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Global hypomethylation in childhood asthma identified by genome-wide DNA-methylation sequencing preferentially affects enhancer regions.

Childhood asthma is a result of a complex interaction of genetic and environmental components causing epigenetic and immune dysregulation, airway inflammation and impaired lung function. Although different microarray based EWAS studies have been conducted, the impact of epigenetic regulation in asthma development is still widely unknown. We have therefore applied unbiased whole genome bisulfite sequencing (WGBS) to characterize global DNA-methylation profiles of asthmatic children compared to healthy controls. Peripheral blood samples of 40 asthmatic and 42 control children aged 5-15 years from three birth cohorts were sequenced together with paired cord blood samples. Identified differentially methylated regions (DMRs) were categorized in genotype-associated, cell-type-dependent, or prenatally primed. Network analysis and subsequent natural language processing of DMR-associated genes was complemented by targeted analysis of functional translation of epigenetic regulation on the transcriptional and protein level. In total, 158 DMRs were identified in asthmatic children compared to controls of which 37% were related to the eosinophil content. A global hypomethylation was identified affecting predominantly enhancer regions and regulating key immune genes such as IL4, IL5RA, and EPX. These DMRs were confirmed in n 267 samples and could be linked to aberrant gene expression. Out of the 158 DMRs identified in the established phenotype, 56 were perturbed already at birth and linked, at least in part, to prenatal influences such as tobacco smoke exposure or phthalate exposure. This is the first epigenetic study based on whole genome sequencing to identify marked dysregulation of enhancer regions as a hallmark of childhood asthma.

Temporal trends and outcomes in acute ischaemic stroke patients with a current or historical diagnosis of cancer.

The aim was to evaluate the temporal trends, characteristics and in-hospital outcomes of patients hospitalized with acute ischaemic stroke (AIS) between those with and without current or historical malignancies. Adult hospitalizations with a primary diagnosis of AIS were identified from the National Inpatient Sample database 2007-2017. Logistic regression was used to compare the differences in the utilization of AIS interventions and in-hospital outcomes. For further analysis, subgroup analyses were performed stratified by cancer subtypes. There were 892,862 hospitalizations due to AIS, of which 108,357 (12.14%) had a concurrent diagnosis of current cancer (3.41%) or historical cancer (8.72%). After adjustment for confounders, patients with current malignancy were more likely to have worse clinical outcomes. The presence of historical cancers was not associated with an increase in poor clinical outcomes. Additionally, AIS patients with current malignancy were less likely to receive intravenous thrombolysis (adjusted odds ratio 0.66, 95% confidence interval 0.63-0.71). Amongst the subgroups of AIS patients treated with intravenous thrombolysis or mechanical thrombectomy, outcomes varied by cancer types. Notably, despite these acute stroke interventions, outcome remains poor in AIS patients with lung cancer. Although AIS patients with malignancy generally have worse in-hospital outcomes versus those without, there were considerable variations in these outcomes according to different cancer types and the use of AIS interventions. Finally, treatment of these AIS patients with a current or historical cancer diagnosis should be individualized.

Pharmacokinetic and dose-finding study of osimertinib in patients with impaired renal function and low body weight.

The safety of osimertinib is limited in patients with severe or moderate renal impairment, or low body weight. This study aimed to investigate the safety, pharmacokinetics (PK) and recommended dose (RD) of osimertinib in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with impaired renal function and low body weight. Thirty-one eligible patients were enrolled and allocated into four cohorts A, normal renal function (estimated glomerular filtration rate eGFR ≥ 50 mLmin1.73 m

Tumor-identification method for predicting recurrence of early-stage lung adenocarcinoma using digital pathology images by machine learning.

Lung cancer is one of the cancers with the highest morbidity and mortality in the world. Recurrence often occurs even after complete resection of early-stage lung cancer, and prediction of recurrence after resection is clinically important. However, the pathological characteristics of the recurrence of pathological stage IB lung adenocarcinoma (LAIB) have not yet been elucidated. Therefore, the problem is what type of histological image of lung adenocarcinoma recurs, and it is important to examine the histological image of recurrence. We attempted to predict recurrence of early lung adenocarcinoma after resection on the basis of digital pathological images of hematoxylin and eosin-stained specimens and machine learning applying a convolutional neural network. We constructed a model that extracts the features of two-color spaces and a switching model that automatically switches between our extraction model and one that extracts the features of one-color space for each image. We then developed a tumor-identification method for predicting the presence or absence of LAIB recurrence using these models. We conducted an experiment involving 55 patients with LAIB who underwent surgical resection to evaluate the proposed method. The proposed method determined LAIB recurrence with an accuracy of 84.8%. The use of digital pathology and machine learning can be used for highly accurate prediction of LAIB recurrence after surgical resection. The proposed method has the potential for objective postoperative follow-up observation.

Long-term benefit of immunotherapy in a patient with squamous lung cancer exhibiting mismatch repair deficienthigh microsatellite instabilityhigh tumor mutational burden A case report and literature review.

Genetic mutations that render mismatch repair defective may result in microsatellite instability, which is common in colorectal carcinomas and gastric cancers as well as Lynch syndrome. Mismatch repair deficiencyhigh microsatellite instability (dMMRMSI-H) predicts the tumor response to immune checkpoint inhibitors. However, few studies have evaluated the efficacy of immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) patients with dMMRMSI-H. In this work, we present a patient with advanced squamous lung cancer with dMMRMSI-H and a high tumor mutational burden (TMB-H) who obtained a long-term benefit from immunotherapy. NSCLC patients with dMMRMSI-HTMB-H may thus benefit from immune checkpoint inhibitors.

Nintedanib in an elderly non-small-cell lung cancer patient with severe steroid-refractory checkpoint inhibitor-related pneumonitis A case report and literature review.

Immune checkpoint inhibitors tremendously improve cancer prognosis however, severe-grade immune-related adverse events may cause premature death. Current recommendations for checkpoint inhibitor-related pneumonitis (CIP) treatment are mainly about immunosuppressive therapy, and anti-fibrotic agents are also needed, especially for patients with poor response to corticosteroids and a longer pneumonitis course. This is because fibrotic changes play an important role in the pathological evolution of CIP. Here, we report a case demonstrating that nintedanib is a promising candidate drug for CIP management or prevention, as it has potent anti-fibrotic efficacy and a safety profile. Moreover, nintedanib could partially inhibit tumor growth in patients with non-small-cell lung cancer, and its efficacy can be improved in combination with other anti-tumor therapies.

Upregulation of NDUFAF2 in Lung Adenocarcinoma Is a Novel Independent Prognostic Biomarker.

NADH dehydrogenase (ubiquinone) 1 alpha subcomplex assembly factor 2 (NDUFAF2) acts as a molecular chaperone for the assembly of complex I on the mitochondrial membrane, which is involved in the transfer of electrons in the respiratory chain. However, whether NDUFAF2 plays a role in lung adenocarcinoma (LUAD) is largely unexplored. Expression profiles were obtained from the TCGA and GEO databases and integrated via R3.6.3 and several bioinformatics platforms. Western blotting analysis and immunohistochemistry staining were used to examine the expressions of NDUFAF2 in clinical samples. Moreover, the diagnostic and prognostic value of NDUFAF2 expression level was also assessed. GO, KEGG, and gene set enrichment analysis (GSEA) were adopted to investigate NDUFAF2-related molecular functions, signaling pathways, and life activity processes. NDUFAF2 was predominantly expressed in LUAD, and it is identified as a promising biomarker in the diagnosis of LUAD and its prognostic prediction. Overexpression of NDUFAF2 was correlated with N stage, T stage, and pathologic stage in LUAD, leading to worse overall survival (OS). Besides, the level of NDUFAF2 was independently associated with OS through a multivariate Cox analysis (HR 1.538, 95% (1.086-2.177), Collectively, NDUFAF2 is a promising independent prognostic biomarker and target in LUAD. In addition, NDUFAF2 might affect the prognosis of LUAD via DNA replication, diseases of mitotic cell cycle, cell cycle pathway, and cell cycle.

Effects of Lipid Metabolism-Related Genes PTGIS and HRASLS on Phenotype, Prognosis, and Tumor Immunity in Lung Squamous Cell Carcinoma.

Lipid metabolism reprogramming played an important role in cancer occurrence, development, and immune regulation. The aim of this study was to identify and validate lipid metabolism-related genes (LMRGs) associated with the phenotype, prognosis, and immunological characteristics of lung squamous cell carcinoma (LUSC). In the TCGA cohort, bioinformatics and survival analysis were used to identify lipid metabolism-related differentially expressed genes (DEGs) associated with the prognosis of LUSC. PTGISHRASLS knockdown and overexpression effects on the LUSC phenotype were analyzed in vitro experiments. Based on the expression distribution of PTGISHRASLS, LUSC patients were divided into two clusters by consensus clustering. Clinical information, prognosis, immune infiltration, expression of immune checkpoints, and tumor mutation burden (TMB) level were compared between the TCGA and GSE4573 cohorts. The genes related to clustering and tumor immunity were screened by weighted gene coexpression network analysis (WGCNA), and the target module genes were analyzed by functional enrichment analysis, protein-protein interaction (PPI) analysis, and immune correlation analysis. 191 lipid metabolism-related DEGs were identified, of which 5 genes were independent prognostic genes of LUSC. PTGISHRASLS were most closely related to LUSC prognosis and immunity. RT-qPCR, western blot (WB) analysis, and immunohistochemistry (IHC) showed that the expression of PTGIS was low in LUSC, while HRASLS was high. Functionally, PTGIS promoted LUSC proliferation, migration, and invasion, while HRASLS inhibited LUSC proliferation, migration, and invasion. The two clusters expression and distribution of PTGISHRASLS had the opposite trend. Cluster 1 was associated with lower pathological staging (pT, pN, and pTNM stages), better prognosis, stronger immune infiltration, higher expression of immune checkpoints, and higher TMB level than cluster 2. WGCNA found that 28 genes including CD4 and IL10RA were related to the expression of PTGISHRASLS and tumor immune infiltration. PTGISHRASLS in the GSE4573 cohort had the same effect on LUSC prognosis and tumor immunity as the TCGA cohort. PTGIS and HRASLS can be used as new therapeutic targets for LUSC as well as biomarkers for prognosis and tumor immunity, which has positive significance for guiding the immunotherapy of LUSC.

Combining with lab-on-chip technology and multi-organ fusion strategy to estimate post-mortem interval of rat.

The estimation of post-mortem interval (PMI) is one of the most important problems in forensic pathology all the time. Although many classical methods can be used to estimate time since death, accurate and rapid estimation of PMI is still a difficult task in forensic practice, so the estimation of PMI requires a faster, more accurate, and more convenient method. In this study, an experimental method, lab-on-chip, is used to analyze the characterizations of polypeptide fragments of the lung, liver, kidney, and skeletal muscle of rats at defined time points after death (0, 1, 2, 3, 5, 7, 9, 12, 15, 18, 21, 24, 27, and 30 days). Then, machine learning algorithms (base model LR, SVM, RF, GBDT, and MLPC ensemble model stacking, soft voting, and soft-weighted voting) are applied to predict PMI with single organ. Multi-organ fusion strategy is designed to predict PMI based on multiple organs. Then, the ensemble pruning algorithm determines the best combination of multi-organ. The kidney is the best single organ for predicting the time of death, and its internal and external accuracy is 0.808 and 0.714, respectively. Multi-organ fusion strategy dramatically improves the performance of PMI estimation, and its internal and external accuracy is 0.962 and 0.893, respectively. Finally, the best organ combination determined by the ensemble pruning algorithm is all organs, such as lung, liver, kidney, and skeletal muscle. Lab-on-chip is feasible to detect polypeptide fragments and multi-organ fusion is more accurate than single organ for PMI estimation.

Expert guidance on prophylaxis and treatment of dermatologic adverse events with Tumor Treating Fields (TTFields) therapy in the thoracic region.

Tumor Treating Fields (TTFields) are electric fields, delivered via wearable arrays placed on or near the tumor site, that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. As a first-in-class treatment, TTFields therapy is approved for use in newly diagnosed glioblastoma, recurrent glioblastoma, and pleural mesothelioma. Additionally, TTFields therapy is being investigated in non-small cell lung cancer (NSCLC), brain metastases from NSCLC, pancreatic cancer, ovarian cancer, hepatocellular carcinoma, and gastric adenocarcinoma. Because TTFields therapy is well tolerated and delivery is locoregional, there is low risk of additive systemic adverse events (AEs) when used with other cancer treatment modalities. The most common AE associated with TTFields therapy is mild-to-moderate skin events, which can be treated with topical agents and may be managed without significant treatment interruptions. Currently, there are no guidelines for oncologists regarding the management of TTFields therapy-related skin AEs in the thoracic region, applicable for patients with pleural mesothelioma or NSCLC. This publication aims to provide guidance on preventing, minimizing, and managing dermatologic AEs in the thoracic region to help improve patient quality of life and reduce treatment interruptions that may impact outcomes with TTFields therapy.

Can the sustainable development goals for cancer be met in Brazil A population-based study.

A one-third reduction in premature mortality (30-69 years) from chronic noncommunicable diseases is goal 3.4 of the United Nations Sustainable Development Goals (UN SDG). The burden of NCDs is expected to continue to increase in low- and middle-income countries, including Brazil. The aim of this study was to assess geographical and temporal patterns in premature cancer mortality in Brazil between 2001 and 2015 and to predict this to 2030 in order to benchmark against the 3.4 SDG target. We used data on deaths from cancer in those aged 30-69, by age group, sex and cancer site, between 2001 and 2015 from the National Mortality Information System of Brazil (SIM). After correcting for ill-defined causes, crude and world age-standardised mortality rates per 100,000 inhabitants were calculated nationally and for the 5 regions. Predictions were calculated using NordPred, up to 2030. The difference in observed (2011-2015) and predicted (2026-2030) mortality was compared against the SDG 3.4 target. Between 2011-2015 and 2026-2030 a 12.0% reduction in premature cancer age-standardised mortality rate among males and 4.6% reduction among females is predicted nationally. Across regions this varied from 2.8% among females in North region to 14.7% among males in South region. Lung cancer mortality rates are predicted to decrease among males but not among females nationally (men 28%, females 1.1% increase) and in all regions. Cervical cancer mortality rates are projected to remain very high in the North. Colorectal cancer mortality rates will increase for both sexes in all regions except the Southeast. Cancer premature mortality is expected to decrease in Brazil, but the extent of the decrease will be far from the SDG 3.4 target. Nationally, only male lung cancer will be close to reaching the SDG 3.4 target, reflecting the governments long-term efforts to reduce tobacco consumption. Projected colorectal cancer mortality increases likely reflect the epidemiological transition. This and, cervical cancer control will continue to be major challenges. These results will help inform strategic planning for cancer primary prevention, early detection and treatment programs such initiatives should take cognizance of the regional differences highlighted here.

Wnt signaling pathway-derived score for predicting therapeutic resistance and tumor microenvironment in lung adenocarcinoma.

Analysis of genomic and immune intratumor heterogeneity in linitis plastica via multiregional exome and T-cell-receptor sequencing.

The molecular landscape and the intratumor heterogeneity (ITH) architecture of gastric linitis plastica (LP) are poorly understood. We performed whole-exome sequencing (WES) and T-cell receptor (TCR) sequencing on 40 tumor regions from four LP patients. The landscape and ITH at the genomic and immunologic levels in LP tumors were compared with multiple cancers previously reported. The lymphocyte infiltration was further assessed by immunohistochemistry (IHC) in LP tumors. In total, we identified 6,339 non-silent mutations from multi-samples, with a median tumor mutation burden (TMB) of 3.30 mutationsMb, comparable to gastric adenocarcinoma from the Cancer Genome Atlas (TCGA) cohort (P0.53). An extremely high level of genomic ITH was observed, with only 12.42, 5.37, 5.35 and 30.67% of mutations detectable across 10 regions within the same tumors of each patient, respectively. TCR sequencing revealed that TCR clonality was substantially lower in LP than in multi-cancers. IHC using antibodies against CD4, CD8 and PD-L1 demonstrated scant T-cell infiltration in the four LP tumors. Furthermore, profound TCR ITH was observed in all LP tumors, with no T-cell clones shared across tumor regions in any of the patients, while over 94% of T-cell clones were restricted to individual tumor regions. The Morisita overlap index (MOI) ranged from 0.21 to 0.66 among multi-regions within the same tumors, significantly lower than that of lung cancer (P0.002). Our results show that LP harbored extremely high genomic and TCR ITH and suppressed T-cell infiltration, suggesting a potential contribution to the frequent recurrence and poor therapeutic response of this adenocarcinoma.

An evaluation of radiation therapy patient body mass index trends and potential impact on departmental resource planning.

Radiation therapy (RT) offers a less invasive management option for bariatric cancer patients. As the proportion of Australians categorised overweight or obese approaches 70%, it is not well understood how this growth will impact RT departments. The aim of this study was to evaluate the current and potential future body mass index (BMI) of RT patients at one centre, with the purpose of identifying variables that may impact resource planning decisions. De-identified demographic data including gender, age, diagnosis code, activity code and BMI were obtained from MOSAIQ® oncology information system for 5548 courses of RT commenced between 2017 and 2020, and retrospectively analysed. Descriptive statistics were used to summarise the data. Simple and multiple linear regression was used to analyse for statistically significant relationships between variables. Of all patient courses, 64% were overweight or obese. Average BMI increased over time by 0.3 kgm Results demonstrate that patient BMI is increasing. Resources related to breast courses (breast board, prone board) and thorax courses (lung board) may experience increased strain in the future. Modifications to department workflow and scheduling are likely required. Further research into staffing implications is recommended.

The role of lncRNAsmiRNAsSirt1 axis in myocardial and cerebral injury.

In recent years, researchers have begun to realize the importance of the role of non-coding RNAs in the treatment of cancer and cardiovascular and neurological diseases. LncRNAs and miRNAs are important non-coding RNAs, which regulate gene expression and activate mRNA translation through binding to diverse target sites. Their involvement in the regulation of protein function and the modulation of physiological and pathological conditions continues to be investigated. Sirtuins, especially Sirt1, have a critical function in regulating a variety of physiological processes such as oxidative stress, inflammation, apoptosis, and autophagy. The lncRNAsmiRNAsSirt1 axis may be a novel regulatory mechanism, which is involved in the progression andor prevention of numerous diseases. This review focuses on recent findings on the crosstalk between non-coding RNAs and Sirt1 in myocardial and cerebral injuries and may provide some insight into the development of novel approaches in the treatment of these disorders.

Tumor necroptosis-mediated shedding of cell surface proteins promotes metastasis of breast cancer by suppressing anti-tumor immunity.

Necroptosis is a form of regulated necrosis and is executed by MLKL when MLKL is engaged in triggering the rupture of cell plasma membrane. MLKL activation also leads to the protease, ADAMs-mediated ectodomain shedding of cell surface proteins of necroptotic cells. Tumor necroptosis often happens in advanced solid tumors, and blocking necroptosis by MLKL deletion in breast cancer dramatically reduces tumor metastasis. It has been suggested that tumor necroptosis affects tumor progression through modulating the tumor microenvironment. However, the exact mechanism by which tumor necroptosis promotes tumor metastasis remains elusive. Here, we report that the ectodomain shedding of cell surface proteins of necroptotic cells is critical for the promoting effect of tumor necroptosis in tumor metastasis through inhibiting the anti-tumor activity of T cells. We found that blocking tumor necroptosis by MLKL deletion led to the dramatic reduction of tumor metastasis and significantly elevated anti-tumor activity of tumor-infiltrating and peripheral blood T cells. Importantly, the increased anti-tumor activity of T cells is a key cause for the reduced metastasis as the depletion of CD8 T cells completely restored the level of metastasis in the Mlkl KO mice. Interestingly, the levels of some soluble cell surface proteins including sE-cadherin that are known to promote metastasis are also dramatically reduced in MLKL null tumorsmice. Administration of ADAMs pan inhibitor reduces the levels of soluble cell surface proteins in WT tumorsmice and leads to the dramatic decrease in metastasis. Finally, we showed the sE-cadherinKLRG1 inhibitory receptor is the major pathway for necroptosis-mediated suppression of the anti-tumor activity of T cells and the promotion of metastasis. Hence, our study reveals a novel mechanism of tumor necroptosis-mediated promotion of metastasis and suggests that tumor necroptosis and necroptosis-activated ADAMs are potential targets for controlling metastasis.

Medical insurance payment schemes and patient medical expenses a cross-sectional study of lung cancer patients in urban China.

As the main cause of cancer death, lung cancer imposes seriously health and economic burdens on individuals, families, and the health system. In China, there is no national study analyzing the hospitalization expenditures of different payment methods by lung cancer inpatients. Based on the 2010-2016 database of insured urban resident lung cancer inpatients from the China Medical Insurance Research Association (CHIRA), this paper aims to investigate the characteristics and cost of hospitalized lung cancer patient, to examine the differences in hospital expenses and patient out-of-pocket (OOP) expenses under four medical insurance payment methods fee-for-service (FFS), per-diem payments, capitation payments (CAP) and case-based payments, and to explore the medical insurance payment method that can be conducive to controlling the cost of lung cancer. This is a 2010-2016, 7-year cross-sectional study. CHIRA data are not available to researchers after 2016. The Medical Insurance Database of CHIRA was screened using the international disease classification system to yield 28,200 inpatients diagnosed with lung cancer (ICD-10 C34, C34.0, C34.1, C34.2, C34.3, C34.8, C34.9). The study includes descriptive analysis and regression analysis based on generalized linear models (GLM). The average patient age was 63.4 years and the average length of hospital stay (ALOS) was 14.2 day 60.7% of patients were from tertiary hospitals and 45% were insured by FFS. The per-diem payment had the lowest hospital expenses (RMB7496.00US$1176.87), while CAP had the lowest OOP expenses (RMB1328.18US$208.52). Compared with FFS hospital expenses, per-diem was 21.3% lower (95% CI -0.265, -0.215) and case-based payment was 8.4% lower (95% CI -0.151, -0.024). Compared with the FFS, OOP expenses, per-diem payments were 9.2% lower (95% CI -0.130, -0.063) and CAP was 15.1% lower (95% CI -0.151, -0.024). For lung cancer patients, per-diem payment generated the lowest hospital expenses, while CAP meant patients bore the lowest OOP costs. Policy makers are suggested to give priority to case-based payments to achieve a tripartite balance among medical insurers, hospitals, and insured members. We also recommend future studies comparing the disparities of various diseases for the cause of different medical insurance schemes.

Exploring the relationships between hormone receptor, HER2 status, and bone involvement in the first distant metastases of in Chinese breast cancer patients who lacked HER2 targeted therapy.

This retrospective study explored the relationship between hormone receptor (HR), human epidermal growth factor receptor 2 (HER2) status, and bone involvement in the first distant metastases (DM) of Chinese breast cancer (BC) patients who lacked the HER2 targeted therapy. Such therapy was rarely received due to its lag approval or high cost in China compared with the developed countries. All eligible women with primary unilateral stage I - III BC and first DM diagnosed in 2008-2018 at one cancer center were identified for enrollment. Based on chart records, a full or nopartial compliance status of endocrine therapy (ET) was assigned for HR-positive patients. Multivariate logistic regression was used to estimate the adjusted odd ratio (aOR), its 95%CI and p value. Four hundred eighteen patients had an average age of 50.7 years and median disease-free survival of 27.1 months at DM. Bone, lung, liver and brain metastasis rates in patients were 55.7%, 34.7%, 33.0% and 8.1%, respectively. Compared to HR-negative patients, HR-positive patients with the full and nonpartial compliance of ET were significantly associated with higher risk of bone involvement with an aOR of 2.329 (1.316 - 1.741, p 0.004) and 2.317 (1.330 - 4.036, p 0.003), respectively. No difference of such risk was found between the two groups of ET compliance (p 0.984) nor between HER2-negative and HER2-positive patients (aOR 0.827, p 0.431). Stratified analyses further indicated that HR-positive was associated with bone involvement only in HER2-negative BC patients (p 0.006-0.015). HR-positive tumors are significantly associated with bone involvement in HER2-negative metastatic BC patients. ET does not appear to impact this association. HER2 status per se is not associated with such risk.

Spectral CT-based radiomics signature for distinguishing malignant pulmonary nodules from benign.

To evaluate the discriminatory capability of spectral CT-based radiomics to distinguish benign from malignant solitary pulmonary solid nodules (SPSNs). A retrospective study was performed including 242 patients with SPSNs who underwent contrast-enhanced dual-layer Spectral Detector CT (SDCT) examination within one month before surgery in our hospital, which were randomly divided into training and testing datasets with a ratio of 73. Regions of interest (ROIs) based on 40-65 keV images of arterial phase (AP), venous phases (VP), and 120kVp of SDCT were delineated, and radiomics features were extracted. Then the optimal radiomics-based score in identifying SPSNs was calculated and selected for building radiomics-based model. The conventional model was developed based on significant clinical characteristics and spectral quantitative parameters, subsequently, the integrated model combining radiomics-based model and conventional model was established. The performance of three models was evaluated with discrimination, calibration, and clinical application. The 65 keV radiomics-based scores of AP and VP had the optimal performance in distinguishing benign from malignant SPSNs (AUC Among the 40-65 keV radiomics-based scores based on SDCT, 65 keV radiomics-based score had the optimal performance in distinguishing benign from malignant SPSNs. The integrated model combining radiomics-based model based on 65 keV images of AP and VP with Z

Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing.

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

Up-front single-session radiosurgery for large brain metastases-volumetric responses and outcomes.

Patients presenting with large brain metastases (LBM) pose a management challenge to the multidisciplinary neuro-oncologic team. Treatment options include surgery, whole-brain or large-field radiation therapy (WBRT), stereotactic radiosurgery (SRS), or a combination of these. To determine if corticosteroid therapy followed by SRS allows for efficient minimally invasive care in patients with LBMs not compromised by mass effect. We analyzed the change in tumor volume to determine the efficacy of single-session SRS in the treatment of LBM in comparison to other treatment modalities. Twenty-nine patients with systemic cancer and brain metastasis (≥ 2.7 cm in greatest diameter) who underwent single-session SRS were included. Among 29 patients, 69% of patients had either lung, melanoma, or breast cancer. The median initial tumor size (maximal diameter) was 32 mm (range 28-43), and the median initial tumor volume was 9.56 cm Initial high-dose corticosteroid therapy followed by prompt single-stage SRS is a safe and efficacious method to manage patients with LBMs (defined as ≥ 2.7 cm).

Persistent mutation burden drives sustained anti-tumor immune responses.

Tumor mutation burden is an imperfect proxy of tumor foreignness and has therefore failed to consistently demonstrate clinical utility in predicting responses in the context of immunotherapy. We evaluated mutations in regions of the genome that are unlikely to undergo loss in a pan-cancer analysis across 31 tumor types (n 9,242) and eight immunotherapy-treated cohorts of patients with non-small-cell lung cancer, melanoma, mesothelioma, and head and neck cancer (n 524). We discovered that mutations in single-copy regions and those present in multiple copies per cell constitute a persistent tumor mutation burden (pTMB) which is linked with therapeutic response to immune checkpoint blockade. Persistent mutations were retained in the context of tumor evolution under selective pressure of immunotherapy and tumors with a high pTMB content were characterized by a more inflamed tumor microenvironment. pTMB imposes an evolutionary bottleneck that cancer cells cannot overcome and may thus drive sustained immunologic tumor control in the context of immunotherapy.

Three-dimensional structured illumination microscopy with enhanced axial resolution.

The axial resolution of three-dimensional structured illumination microscopy (3D SIM) is limited to ∼300 nm. Here we present two distinct, complementary methods to improve axial resolution in 3D SIM with minimal or no modification to the optical system. We show that placing a mirror directly opposite the sample enables four-beam interference with higher spatial frequency content than 3D SIM illumination, offering near-isotropic imaging with ∼120-nm lateral and 160-nm axial resolution. We also developed a deep learning method achieving ∼120-nm isotropic resolution. This method can be combined with denoising to facilitate volumetric imaging spanning dozens of timepoints. We demonstrate the potential of these advances by imaging a variety of cellular samples, delineating the nanoscale distribution of vimentin and microtubule filaments, observing the relative positions of caveolar coat proteins and lysosomal markers and visualizing cytoskeletal dynamics within T cells in the early stages of immune synapse formation.

Synergy of ruthenium metallo-intercalator, Ru(dppz)

Poly(ADP-ribose) polymerase (PARP) are critical DNA repair enzymes that are activated as part of the DNA damage response (DDR). Although inhibitors of PARP (PARPi) have emerged as small molecule drugs and have shown promising therapeutic effects, PARPi used as single agents are clinically limited to patients with mutations in germline breast cancer susceptibility gene (BRCA). Thus, novel PARPi combination strategies may expand their usage and combat drug resistance. In recent years, ruthenium polypyridyl complexes (RPCs) have emerged as promising anti-cancer candidates due to their attractive DNA binding properties and distinct mechanisms of action. Previously, we reported the rational combination of the RPC DNA replication inhibitor Ru(dppz)

Adaptive resistance to lorlatinib via EGFR signaling in ALK-rearranged lung cancer.

Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors rarely elicit complete responses in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC), as a small population of tumor cells survives due to adaptive resistance. Therefore, we focused on the mechanisms underlying adaptive resistance to lorlatinib and therapeutic strategies required to overcome them. We found that epidermal growth factor receptor (EGFR) signaling was involved in the adaptive resistance to lorlatinib in ALK-rearranged NSCLC, activation of which was induced by heparin-binding EGF-like growth factor production via c-Jun activation. EGFR inhibition halted ALK-rearranged lung cancer cell proliferation by enhancing ALK inhibition-induced apoptosis via suppression of Bcl-xL. Xenograft models showed that the combination of EGFR inhibitor and lorlatinib considerably suppressed tumor regrowth following cessation of these treatments. This study provides new insights regarding tumor evolution due to EGFR signaling after lorlatinib treatment and the development of combined therapeutic strategies for ALK-rearranged lung cancer.

Inhibition of autophagy and MEK promotes ferroptosis in Lkb1-deficient Kras-driven lung tumors.

LKB1 and KRAS are the third most frequent co-mutations detected in non-small cell lung cancer (NSCLC) and cause aggressive tumor growth. Unfortunately, treatment with RAS-RAF-MEK-ERK pathway inhibitors has minimal therapeutic efficacy in LKB1-mutant KRAS-driven NSCLC. Autophagy, an intracellular nutrient scavenging pathway, compensates for Lkb1 loss to support Kras-driven lung tumor growth. Here we preclinically evaluate the possibility of autophagy inhibition together with MEK inhibition as a treatment for Kras-driven lung tumors. We found that the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and the MEK inhibitor Trametinib displays synergistic anti-proliferative activity in Kras

Face to a bilateral pneumothorax, just scratch your head.

Head and neck skin angiosarcoma is a rare and aggressive tumor (1 % of head and neck tumors). Prognosis remains poor, with a 5-year survival rate ranging from 10 to 54%, depending on the initial stage. Metastatic disease markedly worsens the prognosis. Metastatic lung involvement is classic and can take on several forms. The cystic form is responsible for numerous complications, particularly pneumothorax. In this case, an 83-year-old patient was diagnosed with bilateral pneumothorax complicating cystic interstitial lung disease, which was revealed by hemoptoic sputum. Skin examination revealed two large necrotic lesions of the calvaria. Anatomo-pathological examination confirmed cutaneous angiosarcoma on both skin biopsy and lung resection. At a metastatic stage, only systemic treatment with paclitaxel can be proposed. The clinical course was unfavorable, leading to death before any specific treatment. This observation highlights the importance of a complete clinical skin examination in the assessment of pulmonary cystic lesions.

Improving representativeness in trials a call to action from the Global Cardiovascular Clinical Trialists Forum.

Participants enrolled in cardiovascular disease (CVD) randomized controlled trials are not often representative of the population living with the disease. Older adults, children, women, Black, Indigenous and People of Color, and people living in low- and middle-income countries are typically under-enrolled in trials relative to disease distribution. Treatment effect estimates of CVD therapies have been largely derived from trial evidence generated in White men without complex comorbidities, limiting the generalizability of evidence. This review highlights barriers and facilitators of trial enrollment, temporal trends, and the rationale for representativeness. It proposes strategies to increase representativeness in CVD trials, including trial designs that minimize the research burden on participants, inclusive recruitment practices and eligibility criteria, diversification of clinical trial leadership, and research capacity-building in under-represented regions. Implementation of such strategies could generate better and more generalizable evidence to reduce knowledge gaps and position the cardiovascular trial enterprise as a vehicle to counter existing healthcare inequalities.

Relationship between ethnicity and stage at diagnosis in England a national analysis of six cancer sites.

Cancer stage at diagnosis is a determinant of treatment options and survival. Previous research has shown differences in barriers to presentation with cancer between ethnic groups. The completeness and quality of cancer stage and ethnicity data has improved markedly over recent years in England, allowing for comparison of stage distributions at diagnosis between ethnic groups. This study aimed to assess relationships between ethnic group and two outcomes unknown stage cancer and late stage (stages 3 and 4) cancer, after adjustment for confounders. A retrospective secondary data analysis using data from NHS Digitals National Cancer Registration and Analysis Service and Hospital Episode Statistics records from 2012 to 2016. This study analysed newly diagnosed breast, colon, non-small cell lung cancer (NSCLC), ovary, prostate and uterine cancers in white British, Caribbean, African, Chinese and Asian patients aged 15-99 in England. Caribbean, African and Asian women with breast or ovarian cancer, Caribbean and African women with uterine or colon cancer, Caribbean women with NSCLC and Caribbean men with colon cancer had increased odds of late-stage disease at diagnosis compared with the white British cohort. In contrast, Caribbean and African men with prostate cancer had decreased odds of late-stage cancer. Where stage was known, there were variations in late-stage cancer by ethnic group. Low symptom awareness and barriers to presentation can cause delays, resulting in later stage diagnosis. Targeted intervention campaigns to help raise awareness of cancer signs and symptoms and the benefits of early diagnosis, along with removing barriers to appropriate referrals, could help to improve these inequalities.

Radiolabeled GPVI-Fc for PET imaging of multiple extracellular matrix fibers A new look into pulmonary fibrosis progression.

Invariably fatal and with a particularly fast progression, pulmonary fibrosis (PF) is currently devoid of curative treatment option. Routine clinical diagnosis relies on breathing tests and visualizing the changes in lung structure by computed tomography (CT), but anatomical information is often not sufficient to identify early signs of progressive PF. For more efficient diagnosis, additional imaging techniques were investigated in combination with CT, such as

Cisplatin is a potent first-line therapy for many solid malignancies such as breast, ovarian, lung, testicular and head and neck cancer. However, acute kidney injury (AKI) is a major dose-limiting toxicity in cisplatin therapy, which often hampers the continuation of cisplatin treatment. The endocannabinoid system, consisting of anandamide (AEA) and 2-arachidonoylglycerol and cannabinoid receptors, participates in different kidney diseases. Inhibition of fatty acid amide hydrolase (FAAH), the primary enzyme for the degradation of AEA and AEA-related N-acylethanolamines, elicits anti-inflammatory effects however, little is known about its role in cisplatin nephrotoxicity. The current study tested the hypothesis that genetic deletion of

Palliative care and COVID-19 a bibliometric analysis.

To assess the impact of COVID-19 on the palliative care (PC) publication trend in the last 10 years and the collaboration between countries and main topics that were discussed in the papers. We used Scopus to identify publications on PC between 2012 and 2021 and publications about PC and COVID-19 between 2020 and 2021. We used VOSviewer to assess the main topics using the keywords from the papers and to assess country collaboration. 1937 publications resulted. An increase in publications about PC was observed during the pandemic, only partially explained by OVID-19-related publications. Cancer-related PC publications were the ones with the most marked increase. We identified six clusters in the distribution of the keywords bioethics, cancer, nursing hometelemedicine, public health, caring and PC following the WHO definition. The countries with higher number of publications were the United States and England. We showed an increase in the number of PC publications in the last 2 years that was only partially explained by COVID-19-related publications. Most of the publications increase was due to cancer-related publications, since, during the time of the pandemic, publications on cancer and PC increased markedly, while those on heart failure, lung disease and dementia, remained constant.

GATA3 Expression in Primary Lung Carcinomas Correlation with Histopathologic Features and TTF-1, Napsin A, and p40 Expression.

This study assessed the expression of GATA3 in primary lung carcinomas and correlated it with tumor histology and immunostains routinely utilized in the work up of primary lung cancers. Tissue microarrays (TMAs) were constructed from a cohort of 184 non-small cell carcinomas, stained with GATA3, p40, TTF-1, and napsin A, and analyzed semi-quantitatively. All TMA cases with GATA3 expression were further analyzed using corresponding whole slide sections. Positive GATA3 staining was present in sixteen cases (9%), including 7 squamous cell carcinomas (SqCCs) (4%), 4 adenocarcinomas (AdCs) (2%), 2 adenosquamous carcinomas (AdSqCs) (1%), 2 large cell carcinomas (LCCs) (1%), and 1 sarcomatoid carcinoma (SC) (<1%). Among tumor histotypes, SqCC was more likely to stain with GATA3 (749, 14%), while AdC was less likely (4111, 4%) (p 0.04). In GATA3-positive cases, high-level expression was observed in 9 cases (56%), including 5 p40-positive SqCCs (3 were nonkeratinizing), 1 p40-positive AdSqC negative for TTF-1 and napsin A, and 1 AdC (solid), 1 LCC, and 1 SC, each negative for p40, TTF-1, and napsin A. Low-level GATA3 expression was found in 3 AdCs (1 was lepidic and 2 were acinar predominant), 2 SqCCs (keratinizing), 1 AdSqC, and 1 LCC. These findings indicate that GATA3 expression occurs in a minor but significant proportion of primary non-small cell lung carcinomas, most often involves SqCC, and tends to show increasing levels of expression in more poorly differentiated subtypes. Caution should be exercised when interpreting GATA3 expression, and a panel of immunostains should be utilized when assigning tumor origin.

Legumain inhibitor prevents breast cancer bone metastasis by attenuating osteoclast differentiation and function.

Breast cancer is the main lethal disease among females, and metastasis to lung and bone poses a serious threat to patients life. Therefore, identification of novel molecular mediators that can potentially be exploited as therapeutic targets for treating osteolytic bone metastases is needed. A murine model of breast cancer bone metastasis was developed by injection of 4 T1.2 cells into the left ventricle and hence directly into the arterial system leading to bone. AEP (Asparagine endopeptidase) inhibitor combined with epirubicin or epirubicin alone was administered by intraperitoneal injection into animal model. The presence of bone metastatic and osteolytic lesions in bone were assessed by bioluminescent imaging and X-rays analysis. The expression of EMT (Epithelial-Mesenchymal Transition) relevant genes were examined by Western blotting. Cell migration and invasion were investigated with a transwell assay. Compound BIC-113, small molecule inhibitors of AEP, inhibited AEP enzymatic activity in breast cancer cell lines, and affected invasion and migration of cancer cells, but had no effect on cell growth. In animal model of breast cancer bone metastasis, compound BIC-113 combined with epirubicin inhibited breast cancer bone metastasis and attenuated breast cancer osteolytic lesions in bone by inhibiting osteoclast differentiation and EMT. These results indicate that compound BIC-113 combined with epirubicin has the potential to be used in breast cancer therapy by preventing bone metastasis via improving E-cadherin expression and inhibition of osteoclast formation.

Targeted metabolomics analysis identified the role of FOXA1 in the change in glutamate-glutamine metabolic pattern of BaP malignantly transformed 16HBE cells.

The carcinogenic mechanism of benzoapyrene (BaP) is far from being elucidated. FOXA1 has been confirmed to play an oncogenic role in BaP-transformed cell THBEc1. To explore the changes in amino acid metabolic patterns, especially glutamate-glutamine (Glu-Gln) metabolic pattern caused by BaP-induced transformation and the possible role FOXA1 might play in it, we compared amino acid metabolic characteristics between THBEc1 cells and control 16HBE cells using a targeted metabolomics method and determined the effects of FOXA1 knockout on the amino acid metabolic pattern using FOXA1 knockout cell THBEc1-ΔFOXA1-c34. The amino acid metabolic patterns of THBEc1 and 16HBE cells were different, which was manifested by the differential consumption of 18 amino acids and the difference in the intracellular content of 21 amino acids. The consumption and intracellular content of Glu and Gln are different between the two types of cells, accompanied by upregulation of FOXA1, GLUL, SLC1A3, SLC1A4, SLC1A5 and SLC6A14, and downregulation of FOXA2 and GPT2 in THBEc1 cells. FOXA1 knockout changed the consumption of 19 amino acids and the intracellular content of 21 amino acids and reversed the metabolic pattern of Glu and the changes in FOXA2, GLUL, SLC1A3 and SLC6A14 in THBEc1 cells. Additionally, FOXA1 knockout inhibited cell proliferation and further increased the dependence of THBEc1 cells on Glu. In conclusion, FOXA1 knockout partially reversed the change in Glu-Gln metabolism caused by BaP-induced transformation by upregulating the expression of GLUL and SLC1A3. Our findings provide a clue for the possible role of FOXA1 in amino acid metabolism regulation.

P4HA1 activates HMGCS1 to promote nasopharyngeal carcinoma ferroptosis resistance and progression.

Ferroptosis is a novel type of iron-dependent regulatory cell death. To date, the regulatory mechanism of ferroptosis in nasopharyngeal carcinoma (NPC) remains poorly understood. In this study, we found that the prolyl 4-hydroxylase (P4H) subunit P4HA1 protects NPC cells from erastin-induced ferroptosis by activating HMGCS1, a key enzyme in the mevalonate pathway. We also found that the P4HA1HMGCS1 axis promoted NPC cell proliferation in vitro. In vivo, downregulation of the P4HA1HMGCS1 axis inhibited the growth of NPC cell xenografts and enhanced the inhibitory effect of erastin on tumor growth. Extracellular matrix (ECM) detachment is an important trigger for ferroptosis. We found that the P4HA1HMGCS1 axis promoted the ferroptosis resistance and survival of ECM-detached NPC cells. In vivo, downregulation of the P4HA1HMGCS1 axis inhibited the lung colonization of NPC cells and enhanced the inhibitory effect of erastin on NPC lung metastasis. Moreover, the high expression of P4HA1 predicted a poor prognosis and served as a potential independent prognostic factor in patients with NPC. In conclusion, P4HA1 is a novel molecular marker of NPC ferroptosis resistance and a poor prognosis, and the P4HA1HMGCS1 axis provides a new target for the treatment of NPC progression.

PM

Ninety-six fine particulate matter (PM

Mapping Multiple Factors-mediated Chromatin Interactions to Assess Dysregulation of Lung Cancer-related Genes.

Studies on the lung cancer genome are indispensable for developing a cure for lung cancer. Whole-genome resequencing, genome-wide association studies, and transcriptome sequencing have greatly improved our understanding of the cancer genome. However, dysregulation of long-range chromatin interactions in lung cancer remains poorly described. To better understand the three-dimensional (3D) genomic interaction features of the lung cancer genome, we used the A549 cell line as a model system and generated high-resolution chromatin interactions associated with RNA polymerase II (RNAPII), CCCTC-binding factor (CTCF), enhancer of zeste homolog 2 (EZH2), and histone 3 lysine 27 trimethylation (H3K27me3) using long-read chromatin interaction analysis by paired-end tag sequencing (ChIA-PET). Analysis showed that EZH2H3K27me3-mediated interactions further repressed target genes, either through loops or domains, and their distributions along the genome were distinct from and complementary to those associated with RNAPII. Cancer-related genes were highly enriched with chromatin interactions, and chromatin interactions specific to the A549 cell line were associated with oncogenes and tumor suppressors, such as additional repressive interactions on FOXO4 and promoter-promoter interactions between NF1 and RNF135. Knockout of an anchor associated with chromatin interactions reversed the dysregulation of cancer-related genes, suggesting that chromatin interactions are essential for proper expression of lung cancer-related genes. These findings demonstrate the 3D landscape and gene regulatory relationships of the lung cancer genome.

Experimental and computational studies of silver(I) dibenzoylmethane-based complexes, interaction with DNARNABSA biomolecules, and in vitro cytotoxic activity.

Two silver(I) complexes of composition Ag

OWL an optimized and independently validated machine learning prediction model for lung cancer screening based on the UK Biobank, PLCO, and NLST populations.

A reliable risk prediction model is critically important for identifying individuals with high risk of developing lung cancer as candidates for low-dose chest computed tomography (LDCT) screening. Leveraging a cutting-edge machine learning technique that accommodates a wide list of questionnaire-based predictors, we sought to optimize and validate a lung cancer prediction model. We developed an Optimized early Warning model for Lung cancer risk (OWL) using the XGBoost algorithm with 323,344 participants from the England area in UK Biobank (training set), and independently validated it with 93,227 participants from UKB Scotland and Wales area (validation set 1), as well as 70,605 and 66,231 participants in the Prostate, Lung, Colorectal, and Ovarian cancer screening trial (PLCO) control and intervention subpopulations, respectively (validation sets 2 3) and 23,138 and 18,669 participants in the United States National Lung Screening Trial (NLST) control and intervention subpopulations, respectively (validation sets 4 5). By comparing with three competitive prediction models, i.e., PLCO modified 2012 (PLCO For general population, with validation set 1, OWL (AUC 0.855, 95% CI 0.829-0.880) presented a better discriminative capability than PLCO OWL, with a high degree of predictive accuracy and robustness, is a general framework with scientific justifications and clinical utility that can aid in screening individuals with high risks of lung cancer. National Natural Science Foundation of China, the US NIH.

WDR74 rs11231247 contributes to the susceptibility and prognosis of non-small cell lung cancer.

WD repeat-containing protein 74 (WDR74) has been linked with the development of lung cancer. This study aims to investigate the relationship between WDR74 rs11231247 and non-small cell lung cancer (NSCLC) susceptibility and the prognosis of NSCLC patients. UALCAN, MethPrimer, ensembl and Pancan meQTL databases were used for bioinformatics analysis. The case-control study included 462 NSCLC patients and 462 health controls. WDR74 rs11231247 genotype was determined by PCR-RFLP. Logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (95% CI) for analyzing the association of WDR74 SNP with the risk of NSCLC. Log-rank test and Cox regression analysis were used to evaluate the effect of WDR74 genetic variation on the prognosis of NSCLC. Compared with normal tissues, WDR74 expression level was higher and methylation level was lower in LUAD tissues. There were two CpG islands presented in the promoter of WDR74. And rs11231247 was in the second CpG island. We then discovered that rs11231247 CC and CT were more likely modified by methylation. LUAD case-control study demonstrated that rs11231247 CC genotype was associated with NSCLC risk with OR (95%CI) of 5.29 (2.59-10.79). Stratified analysis showed that rs11231247 T > C polymorphism could increase NSCLC risk in younger subjects (age≤58) (OR 1.64, 95%CI 1.06-2.54, P 0.027). Survival analysis and Cox regression analysis showed rs11231247 CC genotype contributed to a poor prognosis of NSCLC patients (MST21, HR2.09, 95%CI1.17-3.75). WDR74 rs11231247 polymorphism affected the risk and prognosis of NSCLC.

Predictors of Post-Chemoradiotherapy Pulmonary Complication in Locally Advanced Non-Small Cell Lung Cancer.

We investigated the clinical effects and predictive factors of severe post-chemoradiotherapy pulmonary complications (PCPC) in locally advanced non-small cell lung cancer (LA-NSCLC). Medical records of 317 patients who underwent definitive concurrent chemoradiation (CCRT) for LA-NSCLC were reviewed retrospectively. PCPC was defined as an event of admission or emergency department visit for acute or subacute pulmonary inflammatory complications, including pneumonitis and pneumonia, within 6 months after CCRT initiation. Patient characteristics, baseline lung function tests, radiation dosimetric parameters, and laboratory tests were analysed to investigate their association with PCPC. Prognostic endpoints were disease progression rate (DPR) and overall survival (OS). PCPC was reported in 53 (16.7%) patients. The OS of patients with PCPC was significantly worse (35.0% in 2 years) than that of patients without PCPC (67.0% in 2 years, p<0.001). However, 2-year DPRs were 77.0% and 70.7% in patients with and without PCPC, respectively, which were not significantly different (p0.087). In multivariate logistic regression, PCPC was independently associated with grade≥1 hypoalbuminaemia during CCRT (odds ratio OR 5.670, 95% confidence interval CI 2.487-13.40, p<0.001), lower diffusing capacity of carbon monoxide (DLCO) (per mlminmmHg, OR 0.855, 95% CI 0.743-0.974, p0.022), and higher lung V5 (per 10%, OR 1.872, 95% CI 1.336-2.699, p<0.001). PCPC might be a clinical endpoint to evaluate complications and predict the survival of patients subjected to CCRT for LA-NSCLC. Hypoalbuminaemia, DLCO, and lung V5 might predict PCPC in LA-NSCLC.

MLL4 Regulates the Progression of Non-Small-Cell Lung Cancer by Regulating the PI3KAKTSOX2 Axis.

Mixed-lineage leukemia protein 4 (MLL4KMT2D) is a histone methyltransferase, and its mutation has been reported to be associated with a poor prognosis in many cancers, including lung cancer. We investigated the function of MLL4 in lung carcinogenesis. RNA sequencing (RNA-seq) in A549 cells transfected with control siRNA or MLL4 siRNA was performed. Also, we used EdU incorporation assay, colony formation assays, growth curve analysis, transwell invasion assays, immunohistochemical staining and in vivo bioluminescence assay to investigate the function of MLL4 in lung carcinogenesis. We found that MLL4 expression was down-regulated in non-small cell lung cancer (NSCLC) tissues compared to adjacent normal tissues and tended to decrease with disease stage progression. We analyzed the transcriptomes in control and MLL4-deficient cells using high-throughput RNA deep sequencing (RNA-seq) and identified a cohort of target genes, such as SOX2, ATF1, FOXP4, PIK3IP1, SIRT4, TENT5B, and LFNG, some of which are related to proliferation and metastasis. Our results showed that low expression of MLL4 promotes NSCLC cell proliferation and metastasis and is required for the maintenance of non-small cell lung cancer stem cell properties. Our findings identify an important role of MLL4 in lung carcinogenesis through transcriptional regulation of PIK3IP1, affecting the PI3KAKTSOX2 axis, and suggest that MLL4 could be a potential prognostic indicator and target for non-small cell lung cancer therapy.

Loss of smell in lung cancer patients undergoing chemotherapy Prevalence and relationship with food habit changes.

Cancer patients undergoing cytotoxic chemotherapies exhibit a series of adverse side effects including smell and taste alterations, which can have a significant impact on their food behavior and quality of life. Particularly, olfactory alterations are often underestimated, although declared as frequent by cancer patients. In the present study, we set out to examine loss of smell in lung cancer patients undergoing chemotherapy and its relationship to food habits. Forty-four bronchial cancer patients receiving cisplatin and 44 controls age and gender matched participants were tested for olfactory and gustatory functions using the European Test of Olfactory Capabilities and the Taste Strips test. Participants reported their food and dietary habits by filling a self-administered questionnaire. Patients were tested under two different sessions i) before the beginning of the treatment, and ii) 6 weeks later, after 2 cycles of chemotherapy. Controls were tested under the same protocol with two sessions separated by 6 weeks. The results highlighted decreased smell and taste abilities in almost half of the lung patients group even before the exposition to Cisplatin. On a perceptual level, patients rated typical food odors as less edible compared to controls. Moreover, within the patients group, hyposmics reported using more condiments, possibly as a compensatory mechanism to their decreased sensory abilities. Taken together, these findings showed that loss of smell is prevalent in lung cancer patients and is related to changes in dietary practices including seasoning. Future studies will provide a better understanding of these sensory compensation mechanisms associated with olfactory loss and their effects on food pleasure in this patient population.

A lung squamous cell carcinoma-associated membranous nephropathy patient free of tumor and membranous nephropathy after the treatment of surgery and radiochemotherapy following pembrolizumab A rare case report.

Membranous nephropathy (MN) is an autoimmune disease, which is classified into primary and secondary MN. Malignancy-associated MN (M-MN) accounts for about 10% of secondary MN cases. Lung cancer is the most common type of malignancy among M-MN patients. Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) have showed promising efficacy and good safety in many types of solid tumors, including non-small cell lung cancer. To date, whether ICIs could be a treatment option for M-MN patients with PD-L1 expression and or high tumor mutation burden (TMB) level has not been documented. A 68-year-old male patient presented with edema of the lower limbs with increased urine foam in August 2018. Biopsy on the right kidney showed MN at stage I with subepithelially localized immune deposits. Lung squamous cell carcinoma (LSCC)-associated MN with PD-L1 expression (20%) and high TMB level (26.2 mutationsMb). The patient received immunosuppressive therapy targeting the initially diagnosed primary MN as first-line treatment plus surgery and radiochemotherapy following pembrolizumab targeting the definitively diagnosed lung cancer as second-line treatment. The patient benefited from radiochemotherapy following pembrolizumab (lasting more than 38 months) rather than immunosuppressive therapy. Our work suggests that combined ICIs might be an effective treatment option for M-MN patients who harbor PD-L1 expression. Our work highlights that the presence of malignancy should not be neglected at the initial diagnosis of MN.

Bone metastatic carcinoma with EGFR amplification and mutation A case report and literature review.

Mutations in the epidermal growth factor receptor (EGFR) gene are highly prevalent in non-small cell lung cancer, while rare in other cancers. Primarily its hardly present in bone metastases from cancer of unknown primary (BMCUP). Currently, no specific treatment options for bone metastases from unknown primary cancers exist. The right shoulder and back pain of a 72-years-old man had been persistent for 2 weeks and had developed worse on 1 particular day. The right upper arm was compromised, which also hindered the arms ability to raise and flex, and nighttime sleep was impacted. After applying the analgesic patch externally, the symptoms did not improve. No coughing or sputum production, chest tightness, shortness of breath, acid reflux, belching, abdominal pain, distension, diarrhea, backache, hematuria, black or bloody feces, or other discomforts appeared over the course of the illness. The patient had a particular type of bone metastases from primary cancers with genetic test results indicating EGFR amplification and mutation. A third-generation tyrosine kinase inhibitors drug, oral Osimertinib 80 mg once a day with bisphosphonates anti-bone destruction treatment was performed on schedule. Following treatment, the patients tumor-related symptoms were significantly improved by controlling the disease for up to 11 months and providing great pain relief. EGFR-based genetic testing has emerged as a key measure for targeted therapy in non-small cell lung cancer. However, there are fewer relevant studies for other tumor types like BMCUP. Combined with literature reviews and our report, we provide evidence that targeting EGFR mutations according to the basket theory for the treatment of BMCUP is effective.

NCAPD2 is a novel marker for the poor prognosis of lung adenocarcinoma and is associated with immune infiltration and tumor mutational burden.

Lung adenocarcinoma (LUAD) is at present the most prevalent subtype of lung cancer worldwide. Non-SMC condensin I complex subunit D2 (NCAPD2) is one of the 3 non-SMC subunits in condensin I. Previous studies have confirmed that NCAPD2 plays a critical role in chromosome cohesion and segregation. NCAPD2 may be involved in tumorigenesis and progression by participating in abnormal cell cycle division, but the prognostic value of NCAPD2 in LUAD remains unclear. We investigated differences in the expression levels of NCAPD2 and determined their association with clinical features, as well as their diagnostic and prognostic value using the cancer genome atlas database. The function of NCAPD2 was analyzed using gene ontology, Kyoto encyclopedia of genes and genomes, and gene set enrichment analysis. CIBERSORT, single-sample gene set enrichment analysis, and ESTIMATE were used to analyze the immune microenvironment of tumor patients. Tumor mutational burden (TMB) and immune checkpoints were analyzed, while hub genes were identified using weighted gene coexpression network analysis and were used to construct prognostic models. Subsequently, the competing endogenous RNAs network of NCAPD2 in LUAD was explored. Finally, we performed qPCR to verify differences in NCAPD2 expression between the tumor and normal tissues. The expression of NCAPD2 in LUAD was significantly upregulated compared with normal lung tissues. NCAPD2 has been linked to the T stage, N stage, and tumor stage. The elevated expression of NCAPD2 in LUAD can predict a poor prognosis. Functional enrichment analysis indicated that the main function of NCAPD2 was in cell cycle regulation. Moreover, NCAPD2 was also associated with immune cell infiltration and TMB. NCAPD2 is a novel prognostic marker in LUAD and is associated with immune infiltration and TMB.

First-in-Human Study of OBI-999, a Globo H-Targeting Antibody-Drug Conjugate, in Patients With Advanced Solid Tumors.

OBI-999 is a novel antibody-drug conjugate comprising the Globo H-targeting antibody (OBI-888) linked to the cytotoxic payload monomethyl auristatin E. OBI-999 demonstrated excellent dose-dependent tumor growth inhibition in breast, gastric, and pancreatic cancer xenograft models as well as a lung cancer patient-derived xenograft model. We conducted a phase I study of OBI-999 monotherapy in patients with advanced cancer (ClinicalTrials.gov identifier NCT04084366). OBI-999 was administered intravenously at doses of 0.4, 0.8, 1.2, and 1.6 mgkg every 21 days as part of a 3 3 trial design. Primary end points were the incidence of dose-limiting toxicities and adverse events and determination of the maximum tolerated dose (MTD)recommended phase II dose. Fifteen adult patients were treated. OBI-999 was well tolerated up to 1.2 mgkg, the maximum tolerated dose. The most common treatment-emergent adverse events were neutropenia and anemia. OBI-999 exhibited nonlinear pharmacokinetics at all doses, with lower clearance at higher doses. The three patients treated at the 1.6 mgkg dose level developed grade 4 neutropenia during cycles 1 and 2. Five (33.3%) patients had stable disease (SD) including one patient with adenoid cystic carcinoma of the oropharynx with SD for 13 cycles and one patient with gastroesophageal junction adenocarcinoma with SD for eight cycles. OBI-999 was well tolerated however, dose-dependent, noncumulative neutropenia was dose-limiting. The recommended phase II dose was determined to be 1.2 mgkg once every 3 weeks. A phase II cohort-expansion study is now enrolling patients with pancreatic, colorectal, and other cancers expressing high levels of Globo H.

Pixel-Level Classification of Five Histologic Patterns of Lung Adenocarcinoma.

Lung adenocarcinoma is the most common histologic type of lung cancer. The pixel-level labeling of histologic patterns of lung adenocarcinoma can assist pathologists in determining tumor grading with more details than normal classification. We manually annotated a dataset containing a total of 1000 patches (200 patches for each pattern) of 512 × 512 pixels and 420 patches (contains test sets) of 1024 × 1024 pixels according to the morphological features of the five histologic patterns of lung adenocarcinoma (lepidic, acinar, papillary, micropapillary, and solid). To generate an even large amount of data patches, we developed a data stitching strategy as a data augmentation for classification in model training. Stitched patches improve the Dice similarity coefficient (DSC) scores by 24.06% on the whole-slide image (WSI) with the solid pattern. We propose a WSI analysis framework for lung adenocarcinoma pathology, intelligently labeling lung adenocarcinoma histologic patterns at the pixel level. Our framework contains five branches of deep neural networks for segmenting each histologic pattern. We test our framework with 200 unclassified patches. The DSC scores of our results outpace comparing networks (U-Net, LinkNet, and FPN) by up to 10.78%. We also perform results on four WSIs with an overall accuracy of 99.6%, demonstrating that our network framework exhibits better accuracy and robustness in most cases.

Machine learning for prediction of in-hospital mortality in lung cancer patients admitted to intensive care unit.

The in-hospital mortality in lung cancer patients admitted to intensive care unit (ICU) is extremely high. This study intended to adopt machine learning algorithm models to predict in-hospital mortality of critically ill lung cancer for providing relative information in clinical decision-making. Data were extracted from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) for a training cohort and data extracted from the Medical Information Mart for eICU Collaborative Research Database (eICU-CRD) database for a validation cohort. Logistic regression, random forest, decision tree, light gradient boosting machine (LightGBM), eXtreme gradient boosting (XGBoost), and an ensemble (random forestLightGBMXGBoost) model were used for prediction of in-hospital mortality and important feature extraction. The AUC (area under receiver operating curve), accuracy, F1 score and recall were used to evaluate the predictive performance of each model. Shapley Additive exPlanations (SHAP) values were calculated to evaluate feature importance of each feature. Overall, there were 653 (24.8%) in-hospital mortality in the training cohort, and 523 (21.7%) in-hospital mortality in the validation cohort. Among the six machine learning models, the ensemble model achieved the best performance. The top 5 most influential features were the sequential organ failure assessment (SOFA) score, albumin, the oxford acute severity of illness score (OASIS) score, anion gap and bilirubin in random forest and XGBoost model. The SHAP summary plot was used to illustrate the positive or negative effects of the top 15 features attributed to the XGBoost model. The ensemble model performed best and might be applied to forecast in-hospital mortality of critically ill lung cancer patients, and the SOFA score was the most important feature in all models. These results might offer valuable and significant reference for ICU clinicians decision-making in advance.

Radiolabeled Biodistribution of Expansile Nanoparticles Intraperitoneal Administration Results in Tumor Specific Accumulation.

Nanoparticle biodistribution

Association Between Age and Survival Trends in Advanced Non-Small Cell Lung Cancer After Adoption of Immunotherapy.

The introduction of immune checkpoint inhibitors (ICIs) has transformed the care of advanced non-small cell lung cancer (NSCLC). Although clinical trials suggest substantial survival benefits, it is unclear how outcomes have changed in clinical practice. To assess temporal trends in ICI use and survival among patients with advanced NSCLC across age strata. This cohort study was performed in approximately 280 predominantly community-based US cancer clinics and included patients aged 18 years or older who had stage IIIB, IIIC, or IV NSCLC diagnosed between January 1, 2011, and December 31, 2019, with follow-up through December 31, 2020. Data were analyzed April 1, 2021, to October 19, 2022. Median overall survival and 2-year survival probability. The predicted probability of 2-year survival was calculated using a mixed-effects logit model adjusting for demographic and clinical characteristics. The study sample included 53 719 patients (mean SD age, 68.5 9.3 years 28 374 men 52.8%), the majority of whom were White individuals (36 316 67.6%). The overall receipt of cancer-directed therapy increased from 69.0% in 2011 to 77.2% in 2019. After the first US Food and Drug Administration approval of an ICI for NSCLC, the use of ICIs increased from 4.7% in 2015 to 45.6% in 2019 (P < .001). Use of ICIs in 2019 was similar between the youngest and oldest patients (aged <55 years, 45.2% vs aged ≥75 years, 43.8% P .59). From 2011 to 2018, the predicted probability of 2-year survival increased from 37.7% to 50.3% among patients younger than 55 years and from 30.6% to 36.2% in patients 75 years or older (P < .001). Similarly, median survival in patients younger than 55 years increased from 11.5 months to 16.0 months during the study period, while survival among patients 75 years or older increased from 9.1 months in 2011 to 10.2 months in 2019. This cohort study found that, among patients with advanced NSCLC, the uptake of ICIs after US Food and Drug Administration approval was rapid across all age groups. However, corresponding survival gains were modest, particularly in the oldest patients.

Neoadjuvant Immunotherapy for Patients With Non-Small Cell Lung Cancer-Is a New Era Coming

The Viepoint discusses several points regarding whether there is enough data to accept neoadjuvant immunotherapy as a daily practice for patients with operable non–small cell lung cancer.

The endothelial-enriched lncRNA LINC00607 mediates angiogenic function.

Long non-coding RNAs (lncRNAs) can act as regulatory RNAs which, by altering the expression of target genes, impact on the cellular phenotype and cardiovascular disease development. Endothelial lncRNAs and their vascular functions are largely undefined. Deep RNA-Seq and FANTOM5 CAGE analysis revealed the lncRNA LINC00607 to be highly enriched in human endothelial cells. LINC00607 was induced in response to hypoxia, arteriosclerosis regression in non-human primates, post-atherosclerotic cultured endothelial cells from patients and also in response to propranolol used to induce regression of human arteriovenous malformations. siRNA knockdown or CRISPRCas9 knockout of LINC00607 attenuated VEGF-A-induced angiogenic sprouting. LINC00607 knockout in endothelial cells also integrated less into newly formed vascular networks in an in vivo assay in SCID mice. Overexpression of LINC00607 in CRISPR knockout cells restored normal endothelial function. RNA- and ATAC-Seq after LINC00607 knockout revealed changes in the transcription of endothelial gene sets linked to the endothelial phenotype and in chromatin accessibility around ERG-binding sites. Mechanistically, LINC00607 interacted with the SWISNF chromatin remodeling protein BRG1. CRISPRCas9-mediated knockout of BRG1 in HUVEC followed by CUTRUN revealed that BRG1 is required to secure a stable chromatin state, mainly on ERG-binding sites. In conclusion, LINC00607 is an endothelial-enriched lncRNA that maintains ERG target gene transcription by interacting with the chromatin remodeler BRG1 to ultimately mediate angiogenesis.

Inhibition of STAT6 with Antisense Oligonucleotides Enhances the Systemic Antitumor Effects of Radiotherapy and Anti-PD1 in Metastatic Non-Small Cell Lung Cancer.

Diverse factors contribute to the limited clinical response to radiotherapy (RT) and immunotherapy in metastatic non-small cell lung cancer (NSCLC), among which is the ability of these tumors to recruit a retinue of suppressive immune cells - such as M2 tumor-associated macrophages (TAMs) - thereby establishing an immunosuppressive-tumor microenvironment that contributes to tumor progression and radio-resistance. M2 TAMs are activated by the signal transducer and activator of transcription 6 (STAT6) signaling pathway. Therefore, we targeted STAT6 using an antisense oligonucleotide (ASO) along with hypofractionated RT (hRT) (3 fractions of 12 Gy each) to primary tumors in three bilateral murine NSCLC models (Lewis lung carcinoma, 344SQ-parental, and anti-PD1-resistant 344SQ lung adenocarcinomas). We found that STAT6 ASO plus hRT slowed growth of both primary and abscopal tumors, decreased lung metastases, and extended survival. Interrogating the mechanism of action showed reduced M2 macrophage tumor infiltration, enhanced TH1 polarization, improved T cell and macrophage function, and decreased TGFβ levels. The addition of anti-PD-1 further enhanced systemic antitumor responses. These results provide a pre-clinical rationale for the pursuit of an alternative therapeutic approach for patients with immune-resistant NSCLC.

Comprehensive analysis of SARS-CoV-2 receptor proteins in human respiratory tissues identifies alveolar macrophages as potential virus entry site.

COVID-19 has had enormous consequences on global health care and resulted in millions of fatalities. The exact mechanism and site of SARS-CoV-2 entry into the body remains insufficiently understood. Recently, novel virus receptors were identified, and alveolar macrophages were suggested as a potential viral entry cell type and vector for intra-alveolar virus transmission. Here, we investigated the protein expression of ten well-known and novel virus entry molecules along potential entry sites in humans using immunohistochemistry. Samples of different anatomic sites from up to 93 patients were incorporated into tissue microarrays. Protein expression of ACE2, TMPRSS2, furin, CD147, C-type lectin receptors (CD169, CD209, CD299), neuropilin-1, ASGR1 and KREMEN1 were analyzed. In lung tissues, at least one of the three receptors ACE2, ASGR1 or KREMEN1 was expressed in the majority of cases. Moreover, all of the investigated molecules were found to be expressed in alveolar macrophages, and colocalization with SARS-CoV-2 N-protein was demonstrated using dual immunohistochemistry in lung tissue from a COVID-19 autopsy. While CD169 and CD209 showed consistent protein expression in sinonasal, conjunctival and bronchiolar tissues, neuropilin-1 and ASGR1 were mostly absent, suggesting a minor relevance of these two molecules at these specific sites. Our results extend recent discoveries indicating a role for these molecules in virus entry at different anatomic sites. Moreover, they support the notion of alveolar macrophages being a potential entry cell for SARS-CoV-2.

Cost-effectiveness of nivolumab plus ipilimumab versus chemotherapy as first-line therapy in advanced non-small cell lung cancer.

First-line treatment with nivolumab plus ipilimumab has been shown to improve overall survival (OS) and progression-free survival (PFS) for patients with advanced non-small cell lung cancer (NSCLC). The current study evaluated the cost-effectiveness of nivolumab plus ipilimumab versus chemotherapy in advanced NSCLC from the perspective of Chinese healthcare system. A three state-transition Markov model was employed to evaluate the cost and effectiveness of nivolumab plus ipilimumab versus chemotherapy in the first-line treatment of advanced NSCLC. Key clinical data in the model were derived from Part 1 of the phase 3 CheckMate 227 trial (NCT02477826). Costs and utilities were obtained from published literatures. The main endpoints of the model were costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were performed to assess the model uncertainty. Nivolumab plus ipilimumab was associated with an increase in overall cost of $95,867.82 and improved effectiveness of 0.98 QALYs compared with chemotherapy, yielding an ICER of $97,676.24 per QALY. In one-way sensitivity analysis, the variables that had the greatest influence on the ICER were hazard ratio for OS and body weight. In probabilistic analysis, nivolumab plus ipilimumab had a 0% probability of being cost-effective at a willingness-to-pay (WTP) threshold of $37,663.26QALY in China. However, the combination therapy would become cost-effective when the cost of nivolumab and ipilimumab were discounted by 65%. First-line nivolumab plus ipilimumab treatment for advanced NSCLC was found to be not cost-effective compared with chemotherapy at a WTP threshold of $37,663.26QALY in China.

Opioid medication use and blood DNA methylation epigenome-wide association meta-analysis.

Distinguishing Brain Metastasis Progression From Radiation Effects After Stereotactic Radiosurgery Using Longitudinal GRASP Dynamic Contrast-Enhanced MRI.

Differentiating brain metastasis progression from radiation effects or radiation necrosis (RN) remains challenging. Golden-angle radial sparse parallel (GRASP) dynamic contrast-enhanced MRI provides high spatial and temporal resolution to analyze tissue enhancement, which may differ between tumor progression (TP) and RN. To investigate the utility of longitudinal GRASP MRI in distinguishing TP from RN after gamma knife stereotactic radiosurgery (SRS). We retrospectively evaluated 48 patients with brain metastasis managed with SRS at our institution from 2013 to 2020 who had GRASP MRI before and at least once after SRS. TP (n 16) was pathologically confirmed. RN (n 16) was diagnosed on either resected tissue without evidence of tumor or on lesion resolution on follow-up. As a reference, we included a separate group of patients with non-small-cell lung cancer that showed favorable response with tumor control and without RN on subsequent imaging (n 16). Mean contrast washin and washout slopes normalized to the superior sagittal sinus were compared between groups. Receiver operating characteristic analysis was performed to determine diagnostic performance. After SRS, progression showed a significantly steeper washin slope than RN on all 3 follow-up scans (scan 1 0.29 ± 0.16 vs 0.18 ± 0.08, P .021 scan 2 0.35 ± 0.19 vs 0.18 ± 0.09, P .004 scan 3 0.32 ± 0.12 vs 0.17 ± 0.07, P .002). No significant differences were found in the post-SRS washout slope. Post-SRS washin slope differentiated progression and RN with an area under the curve (AUC) of 0.74, a sensitivity of 75%, and a specificity of 69% on scan 1 an AUC of 0.85, a sensitivity of 92%, and a specificity of 69% on scan 2 and an AUC of 0.87, a sensitivity of 63%, and a specificity of 100% on scan 3. Longitudinal GRASP MRI may help to differentiate metastasis progression from RN.

Origin recognition complex subunit 1 (ORC1) augments malignant behaviors of lung adenocarcinoma cells via targeting Wnt signaling.

It has been reported that origin recognition complex subunit 1 (ORC1) plays an oncogenic role in certain human cancers. Nevertheless, its regulatory function in lung adenocarcinoma (LUAD) progression was poorly understood. In this study, gene and protein levels were measured via RT-qPCR and Western blotting. LUAD cell viability, apoptosis, and metastasis were determined via CCK-8, TUNEL, and Transwell assays. Bioinformatics analyses were performed using Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases. Herein, it was revealed that ORC1 was evidently upregulated and positively correlated to unsatisfactory prognosis in LUAD. Besides, single-sample gene set enrichment analysis (ssGSEA) revealed that ORC1 is negatively associated with 17 immune infiltrating cells and differently expressed in several kinds of immune cells. Also, Gene Ontology (GO) analysis indicated the involvement of ORC1 in several molecular functions. In addition,

Efficacy and safety of carboplatin and etoposide in older extensive-stage small-cell lung cancer patients with a poor performance status.

Carboplatin plus etoposide is a standard treatment for older extensive-stage small-cell lung cancer (ES-SCLC) patients with performance status (PS) 2. However, older patients often exhibit poor PS (3, 4), and the treatment effect in them is poorly understood. To determine the therapeutic efficacy and safety of carboplatin plus etoposide therapy for this population, we retrospectively analyzed 63 patients with ES-SCLC with PS ≥2, aged ≥71 years, who had received first-line carboplatin plus etoposide therapy. We compared the treatment efficacy and safety in patients with baseline PS 2 versus those with PS 3-4. In the PS 2 (38 patients) and PS ≥3 (25 patients) groups, the overall response rate was 71.1% and 72.0%, median progression-free survival was 4.6 and 3.1 months, and overall survival was 7.7 and 5.1 months, respectively. PS improved to 0-1 post-treatment in 65.8% and 48.0% of the patients in the PS 2 and PS ≥3 groups, respectively. Patients with PS ≥3 showing improved PS had a progression-free survival of 6.1 months. A higher incidence of grade ≥3 decreased neutrophil counts, febrile neutropenia, and treatment-related death was observed in the PS ≥3 group. The progression-free survival of patients administered prophylactic granulocyte colony-stimulating factor (G-CSF) was 5.2 and 6.1 months in the PS2 and PS ≥3 groups. Overall, carboplatin plus etoposide therapy provided comparable tumor shrinkage, but shorter progression-free and overall survival in older ES-SCLC patients with PS ≥3 than in those with PS 2. Thus, supportive care, such as prophylactic G-CSF administration, may be necessary to ensure safety and survival.

Cannabinoid receptor 2 plays a pro-tumorigenic role in non-small cell lung cancer by limiting anti-tumor activity of CD8

Cannabinoid (CB) receptors (CB

Intratumoral STING activation causes durable immunogenic tumor eradication in the KP soft tissue sarcoma model.

Soft tissue sarcomas (STS) are highly metastatic, connective-tissue lineage solid cancers. Immunologically, sarcomas are frequently characterized by a paucity of tumor infiltrating lymphocytes and an immune suppressive microenvironment. Activation of the STING pathway can induce potent immune-driven anti-tumor responses within immunogenic solid tumors however, this strategy has not been evaluated in immunologically cold sarcomas. Herein, we assessed the therapeutic response of intratumoral STING activation in an immunologically cold murine model of undifferentiated pleomorphic sarcoma (UPS). A single intratumoral injection of the murine STING agonist, DMXAA resulted in durable cure in up to 60% of UPS-bearing mice. In mice with synchronous lung metastases, STING activation within hindlimb tumors resulted in 50% cure in both anatomic sites. Surviving mice all rejected UPS re-challenge in the hindlimb and lung. Therapeutic efficacy of STING was inhibited by lymphocyte deficiency but unaffected by macrophage deficiency. Immune phenotyping demonstrated enrichment of lymphocytic responses in tumors at multiple timepoints following treatment. Immune checkpoint blockade enhanced survival following STING activation. These data suggest intratumoral activation of the STING pathway elicits local and systemic anti-tumor immune responses in a lymphocyte poor sarcoma model and deserves further evaluation as an adjunctive local and systemic treatment for sarcomas.

Study of the clinicopathological features of soluble PD-L1 in lung cancer patients.

Regulation of the Inflammatory Response, Proliferation, Migration, and Epithelial-Mesenchymal Transition of Human Lens Epithelial Cells by the lncRNA-MALAT1miR-26a-5pTET1 Signaling Axis.

The ocular inflammatory microenvironment has been reported to be closely associated with the occurrence and progression of highly myopic cataract (HMC). Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) could alter the biological properties of mammalian cells by modulating the expression of inflammatory mediators therefore, it may contribute to the development of HMC. To investigate the function of MALAT1 in the inflammatory response, proliferation, migration, and epithelial-mesenchymal transition (EMT) of inflammatory and injured human lens epithelial cells (HLECs) and to reveal the underlying molecular signals. Patients with HMC and age-related cataract (ARC) with an axial length of more than 26 mm were selected, and the anterior capsular tissue was obtained during cataract surgery. TNF- The expression of MALAT1 and the inflammatory mediators IL-6, MMP-2, and MMP-9 were significantly higher in HMC anterior capsule tissues than in ARC. TNF- The inflammatory environment and MALAT1 expression could be reciprocally induced in HLECs. MALAT1 may act as a ceRNA via the sponge miR-26a-5p and target TET1 to regulate the inflammatory response, proliferation, migration, and EMT processes in HLECs.

Trachea repair using an autologous pericardial patch combined with a 3D carbon fiber stent A case report.

This study is the first to use an autologous pericardial patch combined with a 3D carbon fiber stent for the plastic repair of a large trachea defect. Radical surgery is the optimal therapy for primary malignant tracheal tumors. Tracheoplasty or repair is required to guarantee trachea integrity and normal ventilation function after tracheal tumor resection. Here, we present a case of plastic repair of the trachea using an autologous pericardial patch and a 3D custom-made carbon fiber stent. A 4 cm trachea defect was successfully repaired after resecting a malignant schwannoma. The postoperative ventilatory function was normal without obvious symptoms of discomfort. Fiberoptic bronchoscopy showed a smooth mucosal surface of the endotracheal wall and patency of the airway. CT scans performed 3 years after surgery showed no recurrence. Therefore, we can conclude that a 3D carbon fiber stent is feasible for abolishing patch floating and preventing tracheal stenosis.

Prognostic value of preoperative modified Glasgow prognostic score in surgical non-small cell lung cancer A meta-analysis.

The predictive role of modified Glasgow prognostic score (mGPS) for long-term survival in several types of cancers has been well manifested. We supposed that preoperative mGPS might also be associated with long-term survival of operated non-small cell lung cancer (NSCLC) patients. The aim of this meta-analysis was to identify the prognostic value of preoperative mGPS in surgical NSCLC patients. The PubMed, Web of Science, EMBASE and CNKI databases were searched for relevant studies up to November 7, 2022. The primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS), respectively. The hazard ratios (HRs) and 95% confidence intervals (CIs) were combined. A total of 3,803 patients from 11 studies were enrolled and analyzed. The combined results demonstrated elevated preoperative mGPS was significantly related to poorer OS (HR 2.11, 95% CI 1.83-2.44, Preoperative mGPS was significantly associated with prognosis in NSCLC and patients with elevated preoperative mGPS experienced poorer long-term survival.

Synchronous Diagnosis of Squamous Cell Carcinoma of the Lung and Mixed Cellularity Hodgkin Lymphoma of the Nasopharynx.

Hodgkin lymphoma (HL) is a highly curable B cell lymphoproliferative neoplasm with a bimodal age distribution. Lung cancer is the leading cause of cancer-related deaths in both sexes. We present a rare case of synchronous squamous cell carcinoma (SCC) of the lung and mixed cellularity HL of the nasopharynx. A gentleman in his 70s presented with right-sided chest pain and shortness of breath. CT of the chest showed a peripheral lung mass, and a biopsy confirmed SCC of the lung. The patient underwent a positron emission tomographycomputed tomography (PETCT) for staging that revealed an

5-mRNA-based prognostic signature of survival in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common non-small-cell lung cancer, with a high incidence and a poor prognosis. To construct effective predictive models to evaluate the prognosis of LUAD patients. In this study, we thoroughly mined LUAD genomic data from the Gene Expression Omnibus (GEO) (GSE43458, GSE32863, and GSE27262) and the Cancer Genome Atlas (TCGA) datasets, including 698 LUAD and 172 healthy (or adjacent normal) lung tissue samples. Univariate regression and LASSO regression analyses were used to screen differentially expressed genes (DEGs) related to patient prognosis, and multivariate Cox regression analysis was applied to establish the risk score equation and construct the survival prognosis model. Receiver operating characteristic curve and Kaplan-Meier survival analyses with clinically independent prognostic parameters were performed to verify the predictive power of the model and further establish a prognostic nomogram. A total of 380 DEGs were identified in LUAD tissues through GEO and TCGA datasets, and 5 DEGs (TCN1, CENPF, MAOB, CRTAC1 and PLEK2) were screened out by multivariate Cox regression analysis, indicating that the prognostic risk model could be used as an independent prognostic factor (Hazard ratio 1.520, A 5-mRNA-based model was constructed to predict the prognosis of lung adenocarcinoma, which may provide clinicians with reliable prognostic assessment tools and help clinical treatment decisions.

Expanded NK cells used for adoptive cell therapy maintain diverse clonality and contain long-lived memory-like NK cell populations.

Multiple clinical trials exploring the potential of adoptive natural killer (NK) cell therapy for cancer have employed

The role of serine metabolism in lung cancer From oncogenesis to tumor treatment.

Metabolic reprogramming is an important hallmark of malignant tumors. Serine is a non-essential amino acid involved in cell proliferation. Serine metabolism, especially the

Pan-cancer analysis identifies proteasome 26S subunit, ATPase (PSMC) family genes, and related signatures associated with prognosis, immune profile, and therapeutic response in lung adenocarcinoma.

Screening and identifying a novel M-MDSCs-related gene signature for predicting prognostic risk and immunotherapeutic responses in patients with lung adenocarcinoma.

PBRM1 mutation as a predictive biomarker for immunotherapy in multiple cancers.

DenVar density-based variation analysis of multiplex imaging data.

Multiplex imaging platforms have become popular for studying complex single-cell biology in the tumor microenvironment (TME) of cancer subjects. Studying the intensity of the proteins that regulate important cell-functions becomes extremely crucial for subject-specific assessment of risks. The conventional approach requires selection of two thresholds, one to define the cells of the TME as positive or negative for a particular protein, and the other to classify the subjects based on the proportion of the positive cells. We present a threshold-free approach in which distance between a pair of subjects is computed based on the probability density of the protein in their TMEs. The distance matrix can either be used to classify the subjects into meaningful groups or can directly be used in a kernel machine regression framework for testing association with clinical outcomes. The method gets rid of the subjectivity bias of the thresholding-based approach, enabling easier but interpretable analysis. We analyze a lung cancer dataset, finding the difference in the density of protein HLA-DR to be significantly associated with the overall survival and a triple-negative breast cancer dataset, analyzing the effects of multiple proteins on survival and recurrence. The reliability of our method is demonstrated through extensive simulation studies. The associated Supplementary data are available at

Learning from small medical data-robust semi-supervised cancer prognosis classifier with Bayesian variational autoencoder.

Cancer is one of the worlds leading mortality causes, and its prognosis is hard to predict due to complicated biological interactions among heterogeneous data types. Numerous challenges, such as censorship, high dimensionality and small sample size, prevent researchers from using deep learning models for precise prediction. We propose a robust Semi-supervised Cancer prognosis classifier with bAyesian variational autoeNcoder ( The source codes reproducing the main results are available on GitHub httpsgitfront.ioruser-431667336e8714573f3fbfa0b24690af5d1a9d5ca159cf4scan. Supplementary data are available at

PARP inhibition utilized in combination therapy with Olaparib-Temozolomide to achieve disease stabilization in a rare case of BRCA1-mutant, metastatic myxopapillary ependymoma.

Myxopapillary ependymoma (MPE) is a primary tumor of the central nervous system (CNS), characteristically an indolent malignancy involving the spinal conus medullaris, Filum terminale or cauda equina. We present a rare case of MPE, recurrent in the pelvic soft tissue with eventual pleural and intra-pulmonary metastasis. Refractory to repeated gross resection, adjuvant radiotherapy, platinum-based chemotherapy and temozolomide exploitation of mutant somatic BRCA1 status with the addition of a poly (ADP-ribose) polymerase inhibitor (PARPi) in a novel combination regimen with olaparib-temozolomide (OT) has achieved stable radiological disease after 10 cycles.

A Primary Lung and Breast Cancer Patient with Germline

For advanced non-small cell lung cancer (NSCLC) patients with common epidermal growth factor receptor (

Toxic epidermal necrosis associated with afatinib A case report and literature review.

To report a case of afatinib-induced toxic epidermal necrosis (TEN), in a patient with metastatic non-small cell lung cancer (NSCLC) and compare these findings with that of evaluate similarities and differences to other cases reported in the literature. With use of the algorithm of drug causality for epidermal necrolysis (ALDEN), the effects of afatinib were evaluated in a NSCLC patient who developed TEN. In addition, previous case reports on this topic were included to provide a review of patients clinical characteristics, treatment regimens and therapy outcomes in response to afatinib treatment. In our case, toxic epidermal necrolysis was observed at five days after afatinib therapy, while other Stevens-Johnson syndrometoxic epidermal necrolysis responses, as associated with afatinib, did not seem to be induced until a latency period of over thirty days post-afatinib. Treatment with corticosteroids resulted in significant improvements of these clinical symptoms, and eventually to a complete remission. Afatinib can result in grade four cutaneous adverse effects like SJSTEN, with an uncertain latency period. The skin lesions which appear during this period of afatinib treatment should be closely monitored.

Successful treatment of a patient with advanced lung adenocarcinoma (EGFR-T790M and C797S cis) with lazertinib A case report and literature review.

Lazertinib has been shown to treat non-small cell lung cancer (NSCLC) patients with EGFR-T790M, Ex19del, and L858R mutations. However, there are still no studies to prove that lazertinib could be used in patients with EGFR-T790M and C797s cis mutations in NSCLC. We report a case of a patient with advanced lung adenocarcinoma with EGFR-T790M and C797s cis mutations who were treated with lazertinib and achieved satisfactory efficacy without serious side effects. And the scratch assay and colony-forming unit assay were performed using lung adenocarcinoma cells from patients, the results showed that both lazertinib and amivantamab could inhibit the proliferation and migration of lung adenocarcinoma cells to some extent, and the inhibitory effect of lazertinib was better than that of amivantamab (

Prediction of bone metastasis in non-small cell lung cancer based on machine learning.

The purpose of this paper was to develop a machine learning algorithm with good performance in predicting bone metastasis (BM) in non-small cell lung cancer (NSCLC) and establish a simple web predictor based on the algorithm. Patients who diagnosed with NSCLC between 2010 and 2018 in the Surveillance, Epidemiology and End Results (SEER) database were involved. To increase the extensibility of the research, data of patients who first diagnosed with NSCLC at the First Affiliated Hospital of Nanchang University between January 2007 and December 2016 were also included in this study. Independent risk factors for BM in NSCLC were screened by univariate and multivariate logistic regression. At this basis, we chose six commonly machine learning algorithms to build predictive models, including Logistic Regression (LR), Decision tree (DT), Random Forest (RF), Gradient Boosting Machine (GBM), Naive Bayes classifiers (NBC) and eXtreme gradient boosting (XGB). Then, the best model was identified to build the web-predictor for predicting BM of NSCLC patients. Finally, area under receiver operating characteristic curve (AUC), accuracy, sensitivity and specificity were used to evaluate the performance of these models. A total of 50581 NSCLC patients were included in this study, and 5087(10.06%) of them developed BM. The sex, grade, laterality, histology, T stage, N stage, and chemotherapy were independent risk factors for NSCLC. Of these six models, the machine learning model built by the XGB algorithm performed best in both internal and external data setting validation, with AUC scores of 0.808 and 0.841, respectively. Then, the XGB algorithm was used to build a web predictor of BM from NSCLC. This study developed a web predictor based XGB algorithm for predicting the risk of BM in NSCLC patients, which may assist doctors for clinical decision making.

Research landscape and trends of melanoma immunotherapy A bibliometric analysis.

Immunotherapy for lung cancer has been a hot research area for years. This bibliometric analysis was intended to present research trends on melanoma immunotherapy. On April 1, 2022, the authors identified 2,109 papers on melanoma immunotherapy using the Web of Science and extracted their general information and the total number of citations. The authors then conducted a bibliometric analysis to present the research landscape, clarify the research trends, and determine the most cited papers (top-papers) as well as major journals on melanoma immunotherapy. Subsequently, recent research hotspots were identified by analyzing the latest articles in major journals. The total and median number of citations of these 2,109 papers on melanoma immunotherapy was 137,686 and 11, respectively. Improved survival with ipilimumab in patients with metastatic melanoma by Hodi et al. was the most cited paper (9,824 citations). Among the journals, the top-paper number (16), average citations per paper (2,510.7), and top-papers rate (100%) of This bibliometric analysis comprehensively and quantitatively presents the research trends and hotspots based on 2,109 relevant publications, and further suggests future research directions. The researchers can benefit in selecting journals and in finding potential collaborators. This study can help researchers gain a comprehensive impression of the research landscape, historical development, and current hotspots in melanoma immunotherapy and can provide inspiration for future research.

Cardiac toxicity in patients with lung cancer receiving thoracic radiotherapy and immunotherapy.

Immune checkpoint inhibitors (ICIs) are used to treat locally-advanced and metastatic lung cancer, which can lead to severe immunogenic-related cardiotoxicities. We assessed the risk of cardiotoxicity in ICI-treated lung cancer patients with or without cardiac radiation from thoracic radiotherapy. Retrospective data was collected on Stage III-IV lung cancer patients who received ICIs between 2015 and 2018. All cardiotoxicities associated with ICI were assessed in correlation with the timing of radiotherapy (RT) in relation to ICI, and the mean RT heart dose. The rate of cardiac events in relation to RT timing and heart dose was compared using multiple logistic regression including the Framingham risk score and steroid use prior to ICI therapy. Of 194 ICI-treated patients evaluated, 55.2% (n107194) patients had received thoracic RT at a median dose of 60.4 Gy (range, 15-75). Cardiotoxicities such as non-ST elevated myocardial infarction and new onset supraventricular tachycardias were observed in 13 (12.2%) of those who had thoracic RT versus 9 (10.3%) who did not (p0.87). 38 patients who received RT concurrently with ICI did not develop any cardiotoxicity whereas 14.1% (n22156) of those who did not receive concurrent RT developed cardiotoxicities (univariate, p0.030 multivariate, p0.055). There were no significant differences in the mean heart RT dose, Framingham risk score, and steroid treatment between patients that received concurrent RT with ICI versus non-concurrent RTICI. ICI-related cardiotoxicities were not significantly associated with patients who received concurrent thoracic radiotherapy in this retrospective review. Further validation of prospective studies is needed to confirm these results.

Investigation of racial differences in survival from non-small cell lung cancer with immunotherapy use A Texas study.

The use of immunotherapy is associated with improved survival among patients with Non-Small Cell Lung Cancer (NSCLC) and has gained widespread use in its management. However, there is limited information on whether the survival benefits associated with immunotherapy differ among races and ethnicities. This study aimed to investigate racial differences in survival amongst patients with NSCLC who received immunotherapy as the first-line treatment in Texas. Patients with NSCLC who received immunotherapy between October 2015 to December 2018 were identified from the Texas Cancer Registry (TCR). Disease-specific survival was evaluated and compared among patients across racialethnic categories using the Kaplan-Meier survival analysis, log-rank test, and a multivariable Cox proportional hazard regression model following an inverse probability treatment weighting (IPTW) propensity score analysis. A total of 1453 patients were included in the analysis. Median survival (in months) was longest among Asians (34, 95% CI 15-Not Estimable), followed by African Americans (AAs) (23, 95% CI 15-34), Hispanics (22, 95% CI 16-26), and Whites (19, 95% CI 17-22). The adjusted regression estimates had no statistically significant differences in survival among AAs (aHR 0.97 95% CI 0.78-1.20 P 0.77) and Hispanics (aHR 0.96 95% CI 0.77-1.19, P 0.73) when compared to White patients. Asians on the other hand, had 40% reduction in mortality risk compared to Whites (aHR 0.60 95% CI 0.39-0.94, P 0.03). Our study indicated that African Americans and Hispanics do not have poorer survival compared to White patients when receiving immunotherapy as first-line treatment. Asians however had longer survival compared to Whites. Our findings suggest that existing racial disparity in NSCLC survival might be mitigated with the use of immunotherapy and should be considered in providing care to these minority groups.

Efficacy and safety of bevacizumab biosimilar compared with reference bevacizumab in locally advanced and advanced non-small cell lung cancer patients A retrospective study.

Bevacizumab has played an important role in the systemic treatment of patients with advanced non-small-cell lung cancer (NSCLC) without gene mutation. In recent years, bevacizumab biosimilar has received marketing approval based on the results of phase III clinical studies. However, more clinical data are needed to verify the efficacy and safety of bevacizumab biosimilar in clinical application. We identified 946 patients with locally advanced or metastatic NSCLC who were treated with bevacizumab biosimilar or bevacizumab from January 1, 2019 to November 30, 2021. Comparisons and statistical analyses of bevacizumab biosimilar and bevacizumab were made in terms of efficacy and safety. Efficacy evaluation was performed directly in accordance with RECIST v1.1. Adverse events were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. The objective response rates (ORRs) were 28.9% in the biosimilar group (n551) and 30.9% in the reference group (n395 unstratified ORR risk ratio 0.934, 95% confidence interval CI 0.677-1.138 unstratified ORR risk difference -0.020, 95% CI -0.118-0.035). The estimated median progression-free survival (mPFS) were 6.27 (95% CI 5.53-7.01) and 4.93 (95% CI 4.24-5.62) months in the biosimilar and reference groups, respectively ( Bevacizumab biosimilar is equivalent in efficacy to bevacizumab in patients with locally advanced and advanced NSCLC. It showed acceptable toxicity profile and no new adverse events. Patients who were excluded by clinical trials can also benefit from bevacizumab biosimilar.

Engineered Microparticles for Treatment of Murine Brain Metastasis by Reprograming Tumor Microenvironment and Inhibiting MAPK Pathway.

Brain metastases (BRM) are common in advanced lung cancer. However, their treatment is challenging due to the blood-brain barrier (BBB) and the immunosuppressive tumor microenvironment (ITME). Microparticles (MPs), a type of extracellular vesicle, can serve as biocompatible drug delivery vehicles that can be further modulated with genetic engineering techniques. MPs prepared from cells induced with different insults are compared and it is found that radiation-treated cell-released microparticles (RMPs) achieve optimal targeting and macrophage activation. The enzyme ubiquitin-specific protease 7 (USP7), which simultaneously regulates tumor growth and reprograms M2 macrophages (M2Φ), is found to be expressed in BRM. Engineered RMPs are then constructed that comprise 1) the RMP carrier that targets and reprograms M2Φ 2) a genetically expressed SR-B1-targeting peptide for improved BBB permeability and 3) a USP7 inhibitor to kill tumor cells and reprogram M2Φ. These RMPs successfully cross the BBB and target M2Φ in vitro and in vivo in mice, effectively reprogramming M2Φ and improving survival in a murine BRM model. Therapeutic effects are further augmented when combined with immune checkpoint blockade. This study provides proof-of-concept for the use of genetically engineered MPs for the treatment of BRM.

Alvopem

Lung cancer is the leading cause of cancer deaths worldwide in both men and women, and non-small cell lung cancer (NSCLC) accounts for the majority ( 85%) of lung cancers. This post-marketing surveillance (PMS) study aimed to evaluate the safety of Pemetrexed (Alvopem The present study is an observational, single-center, open-label, and post-authorization study. All eligible non-squamous NSCLC and malignant pleural mesothelioma (MPM) patients who received pemetrexed based on the physicians decision, were enrolled. A total of 199 patients with non-squamous NSCLC 186 patients (93.47%) or MPM (12 patients (6.03%) were enrolled from March 2016 to February 2020. The most common reported adverse event (AE) was anemia (89.39%), followed by neutropenia (28.79%) and leukopenia (24.75%). The most important grade 3 AEs were anemia and neutropenia, with the incidence rate of 3.54% and 7.58%, respectively. No grade 4 AEs were reported. Moreover, the results of our study showed negative statistically significant correlations between patients age and mean neutrophil count (r - 0.17 P 0.0156) and hemoglobin (r - 0.16 P 0.0201) in all six visits. The results of this open-label, observational PMS showed that Pemetrexed (Alvopem The trial was registered at ClinicalTrials.gov (NCT04843007) in April 13th, 2021.

Mutations in the MET tyrosine kinase domain and resistance to tyrosine kinase inhibitors in non-small-cell lung cancer.

The Mesenchymal epithelial transition factor (MET) gene encodes a receptor tyrosine kinase with pleiotropic functions in cancer. MET exon 14 skipping alterations and high-level MET amplification are oncogenic and targetable genetic changes in patients with non-small-cell lung cancer (NSCLC). Resistance to tyrosine kinase inhibitors (TKIs) has been a major challenge for targeted therapies that impairs their clinical efficacies. Eighty-six NSCLC patients were categorized into three cohorts based on the time of detecting MET tyrosine kinase domain (TKD) mutations (cohort 1 at baseline cohort 2 after MET-TKI treatment cohort 3 after EGFR-TKI treatment). Baseline and paired TKI treatment samples were analyzed by targeted next-generation sequencing. MET TKD mutations were highly prevalent in METex14-positive NSCLC patients after MET-TKI treatment, including L1195V, D1228NHYE, Y1230CHNS, and a double-mutant within codons D1228 and M1229. Missense mutations in MET TKD were also identified at baseline and in post-EGFR-TKI treatment samples, which showed different distribution patterns than those in post-MET-TKI treatment samples. Remarkably, H1094Y and L1195F, absent from MET-TKI-treated patients, were the predominant type of MET TKD mutations in patients after EGFR-TKI treatment. D1228H, which was not found in treatment-naïve patients, also accounted for 14.3% of all MET TKD mutations in EGFR-TKI-treated samples. Two patients with baseline EGFR-sensitizing mutations who acquired MET-V1092I or MET-H1094Y after first-line EGFR-TKI treatment experienced an overall improvement in their clinical symptoms, followed by targeted therapy with MET-TKIs. MET TKD mutations were identified in both baseline and patients treated with TKIs. MET-H1094Y might play an oncogenic role in NSCLC and may confer acquired resistance to EGFR-TKIs. Preliminary data indicates that EGFR-mutated NSCLC patients who acquired MET-V1092I or MET-H1094Y may benefit from combinatorial therapy with EGFR-TKI and MET-TKI, providing insights into personalized medical treatment.

Prognostic significance of frailty status in patients with primary lung cancer.

Lung cancer has one of the highest morbidity and mortality rates in the world. Frailty is common in many countries and is a major cause of premature functional decline and premature death in older adults, and may affect the treatment and prognosis of lung cancer patients. To investigate the predictive value of frailty at diagnosis on all-cause mortality in lung cancer patients, this study retrospectively collected and analysed clinical information on lung cancer patients from 2015-2018. A total of 1667 patients with primary lung cancer were finally included in this study. The median follow-up time of patients was 650 (493, 1001.5) days. A total of 297(17.8%) patients had FI-LAB(the frailty index based on laboratory test) status of frail at the moment of diagnosis and the all-cause mortality rate for all patients was 61.1% (10181667). In a univariate model, we found a higher total all-cause mortality risk in frail patients (frail vs. robust, HR(hazard ratio) 1.616, 95% CI(confidence interval) 1.349,1.936), after balancing other variables combined into model 1 to model 6. The results were analyzed visually using ROC(Receiver operating characteristic) curves with nomogram and the AUC values ranged from 0.866-0.874. The final inclusion of age, TNM stage, CCI(Charlson comorbidity index) score, surgery history and chemotherapy into a multifactorial model balanced the predictive power of frailty grading on all-cause mortality. The study showed that for lung cancer patients, the higher the level of frailty at diagnosis, the higher the risk of all-cause mortality. In the context of widespread electronic medical records in hospitals, it is convenient and feasible to use FI-LAB to assess the prognosis of lung cancer patients.

Real world practice of postoperative radiotherapy for patients with completely resected pIIIA-N2 non-small cell lung cancer a national survey of radiation oncologists in China.

Results from Lung ART and PORT-C trials suggest that postoperative radiotherapy (PORT) cannot routinely be recommended as standard treatment in completely resected pIIIA-N2 NSCLC patients, but their effects on the real-world practice of PORT in China remain unclear. A national cross-section survey was conducted by using an online survey service. Participants were voluntarily recruited using a river sampling strategy. A link to the survey was posted on websites of radiation oncologist associations and tweets from public WeChat accounts. The survey collected the real names of participants to ensure that they were board-certified radiation oncologists. A total of 484 radiation oncologists were included with a median age of 40 years (IQR, 35-47). A total of 377 (77.9%) participants were male, and 282 (58.1%) had more than 10 years of clinical experience practicing thoracic radiotherapy. Before Lung ART and PORT-C trials were published, 313 (64.7%) respondents recommended PORT, 11 (2.3%) did not recommend it, and 160 (33.1%) reported that they made decisions based on risk factors. After the presentation of two trials, only 42 (8.7%) did not recommend PORT, while 108 (22.3%) recommended it, and 334 (69.0%) made decisions based on risk factors. The five most commonly considered risk factors among these 334 respondents were as follows nodal extracapsular extension, the highest lymph node (LN) station involved, the number of dissected mediastinal LN stations, the number of positive mediastinal LN stations, and surgical approaches. In addition, the majority of all 484 respondents recommended a total dose of 50 Gy, lung stump ipsilateral hilus regions containing positive LNs as the targeted region, lung V20 < 25%, and heart V30 < 40% as dose constraints for PORT. Most Chinese radiation oncologists recommended PORT for completely resected IIIA-N2 NSCLC patients based on risk factors, especially status of LN station.

Bleeding after endobronchial biopsy sometimes frightening, often safe, always careful.

We explain to Dr. Govindasaamis several comments on our published article Association between blood pressure and the risk of biopsy-induced endobronchial hemorrhage during bronchoscopy.

Peripheral blood lymphocytes differentiation patterns in responses outcomes to immune checkpoint blockade therapies in non-small cell lung cancer a retrospective study.

Programmed Cell Death-1 Programmed Death-ligand 1 (PD-1 PD-L1) inhibitor therapies targeting immunocytes induce persistent tumor remission in various cancers. However, the appropriate biomarkers for the therapeutic efficacy of PD-L1 and PD-1 blockade remain elusive. For a comprehensive analysis of peri-treatment lymphocyte differentiation, in the current study, we enrolled 146 non-small cell lung cancer patients who received α-PD-1 therapies for exploring the peripheral blood lymphocyte differentiation pattern at baseline and post-treatment (dynamic changes) by flow cytometry. At baseline, CD4 Patients with favorable clinical responses outcomes have distinctive peripheral blood immunocyte differentiation characteristics, indicating the potential of utilizing the peripheral immunocyte differentiation patterns for predicting ICB responses outcomes.

CYTOR Promotes Proliferation of Lung Cancer Cell by Targeting miR-103a-3p to Upregulate HMGB1.

Lung cancer is one of the most dangerous malignant tumors to human health in the world. Previous researches have shown that cytoskeleton regulator RNA (CYTOR), a long noncoding RNA was involved in the occurrence and development of various types of cancer. The aim of this study is to investigate the clinical significance and biological function of CYTOR in lung cancer. Real-time quantitative PCR was applied to detect the expression of CYTOR. The proliferation of A549 and H1299 cells was analyzed by CCK8 assay. The luciferase reporter assay and RNA pull-down assay were used to reveal the interactions between CYTOR and its downstream targets. Western blot was used to detect the expression of high-mobility group protein B1 (HMGB1). Here we found CYTOR was upregulated in lung cancer tissues and cell lines. The proliferation of A549 and H1299 cells was inhibited after CYTOR silencing. In addition, CYTOR could directly interact with and negatively regulate miR-103a-3p, and miR-103a-3p inhibited cell proliferation by targeting HMGB1. The CYTORmiR-103a-3pHMGB1 axis promoted lung cancer cell proliferation. CYTOR sponges miR-103a-3p to promote the proliferation of lung cancer cells through HMGB1. The CYTORmiR-103a-3pHMGB1 axis plays a critical role in the progression of lung cancer.

Pacritinib inhibits glucose consumption in squamous cell lung cancer cells by targeting FLT3.

Squamous cell lung cancer maintains its growth through elevated glucose consumption, but selective glucose consumption inhibitors are lacking. Here, we discovered using a high-throughput screen new compounds that block glucose consumption in three squamous cell lung cancer cell lines and identified 79 compounds that block glucose consumption in one or more of these cell lines. Based on its ability to block glucose consumption in all three cell lines, pacritinib, an inhibitor of FMS Related Receptor Tyrosine Kinase 3 (FLT3) and Janus Kinase 2 (JAK2), was further studied. Pacritinib decreased glucose consumption in squamous cell lung cancer cells in cell culture and in vivo without affecting glucose consumption in healthy tissues. Pacritinib blocked hexokinase activity, and Hexokinase 1 and 2 mRNA and protein expression. Overexpression of Hexokinase 1 blocked the ability of pacritinib to inhibit glucose consumption in squamous cell lung cancer cells. Overexpression of FLT3 but not JAK2 significantly increased glucose consumption and blocked the ability of pacritinib to inhibit glucose consumption in squamous cell lung cancer cells. Additional FLT3 inhibitors blocked glucose consumption in squamous cell lung cancer cells. Our study identifies FLT3 inhibitors as a new class of inhibitors that can block glucose consumption in squamous cell lung cancer.

Characterization of circSCL38A1 as a novel oncogene in bladder cancer via targeting ILF3TGF-β2 signaling axis.

The regulatory role of circRNAs in cancer metastasis has become a focused issue in recent years. To date, however, the discovery of novel functional circRNAs and their regulatory mechanisms via binding with RBPs in bladder cancer (BC) are still lacking. Here, we screened out circSLC38A1 based on our sequencing data and followed validation with clinical tissue samples and cell lines. Functional assays showed that circSLC38A1 promoted BC cell invasion in vitro and lung metastasis of mice in vivo. By conducting RNA pull-down, mass spectrum, and RIP assays, circSLC38A1 was found to interact with Interleukin enhancer-binding factor 3 (ILF3), and stabilize ILF3 protein via modulating the ubiquitination process. By integrating our CUTTag-seq and RNA-seq data, TGF-β2 was identified as the functional target of the circSLC38A1-ILF3 complex. In addition, m6A methylation was enriched in circSLC38A1 and contributed to its upregulation. Clinically, circSLC38A1 was identified in serum exosomes of BC patients and could distinguish BC patients from healthy individuals with a diagnostic accuracy of 0.878. Thus, our study revealed an essential role and clinical significance of circSLC38A1 in BC via activating the transcription of TGF-β2 in an ILF3-dependent manner, extending the understanding of the importance of circRNA-mediated transcriptional regulation in BC metastasis.

Primary salivary duct carcinoma of the lung clinicopathological features, diagnosis and practical challenges.

To investigate the clinicopathological features, molecular characteristics and diagnostic criteria of primary salivary duct carcinoma of the lung (LSDC). We analysed the clinicopathological and molecular features of five cases of LSDC retrieved from the archives of Shanghai Pulmonary Hospital from 2020 to 2022, and reviewed the relevant literature. All patients were men, with an average age of 66 years (age range 49-79 years), and all lesions were central masses with a mean maximum diameter of 42.6 mm (range 16-70 mm). Morphologically, LSDC comprised of intraductal and invasive components. Both the intraductal and invasive components of LSDC can exhibit papillary, micropapillary, cribriform, tubule structures and solid proliferation. The intraductal component can exhibit Roman bridge structures, which were usually accompanied by central comedo-like necrosis. Immunohistochemically, LSDCs consistently expressed cytokeratin (CK)7 (5 of 5) and showed variable positivity of androgen receptor (AR) (5 of 5) focally or diffusely additionally, the tumour cells expressed human epidermal growth factor receptor 2 (HER2) (3, n3 2, n2), GATA-binding protein 3 (3 of 5), and gross cystic disease fluid protein-15 (1 of 5), and all of which were negative for thyroid transcription factor-1, napsin A, p40, CK56 and p63. The residual basalmyoepithelial cells surrounding the in situ carcinoma expressed p40, CK56 and p63. TP53 mutation and HER2 gene amplification (3 of 5) were the most frequent genetic alterations in LSDC. All patients who underwent surgical lobectomies were alive without recurrence or metastasis. LSDC is a highly rare malignant tumour. The distinctive architecture of in situ carcinoma and tumour cells expressing AR can provide diagnostic indications for LSDC.

Cause-Specific Mortality in Patients With Advanced Chronic Kidney Disease in the ISCHEMIA-CKD Trial.

In ISCHEMIA-CKD, 777 patients with advanced chronic kidney disease and chronic coronary disease had similar all-cause mortality with either an initial invasive or conservative strategy (27.2% vs 27.8%, respectively). This prespecified secondary analysis from ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) was conducted to determine whether an initial invasive strategy compared with a conservative strategy decreased the incidence of cardiovascular (CV) vs non-CV causes of death. Three-year cumulative incidences were calculated for the adjudicated cause of death. Overall and cause-specific death by treatment strategy were analyzed using Cox models adjusted for baseline covariates. The association between cause of death, risk factors, and treatment strategy were identified. A total of 192 of the 777 participants died during follow-up, including 94 (12.1%) of a CV cause, 59 (7.6%) of a non-CV cause, and 39 (5.0%) of an undetermined cause. The 3-year cumulative rates of CV death were similar between the invasive and conservative strategies (14.6% vs 12.6%, respectively HR 1.13, 95% CI 0.75-1.70). Non-CV death rates were also similar between the invasive and conservative arms (8.4% and 8.2%, respectively HR 1.25 95% CI 0.75-2.09). Sudden cardiac death (46.8% of CV deaths) and infection (54.2% of non-CV deaths) were the most common cause-specific deaths and did not vary by treatment strategy. In ISCHEMIA-CKD, CV death was more common than non-CV or undetermined death during the 3-year follow-up. The randomized treatment assignment did not affect the cause-specific incidences of death in participants with advanced CKD and moderate or severe myocardial ischemia. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease ISCHEMIA-CKD NCT01985360).

Somatostatin Receptor PETMR Imaging of Inflammation in Patients With Large Vessel Vasculitis and Atherosclerosis.

Assessing inflammatory disease activity in large vessel vasculitis (LVV) can be challenging by conventional measures. We aimed to investigate somatostatin receptor 2 (SST In a prospective, observational cohort study, in vivo arterial SST Sixty-one participants (LVV n 27 recent atherosclerotic myocardial infarction of ≤2 weeks n 25 control subjects with an oncologic indication for imaging n 9) were included. Index vessel SST SST

Cumulative Incidence of Thromboembolism and Prognostic Impact of Stroke in

Cancer and ischemic stroke are closely associated. Thromboembolism susceptibility in lung cancer may differ depending on oncogenic alterations. However, the clinical characteristics of thromboembolism in patients with BRAF-mutant non-small-cell lung cancer remain unknown. Thus, this study aimed to evaluate the cumulative incidence of thromboembolism in this population and describe such cases in detail. We retrospectively investigated consecutive patients with BRAF V600E-mutant non-small-cell lung cancer. Cumulative incidence was calculated using a competing risk analysis. Of 10 patients with BRAF-V600E mutant lung cancer, five developed a total of seven thromboembolic events, showing a 1-year cumulative incidence of 43% (95% confidence interval11-72%). These events consisted of four cancer-related stroke (CRS) events and three venous events including deep vein thrombosis or pulmonary embolism. Of note, most of the early thrombotic events were CRS. Two patients with CRS had multiple brain infarctions during anticancer drug therapy, characterized by high D-dimer levels, resulting in short-term mortality (13 and 22 days after stroke onset). A substantial proportion of patients with BRAF V600E-mutant lung cancer experienced thromboembolism during their disease course. CRS of undetermined source may predict a worse prognosis in this population.

Intramedullary Spinal Cord Metastases from Breast Cancer A Systematic Review.

Intramedullary spinal cord metastases (ISCM) are deemed extremely aggressive, as confirmed by the low life expectancy since the diagnosis. Up to 26.5% of total ISCM stem from breast cancer (BC), representing the second most frequent primary site after the lung. The increasing incidence of BC and the widespread use of MRI for the diagnosis could therefore lead to an earlier diagnosis and, therefore, to a progressively longer survival in patients affected by ISCM from BC. This systematic review is intended to provide an orientation through a management algorithm for the most appropriate therapeutic approach in these patients. The research strategy initially relied on title and abstract analysis. The articles full text was retrieved for further investigation if the title and abstract met the inclusion criteria. The extracted data included the following authors, publication time, study design, patient characteristics, ISCM location, treatment modalities, time interval from initial cancer diagnosis to ISCM diagnosis, clinical outcomes, and survival time. This systematic search regarding ISCM from BC yielded 574 articles. After screening, a total of 44 studies were included in this systematic review. A total of 123 patients were evaluated. The mean patient age was 53.2 years with a standard deviation of 10.4 years. Female patients were 122. There was only one male patient. ISCM from BC have a better prognosis than lung metastases and, thanks to recent advances in diagnostic imaging and intraoperative planning and neuromonitoring, an early diagnosis and a prompt multidisciplinary treatment may be accomplished. Prospective studies to generate evidence-based data regarding the most appropriate treatment for ISCM are mandatory.