and went away in about 2 days. Skin-related side effects started after about 9 days and went away in about 2.5 months. One-fifth of patients who had to receive a smaller amount of mobocertinib because of side effects responded to treatment compared with one-third of patients who received the recommended mobocertinib amount. Managing side effects quickly can better help patients with lung cancer who are treated with mobocertinib.

MicroRNA-9-5p Is Involved in Lipopolysaccharide-Induced Acute Lung Injury Via the Regulation of Macrophage Polarization.

MicroRNA (miR)-9-5 p has been shown to affect lung cancer progression and lung fibrosis, but the efficacy of miR-9-5 p in acute lung injury (ALI) remained indefinite. The study was performed to probe the modulating mechanism of miR-9-5 p in ALI via regulating macrophage polarization. The ALI mouse model was established and blood samples of ALI patients were obtained. MiR-9-5 p levels in ALI mice and ALI patients were detected. Mouse pulmonary macrophages were extracted from bronchoalveolar lavage fluid and polarized into M1 and M2 macrophages. Intervention of miR-9-5 p expression was performed to observe the effects on M1 polarization and M2 polarization in lung macrophages, inflammatory factors in BALF, wetdry weight ratio (WD) in lung tissues, myeloperoxidase (MPO) activity in lung tissues, and lung tissue lesion condition. MiR-9-5 p levels were elevated in the lung tissues of ALI mice and ALI patients. MiR-9-5 p silencing could repress lung macrophages in ALI mice polarized toward the M1 phenotype and promoted the polarization toward the M2 phenotype, reduced the lung lesions, the lung water content, and the secretion levels of the pro-inflammatory factors TNF-α, IL-6, and IL-1β in BALF, increased the secretion of the anti-inflammatory factor IL-10, as well as impeded the MPO activity in the lung tissues of ALI mice. MiR-9-5 p deletion ameliorates LPS-induced inflammatory infiltration in lung tissues via inhibiting the polarization of mouse lung macrophages to the M1 phenotype and promoting the polarization to the M2 phenotype.

Comprehensive Analysis of Circular RNA Expression Profiles in Gefitinib-Resistant Lung Adenocarcinoma Patients.

Pulmonary nodules in children.

Clinicians and radiologist nowadays frequently encounter pulmonary nodules in children, thanks to the widespread use of computed tomography (CT) thorax. Most pulmonary nodules are benign however, a small number of pulmonary nodules indicate pulmonary malignancy in children, requiring prompt diagnosis and treatment. Incidentally diagnosed pulmonary nodules are common and naturally cause anxiety in families and in clinicians, leading to successive examinations. For this reason, the creation of algorithms for the diagnosis and follow-up of pulmonary nodules, and the definition of advanced imaging requirements will facilitate the management of these patients early diagnosis and treatment will be provided in patients with malignant tumors, and unnecessary interventions will be minimized in patients with benign nodules. This review is designed to explore current information on nodule definition, diagnostic evaluation, and management in the pediatric age group based on previously obtained data.

The clinical utility of the LENT score in patients with malignant pleural mesothelioma.

In malignant pleural mesothelioma (MPM), useful tools are needed to predict survival. Thus, we aimed to evaluate the LENT score, and demonstrate the performance of the LENT score in predicting survival in patients with MPM. This was a retrospective, observational single-center study. Sixty-nine patients diagnosed with MPM who had pleural effusion (March 2009-December 2020) were divided into groups according to their LENT score and compared. Median survivals were estimated and compared according to the LENT score and parameters of the LENT score. Fifty-four patients were in the low-LENT score group, 15 patients were in the moderate-LENT score group, and there were no patients in the highLENT score group. The two groups had similar characteristics in terms of age, gender, and histological subtype distribution. There were no patients with ECOG-PS 0 in the moderate-LENT score group. Serum neutrophil-tolymphocyte ratio (NLR), pleural lactate dehydrogenase (LDH), patients with serum NLR> 9, and patients with pleural LDH> 1500 were significantly higher in the moderate-LENT score group (p 0.002, 0.001, <0.01, <0.01, respectively). Fifty patients had died during a median follow-up of 38.6 ± 6.5 (95% CI 25.84-51.41) months. The median survival for all patients was 28.63 ± 3.2 (95% CI 22.33-34.92) months, higher than the original study. It was 30.97 ± 2 months in the low-LENT score group, and 20.7 ± 3.4 months in the moderate-LENT score group (p 0.98). The median survival for patients with pleural LDH<1500 was significantly higher than for patients with pleural LDH> 1500 (p 0.006) (30.97 vs. 16.73 months), while ECOG-PS (0 vs. 1) and NLR (<9 vs. >9) showed no differences. The survival in our resultant groups was higher than those reported in the original study, and the LENT score had no discriminatory ability for predicting survival in patients with MPM. We nevertheless believe that before reaching more definite conclusions, further large-scale multicenter prospective studies are needed to better define the clinical utility of the LENT score.

F-18 FDG PETCT findings of intrathoracic lymphadenopathy in EBUS-TBNA-proven anthracosis.

Anthracosis is a kind of pneumoconiosis that may cause parenchymal and bronchiolar injury and mediastinal lymphadenopathy. In this study, we aimed to investigate F-18 fluorodeoxyglucose (FDG) positron emission tomographycomputerized tomography (PETCT) findings of patients who had anthracosis diagnosis with endobronchial ultrasonography (EBUS). The patients who underwent EBUS-transbronchial needle aspiration (TBNA) and were diagnosed with anthracosis in a five year period were included in the study. The diagnosis was confirmed by surgery radiological stability. Demographic characteristics such as age, sex, smoking status, and occupational and environmental exposures were recorded. The characteristics diameter (short axis), shape, central hilar structure, necrosis sign, echogenicity, and margins measured by EBUS, and maximum standardized uptake value (SUV max value) by PETCT of the lymph node stations were evaluated. One hundred thirty-three patients with 239 lymph node stations were investigated. Biomass exposure was detected in nearly half of the patients (n 55, 41.4%) and occupational exposure was detected in 32 (24.1%) patients. Eighty-six (64.7%) patients had more than 20 packsyears of smoking history. Most of the lymph nodes (80.8%) have a higher PETCT SUV max value than 2.5. The mean diameter of the lymph nodes measured by thorax CT (16.2 ± 6.5 mm) and EBUS (12.7 ± 5.6 mm) did not show any difference according to PETCT SUV max value of ≥2.5 or not (p> 0.05). Subcarinal lymph nodes were significantly larger than the other lymph node stations. The lymph nodes with necrosis sign (p 0.028), absence of central hilar structure (p 0.013), and heterogeneous echogenicity (p 0.008) were statistically significantly related to higher SUV max value. Anthracosis should be considered as a cause of false-positive PETCT results for mediastinal lymph nodes, especially in patients with a history of occupational and environmental exposure including biomass and smoking.

Usefulness of serum S100A4 and positron-emission tomography on lung cancer accompanied by interstitial pneumonia.

The S100 calcium-binding protein A4 (S100A4) and the accumulation of 18F-fluoro-2-deoxy-D-glucose (FDG) in noncancerous interstitial pneumonia (IP) area are predictors of postoperative acute exacerbation (AE) of IP after pulmonary resection for lung cancer with IP. However, the significance of combining these markers for predicting short-term outcome and long-term prognosis is not known. Patients diagnosed with IP on preoperative high-resolution computed tomography and who had undergone pulmonary resection for primary lung cancer between April 2010 and March 2019 at Hiroshima University were included in this study. Predictive factors for the cumulative incidence of death from other than lung cancer (CIDOL) were investigated using the Fine and Gray model. CIDOL, perioperative outcome, and cumulative incidence of all death (CIAD) were retrospectively compared based on serum S100A4 and FDG accumulation. A total of 121 patients were included in this study. High S100A4 (hazard ratio HR, 2.541 p 0.006) and FDG accumulation (HR, 3.199 p 0.038) were significant predictors of CIDOL. AE of IP occurred only in patients with high S100A4FDG (). CIDOL of patients with high S100A4FDG () was higher than those with high S100A4FDG (-) or low S100A4FDG () (p < 0.001), and CIAD of patients with high S100A4FDG () was also higher than those with high S100A4FDG (-) or low S100A4FDG () patients (p 0.021). Serum S100A4 and FDG accumulation in the noncancerous IP area were significant predictors of CIDOL after lung resection for lung cancer with IP and may help decide the treatment strategy.

Deregulation of HSF1-mediated endoplasmic reticulum unfolded protein response promotes cisplatin resistance in lung cancer cells.

Mild hypothermia can induce apoptotic cell death in many cancer cells, but the underlying mechanisms remain unclear. In a genetic screen in Caenorhabditis elegans, we found that impaired endoplasmic reticulum unfolded protein response (UPR

Molecular signaling network and therapeutic developments in breast cancer brain metastasis.

Breast cancer (BC) is one of the most frequently diagnosed cancers in women worldwide. It has surpassed lung cancer as the leading cause of cancer-related death. Breast cancer brain metastasis (BCBM) is becoming a major clinical concern that is commonly associated with ER-ve and HER2ve subtypes of BC patients. Metastatic lesions in the brain originate when the cancer cells detach from a primary breast tumor and establish metastatic lesions and infiltrate near and distant organs via systemic blood circulation by traversing the BBB. The colonization of BC cells in the brain involves a complex interplay in the tumor microenvironment (TME), metastatic cells, and brain cells like endothelial cells, microglia, and astrocytes. BCBM is a significant cause of morbidity and mortality and presents a challenge to developing successful cancer therapy. In this review, we discuss the molecular mechanism of BCBM and novel therapeutic strategies for patients with brain metastatic BC.

Clinical Utility Validation of an Automated Ultrarapid Gene Fusion Assay for NSCLC.

Gene rearrangements are frequent oncologic drivers in NSCLC, and many are suitable for treatment with Food and Drug Administration-approved or experimental targeted therapies. We evaluated the accuracy, specimen acceptance profile, and limits of detection of a rapid fusion assay (Idylla GeneFusion Assay), a commercially available ultrarapid molecular assay, for its clinical utility. A collection of 97 specimens which had previously undergone next-generation sequencing testing were analyzed using the rapid fusion assay. Accuracy was evaluated by sensitivity and specificity compared with the next-generation sequencing results. The performance characteristics were tested by using a variety of different clinically relevant specimen types. Limits of detection were assessed by evaluating different input of tumor percentage and material amount. The rapid fusion assay was found to have 100% sensitivity in detecting fusions of The rapid fusion assay is quick, accurate, and versatile, allowing reliable detection of

Development and Validation of a Comprehensive Model for Predicting Distant Metastasis of Solid Lung Adenocarcinoma 3D Radiomics, 2D Radiomics and Clinical Features.

To develop and validate models for predicting distant metastases in patients with solid lung adenocarcinomas using 3D radiomic features, 2D radiomic features, clinical features, and their combinations. This retrospective study included 253 eligible patients with solid adenocarcinoma of the lung diagnosed at our hospital between August 2018 and August 2021. 3D and 2D regions of interest were segmented from computed tomography-enhanced thin-slice images of the venous phase, and 851 radiomic features were extracted in each region. The Least Absolute Shrinkage and Selection Operator (LASSO) algorithm was used to select radiomic features and calculate radiomic scores, and logistic regression was used to develop the model. Development of a 3D radiomics model (model 1), a 2D radiomics model (model 2), a combined 3D radiomics and 2D radiomics model (model 3), a clinical model (model 4), and a comprehensive model (model 5) for the prediction of distant metastases in patients with solid lung adenocarcinomas. Nomograms were drawn to illustrate model 5, and receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used for model evaluation. The AUC (area under the curve) of model 1, model 2, model 3, model 4, and model 5 in the test set was 0.711, 0.769, 0.775, 0.829, and 0.892, respectively. The Delong test showed that AUC values were statistically different between model 5 and model 1 (p0.001), and there was no statistical difference in AUC between the other models. Based on a comprehensive review of DCA, ROC curve, and Akaike information criterion (AIC), Model 5 is demonstrated to have better clinical utility, goodness of fit, and parsimony. A comprehensive model based on 3D radiomic features, 2D radiomic features, and clinical features has the potential to predict distant metastasis in patients with solid lung adenocarcinomas.

Development and Validation of a Prognostic Nomogram for Lung Adenocarcinoma A Population-Based Study.

To establish an effective and accurate prognostic nomogram for lung adenocarcinoma (LUAD). 10 prognostic factors associated with OS were identified, including age, sex, race, marital status, American Joint Committee on Cancer (AJCC) TNM stage, tumor size, grade, and primary site. A nomogram was established based on these results. C-indexes of the nomogram model reached 0.777 (95% confidence interval (CI), 0.773 to 0.781) and 0.779 (95% CI, 0.775 to 0.783) in the training and validation cohorts, respectively. The calibration curves were well-fitted for both cohorts. The AUC for the 3- and 5-year OS presented great prognostic accuracy in the training cohort (AUC 0.832 and 0.827, respectively) and validation cohort (AUC 0.835 and 0.828, respectively). The Kaplan-Meier curves presented significant differences in OS among the groups. The nomogram allows accurate and comprehensive prognostic prediction for patients with LUAD.

Research progression of gene fusion detection technology based on next generation sequencing in tumor companion diagnostics.

Gene fusion is one of the mechanisms that promote tumor development. It is also an important cause for the poor prognosis of patients. The detection of gene fusion is crucial for the recognition of tumor biomarker, cancer subtype classification, and clinical medication guidance. Appropriate methods can help the early diagnosis and avoid ineffective medication. Traditional tests include fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), reverse transcription of PCR (RT-PCR), and next generation sequencing (NGS). The next generation sequencing (NGS) mainly includes whole genome sequencing (WGS), whole transcriptome sequencing (WTS) and target sequencing (hybridization capture methodamplicon method). In clinical concomitant diagnostic applications, some factors such as operability, timemoney costs, and the level of expertise required for data analysis should be considered. This article concludes with a discussion of the technical principles of different detection methods and advantageslimitations. Meanwhile, it provides reference opinions for the detection methods of gene fusion. 基因融合是促肿瘤发展的基因组机制之一，也是影响患者预后不良的重要原因。基因融合的检测对于肿瘤生物标志物的识别、癌症亚型分类以及最终的临床用药指导至关重要，适宜的方法有助于肿瘤早期诊断及避免无效用药。传统的检测方法包括荧光原位杂交（fluorescence in situ hybridization，FISH）、免疫组化（immunohistochemical，IHC）、逆转录PCR（reverse transcription-polymerase chain reaction，RT-PCR）以及下一代测序技术（next generation sequencing，NGS）。下一代测序主要有全基因组测序（whole genome sequencing，WGS）、转录组测序（whole transcriptome sequencing，WTS）和目标区域测序（杂交捕获法扩增子法）等技术。在临床伴随诊断的应用中，检测方法的选择需要综合考虑可操作性、时间和费用以及数据分析所需的专业知识水平等因素。本文综合阐述针对基因融合的不同检测方法、技术原理以及各自优点和局限性，为基因融合检测方法的选择提供参考依据。.

Advances in the relationship between lung cancer and microbiota.

Interaction exists in lung cancer and microbiota. Lung microecological homeostasis can improve the immune tolerance, enhance immune suppression, and inhibit inflammatory responses, to reduce the lung cancer while lung cancer can lead to pulmonary microecological imbalance, change the lung environment, and promote tumor cell proliferation. Therefore, modulating microbial flora and microecological immunotherapy may be a potential and preventive treatment for lung cancer, to restore tumor immunosuppression and improve patient survival. However, the individual differences in the lung microecology, because of different genetics, ethnic characteristics, and dietary habits, increasing the difficulty of precise diagnosis and treatment, which is also the current bottleneck in the application of microecological immunotherapy. Otherwise, the effectiveness of regulatory measures such as probiotics, prebiotics or antimicrobials is questionable. The research on microbial flora is still in its infancy, and further exploration is needed to form a standardized, effective, and precise treatment plan. So, standardized, effective, and precise microbial flora treatment strategies need to be further explored. 肺癌与肺部微生物菌群存在相互影响。肺部微生态稳态可提高机体的免疫耐受，增强免疫抑制能力，抑制炎症反应，从而减少肺癌发生；而肺癌则可导致肺部微生态失衡和菌群失调，改变肺部环境，形成有利于肿瘤细胞增殖的肿瘤微环境。因此，调节微生物菌群及微生态免疫疗法可能是潜在的新型治疗和预防治疗肺癌的方案，有利于恢复肿瘤免疫抑制，提高患者生存率。然而，肺部微生态因宿主遗传、种族特征及饮食习惯不同而存在个体化差异，增加了精准诊疗的难度，也是目前微生态免疫疗法的应用瓶颈，益生菌、益生元或抗微生物药物等调节措施的有效性也值得商榷。微生物菌群的研究还处于起步阶段，形成规范、有效、精准的治疗方案还需进一步探索。.

Prognostic value of RILPL2 and its correlation with tumor immune microenvironment and glycolysis in non-small cell lung cancer.

Rab-interacting lysosomal protein - like 2 (RILPL2) has been reported to be associated with prognosis and tumor biological functions in breast cancer and endometrial carcinoma. However, its expression and functional role in non-small cell lung cancer (NSCLC) remain unclear. The expression and clinical data of lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) were downloaded from the TCGA database. The expression of RILPL2 in NSCLC cell lines was verified by the Western blot. We used online databases and bioinformatics analysis tools to explore its prognostic value, potential biological functions, and correlations with tumor immune microenvironment.The expression of RILPL2 was significantly lower in NSCLC compared with adjacent normal tissues. Low RILPL2 expression was associated with worse overall survival (OS) in NSCLC. The GO analysis showed RILPL2 was comprehensively involved in immune activity. RILPL2 expression was significantly positively correlated with the infiltration levels of B cells, CD8T cells, CD4T cells, macrophages, neutrophils, dendritic cells (P < 0.001), and it was also significantly positively correlated with programmed cell death ligand 1 (PD-L1CD274) (P < 0.001). High RILPL2 expression could predict better immunotherapy response and prognosis in the immunotherapy cohort. The GSEA analysis showed low RILPL2 expression was associated with glycolysis process in LUAD, which was verified in vitro.These results showed RILPL2 expression was correlated with prognosis, tumor microenvironment, and immunotherapy response in NSCLC. Besides, RILPL2 may regulate glycolysis in LUAD.

Proteomics analysis of meclofenamic acid-treated small cell lung carcinoma cells revealed changes in cellular energy metabolism for cancer cell survival.

Small cell lung carcinoma (SCLC) is a highly aggressive cancer with low survival rate. Although initial response to chemotherapy in SCLC patients is well-rated, the treatments applied after the disease relapses are not successful. Drug resistance is accepted to be one of the main reasons for this failure. Therefore, there is an urgent need for new treatment strategies for SCLC. Meclofenamic acid, a nonsteroidal anti-inflammatory drug, has been shown to have anticancer effects on various types of cancers via different mechanisms. The aim of this study was to investigate the alterations that meclofenamic acid caused on a SCLC cell line, DMS114 using the tools of proteomics namely two-dimensional gel electrophoresis coupled to MALDI-TOFTOF and nHPLC coupled to LC-MSMS. Among the proteins identified by both methods, those showing significantly altered expression levels were evaluated using bioinformatics databases, PANTHER and STRING. The key altered metabolism upon meclofenamic acid treatment appeared to the cellular energy metabolism. Glycolysis was suppressed, whereas mitochondrial activity and oxidative phosphorylation were boosted. The cells underwent metabolic reprogramming to adapt into their new environment for survival. Metabolic reprogramming is known to cause drug resistance in several cancer types including SCLC. The identified differentially regulated proteins in here associated with energy metabolism hold value as the potential targets to overcome drug resistance in SCLC treatment.

Osimertinib showed efficacy on contralateral multiple ground-glass nodules after segmentectomy for lung adenocarcinoma harboring primary EGFR-T790M mutation a case report and review of the literature.

Multiple ground-glass nodules (mGGNs) in the lung has been defined as synchronous multiple primary lung cancer (SMPLC), it is has been very difficult challenging to differentiate SMPLC from intrapulmonary metastases, and its treatment remains controversial. We report a case simultaneously involving mGGNs and lung adenocarcinoma harboring primary EGFR-T790M mutation, in which the patient underwent the radical resection of lesions in the left upper lung, and continued the osimertinib treatment for the residual mGGNs in all lobes of the right lung. These mGGNs displayed different responses to osimertinib. We reported a successful strategy on the postoperative treatment for mGGNs. For those that cannot be completely resected, the chemotherapy, radiotherapy, stereotactic body radiation therapy, immunotherapy and targeted therapy have been performed instead. The EGFR-TKI therapy strategy showed significant advantages, but how to achieve even better therapeutic effect needs more researches.

HNRNPC, a predictor of prognosis and immunotherapy response based on bioinformatics analysis, is related to proliferation and invasion of NSCLC cells.

Little is known about the relationship between N6-methyladenosine (m6A)-related genes and tumor immune microenvironment (TIME) in non-small cell lung cancer (NSCLC). It is unclear which m6A regulators are essential for NSCLC progression. The aim of this work was to excavate the role of m6A-related genes in the TIME and progression of NSCLC. Based on bioinformatics analysis, heterogeneous nuclear ribonucleoprotein C (HNRNPC) was considered as the most influential m6A regulator. Further study was investigated using patient samples, stable cell lines, and xenograft mice models. The differentially expressed profiles of m6A-related genes were established in NSCLC, and the NSCLC samples were clustered into two subtypes with different immune infiltration and survival time. Next, we found that the risk score (RS) based on m6A-related genes was a predictor of prognosis and immunotherapy response for NSCLC, in which HNRNPC was considered as the most influential m6A regulator. In NSCLC patients, we confirmed that HNRNPC predicted poor prognosis and correlated with tumor invasion and lymph node metastasis. RNA-seq data revealed that HNRNPC was involved in cell growth, cell migration, extracellular matrix organization and angiogenesis. In vitro, we verified that HNRNPC knockdown attenuated the cell proliferation, clonogenicity, invasion and migration. In vivo, HNRNPC knockdown inhibited the tumor growth and lung metastasis. Additionally, HNRNPC knockdown was associated with high CD8 T cell infiltration, along with elevated CD4 T cell infiltration, collagen production and angiogenesis. M6A regulator HNRNPC, a predictor of prognosis and immunotherapy response based on bioinformatics analysis, is related to proliferation and invasion of NSCLC cells.

Tumor cells-derived conditioned medium induced pro-tumoral phenotypes in macrophages through calcium-nuclear factor κB interaction.

The malignant behaviors of lung cancers are affected by not only cancer cells but also many kinds of stromal cells in tumor microenvironment (TME), including macrophages. Macrophages have been proven to extensively influence tumor progression through several mechanisms, among which switching of macrophages from pro-inflammatory phenotypes (M1-like) to anti-inflammatory phenotypes (M2-like) mediated by transcription factors such as nuclear factor κB (NF-κB) is the most crucial event. The regulation of NF-κB has been well studied, however some details remain fuzzy. Mouse primary bone marrow-derived macrophages (BMDMs) were cultured in Lewis lung carcinoma cell line LL-2-derived conditioned medium (LL-2-CM). Proliferation, migration, and polarization of BMDMs were tested by CCK8, scratch test, transwell, and flow cytometry. Secretion of several cytokines were detected by ELISA or cytometric bead array. To further explore the underlying mechanisms, BMDMs cultured in LL-2-CM were harvested for RNA-seq. Cytosolic calcium was detected by calcium probe Fluo-4-AM. Western blot was applied to exam the activation of NF-κB signal. BAPTA-AM was applied to sequestrate cytosolic calcium to further investigate the relationship between calcium and NF-κB signal. The polarization, calcium alteration, and NF-κB signal activation were further validated in BMDMs treated by CMT-64-derived conditioned medium (CMT-64-CM). LL-2-CM promoted proliferation, migration, and M2-like polarization of BMDMs and inhibited M1-like polarization of BMDMs. However two pro-inflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-Formula see text (TNF-Formula see text) were secreted. RNA-seq indicated that LL-2-CM activated both canonical and non-canonical NF-κB signal in BMDMs. Western blot showed that canonical NF-κB was temporarily elicited and attenuated at 24 h, while non-canonical NF-κB was consistently activated. At the same time, expression of genes that regulate cytosolic calcium ion concentration were down regulated, which caused diminution of cytosolic calcium in BMDMs treated with LL-2-CM. The decreased cytosolic calcium, M2-like polarization, and NF-κB activation was also observed in CMT-64-CM treated BMDMs. On the contrary, elevated cytosolic calcium was observed during M1-like polarization of BMDMs elicited by lipopolysaccharide (LPS). Interestingly, administration of calcium chelator, BAPTA-AM, impeded activation of canonical NF-κB and expression of M1-like marker induced by LPS, which further confirmed the relationship between cytosolic calcium and canonical NF-κB signal. In summary, lung cancer cell-derived conditioned medium promoted migration, proliferation, and M2-like polarization of BMDMs. The suppressed M1-like polarization was achieved through mitigating canonical NF-κB pathway via diminishing cytosolic calcium concentration. As far as we know, our work firstly revealed that cytosolic calcium is the key during inhibition of canonical NF-κB and M1-like polarization in macrophages by tumor cells.

Stem cell therapy a novel approach against emerging and re-emerging viral infections with special reference to SARS-CoV-2.

The past several decades have witnessed the emergence and re-emergence of many infectious viral agents, flaviviruses, influenza, filoviruses, alphaviruses, and coronaviruses since the advent of human deficiency virus (HIV). Some of them even become serious threats to public health and have raised major global health concerns. Several different medicinal compounds such as anti-viral, anti-malarial, and anti-inflammatory agents, are under investigation for the treatment of these viral diseases. These therapies are effective improving recovery rates and overall survival of patients but are unable to heal lung damage caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, there is a critical need to identify effective treatments to combat this unmet clinical need. Due to its antioxidant and immunomodulatory properties, stem cell therapy is considered a novel approach to regenerate damaged lungs and reduce inflammation. Stem cell therapy uses a heterogeneous subset of regenerative cells that can be harvested from various adult tissue types and is gaining popularity due to its prodigious regenerative potential as well as immunomodulatory and anti-inflammatory properties. These cells retain expression of cluster of differentiation markers (CD markers), interferon-stimulated gene (ISG), reduce expression of pro-inflammatory cytokines and, show a rapid proliferation rate, which makes them an attractive tool for cellular therapies and to treat various inflammatory and viral-induced injuries. By examining various clinical studies, this review demonstrates positive considerations for the implications of stem cell therapy and presents a necessary approach for treating virally induced infections in patients.

Thermal ablation versus radiotherapy for inoperable stage III non-small cell lung cancer a propensity score matching analysis.

To compare the survival benefits of thermal ablation (TA) and radiotherapy in inoperable patients with stage III non-small cell lung cancer (NSCLC). A retrospective analysis was conducted using the data from the Surveillance, Epidemiology, and End Results (SEER) program. Propensity score matching (PSM) was conducted to balance potential baseline confounding factors. Survival analyses were conducted using Kaplan-Meier and Cox regression methods. The present study included 33,393 inoperable patients with stage III NSCLC, including 106 patients treated with TA and 33,287 patients treated with radiotherapy. No statistical difference in overall survival (OS) ( For inoperable stage III NSCLC, the survival benefit of TA was comparable to radiotherapy. TA may be a potential therapeutic modality for inoperable stage III NSCLC.

High incidence and reversible bradycardia events following alectinib initiation.

With the widespread use of alectinib in patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), its cardiotoxicity has gradually emerged, including new-onset sinus bradycardia (SB). However, the incidence, timing, severity, and risk factors of alectinib-induced bradycardia remain unknown. From January 2020 to June 2022, 93 patients with ALK-positive NSCLC treated with alectinib were enrolled in this retrospective analysis. These patients had heart rate (HR) recorded before and after alectinib administration. By reviewing electronic medical records and follow-up, the HR changes of patients during medication were recorded. The potential risk factors associated with alectinib-induced SB were explored. According to an HR cut-off of 60 beats per minute (bpm), 47 patients (50.54%) experienced at least one recorded bradycardia. The mean HR of total participants before alectinib administration was 78.32 (standard deviation SD, 9.48) and after was 64.88 (SD, 12.21). The median maximum change in HR (range) for all patients was 11 (-55, 4) bpm. For the bradycardia subgroup, the HR of most patients (76.60%) hovered around 50-60 bpm, and 61.70% of SB occurred within 3 months after alectinib administration. Multivariate analysis indicated that baseline HR (odds ratio OR 0.86, 95% confidence interval CI 0.79-0.93, p < 0.001) and history of hypertension (OR 13.71, 95% CI 2.49-76.38, p 0.003) were independent risk factors for alectinib-related bradycardia. Alectinib-induced bradycardia had a high incidence, appeared relatively early, and was reversible by dose reduction or withdrawal.

Cardiac Morbidity Following Chemoradiation in Stage III Non-small Cell Lung Cancer Patients A Population-Based Cohort Study.

To assess the risk of cardiac toxicity following radical radiotherapy in advanced lung cancer patients. Patients with a diagnosis of stage III non-small cell lung cancer (NSCLC) receiving chemoradiotherapy were extracted from a population-based cohort in Ontario, Canada. The primary outcome of cardiac toxicity, defined as cardiac events or congestive heart failure, was assessed at 1 and 5 years following chemoradiotherapy. Secondary outcomes included overall survival, survival in relationship to post-treatment cardiac events and the effect of radiotherapy technique on cardiac toxicity. In total, 2031 NSCLC patients were included. The cumulative incidence of cardiac toxicity at 5 years was 20.3% (18.4-22.3). The median survival was 13.7 months in NSCLC patients who had a cardiac event post-chemoradiotherapy compared with 23.4 months in those who did not (P 0.012). There was a trend towards increased cumulative cardiac toxicity (hazard ratio 3.37, P 0.14) with three-dimensional conformal radiotherapy compared with intensity-modulated or volumetric arc radiotherapy techniques. The risk of cardiac events and congestive heart failure 5 years after radical thoracic radiotherapy appears high and survival is inferior at 1 year in those patients who experience a cardiac event post-treatment. More conformal radiotherapy techniques may help reduce cardiac toxicity. Further studies should investigate adaptive treatment planning and close monitoring and intervention in this high-risk group after chemoradiotherapy.

Robotic bronchoscopic needle-based confocal laser endomicroscopy to diagnose peripheral lung nodules.

Robotic bronchoscopy has demonstrated high navigational success in small peripheral lung nodules but the diagnostic yield is discrepantly lower. Needle based confocal laser endomicroscopy (nCLE) enables real-time microscopic imaging at the needle tip. We aim to assess feasibility, safety and needle repositioning based on real-time nCLE-guidance during robotic bronchoscopy in small peripheral lung nodules. Patients with suspected peripheral lung cancer underwent fluoroscopy and radial EBUS assisted robotic bronchoscopy. After radial EBUS nodule identification, nCLE-imaging of the target area was performed. nCLE-malignancy and airwaylung parenchyma criteria were used to identify the optimal sampling location. In case airway was visualized, repositioning of the biopsy needle was performed. After nCLE tool-in-nodule confirmation, needle passes and biopsies were performed at the same location. Twenty patients were included (final diagnosis n 17 (lung) cancer) with a median lung nodule size of 14.5 mm (range 8-28 mm). No complications occurred. In 1920 patients, good quality nCLE-videos were obtained. In 9 patients (45%), real-time nCLE-imaging revealed inadequate positioning of the needle and repositioning was performed. After repositioning, nCLE-imaging provided tool-in-nodule-confirmation in 1920 patients. Subsequent ROSE demonstrated representative material in 920 patients (45%) and overall diagnostic yield was 80% (1620). Of the three patients with malignant nCLE-imaging but inadequate pathology, two were diagnosed with malignancy during follow-up. Robotic bronchoscopic nCLE-imaging is feasible and safe. nCLE-imaging in small, difficult-to-access lung nodules provided additional real-time feedback on the correct needle positioning with the potential to optimize the sampling location and diagnostic yield.

High-Performance Electrochemiluminescence of a Coordination-Driven J-Aggregate K-PTC MOF Regulated by Metal-Phenolic Nanoparticles for Biomarker Analysis.

The elimination of aggregation-caused quenching of polycyclic aromatic hydrocarbons by metal-ligand coordination is of immense scientific interest in solid-state electrochemiluminescence (ECL) sensing. Herein potassium ion (K

Surgical Treatment of the Five Most Common Types of Cancer in Brazil 7 Years Analysis Overview.

Surgery is the main treatment for the majority of solid cancers. Studies investigating surgical interventions are a critical asset in improving patient health outcomes. We aim to analyze the temporal and spatial distribution of the surgical treatment of Brazils 5 most common types of cancer. The selected cancers were stomach, colorectal and rectosigmoid junction, bronchial and lung, breast, and prostatic. Surgical data were collected from the DATASUS database from 2013 to 2019. Statistical analyses included linear regression tests with a significance level of .05. From 2013 to 2019, 19.72% of the diagnoses of all cancers were treated surgically. Only breast cancer didnt have a significant linear increase in surgeries ( Brazils surgical oncology scenario is progressing positively through the analyzed period. The analysis of the 5 most common types of cancer in Brazil and their progression over the years provides an idea of the cancer surgery capacity in Brazil. There were disparities between the Brazilian regions in all types of cancer. Our study is the first step to better comprehending cancer care in Brazil and the access issues that some areas have. With that, it will be possible to provide better care to cancer patients needing surgical treatment.

Prognostic Factors in Patients with Clinic Locally Advanced T4 Lung Cancer Surgical Considerations.

Inclusion of surgery in the treatment of T4 lung cancer has been a debate for the last two decades. The aim of this study is to investigate the potential prognostic factors which could affect the outcome. Fifty-seven clinical T4 non-small cell lung carcinoma (NSCLC) patients out of 716 lung resections, who were operated at a single institution in 7 years period, were included in this study. Patients are grouped into three groups as patients with neoadjuvant treatment group (group 1 Mean overall survival (OS) was 48.43 ± 4.4 months and mean disease-free survival (DFS) 40.55 ± 4.46 months for all patients. Thirty days mortality was 5.2% and complication rates were 63.1%. Two years OS was 61.4 ± 6.4%, DFS was 58.1 ± 7.8%. Group 1, Group 2, and Group 3 patients had mean 39.14 ± 5.6, 44.7 ± 7.1, and 62.9 ± 4.8 months for OS ( According to our outcomes, surgery should be included in the treatment of clinical T4 lung cancer when physiologically and oncologically possible with careful patient selection. This study demonstrates that patients receiving straightforward surgery have longer survival, in spite of higher perioperative mortality rate. Risks and benefits should be considered carefully.

Improving Lung Cancer Diagnosis with Computed Tomography Radiomics and Serum Histoplasmosis Testing.

Indeterminate pulmonary nodules (IPNs) are a diagnostic challenge in regions where pulmonary fungal disease and smoking prevalence are high. We aimed to determine the impact of a combined fungal and imaging biomarker approach compared to a validated prediction model (Mayo) to rule out benign disease and diagnose lung cancer. Adults aged 40-90 years with 6-30 mm IPNs were included from four sites. Serum samples were tested for Histoplasmosis IgG and IgM antibodies by enzyme immunoassay and a computed tomography based risk score was estimated from a validated radiomic model. Multivariable logistic regression models including Mayo score, radiomics score, and IgG and IgM Histoplasmosis antibody levels were estimated. The areas under the receiver-operating characteristics curves (AUC) of the models were compared among themselves and to Mayo. Bias-corrected clinical net reclassification index (cNRI) was estimated to assess clinical reclassification using a combined biomarker model. We included 327 patients 157 from Histoplasmosis-endemic regions. The combined biomarker model including radiomics, Histoplasmosis serology, and Mayo score demonstrated improved diagnostic accuracy when endemic Histoplasmosis was accounted for (AUC 0.84, 95% CI 0.79-0.88, p<0.0001 compared to 0.73, 95%CI 0.67-0.78 for Mayo). The combined model demonstrated improved reclassification with cNRI of 0.18 among malignant nodules. Fungal and imaging biomarkers may improve diagnostic accuracy and meaningfully reclassify IPNs. The endemic prevalence of Histoplasmosis and cancer impact model performance when using disease related biomarkers. Integrating a combined biomarker approach into the diagnostic algorithm of IPNs could decrease time to diagnosis.

Single-Cell Analysis Reveals Transcriptomic Features of Drug-Tolerant Persisters and Stromal Adaptation in a Patient-Derived EGFR-Mutated Lung Adenocarcinoma Xenograft Model.

Targeted therapies require life-long treatment, as drug discontinuation invariably leads to tumor recurrence. Recurrence is mainly driven by minor subpopulations of drug-tolerant persister (DTP) cells that survive the cytotoxic drug effect. In lung cancer, DTP studies have mainly been conducted with cell line models. We conducted an in vivo DTP study using a lung adenocarcinoma patient-derived xenograft tumor driven by an EGFR mutation. Daily treatment of tumor-bearing mice for 5 to 6 weeks with the EGFR inhibitor erlotinib markedly shrunk tumors and generated DTPs, which were analyzed by whole exome, bulk population transcriptome, and single-cell RNA sequencing. The DTP tumors maintained the genomic clonal architecture of untreated baseline (BL) tumors but had reduced proliferation. Single-cell RNA sequencing identified a rare (approximately 4%) subpopulation of BL cells (DTP-like) with transcriptomic similarity to DTP cells and intermediate activity of pathways that are up-regulated in DTPs. Furthermore, the predominant transforming growth factor-β activated cancer-associated fibroblast (CAF) population in BL tumors was replaced by a CAF population enriched for IL6 production. In vitro experiments indicate that these populations interconvert depending on the levels of transforming growth factor-β versus NF-κB signaling, which is modulated by tyrosine kinase inhibitor presence. The DTPs had signs of increased NF-κB and STAT3 signaling, which may promote their survival. The DTPs may arise from a specific preexisting subpopulation of cancer cells with partial activation of specific drug resistance pathways. Tyrosine kinase inhibitor treatment induces DTPs revealing greater activation of these pathways while converting the major preexisting CAF population into a new state that may further promote DTP survival.

Predicted Inferior Outcomes for Lung SBRT With Treatment Planning Systems That Fail Independent Phantom-Based Audits.

More than 15% of radiation therapy clinics fail external audits with anthropomorphic phantoms conducted by Imaging and Radiation Oncology Core-Houston (IROC-H) while passing other industry-standard quality assurance (QA) tests. We seek to evaluate the predicted effect of such failed plans on outcomes for patients treated with stereotactic body radiation therapy (SBRT) for lung tumors. We conducted a retrospective study of 55 patients treated with SBRT for lung tumors with a prescription biologically equivalent dose (BED) A leaf-tip offset value of -1.0 mm decreased the fraction of plans receiving a planning treatment volume of BED Simulated treatment plans with modest MLC leaf offsets result in lung SBRT plans that significantly underdose tumor or exceed OAR constraints. These dosimetric endpoints translate to significant detriments in TCP. These simulated plans mimic planning systems that pass internal QA measures but fail independent phantom-based tests, underscoring the need for enhanced quality assurance including external audits of TPS.

Efficacy and safety of first-line lorlatinib versus crizotinib in patients with advanced, ALK-positive non-small-cell lung cancer updated analysis of data from the phase 3, randomised, open-label CROWN study.

After a median follow-up of 18·3 months, the third-generation anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor, lorlatinib, improved progression-free survival in patients with treatment-naive, ALK-positive non-small-cell lung cancer in the phase 3 CROWN study. Here we report updated efficacy data, including intracranial activity, from an unplanned analysis after 3 years of follow-up. CROWN is an ongoing, international, randomised, open-label phase 3 trial done in 104 centres in 23 countries worldwide. Eligible participants were aged 18 years and older or aged 20 years and older (depending on local regulations) with advanced, ALK-positive non-small-cell lung cancer, had received no previous systemic treatment for metastatic disease, had at least one extracranial measurable target lesion (according to the Response Evaluation Criteria in Solid Tumours RECIST, version 1.1), and had an Eastern Cooperative Oncology Group performance status score of 0-2. Patients were randomly assigned (11) to oral lorlatinib 100 mg daily or oral crizotinib 250 mg twice daily in 28-day cycles. Randomisation was stratified by the presence or absence of brain metastasis, and by ethnicity. Since the primary endpoint of the study had been met at the planned interim analysis, no further formal analysis of progression-free survival was planned, per protocol. The current unplanned analysis was done to further characterise tumour-related endpoints with a longer follow-up and is presented descriptively. For the planned study, the primary endpoint was progression-free survival assessed by blinded independent central review. Secondary endpoints included progression-free survival (investigator), objective response rate, intracranial objective response rate, time to intracranial progression, duration of response, intracranial duration of response, and safety. Efficacy endpoints were also assessed by the presence or absence of baseline brain metastases. This study is registered with ClinicalTrials.gov, NCT03052608. Between May 11, 2017, and Feb 28, 2019, 425 patients were screened for eligibility, of whom 296 were enrolled and randomly assigned to the lorlatinib (n149) or crizotinib (n147) group. At data cutoff for this unplanned analysis (Sept 20, 2021), median duration of follow-up for progression-free survival was 36·7 months (IQR 31·3-41·9) for lorlatinib and 29·3 months (10·8-35·0) for crizotinib. Median progression-free survival by blinded independent central review was not reached (95% CI not reached-not reached) for lorlatinib and was 9·3 months (7·6-11·1) for crizotinib (hazard ratio HR 0·27 95% CI 0·18-0·39). 3-year progression-free survival was 64% (95% CI 55-71) in the lorlatinib group and 19% (12-27) in the crizotinib group. Progression-free survival (investigator), objective response rate, intracranial objective response rate, time to intracranial progression, and duration of response were improved with lorlatinib versus crizotinib. In patients with baseline brain metastases (n37 lorlatinib n39 crizotinib), the HR for time to intracranial progression for lorlatinib versus crizotinib was 0·10 (95% CI 0·04-0·27) in patients without baseline brain metastases (n112 lorlatinib n108 crizotinib), the HR was 0·02 (95% CI 0·002-0·14). In patients without brain metastases, one (1%) in the lorlatinib group and 25 (23%) in the crizotinib group had intracranial progression. Grade 3-4 adverse events occurred in 113 (76%) of 149 patients (most commonly due to altered lipid levels) with lorlatinib and in 81 (57%) of 142 patients with crizotinib. Adverse events led to treatment discontinuation in 11 (7%) patients in the lorlatinib group and 14 (10%) patients in the crizotinib group. There were no new safety signals. These updated, long-term data from CROWN show the durable benefit of lorlatinib over crizotinib in patients with treatment-naive, ALK-positive non-small-cell lung cancer and support the use of first-line lorlatinib in patients with and without baseline brain metastases. Pfizer.

Radiation pneumonitis prediction model with integrating multiple dose-function features on 4DCT ventilation images.

Radiation pneumonitis (RP) is dose-limiting toxicity for non-small-cell cancer (NSCLC). This study developed an RP prediction model by integrating dose-function features from computed four-dimensional computed tomography (4DCT) ventilation using the least absolute shrinkage and selection operator (LASSO). Between 2013 and 2020, 126 NSCLC patients were included in this study who underwent a 4DCT scan to calculate ventilation images. We computed two sets of candidate dose-function features from (1) the percentage volume receiving > 20 Gy or the mean dose on the functioning zones determined with the lower cutoff percentile ventilation value, (2) the functioning zones determined with lower and upper cutoff percentile ventilation value using 4DCT ventilation images. An RP prediction model was developed by LASSO while simultaneously determining the regression coefficient and feature selection through fivefold cross-validation. We found 39.3 % of our patients had a ≥ grade 2 RP. The mean area under the curve (AUC) values for the developed models using clinical, dose-volume, and dose-function features with a lower cutoff were 0.791, and the mean AUC values with lower and upper cutoffs were 0.814. The relative regression coefficient (RRC) on dose-function features with upper and lower cutoffs revealed a relative impact of dose to each functioning zone to RP. RRCs were 0.52 for the mean dose on the functioning zone, with top 20 % of all functioning zone was two times greater than that of 0.19 for these with 60 %-80 % and 0.17 with 40 %-60 % (P < 0.01). The introduction of dose-function features computed from functioning zones with lower and upper cutoffs in a machine learning framework can improve RP prediction. The RRC given by LASSO using dose-function features allows for the quantification of the RP impact of dose on each functioning zones and having the potential to support treatment planning on functional image-guided radiotherapy.

A markerless beams eye view tumor tracking algorithm based on unsupervised deformable registration learning framework of VoxelMorph in medical image with partial data.

To propose an unsupervised deformable registration learning framework-based markerless beams eye view (BEV) tumor tracking algorithm for the inferior quality megavolt (MV) images with occlusion and deformation. Quality assurance (QA) plans for thorax phantom were delivered to the linear accelerator with artificially treatment offsets. Electronic portal imaging device (EPID) images (682 in total) and corresponding digitally reconstructed radiograph (DRR) were gathered as the moving and fixed image pairs, which were randomly divided into training and testing set in a ratio of 0.70.3 to train a non-rigid registration model with Voxelmorph. Simultaneously, 533 pairs of patient images from 21 lung tumor plans were acquired for tumor tracking investigation to offer quantifiable tumor motion data. Tracking error and image similarity measures were employed to evaluate the algorithms accuracy. The tracking algorithm can handle image registration with non-rigid deformation and losses ranging from 10 % to 80 %. The tracking errors in the phantom study were below 3 mm in about 86.8 % of cases, and below 2 mm in about 80 % of cases. The normalized mutual information (NMI) changes from 1.182 ± 0.024 to 1.198 ± 0.024 (p < 0.005). The patient target had an average translation of 3.784 mm and a maximum comprehensive displacement value of 7.455 mm. NMI of patient images changes from 1.209 ± 0.027 to 1.217 ± 0.026 (p < 0.005), indicating the presence of non-negligible non-rigid deformation. The study provides a robust markerless tumor tracking algorithm for multi-modal, partial data and inferior quality image processing.

The use of medical cannabis concomitantly with immune checkpoint inhibitors in non-small cell lung cancer A sigh of relief

The use of medical cannabis has rapidly increased among cancer patients worldwide. Cannabis is often administered concomitantly with cancer medications, including immune checkpoint inhibitors (ICIs). As the cannabinoid receptors are abundantly expressed and modulate immune cells, it has been hypothesised that cannabis may attenuate the activity of ICIs. We aimed to assess the effect of cannabis on ICIs efficiency in patients having non-small cell lung cancer (NSCLC). The murine model of CT26 tumour-bearing mice treated with an anti-PD-1 antibody and Δ9-tetrahydrocannabinol (THC) was used to evaluate the interaction between THC and ICIs in vivo. Correlation between use of medical cannabis and clinical outcome was evaluated in a cohort of 201 consecutive metastatic NSCLC patients treated with monotherapy pembrolizumab as a first-line treatment. Median overall survival (OS) of the mice receiving a control vehicle, THC, anti-PD-1 antibody or their combination was 21, 24, 31 and 54 days, respectively (p < 0.05 for the combination treatment compared to a control vehicle), indicating that THC did not reduce the efficacy of anti-PD-1 therapy. Of 201 NSCLC patients treated with first-line monotherapy pembrolizumab for metastatic disease, 102 (50.7%) patients received licence for cannabis within the first month of treatment. Cannabis-treated patients were younger compared to the cannabis naïve patients (median age 68 versus 74, p 0.003), with female predominance (62, 60.8% versus 34, 34.3%, p 0.002) and with more prevailing brain metastasis (15.7% versus 5%, p 0.013). Similar distribution of histology, smoking status, ECOG (Eastern Cooperative Oncology Group) and programmed death-ligand 1 expression was noted between the groups. Liver metastases were marginally significant (19.6% versus 10.1%, p 0.058). The most common indication for cannabis was pain (71%) followed by loss of appetite (34.3%). Time to tumour progression was similar for cannabis-naive and cannabis-treated patients (6.1 versus 5.6 months, respectively, 95% confidence interval, 0.82 to 1.38, p 0.386), while OS was numerically higher in the cannabis-naive group (54.9 versus 23.6 months) but did not reach statistical significance (95% confidence interval 0.99 to 2.51, p 0.08). In multivariate analyses, we did not identify cannabis use as an independent predictor factor for mortality. Preclinical and clinical data suggest no deleterious effect of cannabis on the activity of pembrolizumab as first-line monotherapy for advanced NSCLC. The differences in OS can most likely be attributed to higher disease burden and more symptomatic disease in the cannabis-treated group. These data provide reassurance regarding the absence of a deleterious effect of cannabis in this clinical setting.

Assessment of RANKRANK-L prevalence and clinical significance in NSCLC European Thoracic Oncology Platform Lungscape cohort and SPLENDOUR randomized clinical trial.

The primary objective of this study is to evaluate the clinical significance of RANKL expression, in both a retrospective cohort of surgically resected stage I-III NSCLC (Lungscape) and a randomized clinical trial-cohort (SPLENDOUR) of advanced NSCLC treated with chemotherapy alone or in combination with denosumab. RANK-L expression was assessed on tissue microarrays (TMAs) in Lungscape and whole sections in SPLENDOUR, using immunohistochemistry, with H-scores values > 0 indicating positivity. Prevalence of RANK positivity and its association with clinicopathological characteristics, and patient outcome was explored in a subset of the ETOP Lungscape cohort and in SPLENDOUR. Also investigated were the prevalence of RANK overexpression (proportion of positive cancer cells ≥ 50%) in the Lungscape cohort, and RANK-L in the SPLENDOUR trial. In the Lungscape cohort, RANK expression was assessed at a median follow-up of 46 months (N 488 patients 4 centers) 35% were female, 44496% adenocarcinomas (AC)squamous cell carcinomas (SCC)other, 482725% with stage IIIIII. Median RFSTTROS were 58Not reached74 months. Prevalence of RANK expression was 31% (95%CI27%-35%) significantly higher in AC 50% (95%CI43%-57%) vs SCC 12% (95%CI8%-16%) (p < 0.001) more frequent in females (42% vs 25%, p < 0.001) and tumors ≤ 4 cm (35.3% vs 23.3%, p 0.0065). No association with outcome was found. In the SPLENDOUR trial (463 patients), the prevalence of membranous and cytoplasmic RANK positivity was 34% (95%CI30%-38%) and 9% (95%CI7%-12%), respectively, while prevalence for RANK-L was 5% (95%CI3%-7%) and 36% (95%CI31%-40%), respectively. Cytoplasmic RANK-L positivity was more common among females (47% vs 31%, p 0.001) and in non-SCC histology (45% vs 10%, p < 0.0001). At the pre-specified 1% significance level, no prognostic or predictive effect was found. Both cohorts indicate that RANK expression is more common in adenocarcinomanon-squamous NSCLC and in female patients. No prognostic effect is found, and in the clinical trial involving addition of denosumab to chemotherapy no predictive effect is detected.

4D lung MRI with high-isotropic-resolution using half-spoke (UTE) and full-spoke 3D radial acquisition and temporal compressed sensing reconstruction.

EarlyCDT Lung blood test for risk classification of solid pulmonary nodules systematic review and economic evaluation.

EarlyCDT Lung (Oncimmune Holdings plc, Nottingham, UK) is a blood test to assess malignancy risk in people with solid pulmonary nodules. It measures the presence of seven lung cancer-associated autoantibodies. Elevated levels of these autoantibodies may indicate malignant disease. The results of the test might be used to modify the risk of malignancy estimated by existing risk calculators, including the Brock and Herder models. The objectives were to determine the diagnostic accuracy, clinical effectiveness and cost-effectiveness of EarlyCDT Lung and to develop a conceptual model and identify evidence requirements for a robust cost-effectiveness analysis. MEDLINE (including Epub Ahead of Print, In-Process Other Non-Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE), EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index, EconLit, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment database, NHS Economic Evaluation Database ( NHS EED ) and the international Health Technology Assessment database were searched on 8 March 2021. A systematic review was performed of evidence on EarlyCDT Lung, including diagnostic accuracy, clinical effectiveness and cost-effectiveness. Study quality was assessed with the quality assessment of diagnostic accuracy studies-2 tool. Evidence on other components of the pulmonary nodule diagnostic pathway (computerised tomography surveillance, Brock risk, Herder risk, positron emission tomography-computerised tomography and biopsy) was also reviewed. When feasible, bivariate meta-analyses of diagnostic accuracy were performed. Clinical outcomes were synthesised narratively. A simulation study investigated the clinical impact of using EarlyCDT Lung. Additional reviews of cost-effectiveness studies evaluated (1) other diagnostic strategies for lung cancer and (2) screening approaches for lung cancer. A conceptual model was developed. A total of 47 clinical publications on EarlyCDT Lung were identified, but only five cohorts (695 patients) reported diagnostic accuracy data on patients with pulmonary nodules. All cohorts were small or at high risk of bias. EarlyCDT Lung on its own was found to have poor diagnostic accuracy, with a summary sensitivity of 20.2% (95% confidence interval 10.5% to 35.5%) and specificity of 92.2% (95% confidence interval 86.2% to 95.8%). This sensitivity was substantially lower than that estimated by the manufacturer (41.3%). No evidence on the clinical impact of EarlyCDT Lung was identified. The simulation study suggested that EarlyCDT Lung might potentially have some benefit when considering intermediate risk nodules (10-70% risk) after Herder risk analysis. Two cost-effectiveness studies on EarlyCDT Lung for pulmonary nodules were identified none was considered suitable to inform the current decision problem. The conceptualisation process identified three core components for a future cost-effectiveness assessment of EarlyCDT Lung (1) the features of the subpopulations and relevant heterogeneity, (2) the way EarlyCDT Lung test results affect subsequent clinical management decisions and (3) how changes in these decisions can affect outcomes. All reviewed studies linked earlier diagnosis to stage progression and stage shift to final outcomes, but evidence on these components was sparse. The evidence on EarlyCDT Lung among patients with pulmonary nodules was very limited, preventing meta-analyses and economic analyses. The evidence on EarlyCDT Lung among patients with pulmonary nodules is insufficient to draw any firm conclusions as to its diagnostic accuracy or clinical or economic value. Prospective cohort studies, in which EarlyCDT Lung is used among patients with identified pulmonary nodules, are required to support a future assessment of the clinical and economic value of this test. Studies should investigate the diagnostic accuracy and clinical impact of EarlyCDT Lung in combination with Brock and Herder risk assessments. A well-designed cost-effectiveness study is also required, integrating emerging relevant evidence with the recommendations in this report. This study is registered as PROSPERO CRD42021242248. This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in People at risk of lung cancer sometimes undergo computerised tomography ( CT ) scans of their lungs. These scans may identify lung nodules that could be cancerous. Currently, CT scans of the lung nodules, or sometimes further positron emission tomography–computerised tomography ( PET-CT ) scans, are used to predict the risk that a nodule is cancerous. EarlyCDT Lung is a blood test that detects substances, called autoantibodies, associated with having cancer. If the autoantibodies are detected, the chance of a lung nodule being cancerous may be substantially increased. This test could help doctors make decisions about whether to treat immediately, carry out further tests or monitor the nodule over time to see if it grows or changes shape. This project examined the evidence on the clinical value of the EarlyCDT Lung test. We reviewed all published studies of EarlyCDT Lung and reanalysed the reported data. We found that there has been little research on EarlyCDT Lung among people with lung nodules (only five studies comprising 695 patients). This makes it difficult to draw any firm conclusions. The evidence suggests that EarlyCDT Lung may not be particularly effective at determining which lung nodules are cancerous, and may not improve diagnosis when compared with using CT and PET - CT scans. However, this is uncertain because the evidence is so limited. This project also looked for evidence on the value for money of the EarlyCDT Lung test in detecting lung cancer, and found no relevant evidence. This means that the value for money of EarlyCDT Lung is largely unknown, and there is currently no good evidence to support further analyses on this. We therefore sought to summarise the information and analyses that would be needed to support a future assessment of the value for money of EarlyCDT Lung.

Normalizing the Immune Macroenvironment via Debulking Surgery to Strengthen Tumor Nanovaccine Efficacy and Eliminate Metastasis.

In tumor nanovaccines, nanocarriers enhance the delivery of tumor antigens to antigen-presenting cells (APCs), thereby ensuring the robust activation of tumor antigen-specific effector T-cells to kill tumor cells. Through employment of their high immunogenicity and nanosize, we have developed a Plug-and-Display delivery platform on the basis of bacterial outer membrane vesicles (OMVs) for tumor nanovaccines (NanoVac), which can rapidly display different tumor antigens and efficiently eliminate lung metastases of melanoma. In this study, we first upgraded the NanoVac to increase their antigen display efficiency. However, we found that the presence of a subcutaneous xenograft seriously hampered the efficiency of NanoVac to eliminate lung metastases, with the subcutaneous xenograft mimicking the primary tumor burden in clinical practice. The primary tumor secreted significant amounts of granulocyte colony-stimulating factor (G-CSF) and altered the epigenetic features of granulocyte monocyte precursor cells (GMPs) in the bone marrow, thus disrupting systemic immunity, particularly the function of APCs, and ultimately resulting in NanoVac failure to affect metastases. These changes in the systemic immune macroenvironment were plastic, and debulking surgery of primary tumor resection reversed the dysfunction of APCs and failure of NanoVac. These results demonstrate that, in addition to the formulation design of the tumor nanovaccines themselves, the systemic immune macroenvironment incapacitated by tumor development is another key factor that cannot be ignored to affect the efficiency of tumor nanovaccines, and the combination of primary tumor resection with NanoVac is a promising radical treatment for widely metastatic tumors.

Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations ASCO Living Guideline, Version 2022.2.

Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations ASCO Living Guideline, Version 2022.2.

Dipeptidyl peptidase 4 (DPP-4) inhibitors and the risk of lung cancer current evidence and future directions.

Recent evidence has linked long-term use of angiotensin converting enzyme (ACE) inhibitors with the risk of developing lung cancer by increasing levels of substance P (SP) and bradykinin in lung tissue. DPP-4 inhibitors, by virtue of their mechanism of action, may increase the level of SP and pose a similar risk of incident lung cancer. Concomitant use of DPP-4 inhibitors and ACE inhibitors may further exaggerate this plausible risk. Here we discuss both direct and indirect evidence involving mechanisms by which DPP-4 inhibitors may increase the risk of lung cancer in treated patients. We highlight that increased levels of SP with DPP-4 inhibitor monotherapy and raised levels of both SP and bradykinin with add-on ACE inhibitor therapy may further enhance this risk. DPP-4 inhibitors are prescribed in type-2 diabetes mellitus patients with or without cardiovascular disease. When used together, ACE inhibitors and DPP-4 inhibitors may act synergistically and further amplify the lung cancer risk. Consequently, physicians should consider this plausible association while prescribing them concomitantly especially in high-risk individuals. Well-planned research studies are required to assess the association of DPP-4 inhibitors with lung cancer and other adverse effects linked to increased levels of SP and bradykinin.

Postoperative hypoxaemic acute respiratory failure after neoadjuvant treatment for lung cancer radiologic findings and risk factors.

To investigate the rate of hypoxaemic acute respiratory failure (hARF) on patients undergoing surgery for non-small-cell lung cancer (NSCLC) after neoadjuvant chemotherapy, to describe clinical and radiological findings and to explore potential risk factors for this complication. Retrospective review of medical records of all patients who underwent surgery for NSCLC after neoadjuvant chemotherapy at a single centre between 2014 and 2021. Computed tomography scans of patients who developed hARF were reviewed by an experienced radiologist to provide a quantitative assessment of radiologic alterations. The final cohort consisted of 211 patients. Major morbidity was 13.3% (28211) and hARF was the most common major complication (n 11, 5.2%). Postoperative mortality was 1.9% (4211) and occurred only in patients who experienced hARF. Most patients who experienced hARF underwent major procedures, including pneumonectomy (n 3), lobectomy with chest wall resection (n 3), bronchial or vascular reconstructions (n 3) and extended or bilateral resections (n 2). Analysis of computed tomography findings revealed that crazy paving and ground glass were the most common alterations and were more represented in the non-operated lung. Male gender, current smoking status, pathologic stage III-IV and operative time resulted significant risk factors for hARF at univariable analysis (P < 0.05). hARF is the main cause of major morbidity and mortality after neoadjuvant therapy and surgery for NSCLC and occurs more frequently after complex and lengthier surgical procedures. Overall, our findings suggest that operative time may represent the most important risk factor for hARF.

Evolutionary characteristics and immunological divergence of lung and brain metastasis lesions in NSCLC.

Brain metastases are one of the main reasons for lung cancer-related deaths but lack prediction methods. Many patients with brain metastases do not benefit from immunotherapy. A comprehensive genomic analysis of matched primary tumors (PTs) and their brain metastasis (BM) lesions may provide new insight into the evolutionary and immune characteristics. To describe evolutionary features and immune characteristic differences, we analyzed whole-exome sequencing (WES) data for 28 paired PT and BM samples from 14 non-small cell lung cancer (NSCLC) patients. In addition, we used another 26 matched PT and BM samples as a validation cohort. We found that total mutational signatures were relatively consistent between paired primary and brain metastatic tumors. Nevertheless, the shared mutations of the two lesions were fewer than the mutations present in each of the lesions alone. In the process of brain metastasis, driver genes undergo evolutionary branches. Typical driver genes, including EGFR and TP53, appear relatively conserved throughout evolution however, specific signals are enriched in brain metastasis lesions. We found several main characteristics of lung cancer brain metastases that were different from primary lung cancer, such as genomic instability, novel driver genes, tumor mutational burden (TMB), and brain metastasis lesion private neoantigens. In addition, the estimated timing of dissemination showed that brain metastases might occur early in lung cancer. Implications Mechanistic insight from this study provides new insight into the biology of the metastatic brain process and a new beneficial approach for preventing and treating lung cancer brain metastases.

Sodium Multivitamin Transporter-Targeted Fluorochrome Facilitates Enhanced Metabolic Evaluation of Tumors Through Coenzyme-R Dependent Intracellular Signaling Pathways.

Intraoperative molecular imaging (IMI)-guided resections have been shown to improve oncologic outcomes for patients undergoing surgery for solid malignancies. The technology utilizes fluorescent tracers targeting cancer cells without the use of any ionizing radiation. However, currently available targeted IMI tracers are effective only for tumors with a highly specific receptor expression profile, and there is an unmet need for IMI tracers to label a broader range of tumor types. Here, we describe the development and testing of a novel tracer (CR)-S0456) targeted to the sodium multivitamin transporter (SMVT). Preclinical models of fibrosarcoma (HT-1080), lung (A549), breast (4T1), and renal cancers (HEK-293 T) in vitro and in vivo were used for assessment of (CR)-S0456 specific tumor labeling via sodium-mediated SMVT uptake in dipotassium phosphate or choline chloride-containing media buffer. Additionally, pharmacologic inhibition of multiple intracellular coenzyme-R obligate signaling pathways, including holocarboxylase synthetase (sulconazole nitrate), PI3KAKTmTOR (omipalisib), and calmodulin-dependent phosphatase (calmidazolium), were investigated to assess (CR)-S0456 uptake kinetics. Human fibrosarcoma-bearing xenografts in athymic nude mice were used for tumor and metabolic-specific labeling. Novel NIR needle confocal laser endomicroscopic (nCLE) intratumoral sampling was performed to demonstrate single-cell specific labeling by CR-S0456. CR-S0456 localization in vitro correlated with highly proliferative cell lines (MTT) and doubling time (p < 0.05) with the highest microscopic fluorescence detected in aggressive human fibrosarcomas (HT-1080). Coenzyme-R-specific localization was demonstrated to be SMVT-specific after competitive inhibition of internal localization with excess administration of pantothenic acid. Inhibiting the activity of SMVT by affecting sodium ion hemostasis prevented the complete uptake of CR-S0456. In vivo validation demonstrated (CR)-S0456 localization to xenograft models with accurate identification of primary tumors as well as margin assessment down to 1 mm These findings suggest that a SMVT-targeted NIR contrast agent can be a suitable tracer for imaging a wide range of malignancies as well as evaluating metabolic response to systemic therapies, similar to PET imaging with immune checkpoint inhibitors.

Immunotherapeutics in lung cancers from mechanistic insight to clinical implications and synergistic perspectives.

Lung cancer is one of the highly lethal forms of cancer whose incidence has worldwide rapidly increased over the past few decades. About 80-85% of all lung cancer cases constitute non-small cell lung cancer (NSCLC), with adenocarcinoma, squamous cell carcinoma and large cell carcinoma as the main subtypes. Immune checkpoint inhibitors have led to significant advances in the treatment of a variety of solid tumors, significantly improving cancer patient survival rates. The cytotoxic drugs in combination with anti-PD-(L)1 antibodies is a new method that aims to reduce the activation of immunosuppressive and cancer cell prosurvival responses while also improving direct cancer cell death. The most commonly utilized immune checkpoint inhibitors for patients with non-small cell lung cancer are monoclonal antibodies (Atezolizumab, Cemiplimab, Ipilimumab, Pembrolizumab etc.) against PD-1, PD-L1, and CTLA-4. Among them, Atezolizumab (TECENTRIQ) and Cemiplimab (Libtayo) are engineered monoclonal anti programmed death ligand 1 (PD-L1) antibodies that inhibit binding of PD-L1 to PD-1 and B7.1. As a result, T-cell proliferation and cytokine synthesis are inhibited leading to restoring the immune homeostasis to fight cancer cells. In this review article, the path leading to the introduction of immunotherapeutic options in lung cancer treatment is described, with analyzing the benefits and shortages of the current immunotherapeutic drugs. In addition, possibilities to co-administer immunotherapeutic agents with standard cancer treatment modalities are also considered.

Genetic and phenotypic determinants of morphologies in 3D cultures and xenografts of lung tumor cell lines.

We previously proposed the classification of lung adenocarcinoma into two groups the bronchial epithelial phenotype (BE phenotype) with high-level expressions of bronchial epithelial markers and actionable genetic abnormalities of tyrosine kinase receptors and the non-BE phenotype with low-level expressions of bronchial Bronchial epithelial (BE) epithelial markers and no actionable genetic abnormalities of tyrosine kinase receptors. Here, we performed a comprehensive analysis of tumor morphologies in 3D cultures and xenografts across a panel of lung cancer cell lines. First, we demonstrated that 40 lung cancer cell lines (23 BE and 17 non-BE) can be classified into three groups based on morphologies in 3D cultures on Matrigel round (n 31), stellate (n 5), and grape-like (n 4). The latter two morphologies were significantly frequent in the non-BE phenotype (123 BE, 817 non-BE, p 0.0014), and the stellate morphology was only found in the non-BE phenotype. SMARCA4 mutations were significantly frequent in stellate-shaped cells (44 stellate, 434 non-stellate, p 0.0001). Next, from the 40 cell lines, we successfully established 28 xenograft tumors (18 BE and 10 non-BE) in NODSCID mice and classified histological patterns of the xenograft tumors into three groups solid (n 20), small nests in desmoplasia (n 4), and acinarpapillary (n 4). The latter two patterns were characteristically found in the BE phenotype. The non-BE phenotype exhibited a solid pattern with significantly less content of alpha-SMA-positive fibroblasts (p 0.0004) and collagen (p 0.0006) than the BE phenotype. Thus, the morphology of the tumors in 3D cultures and xenografts, including stroma genesis, reflects the intrinsic properties of the cancer cell lines. Furthermore, this study serves as an excellent resource for lung adenocarcinoma cell lines, with clinically relevant information on molecular and morphological characteristics and drug sensitivity.

Sarcopenia as a Determinant of the Efficacy of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer A Meta-Analysis.

The impact of pre-immunotherapy sarcopenia in patients with non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs) is elusive. We performed a meta-analysis to investigate the association between sarcopenia and clinical outcomes of ICIs. PubMed, EMBASE, and the Cochrane Library were searched. Thirteen clinical trials were selected. The 1,2-year overall survival rate was lower in the sarcopenia group (odds ratio (OR) 2.44, 95% confidence interval (CI), 1.78-3.35, Pre-immunotherapy sarcopenia was associated with poor clinical outcomes in patients with advanced NSCLC who received ICIs.

The rs41291957 polymorphism of miR-143145 and cancer risk a case-control study and meta-analysis.

Recently, the rs41291957 polymorphism in the promoter region of miR-143145 has been repeatedly investigated for its contribution to cancer susceptibility. However, the results remain conflicting rather than conclusive, which calls for further investigations. Therefore, we here conducted a case-control study and meta-analysis to explore the association between rs41291957 and cancer risk. In the case-control study, a total of 2277 cancer patients (lung, liver, gastric and colorectal cancers) and 800 normal controls were recruited, the genotyping of rs41291957 was performed with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and Sanger sequencing. In the meta-analysis, 5 previously published studies and our present study were included, the STATA 14.0 software was applied to conduct all statistical analyses. The results of case-control study showed that rs41291957 was significantly associated with the risk of gastric cancer, colon cancer, rectal cancer, and colorectal cancer in Hubei Han Chinese population. The results of meta-analysis demonstrated that rs41291957 was significantly associated with overall cancer risk, especially colorectal cancer risk and lung cancer risk. Collectively, the rs41291957 polymorphism of miR-143145 may be a plausible susceptible locus for cancer risk, which should be validated in future studies with larger samples in different ethnic populations.

Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors.

Hyperactivation of mTOR kinase by mutations in the PI3KmTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of bi-steric inhibitors that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRAS

Zebrafish patient-derived xenografts accurately and quickly reproduce treatment outcomes in non-small cell lung cancer patients.

Zebrafish patient-derived xenograft (zPDX) models have shown great potential in predicting the short-term treatment response in various types of tumor cases. However, few studies have used zPDX models for drug screening in non-small cell lung cancer (NSCLC). We aimed to compare the treatment responses of patients with NSCLC with those of the corresponding zPDX models. Tumor cells were obtained from pleural fluid or biopsy procedures from patients with NSCLC and injected into the perivitelline space of zebrafish larvae. Then, the same antineoplastic drugs administered to the corresponding patient were tested in the successfully constructed zPDX model, for 3 days. Responses to treatment were compared. A total of 21 patients with advanced NSCLC were enrolled in our study, and 13 corresponding zPDX models were successfully established. Based on the clinical medication of enrolled patients, we provided a corresponding drug treatment to these zebrafish embryos, including epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), pemetrexedplatinum (AP), or docetaxelplatinum (DP) administration. The chemosensitivity consistency rate between the clinical responses and those obtained from zPDXs was 76.9% (1013). There was a high correlation between patient responses and the corresponding zPDX drug responses. Thus, zPDX can accurately and quickly reproduce patient responses to treatment with EGFR TKIs, AP, and DP and has a considerable potential to serve as a biological platform for predicting treatment effect on patients with NSCLC.

Preoperative inspiratory muscle training in a patient with lung cancer and comorbid chronic obstructive pulmonary disease and respiratory sarcopenia A case report.

Sarcopenia and chronic obstructive pulmonary disease (COPD) are risk factors for postoperative pulmonary complications (PPCs). Preoperative inspiratory muscle weakness is also a risk factor for PPCs. Sarcopenia and COPD are often associated with inspiratory muscle weakness. Respiratory sarcopenia has been defined as the coexistence of whole-body sarcopenia and respiratory muscle weakness. We report our experience with preoperative pulmonary rehabilitation, including inspiratory muscle training (IMT), in a patient with lung cancer and comorbid respiratory sarcopenia and COPD. A 73-year-old man with squamous cell lung cancer (cStage IA2) was hospitalized for pulmonary rehabilitation before lung resection. He had comorbid severe sarcopenia and COPD (GOLD stage III). He also had inspiratory muscle weakness and a thin diaphragm. We conducted IMT on the patient in addition to aerobic exercise and instruction regarding sputum expectoration for 2 weeks before the surgery. Consequently, his pulmonary function, respiratory muscle strength, and exercise capacity improved. Segmentectomy was performed using video-assisted thoracic surgery. No postoperative complications occurred. IMT in a patient with lung cancer and comorbid respiratory sarcopenia and COPD resulted in improved respiratory muscle strength and pulmonary function. IMT may have reduced the risk of PPCs by strengthening the respiratory muscles and improving pulmonary function.

Addressing Lung Cancer Health Disparities in West Virginia An Academic-Industry Collaboration Model.

Lung cancer screening is underused nationwide, particularly in rural areas where incidence and mortality rates are high, suggesting the need for innovative methods to reach underserved populations. Partners from national, state, and community positions can combine the service and science needed to save lives with mobile lung cancer screening.

Racial and ethnic inequities of palliative care use among advanced Non-Small cell lung cancer patients in the US.

With early intervention, palliative care (PC) can improve quality of life and increase survival among advanced-stage non-small cell lung cancer (aNCSLC) patients. However, PC is often offered late in the cancer treatment course and is underused. We characterized racialethnic inequities and the role of healthcare access in PC use among patients with aNSCLC. We used data from the 2004-2016 National Cancer Database, including adults aged 18-90 years with aNSCLC (stage 3 or 4 at diagnosis n 803,618). Based on the NCCN guidelines, PC includes non-curative surgery, radiation, chemotherapy, pain management, or any combination of non-curative care. We examined PC use by sociodemographic and health care-level characteristics. To evaluate the independent associations of raceethnicity and health care access characteristics with PC, we estimated adjusted odds ratios (aOR) with 95% confidence intervals (95% CI). Covariate adjustment sets varied by exposure determined using directed acyclic graphs. Our population was 55% male and 77% non-HispanicLatinx (NH)-White, with a mean age of 68 years. Overall, 19% of patients with aNSCLC used PC. Compared to NH-White patients, NH-Black (aOR0.91,95% CI0.89-0.93) and HispanicLatinx (aOR0.80,95% CI0.77-0.83) patients were less likely to use PC, whereas Indigenous (AIAN) (aOR1.18,95% CI1.06-1.31) and Native HawaiianPacific Islander (aOR2.08,95% CI1.83-2.36) patients were more likely. Overall, compared to the privately-insured, uninsured (aOR1.19,95% CI1.11-1.28) and Medicaid-insured patients (aOR1.19,95% CI1.14-1.25) were more likely to use PC. PC is underutilized among NH-Black and HispanicLatinx patients with aNSCLC. Insurance type may play a role in PC use among patients with aNSCLC.

Expression Profile of Sphingosine Kinase 1 Isoforms in Human Cancer Tissues and Cells Importance and Clinical Relevance of the Neglected 1b-Isoform.

Overexpression of sphingosine kinase 1 (SphK1) is casually associated with many types of cancer, and inhibitors of SphK1 sensitize tumors to chemotherapy. SphK1 is expressed as two major isoforms, SphK1a and SphK1b. To date, no information has been reported on the SphK1 isoform expression profile and its clinical relevance. The objective is to examine the expression profile of the SphK1a and SPhK1b isoforms in human cancer and noncancer tissues and cell lines and explore their clinical relevance. We used PCR to qualitatively examine the expression profile of these two isoforms in breast, liver, and prostate cancer tissues plus paired adjacent tissues and in 11 cancer and normal cell lines (breast, cervical, bone, prostate, colon, brain, mesothelioma tumor and benign, and human kidney cells). We found that SphK1a was ubiquitously expressed in all cancer cells and tissues tested in contrast, SphK1b was only expressed in selective cell types in breast, prostate, and lung cancer. Our data suggest that SphK1a is important for generic SphK1S1P functions, and SphK1b mediates specialized andor unique pathways in a specific type of tissue and could be a biomarker for cancer. This discovery is important for future SphK1-related cancer research and may have clinical implications in drug development associated with SphK1-directed cancer treatment.

Integrative bioinformatic analysis of p53 and pathway alterations in two different lung cancer subtypes.

Whether p53, either wild type (WT) or mutant, plays cell-specific or uniform role remains controversial. Using The Cancer Genome Atlas, we examined p53 in the lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), two lung cancers with different cellular origins and frequent

Diagnostic, Prognostic, and Immunological Roles of FABP4 in Pancancer A Bioinformatics Analysis.

Fatty acid binding protein 4 (FABP4) is mainly involved in the regulation of systemic metabolism through various lipid signaling pathways. Metabolic reprogramming is one of the important factors in the development and progression of cancer. It has been recently reported that FABP4 is closely related to the development of cancer and may be involved in tumor invasion and metastasis. In this study, we explored the expression pattern of FABP4 in pancancer through TCGA and CPTAC. Using TCGA, Kaplan-Meier Plotter, and STRING databases, to explore its diagnostic and prognostic value, and function through GOKEGG and GSEA. Then, using the TIMER2.0 database, we investigated the correlation between FABP4 expression and immune infiltration in cancers, especially stomach adenocarcinomas (STAD) and colorectal adenocarcinoma (COADREAD). Compared with normal tissues, the expression of FABP4 in more than 10 tumor tissues was lower ( FABP4 can be used as a diagnostic and prognostic biomarker in pancancer, and its high expression in gastrointestinal tumors suggests poor prognosis. This may be correlated to the immune infiltration of macrophages and epithelial-mesenchymal transition.

Efficacy, chemical composition, and pharmacological effects of herbal drugs derived from

Transcriptome expression profile of compound-K-enriched red ginseng extract (DDK-401) in Korean volunteers and its apoptotic properties.

Ginseng and ginsenosides have been reported to have various pharmacological effects, but their efficacies depend on intestinal absorption. Compound K (CK) is gaining prominence for its biological and pharmaceutical properties. In this study, CK-enriched fermented red ginseng extract (DDK-401) was prepared by enzymatic reactions. To examine its pharmacokinetics, a randomized, single-dose, two-sequence, crossover study was performed with eleven healthy Korean male and female volunteers. The volunteers were assigned to take a single oral dose of one of two extracts, DDK-401 or common red ginseng extract (DDK-204), during the initial period. After a 7-day washout, they received the other extract. The pharmacokinetics of DDK-401 showed that its maximum plasma concentration (Cmax) occurred at 184.8 ± 39.64 ngmL, Tmax was at 2.4 h, and AUC

Targeting glycolysis in non-small cell lung cancer Promises and challenges.

Metabolic disturbance, particularly of glucose metabolism, is a hallmark of tumors such as non-small cell lung cancer (NSCLC). Cancer cells tend to reprogram a majority of glucose metabolism reactions into glycolysis, even in oxygen-rich environments. Although glycolysis is not an efficient means of ATP production compared to oxidative phosphorylation, the inhibition of tumor glycolysis directly impedes cell survival and growth. This review focuses on research advances in glycolysis in NSCLC and systematically provides an overview of the key enzymes, biomarkers, non-coding RNAs, and signaling pathways that modulate the glycolysis process and, consequently, tumor growth and metastasis in NSCLC. Current medications, therapeutic approaches, and natural products that affect glycolysis in NSCLC are also summarized. We found that the identification of appropriate targets and biomarkers in glycolysis, specifically for NSCLC treatment, is still a challenge at present. However, LDHB, PDK1, MCT2, GLUT1, and PFKM might be promising targets in the treatment of NSCLC or its specific subtypes, and DPPA4, NQO1, GAPDHMT-CO1, PGC-1α, OTUB2, ISLR, Barx2, OTUB2, and RFP180 might be prognostic predictors of NSCLC. In addition, natural products may serve as promising therapeutic approaches targeting multiple steps in glycolysis metabolism, since natural products always present multi-target properties. The development of metabolic intervention that targets glycolysis, alone or in combination with current therapy, is a potential therapeutic approach in NSCLC treatment. The aim of this review is to describe research patterns and interests concerning the metabolic treatment of NSCLC.

Comprehensive serum metabolomics and network analysis to reveal the mechanism of gypenosides in treating lung cancer and enhancing the pharmacological effects of cisplatin.

Gypenosides (GYP) exerted anticancer activity against various cancers. However, the mechanism of GYP against lung cancer (LC)

The Tri-iodothyronine (T3) Level Is a Prognostic Factor for Patients With Advanced NSCLC Receiving Immune Checkpoint Inhibitors and Is Associated With Liver Metastasis.

Endocrine hormones influence tumor progression and the response to treatment. Despite the importance of immune checkpoint inhibitors (ICIs) as treatments for advanced non-small cell lung cancer (NSCLC), few studies have explored the effects of hormone levels in NSCLC patients on the effectiveness of ICI therapies. We thus investigated the effects of baseline blood markers in patients with advanced NSCLC on ICI treatments. Patients with advanced NSCLC who received programmed cell death protein 1 (PD-1)programmed death-ligand 1 (PD-L1) inhibitors at Chungnam National University Hospital between December 2016 and November 2020 and who lacked any history of thyroid gland-related diseases were analyzed retrospectively. We collected clinical information and baseline laboratory data, including the levels of endocrine hormones, cytokines, complete blood counts (CBCs), and peripheral blood chemistry panels. We explored the relationships of hormone levels with clinical outcomes (overall survival OS, progression-free survival PFS, and best response), liver metastasis, and blood markers using the Kaplan-Meier method, Coxs proportional hazards regression, and logistic regression. A total of 113 patients were enrolled. A shorter PFS was independently associated with liver metastasis, higher cortisol levels, and lower hemoglobin (Hb) levels a shorter OS was associated with liver metastasis, lower tri-iodothyronine (T3) levels, higher lactate dehydrogenase (LDH) levels, and lower albumin levels. Patients with low T3 levels exhibited a shorter PFS and OS, and a poorer best response. Patients with low T3 levels tended to have higher disease progression rates, lower levels of adrenocorticotropic hormone (ACTH), C-peptide, albumin, Hb, and neutrophil-to-lymphocyte ratio, and higher levels of interleukin (IL)-6, white blood cells, platelets, compared with those with normal T3 levels. We found a significant association between a low T3 level and liver metastasis. We found the baseline T3 level was associated with both prognosis and the response to ICIs in patients with advanced NSCLC, probably reflecting impaired liver function and systemic inflammation induced by the interaction of T3 with other biomarkers, such as IL-6, ACTH, cortisol, C-peptide, Hb, LDH, and albumin.

A Rare Case of Cardiac Metastasis from Colon Cancer.

It is very rare for colorectal neoplasms to metastasize to the heart in the worldwide medical literature only a single case of well-documented colorectal cancer metastasis to the left atrium was found. The case of a 66-year-old man is explained in this paper, who was suffering from metastatic adenocarcinoma of the colon that included the left atrium. In transthoracic and transesophageal echocardiography, a large multilobulated mass was present in the left atrium. An accidental pulmonary mass was also seen in a lung spiral CT scan. The cardiac mass was taken out, and a biopsy was obtained from the pulmonary mass. Adenocarcinoma was seen in histological assessment. Immunohistochemical staining was carried out to examine the expression of cytokeratin 7, cytokeratin 20, and caudal-related homeobox transcription factor 2 (CDX2) to determine the origin of the adenocarcinoma. In addition, the expression of these proteins was linked to the attributes of the patient and tumor. Post-surgical transesophageal echocardiography showed normal left ventricle and right ventricle function with no evidence of left atrium mass. Therefore, we suggest that asymptomatic cancer patients with a history of colorectal cancer and who have developed cardiac symptoms should be immediately examined for potential cardiac metastasis.

Promising bioactive properties of quercetin for potential food applications and health benefits A review.

Naturally occurring phytochemicals with promising biological properties are quercetin and its derivatives. Quercetin has been thoroughly studied for its antidiabetic, antibacterial, anti-inflammatory, anti-Alzheimers, anti-arthritic, antioxidant, cardiovascular, and wound-healing properties. Anticancer activity of quercetin against cancer cell lines has also recently been revealed. The majority of the Western diet contains quercetin and its derivatives, therefore consuming them as part of a meal or as a food supplement may be sufficient for people to take advantage of their preventive effects. Bioavailability-based drug-delivery systems of quercetin have been heavily studied. Fruits, seeds, vegetables, bracken fern, coffee, tea, and other plants all contain quercetin, as do natural colors. One naturally occurring antioxidant is quercetin, whose anticancer effects have been discussed in detail. It has several properties that could make it an effective anti-cancer agent. Numerous researches have shown that quercetin plays a substantial part in the suppression of cancer cells in the breast, colon, prostate, ovary, endometrial, and lung tumors. The current study includes a concise explanation of quercetins action mechanism and potential health applications.

Omega 3 supplementation reduces C-reactive protein, prostaglandin E

Given the current controversy concerning the efficacy of omega 3 supplements at reducing inflammation, we evaluated the safety and efficacy of omega 3 on reducing inflammation in people with a 6-year lung cancer risk >1.5% and a C reactive protein (CRP) level >2 mgL in a phase IIa cross-over study. Forty-nine healthy participants ages 55 to 80, who were still smoking or had smoked in the past with ≥30 pack-years smoking history, living in British Columbia, Canada, were randomized in an open-label trial to receive 2.4 g eicosapentaenoic acid (EPA) 1.2 g docosahexaenoic acid (DHA)day for 6 months followed by observation for 6 months or observation for 6 months first and then active treatment for the next 6 months. Blood samples were collected over 1 year for measurement of plasma CRP, plasma and red blood cell (RBC) membrane levels of EPA, DHA and other fatty acids, Prostaglandin E Twenty one participants who began the trial within the active arm completed the trial while 20 participants who started in the control arm completed the study. Taking omega 3 resulted in a significant decrease in plasma CRP and PGE Omega 3 fatty acids taken at 3.6 gday significantly reduce systemic inflammation with negligible adverse health effects in people who smoke or have smoked and are at high risk of lung cancer.ClinicalTrials.gov, NCT number NCT03936621.

Case report Brain metastasis necrosis with immune checkpoint inhibitors plus chemotherapy for advanced non-small cell lung cancer.

The emergence of immune checkpoint inhibitors (ICIs) has reshaped the landscape of advanced lung cancer treatment. The brain is the most common metastatic site for lung cancer. Whether conventional criteria can evaluate the intracranial response of ICIs remains unclear. Here, we report a well-documented case of intracranial necrosis confirmed by post-operative pathology after only one cycle of chemo-immunotherapy without any radiation therapy, which suggests that immunotherapy elicits strong anti-tumor responses for intracranial metastasis and promotes intracranial necrosis, resulting in a temporary increase in size of the target lesions. Still, the specific mechanisms and management strategies need to be further explored.

Global research landscape and trends of lung cancer immunotherapy A bibliometric analysis.

Immunotherapy for lung cancer has been a hot research area for years. This bibliometric analysis aims to present the research trends on lung cancer immunotherapy. On 1 July, 2022, the authors identified 2,941 papers on lung cancer immunotherapy by the Web of Science and extracted their general information and the total number of citations. A bibliometric analysis was carried out to present the research landscape, demonstrate the research trends, and determine the most cited papers (top papers) as well as major journals on lung cancer immunotherapy. After that, recent research hotspots were analyzed based on the latest publications in major journals. These 2,941 papers were cited a total of 122,467 times. Nivolumab vs. docetaxel in advanced non-squamous non-small-cell lung cancer published in 2015 by Borghaei H et al. was the most cited paper (5,854 citations). Among the journals, This bibliometric analysis comprehensively and quantitatively presents the research trends and hotspots based on thousands of publications, and further suggests future research directions. Moreover, the results can benefit researchers to select journals and find potential collaborators. This study can help researchers get a comprehensive impression of the research landscape, historical development, and recent hotspots in lung cancer immunotherapy and provide inspiration for further research.

Corrigendum Mouse models of lung-specific SARS-CoV-2 infection with moderate pathological traits.

This corrects the article DOI 10.3389fimmu.2022.1055811..

A prognostic and therapeutic hallmark developed by the integrated profile of basement membrane and immune infiltrative landscape in lung adenocarcinoma.

Basement membranes (BMs) are specialised extracellular matrices that maintain cellular integrity and resist the breaching of carcinoma cells for metastases while regulating tumour immunity. The tumour immune microenvironment (TME) is essential for tumour growth and the response to and benefits from immunotherapy. In this study, the BM score and TME score were constructed based on the expression signatures of BM-related genes and the presence of immune cells in lung adenocarcinoma (LUAD), respectively. Subsequently, the BM-TME classifier was developed with the combination of BM score and TME score for accurate prognostic prediction. Further, Kaplan-Meier survival estimation, univariate Cox regression analysis and receiver operating characteristic curves were used to cross-validate and elucidate the prognostic prediction value of the BM-TME classifier in several cohorts. Findings from functional annotation analysis suggested that the potential molecular regulatory mechanisms of the BM-TME classifier were closely related to the cell cycle, mitosis and DNA replication pathways. Additionally, the guiding value of the treatment strategy of the BM-TME classifier for LUAD was determined. Future clinical disease management may benefit from the findings of our research.

Lung cancer patients with chronic obstructive pulmonary disease benefit from anti-PD-1PD-L1 therapy.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are two of the most fatal respiratory diseases, seriously threatening human health and imposing a heavy burden on families and society. Although COPD is a significant independent risk factor for LC, it is still unclear how COPD affects the prognosis of LC patients, especially when LC patients with COPD receive immunotherapy. With the development of immune checkpoint inhibition (ICI) therapy, an increasing number of inhibitors of programmed cell death-1 (PD-1) and PD-1 ligand (PD-L1) have been applied to the treatment of LC. Recent studies suggest that LC patients with COPD may benefit more from immunotherapy. In this review, we systematically summarized the outcomes of LC patients with COPD after anti-PD-1PD-L1 treatment and discussed the tumor immune microenvironment (TIME) regulated by COPD in LC immunotherapy, which provides novel insights for the clinical treatment of LC patients with COPD.

Long-term survival in extensive-stage small-cell lung cancer treated with different immune checkpoint inhibitors in multiple-line therapies A case report and literature review.

Extensive-stage small-cell lung cancer (ES-SCLC) is highly malignant, is highly prone to recurrence, and has a short survival period. It is very difficult to achieve long-term survival in ES-SCLC, which has not been significantly improved in the last 20 years. For a long time, platinum-based chemotherapy has occupied the core position in the treatment of small-cell lung cancer (SCLC), but there are few options for treatment drugs or regimens, and if disease progression occurs, the options for follow-up regimens are obviously limited. The advent of immunotherapy has changed this situation to some extent, and immunotherapy has shown some effects in improving efficiency and prolonging survival, whether in first- or third-line therapy, but it is still unsatisfactory. A 57-year-old patient with ES-SCLC experienced disease progression after four lines of treatment including synchronous radiotherapy, chemotherapy, and antiangiogenesis. However, the patient still benefited when switching to the programmed cell death receptor-1 (PD-1) inhibitor toripalimab in combination with chemotherapy in the fifth line. Even after the development of immune resistance, the patient still benefited after switching to tislelizumab in combination with different chemotherapy regimens or alone in the sixth and seventh lines. Following the progression of tislelizumab in combination with chemotherapy, the patient again profited after switching to durvalumab in combination with anlotinib and again achieved a progressive-free survival (PFS) of 11 months. Overall, the patient achieved a total of 45 months of PFS and 50 months of overall survival (OS), with a shocking and exciting 30 months of PFS achieved in the immune combination phase alone. We report a patient with ES-SCLC who achieved long-term survival after at least eight lines of therapy including chemotherapy, antiangiogenesis, and different immune checkpoint inhibitors (ICIs). This suggests that long-term survival in SCLC is possible with aggressive, combined, and standardized treatment. Otherwise, immunotherapy postline enablement can still benefit patients, rechallenge after immune resistance is also possible in SCLC, and combination with chemotherapy or antiangiogenic therapy can improve the efficacy and prolong the survival. This will provide new ideas and options for the selection of treatment options for SCLC.

Cardioprotective effects of preconditioning exercise in the female tumor bearing mouse.

Cancer cachexia, a metabolic wasting syndrome, affects up to 80% of cancer patients and leads to the death in up to 20% of cancer patients. While research is growing in the field, there are still no clear diagnostic criteria and cancer cachexia remains an untreated condition. Aerobic exercise has been shown to positively impact cachexia by slowing its development and attenuating muscle loss. The most effective timing, duration, and intensity of exercise as a preventative and protective measure against cancer cachexia remains questionable. Therefore, the purpose of this study was to examine the effects of preconditioning exercise as a protective measure for tumor-mediated muscle wasting. Female LC3 Tg and wildtype mice were randomly separated into four groups, sedentary non-tumor bearing (SED NT), sedentary tumor bearing (SED T), treadmill exercise non-tumor bearing (TM NT), and treadmill exercise tumor bearing (TM T). Mice underwent an 8-week treadmill exercise training protocol (TM) or remained sedentary (SED). Next, mice were implanted with tumor cells (T group 5 × 10

Coronary artery calcium score on standard of care oncologic CT scans for the prediction of adverse cardiovascular events in patients with non-small cell lung cancer treated with concurrent chemoradiotherapy.

Chemoradiotherapy (CRT) has been associated with increased incidence of cardiovascular (CV) adverse events (CVAE). Coronary artery calcium scoring (CAC) has shown to predict coronary events beyond the traditional CV risk factors. This study examines whether CAC, measured on standard of care, non-contrast chest CT (NCCT) imaging, predicts the development of CVAE in patients with non-small cell lung cancer (NSCLC) treated with CRT. Patients with NSCLC treated with CRT at MD Anderson Cancer Center from 72009 until 42014 and who had at least one NCCT scan within 6 months from their first CRT were identified. CAC scoring was performed on NCCT scans by an expert cardiologist and a cardiac radiologist following the 2016 SCCTSTR guidelines. CVAE were graded based on the most recent Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. CVAE were also grouped into (i) coronaryvascular events, (ii) arrhythmias, or (iii) heart failure. All CVAE were adjudicated by a board-certified cardiologist. Out of a total of 193 patients, 45% were female and 91% Caucasian. Mean age was 64 ± 9 years and mean BMI 28 ± 6 kgm Cardiovascular adverse events are frequent in patients with NSCLC treated with CRT. CAC calculated on standard of care NCCT can predict the development of CVAEs and specifically coronaryvascular events, as well as OS, independently from other traditional risk factors and radiation mean heart dose. httpsclinicaltrials.govct2showNCT00915005, identifier NCT00915005.

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The co-occurrence of two or more rare variants, known as compound variants, is rare in non-small cell lung carcinoma with epidermal growth factor receptor (

Supramolecular filaments for concurrent ACE2 docking and enzymatic activity silencing enable coronavirus capture and infection prevention.

Coronaviruses have historically precipitated global pandemics of severe acute respiratory syndrome (SARS) into devastating public health crises. Despite the viruss rapid rate of mutation, all SARS coronavirus 2 (SARS-CoV-2) variants are known to gain entry into host cells primarily through complexation with angiotensin-converting enzyme 2 (ACE2). Although ACE2 has potential as a druggable decoy to block viral entry, its clinical use is complicated by its essential biological role as a carboxypeptidase and hindered by its structural and chemical instability. Here we designed supramolecular filaments, called fACE2, that can silence ACE2s enzymatic activity and immobilize ACE2 to their surface through enzyme-substrate complexation. This docking strategy enables ACE2 to be effectively delivered in inhalable aerosols and improves its structural stability and functional preservation. fACE2 exhibits enhanced and prolonged inhibition of viral entry compared with ACE2 alone while mitigating lung injury

Financial Toxicities Persist for Cancer Survivors Irrespective of Current Cancer Status An Analysis of Medical Expenditure Panel Survey.

This study estimates the out-of-pocket (OOP) expenditures for different cancer types among survivors with current vs no current cancer condition and across sex, which is understudied in the literature. This is a cross-sectional study of Medical Expenditure Panel Survey data for 2009-2018 where the primary outcome was the average per year OOP expenditure incurred by cancer survivors. Of 189 285 respondents, 15 010 (7.93%) were cancer survivors among them, 46.28% had a current cancer condition. Average per year OOP expenditure for female survivors with a current condition of breast cancer ($1730), lung cancer ($1679), colon cancer ($1595), melanoma ($1783), non-Hodgkin lymphoma ($1656), nonmelanomaother skin cancer (NMSC, $2118) and two or more cancers ($2310) were significantly higher than that of women with no history of cancer ($853, all

MicroRNA-340 and MicroRNA-450b-5p Plasma Biomarkers for Detection of Non-Small-Cell Lung Cancer.

Since the inefficient cancer management is caused by inaccurate diagnoses, there is a need for minimally invasive method to improve the diagnostic accuracy of non-small-cell lung (NSCLC). This study intended to detect miR-340 and miR-450b-5p levels in plasma from NSCLC patients and to assess the potential values for the prediction of tumor development and prognosis. A GSE64591 dataset included 200 samples (100 early-stage NSCLC patients and 100 noncancer control) aimed to identify a panel of circulating miRNAs in plasma. The levels of miR-340 and miR-450b-5p in plasma from NSCLC patients ( miR-450b-5p and miR-340 in plasma was significant difference between early-stage NSCLC patients and noncancer control by searching the GSE64591 dataset. When compared with the healthy controls, the plasma miR-340 was decreased in the NSCLC patients, but the plasma miR-450b-5p was increased. NSCLC patients could be distinguished accurately from healthy controls by the circulating miR-340 and miR-450b-5p with the AUC of 0.740 (95% CI 0.6770.804) and of 0.808 (95% CI 0.7540.861), respectively. With these two markers, the specificity and sensitivity were 78.33% and 77.5% with the AUC of 0.862. Patients with advanced T, N, and TNM stage demonstrated lower plasma miR-340 and higher plasma miR-450b-5p, and both of them were correlated with the prognosis of NSCLC patients. Furthermore, plasma miR-340 was also negatively correlated with tumor grade. All clinicopathological variables significantly associated to prognosis were T stage, N stage, TNM stage, tumor grade, and plasma levels of miR-340 and miR-450b-5p in univariate Cox regression analysis. The variables that retained their significance in the multivariate model were T stage, plasma miR-340, and plasma miR-450b-5p. The plasma levels of miR-340 combined with miR-450b-5p potentially define core biomarker signatures for improving the accuracy of NSCLC diagnosis. Moreover, circulating miR-340 and miR-450b-5p are independent biomarkers of survival in nonmetastatic NSCLC patients.

Progress and perspectives of platinum nanozyme in cancer therapy.

Malignant tumors, one of the worst-case scenarios within human health problems, are now posing an increasing threat to the well-being of the global population. At present, the treatment of malignant tumors mainly includes surgery, radiotherapy, chemotherapy, immunotherapy, etc. Radiotherapy and chemotherapy are often applied to inoperable tumors, and some other tumors after surgery as important adjuvant therapies. Nonetheless, both radiotherapy and chemotherapy have a series of side effects, such as radiation-induced lung injury, and chemotherapy-induced bone marrow suppression. In addition, the positioning accuracy of radiotherapy and chemotherapy is not assured and satisfactory, and the possibility of tumor cells not being sensitive to radiation and chemotherapy drugs is also problematic. Nanozymes are nanomaterials that display natural enzyme activities, and their applications to tumor therapy have made great progress recently. The most studied one, platinum nanozyme, has been shown to possess a significant correlation with radiotherapy sensitization of tumors as well as photodynamic therapy. However, there are still several issues that limited the usage of platinum-based nanozymes

Bronchial Leiomyoma Importance of Preoperative Biopsy for Lung Preserving Surgery.

Tracheobronchial leiomyoma is a rare tumor of the airway. They arise from the lower respiratory tract tissue of the bronchi, trachea, and lung. Symptomatology is based on the degree of endoluminal bronchial obstruction, and surgical resection is generally the mainstay of treatment. We present the case of a 33-year-old male who suffered from chronic cough and breathlessness for two years caused by large endobronchial leiomyoma diagnosed by preoperative biopsy. The tumor was surgically resected through bronchotomy and complete preservation of the lung parenchyma. We stress the importance of a definitive preoperative diagnosis of this rare tumor to employ lung preserving surgical techniques.

An efficient five-lncRNA signature for lung adenocarcinoma prognosis, with AL606489.1 showing sexual dimorphism.

Integrated investigation of the prognostic role of HLA LOH in advanced lung cancer patients with immunotherapy.

Although multiple studies have shown that loss of heterozygosity (LOH) at the human leukocyte antigen (HLA) locus is one of the mechanisms of immune escape, the effect of HLA LOH on the immunotherapy response of patients is still unclear. Based on the data of 425 Chinese lung cancer patients, the genomic characteristics with different HLA LOH statuses were analyzed. The driver genes mutation frequency, oncogenic signaling pathways mutation frequency, tumor mutational burden (TMB) and chromosomal instability (CIN) score in the HLA LOH high group was significantly higher than in the HLA LOH negative group. Transcriptome analyses revealed that pre-existing immunologically active tumor microenvironment (TME) was associated with HLA LOH negative patients. Non-small cell lung cancer (NSCLC) patients, especially for lung squamous cell carcinomas (LUSC), with HLA LOH negative have a longer survival period than those with HLA LOH. In addition, the combination of HLA LOH with TMB or programmed cell death-Ligand 1 (PD-L1) expression can further distinguish responders from non-responders. Furthermore, a comprehensive predictive model including HLA LOH status, TMB, PD-L1 expression and CD8

A Review of Studies on the Seasonal Variation of Indoor Radon-222 Concentration.

Due to their electrostatic nature, radon decay products can attach to solid particles and aerosols in the air. Inhalation and ingestion are therefore the two main routes through which people are exposed to radon and its decay products. During the inhalation of these radioactive aerosols, deposition takes place in different regions of the human respiratory tract. The deposited aerosols carrying radon and its progeny undergo a continuous radioactive transformation and expose the lung to ionizing alpha radiation, which can destroy the sensitive cells in the lung, causing a mutation that turns cancerous. Radon which is a colorless, odorless, and tasteless radioactive noble gas is a major health concern and is the second leading cause of lung cancer. To address this, an indoor radon survey was conducted in many countries internationally, with results showing that indoor radon concentration has a seasonal variation. This is due to the fluctuation of environmental parameters and the geological nature of buildings. Its concentration was found to be maximum in the cool (winter) season and a minimum concentration was recorded in the warm (summer) season of the year.

Breast, Colorectal, Lung, Prostate, and Cervical Cancer Screening Prevalence in a Large Commercial and Medicare Advantage Plan, 2008-2020.

This study aimed to comprehensively assess breast, colorectal, cervical, lung, and prostate cancer screening rates and trends in the United States over time among individuals for whom screening is recommended by the United States Preventive Services Task Force (USPSTF). This retrospective study was conducted in two-year intervals from January 1, 2008 to February 29, 2020, using Optums de-identified Clinformatics® Data Mart Database, which includes Medicare Advantage and commercially insured members. Screening-eligible individuals, who had not previously had the cancer being screened and met USPSTF criteria for screening, were identified at various time points within the study timeframe for relevant screening tests within five cancer types breast, colorectal, cervical, lung, and prostate. In the 2020 analysis period, patients who were eligible for cancer screening included breast 1,620,588 colorectal 2,763,736 cervical 1,371,506 lung 1,491,594 prostate 1,126,249. Breast and cervical cancer screening prevalence rates were highest (64.4% and 63.8%, respectively), followed by colorectal (29.5%), prostate (11.7%), and lung (3.8%). BlackAfrican American individuals and Hispanics had moderately low screening rates for cervical (58.6%) and breast (61.8%) cancer, respectively Hispanics had the lowest screening rates for prostate cancer (6.1%). Those residing in the West had lower screening rates for breast (58.9%), cervical (62.1%), and prostate (5.6%) cancer. Screening rates remained stable over time for breast, colorectal, and lung cancer, and changed significantly for cervical (-9.5%, 2012-2020) and prostate (7.3%, 2008-2020) cancer. Real-world cancer screening rates remain suboptimal and low, and efforts to increase screening uptake and reduce cancer health disparities remain critical.

A tumor-associated autoantibody panel for the detection of non-small cell lung cancer.

Lung cancer is the second most frequent malignancy and the leading cause of cancer-associated death worldwide. Compared with patients diagnosed at advanced disease stages, early detection of lung cancer significantly improved the 5-year survival rate from 3.3% to 48.8%, which highlights the importance of early detection. Although multiple technologies have been applied to the screening and early diagnosis of lung cancer so far, some limitations still exist so they could not fully suit the needs for clinical application. Evidence show that autoantibodies targeting tumor-associated antigens(TAAs) could be found in the sera of early-stage patients, and they are of great value in diagnosis. Methods, we identified and screened TAAs in early-stage non-small cell lung cancer(NSCLC) samples using the serological analysis of recombinant cDNA expression libraries(SEREX). We measured the levels of the 36 autoantibodies targeting TAAs obtained by preliminary screening

Diagnostic value of dual-layer spectral detector CT in differentiating lung adenocarcinoma from squamous cell carcinoma.

The pathological type of non-small cell lung cancer is considered to be an important factor affecting the treatment and prognosis. The purpose of this study was to investigate the diagnostic value of spectral parameters of dual-layer spectral detector computed tomography (DLCT) in determining efficacy to distinguish adenocarcinoma (AC) and squamous cell carcinoma (SC), and their combined diagnostic efficacy was also analyzed. This is a single-center prospective study, and we collected 70 patients with lung SC and 127 patients with lung AC confirmed by histopathological examination. Morphological parameters, plain scan CT value, biphasic enhanced CT value, and spectral parameters were calculated. The diagnostic efficiency of morphological parameters, spectral parameters, and spectral parameters combined with morphological parameters was obtained by statistical analysis. In univariate analysis, seven morphological CT features differed significantly between SC and AC tumor location (distribution), lobulation, spicule, air bronchogram, vacuole sign, lung atelectasis andor obstructive pneumonia, and vascular involvement (all The quantitative parameters of the DLCT spectrum are of great value in the diagnosis of SC and AC, and the combination of morphological parameters and spectral parameters is helpful to distinguish SC from AC.

The combination of a seven-autoantibody panel with computed tomography scanning can enhance the diagnostic efficiency of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is still of concern in differentiating it from benign disease. This study aims to validate the diagnostic efficacy of a novel seven-autoantibody (7-AAB) panel for the diagnosis of NSCLC. We retrospectively enrolled 2650 patients who underwent both the 7-AAB panel test and CT scanning. We compared the sensitivity, specificity, and PPV of 7-AAB, CT, and PET-CT in the diagnosis of NSCLC in different subgroups. Then, we established a nomogram based on CT image features and the 7-AAB panel to further improve diagnostic efficiency. Moreover, we compared the pathological and molecular results of NSCLC patients in the 7-AABs positive group and the negative group to verify the prognostic value of the 7-AAB panel. The strategy of a both-positive rule combination of 7-AABs and CT had a specificity of 95.4% and a positive predictive value (PPV) of 95.8%, significantly higher than those of CT or PET-CT used alone (P<0.05). The nomogram we established has passed the calibration test (P0.987>0.05) with an AUC of 0.791. Interestingly, it was found that the 7-AABs positive group was associated with higher proportion of EGFR mutations (P<0.001), lower pathological differentiation degrees (P0.018), more advanced pathological stages (P0.040) and higher Ki-67 indexes (P0.011) in patients with adenocarcinoma. This study shows that combination of a 7-AAB panel with CT has can significantly enhance the diagnostic efficiency of lung cancer. Moreover, the 7-AAB panel also has potential prognostic value and has reference significance for the formulation of the treatment plan.

Development and validation a simple scoring system to identify malignant pericardial effusion.

Malignant pericardial effusion (MPE) is a serious complication in patients with advanced malignant tumors, which indicates a poor prognosis. However, its clinical manifestations lack specificity, making it challenging to distinguish MPE from benign pericardial effusion (BPE). The aim of this study was to develop and validate a scoring system based on a nomogram to discriminate MPE from BPE through easy-to-obtain clinical parameters. In this study, the patients with pericardial effusion who underwent diagnostic pericardiocentesis in Taizhou Hospital of Zhejiang Province from February 2013 to December 2021 were retrospectively analyzed. The eligible patients were divided into a training group (n 161) and a validation group (n 66) according to the admission time. The nomogram model was established using the meaningful indicators screened by the least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression. Then, a new scoring system was constructed based on this nomogram model. The new scoring system included loss of weight (3 points), no fever (4 points), mediastinal lymph node enlargement (2 points), pleural effusion (6 points), effusion adenosine deaminase (ADA≦18UL) (5 points), effusion lactate dehydrogenase (LDH>1033UL) (7 points), and effusion carcinoembryonic antigen (CEA>4.9gmL) (10 points). With the optimal cut-off value was 16 points, the area under the curve (AUC), specificity, sensitivity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), negative likelihood ratio (NLR) for identifying MPE were 0.974, 95.1%, 91.0%, 85.6%, 96.8%, 10.56 and 0.05, respectively, in the training set and 0.950, 83.3%, 95.2%, 90.9%, 90.9%, 17.50, and 0.18, respectively, in the validation set. The scoring system also showed good diagnostic accuracy in differentiating MPE caused by lung cancer from tuberculous pericardial effusion (TPE) and MPE including atypical cell from BPE. The new scoring system based on seven easily available variables has good diagnostic value in distinguishing MPE from BPE.

Lactate increases tumor malignancy by promoting tumor small extracellular vesicles production

Lactate and tumor cell-derived extracellular vesicles (TEVs) both contribute to tumor progression. However, it is still unclear whether lactate can accelerate tumor development by directly promoting TEV production. Here, we show that lactate decreases intracellular cAMP levels and subsequent PKA activation

Distinct gene mutation profiles among multiple and single primary lung adenocarcinoma.

With the development of technologies, multiple primary lung cancer (MPLC) has been detected more frequently. Although large-scale genomics studies have made significant progress, the aberrant gene mutation in MPLC is largely unclear. In this study, 141 and 44 lesions from single and multiple primary lung adenocarcinoma (SP- and MP-LUAD) were analyzed. DNA and RNA were extracted from formalin-fixed, paraffin-embedded tumor tissue and sequenced by using the next-generation sequencing-based YuanSu450TM gene panel. We systematically analyzed the clinical features and gene mutations of these lesions, and found that there were six genes differently mutated in MP-LUAD and SP-LUAD lesions, including RBM10, CDK4, ATRX, NTRK1, PREX2, SS18. Data from the cBioPortal database indicated that mutation of these genes was related to some clinical characteristics, such as TMB, tumor type, et al. Besides, heterogeneity analysis suggested that different lesions could be tracked back to monophyletic relationships. We compared the mutation landscape of MP-LUAD and SP-LUAD and identified six differentially mutated genes (RBM10, CDK4, ATRX, NTRK1, PREX2, SS18), and certain SNV loci in TP53 and EGFR which might play key roles in lineage decomposition in multifocal samples. These findings may provide insight into personalized prognosis prediction and new therapies for MP-LUAD patients.

PABPC1--mRNA stability, protein translation and tumorigenesis.

Mammalian poly A-binding proteins (PABPs) are highly conserved multifunctional RNA-binding proteins primarily involved in the regulation of mRNA translation and stability, of which PABPC1 is considered a central regulator of cytoplasmic mRNA homing and is involved in a wide range of physiological and pathological processes by regulating almost every aspect of RNA metabolism. Alterations in its expression and function disrupt intra-tissue homeostasis and contribute to the development of various tumors. There is increasing evidence that PABPC1 is aberrantly expressed in a variety of tumor tissues and cancers such as lung, gastric, breast, liver, and esophageal cancers, and PABPC1 might be used as a potential biomarker for tumor diagnosis, treatment, and clinical application in the future. In this paper, we review the abnormal expression, functional role, and molecular mechanism of PABPC1 in tumorigenesis and provide directions for further understanding the regulatory role of PABPC1 in tumor cells.

Enhanced cardiac substructure sparing through knowledge-based treatment planning for non-small cell lung cancer radiotherapy.

Radiotherapy (RT) doses to cardiac substructures from the definitive treatment of locally advanced non-small cell lung cancers (NSCLC) have been linked to post-RT cardiac toxicities. With modern treatment delivery techniques, it is possible to focus radiation doses to the planning target volume while reducing cardiac substructure doses. However, it is often challenging to design such treatment plans due to complex tradeoffs involving numerous cardiac substructures. Here, we built a cardiac-substructure-based knowledge-based planning (CS-KBP) model and retrospectively evaluated its performance against a cardiac-based KBP (C-KBP) model and manually optimized patient treatment plans. CS-KBPC-KBP models were built with 27 previously-treated plans that preferentially spare the heart. While the C-KBP training plans were created with whole heart structures, the CS-KBP model training plans each have 15 cardiac substructures (coronary arteries, valves, great vessels, and chambers of the heart). CS-KBP training plans reflect cardiac-substructure sparing preferences. We evaluated both models on 28 additional patients. Three sets of treatment plans were compared (1) manually optimized, (2) C-KBP model-generated, and (3) CS-KBP model-generated. Plans were normalized to receive the prescribed dose to at least 95% of the PTV. A two-tailed paired-sample

Extremely high infiltration of CD8

In recent years, immune checkpoint inhibitors (ICIs), represented by PD-1PD-L1 monoclonal antibodies, have become a research hotspot in the field of oncology treatment. Immunotherapy has shown significant survival advantages in a variety of solid tumors. However, the phenomenon of hyperprogressive disease (HPD) in some patients treated with immunotherapy is gradually getting more attention and focus. An early understanding of the characteristics of HPD is crucial to optimize the treatment strategy. We report a patient with unresectable stage III lung adenocarcinoma who developed HPD with metastasis during consolidation therapy with durvalumab after chemoradiation. To further investigate the potential mechanism of HPD after anti-PD-L1 treatment, primary lung baseline tissue, baseline plasma, post-immunotherapy plasma, and liver metastasis samples of the patient were detected

The role of

Synchronous multiple primary malignant neoplasms occurring at the same time (SMPMNS) are not currently uncommon in clinical oncological practice however, the diagnostic performance of This study aimed to evaluate the application of The clinical and imaging data of 37 patients with SMPMNS who had undergone This retrospective diagnostic study included 74 lesions identified in 37 patients with SMPMNS, with 94.6% of patients having double primary tumors. Of the incidences of SMPMNS, 18.9% occurred in the same organ system, with respiratory tumors being the most common type of neoplasm (43.2%) and the lung being the most common primary site (40.5%). The overall survival of SMPMNS patients without metastases was longer than that of those with metastases (

Identification of a novel gene signature of lung adenocarcinoma based on epidermal growth factor receptor-tyrosine kinase inhibitor resistance.

Tyrosine kinase inhibitors (TKIs) that target epidermal growth factor receptor (EGFR) mutations are commonly administered to EGFR-positive lung cancer patients. However, resistance to EGFR-TKIs (mostly gefitinib and erlotinib) is presently a significant problem. Limited studies have focused on an EGFR-TKI resistance-related gene signature (ERS) in lung adenocarcinoma (LUAD). Gefitinib and erlotinib resistance-related genes were obtained through the differential analyses of three Gene Expression Omnibus datasets. These genes were investigated further in LUAD patients from The Cancer Genome Atlas (TCGA). Patients in the TCGA-LUAD cohort were split into two groups one for training and one for testing. The training cohort was used to build the ERS, and the testing cohort was used to test it. GO and KEGG analyses were explored for the enriched pathways between the high-risk and low-risk groups. Various software, mainly CIBERSORT and ssGSEA, were used for immune infiltration profiles. Somatic mutation and drug sensitivity analyses were also explored. An ERS based on five genes (FGD3, PCDH7, DEPDC1B, SATB2, and S100P) was constructed and validated using the TCGA-LUAD cohort, resulting in the significant stratification of LUAD patients into high-risk and low-risk groups. Multivariable Cox analyses confirmed that ERS had an independent prognostic value in LUAD. The pathway enrichment analyses showed that most of the genes that were different between the two risk groups were related to the immune system. Further immune infiltration results revealed that a lower immune infiltration score was observed in high-risk patients, and that various leukocytes were significantly related to the ERS. Importantly, samples from the high-risk group showed lower levels of PD-1, PD-L1, and CTLA-4, which are important biomarkers for immunotherapy responses. Patients in the high-risk group also had more gene mutation changes and were more sensitive to chemotherapy drugs like docetaxel and sorafenib. The ERS was also validated in the GSE30219, GSE11969 and GSE72094, and showed a favorable prognostic value for LUAD patients. The ERS established during this study was able to predict a poor prognosis for LUAD patients and had great potential for predicting drug responses.

Harnessing DLL3 inhibition From old promises to new therapeutic horizons.

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. The combination of chemotherapy and immune-checkpoint inhibitors brings a new therapeutic era, although the lack of predictive biomarkers of response reduces the efficacy of applying the treatment to the entire population of patients with SCLC. The lack of treatments able to bind to a specific target has always been a substantial difference to the non-small cell lung cancer (NSCLC) counterpart. Delta-like canonical Notch ligand 3 is a protein frequently overexpressed in SCLC and is therefore being explored as a potentially promising therapeutic target in high-grade neuroendocrine lung cancer. In this article, we critically review the activity and efficacy of old DLL3 inhibitors antibody-drug conjugate (ADC) and their failures through new compounds and their possible applications in clinical practice, with a focus on new molecular classification of SCLC.