Datasets:

Gaborandi

/

Lung_Cancer_pubmed_abstracts

like 1

Pretreatment Platelet Count is a Prognostic Marker in Lung Cancer A Danish Registry-based Cohort Study.

Thrombocytosis has been associated with a poor prognosis in a wide range of malignancies. However, the results have been conflicting for lung cancer. Therefore, we evaluated the prognostic value of platelet count in a large cohort of lung cancer patients. All lung cancer patients diagnosed in The Central Denmark Region from 2009 to 2018 were included in the study. Data from the Danish Lung Cancer Registry were combined with data from the clinical laboratory information system on pretreatment platelet count. Platelet count was defined as low, normal, or high based on being below, within, or above the reference intervals. The prognostic value of platelet count was assessed by the Cox proportional hazard model. C-statistics were conducted to investigate if the platelet count added additional prognostic value to existing prognostic markers. Totally, 6,758 patients with non-small-cell lung cancer (NSCLC) and 1150 patients with small-cell lung cancer (SCLC) were included. Low and high platelet count were significantly associated with decreased overall survival (OS) in NSCLC patients (low adjusted hazard ratio (HR)1.75 (95% confidence interval CI 1.49-2.06) high adjusted HR1.24 (95% CI 1.16-1.33)). In SCLC patients, only low platelet count was significantly associated with decreased OS (adjusted HR 2.71 95% CI 2.02-3.65). C-statistics showed that the prognostic models were significantly improved by the addition of platelet count for both NSCLC and SCLC patients (P < .0001). Low and high platelet count were adverse prognostic factors in NSCLC patients, while only low platelet count was a prognostic marker in SCLC patients.

The Impact of Estrogen Receptor Expression on Mutational Status in the Evolution of Non-Small Cell Lung Cancer.

The role of estrogen receptor (ER) status in the carcinogenesis of lung cancer and its impact on prognosis remain unclear. We previously reported a prospective, multicenter, molecular epidemiology study (Japan Molecular Epidemiology for Lung Cancer Study JME). We examined the relationship of ER status with reproductive and hormonal factors, mutational profile, and survival using JME study data. Patients were enrolled between July 2012 and December 2013, with follow-up until November, 2017. Among 441 ever- and 435 never-smokers, ER expression was observed in 46.4% and 53.5%, respectively (P .022). Hormone use and reproductive history of female patients were not associated with ER status. Mutations in EGFR (P .003), TP53 (P .007), and CTNNB1 (P .027) were significantly associated with ER expression. Multivariate analysis showed that mutations in EGFR (P .032) and CTNNB1 (P .026) were significantly associated with ER expression, whereas TP53 mutations exhibited a trend toward significance (P .059). Relapse-free survival (RFS) was longer in all the patients with ER-positive tumors than those with ER-negative tumors (P .021). RFS and overall survival were longer (P .024, P .011, respectively) in the stage I patients with ER-positive tumors than those with ER-negative tumors. ERβ expression is positively associated with EGFR mutations and negatively with TP53 and CTNNB1 mutations. ER-positive tumors can be associated with better prognosis of the patients, suggesting that ER expression with coexisting EGFR mutations and wild-type TP53 contribute to the biology of non-small cell lung cancer.

Updates in the pathological diagnosis of Pleural Malignant Mesothelioma in the WHO classification of thoracic tumors (5(th) edition).

The WHO Classification of Thoracic Tumors (5(th) edition) mainly has the following changes in the chapter of pleural malignant mesothelioma. (1) The concept of mesothelioma in situ and its diagnostic method have been established for the first time (2) The tumour grading of pleural malignant mesothelioma was added, it was divided into low grade and high grade according to the cellular atypia, mitotic activity and presence of necrosis. (3) The morphological features of pleural malignant mesothelioma was classified into architectural pattern, cellular and stromal features, the correlation between histological features and prognosis was refined, and some of the controversial cellular types have been reclassified. In this review, we introduced the changes of related pathologic diagnosis, in the WHO Classification of Thoracic Tumors (5(th) edition) and discussed its clinical significance. 《WHO胸部肿瘤分类（第五版）》在胸膜恶性间皮瘤部分主要有以下几点变化：1.确立了原位间皮瘤的概念及其诊断方法；2.新增了胸膜恶性间皮瘤的肿瘤分级，即根据上皮样间皮瘤的细胞异型性、核分裂活性及有无坏死分为低级别和高级别；3.把胸膜恶性间皮瘤的组织学特征分为组织结构、细胞及间质特征，细化了组织学特征与预后的相关性，同时对部分有争议的组织学形态进行了归类。本文主要围绕新版WHO分类病理学诊断相关的主要变化，对其临床意义进行了讨论。.

Real-time radial reconstruction with domain transform manifold learning for MRI-guided radiotherapy.

MRI-guidance techniques that dynamically adapt radiation beams to follow tumor motion in real time will lead to more accurate cancer treatments and reduced collateral healthy tissue damage. The gold-standard for reconstruction of undersampled MR data is compressed sensing (CS) which is computationally slow and limits the rate that images can be available for real-time adaptation. Once trained, neural networks can be used to accurately reconstruct raw MRI data with minimal latency. Here, we test the suitability of deep-learning-based image reconstruction for real-time tracking applications on MRI-Linacs. We use automated transform by manifold approximation (AUTOMAP), a generalized framework that maps raw MR signal to the target image domain, to rapidly reconstruct images from undersampled radial k-space data. The AUTOMAP neural network was trained to reconstruct images from a golden-angle radial acquisition, a benchmark for motion-sensitive imaging, on lung cancer patient data and generic images from ImageNet. Model training was subsequently augmented with motion-encoded k-space data derived from videos in the YouTube-8M dataset to encourage motion robust reconstruction. AUTOMAP models fine-tuned on retrospectively acquired lung cancer patient data reconstructed radial k-space with equivalent accuracy to CS but with much shorter processing times. Validation of motion-trained models with a virtual dynamic lung tumor phantom showed that the generalized motion properties learned from YouTube lead to improved target tracking accuracy. AUTOMAP can achieve real-time, accurate reconstruction of radial data. These findings imply that neural-network-based reconstruction is potentially superior to alternative approaches for real-time image guidance applications.

Bazedoxifene-induced ROS promote mitochondrial dysfunction and enhance osimertinib sensitivity by inhibiting the p-STAT3SOCS3 and KEAP1NRF2 pathways in non-small cell lung cancer.

Although the advent of osimertinib has brought revolutionary changes to the treatment landscape of non-small cell lung cancer (NSCLC) patients, acquired resistance remains a major obstacle limiting long-term survival benefits for the treatment of cancer. The purpose of this study was to examine the mechanisms involved in the ability of bazedoxifene to synergistically enhance osimertinib sensitivity, which will aid in delaying and overcoming osimertinib resistance to improve patient outcomes. Here, we found that osimertinib increased the production of reactive oxygen species (ROS), promoted mitochondrial fission, diminished mitochondrial membrane potential, and activated cell apoptosis. Moreover, the p-STAT3suppressor of cytokine signaling 3 (SOCS3) and KEAP1NRF2 signaling pathways were activated to scavenge ROS and promote osimertinib resistance. Mechanistically, SOCS3 can directly bind to KEAP1 to prevent the degradation of NRF2, resulting in the activation of an NRF2-dependent transcriptional program. Furthermore, the osimertinib-induced mitochondrial dysfunction and apoptosis were enhanced by bazedoxifene, thereby delaying and overcoming osimertinib resistance by inhibiting these pathways in vitro and in vivo. These findings identified a new critical link in the p-STAT3SOCS3 pathway, KEAP1NRF2 pathway, mitochondrial dysfunction, and osimertinib resistance. The present study demonstrated that bazedoxifene can be used for delaying or overcoming osimertinib resistance in NSCLC.

Chronic graft-versus-host-disease treatment in Brazil analyses of failure-free survival.

Failure-free survival (FFS), defined as the absence of new systemic treatment, recurrence of original malignancy and mortality not associated with recurrence after allogeneic hematopoietic stem cell transplantation (HCT), is a robust clinical measure to interpret results of initial systemic treatment of chronic graft-versus-host disease (cGVHD). We evaluate FFS after initial treatment of cGVHD in a mixed-race cohort from a resource-constrained country. This retrospective study included 354 consecutive patients after their first HCT between January 2014 and August 2020, who received initial systemic treatment for moderate or severe cGVHD at 13 Brazilian centers. Cox regression models were used to identify risk factors for treatment failure. The overall median follow-up among survivors was 28 months (range 1-71) after initial treatment. FFS was 89% at 6 months, 71% at 1 year and 52% at 2 years. New systemic treatment was the major cause of failure. In multivariable models, prior grades II-IV acute GVHD, a National Institutes of Health severity score of 3 in liver, gastrointestinal tract or lung involvement, and onset of initial treatment of cGVHD within 12 months after transplantation were all associated with an increased risk of treatment failure. Our results could serve as a benchmark for the design of future clinical trials evaluating initial treatment of cGVHD in resource-constrained locations.

Ten-year follow-up results of pure ground-glass opacity-featured lung adenocarcinomas after surgery.

Previously, we have demonstrated that the 5-year recurrence free survival (RFS) after surgery of pure ground-glass opacity (GGO)-featured lung adenocarcinoma is 100%. This study aimed to reveal the long-term outcomes of these patients 10 years after surgery. Lung adenocarcinoma patients who underwent surgery between December 2007 and December 2013 were reviewed. Patients with pure GGO-featured lung adenocarcinoma were enrolled. Postoperative survival and the risk of developing second primary lung cancer (SPLC) were analyzed. Overall, 308 pure GGO-featured lung adenocarcinomas were included. Of these patients, 226 (73.4%) were female, 268 (87.0%) were non-smokers, and 187 (60.7%) underwent sublobar resection. The median follow-up period after surgery was 112 months. The 10-year RFS rate of these patients was 100%, and 10-year overall survival rate was 96.9%. Both 5-year and 10-year lung cancer-specific survival were 100%. There was no difference in 10-year RFS rates between patients who underwent lobectomy or sublobar resection (p0.697). EGFR mutations were detected in 55.6% (84151) patients who underwent mutational analysis. The risk of developing SPLC for pure GGO-featured lung adenocarcinoma patients at 10 years after resection were 2.4%, and were not correlated with EGFR mutation status (p0.452). No recurrence was observed in patients with pure GGO-featured lung adenocarcinomas 10 years after surgery, even when pathologically evaluated as invasive adenocarcinoma. Pure GGO can be cured by surgery. Surgery is recommended for the appropriate time window with the view to cure. Our study emphasizes that radiological pure GGO-featured lung adenocarcinomas should be distinguished from other lung adenocarcinomas.

RET-MAP An international multi-center study on clinicobiologic features and treatment response in patients with lung cancer harboring a RET fusion.

Nearly 1-2% of non-small cell lung cancers (NSCLC) harbor RET fusions. Characterization of this rare population is still incomplete. This retrospective multi-center study included patients with any-stage RET NSCLC from 31 cancer centers. Molecular profiling included DNARNA sequencing andor FISH analyses. Clinico-biological features and treatment outcomes (per investigator) with surgery, chemotherapy, immune-checkpoint blockers (ICB), chemotherapy-ICB, multi-tyrosine kinase inhibitors (MTKi) and RET inhibitors (RETi) were evaluated. For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden (TMB) was 2.5 range, 1-4 mutMb and median PD-L1 expression was 10% range, 0-55. The most common metastatic sites were lung (50%), bone (43%) and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent chemotherapy, 46% and 9.6 months with chemotherapy-ICB, 23% and 3.1 months with ICB, 37% and 3 months with MTKi, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 months 37.7-72.1 versus 16.3 months 12.7-28.8, P<0.0001). Patients with RET NSCLC have mainly thoracic and bone disease, and low TMB and PD-L1 expression. RETi significantly improve survival, while ICB may be active in selected patients.

Camrelizumab Plus Carboplatin and Pemetrexed as First-Line Treatment for Advanced Nonsquamous NSCLC Extended Follow-Up of CameL Phase 3 Trial.

In CameL phase 3 study (ClinicalTrials.gov NCT03134872), addition of camrelizumab to first-line chemotherapy significantly improved the progression-free survival in patients with stages IIIB to IV nonsquamous NSCLC. Here, we present outcomes after a minimum follow-up of 43.9 months since last patient randomization. Eligible patients were randomized 11 to 4 to 6 cycles of camrelizumab plus carboplatin and pemetrexed or chemotherapy alone every 3 weeks, followed by maintenance camrelizumab plus pemetrexed or pemetrexed only (n 205 and 207, respectively). Total camrelizumab exposure was up to 2 years. As of January 31, 2022, camrelizumab plus chemotherapy exhibited substantially improved overall survival over chemotherapy alone (median, 27.1 versus 19.8 mo hazard ratio 0.72 95% confidence interval 0.57-0.92). In the chemotherapy-alone group, 95 patients (45.9%) crossed over to camrelizumab monotherapy. After adjustment for crossover, the survival benefit with camrelizumab plus chemotherapy was more pronounced (adjusted hazard ratio 0.55 95% confidence interval 0.42-0.71). In camrelizumab plus chemotherapy group, 33 patients completed 2 years of camrelizumab. Objective response rate was 97.0%, with ongoing responses in 17 of the 32 responses (53.1%), and 93.9% (31 of 33) of the patients were alive at data cutoff. Safety profiles were consistent with the previous report, and no obvious evidence of cumulative toxicity was found with long exposure to camrelizumab. Camrelizumab plus carboplatin and pemetrexed provides long-term survival benefit over chemotherapy, with manageable toxicity and remarkable and durable response in patients receiving 2 years of camrelizumab, further supporting camrelizumab combination as first-line treatment for advanced nonsquamous NSCLC.

Baseline radiomic signature to estimate overall survival in patients with non-small cell lung cancer.

We aimed to define a baseline radiomic signature associated with overall survival (OS) using baseline computed-tomography (CT) images obtained from patients with non-small cell lung cancer (NSCLC) treated with nivolumab or chemotherapy. The radiomics signature was developed in patients with NSCLC treated with nivolumab in CheckMate 017, 026, and 063. Nivolumab-treated patients were pooled and randomized to training, calibration, or validation sets using a 211 ratio. From baseline CT images, volume of tumor lesions was semi-automatically segmented, and 38 radiomic variables depicting tumor phenotype were extracted. Association between the radiomics signature and OS was assessed in the nivolumab-treated (validation set) and chemotherapy-treated (test set) patients in these studies. A baseline radiomic signature was identified using CT images obtained from 758 patients. The radiomic signature used a combination of imaging variables (spatial correlation, tumor volume in the liver, and tumor volume in mediastinal lymph nodes) to output a continuous value, ranging from 0 to 1 (from most to least favorable estimated OS). Given a threshold of 0.55, the sensitivity and specificity of the radiomic signature for predicting 3-month OS were 86% and 77.8%, respectively. The signature was identified in the training set of patients treated with nivolumab and was significantly associated (p < 0.0001) with OS in patients treated with nivolumab or chemotherapy. The radiomic signature provides an early readout of the anticipated OS in patients with NSCLC treated with nivolumab or chemotherapy. This could provide important prognostic information and may support risk stratification in clinical trials.

Metabolic landscape dysregulation in bronchoalveolar lavage fluid of checkpoint inhibitor pneumonitis.

Checkpoint inhibitor pneumonitis (CIP) is a potentially fatal adverse event resulting from immunotherapy in patients with malignant tumors. However, the pathogenesis of CIP remains poorly understood. We collected bronchoalveolar lavage fluid (BALF) from cohorts of patients with CIP, new-onset lung cancer (LC), and idiopathic pulmonary fibrosis (IPF). Non-targeted metabolomics analysis was conducted to analyze metabolic signatures. Flow cytometry was used to evaluate immune cell subsets. Lymphocytes were predominant in the BALF of patients with CIP. A total of 903 metabolites were identified, among which lipid compounds were the most abundant. In a comparison between patients with CIP and LC, enrichment analysis of the altered metabolites showed suppressed amino sugar metabolism, and spermidine and spermine biosynthesis in the CIP group. Metabolism of alpha linolenic acid, linoleic acid, and their fatty acid derivatives was enriched in the CIP group relative to the IPF group. The twelve metabolites found to be enriched in the CIP group were positively correlated with the proportion of CD8 In this study, the metabolomic landscape of BALF in patients with CIP was determined. We elucidated suppressed tumor metabolic signatures, enhanced pulmonary inflammatory signaling, and the characteristics of responsible immune cells, which helps to understand the pathogenesis of CIP.

Feasibility and Safety of Endosonography-Guided Transvascular Needle Aspiration in the Diagnosis of Thoracic and Abdominal Lesions A Meta-Analysis.

Endoscopic techniques, including endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS), are used as the initial approach for the diagnosis and staging of lung cancer and the diagnosis of thoracic and abdominal lesions. Historically, the transvascular approach has been avoided because of concerns about bleeding. This article is a systematic review of studies evaluating the feasibility and safety of transvascular needle aspiration (TVNA) under the guidance of EBUS or EUS in the diagnosis of thoracic and abdominal lesions. We performed a systematic search of the MEDLINE, Embase, and Cochrane databases to identify studies evaluating the application of EBUSEUS-guided TVNA (EBUSEUS-TVNA) for lesions located at the contralateral side of the vessel for which the transvascular approach was the best puncture path. We performed a meta-analysis of diagnostic yield estimations. We also reviewed the complications related to the procedure. Eleven observational studies were included in the final analysis. Meta-analysis yielded a pooled overall diagnostic yield of 82.10% (95% confidence interval, 0.74-0.89) for TVNA, with an I2 value of 52%. No publication bias was detected by Eggers test (p 0.8528). The overall complications included minor bleeding, minor hematoma, pseudo-aneurysm of the aorta, hemoptysis, acute hypoxic respiratory failure, and moderate bleeding. The major complication rate was 2.71%. EBUSEUS-TVNA is feasible and probably safe when performed by experienced endoscopists in carefully selected patients. In view of the potential risks associated with the transvascular approach, especially the development of hematoma and pseudoaneurysm, the fanning technique was avoided, and the area of aspiration should be assessed by EUS for 3 min after each aspiration. Most importantly, EBUSEUS-TVNA should only be performed if the results will impact the clinical management.

Targeting the Notch signaling pathway and the Notch ligand, DLL3, in small cell lung cancer.

Small cell lung cancer (SCLC) is a highly aggressive and poorly differentiated cancer with high-grade neuroendocrine (NE) features, accounting for approximately 15 % of all lung cancers. For decades, chemotherapy and radiotherapy have predominated the treatment strategy for SCLC, but relapses ensue quickly and result in poor survival of patients. Immunotherapy has brought novel insights, yet the efficacy is still restricted to a limited population with SCLC. Notch signaling is identified to play a key role in the initiation and development of SCLC, and the Notch ligand, Delta-like ligand 3 (DLL3) is found broadly and specifically expressed in SCLC cells. Thus, Notch signaling is under active exploration as a potential therapeutic target in SCLC. Herein, we summarized and updated the functional relevance of Notch signaling in SCLC, discussed Notch signaling-targeted therapy for SCLC and the correspondent preclinical and clinical trials, and investigated the promising synergy effects of Notch signaling targeted therapy and immune checkpoint inhibitors (ICIs) treatment.

Serum proteomics profiling identifies a preliminary signature for the diagnosis of early-stage lung cancer.

Lung cancer is the most common cause of death from cancer worldwide, largely due to late diagnosis. Thus, there is an urgent need to develop new approaches to improve the detection of early-stage lung cancer, which would greatly improve patient survival. The quantitative protein expression profiles of microvesicles isolated from the sera from 46 lung cancer patients and 41 high-risk non-cancer subjects were obtained using a mass spectrometry method based on a peptide library matching approach. We identified 33 differentially expressed proteins that allow discriminating the two groups. We also built a machine learning model based on serum protein expression profiles that can correctly classify the majority of lung cancer cases and that highlighted a decrease in the levels of Arysulfatase A (ARSA) as the most discriminating factor found in tumors. Our study identified a preliminary, non-invasive protein signature able to discriminate with high specificity and selectivity early-stage lung cancer patients from high-risk healthy subjects. These results provide the basis for future validation studies for the development of a non-invasive diagnostic tool for lung cancer.

An automatic classification of pulmonary nodules for lung cancer diagnosis using novel LLXcepNN classifier.

A critical step to ameliorate diagnosis and extend patient survival is Benign-malignant Pulmonary Nodule (PN) classification at earlier detection. On account of the noise of Computed Tomography (CT) images, the prevailing Lung Nodule (LN) detection techniques exhibit broad variation in accurate prediction. Thus, a novel Nodule Detection along with Classification algorithm for early diagnosis of Lung Cancer (LC) has been proposed. Initially, employing the Adaptive Mode Ostu Binarization (AMOB) technique, the Lung Volumes (LVs) isextortedas of the image together with the extracted lung regions is pre-processed. Then, detection of LNs takes place, and utilizing Geodesic Fuzzy C-Means Clustering (GFCM) Segmentation Algorithm, it is segmented.Next, the vital features are extracted, and the Nodules are classified by utilizing Logarithmic Layer Xception Neural Network (LLXcepNN) Classifier grounded on the extracted feature. The nodules are classified as Benign Nodules (BN) and Malignant Nodules (MN) by the proposed classifier. Lastly, the Lung CT images are scrutinized. Thus, when weighed against the prevailing techniques, the proposed systems acquired outcomes exhibit that the rate of accuracy of classification is enhanced.

Chemotherapy-induced neutropenia as a prognostic factor in patients with extensive-stage small cell lung cancer.

Chemotherapy-induced neutropenia (CIN) is a dose-limiting factor for cytotoxic chemotherapy, but recently, it was suggested that CIN contributes to prolonged survival. In this study, we examined the association between severe CIN and survival and determined whether CIN affected survival in patients with extensive-stage small cell lung cancer (ES-SCLC). The medical records from 214 patients with ES-SCLC treated with etoposide or irinotecan in combination with cisplatin (EPIP) between 2012 and 2016 were collected and retrospectively analyzed. Landmark analysis was performed at the end of cycle 4, and the relationship between severe CIN and survival was determined by a log-rank test. In addition, a multivariate analysis using the COX proportional hazard model was performed to identify independent predictive factors. The Landmark analysis included 102 patients in the IP group and 47 patients in the EP group. No significant difference was found between grades 0-3 and grade 4 neutropenia and overall survival (OS) in the EP group (P 0.57). Contrariwise, for the IP patients, the median OS was 444 days for grades 0-3 and 633 days for grade 4 neutropenia, which was significantly longer for patients who developed grade 4 neutropenia (P 0.03). Multivariate analysis adjusted for potential factors revealed that the development of grade 4 CIN was identified as a significant predictor of longer OS (hazard ratio HR, 0.50 95% confidence interval (CI), 0.28-0.87, P 0.015). The results indicated that the development of severe CIN with IP therapy is associated with prolonged OS.

Omental vascularized lymph node transplant for the treatment of breast lymphedema A case report.

Breast lymphedema is a type of breast cancer related lymphedema that leads to significant discomfort and negative impact on body image. Conservative therapy and lymphovenous bypass have been previously described as possible treatment methods for breast lymphedema, however, a unified approach to treatment is lacking. The current report describes a case of breast lymphedema successfully treated with vascularized lymph node transfer (VLNT) after failed attempt at management with conservative therapy. The patient is a 48-year-old female with right-sided breast cancer who underwent breast conservation therapy in 2015 and subsequently developed pain and swelling of the right breast. The diagnosis of breast lymphedema was supported by clinical evaluation as well as MRI, lymphoscintigraphy, and lymphography. In consultation with a breast surgeon, breast lymphedema was determined not to be an indication for mastectomy. The patient was offered and underwent an omental VLNT to the right breast. A 20 cm segment of omentum with associated gastroepiploic vessels and lymph nodes was harvested, transferred to the right axilla and gastroepiploic vessels were anastomosed to the recipient thoracodorsal vessels. The patient tolerated the procedure well and there were no complications. Additional donor sites were considered, such as the groin and submental regions, but an omental flap was favored in this case because of the lower risk of donor site lymphedema. In the years following, the patient reported significant improvement in symptoms as well as objective reduction of edema on MRI. We propose the consideration of VLNT for breast lymphedema refractory to other methods of management.

Preoperative visualization of congenital lung abnormalities hybridizing artificial intelligence and virtual reality.

When surgical resection is indicated for a congenital lung abnormality (CLA), lobectomy is often preferred over segmentectomy, mostly because the latter is associated with more residual disease. Presumably, this occurs in children because sublobar surgery often does not adhere to anatomical borders (wedge resection instead of segmentectomy), thus increasing the risk of residual disease. This study investigated the feasibility of identifying eligible cases for anatomical segmentectomy by combining virtual reality (VR) and artificial intelligence (AI). Semi-automated segmentation of bronchovascular structures and lesions were visualized with VR and AI technology. Two specialists independently evaluated via a questionnaire the informative value of regular computed tomography versus three-dimensional (3D) VR images. Five asymptomatic, non-operated cases were selected. Bronchovascular segmentation, volume calculation and image visualization in the VR environment were successful in all cases. Based on the computed tomography images, assignment of the CLA lesion to specific lung segments matched between the consulted specialists in only 1 out of the cases. Based on the three 3D VR images, however, the localization matched in 3 of the 5 cases. If the patients would have been operated, adding the 3D VR tool to the preoperative workup would have resulted in changing the surgical strategy (i.e. lobectomy versus segmentectomy) in 4 cases. This study demonstrated the technical feasibility of a hybridized AI-VR visualization of segment-level lung anatomy in patients with CLA. Further exploration of the value of 3D VR in identifying eligible cases for anatomical segmentectomy is therefore warranted.

Long-term risk of cancer among the first-degree relatives of epithelial ovarian cancer patients A cohort study with 48 years of follow up.

The long-term risk of cancer among first-degree relatives of ovarian cancer patients, especially their offspring, is of apparent clinical importance. Risks caused by known inherited factors such as BRCA1 or BRCA2 pathogenic variants are well established, but these account for only about 15% of ovarian cancer cases. Less is known about the possible familial risks of sporadic ovarian cancers. Using registry data, we conducted a retrospective cohort study with a total of 6501 first-degree relatives of 559 epithelial ovarian cancer patients. We studied the occurrence of overall cancer and cancer in specific sites known or suspected to be associated with ovarian cancer (breast, cervix, colon, endometrium, lung and trachea, skin melanoma, ovary, pancreas, prostate, rectum, and stomach). The overall number of cancers was not increased among the first-degree relatives of epithelial ovarian cancer patients during the up to 48 years of follow up. Among female relatives, the standardized incidence ratio for ovarian cancer was 1.92 (95% CI 1.27-2.79), mostly explained by a 2.30-fold (95% CI 1.46-3.45) risk among the patients sisters. There was a decreasing trend in the standardized incidence ratio for ovarian cancer among patients sisters by increasing age of the index patient. In our study cohort, we did not observe an increase in the overall cancer risk among the first-degree relatives of epithelial ovarian cancer patients in comparison with the general population. The risk for ovarian cancer, however, was increased. Current recommendations suggest prophylactic removal of the fallopian tubes and ovaries only with identified inherited risk factors. Our results emphasize the role of genetic counselling and testing, particularly in young ovarian cancer patients and their close female relatives.

Antioxidants, minerals and vitamins in relation to Crohns disease and ulcerative colitis A Mendelian randomization study.

Evidence for antioxidants, minerals and vitamins in relation to the risk of Crohns disease (CD) and ulcerative colitis (UC) is limited and inconsistent. This mendelian randomization (MR) study aimed to examine the causal associations of circulating levels of antioxidants, minerals and vitamins with CD and UC. Single-nucleotide polymorphisms associated with antioxidants (beta-carotene, lycopene and uric acid), minerals (copper, calcium, iron, magnesium, phosphorus, zinc and selenium), and vitamins (folate, vitamins A, B6, B12, C, D, E and K1) were employed as instrumental variables. Genetic associations with CD and UC were extracted from the UK Biobank, the FinnGen study and the International Inflammatory Bowel Disease Genetics Consortium. The inverse variance weighted method and sensitivity analyses were performed. Genetically predicted higher lycopene (OR 0.94, 95% CI 0.91-0.97), vitamins D (OR 0.65, 95% CI 0.54-0.79) and K1 (OR 0.93, 95% CI 0.90-0.97) levels were inversely associated with CD risk, whereas genetically predicted higher magnesium (OR 1.53, 95% CI 1.23-1.90) levels were positively associated with CD risk. Higher levels of genetically predicted lycopene (OR 0.91, 95% CI 0.88-0.95), phosphorus (OR 0.69, 95% CI 0.58-0.82), selenium (OR 0.91, 95% CI 0.85-0.97), zinc (OR 0.91, 95% CI 0.89-0.94), folate (OR 0.71, 95% CI 0.56-0.92) and vitamin E (OR 0.78, 95% CI 0.69-0.88) were associated with reduced UC risk, whereas genetically predicted high levels of calcium (OR 1.46, 95% CI 1.22-1.76) and magnesium (OR 1.24, 95% CI 1.03-1.49) were associated with increased risk of UC. Our study provided evidence that circulating levels of antioxidants, minerals and vitamins might be causally linked to the development of IBD.

Suppression of Lung Cancer Malignancy by Micellized siRNA through Cell Cycle Arrest.

UBA6-specific E2 conjugation enzyme 1 (USE1) is frequently overexpressed in lung cancer patients. Moreover, the critical role of USE1 in the progression of human lung cancer is also indicated. As the next step, the authors aim to develop USE1-targeted therapeutic agents based on RNA interference (RNAi). In this study, a lipid-modified DNA carrier, namely U4T, which consists of four consecutive dodec-1-ynyluracil (U) nucleobases to increase the cell permeability of siRNA targeting of USE1 is introduced. The U4Ts aggregate to form micelles, and the USE1-silencing siRNA-incorporated soft spherical nucleic acid aggregate (siSNA) can be created simply through base-pairing with siRNA. Treatment with siSNA is effective in suppressing tumor growth in vivo as well as cell proliferation, migration, and invasion of lung cancer cells. Furthermore, siSNA inhibited tumor cell growth by inducing cell cycle arrest in the G1 phase and apoptosis. Thus, the anti-tumor efficacy of siSNA in lung cancer cell lines and that siSNA possesses effective cell-penetrating ability without using cationic transfection moieties are confirmed. Collectively, these results suggest that siSNA can be applied to the clinical application of RNAi-based therapeutics for lung cancer treatment.

Discovering Gummadiol and Isoarboreol as potential inhibitors of sphingosine kinase 1 virtual screening and MD simulation studies.

Sphingosine kinase 1 (SphK1) dysfunction is well-known to be linked to various severe diseases, including breast, lung, prostate, and hematological cancers. Due to its crucial function in the onset of cancer and its progression, it is considered a notable drug target for anticancer therapy. Small molecule inhibitors with high specificity and efficacy towards SphK1 are needed for their therapeutic use. In order to find possible SphK1 inhibitors, we conducted a stepwise structure-based virtual screening of plant-based molecules available from the IMPPAT library. A multi-step virtual screening, including physicochemical and ADMET evaluation, PAINS, molecular docking, PASS analysis followed by molecular dynamics (MD) simulation and principal component analysis, identifies two compounds, Gummadiol and Isoarboreol, against SphK1. All-atom MD simulations were performed for 100 ns which examined the structural changes and stability of the docked complexes in the aqueous environment. The time evolution data of structural deviations and compactness, PCA and free energy landscapes suggested that the binding of Gummadiol and Isoarboreol with SphK1 is considerably stable throughout the trajectory. The study highlighted the use of phytochemicals in anticancer therapeutics and presented Gummadiol and Isoarboreol as promising inhibitors of SphK1.Communicated by Ramaswamy H. Sarma.

NR2F1-AS1 A Functional Long Noncoding RNA in Tumorigenesis.

NR2F1-AS1 is a long non-coding RNA (lnc RNA) that is involved in different biological processes. It plays an integral role in the pathophysiology of human diseases, especially tumorigenesis and progression. Therefore, it may be a promising target for numerous tumor biotherapeutics. The current review study aimed to show the pathophysiological activities and processes of RNA NR2F1-AS1 in cancer cells. The contents of the present review were based on information obtained from PubMed. In the data search, NR2F1-AS1 was chosen as the first keyword, whereas cancer was chosen as the second keyword. This review selected and summarized studies published between 2019-2021, concerning the biological functions and mechanisms of NR2F1-AS1 in the development of tumorigenesis. It was found that NR2F1-AS1 regulates a variety of biological activities such as proliferation, invasion, migration, and apoptosis. It acts as an oncogene because it is abnormally expressed and promotes the progression of cancer in a variety of malignancies, including esophageal squamous cell carcinoma, non-small cell lung cancer, breast cancer, neuroblastoma, endometrial cancer, thyroid cancer, and gastric cancer. However, it was evident that NR2F1-AS1 inhibits the progression of cancer in cervical squamous cell carcinoma. NR2F1-AS1 is a potential new biomarker and therapeutic target for the treatment of different cancers.

A FLEXIBLE SENSITIVITY ANALYSIS APPROACH FOR UNMEASURED CONFOUNDING WITH MULTIPLE TREATMENTS AND A BINARY OUTCOME WITH APPLICATION TO SEER-MEDICARE LUNG CANCER DATA.

In the absence of a randomized experiment, a key assumption for drawing causal inference about treatment effects is the ignorable treatment assignment. Violations of the ignorability assumption may lead to biased treatment effect estimates. Sensitivity analysis helps gauge how causal conclusions will be altered in response to the potential magnitude of departure from the ignorability assumption. However, sensitivity analysis approaches for unmeasured confounding in the context of multiple treatments and binary outcomes are scarce. We propose a flexible Monte Carlo sensitivity analysis approach for causal inference in such settings. We first derive the general form of the bias introduced by unmeasured confounding, with emphasis on theoretical properties uniquely relevant to multiple treatments. We then propose methods to encode the impact of unmeasured confounding on potential outcomes and adjust the estimates of causal effects in which the presumed unmeasured confounding is removed. Our proposed methods embed nested multiple imputation within the Bayesian framework, which allow for seamless integration of the uncertainty about the values of the sensitivity parameters and the sampling variability, as well as use of the Bayesian Additive Regression Trees for modeling flexibility. Expansive simulations validate our methods and gain insight into sensitivity analysis with multiple treatments. We use the SEER-Medicare data to demonstrate sensitivity analysis using three treatments for early stage non-small cell lung cancer. The methods developed in this work are readily available in the R package SAMTx.

TRIM58 Interacts with ZEB1 to Suppress NSCLC Tumor Malignancy by Promoting ZEB1 Protein Degradation via UPP.

Currently, how to successfully control refractory and metastatic diseases remains a fundamental goal for clinicians to improve therapeutic effects for patients with non-small cell lung cancer (NSCLC). Several studies have discovered that TRIM58, a member of tripartite motif protein family, shows antitumor effect in multiple types of cancer. In this study, we aimed to further clarify the molecular regulatory network of TRIM58 and corresponding targets for NSCLC patients. TRIM58 expression in clinical tumor tissue samples and cancer cell lines was examined. Functional experiments including cellular invasion, cell metastasis, chemoresistance assay, and ubiquitination evaluation experiments were conducted to investigate the interaction between TRIM58 and ZEB1, which is a prime element of transcription factor network that controls epithelial-to-mesenchymal transition. TRIM58 expression was characteristically decreased in NSCLC tumor tissues and cancer cell lines. Functional experiments demonstrated that TRIM58 suppression enhanced malignant biological behaviors including cellular survivability, migration, and invasion, as well as stem-like cellular phenotype of tumor cells. TRIM58 silencing also significantly enhanced the chemoresistance of NSCLC cells to chemoagents. TRIM58-ZEB1 interaction accelerated degradation of ZEB1 protein, thus further leading to the augment of tumor behaviors. Further detailed molecular experiments revealed that the interaction between TRIM58 and ZEB1 was mediated TRIM58 suppressed NSCLC through interacting with ZEB1 and promoting ZEB1 protein degradation

ATR inhibition overcomes platinum tolerance associated with ERCC1- and p53-deficiency by inducing replication catastrophe.

ERCC1XPF is a heterodimeric DNA endonuclease critical for repair of certain chemotherapeutic agents. We recently identified that ERCC1- and p53-deficient lung cancer cells are tolerant to platinum-based chemotherapy. ATR inhibition synergistically re-stored platinum sensitivity to platinum tolerant ERCC1-deficient cells. Mechanistically we show this effect is reliant upon several functions of ATR including replication fork protection and altered cell cycle checkpoints. Utilizing an inhibitor of replication protein A (RPA), we further demonstrate that replication fork protection and RPA availability are critical for platinum-based drug tolerance. Dual treatment led to increased formation of DNA double strand breaks and was associated with chromosome pulverization. Combination treatment was also associated with increased micronuclei formation which were capable of being bound by the innate immunomodulatory factor, cGAS, suggesting that combination platinum and ATR inhibition may also enhance response to immunotherapy in ERCC1-deficient tumors.

Awareness of COPD and Its Risk Factors Among the Adult Population of the Aseer Region, Saudi Arabia.

Epidemiological studies are urgently needed to assess the prevalence of COPD in the region to determine the baseline, against which the future trends in the risk factor levels can be assessed and preventive strategies be planned to promote health among the population. Therefore, this study was undertaken to assess the awareness of COPD and its risk factors in Saudi Arabia. The cross-sectional study was conducted among the general adult population aged 18 years and above living in the Aseer region. A minimum sample of 385 was targeted, using the Raosoft sample size calculator. An online questionnaire was prepared in both English and Arabic language using Google forms and distributed among participants through social media. It was observed that less than one-third (116, 30.12%) of the study population had ever heard about COPD. Nearly one-third spent time with smokers. Among all, 223 (57.3%) respondents had never heard and 46 (11.9%) respondents did not know anything about COPD. The majority correctly knew that the lungs are the primary organ affected by COPD (92, 79.3%). Age, sex, marital status, income, and occupation showed a significant association with COPD awareness. Nearly 41.4% knew that COPD progresses exclusively with age, COPD is more expensive for society than lung cancer (49.0%), cigarette smoking affects COPD (34.5%), COPD is fully recoverable with short-term antibiotics (35.0%), COPD lasts more than 18 months (48.1%), COPD can worsen with smoke exposure (37.4%), lead to disability (46.7%) and quitting smoking has an important role in preventing COPD (34.0%). The awareness regarding the disease was low among the respondents. Only one-third correctly knew that quitting smoking has an important role in preventing COPD. This study projects an urgent need of improving awareness of COPD and its risk factors in the general population.

A novel nomogram predicting cancer-specific survival in small cell lung cancer patients with brain metastasis.

Brain metastasis (BM) is one of the most common metastatic sites in patients with small cell lung cancer (SCLC), and the prognosis remains very poor. This study aimed to establish a novel nomogram for predicting the cancer-specific survival (CSS) in SCLC patients with BM. SCLC patients with BM from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015 were retrospectively collected. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors, which were further used to construct the prognostic nomogram. The discrimination and calibration of nomogram were evaluated by concordance index (C-index), receiver operating characteristic (ROC) curve, the area under ROC curve (AUC) and calibration plot. Decision curve analysis (DCA) was used to assess the clinical usefulness. Kaplan-Meier survival curve was applied to analyze the survival outcome. A total of 2,462 patients were enrolled in this study, and randomly assigned into training cohort (n1,723) and validation cohort (n739). Age, N stage, surgery, radiation, chemotherapy, bone metastasis, liver metastasis and lung metastasis were identified as independent prognostic factors of CSS. The C-indexes of nomogram was 0.683 95% confidence interval (CI) 0.667-0.699 in the training cohort, and 0.659 (95% CI 0.634-0.684) in the validation cohort. The AUC values of 6-, 9- and 12-month CSS were 0.723, 0.742 and 0.737 respectively in the training cohort, while 0.715, 0.737 and 0.739 in the validation cohort. The ROC, calibration and DCA curves showed good discrimination, calibration and clinical applicability of this nomogram in predicting prognosis. Moreover, patients in high-risk group had a worse survival outcome than patients in medium-risk and low-risk groups. A novel nomogram was constructed and validated for predicting individual prognosis in SCLC patients with BM. This nomogram could help clinicians make effective treatment strategies for patients.

Evaluation of a lung cancer screening programme attracting a cohort to actively participate in screening Honghe Lung Cancer Medical Center Programme.

A lung cancer screening project was conducted by attracting active participation to evaluate its feasibility and effectiveness in areas with poor basic medical education. This project entailed a prospective, single-arm study which was conducted by means of delivering a lecture on lung cancer at the Honghe Lung Cancer Medical Center to attract public attention and attendance from 28 November 2020 to 21 December 2021. A questionnaire comprising 7 high-risk factors was completed by participants to identify high-risk individuals for further chest low-dose computed tomography examination. Non calcified nodules with a diameter ≥5 mm were deemed positive nodules. The positive nodules were discussed by a multidisciplinary team and treatment suggestions were given. Finally, we analyzed participant information, examination adherence, lung cancer detection rate, and staging. A total of 6,121 individuals were attracted to the project, and 5,925 (96.8%) agreed to participate. Of these, 5,889 (99.4%) completed the survey, with 4,627 (78.6%) in the high-risk group and 1,262 (21.4%) in the non-high-risk group. The proportion of males in the high-risk group was higher than that in the non-high-risk group, and the difference was statistically significant among those aged 40-49 years, 50-59, years and 60-69 years P<0.01. In the high-risk population, 4,536 (98.0%) of participants adhered to examination, among whom 2,007 (44.2%) with positive nodules, 1,220 (26.9%) with negative nodules, and 1,309 (28.9%) without nodules showed statistical differences in age P<0.01. The detection rate of lung cancer was 2.2% (994,536) 94.0% (9399) of whom were stage 0-I patients. A health lecture-based approach to improving public participation in regions with poor health education is likely to be effective in promoting the early detection of lung cancer.

Long-term survival of a non-small cell lung cancer patient with

Lung cancer is the leading cause of cancer-related death worldwide. Up to 85% of lung cancer is non-small cell lung cancer (NSCLC) and most patients present with advanced disease at first diagnosis. Targeted therapy plays an important role in the treatment of advanced NSCLC. Epidermal growth factor receptor ( This article details a patient with Our case demonstrates that it is possible to achieve long-term survival in advanced

High-grade B-cell lymphoma with gastroduodenal involvement showing paraneoplastic cerebellar degeneration a case report.

Paraneoplastic cerebellar degeneration (PCD), which displays ataxia and other cerebellar symptoms, is the most common paraneoplastic neurological syndrome (PNS). PCD is more likely to occur in individuals with small cell lung cancer (SCLC), gynecological malignancies, and Hodgkin disease, but it is rarely associated with non-Hodgkin lymphoma (NHL). We report a case of PCD accompanying high-grade B-cell lymphoma embedded in an individuals stomach and duodenum, who also presented with acute onset of gait ataxia and slurred speech. The results of the common laboratory tests for neurological disorders, including the paraneoplastic antibody test, were negative. The key to the accurate diagnosis was the positron emission tomographycomputed tomography findings. The final diagnosis of high-grade B-cell lymphoma was unclear until the performance of repeated esophagogastroscopy with multipoint deep excavation biopsies. After standard chemotherapy, the patients gastric tumor was significantly alleviated and cerebellar syndrome was significantly improved. This case highlights the challenges of diagnosing PNS associated with occult malignancy. PNS patients may present with a variety of neurological disorders Thus, if any unexplained neurological symptoms appear after a series of specific laboratory and imaging tests, a diagnosis of PNS should be taken into consideration in the differential diagnosis list, as it may help clinicians identify asymptomatic malignancies and ensure patients receive correct treatments in a timely manner. A high-quality endoscopic biopsy is essential, as it helps hematologists make an accurate diagnosis of lymphoma with gastroduodenal involvement based on pathology.

Pilot clinical study on the prevention of complications after lung biopsy by the MIPP kit PNX device.

Pneumothorax (PNX), pulmonary hemorrhage, hemothorax and chest wall hematoma are the most commonly reported complications of percutaneous lung biopsy (PLB). Sealing the biopsy tract with different types of materials is an emerging way to prevent PLB complications. To investigate the safety and efficacy of a new device, Minimally Invasive Percutaneous Procedure Kit for Pneumothorax (MIPP-Kit PNX), when used in association with a resorbable bio-compatible glue in the prevention of PLB complications. A prospective, multicenter, open-label, single-arm study was performed to evaluate the complication rate after glue administration by the new investigational device during PLBs. Fourty-three patients were enrolled after informed consent signature (40 underwent PLB, while three were screening failures). Only 3 patients (7.5%, 95% CI 0.0-15.7%) developed complications within 48 h after glue injection during PLB two developed minor pneumothoraces and one a pulmonary hemorrhage. No patients who showed procedural complications before glue administration were reported with any recurrent or new complications after glue administration. In comparison with the data reported in the literature, this trial results support the safe and effective use of the MIPP kit PNX in the prevention of PLB complications. These promising preliminary results warrant further confirmation in larger clinical trials. ClinicalTrials.gov identifier NCT04071509.

P40 and TTF-1 double-expressing non-small cell lung cancer with EML4-ALK and PIK3CA gene mutations A case report and review of the literature.

P40 and thyroid transcription factor-1 (TTF-1) dual expression in non-small cell lung cancer (NSCLC) is a rare occurrence. However, the presence of EML4-ALK and PIK3CA gene mutations in this type of cancer is unknown. The present study describes the case of a 38-year-old male patient who had never smoked. A 4.5-cm mass adjacent to his right upper mediastinum was detected by a computed tomography (CT) scan of the chest. Biopsy of the level four lymph nodes in the right mediastinum revealed microscopic morphological features typical of high-grade NSCLC. Immunohistochemical findings resembled those reported previously for several cases of NSCLC with the dual expression of P40 and TTF-1 markers. In addition, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit a (PIK3CA) gene mutations were detected using high-throughput next-generation sequencing. To the best of our knowledge, this is the first report of NSCLC with the expression of P40 and TTF-1 as well as EML4-ALK and PIK3CA gene mutations. The presence of this type of tumor should be considered in patients with NSCLC who have never smoked and may have unique clinicopathological features.

A pregnant patient with ALK-positive non-small cell lung cancer treated with alectinib A case report and review of the literature.

Oncogenic rearrangements in the anaplastic lymphoma kinase (ALK) gene account for 5% of non-small cell lung cancer (NSCLC) cases. ALK inhibitors have markedly improved the outcome of metastatic ALK-positive NSCLC (ALK

Side effects of tyrosine kinase inhibitors therapy in patients with non-small cell lung cancer and associations with

Rash and diarrhea are common side effects of tyrosine kinase inhibitor (TKI) therapy administered to patients with non-small cell lung cancer (NSCLC). The polymorphisms of the epidermal growth factor receptor (

Left Heart and Systemic Arterial Circulation Air Embolus During CT-Guided Lung Biopsy.

A transthoracic needle biopsy (TTNB) of the lung, commonly referred to as a lung biopsy, is a commonly performed procedure in Interventional Radiology. It is usually associated with well-known risks including pneumothorax and hemothorax. One of the rare and lesser-known risks of TTNB, however, is a phenomenon called an air embolism. The term air embolism alone may be somewhat ambiguous, as it could indicate i) air entering the systemic veins, or ii) air entering the pulmonary veins. Here, we present a case of an air embolus entering the pulmonary veins. The pulmonary veins naturally drain into the left side of the heart (left atrium and ventricle) which provides oxygenated blood to the major arteries of the body including the coronary, carotid, and major abdominal visceral branches. Therefore, an air embolism in this vasculature can lead to potentially devastating hemodynamic consequences downstream.

Lung Cancer in Non-Smokers Clinicopathological and Survival Differences from Smokers.

Background Lung cancer in non-smokers is a clinically distinct entity based on unique epidemiology, clinicopathology, genetics, treatment response, and outcome. Data from Indian centres are scarce. The objective of this study was to compare the frequency, clinical characteristics, driver mutations, and survival of non-smoking and smoking lung cancer patients treated at a tertiary cancer centre in North India. Methodology Two years of data on 724 consecutive lung cancer patients were assessed. Clinical, demographics, smoking history, and EGFR and ALK mutation test results were collected. Descriptive and inferential statistics were applied. Survival analysis was performed using the Kaplan-Meier method. Results Non-smokers comprised 40.9% of the study sample. Non-smokers were more likely than smokers to experience disease onset at a younger age (P 0.004) and metastasis (P < 0.001). The tumor histology showed significant differences (P < 0.001), with non-smokers more likely to be diagnosed with adenocarcinoma (77.4%), while squamous and small cell histologies were commonly found among smokers (37.6% and 13.8%, respectively). The EGFR mutation and ALK rearrangement rates in the cohort were 23.3% and 10.1%, respectively, and were more frequent in non-smoking patients. Overall, 10-year survival was 7%, with a significantly better survival rate of non-smokers than smokers (median survival time of 15.13 vs 10.17 months P 0.012). Conclusions About four out of 10 patients diagnosed with lung cancer at our centre were non-smokers. They were more often young, diagnosed at an advanced stage, with predominantly adenocarcinoma histology, and had a threefold higher frequency of EGFR mutations than smokers. In our cohort, non-smokers appear to be a targetable group with better survival than smokers.

The IASLC grading system for invasive pulmonary adenocarcinoma a potential prognosticator for patients receiving neoadjuvant therapy.

Grading system for resected invasive pulmonary adenocarcinoma proposed by the International Association for the Study of Lung Cancer (IASLC) was validated as a strong prognostic indicator. Nonetheless, the efficacy of utilizing such grading system in prognostic assessment of patients receiving neoadjuvant therapy still needs elucidating. A retrospective study was conducted including patients with resected adenocarcinoma following neoadjuvant chemotherapy or targeted therapy from August 2012 to December 2020 in Shanghai Pulmonary Hospital. All the surgical specimens were re-evaluated and graded. The prognostic value of the grading system was further validated. Ultimately, a total of 198 patients were enrolled in this study, and subdivided into three cohorts according to the grading system. There were 13 (6.6%), 37 (18.7%), and 148 (74.7%) patients belonging to Grades 1, 2, and 3, respectively. IASLC grading system demonstrated significant power in prognosis differentiation of the entire cohort recurrence-free survival (RFS), The prognostic efficacy of pathological evaluation of the residual proportion of pulmonary adenocarcinoma post-neoadjuvant therapy using IASLC grading system was preliminarily verified. Such grading system might assist prognostic evaluation of neoadjuvant cohort other than traditional pathological parameters.

The postoperative prognosis of skip-N2 metastasis is favorable in small-cell lung carcinoma patients with pathological N2 classification a propensity-score-adjusted retrospective multicenter study.

The study on skip-N2 metastasis in small-cell lung cancer (SCLC) is lacking. Therefore, this study aimed to explore the prognostic significance of skip-N2 metastasis based on a multicenter cohort. We collected 176 SCLC patients with pathological categories T1-4N1-2M0 from four hospitals in China. Survival curves were drawn through the Kaplan-Meier method and compared by the log-rank test. The Cox regression method was used to calculate the hazard ratio (HR) and 95% confidence interval of the characteristics for cancer-specific survival (CSS). Two propensity-score methods were used to reduce the bias, including the inverse probability of treatment weighting (IPTW) and propensity-score matching (PSM). This multicenter database included 64 pN1 patients, 63 non-skip-N2 cases, and 49 skip-N2 cases. Skip-N2 and the non-skip-N2 patients had gap CSS rates (skip-N2 no Skip-N2 patients were confirmed to have a better prognosis than non-skip-N2 patients. Besides, there was no survival difference between pN1 and skip-N2 cases. Therefore, we propose that the next tumor-node-metastasis staging system needs to consider the situation of skip metastasis with lymph nodes in SCLC.

Exosomes derived from M1 macrophages inhibit the proliferation of the A549 and H1299 lung cancer cell lines via the miRNA-let-7b-5p-GNG5 axis.

Almost all cells are capable of secreting exosomes (Exos) for intercellular communication and regulation. Therefore, Exos can be used as a natural therapeutic platform to regulate genes or deliver drugs to treat diseases. M1 macrophages inhibit tumor growth by releasing pro-inflammatory factors. This study explored the applicability of M1 macrophage exosomes (M1-Exos) as gene carriers and the effects on GNG5 protein, and further examined whether macrophage repolarization could inhibit tumor activity. M0 macrophages were polarized toward M1 using vitexin. Exos were obtained from M1 macrophages by ultra-centrifugation. The transwell non-contact co-culture system was used to co-culture M1 macrophages with HLF- The results showed that, under the M1 macrophage co-culture system, lung cancer cell viability, invasion, and migration ability decreased, and the number of apoptotic cells increased, will all indicators being statistically significant ( M1-Exos inhibit the proliferation, invasion, and metastasis of lung cancer cells through miRNA-let-7b-5p and GNG5 signaling pathways and inhibit the anti-apoptotic ability of lung cancer cells.

CMTM6 is highly expressed in lung adenocarcinoma and can be used as a biomarker of a poor diagnosis.

CMTM6 which is chemokine-like factor (CKLF)-like Marvel transmembrane domain containing family member 6 is involved in the occurrence and progression of various tumors. However, the role of CMTM6 is still unclear in lung adenocarcinoma (LUAD). Immunohistochemical, Western blotting and RT‒PCR methods were used to detect the expression of CMTM6 in LUAD. Cox regression and the Kaplan‒Meier method were performed to assess overall survival. Immunogenic features were evaluated according to immune cell infiltrations, immune checkpoints. The sensitivity to chemotherapy agents was estimated using the pRRophetic package. In LUAD, the expression of CMTM6 was obviously upregulated and was significantly associated with T stage ( This study confirmed that CMTM6 is highly expressed in LUAD and is a new independent poor prognostic factor. In addition, the high expression of CMTM6 is closely related to the tumor microenvironment and immunotherapy, providing new ideas for the treatment of posterior LUAD.

Computed tomography-based radiomics machine learning models for prediction of histological invasiveness with sub-centimeter subsolid pulmonary nodules a retrospective study.

To improve the accuracy of preoperative diagnoses and avoid over- or undertreatment, we aimed to develop and compare computed tomography-based radiomics machine learning models for the prediction of histological invasiveness using sub-centimeter subsolid pulmonary nodules. Three predictive models based on radiomics were built using three machine learning classifiers to discriminate the invasiveness of the sub-centimeter subsolid pulmonary nodules. A total of 203 sub-centimeter nodules from 177 patients were collected and assigned randomly to the training set (

Retracted Analysis of the Mechanism and Safety of Bisphosphonates in Patients with Lung Cancer and Bone Metastases.

This retracts the article DOI 10.115520215343104..

Computational Exploration of Anti-cancer Potential of Flavonoids against Cyclin-Dependent Kinase 8 An

Over the centuries, cancer has been considered one of the significant health threats. It holds the position in the list of deadliest diseases over the globe. In women, breast cancer is the most common among many cancers and is the second most common cancer all over the world, while lung cancer is the first. Cyclin-dependent kinase 8 (CDK8) has been identified as a critical oncogenic driver that is found in breast cancer and associated with tumor progression. Flavonoids were virtually screened against CDK8 using molecular docking, drug-likeness, ADMET prediction, and a molecular dynamics (MD) simulation approach to determine the potential flavonoid structure against CDK8. The results indicated that ZINC000005854718 showed the highest negative binding affinity of -10.7 kcalmol with the targeted protein and passed all the drug-likeness parameters. Performed molecular dynamics simulation showed that docked complex systems have good conformational stability over 100 ns in different temperatures (298, 300, 305, 310, and 320 K). The comparison between calculated binding free energy

Advances in Lung Cancer Treatment Using Nanomedicines.

Carcinoma of the lungs is among the most menacing forms of malignancy and has a poor prognosis, with a low overall survival rate due to delayed detection and ineffectiveness of conventional therapy. Therefore, drug delivery strategies that may overcome undesired damage to healthy cells, boost therapeutic efficacy, and act as imaging tools are currently gaining much attention. Advances in material science have resulted in unique nanoscale-based theranostic agents, which provide renewed hope for patients suffering from lung cancer. Nanotechnology has vastly modified and upgraded the existing techniques, focusing primarily on increasing bioavailability and stability of anti-cancer drugs. Nanocarrier-based imaging systems as theranostic tools in the treatment of lung carcinoma have proven to possess considerable benefits, such as early detection and targeted therapeutic delivery for effectively treating lung cancer. Several variants of nano-drug delivery agents have been successfully studied for therapeutic applications, such as liposomes, dendrimers, polymeric nanoparticles, nanoemulsions, carbon nanotubes, gold nanoparticles, magnetic nanoparticles, solid lipid nanoparticles, hydrogels, and micelles. In this Review, we present a comprehensive outline on the various types of overexpressed receptors in lung cancer, as well as the various targeting approaches of nanoparticles.

A comprehensive review on algal nutraceuticals as prospective therapeutic agent for different diseases.

Ongoing research in the food supplement sector provides insightful information regarding algae as a new-generation nutritional supplement and is also referred to as a superfood. Due to the diverse nutritional components, algae have documented numerous health benefits like fighting microbial diseases, hypertension, obesity, and diabetes. Therefore, algae-derived nutraceuticals account for a rapidly expanding market in the food supplements sector. The concept of algal prebiotics and their role in modulating gut microbiota have also been a chief contributor to this. This review evaluates the use of possible algal species and their specific bioactive compounds for the management of several chronic diseases. Proteins, peptides, polysaccharides, phenolics, and vitamins give an insight into the significance of algae in boosting the immune system and improving the bodys nutritional makeup. In addition, phyco-compounds such as polysaccharides and polyphenols are also receiving a lot more interest in cosmeceutical applications for protecting skin from photodamage. The incorporation of algae in the diet for the management and prevention of chronic diseases like cancer, lung, and heart disease has been discussed in this review along with their action mechanism. This review provides a brief overview of several bioactive compounds present in micro and macroalgae and their therapeutic effect on lifestyle diseases, gastrointestinal diseases as well as neurodegenerative diseases.

Role of subxiphoid uniportal video-assisted thoracoscopic surgery in pulmonary metastasectomy.

Optimal management for patients with pulmonary metastasis is still debated. True survival benefit from widely practiced pulmonary metastasectomy (PM) is yet to be proved from high-quality randomized controlled trials. The ideal surgical approach for PM is also not generally agreed. VATS offers enhanced recovery and superior functional outcomes but at the expense of less detection of lung nodules and higher possibility of narrowpositive resection margins. The subxiphoid uniportal VATS (uVATS) approach is an evolving new approach with potential advantages including simultaneous access to both lung fields, less pain and faster rehabilitation. These advantages make it a favorable approach for PM, particularly in the setting of bilateral metastases. However, its use is still limited to case reports of a small number of patients. There is room for improvements in subxiphoid uVATS due to reported technical challenges and limitations. Herein, we aim to publicize a comprehensive review of literature on applications of subxiphoid uVATS in PM.

Role of video-assisted thoracoscopic surgery in pulmonary metastasectomy.

There are sparse prospective studies investigating the role of video-assisted thoracoscopic surgery (VATS) in management of pulmonary metastasis. To prospectively investigate short-term surgical and pathological outcomes for PM patients operated on by VATS or open thoracotomy (OT) for management of lung secondaries. Between October 2017 and December 2020, patients undergoing pulmonary metastasectomy were recruited. Patients were assigned to undergo resection with either thoracotomy (group 1) or VATS (group 2) after multidisciplinary team discussions based on the number, size and location of pulmonary metastasis and underlying lung function. All related short-term surgical and pathologic outcomes for both groups were collected for analysis. Of 58 patients enrolled, 21 were in group 1 and 37 in group 2. Colorectal cancer primary represented 40% of the cases. Patients in the VATS group were more likely to have solitary lesions that are peripherally located and removed by wedge resection, as opposed to patients in the thoracotomy group, who had more anatomical lung resections. More new nodules were likely to be detected during surgery in thoracotomy than VATS cases ( In a highly selected cohort of pulmonary metastasis patients with favorable criteria (peripherally located, small, solitaryoligo-metastasis and cN0), VATS may provide acceptable onco-pathologic outcomes as compared to the standard open thoracotomy.

Cerebrospinal fluid-derived circulating tumor DNA is more comprehensive than plasma in NSCLC patients with leptomeningeal metastases regardless of extracranial evolution.

Metastases to the central nervous system (CNS) are devastating neurological complications. Circulating cell-free tumor DNA (ctDNA) from cerebrospinal fluid (CSF) better represents genomic alterations in CNS tumors compared to plasma (PLA). However, the clinical value of cerebrospinal fluid (CSF) as a liquid biopsy medium in non-small cell lung cancer patients with leptomeningeal metastases (NSCLC-LM), regardless of extracranial evolution, remains unclear. 1448 NSCLC-BM patients and 3448 NSCLC-LM patients were enrolled in this study. The genomic mutation profiles in CSF and matched PLA for patients with single CNS progression (cohort one, N 22) or intracranial progression with extracranial disease progression (cohort two, N 12) were compared. ctDNA in the CSF and simultaneously collected PLA was subjected to next-generation target sequencing (NGS) of 168 cancer-relevant genes. CSF is more comprehensive of driver genomic mutation profile than in matched PLA in patients with a single CNS progression. In addition, potential prognostic markers are much higher in CSF samples than related PLA. For example, the detection rate of For NSCLC -LM patients, regardless of single intracranial progression or intracranial progression simultaneously with extracranial evolution, CSF is superior to matched PLA.

The effect of silica exposure on the risk of lung cancer A meta-analysis.

Lung cancer is an incurable disease with an increased mortality rate caused by the inhalation of dust-containing crystalline silica particles. Silica exposure is one of the most important occupational hazards in the world. Whether the association between silica exposure and lung cancer is because of the fibrotic process or to the effect of respirable silica itself is unclear. The International Agency for Research on Cancer (IARC) classified silica as a human lung carcinogen. The opinion of lung cancer is a question that has been addressed in this review. Three electronic databases, including MEDLINE, Scopus, and Web of Science, were used to search for relevant literature from 2000 to 2022. To evaluate the relationship between exposure to silica and developing lung cancer, we performed a meta-analysis using the random-effects model. For each study, the overall odds ratio (OR), relative risk (RR) with 95% confidence intervals (CI), and p values were calculated. An extensive database search resulted in the selection of 20 (case-control and nested case-control studies were selected) out of 527 studies. Among the 20 selected studies, 7 studies showed a significant association between silica exposure and an increased risk of lung cancer. Further analysis showed that among the selected studies, six studies showed a significant correlation between combined exposure to silica and smoking with an increased risk of lung cancer. The data from the present study showed that smoking habits increased the impact of silica exposure on the initiation of lung carcinogenesis in exposed workers.

Indocyanine green navigation in minimally invasive resection of multiple metachronous pulmonary metastases of hepatoblastoma.

Pulmonary metastases from hepatoblastoma (HB) have traditionally been identified by preoperative computed tomography scan image evaluation, and intraoperative visual and palpatory examinations through thoracotomy have been generally recommended. However, the safety and accuracy of surgery can be problematic in patients with small multiple lung metastases due to postoperative respiratory dysfunction risk secondary to decreased residual lung capacity in wedge resections. We present an 8-month-old patient with metastatic HB with multiple metachronous pulmonary lesions in whom thoracoscopic lung resections were performed guided by indocyanine green (ICG) administered intravenously 24 h earlier (0.5 mgkg). ICG fluorescence allowed identification and limited resection of lung parenchyma, avoiding postoperative respiratory dysfunction. A total of 16 lung lesions were resected during four operations (two bilateral and two right thoracoscopies), with no postoperative complications. ICG-guided thoracoscopic surgery allowed identification and resection of metastatic nodules in both lungs during the same procedure, achieving a hospital stay of less than 3 days for each intervention. The patient is currently 24 months old and remains asymptomatic, with no distant disease at the last imaging control. ICG-guided resection via a thoracoscopic approach is particularly useful in patients with multiple andor metachronous metastases requiring multiple surgical interventions.

Nuclear Fructose-1,6-Bisphosphate Inhibits Tumor Growth and Sensitizes Chemotherapy by Targeting HMGB1.

Metabolites are important for cell fate determination. Fructose-1,6-bisphosphate (F1,6P) is the rate-limiting product in glycolysis and the rate-limiting substrate in gluconeogenesis. Here, it is discovered that the nuclear-accumulated F1,6P impairs cancer cell viability by directly binding to high mobility group box 1 (HMGB1), the most abundant non-histone chromosome structural protein with paradoxical roles in tumor development. F1,6P disrupts the association between the HMGB1 A-box and C-tail by targeting K43K44 residues, inhibits HMGB1 oligomerization, and stabilizes P53 protein by increasing P53-HMGB1 interaction. Moreover, F1,6P lowers the affinity of HMGB1 for DNA and DNA adducts, which sensitizes cancer cells to chemotherapeutic drug(s)-induced DNA replication stress and DNA damage. Concordantly, F1,6P resensitizes cancer cells with chemotherapy resistance, impairs tumor growth and enhances chemosensitivity in mice, and impedes the growth of human tumor organoids. These findings reveal a novel role for nuclear-accumulated F1,6P and underscore the potential utility of F1,6P as a drug for cancer therapy.

Model-based meta-analysis of non-small cell lung cancer with standard of care PD-1 inhibitors and chemotherapy for early development decision making.

Single-arm cohortstrials are often used in early phase oncology programs to support preliminary clinical activity assessments for investigational products, administered alone or in combination with standard of care (SOC) agents. Benchmarking clinical activity of those combinations against other treatments, including SOC, requires indirect comparisons against external trials, which presents challenges including cross-study differences in trial populationsother factors. To facilitate such nonrandomized comparisons, we developed a comprehensive model-based meta-analysis (MBMA) framework to quantitatively adjust for factors related to efficacy in metastatic non-small cell lung cancer (mNSCLC). Data were derived from 15 published studies assessing key programmed cell death protein-1 (PD-1) inhibitors pembrolizumab (n 8) and nivolumab (n 7), representing current SOC in mNSCLC. In the first stage, a mixed-effects logistic regression model for overall response rate (ORR) was developed accounting for effects of various population covariates on ORR. The ORR model results indicated an odds ratio (OR) of 1.02 for squamous versus non-squamous histology and OR of 1.20 for PD-ligand 1 tumor proportion score (TPS) per every 10% increase of TPS level. Next, a nonparametric mixed-effects model for overall survival (OS) was developed with ORRother clinical covariates as input. Subsequently, MBMA simulations of relevant hypothetical scenarios involving single-arm trial design predicted OS hazard ratios as a function of ORR with matched patient characteristics. Findings from this MBMA and derived parameter estimates can be generally applied by the reader as a framework for interpreting efficacy data from early phase trials to support ORR-based gono-go decisions and futility rules, illustrated through examples in this report.

Targeting polymerase θ impairs tumorigenesis and enhances radiosensitivity in lung adenocarcinoma.

Radioresistance remains a major obstacle to efficacious radiotherapy in non-small-cell lung cancer (NSCLC). DNA replication proteins are novel targets for radiosensitizers. POLQ is a DNA polymerase involved in DNA damage response and repair. We found that POLQ is overexpressed in NSCLC and is clinically correlated with high tumor stage, poor prognosis, increased tumor mutational burden, and ALK and TP5 mutation status POLQ inhibition impaired lung tumorigenesis. Notably, POLQ expression was higher in radioresistant lung cancer cells than in wild-type cancer cells. Moreover, POLQ expression was further increased in radioresistant cells after radiation. Enhanced radioresistance is through a prolonged G2M phase and faster repair of DNA damage, leading to reduced radiation-induced apoptosis. Novobiocin (NVB), a POLQ inhibitor, specifically targeted cancer cells. Genetic knockdown of POLQ or pharmacological inhibition by NVB decreased radioresistance in lung adenocarcinoma while causing little toxicity to normal pulmonary epithelial cells. In conclusion, POLQ is a promising and practical cancer-specific target to impair tumorigenesis and enhance radiosensitivity in NSCLC.

Antitumor activity and mechanism of cucurbitacin B in A549DDP cells.

Cucurbitacin B (CuB) is a class of tetracyclic triterpenoids isolated from Cucurbitaceae with a wide range of anti-inflammatory and anti-tumor activities, mainly used in hepatitis and hepatocellular carcinoma, while there is relatively little research and application of this drug for lung cancer. In this study, CuB was administered on A549DDP cells to observe how it affected the cells and their mechanism of action. CuB demonstrated good anti-tumor activity against A549DDP cells in a dose-dependent manner and caused changes in the hedgehog (Hh) pathway. The results showed that CuB greatly inhibits the proliferation and the invasion of A549DDP cells, and promoted apoptosis of A549DDP cells. Meanwhile, it changed the expression of p53-related genes at the RNA and protein level. In conclusion, this experiment provides a theoretical basis for new applications of CuB and new thoughts on the mechanism of its anti-tumor activity, and provides a direction for deep research.

Timeliness of Lung Cancer Care From the Point of Suspicious Image at an Urban Safety Net Hospital.

Timeliness of care is an important metric for lung cancer patients, and care delays in the safety-net setting have been described. Timeliness from the point of the suspicious image is not well-studied. Herein, we evaluate time intervals in the workup of lung cancer at an urban, safety net hospital and assess for disparities by demographic and clinical factors. We performed a retrospective analysis of lung cancer patients receiving some portion of their care at Boston Medical Center between 2015 and 2020. A total of 687 patients were included in the final analysis. Median times from suspicious image to first treatment (SIT), suspicious image to diagnosis (SID), and diagnosis to treatment (DT) were calculated. Nonparametric tests were applied to assess for intergroup differences in time intervals. SIT, SID, and DT for the entire cohort was 78, 34, and 32 days, respectively. SIT intervals were 87 days for females and 72 days for males (p < .01). SIT intervals were 106, 110, 81, and 41 days for stages I, II, III, and IV, respectively (p < .01). SID intervals differed between black (40.5) and Hispanic (45) patients compared to white (28) and Asian (23) patients (p < .05). Advanced stage at presentation and male gender were associated with more timely treatment from the point of suspicious imaging while white and Asian were associated with more timely lung cancer diagnosis. Future analyses should seek to elucidate drivers of timeliness differences and assess for the impact of timeliness disparities on patient outcomes in the safety net setting.

Immune checkpoint therapy and response biomarkers in non-small-cell lung cancer Serum NY-ESO-1 and XAGE1 antibody as predictive and monitoring markers.

Immune checkpoint inhibitors (ICI) are key drugs in systemic therapy for advanced non-small-cell lung cancer (NSCLC) and have recently been incorporated into neoadjuvant and adjuvant settings for surgical resection. Currently, ICI combinations with cytotoxic agents are frequently used in clinical practice, although several ICI clinical trials have failed to produce long-term clinical benefits. Unfortunately, clinical benefit is moderate and limited considering physical and financial burden. Therefore, selecting appropriate patients and regimens for ICI therapy is important, and biomarkers are necessary for their selection. Tumor PD-L1 expression is universally used as a biomarker however, PD-L1 assays show low analytical validity and reproducibility due to the visual-scoring system by pathologists. Recent tumor immunology studies explore that neoantigens derived from somatic mutations and the collaboration between T and B cells efficiently elicit antitumor responses. This suggests that high tumor mutational burden and T-cell infiltration are predictive biomarkers. However, B cells producing antibody (Ab) remain poorly understood and analyzed as biomarkers. We found that NY-ESO-1 and XAGE1 of cancer-testis antigen frequently elicit spontaneous humoral and cellular immune responses in NSCLC. Serum Ab against these antigens were detected in approximately 25% of NSCLC patients and predicted ICI monotherapy responses. In addition, the Ab levels were decreased with tumor shrinkage after ICI therapy. Thus, NY-ESO-1 and XAGE1 Ab are potentially biomarkers predicting and monitoring response to ICI therapy. For clinical applications, a fully-automated assay system measuring the Ab was developed. Here, we review current ICI therapy, tumor immunology, and biomarkers in NSCLC, and discuss the applicability of the serum biomarkers NY-ESO-1 and XAGE1 Ab.

Therapeutic strategies for non-small cell lung cancer Experimental models and emerging biomarkers to monitor drug efficacies.

While new targeted therapies have considerably changed the treatment and prognosis of non-small cell lung cancer (NSCLC), they are frequently unsuccessful due to primary or acquired resistances. Chemoresistance is a complex process that combines cancer cell intrinsic mechanisms including molecular and genetic abnormalities, aberrant interactions within the tumor microenvironment, and the pharmacokinetic characteristics of each molecule. From a pharmacological point of view, two levers could improve the response to treatment (i) developing tools to predict the response to chemo- and targeted therapies and (ii) gaining a better understanding of the influence of the tumor microenvironment. Both personalized medicine approaches require the identification of relevant experimental models and biomarkers to understand and fight against chemoresistance mechanisms. After describing the main therapies in NSCLC, the scope of this review will be to identify and to discuss relevant in vitro and ex vivo experimental models that are able to mimic tumors. In addition, the interests of these models in the predictive responses to proposed therapies will be discussed. Finally, this review will evaluate the involvement of novel secreted biomarkers such as tumor DNA or micro RNA in predicting responses to anti-tumor therapies.

Safety and Efficacy of Combined Resveratrol and Sirolimus in Lymphangioleiomyomatosis.

A critical need exists to develop remission-inducing therapies for lymphangioleiomyomatosis. Is the addition of resveratrol safe and more efficacious than sirolimus alone in patients with lymphangioleiomyomatosis We conducted a phase 2, dose-escalating, open-label trial of resveratrol in patients with lymphangioleiomyomatosis receiving a stable regimen of sirolimus. Resveratrol was started at 250 mgd and escalated every 8 weeks to maximum dose of 1,000 mgd over 24 weeks. The primary outcome was ≥ 42% decline in serum vascular endothelial growth factor D (VEGF-D) levels on combined therapy compared with baseline VEGF-D levels on sirolimus. Secondary objectives included an assessment of the safety profile and the effect on lung function and health-related quality of life (HRQOL). Longitudinal change in outcome measures was assessed using linear mixed models. Adverse effects were tabulated using the National Cancer Institutes Common Terminology Criteria for Adverse Events version 4. Twenty-five patients with lymphangioleiomyomatosis with a median age of 51 years were enrolled. Pulmonary function parameters at study inclusion were FEV The addition of resveratrol was safe and well tolerated in patients with lymphangioleiomyomatosis taking sirolimus and was associated with modest improvement in HRQOL. Larger controlled trials of this combination might be warranted to assess definitively the usefulness of resveratrol as an additive therapy in lymphangioleiomyomatosis. ClinicalTrials.gov No. NCT03253913 URL www. gov.

ANP32B promotes lung cancer progression by regulating VDAC1.

It has been reported before that acidic leucine-rich nuclear phosphoprotein 32 family member B (ANP32B) plays roles in many cancers, yet no report of its role in lung cancer exists. In this study, we documented an elevation of ANP32B within lung cancer tissues and cells. Knockdown of ANP32B hindered the proliferation as well as migration of lung cancer cells, whereas overexpression of ANP32B helps to promote the malignant progression of lung cancer. ANP32B also regulates lung cancer cells apoptosis and cell cycling. In addition, voltage-dependent anion channel 1 (VDAC1) has been found to be a downstream targeted gene of ANP32B and is positively regulated by ANP32B in lung cancer cells. According to our research, the expression of VDAC1 was positively associated with ANP32B expression in lung adenocarcinoma (r 0.61, P < 0.001) samples by Pearsons correlation coefficient analysis. Furthermore, rescue experiments demonstrated that VDAC1 could rescue the effect of ANP32B expression on lung cancer cell proliferation and migration. Our results suggest that ANP32B overexpression facilitates lung cancer progression by increasing the expression of VDAC1. As such, we have revealed a novel mechanism regulating the connection between ANP32B and VDAC1 and a potential role of ANP32B as an oncogene and a clinical therapeutic target in lung cancer.

A Clinical Series in Patients with Naso-Pharyngeal Cancer and Their Outcomes with Stent Graft Treatment for Sentinel Bleeding to Prevent Frank Carotid Rupture.

The purpose of this study was to evaluate the safety and effectiveness of heparin-bonded VIABAHN stent graft for carotid rupture in patients with nasopharyngeal carcinoma (NPC). A total of 1,596 patients with NPC were enrolled. Fifteen patients (8 male and 7 female), who developed carotid artery rupture (CAR) after radiotherapy between January 2016 and June 2019, were retrospectively analyzed. Complications and mortality were assessed at 12 months postoperatively. The incidence of carotid burst syndrome in the NPC cohort was 0.94%. The distribution of site of arterial rupture was as follows common carotid artery (4 cases), C1 segment of internal carotid artery (8 cases), and C2 segment of internal carotid artery (3 cases). All patients successfully underwent emergency deployment of the heparin-bonded VIABAHN to seal off the ruptured carotid artery. The survival rate as of 12-month follow-up was 80.0%. Three patients died of short-term rebleeding, lung infection, and tumor progression. No stent-related complications occurred in our cohort. Heparin-bonded VIABAHN-covered stents may be a safe and effective treatment option for carotid rupture in patients with NPC.

Impact of Duration of Diagnostic Workup on Prognosis for Early Lung Cancer.

Growth assessment for pulmonary nodules is an important diagnostic tool, however, the impact on prognosis due to time delay for follow-up diagnostic scans needs to be considered. Using the data between 2003 and 2019 from the International Early Lung Cancer Action Program (I-ELCAP), a prospective cohort study, we determined the size specific 10-year Kaplan-Meier lung cancer (LC) survival rates as surrogates for cure rates. We estimated the change in LC diameter after delays of 90-, 180-, and 365-days using three representative LC volume doubling times (VDTs) of 60(fast), 120(moderate), and 240(slow). We then estimated the decrease in the lung cancer (LC) cure rate resulting from time between CT scans to assess for growth during the diagnostic workup. Using a regression model of the 10-year LC survival rates on LC diameter, the estimated LC cure rate of a 4.0 mm LC with fast (60-day) VDT is 96.0%(95% CI 95.2%-96.7%) initially, but it would decrease to 94.3%(95% CI 93.2%-95.%), 92.0%(95% CI 90.5%-93.4%) and 83.6%(95% CI 80.6%-86.6%) after delays of 90, 180, and 365 days, respectively. A 20.0 mm LC with the same VDTs has an initial lower LC cure rate of 79.9%(95% CI 76.2%-83.5%) initially, and decreases more rapidly to 71.5%(95% CI 66.4%-76.7%), 59.8%(95%CI52.4%-67.1%) and 17.9%(95% CI 3.0%-32.8%) after the same delays of 90, 180, and 365 days. Time between scans required to measure growth of lung nodules impacts prognosis with the effect being greater for fast-growing and larger cancers. Quantifying the extent of change in prognosis is required to understand efficiencies of different management protocols.

Multicenter analysis of stereotactic radiosurgery for multiple brain metastases from EGFR and ALK driven non-small cell lung cancer.

Patients with brain metastases (BrMs) arising from EGFR and ALK driven non-small cell lung cancer (NSCLC) have favorable prognoses and evolving treatment options. We evaluated multicenter outcomes for stereotactic radiosurgery (SRS) to multiple (≥4) BrMs, where randomized data remain limited. Data were collected retrospectively from 5 academic centers on EGFR and ALK NSCLC who received SRS to ≥4 BrMs with their first SRS treatment between 2008 and 2018. Analyzed endpoints included overall survival (OS), freedom from CNS progression (FFCNSP), and freedom from whole-brain radiotherapy (FFWBRT). Eighty-nine patients (50 EGFR, 39 ALK) received a total of 159 SRS treatments to 1,080 BrMs, with a median follow up of 51.3 months. The median number of BrMs treated with SRS treatment-1 was 6 (range 4-26) and median for all treatments was 9 (range 4-47). Sixteen patients (18 %) had received WBRT prior to SRS treatment-1. The median OS was 24.2, 21.2, and 33.2 months for all patients, EGFR, and ALK subsets, respectively. After multivariable adjustment, only receipt of a next-generation tyrosine kinase inhibitor was associated with OS (HR 0.40, p 0.005). No differences in OS were observed based on number of BrMs treated. The median FFCNSP was 9.4, 11.6, and 7.5 months, for all patients, EGFR, and ALK subsets, respectively. After multivariable adjustment, the number of BrMs (continuous) treated during treatment-1 was the only negative prognostic factor associated with FFCNSP (HR 1.071, p 0.045). The 5-year FFWBRT was 73.6 %. This multicenter analysis over a >10-year period demonstrated favorable OS, FFCNSP, and FFWBRT, in patients with EGFR and ALK driven NSCLC receiving SRS to ≥4 BrMs. These data support SRS as an option in the upfront and salvage setting for higher burden CNS disease in this population.

Synergistic therapeutic potential of alpelisib in cancers (excluding breast cancer) Preclinical and clinical evidences.

The phosphoinositide 3-kinase (PI3K) signaling pathway is well-known for its important role in cancer growth, proliferation and migration. The activation of PI3K pathway is always connected with endocrine resistance and poor prognosis in cancers. Alpelisib, a selective inhibitor of PI3K, has been demonstrated to be effective in combination with endocrine therapy in HR PIK3CA-mutated advanced breast cancer in preclinical and clinical trials. Recently, the synergistic effects of alpelisib combined with targeted agents have been widely reported in PIK3CA-mutated cancer cells, such as breast, head and neck squamous cell carcinoma (HNSCC), cervical, liver, pancreatic and lung cancer. However, previous reviews mainly focused on the pharmacological activities of alpelisib in breast cancer. The synergistic therapeutic potential of alpelisib in other cancers has not yet been well reviewed. In this review, an extensive study of related literatures (published until December 20, 2022) regarding the anti-cancer functions and synergistic effects of alpelisib was carried out through the databases. Useful information was extracted. We summarized the preclinical and clinical studies of alpelisib in combination with targeted anti-cancer agents in cancer treatment (excluding breast cancer). The combinations of alpelisib and other targeted agents significantly improved the therapeutic efficacy both in preclinical and clinical studies. Unfortunately, synergistic therapies still could not effectively avoid the possible toxicities and adverse events during treatment. Finally, some prospects for the combination studies in cancer treatment were provided in the paper. Taken together, this review provided valuable information for alpelisib in preclinical and clinical applications.

Recent advancements in immunotherapy of melanoma using nanotechnology-based strategies.

Melanoma is a malignant tumor that accounts for the deadliest form of skin cancers. Despite the significant efforts made recently for development of immunotherapeutic strategies including using immune checkpoint inhibitors and cancer vaccines, the clinical outcomes are unsatisfying. Different factors affect efficient cancer immunotherapy such as side-effects, immunosuppressive tumor microenvironment, and tumor heterogeneity. In the past decades, various nanotechnology-based approaches have been developed to enhance the efficacy of cancer immunotherapy, in addition to diminishing the toxicity associated with it. Several studies have shown that proper application of nanomaterials can revolutionize the outcome of immunotherapy in diverse melanoma models. This review summarizes the recent advancement in the integration of nanotechnology and cancer immunotherapy in melanoma treatment. The importance of nanomaterials and their therapeutic advantages for patients with melanoma are also discussed.

Acute respiratory distress syndrome enhances tumor metastasis into lungs Role of BRD4 in the tumor microenvironment.

Acute respiratory distress syndrome (ARDS) is associated with severe lung inflammation, edema, hypoxia, and high vascular permeability. The COVID-19-associated pandemic ARDS caused by SARS-CoV-2 has created dire global conditions and has been highly contagious. Chronic inflammatory disease enhances cancer cell proliferation, progression, and invasion. We investigated how acute lung inflammation activates the tumor microenvironment and enhances lung metastasis in LPS induced in vitro and in vivo models. Respiratory illness is mainly caused by cytokine storm, which further influences oxidative and nitrosative stress. The LPS-induced inflammatory cytokines made the conditions suitable for the tumor microenvironment in the lungs. In the present study, we observed that LPS induced the cytokine storm and promoted lung inflammation via BRD4, which further caused the nuclear translocation of p65 NF-κB and STAT3. The transcriptional activation additionally triggers the tumor microenvironment and lung metastasis. Thus, BRD4-regulated p65 and STAT3 transcriptional activity in ARDS enhances lung tumor metastasis. Moreover, LPS-induced ARDS might promote the tumor microenvironment and increase cancer metastasis into the lungs. Collectively, BRD4 plays a vital role in inflammation-mediated tumor metastasis and is found to be a diagnostic and molecular target in inflammation-associated cancers.

Exosomal LOC85009 inhibits docetaxel resistance in lung adenocarcinoma through regulating ATG5-induced autophagy.

This study aims at investigating the role of a neighbor long non-coding RNA (lncRNA) of HDAC4 (LOC85009) in docetaxel (DTX) resistance of lung adenocarcinoma (LUAD). RT-qPCR was used to analyze LOC85009 expression in DTX-resistant LUAD cells. In vitro and in vivo experiments were applied to detect the influence of LOC85009 on LUAD cell growth and xenograft tumor growth. DNA pull down assay, RNA pull down assay, ChIP assay, CoIP assay and RIP assay were performed to identify the direct interactions between factors. LOC85009 was lowly-expressed in DTX-resistant LUAD cells. Functionally, LOC85009 overexpression inhibited DTX resistance and cell proliferation but triggered cell apoptosis. Moreover, we identified that LOC85009 was transferred from LUAD cells to DTX-resistant LUAD cells via exosomes. Exosomal LOC85009 inhibited DTX resistance, proliferation and autophagy while induced apoptosis in DTX-resistant cells. Additionally, we found that LOC85009 sequestered ubiquitin-specific proteinase 5 (USP5) to destabilize upstream transcription factor 1 (USF1) protein, thereby inactivating ATG5 transcription. Exosomal LOC85009 inhibits DTX resistance through regulation of ATG5-induced autophagy via USP5USF1 axis, suggesting that LOC85009 might be a potential target to reverse DTX resistance in the treatment of LUAD.

Mechanism of andrographis paniculata on lung cancer by network pharmacology and molecular docking.

Traditional Chinese medicine (TCM) has been widely recognized and accepted worldwide to provide favorable therapeutic effects for cancer patients. As Andrographis paniculata has an anti-tumor effect, it might inhibit lung cancer. The drug targets and related pathways involved in the action of Andrographis paniculata against lung cancer were predicted using network pharmacology, and its mechanism was further explored at the molecular level. This work selected the effective components and targets of Andrographis paniculata against the Traditional Chinese Medicine System Pharmacology (TCMSP) database. Targets related to lung cancer were searched for in the GEO database (accession number GSE136043). The volcanic and thermal maps of differential expression genes were produced using the software R. Then, the target genes were analyzed by GO and KEGG analysis using the software R. This also utilized the AutoDock tool to study the molecular docking of the active component structures downloaded from the PubChem database and the key target structures downloaded from the PDB database, and the docking results were visualized using the software PyMol. The results of molecular docking show that wogonin, Mono-O-methylwightin, Deoxycamptothecine, andrographidine Fqt, Quercetin tetramethyl (3,4,5,7) ether, 14-deoxyandrographolide, andrographolide-19-β-D-glucosideqt and 14-deoxy-11-oxo-andrographolide were potential active components, while AKT1, MAPK14, RELA and NCOA1 were key targets. This study showed the main candidate components, targets, and pathways involved in the action of Andrographis paniculata against lung cancer.

Mutational signature of extracranial meningioma metastases and their respective primary tumors.

Extracranial metastases of intracranial meningiomas are rare. Little is known about the mutational pattern of these tumors and their metastatic seeding. Here, we retrospectively explored the molecular alterations of these metastatic lesions and their respective intracranial tumor manifestations.Histology and genome sequencing were performed in intracranial meningiomas and their extracranial metastatic lesions operated upon between 2002 and 2021. Next-generation DNARNA sequencing (NGS) and methylome analysis were performed to determine molecular alterations.We analyzed the tumors of five patients with clinically suspected metastases of a meningioma using methylome analysis and next generation panel sequencing of the primary tumors as well as the metastatic lesions. Metastases were found in the spinal cord and one in the lung. In four of these patients, molecular analyses confirmed metastatic disease, while the fifth patient was found to harbor two molecularly distinct meningiomas. On pathological assessment, the primary lesions ranged from CNS WHO grades 1 to 3 (integrated molecular-morphologic meningioma classification scores 2 to 6). Of the four true metastatic cases, three out of the four metastasizing tumors harbored alterations in the BAP1 gene, comprising a stop-mutation combined with copy-number loss (WHO grade 1), copy number loss (WHO grade 3) and a frameshift mutation (WHO grade 2). Furthermore, the latter was confirmed to harbor a BAP1 tumor predisposition syndrome. The fourth metastasizing tumor had copy-number losses in NF2 and PTEN. Only one of four showed CDKN2A homozygous deletion none showed TERT promotor mutation.Our results molecularly confirm true metastatic disease in four meningioma patients. BAP1 gene alterations were the most frequent. Larger cohorts, most likely from multicenter studies are necessary to evaluate the role of BAP-1 alterations to further understand the metastatic spread in meningiomas. for metastatic spread and might indicate patients at risk for metastatic spread. Further explorations within larger cohorts are necessary to validate these findings which might influence the clinical management in the future.

Evolocumab as treatment in lorlatinib-related hyperlipidemia.

Anti-PCSK9 monoclonal antibodies have reduced the risk of cardiovascular events in patients with atheroesclerosis cardiovascular disease. However, its use has not been described in hyperlipidemia associated with lorlatinib, a third-generation ALK tyrosin kinasa inhibitor approved as treatment for ALK-positive non-small cell lung cancer.

Treatment Patterns and Outcomes in Resected Early-stage Non-small Cell Lung Cancer An Analysis of the SEER-Medicare Data.

As the non-small cell lung cancer (NSCLC) adjuvant treatment landscape evolves, an evaluation of treatment patterns and outcomes of patients with early-stage, resected NSCLC eligible for adjuvant treatment in routine clinical practice is needed to better understand the unmet needs in this patient population. Data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2007-2019) were used to identify patients with newly diagnosed stage IB (tumor size ≥4cm)-IIIA (AJCC 7th edition) NSCLC who received primary surgery (index date). We assessed adjuvant treatment patterns, real-world disease-free survival (rwDFS time from index date to first recurrence or death) and overall survival (OS time from index date to death), and loco-regional recurrence pattern and treatment distribution. Among 1761 patients with primary surgery, mean age was 73.8 years 47.9% were male and 83.9% were white. Approximately 41% of patients received adjuvant chemotherapy median time from surgery to adjuvant chemotherapy initiation was 48 days, and the most frequently observed adjuvant chemotherapy regimen was carboplatinpaclitaxel (24.5%). In the overall population, median rwDFS was 24.8 months and OS was 76.7 months 5-year rwDFS and OS rates were 29.3% and 57.5%, respectively. Among 392 patients with loco-regional recurrence, the most frequently observed treatment was curative radiation monotherapy (28.2%). Despite clinical guideline recommendations, rate of adjuvant chemotherapy among patients with resected early-stage NSCLC was low in clinical practice. Overall, among patients with early-stage NSCLC treated with conventional primary surgery, poor survival outcomes were observed, highlighting the need for and importance of more effective adjuvant treatments.

Frailty Index is Associated with Treatment Decisions for Stage I Non-Small Cell Lung Cancer at a High-Burden Safety-Net Hospital.

Lobectomy remains the cornerstone of care for stage I NSCLC while sublobar resection and stereotactic body radiation therapy (SBRT) are reserved for patients with smaller tumors andor poor operative risk. Herein, we investigate the effect of patient frailty on treatment modality for stage I NSCLC at a safety-net hospital. A retrospective chart review was performed of stage I NSCLC patients between 2006 and 2015. Demographics, patient characteristics, and treatment rates were compared to a National Cancer Database cohort of stage 1 NSCLC patients. Patient frailty was assessed using the MSK-FI. In our cohort of 304 patients, significantly fewer patient were treated via lobectomy compared to national rates (P < .001). Advanced age (P .02), lower FEV1 (P < .001) and DLCO (P < .001), not socioeconomic factors, were associated with higher utilization of non-lobectomy (sublobar resection or SBRT). Patients with lower MSK-FI were more likely to receive any surgical treatment (P .01) and lobectomy (P .03). Lower MSK-FI was an independent predictor for use of lobectomy over other modalities (OR 0.75, P .04). MSK-FI (OR 0.64, P .02), and FEV1 (OR 1.03, P < .001) were independently associated with use of SBRT over any surgery. Our safety-net hospital performed fewer lobectomies and lung resections compared to national rates. Patient frailty and clinical factors were associated with use of SBRT or sublobar resection suggesting that the increased illness burden of a safety-net population may drive the lower use of lobectomy. The MSK-FI may help physicians stratify patient risk to guide stage I NSCLC management.

Programmable CRISPR-Cas12a and self-recruiting crRNA assisted dual biosensing platform for simultaneous detection of lung cancer biomarkers hOGG1 and FEN1.

Human 8-oxoguanine DNA glycosylase (hOGG1) and flap endonuclease 1 (FEN1) are recognized as potential biomarkers in lung cancer investigations. Developing analytical platforms of simultaneously targeting hOGG1 and FEN1 with high selectivity, sensitivity, especially programmability and universality is highly valuable for clinical research. Herein, we established a signal-amplified platform for simultaneously detecting hOGG1 and FEN1 on the basis of cleavage-induced ligation of DNA dumbbell probes, rolling circle transcription (RCT) and CRISPR-Cas12a. A hOGG1 cleavable site and FEN1 cleavable flap were dexterously designed at the 5 end of DNA flapped dumbbell probes (FDP) for hOGG1 and FEN1. After cleavage, the resulting nick sites with juxtaposition of 5 phosphate and 3 hydroxyl terminus could be linked to closed DNA dumbbell probes (CDP) by DNA ligase. The CDP served as a template for RCT, producing plentiful crRNA repeats to activate the trans-cleavage activity of CRISPR-Cas12a which could cleave fluorophores (TAMRA and FAM) and quenchers (BHQ2 and BHQ1) double-labeled ssDNA reporters. Then, hOGG1 and FEN1 could be detected by the recovered fluorescence signal, allowing for the highly sensitive calculated detection limits of 0.0013 and 0.0052 UmL, respectively. Additionally, this method made it possible to evaluate the inhibitory effects, even to measure hOGG1 and FEN1 activities at the single-cell level. This novel target enzyme-initiated, circles-transcription without promoters, real-time generation, and self-assembly features of FDP-RCT-Cas12a system suppressed nonspecific background remarkably and relieved rigorous requirement of protospacer adjacent motif site. Hence, the universality of FDP-RCT-Cas12a system toward various disease-related non-nucleic acid targets which are tested without using aptamers was extremely improved.

Influence of lung cancer model characteristics on tumor targeting behavior of nanodrugs.

Evidence is mounting that there is a significant gap between the antitumor efficacy of nanodrugs in preclinical mouse tumor models and in clinical human tumors, and that differences in tumor models are likely to be responsible for this gap. Herein, we investigated the enhanced permeability and retention (EPR) effect in mouse lung cancer models with different tumor growth rates, volumes and locations, and analyzed the nanodrug tumor targeting behaviors limited by tumor vascular pathophysiological characteristics in various tumor models. The results showed that the fast-growing tumors were characterized by lower vascular tight junctions, leading to higher vascular paracellular transport activity and nanodrug tumor accumulation. The paracellular transport activity increased with the growth of tumor, but the vascular density and transcellular transport activity decreased, and as a result, the average tumor accumulation of passive targeting nanodrugs decreased. Orthotopic tumors were rich in blood vessels, but had low vascular transcellular and paracellular transport activities, making it difficult for nanodrug accumulation in orthotopic tumors via passive targeting strategies. The antitumor efficacy of passive targeting nanodrugs in various lung cancer-bearing mice validated the aforementioned nanodrug accumulation behavior, and nanodrugs based on the angiogenesis-tumor sequential targeting strategy achieved obviously improved efficacy in orthotopic lung cancer-bearing mice. These results suggest that the EPR effect varies in different tumor models and should not be used as a universal targeting strategy for antitumor nanodrugs. Besides, attention should be paid to the animal tumor models in the evaluation of nanodrugs so as to avoid exaggerating the antitumor efficacy.

CD73 Inhibitor Oleclumab Plus Osimertinib in Previously Treated Patients With Advanced T790M-Negative EGFR-Mutated NSCLC A Brief Report.

CD73 is overexpressed in EGFR-mutated NSCLC and may promote immune evasion, suggesting potential for combining CD73 blockers with EGFR tyrosine kinase inhibitors (TKIs). This phase 1b-2 study (NCT03381274) evaluated the anti-CD73 antibody oleclumab plus the third-generation EGFR TKI osimertinib in advanced EGFR-mutated NSCLC. Patients had tissue T790M-negative NSCLC with TKI-sensitive EGFR mutations after progression on a first- or second-generation EGFR TKI and were osimertinib naive. They received osimertinib 80 mg orally once daily plus oleclumab 1500 mg (dose level 1 DL1) or 3000 mg (DL2) intravenously every 2 weeks. Primary end points included safety and objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1. By July 9, 2021, five patients received DL1 and 21 received DL2. Of these patients, 60.0% and 85.7% had any-grade treatment-related adverse events (TRAEs) and 20.0% and 14.3% had grade 3 TRAEs, respectively. No dose-limiting toxicities, serious TRAEs, or deaths occurred. Four patients were T790M positive on retrospective circulating tumor DNA (ctDNA) testing three had objective partial responses. In patients who were T790M negative in tumor and ctDNA, objective response rate was 25.0% at DL1 and 11.8% at DL2 (all partial responses) response durations at DL2 were 14.8 and 16.6 months. In patients receiving DL2, excluding those who were T790M positive by ctDNA, median progression-free survival was 7.4 months, and median overall survival was 24.8 months. DL2 was the recommended phase 2 dose. Oleclumab plus osimertinib was found to have moderate activity with acceptable tolerability in previously treated patients with advanced EGFR-mutated NSCLC.

The Impact of COVID-19 on Lung Cancer Incidence in England Analysis of the National Lung Cancer Audit 2019 and 2020 Rapid Cancer Registration Datasets.

The COVID-19 pandemic has caused significant disruption to health-care services and delivery worldwide. The impact of the pandemic and associated national lockdowns on lung cancer incidence in England have yet to be assessed. What was the impact of the first year of the COVID-19 pandemic on the incidence and presentation of lung cancer in England In this retrospective observational study, incidence rates for lung cancer were calculated from The National Lung Cancer Audit Rapid Cancer Registration Datasets for 2019 and 2020, using midyear population estimates from the Office of National Statistics as the denominators. Rates were compared using Poisson regression according to time points related to national lockdowns in 2020. Sixty-four thousand four hundred fifty-seven patients received a diagnosis of lung cancer across 2019 (n 33,088) and 2020 (n 31,369). During the first national lockdown, a 26% reduction in lung cancer incidence was observed compared with the equivalent calendar period of 2019 (adjusted incidence rate ratio IRR, 0.74 95% CI, 0.71-0.78). This included a 23% reduction in non-small cell lung cancer (adjusted IRR, 0.77 95% CI, 0.74-0.81) and a 45% reduction in small cell lung cancer (adjusted IRR, 0.55 95% CI, 0.46-0.65) incidence. Thereafter, incidence rates almost recovered to baseline, without overcompensation (adjusted IRR, 0.96 95% CI, 0.94-0.98). The incidence rates of lung cancer in England fell significantly by 26% during the first national lockdown in 2020 and did not compensate later in the year.

Guided Bronchoscopy for the Evaluation of Pulmonary Lesions An Updated Meta-analysis.

Guided bronchoscopy is increasingly used to diagnose peripheral pulmonary lesions (PPLs). A meta-analysis published in 2012 demonstrated a pooled diagnostic yield of 70% however, recent publications have documented yields as low as 40% and as high as 90%. Has the diagnostic yield of guided bronchoscopy in patients with PPLs improved over the past decade A comprehensive search was performed of studies evaluating the diagnostic yield of differing bronchoscopic technologies used to reach PPLs. Study quality was assessed using the Quality assessment of diagnostic accuracy of studies (QUADAS-2) assessment tool. Number of lesions, type of technology used, overall diagnostic yield, and yield by size were extracted. Adverse events were recorded. Meta-analytic techniques were used to summarize findings across all studies. A total of 16,389 lesions from 126 studies were included. There was no significant difference in diagnostic yield prior to 2012 (39 studies 3,052 lesions yield 70.5%) vs after 2012 (87 studies 13,535 lesions yield 69.2%) (P > .05). Additionally, there was no significant difference in yield when comparing different technologies. Studies with low risk of overall bias had a lower diagnostic yield than those with high risk of bias (66% vs 71%, respectively P .018). Lesion size > 2 cm, presence of bronchus sign, and reports with a high prevalence of malignancy in the study population were associated with significantly higher diagnostic yield. Significant (P < .0001) between-study heterogeneity was also noted. Despite the reported advances in bronchoscopic technology to diagnose PPLs, the diagnostic yield of guided bronchoscopy has not improved.

Overcoming inter-observer planning variability in target volume contouring and dose planning for high-risk neuroblastoma - an international multicenter effort of the SIOPEN Radiotherapy Committee.

To establish an international quality standard for contouring and planning for high-risk neuroblastoma within the prospective High-Risk Neuroblastoma Study 2 of SIOP-Europe-Neuroblastoma (SIOPEN HR-NBL2), which includes a randomized question on dose escalation for residual disease. Data on four patients with high-risk neuroblastoma were selected and distributed to the radiotherapy committee of the HR-NBL2 study for independent contouring and planning. Differences in contouring were analyzed using apparent and kappa-corrected agreement. Plans were analyzed regarding the dose-volume histogram metrics. Results were discussed among experts and agreement was obtained. Substantial agreement was found for contouring of the heart (0.64), liver (0.70), left lung (0.74), and right lung (0.74). For contouring of the gastrointestinal tract (0.54), left kidney (0.60), and right kidney (0.59) moderate agreement was obtained. For target volume delineation, agreement for preoperative tumour extent was moderate (0.42), for CTV fair (0.35) and only low (0.06) for residual tumour, respectively. The dose planning strategies appeared to be relatively homogeneous among all experts. Considerable variability was found for the delineation of target volumes, particularly the boost volume, whereas the contouring of the organs at risk and the planning strategy were reasonably consistent. In order to obtain reliable results from the randomized HR-NBL2 trial, standardization of target volume delineation based on adequate imaging is crucial.

Impact of interstitial lung abnormality on survival after adjuvant durvalumab with chemoradiotherapy for locally advanced non-small cell lung cancer.

Concurrent chemoradiotherapy (CCRT) has been the standard of care for patients with locally advanced non-small cell lung cancer (LA-NSCLC). The results of the PACIFIC trial established the use of consolidative durvalumab after concurrent chemoradiotherapy (CCRT) as the standard of care for patients with locally advanced non-small cell lung cancer (LA-NSCLC). A subgroup analysis of the PACIFIC trial reported a better progression-free survival (PFS) in Asians. Although real-world data on LA-NSCLC patients who received CCRT plus durvalumab have been reported, there have been few large-scale reports on Asians. In this study, we investigated prognostic factors in the largest real-world data set in Asia of only Japanese LA-NSCLC patients treated with CCRT plus durvalumab. One hundred and thirteen LA-NSCLC patients who received definitive CCRT and consolidative durvalumab at our institution between May 2018 and April 2021 were analyzed. Overall survival (OS), cause-specific survival (CSS), PFS, distant metastasis-free survival (DMFS), and in-field progression-free survival (IFPFS) were investigated as treatment outcomes using competing risk analyses. During a median follow-up of 24 months (range, 5-47) after the initiation of durvalumab therapy, 31 patients died, of whom 23 died of lung cancer. In the multivariate analysis, the pretreatment factors that correlated with OS were ILA scores, adenocarcinoma, and performance status at the initiation of durvalumab. Furthermore, ILA score and programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 1 % were significantly correlated with CSS, and PD-L1 TPS ≥ 1 % was significantly correlated with PFS and IFPFS. Pretreatment ILA, adenocarcinoma, and performance status may have an impact on OS of LA-NSCLC patients receiving CCRT plus durvalumab.

Novel TAK1 inhibitor handelin inhibits NF-kB and AP-1 to alleviate elastase-induced emphysema in mice.

Emphysema, one of the two major components of chronic obstructive pulmonary disease (COPD), is driven by aberrant inflammatory responses and associated with irreversible lung parenchymal destruction. As effective therapy for preventing or treating COPDemphysema is yet unavailable, development of molecular targets and therapeutic agents for COPDemphysema is required. We identified handelin-a guaianolide dimer of sesquiterpene lactones- from a chemical library of 431 natural products as it exhibited potent inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) and reactive oxygen species (ROS) production, LPS-induced activation of nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK)AP-1, and expression of proinflammatory mediators in macrophage cells. In silico docking and biochemical studies enabled the identification of the ATP-binding pocket of transforming growth factor beta-activated kinase 1 (TAK1), a kinase upstream of NF-kB and MAPKAP-1 pathways, as a molecular target for handelin. Moreover, oral administration of handelin (10 mgkg) suppressed elastase-induced development of emphysematous phenotypes, including lung function disturbance, airspace enlargement, and increases in the level of neutrophils and CD8 T cells in lung tissues, without overt toxicity. Consistent with in vitro results, analyses of lung tissues revealed that treatment with handelin suppressed elastase-induced NF-κB and AP-1 activation in the lungs, followed by downregulation of their targets including interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and matrix metalloproteinases (MMP9). These findings suggest that handelin, as a TAK1 inhibitor, effectively prevents development of emphysema in an elastase-induced mouse model by inhibiting a proinflammatory mediators mediated by NF-κB and AP-1.

Engineering c-Met-CAR NK-92 cells as a promising therapeutic candidate for lung adenocarcinoma.

Mesenchymal-epithelial transition factor (C-Met) has been acknowledged as a significant therapeutic target for treating lung adenocarcinoma (LUAD). However, the potential application of chimeric antigen receptors (CAR)-modified natural killer (NK) cells targeting c-Met in LUAD is rarely explored. In this study, bioinformatic databases were searched and a tissue microarray (TMA) was enrolled to investigate expression status and prognostic role of c-Met in LUAD. Then, four types of c-Met-CAR structures were designed and prepared. The engineering CAR-NK cells containing c-Met-CARs were transfected, verified and characterized. The tumor-inhibitory role of c-Met-CAR-NK cells was finally evaluated in vitro and in vivo. The results demonstrated that c-Met expression elevated and confirmed that high c-Met expression was significantly associated with unfavorable prognosis in LUAD. Then, C-Met-CAR-NK cells were successfully constructed and DAP10 designed in CAR structure was a favorable stimulator for NK cell activation. CCN4 containing DAP10 co-stimulator exhibited the strongest cytotoxicity compared with other CAR-NK cells. Furthermore, CCN4 cells also exerted the prominent tumor-inhibitory effect on xenograft tumor growth. Collectively, this study suggests that DAP10 is a potent stimulator in CAR structure for NK cell activation, and CCN4-based immunotherapy may represent a promising strategy for the treatment of c-Met-positive LUAD.

Hemicolectomy versus appendectomy for patients with appendiceal neuroendocrine tumours 1-2 cm in size a retrospective, Europe-wide, pooled cohort study.

Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1-2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1-2 cm in size in patients with or without right-sided hemicolectomy. In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1-2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693. 282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1-2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0-15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 -21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 95% CI 0·36-2·17 p0·71). This study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1-2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort. Swiss Cancer Research foundation.

Autotaxin facilitates selective LPA receptor signaling.

Autotaxin (ATX ENPP2) produces the lipid mediator lysophosphatidic acid (LPA) that signals through disparate EDG (LPA

Near complete response to ceritinib in a pediatric patient with metastatic ALK-rearranged lung adenocarcinoma.

Anaplastic lymphoma kinase (ALK) inhibitors have significant efficacies in ALK-rearranged non-small cell lung cancers (NSCLC). In regard to pediatric NSCLC patients, however, there is a paradox in that on the one hand, they may have a higher probability of ALK-rearrangement positive, but on the other hand, there is no sufficient data for efficacies of ALK inhibitors in pediatric NSCLC patients. Here, we present an 11-year-old boy diagnosed with metastatic ALK-rearranged lung adenocarcinoma. He was treated with ceritinib 450 mg with food once daily and has obtained near complete response in 18th month, with a largely regressed intrathoracic lesion and only localized residual distant metastatic disease. Meanwhile, he showed continued good tolerance after a short period of side effects at the beginning of the dose. This is the first report of the use of ceritinib in pediatric patient with NSCLC.

Challenges and knowledge gaps with immune checkpoint inhibitors monotherapy in the management of patients with non-small-cell lung cancer a survey of oncologist perceptions.

Immune checkpoint-inhibitors (ICIs) are changing outcomes in different cancer settings, notably for patients with non-small-cell lung cancer (NSCLC). There are, however, still important gaps of evidence for clinical practice when using these novel treatments. In this study, we assessed physicians opinion and experience on challenges for clinical practice with ICIs monotherapy in NSCLC. A survey was conducted on experienced physicians treating patients with NSCLC with ICIs. Two rounds of pilot tests were carried out for validation among a group of experts. Topics under analysis were in relation to treatment of elderly populations, performance status, brain metastases, use of steroids or antibiotics, the effects of gut microbiome, autoimmune diseases, human immunodeficiency virus infection, solid organ transplants, use of anti-programmed cell death protein 1 versus anti-programmed death-ligand 1 drugs, atypical tumour responses, predictors of response, duration of treatment and a final open question on additional relevant challenges. Two hundred and twenty-one answers were collected, including 106 (48%) valid answers from experts for final analysis (physicians who have treated at least 20 patients with NSCLC with ICIs). The vast majority agreed that the selected topics in this study are important challenges ahead and more evidence is needed. Moreover, predictors of response, treating brain metastasis, shorter duration of treatment, the effects of gut microbiome and concomitant use of steroids were voted the most important topics to be further addressed in prospective clinical research. This survey contributed to understanding which are the main challenges for clinical practice with ICIs monotherapy in NSCLC. It can also contribute to guide further clinical research, considering the opinions and experience of those who regularly treat NSCLC patients with ICIs.

A peptide binding to the tetraspanin CD9 reduces cancer metastasis.

As an organizer of multi-molecular membrane complexes, the tetraspanin CD9 has been implicated in a number of biological processes, including cancer metastasis, and is a candidate therapeutic target. Here, we evaluated the suppressive effects of an eight-mer CD9-binding peptide (CD9-BP) on cancer cell metastasis and its mechanisms of action. CD9-BP impaired CD9-related functions by adversely affecting the formation of tetraspanin webs-networks composed of CD9 and its partner proteins. The anti-cancer metastasis effect of CD9-BP was evidenced by the in vitro inhibition of cancer cell migration and invasion as well as exosome secretion and uptake, which are essential processes during metastasis. Finally, using a mouse model, we showed that CD9-BP reduced lung metastasis in vivo. These findings provide insight into the mechanism by which CD9-BP inhibits CD9-dependent functions and highlight its potential application as an alternative therapeutic nano-biomaterial for metastatic cancers.

Over-expression of USP15MMP3 predict poor prognosis and promote growth, migration in non-small cell lung cancer cells.

Aberrant ubiquitin modifications caused by an imbalance in the activities of ubiquitinases and de-ubiquitinases are emerging as important mechanisms underlying non-small cell lung cancer (NSCLC) progression. The deubiquitinating enzyme ubiquitin-specific peptidase 15 (USP15) has been identified as an important factor in oncogenesis and a potential therapeutic target. However, the expression profile and function of USP15 in NSCLC remain elusive. In the present study, we investigated the expression pattern and the potential biological functions of USP15 in NSCLC both in cells and animal models. Our data revealed that USP15 was highly expressed in NSCLC tissues and cells compared with normal counterpart. We subsequently knocked down USP15 expression in two NSCLC cell lines, which significantly suppressed cell proliferation. In addition, knocking down USP15 expression reduced NSCLC cell migration and invasion according to the results from Matrigel-Transwell analysis. NSCLC animal model results showed that USP15 knockdown also reduced NSCLC size. Biochemical analysis revealed that USP15 knockdown inhibited matrix metalloproteinase (MMP)3 and MMP9 expression. Furthermore, high levels of USP15 and MMP3 expression were associated with poor prognosis in NSCLC. In conclusion, the results from the present study suggest that the high expression of USP15 promotes NSCLC tumorigenesis. Therefore, it is proposed that USP15 and MMPs may represent novel biomarkers for NSCLC progression and prognosis.

Label-free electrochemical detection of cancer biomarkers DNA and anti-p53 at tin oxide quantum dot-gold-DNA nanoparticle modified electrode.

Lung cancer is one of the deadliest types of cancer and accounts for 8.1% of all cancer related deaths. To prevent a growing death rate, it is crucial to identify lung cancer at an early stage by single polynucleotide morphism detection. In this paper, we present a novel label-free electrochemical biosensor based on composites of tin oxide quantum dots and gold nanoparticles (SnO

Ultralow Background Near-Infrared Fluorophores with Dual-Channel Intraoperative Imaging Capability.

Two of the most pressing challenges facing bioimaging are nonspecific uptake of intravenously administered contrast agents and incomplete elimination of unbound targeted agents from the body. Designing a targeted contrast agent that shows fast clearance from background tissues and eventually the body after complete targeting is key to the success of image-guided interventions. Here, this work describes the development of renally clearable near-infrared contrast agents and their potential use for dual-channel image-guided tumor targeting. cRGD-ZW800-PEG (800 nm channel) and ZW700-PEG (700 nm channel) are able to visualize tumor margins and tumor vasculature simultaneously and respectively. These targeted agents show rapid elimination from the bloodstream, followed by renal clearance, which together significantly lower off-target background signals and potential toxicity. To demonstrate its applicability, this multispectral imaging is performed in various tumor-bearing animal models including lung cancer, pancreatic neuroendocrine tumors, breast, and ovarian cancer.

A multiplexed in vivo approach to identify driver genes in small cell lung cancer.

Small cell lung cancer (SCLC) is a lethal form of lung cancer. Here, we develop a quantitative multiplexed approach on the basis of lentiviral barcoding with somatic CRISPR-Cas9-mediated genome editing to functionally investigate candidate regulators of tumor initiation and growth in genetically engineered mouse models of SCLC. We found that naphthalene pre-treatment enhances lentiviral vector-mediated SCLC initiation, enabling high multiplicity of tumor clones for analysis through high-throughput sequencing methods. Candidate drivers of SCLC identified from a meta-analysis across multiple human SCLC genomic datasets were tested using this approach, which defines both positive and detrimental impacts of inactivating 40 genes across candidate pathways on SCLC development. This analysis and subsequent validation in human SCLC cells establish TSC1 in the PI3K-AKT-mTOR pathway as a robust tumor suppressor in SCLC. This approach should illuminate drivers of SCLC, facilitate the development of precision therapies for defined SCLC genotypes, and identify therapeutic targets.

Association between pre-treatment chest imaging and pulmonary function abnormalities and immune checkpoint inhibitor pneumonitis.

Immune checkpoint inhibitors (ICIs) are a first-line treatment for various metastatic solid tumors. Pneumonitis is a potentially devastating complication of ICI treatment and a leading cause of ICI-related mortality. Here, we evaluate whether abnormal pre-treatment pulmonary function tests (PFTs) or interstitial abnormalities on computed tomography of the chest (CT chest) prior to ICI are associated with the development of ICI-pneumonitis (ICI-p). We conducted a retrospective cohort study of consecutive patients who received at least one dose of ICI from 2011 to 2017 at The Ohio State University. Potential risk factors for ICI-p, including abnormal PFTs and CT chest, were recorded. These risk factors were compared between patients with and without pneumonitis. In total, 1097 patients were included, 46 with ICI-p and 1051 without. Ninety percent of patients had pre-treatment chest imaging, while only 10% had pre-treatment PFTs. On multivariable analysis, interstitial abnormalities and reduced total lung capacity (TLC) were significantly associated with development of ICI-p (hazard ratio of 42.42 95% CI 15.04-119.67 and hazard ratio of 4.04 95% CI 1.32-12.37), respectively. No other PFT abnormality was associated with increased risk of ICI-p. There was no significant difference in overall survival in patients who did or did not develop ICI-p (p 0.332). Pre-existing interstitial abnormalities on CT chest and reduced TLC were strongly associated with developing ICI-p. Prospective studies are warranted to further explore the role of PFTs as a potential tool for identifying patients at highest risk for developing ICI-p.

Predictors of response to anamorelin in gastrointestinal cancer patients with cachexia a retrospective study.

Anamorelin, a ghrelin receptor agonist, has recently been approved for gastric, pancreatic, and colorectal cancer patients with cachexia in Japan. However, only few studies have investigated the predictors of response to anamorelin in clinical settings. Thus, our study aimed to investigate the predictors of the response, in addition to its efficacy and safety. The clinical outcomes of 20 patients were evaluated during administration. They were divided into two groups based on lean body mass, responders and non-responders, and their clinical characteristics were compared. The mean ± standard error (SE) variations at 12 weeks in lean body mass and handgrip strength were 2.63 ± 0.79 kg and - 1.53 ± 1.20 kg, respectively. The mean ± SE variations at 8 weeks in fasting blood glucose and hemoglobin A1c were 32.88 ± 13.77 mgdL and 0.90 ± 0.18%, respectively. Total protein, albumin, transferrin, and prognostic nutritional index at baseline were significantly higher in responders (n 8) than in non-responders (n 12), whereas the neutrophillymphocyte and C-reactive proteinalbumin ratios at baseline were significantly higher in non-responders than in responders. The study confirmed the efficacy and safety of anamorelin and identified nutritional or systemic inflammatory markers as predictors of anamorelin response in advanced gastrointestinal cancer patients.

Detection of Novel Autoantibodies to Nucleolins RNA-binding Domains as a Serum Tumor Biomarker Through ELISA.

Expression and location of nucleolin are often abnormal in malignancies, which may result in the production of autoantibodies. Despite this, the identification of such autoantibodies may be essential for the early diagnosis and prognosis of cancers. In this investigation, the recombinant nucleolin protein was generated using an Escherichia coli expression system and was used an indirect enzyme-linked immunosorbent assay to detect anti-nucleolin autoantibodies in cancer patients sera. Lung cancer patients autoantibodies displayed the highest seroreactivity with the recombinant protein, with area under the curve of 0.948 and sensitivity and specificity of 85% and 96.67%, respectively (accuracy92%). Anti-nucleolin autoantibodies were linked with lung tumor size (r0.793), tumor, node, metastasis staging (r0.643), and proliferation (r0.744). These autoantibodies distinguished patients with early-stage lung cancer from healthy controls. Since anti-nucleolin autoantibodies are strongly linked to tumor size, clinical staging, and growth, they can be used to measure how well a treatment is working.

Compound clear cell sarcoma with EWSR1CREM fusion.

Cutaneous clear cell sarcomas may be confused with melanomas as a result of overlapping histopathology and immunohistochemical staining. We report a case of a 41-year-old woman with a purported history of acral melanoma of the great toe. Twenty-one months after excision of the primary tumor, the patient developed a groin mass, diagnosed as metastatic melanoma on excision. Five months later, a biopsy of a lung mass was reported as metastatic melanoma. The patient was referred to our institution for treatment, which prompted molecular testing on the groin metastasis by targeted next-generation sequencing. Molecular testing results revealed TP53 and TERT promoter mutations and the absence of BRAF, KRAS, and KIT mutations it also revealed an EWSR1CREM fusion that was confirmed by Archer FusionPlex. The alleged acral melanoma was re-reviewed, showing an invasive amelanotic spindle cell neoplasm in the dermis with neoplastic nests at the dermal-epidermal junction the tumor cells expressed markers of melanocytic differentiation but were negative for PRAME and BRAF immunohistochemical staining. Molecular testing of the toe and lung metastasis revealed the same EWSR1CREM fusion. In light of the molecular findings, the diagnosis was revised to a primary acral compound clear cell sarcoma with EWSR1CREM fusion.

3D multi-view squeeze-and-excitation convolutional neural network for lung nodule classification.

Early screening is crucial to improve the survival rate and recovery rate of lung cancer patients. Computer-aided diagnosis system (CAD) is a powerful tool to assist clinicians in early diagnosis. Lung nodules are characterized by spatial heterogeneity. However, many attempts use the two-dimensional multi-view (MV) framework to learn and simply integrate multiple view features. These methods suffer from the problems of not capturing the spatial characteristics effectively and ignoring the variability of multiple views. In this paper, we propose a three-dimensional MV convolutional neural network (3D MVCNN) framework and embed the squeeze-and-excitation (SE) module in it to further address the variability of each view in the MV framework. First, the 3D multiple view samples of lung nodules are extracted by the spatial sampling method, and a 3D CNN is established to extract 3D abstract features. Second, build a 3D MVCNN framework according to the 3D multiple view samples and 3D CNN. This framework can learn more features of different views of lung nodules, taking into account the characteristics of spatial heterogeneity of lung nodules. Finally, to further address the variability of each view in the MV framework, a 3D MVSECNN model is constructed by introducing a SE module in the feature fusion stage. For training and testing purposes we used independent subsets of the public LIDC-IDRI dataset. For the LIDC-IDRI dataset, this study achieved 96.04% accuracy and 98.59% sensitivity in the binary classification, and 87.76% accuracy in the ternary classification, which was higher than other state-of-the-art studies. The consistency score of 0.948 between the model predictions and pathological diagnosis was significantly higher than that between the clinicians annotations and pathological diagnosis. The results show that our proposed method can effectively learn the spatial heterogeneity of nodules and solve the problem of multiple view variability. Moreover, the consistency analysis indicates that our method can provide clinicians with more accurate results of benign-malignant lung nodule classification for auxiliary diagnosis, which is important for assisting clinicians in clinical diagnosis.

Lysophosphatidylcholine inhibits lung cancer cell proliferation by regulating fatty acid metabolism enzyme long-chain acyl-coenzyme A synthase 5.

Lung cancer is a widespread malignancy with a high death rate and disorder of lipid metabolism. Lysophosphatidylcholine (lysoPC) has anti-tumour effects, although the underlying mechanism is not entirely known. The purpose of this study aims at defining changes in lysoPC in lung cancer patients, the effects of lysoPC on lung cancer cells and molecular mechanisms. Lung cancer cell sensitivity to lysoPC was evaluated and decisive roles of long-chain acyl-coenzyme A synthase 5 (ACSL5) in lysoPC regulation were defined by comprehensively evaluating transcriptomic changes of ACSL5-downregulated epithelia. ACSL5 over-expressed in ciliated, club and Goblet cells in lung cancer patients, different from other lung diseases. LysoPC inhibited lung cancer cell proliferation, by inducing mitochondrial dysfunction, altering lipid metabolisms, increasing fatty acid oxidation and reprograming ACSL5phosphoinositide 3-kinaseextracellular signal-regulated kinase-regulated triacylglycerol-lysoPC balance. Thus, this study provides a general new basis for the discovery of reprogramming metabolisms and metabolites as a new strategy of lung cancer precision medicine.

Lower SLC7A2 expression is associated with enhanced multidrug resistance, less immune infiltrates and worse prognosis of NSCLC.

Solute carrier family 7 member 2 (SLC7A2), a cationic amino acid transporter, is lowly expressed in ovarian and hepatocellular cancers, which is associated with their worse prognosis. However, its roles in the prognosis, drug resistance and immune infiltration in non-small-cell lung cancer (NSCLC) are unclear. We chose SLC7A2 from RNA-Seq of paclitaxelcisplatin-resistant A549 cells, then bioinformatics, cell lines construction, RT-qPCR, and CCK8 were performed to investigate SLC7A2 role. We analyzed the 223 differentially expressed genes (DEGs) from RNA-Seq of paclitaxelcisplatin-resistant A549 cells and found that SLC7A2 expression was down-regulated in NSCLC. Lower SLC7A2 expression was associated with worse recurrence-free survival (RFS) in NSCLC. SLC7A2 silencing enhanced the proliferation of NSCLC cells and their insensitivity to paclitaxel, cisplatin, and gemcitabine in vitro. Activation of AMPK has up-regulated SLC7A2 expression and enhanced the sensitivity of NSCLC cells to anti-tumor drugs, which could be attributed to E2F1s regulation. In addition, the levels of SLC7A2 expression were correlated to the numbers of infiltrated neutrophils, macrophages, dendritic cells and their marker genes, like CD86, HLA-DPA1 and ITGAM. SLC7A2 may act as a tumor suppressor to modulate drug sensitivity, immune infiltration and survival in NSCLC. Video abstract.

Evolution of treatment patterns and survival outcomes in patients with advanced non-small cell lung cancer treated at Frankfurt University Hospital in 2012-2018.

Immune checkpoint inhibitors (ICIs) have improved outcomes for patients with advanced non-small cell lung cancer (NSCLC) versus chemotherapy in clinical trials. In Germany, ICIs have been used clinically since 2015 for patients with advancedmetastatic NSCLC without epidermal growth factor receptor (EGFR)anaplastic lymphoma kinase (ALK) aberrations. As part of I-O Optimise, a multinational research program utilizing real-world data on thoracic malignancies, we describe real-world treatment patterns and survival following reimbursement of ICIs for advanced NSCLC in Germany. This retrospective cohort study included patients with locally advancedmetastatic NSCLC without known EGFRALK aberrations who received a first line of therapy at Frankfurt University Hospital between January 2012 and December 2018, with follow-up to December 2019 or death, whichever occurred first. Using electronic medical records, treatment patterns and survival outcomes were described by histology (squamous cell SQ non-squamous cell NSQother) and time period (pre- and post-ICI approval). Among eligible patients who started first-line treatment, 136 (pre-ICI) and 126 (post-ICI) had NSQother histology, and 32 (pre-ICI) and 38 (post-ICI) had SQ histology. Use of an ICI in the NSQother cohort increased from 5.9% (all second- or third-line) in the pre-ICI period to 57.1% (22.2% in first-line, including 13.5% as monotherapy and 8.7% combined with chemotherapy) in the post-ICI period. This was paralleled by a significant (P < 0.0001) prolongation of median (95% CI) OS from 9.4 (7.1-11.1) to 14.8 (12.7-20.5) months between the pre-ICI and post-ICI periods. A similar increase in the uptake of ICI was observed for the SQ cohort (from 3.1% pre-ICI fourth-line to 52.6% post-ICI 28.9% as first-line, including 15.8% as monotherapy and 13.2% combined with chemotherapy) however, analysis of survival outcomes was limited by small group sizes. These real-world data complement clinical trial evidence on the effectiveness of ICIs in patients with advanced NSCLC and NSQother histology in Germany.

Repurposing nitric oxide donating drugs in cancer therapy through immune modulation.

Nitric oxide-releasing drugs are used for cardiovascular diseases however, their effects on the tumor immune microenvironment are less clear. Therefore, this study explored the impact of nitric oxide donors on tumor progression in immune-competent mice. The effects of three different nitric oxide-releasing compounds (SNAP, SNP, and ISMN) on tumor growth were studied in tumor-bearing mouse models. Three mouse tumor models were used B16F1 melanoma and LL2 lung carcinoma in C57BL6 mice, CT26 colon cancer in BALBc mice, and LL2 lung carcinoma in NODSCID mice. After nitric oxide treatment, splenic cytokines and lymphocytes were analyzed by cytokine array and flow cytometry, and tumor-infiltrating lymphocytes in the TME were analyzed using flow cytometry and single-cell RNA sequencing. Low doses of three exogenous nitric oxide donors inhibited tumor growth in two immunocompetent mouse models but not in NODSCID immunodeficient mice. Low-dose nitric oxide donors increase the levels of splenic cytokines IFN-γ and TNF-α but decrease the levels of cytokines IL-6 and IL-10, suggesting an alteration in Th2 cells. Nitric oxide donors increased the number of CD8 Low concentrations of exogenous nitric oxide donors inhibit tumor growth in vivo by regulating T cells and macrophages. CD8

STRIP2 motivates non-small cell lung cancer progression by modulating the TMBIM6 stability through IGF2BP3 dependent.

Striatin interacting protein 2 (STRIP2) is a core component of the striatin-interacting phosphatase and kinase (STRIPAK) complexes, which is involved in tumor initiation and progression via the regulation of cell contractile and metastasis. However, the underlying molecular mechanisms of STRIP2 in non-small cell lung cancer (NSCLC) progression remain largely unknown. The expressions of STRIP2 and IGF2BP3 in human NSCLC specimens and NSCLC cell lines were detected using quantitative RT-PCR, western blotting, and immunohistochemistry (IHC) analyses. The roles and molecular mechanisms of STRIP2 in promoting NSCLC progression were investigated in vitro and in vivo. Here, we found that STRIP2 expression was significantly elevated in NSCLC tissues and high STRIP2 expression was associated with a poor prognosis. Knockdown of STRIP2 suppressed tumor growth and metastasis in vitro and in vivo, while STRIP2 overexpression obtained the opposite effect. Mechanistically, P300CBP-mediated H3K27 acetylation activation in the promoter of STRIP2 induced STRIP2 transcription, which interacted with insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and upregulated IGF2BP3 transcription. In addition, STRIP2-IGF2BP3 axis stimulated m6A modification of TMBIM6 mRNA and enhanced TMBIM6 stability. Consequently, TMBIM6 involved NSCLC cell proliferation, migration and invasion dependent on STRIP2 and IGF2BP3. In NSCLC patients, high co-expression of STRIP2, IGF2BP3 and TMBIM6 was associated with poor outcomes. Our findings indicate that STRIP2 interacts with IGF2BP3 to regulate TMBIM6 mRNA stability in an m6A-dependent manner and may represent a potential prognostic biomarker and therapeutic target for NSCLC.