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A modifiable universal cotinine-chimeric antigen system of NK cells with multiple targets.

Natural killer (NK) cells are immune effector cells with outstanding features for adoptive immunotherapy. Immune effector cells with chimeric antigen receptors (CARs) are promising targeted therapeutic agents for various diseases. Because tumor cells exhibit heterogeneous antigen expression and lose cell surface antigen expression during malignant progression, many CARs fixed against only one antigen have limited efficacy and are associated with tumor relapse. To expand the utility of CAR-NK cells, we designed a split and universal cotinine-CAR (Cot-CAR) system, comprising a Cot-conjugator and NK92 cells (α-Cot-NK92 cells) engineered with a CAR containing an anti-Cot-specific single-chain variable fragment and intracellular signaling domain. The efficacy of the Cot-CAR system was assessed

Integrated analysis of transcription factor-mRNA-miRNA regulatory network related to immune characteristics in medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC), a thyroid C cell-derived malignancy, is poorly differentiated and more aggressive than papillary, follicular and oncocytic types of thyroid cancer. The current therapeutic options are limited, with a third of population suffering resistance. The differential gene expression pattern among thyroid cancer subtypes remains unclear. This study intended to explore the exclusive gene profile of MTC and construct a comprehensive regulatory network via integrated analysis, to uncover the potential key biomarkers. Multiple datasets of thyroid and other neuroendocrine tumors were obtained from GEO and TCGA databases. Differentially expressed genes (DEGs) specific in MTC were identified to construct a transcription factor (TF)-mRNA-miRNA network. The impact of the TF-mRNA-miRNA network on tumor immune characteristics and patient survival was further explored by single-sample GSEA (ssGSEA) and ESTIMATE algorithms, as well as univariate combined with multivariate analyses. RT-qPCR, cell viability and apoptosis assays were performed for in vitro validation. We identified 81 genes upregulated and 22 downregulated in MTC but not in other types of thyroid tumor compared to the normal thyroid tissue. According to the L1000CDS2 database, potential targeting drugs were found to reverse the expressions of DEGs, with panobinostat (S1030) validated effective for tumor repression in MTC by in vitro experiments. The 103 DEGs exclusively seen in MTC were involved in signal release, muscle contraction, pathways of neurodegeneration diseases, neurotransmitter activity and related amino acid metabolism, and cAMP pathway. Based on the identified 15 hub genes, a TF-mRNA-miRNA linear network, as well as REST-cored coherent feed-forward loop networks, namely REST-KIF5C-miR-223 and REST-CDK5R2-miR-130a were constructed via online prediction and validation by public datasets and our cohort. Hub-gene, TF and miRNA scores in the TF-mRNA-miRNA network were related to immune score, immune cell infiltration and immunotherapeutic molecules in MTC as well as in neuroendocrine tumor of lung and neuroblastoma. Additionally, a high hub-gene score or a low miRNA score indicated good prognoses of neuroendocrine tumors. The present study uncovers underlying molecular mechanisms and potential immunotherapy-related targets for the pathogenesis and drug discovery of MTC.

Cooperative ETS Transcription Factors Enforce Adult Endothelial Cell Fate and Cardiovascular Homeostasis.

Current dogma dictates that during adulthood, endothelial cells (ECs) are locked in an immutable stable homeostatic state. By contrast, herein we show that maintenance of EC fate and function are linked and active processes, which depend on the constitutive cooperativity of only two ETS-transcription factors (TFs) ERG and Fli1. While deletion of either Fli1 or ERG manifest subtle vascular dysfunction, their combined genetic deletion in adult EC results in acute vasculopathy and multiorgan failure, due to loss of EC fate and integrity, hyperinflammation, and spontaneous thrombosis, leading to death. ERG and Fli1 co-deficiency cause rapid transcriptional silencing of pan- and organotypic vascular core genes, with dysregulation of inflammation and coagulation pathways. Vascular hyperinflammation leads to impaired hematopoiesis with myeloid skewing. Accordingly, enforced ERG and FLI1 expression in adult human mesenchymal stromal cells activates vascular programs and functionality enabling engraftment of perfusable vascular network. GWAS-analysis identified vascular diseases are associated with FLI1Erg mutations. Constitutive expression of ERG and Fli1 uphold EC fate, physiological function, and resilience in adult vasculature while their functional loss can contribute to systemic human diseases.

SCCPMD Probability matrix decomposition method subject to corrected similarity constraints for inferring long non-coding RNA-disease associations.

Accumulating evidence has demonstrated various associations of long non-coding RNAs (lncRNAs) with human diseases, such as abnormal expression due to microbial influences that cause disease. Gaining a deeper understanding of lncRNA-disease associations is essential for disease diagnosis, treatment, and prevention. In recent years, many matrix decomposition methods have also been used to predict potential lncRNA-disease associations. However, these methods do not consider the use of microbe-disease association information to enrich disease similarity, and also do not make more use of similarity information in the decomposition process. To address these issues, we here propose a correction-based similarity-constrained probability matrix decomposition method (SCCPMD) to predict lncRNA-disease associations. The microbe-disease associations are first used to enrich the disease semantic similarity matrix, and then the logistic function is used to correct the lncRNA and disease similarity matrix, and then these two corrected similarity matrices are added to the probability matrix decomposition as constraints to finally predict the potential lncRNA-disease associations. The experimental results show that SCCPMD outperforms the five advanced comparison algorithms. In addition, SCCPMD demonstrated excellent prediction performance in a case study for breast cancer, lung cancer, and renal cell carcinoma, with prediction accuracy reaching 80, 100, and 100%, respectively. Therefore, SCCPMD shows excellent predictive performance in identifying unknown lncRNA-disease associations.

High Expression of DLGAP5 Indicates Poor Prognosis and Immunotherapy in Lung Adenocarcinoma and Promotes Proliferation through Regulation of the Cell Cycle.

Lung adenocarcinoma (LUAD) is one of the most common types of cancer in the respiratory system, with a high mortality and recurrence rate. The role of disc large-associated protein 5 (DLGAP5) in LUAD progression and tumor microenvironment (TME) remains unclear. This study is aimed at revealing the functional role of DLGAP5 in LUAD based on bioinformatics analysis and experimental validation. Differential expression analysis, protein-protein interaction (PPI) network, and Cox regression analysis were applied to screen potential prognostic biomarkers. The mRNA and protein levels of DLGAP5 were analyzed using The Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA) databases. The CCK-8 and colony formation assays were performed to assess the effect of DLGAP5 on cell proliferation. RNA sequencing (RNA-seq) and enrichment analyses were utilized to explore the biological functions of DLGAP5. Furthermore, flow cytometry was used to explore the role of DLGAP5 on the cell cycle. The ssGSEA algorithm in the R package GSVA was applied to quantify immune infiltrating cells, and the tumor immune dysfunction and exclusion (TIDE) algorithm was used to predict the efficacy of immunotherapy. Moreover, analyses using the cBioPortal and MethSurv databases were performed to evaluate the mutation and methylation of DLGAP5, respectively. Finally, the prognostic value of DLGAP5 was estimated using the TCGA and the Gene Expression Omnibus (GEO) databases. The nomogram model was constructed using the TCGA-LUAD cohort and evaluated by adopting calibration curves, time-dependent receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). DLGAP5 mRNA and protein abundance were significantly elevated in LUAD, and knockdown of DLGAP5 remarkably suppressed lung cancer cell proliferation through induction of cell cycle G1 arrest. In addition, DLGAP5 expression was positively correlated with Th2 cells and negatively correlated with B cells, T follicular helper cells, and mast cells. LUAD patients with high DLGAP5 expression may be resistant to immunotherapy. Hypermethylation levels of the cg23678254 site of DLGAP5 or its enhanced expression were unfavorable for the survival of LUAD patients. Meanwhile, DLGAP5 expression was associated with TNM stages, tumor status, and therapy outcome. Notably, the prognostic model constructed based on DLGAP5 expression exhibited great predictive capability, which was promising for clinical applications. DLGAP5 promotes lung cancer cell proliferation through regulation of the cell cycle and is associated with multiple immune infiltrating cells. Furthermore, DLGAP5 predicts poor prognosis and response to immunotherapy in lung adenocarcinoma.

Identification of two molecular subtypes and a novel prognostic model of lung adenocarcinoma based on a cuproptosis-associated gene signature.

Lung adenocarcinoma is the most common subtype of lung cancer clinically, with high mortality and poor prognosis. Cuproptosis present a newly discovered mode of cell death characterized by aggregation of fatty acylated proteins, depletion of iron-sulfur clusterin, triggering of HSP70, and induction of intracellular toxic oxidative stress. However, the impact of cuproptosis on lung adenocarcinoma development, prognosis, and treatment has not been elucidated. By systematically analyzing the genetic alterations of 10 cuproptosis-related genes in lung adenocarcinoma, we found that CDKN2A, DLAT, LIAS, PDHA1, FDX1, GLS, and MTF1 were differentially expressed between lung cancer tissues and adjacent tissues. Based on the expression levels of 10 cuproptosis-related genes, we classified lung adenocarcinoma patients into two molecular subtypes using the Consensus clustering method, of which subtype 2 had a worse prognosis. Differential expression genes associated with prognosis between the two subtypes were obtained by differential analysis and survival analysis, and cox lasso regression was applied to construct a cuproptosis-related prognostic model. Its survival predicting ability was validated in three extrinsic validation cohorts. The results of multivariate cox analysis indicated that cuproptosis risk score was an independent prognostic predictor, and the mixed model formed by cupproptosis prognostic model combined with stage had more robust prognostic prediction accuracy. We found the differences in cell cycle, mitosis, and p53 signaling pathways between high- and low-risk groups according to GO and KEGG enrichment analysis. The results of immune microenvironment analysis showed that the enrichment score of activated dendritic cells, mast cells, and type 2 interferon response were down-regulated in the high-risk group, while the fraction of neutrophils and M0 macrophages were upregulated in the high-risk group. Compared with the high-risk group, subjects in the low-risk group had higher Immunophenoscore and may be more sensitive to immunotherapy. We identified seven chemotherapy agents may improve the curative effect in LUAD samples with higher risk score. Overall, we discovered that cuproptosis is closely related to the occurrence, prognosis, and treatment of lung adenocarcinoma. The cuproptosis prognostic model is a potential prognostic predictor and may provide new strategies for precision therapy in lung adenocarcinoma.

Accuracy of Classifying Lung Carcinoma Using Immunohistochemical Markers on Limited Biopsy Material A Two-Center Study.

Introduction Accurate classification of lung cancer into primary and metastatic carcinomas is critical for treatment approaches. Immunohistochemistry (IHC) has always been pivotal in unveiling the diverse cell differentiation lineages present in lung cancer by using specific biomarkers such as TTF1 and p63p40, which closely reflect the relationship between genotype and phenotype.. Methods A retrospective cross-sectional study was conducted to evaluate 57 Tru-Cut biopsies over two years, from 2020-2022. Tumour morphology was evaluated, and IHC for TTF-1, Napsin A, CK-7, P-63, P-40, and CD-56 was performed in two steps. Results Of the lung cancer cases, 58.5% were adenocarcinoma (ADC), 24.5% were squamous cell carcinoma (SCC), 9.4% were small cell carcinoma, and 7.5% were poorly differentiated carcinoma. TTF1 stain had sensitivity and specificity of 78.9% and 50% in 33 cases of ADC, respectively, while CK7 and Napsin A had 100% sensitivity. P63 stain had 77% sensitivity and 50% specificity in 15 cases of SCC, while P-40 had 100% sensitivity. The CD56 stain was 100% sensitive in five cases of small cell carcinoma. Conclusion IHC staining on small lung biopsies allows accurate sub-classification of poorly differentiated lung cancers however, there is still significant variability. Surgical resection specimens can be further classified due to architectural features that biopsies lack. Morphological findings would be beneficial in the development of an algorithm for sub-classifying lung carcinoma using a variety of markers.

Natural product manoalide promotes EGFR-TKI sensitivity of lung cancer cells by KRAS-ERK pathway and mitochondrial Ca

Open questions in human lung organoid research.

Organoids have become a prominent model system in pulmonary research. The ability to establish organoid cultures directly from patient tissue has expanded the repertoire of physiologically relevant preclinical model systems. In addition to their derivation from adult lung stemprogenitor cells, lung organoids can be derived from fetal tissue or induced pluripotent stem cells to fill a critical gap in modelling pulmonary development

A single high-dose irradiation changes accumulation of methotrexate and gene expression levels of SLC and ABC transporters in cancer cells.

Chemoradiotherapy is frequently used to treat cancer. Stereotactic body radiotherapy (SBRT) is a single high-dose radiotherapy used to treat a variety of cancers. The anticancer drug methotrexate (MTX) shows affinity for solute carrier (SLC) and ATP-binding cassette (ABC) transporters. This study investigated relationships between accumulation of methotrexate and gene expression levels of solute carrier and ATP-binding cassette transporters in cancer cells after a single and high-dose X-ray irradiation. Cancer cell lines were selected from lung and cervical cancer cell line that are commonly used for stereotactic body radiotherapy and effective with methotrexate. We examined expression levels of organic anion-transporting polypeptide (OATP)1B1, OATP1B3, OATP1B7, and organic anion transporter (OAT)1 as solute carrier transporters and multidrug resistance-associated protein (MRP)1 and MRP2 as ATP-binding cassette transporters, using real-time polymerase chain reaction and accumulation of

Crosstalk between microwave ablation and ferroptosis The next hot topic

Microwave ablation has been one form of thermal ablation in treatments for many tumors, which can locally control unresectable tumors. Ferroptosis is iron-dependent cell death caused by the cumulative reactive oxygen species and lipid peroxidation products. Recently, increasing evidence has shown that ferroptosis might play a vital role in MWA-induced tumor suppression. In this article, we briefly illustrate the concept of ferroptosis, the related signal pathways and inducers, the basic principle of microwave ablation in killing tumors, and the key molecules released after microwave ablation. Then, we describe the cross-talking molecules between microwave ablation and ferroptosis, and discussed the potential mechanism of microwave ablation-induced ferroptosis. This review explores the therapeutic target of ferroptosis in enhancing the systemic antitumor effect after microwave ablation, providing theoretical support in combinational microwave ablation with pro-ferroptosis therapy.

Association between radiotherapy and risk of death from cardiovascular diseases in lung and bronchus cancer.

Radiotherapy plays an important role in the treatment of lung cancer. However, radiation-related deaths from cardiovascular disease (CVD) are a concern in these patients, and few studies have examined CVD-related death associated with lung cancer. We aimed to evaluate the risk of CVD-related death after radiotherapy in patients with lung and bronchus cancer. Data were extracted from the surveillance, epidemiology, and end results database. Propensity score matching (PSM) was applied to reduce possible bias between patients who received radiotherapy and those who did not. The Kaplan-Meier method was used to estimate cardiovascular-specific survival (CVSS), and the log-rank test was used to compare CVSS between the radiotherapy and no radiotherapy groups. Cox proportional hazards regression analysis was performed to estimate the hazard ratio (HR) of CVD-related death. A total of 225,570 patients with lung and bronchus cancer were included, and 201,282 patients remained after PSM. Radiotherapy was identified as an independent risk factor for CVSS among patients with lung and bronchus cancer before PSM (HR 1.18, Radiotherapy is associated with an increased risk of CVD-related death, especially death from heart disease, in patients with lung and bronchus cancer. More efforts are needed to monitor cardiovascular health after radiotherapy.

Malignant retroperitoneal PEComa A case report with emphasis on radiological findings.

A perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm with distinctive perivascular epithelioid cells that usually demonstrates myomelanocytic differentiation. PEComas can arise in various organs and generally are benign. Uncommonly PEComas have been documented to be malignant with metastasis most frequently to the lung, liver, lymph nodes, and bone. Here, we present the case of a 59-year-old male with a malignant retroperitoneal PEComa with confirmed metastasis to the femur and suspected metastasis to the liver and lung. The purpose of this case study is to present the progression and findings of a metastatic malignant PEComa.

Somatic mutation but not aneuploidy differentiates lung cancer in never-smokers and smokers.

Lung cancer in never-smokers disproportionately affects older women. To understand the mutational landscape of this cohort, we performed detailed genome characterization of 73 lung adenocarcinomas from participants of the Women’s Health Initiative (WHI). We find enrichment of

Ferroptosis Promotes Pulmonary Hypertension.

The accumulation of iron-dependent lipid peroxides induces ferroptosis, a nonapoptotic form of cell death that integrates metabolic derangements with oxidative stress

MCB-613 exploits a collateral sensitivity in drug resistant

Targeted therapies have revolutionized cancer chemotherapy. Unfortunately, most patients develop multifocal resistance to these drugs within a matter of months. Here, we used a high-throughput phenotypic small molecule screen to identify MCB-613 as a compound that selectively targets

EpiMix an integrative tool for epigenomic subtyping using DNA methylation.

DNA methylation (DNAme) is a major epigenetic factor influencing gene expression with alterations leading to cancer, immunological, and cardiovascular diseases. Recent technological advances enable genome-wide quantification of DNAme in large human cohorts. So far, existing methods have not been evaluated to identify differential DNAme present in large and heterogeneous patient cohorts. We developed an end-to-end analytical framework named EpiMix for population-level analysis of DNAme and gene expression. Compared to existing methods, EpiMix showed higher sensitivity in detecting abnormal DNAme that was present in only small patient subsets. We extended the model-based analyses of EpiMix to cis-regulatory elements within protein-coding genes, distal enhancers, and genes encoding microRNAs and lncRNAs. Using cell-type specific data from two separate studies, we discovered novel epigenetic mechanisms underlying childhood food allergy and survival-associated, methylation-driven non-coding RNAs in non-small cell lung cancer.

Small cell lung cancer co-culture organoids provide insights into cancer cell survival after chemotherapy.

Small-cell-lung-cancer (SCLC) has the worst prognosis of all lung cancers because of a high incidence of relapse after therapy. We developed a bioengineered 3-dimensional (3D) SCLC co-culture organoid as a phenotypic tool to study SCLC tumor kinetics and SCLC-fibroblast interactions during relapse. We used functionalized alginate microbeads as a scaffold to mimic lung alveolar architecture and co-cultured SCLC cell lines with primary adult lung fibroblasts (ALF). We found that SCLCs in the model proliferated extensively, invaded the microbead scaffold and formed tumors within just 7 days. We compared the bioengineered tumors with patient tumors and found them to recapitulate the pathology and immunophenotyping of the patient tumors better than the PDX model developed from the same SCLC cell line. When treated with standard chemotherapy drugs, etoposide and cisplatin, the organoid recapitulated relapse after chemotherapy. Co-culture of the SCLC cells with ALFs revealed that the fibroblasts play a key role in inducing faster and more robust SCLC cell regrowth in the model. This was a paracrine effect as conditioned medium from the same fibroblasts was responsible for this accelerated cell regrowth. This model is also amenable to high throughput phenotypic or targeted drug screening to find new therapeutics for SCLC.

Functional microRNA-Targeting Drug Discovery by Graph-Based Deep Learning.

MicroRNAs are recognized as key drivers in many cancers, but targeting them with small molecules remains a challenge. We present RiboStrike, a deep learning framework that identifies small molecules against specific microRNAs. To demonstrate its capabilities, we applied it to microRNA-21 (miR-21), a known driver of breast cancer. To ensure the selected molecules only targeted miR-21 and not other microRNAs, we also performed a counter-screen against DICER, an enzyme involved in microRNA biogenesis. Additionally, we used auxiliary models to evaluate toxicity and select the best candidates. Using datasets from various sources, we screened a pool of nine million molecules and identified eight, three of which showed anti-miR-21 activity in both reporter assays and RNA sequencing experiments. One of these was also tested in mouse models of breast cancer, resulting in a significant reduction of lung metastases. These results demonstrate RiboStrike’s ability to effectively screen for microRNA-targeting compounds in cancer.

Active Gαio mutants accelerate breast tumor metastasis via the c-Src pathway.

Constitutively active mutations in the Gα

Neuronal-Activity Dependent Mechanisms of Small Cell Lung Cancer Progression.

Neural activity is increasingly recognized as a critical regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth both through paracrine mechanisms and through electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses, while perisynaptic neurotransmitter signaling drives breast cancer brain metastasis growth. Outside of the CNS, innervation of tumors such as prostate, breast, pancreatic and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression. However, the extent to which the nervous system regulates lung cancer progression, either in the lung or when metastatic to brain, is largely unexplored. Small cell lung cancer (SCLC) is a lethal high-grade neuroendocrine tumor that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that, similar to glioma, metastatic SCLC cells in the brain co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Optogenetic stimulation of cortical neuronal activity drives proliferation and invasion of SCLC brain metastases. In the brain, SCLC cells exhibit electrical currents and consequent calcium transients in response to neuronal activity, and direct SCLC cell membrane depolarization is sufficient to promote the growth of SCLC tumors. In the lung, vagus nerve transection markedly inhibits primary lung tumor formation, progression and metastasis, highlighting a critical role for innervation in overall SCLC initiation and progression. Taken together, these studies illustrate that neuronal activity plays a crucial role in dictating SCLC pathogenesis in both primary and metastatic sites.

Digital maturity and its determinants in General Practice A cross-sectional study in 20 countries.

The extent to which digital technologies are employed to promote the delivery of high-quality healthcare is known as Digital Maturity. Individual and systemic digital maturity are both necessary to ensure a successful, scalable and sustainable digital transformation in healthcare. However, digital maturity in primary care has been scarcely evaluated. This study assessed the digital maturity in General Practice (GP) globally and evaluated its association with participants demographic characteristics, practice characteristics and features of Electronic Health Records (EHRs) use. GPs across 20 countries completed an online questionnaire between June and September 2020. Demographic data, practice characteristics, and features of EHRs use were collected. Digital maturity was evaluated through a framework based on usage, resources and abilities (divided in this study in its collective and individual components), interoperability, general evaluation methods and impact of digital technologies. Each dimension was rated as 1 or 0. The digital maturity score was calculated as the sum of the six dimensions and ranged between 0 to 6 (maximum digital maturity). Multivariable linear regression was used to model the total score, while multivariable logistic regression was used to model the probability of meeting each dimension of the score. One thousand six hundred GPs (61% female, 68% Europeans) participated. GPs had a median digital maturity of 4 (P25-P75 3-5). Positive associations with digital maturity were found with male gender Our study demonstrated notable factors that impact digital maturity and exposed discrepancies in digital transformation across healthcare settings. It provides guidance for policymakers to develop more efficacious interventions to hasten the digital transformation of General Practice.

Identifying M1-like macrophage related genes for prognosis prediction in lung adenocarcinoma based on a gene co-expression network.

Macrophages are one of the most important players in the tumor microenvironment. But the contribution of macrophages to lung adenocarcinoma (LUAD) is still controversial. The current study aimed to display an immune landscape to clarify the function of macrophages and detect prognostic hub genes in LUAD. The transcriptome data were adopted to screen differently expressed genes (DEGs) in The Cancer Genome Atlas database (TCGA). The cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm was used to reveal the immune landscape. Weighted gene co-expression network analysis (WGCNA) analysis was performed to identify the hub module associated with macrophages. Function Enrichment analysis was conducted on hub module genes. Moreover, univariate and multivariate Cox regression analyses were performed to identify prognostic hub genes. Kaplan-Meier (KM) and Time-dependent receiver operating characteristic (ROC) curves were plotted to assess the prognostic capacity of the four prognostic hub genes. The GES1196959 dataset from the Gene Expression Omnibus (GEO) database was downloaded to verify the differential expression of the 4 prognostic hub genes.

Linear-like polypeptide-based micelle with pH-sensitive detachable PEG to deliver dimeric camptothecin for cancer therapy.

Nano drug delivery systems have made significant progress in delivering anticancer drugs camptothecin (CPT). However, many challenges for CPT delivery remain, including low drug loading efficiency, premature drug leakage, and poor cellular internalization. Herein, we report a novel dual-sensitive polypeptide-based micelle with remarkably high drug loading of CPT for cancer therapy. This self-assembled micelle possesses the following essential components for CPT (1) pH-sensitive PEG (OHC-PEG-CHO) for prolonging blood circulation and allowing biocompatibility by shielding the cationic micelles, which can be detached under the tumor acidic microenvironment and facilitates the cellular uptake (2) polypeptide polylysine-polyphenylalanine (PKF) synthesized

Role of transcription factors and chromatin modifiers in driving lineage reprogramming in treatment-induced neuroendocrine prostate cancer.

Therapy-induced neuroendocrine prostate cancer (NEPC) is a highly lethal variant of prostate cancer that is increasing in incidence with the increased use of next-generation of androgen receptor (AR) pathway inhibitors. It arises

LncRNA SNHG5 Suppresses Cell Migration and Invasion of Human Lung Adenocarcinoma via Regulation of Epithelial-Mesenchymal Transition.

Long noncoding RNAs (lncRNAs) are gradually being annotated as important regulators of multiple cellular processes. The goal of our study was to investigate the effects of the lncRNA small nucleolar RNA host gene 5 (SNHG5) in lung adenocarcinoma (LAD) and its underlying mechanisms. The findings revealed a substantial drop in SNHG5 expression in LAD tissues, which correlated with clinical-pathological parameters. Transcriptome sequencing analysis demonstrated that the inhibitory effect of SNHG5 was associated with cell adhesion molecules. Moreover, the expression of SNHG5 was shown to be correlated with epithelial-mesenchymal transition (EMT) markers in western blots and immunofluorescence. SNHG5 also had significant effects of antimigration and anti-invasion on LAD cells

Clinical perspectives on serum tumor marker use in predicting prognosis and treatment response in advanced non-small cell lung cancer.

The optimal positioning and usage of serum tumor markers (STMs) in advanced non-small cell lung cancer (NSCLC) care is still unclear. This review aimed to provide an overview of the potential use and value of STMs in routine advanced NSCLC care for the prediction of prognosis and treatment response. Radiological imaging and clinical symptoms have shown not to capture a patients entire disease status in daily clinical practice. Since STM measurements allow for a rapid, minimally invasive, and safe evaluation of the patients tumor status in real time, STMs can be used as companion decision-making support tools before start and during treatment. To overcome the limited sensitivity and specificity associated with the use of STMs, tests should only be applied in specific subgroups of patients and different test characteristics should be defined per clinical context in order to answer different clinical questions. The same approach can similarly be relevant when developing clinical applications for other (circulating) biomarkers. Future research should focus on the approaches described in this review to achieve STM test implementation in advanced NSCLC care.

Association of immune-related adverse events and efficacy in advanced non-small-cell lung cancer a systematic review and meta-analysis.

Immune-related adverse events (irAEs) are a series of adverse events that occur during the application of immune checkpoint inhibitors. The correlation between irAEs and ICI efficacy is controversial. In this meta-analysis, we analyzed the association of irAEs with the efficacy of immune checkpoint inhibitors in patients with advanced non-small-cell lung cancer (NSCLC). A total of 35 studies covering 8435 patients with NSCLC at advanced stage were included. Pooled analysis demonstrated that patients with irAEs got a significantly higher objective response rate than those without irAEs. Besides this, patients with irAEs had a more favorable survival outcome than those without. This study indicated that the occurrence of irAEs was associated with better survival outcome and higher tumor efficacy for patients with advanced NSCLC.

Yifei Sanjie Formula or Placebo With Anlotinib as Second-Line or Above Treatment for Metastatic Non-Small-Cell Lung Cancer Study Protocol for a Double-Blind, Placebo-Controlled Randomized Pilot Study.

Anlotinib is used as a third-line treatment for advanced non-small-cell lung cancer (NSCLC), but has limited clinical benefits and several side effects, such as diarrhea and acneiform skin rash. Traditional Chinese Medicine (TCM) is commonly used to treat cancers in China. Chinese herbal medicines may have the potential as adjuvant therapies to reduce toxicity and improve the efficacy of treatments for NSCLC. Given the positive outcomes of basic research, we plan to evaluate whether the addition of the Chinese herbal medicine Yifei Sanjie formula (YFSJF) to anlotinib can improve the progression-free survival (PFS) of advanced NSCLC patients. A multicenter, randomized, double-blind, placebo-controlled parallel-group controlled pilot trial will be performed. Forty eligible patients will be randomized in a ratio of 11 to the intervention (YFSJF anlotinib) and control (placebo anlotinib) groups. Participants will be advised to take 12 mgday of anlotinib on days 1 to 14 of each 21-day cycle. YFSJF or placebo will be administered (15 g twice daily) during each cycle until progression of disease (PD). The primary outcome will be progression-free survival (PFS), and the secondary outcomes will be overall survival (OS), the objective response rate (ORR), and patient-reported outcomes (PRO). Tumors will be assessed based on RECIST v. 1.1 after every 2 cycles of treatment. The M. D. Anderson Symptom Inventory-Lung Cancer (MDASI-LC) will be used to evaluate PRO at baseline and weekly thereafter until PD. This will be the first trial to evaluate the effectiveness and safety of TCM combined with anlotinib for the treatment of NSCLC. The results of this randomized controlled trial will fill a gap in the research by showing whether YFSJF combined with anlotinib can improve PFS in NSCLC patients. The study was registered on June 8th, 2021 on Chinese Clinical Registry registration number ChiCTR2100047143. (httpswww.chictr.org.cnindex.aspx). The Ethics Committee of the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine approved the study protocol (approval no. K2020151, 20210819). The study will also be supervised and managed by the Ethics Committee.

Prognostic prediction of lung adenocarcinoma by integrative analysis of RHOH expression and methylation.

The development of epigenetics holds great promise for diagnosis and treatment of lung adenocarcinoma (LUAD). The purpose of this work was to analyze the correlation between Ras Homolog Gene Family Member H (RHOH) expression and methylation in patients with LUAD and its association with survival. Data related to gene expression, DNA methylation, and clinical features of LUAD from The Cancer Genome Atlas (TCGA) database were analyzed. A total of 50 patients were included in verification group. The methylation level of RHOH in verification group was detected by bisulfite amplicon sequencing. The RHOH methylation level in TCGA cohort was significantly and negatively correlated with its expression level (Cor -0.5, p 2.687e-33). Patients with hypermethylation and low expression of RHOH had significantly worse prognosis than patients with hypomethylation and low expression of RHOH (TCGA p 0.004 validation cohort p 0.006, HR 4.740, 95% CI 1.567-14.340). Our research revealed that RHOH may prove to be a new potential prognostic predictor for LUAD patients.

Systematic analysis of the oncogenic role of FAM83D across cancers based on data mining.

Family with sequence similarity of 83D (FAM83D) is overexpressed in various cancers. However, no pan-cancer analysis is presently available. In the present study, we used a bioinformatics analysis to explore the diagnostic and prognostic value of FAM83D expression levels in human cancers. The GEPIA 2, TIMER 2.0, ENCORI, and DriverDBV3 databases were used to evaluate FAM83D expression levels. The potential prognostic value of FAM83D expression was analyzed using the GEPIA 2, UALCAN, and TISIB databases. The driver gene and promoter methylation levels regarding FAM83D were evaluated using the TIMER 2.0 and UALCAN databases. To further analyze interactive networks for FAM83D, FAM83D-binding proteins and related genes were determined using STRING and Gene MANIA analytic tools. Highly expressed FAM83D could be associated with mutated

A cell fate reprogramming strategy reverses epithelial-to-mesenchymal transition of lung cancer cells while avoiding hybrid states.

The epithelial-to-mesenchymal transition (EMT) of primary cancer contributes to the acquisition of lethal properties, including metastasis and drug resistance. Blocking or reversing EMT could be an effective strategy to improve cancer treatment. However, it is still unclear how to achieve complete EMT reversal (rEMT) as cancer cells often transition to hybrid EMT states with high metastatic potential. To tackle this problem, we employed a systems biology approach and identified a core-regulatory circuit that plays the primary role in driving rEMT without hybrid properties. Perturbation of any single-node was not sufficient to completely revert EMT. Inhibition of both SMAD4 and ERK signaling along with p53 activation could induce rEMT in cancer cells even with TGF-β stimulation, a primary inducer of EMT. Induction of rEMT in lung cancer cells with the triple combination approach restored chemosensitivity. This cell-fate reprogramming strategy based on attractor landscapes revealed potential therapeutic targets that can eradicate metastatic potential by subverting EMT while avoiding hybrid states.

Patient and carer experiences of lung cancer referral pathway in a regional health service, a qualitative study.

Lung cancer referral pathways aim to reduce delays and improve referral patterns of people with suspected lung cancer. As part of implementing lung cancer referral pathway at a regional Australian hospital, this study aimed to explore the experiences and perceptions of people with lung cancer and their carers. In-depth interviews were used to elicit data for thematic analysis in this cross-sectional descriptive qualitative study. Newly diagnosed lung cancer patients and their carers at a regional academic cancer centre were invited to participate in interviews. Five interviews were conducted face-to-face, and fourteen interviews were conducted by telephone (as per interviewee preference). Interviews were audio-recorded, transcribed, and qualitatively analysed. Descriptive phrases were used to generate initial inductive codes and themes. Nineteen participants approached agreed to take part in the study. Factors which positively impacted the care experience were good communication, timeliness and patient advocacy and support. Improper communication, long waiting times for investigations and appointments, uncertainty about the process and inconsistent advice from providers negatively impacted the care experience. Participants preferred face to face or video-linked consultations over telephone consultations. Understanding the experiences of rural and regional patients and carers with the TLCRP is important to improve quality of care. Implementing changes to Townsville Lung Cancer Referral Pathway to improve patient and carer experiences needs to be an ongoing quality improvement exercise. This article is protected by copyright. All rights reserved.

Next-generation sequencing clarified why first-line treatment with osimertinib was ineffective in an autopsied case of EGFR-mutated lung squamous cell carcinoma.

Epidermal growth factor receptor (EGFR)-mutated squamous cell carcinoma (SCC) is less common than adenocarcinoma. The third-generation EGFR-tyrosine kinase inhibitor, osimertinib, is effective in EGFR-mutated lung adenocarcinoma, but its efficacy in EGFR-mutated lung SCC is unclear. The patient was an 83-year-old male. He was diagnosed with SCC of the lung, and molecular analysis revealed that the tumor was positive for EGFR exon19 deletion. He was treated with osimertinib 80 mgday. No adverse events were observed, but after 18 days of therapy, he complained of dyspnea, and a computed tomography scan showed enlarged lung cancer. The case was categorized as a progressive disease. The patient died 3 weeks later. The autopsy findings confirmed the diagnosis of lung SCC, with morphology and immunohistochemical staining identical to the tumor obtained by bronchoscopy. Next-generation sequencing showed the presence of TP53 R158L, CDK6, and KRAS amplifications. The current case report shows that next-generation sequencing can explain why osimertinib is ineffective in EGFR-mutated SCC.

Preliminary Recommendations on the Timing of Lung Surgery after Novel Coronavirus Infection in Patients with Pulmonary Nodules and Lung Cancer.

In recent years, the corona virus disease 2019 (COVID-19) pandemic has had a huge impact on the global medical, political and economic fields. Since the beginning of the COVID-19 epidemic, our understanding of the impact of COVID-19 has grown exponentially. Recently, the COVID-19 epidemic has changed rapidly in China, and there has been controversy over how to carry out surgical operations for patients with lung neoplastic lesions. Some studies have shown that lung cancer patients undergoing surgery are more likely to experience respiratory failure and perioperative death after contracting COVID-19 than the general population, however, delays in cancer treatment are also associated with increased mortality among these patients. In particular, the novel coronavirus Omikron variant has a higher transmissibility and may escape the immunity obtained through the previous novel coronavirus infection and vaccination. In order to minimize the risk of novel coronavirus infection in surgical patients, it is necessary to develop new treatment guidelines, expert consensus and preventive measures. However, the current rapid change of the epidemic situation has led to insufficient time and evidence to develop guidelines and consensus. Therefore, thoracic surgeons need to evaluate specific patient populations at higher risk of severe complications before surgery and weigh the benefit of surgical treatment against the risk of novel coronavirus infection. We try to give some recommendations on lung surgery during the current domestic epidemic situation based on the guidelines and consensus of oncology and thoracic surgery organizations in different regions on lung surgery. . 【中文题目：肺部结节及肺癌患者新型冠状病毒感染后 肺部手术时机的初步建议】 【中文摘要：近年来，新型冠状病毒感染疫情给全球医疗、政治、经济领域带来了巨大的影响。自新型冠状病毒感染疫情流行开始以来，我们对新型冠状病毒感染影响的了解有了几何数级的增长，近期国内新型冠状病毒感染疫情变化迅速，对于肺部发现肿瘤性病变患者的外科手术如何开展也因近期疫情的变化而出现了争议。一些研究表明，接受肺癌手术的患者感染新型冠状病毒后较普通患者更易发生呼吸衰竭和围术期死亡事件，然而，癌症治疗的推迟也与患者死亡率的上升有关。特别是新型冠状病毒奥密克戎变异株具有更高的传播性，并有可能逃避通过以前的新型冠状病毒感染、疫苗接种获得的免疫力，为了将手术患者发生新型冠状病毒感染的风险降至最低，有必要制定新的治疗指南、专家共识和预防措施，但目前疫情的快速变化导致我们没有充足的时间和证据来制定指南和共识。胸外科医生急需在术前评估发生严重并发症风险较高的特定患者人群的标准，权衡外科治疗的获益与新型冠状病毒感染的风险孰轻孰重。因此，我们尝试结合在新型冠状病毒感染流行情况下不同地区肿瘤学及胸外科学组织对于肺癌手术的指南及共识，给出一些目前国内疫情期间肺部结节及肺癌患者新型冠状病毒感染后肺部手术时机的初步建议，并希望能引发更深入的讨论和建议。 】 【中文关键词：新型冠状病毒感染；肺肿瘤；肺部手术】.

Mass cytometry to characterize the immune lung cancer microenvironment.

The human tumor microenvironment requires use of high-dimensional single-cell tools to uncover its cellular complexity and functional variety. For decades, flow cytometry has been the technology of choice to explore immune cell diversity in different pathological contexts. Recently, a new format for flow cytometry - termed mass cytometry - has been developed. It allows for simultaneous interrogation of more than 40 different molecular markers, without the need for spectral compensation, which significantly augments the ability of cytometry to evaluate complex cellular systems and processes. Currently, different multiparametric single-cell analysis approaches are being widely adopted to interrogate the human tumor microenvironment. However, important challenges must be addressed when solid tissues are analyzed by single-cell technologies. This protocol describes the challenge and better use of single-cell mass cytometry to dissect tumor infiltrating leukocytes from surgically resected tumoral lung tissues.

Cardiac toxicity associated with pharmacokinetic drug-drug interaction between crizotinib and sofosbuvirvelpatasvir A case report.

This case report describes a pharmacokinetic drug-drug interaction between crizotinib, a tyrosine kinase inhibitor, and sofosbuvirvelpatasvir, a direct-acting antiviral drug, leading to cardiac toxicity. A 75-year-old man, with no cardiovascular history but a diagnosis of metastatic nonsmall cell lung cancer with mesenchymal-epithelial transition exon-14 deletion and hepatitis C virus infection genotype 1A, received both crizotinib and sofosbuvirvelpatasvir. Crizotinib was well tolerated, but 1 week after sofosbuvirvelpatasvir initiation, the patient experienced bilateral lower-limb oedema and class III New York Heart Association dyspnoea. We assumed that increased exposure to crizotinib could account for this cardiac toxicity. Drug causality was probable according to the Naranjo scale. We hypothesized a reciprocal interaction between crizotinib and velpatasvir, mediated by both cytochrome 3A4 (CYP3A4) and P-glycoprotein (P-gp). Clinicians should be aware of the risk of drug-drug interactions between direct-acting antiviral agents that inhibit CYP3A4 (glecaprevir) andor P-gp (voxilaprevir, velpatasvir) and anticancer tyrosine kinase inhibitors that are mostly CYP3A4 andor P-gp substrates (gefitinib, afatinib, erlotinib, crizotinib, ceritinib, lorlatinib, brigatinib, capmatinib etc.).

Correlation between the mRNA levels of BCRP and LUNX genes and pathological types and stages of patients with non-small cell lung cancer.

To analyze the correlation between the mRNA levels of breast cancer resistance protein (BCRP) and lung-specific X protein (LUNX) genes with pathological types and stages of patients with non-small cell lung cancer (NSCLC) and their significance for prognosis. Eighty nine patients with NSCLC admitted to Huaihe Hospital of Henan University between June 2015 and June 2018 were recruited, with 55 patients with benign lung lesions admitted during the same period of time selected as the control group. The mRNA levels of BCRP and LUNX genes were detected in the peripheral blood samples from the two groups, and their correlation with the clinicopathological characteristics and prognosis of the patients was analyzed. The expression rates of BCRP and LUNX mRNA in the NSCLC group were significantly higher compared with the control group (P < 0.05). The level of BCRP mRNA of the NSCLC patients has correlated with the degree of differentiation and TNM staging (P < 0.05), but not with gender, age, smoking, pathological types and lymph node metastasis (P > 0.05). The level of LUNX mRNA of them has correlated with the degree of differentiation, TNM staging and lymph node metastasis (P < 0.05), but not with gender, age, smoking, and pathological types (P > 0.05). Compared with those with no expression, the overall survival rate of patients with BCRP and LUNX expression was significantly lower (P < 0.05). The degree of differentiation, TNM staging, lymph node metastasis, and expression of the BCRP and LUNX mRNA may all affect the prognosis of the patients. The levels of BCRP and LUNX mRNA in the peripheral blood of patients with NSCLC are significantly increased. The expression of BCRP mRNA is correlated with the degree of differentiation and TNM staging, whilst the expression of LUNX mRNA is correlated with the differentiation degree, TNM staging and lymph node metastasis. Both may be used as independent predictors for the prognosis of patients with NSCLC.

Irradiated lung cancer cell-derived exosomes modulate macrophage polarization by inhibiting MID1 via miR-4655-5p.

Radiation Pneumonitis (RP) is one of the most common and severe complication in patients receiving thoracic radiotherapy. The release of cytokines contribute to activating the RP process. Macrophages also play an important role in the pathogenesis of RP. The differential activation of macrophages is regulated by microRNA (miRNA). Exosomes containing miRNAs are one of the important ways to mediate cellular communication. However, the exosomes mediate communication between tumor cells and macrophages during the pathogenesis of RP remains understudied. In this study, we isolated and characterized the exosomes secreted by lung cancer cells after irradiation. Co-culture of exosomes with macrophages revealed that exosomes could induce macrophage proliferation activation and M2 polarization. miRNA array was used to analyze the differential expression of miRNAs in exosomes, and it was found that miR-4655-5p was stably and highly expressed in exosomes. The function of miR-4655-5p in macrophages was confirmed by overexpressioninhibition of miR-4655-5p expression in macrophages. The targeting association between miR-4655-5p and MID1 was determined by bioinformatics prediction followed by a confirmatory dual luciferase reporter assay. We showed that miR-4655-5p regulate the macrophage proliferation and inflammatory response by forming a negative regulatory loop that alters MID1 activity and its downstream PP2Ac. Overall, our results indicated that exosomal miR-4655-5p secreted by lung cancer cells after irradiation promoted the proliferation and M2 polarization of macrophages. It can be speculated that exosomes play an immunomodulatory role in the pathogenesis of RP and provided a new target for the prevention and treatment of RP.

Systemic treatment with or without ablative therapies in oligometastatic breast cancer A single institution analysis of patient outcomes.

Local ablative treatment (LAT) is increasingly combined with systemic therapy in oligometastatic breast cancer (OMBC), without a high-level evidence to support this strategy. We evaluated the addition of LAT to systemic treatment in terms of progression-free survival (PFS) and overall survival (OS). Secondary endpoints were local control (LC) and toxicity. We sought to identify prognostic factors associated with longer OS and PFS. We identified consecutive patients treated between 2014 and 2018 for synchronous or metachronous OMBC (defined as ≤ 5 metastases). LAT included stereotactic body radiation therapy (SBRT) and volumetric modulated arc therapy (VMAT), surgery, cryotherapy and percutaneous radiofrequency ablation (PRA). PFS and OS were calculated, and Cox regression models analyzed for potential predictors of survival. One hundred two patients were included (no-LAT, n 62 LAT, n 40). Sixty-four metastases received LAT. Median follow-up was 50.4 months (95% CI 44.4 53.4). One patient experienced grade 3 toxicity in the LAT group. Five-year PFS and OS were 34.75% (95% CI 24.42-45.26) and 63.21% (95% CI 50.69-73.37) respectively. Patients receiving both LAT and systemic therapy had longer PFS and OS than those with no-LAT (HR 0.39, p 0.002) and (HR 0.31, p 0.01). The use of LAT, HER2-positive status and hormone-receptor positivity were associated with longer PFS and OS whereas liver metastases led to worse PFS. LAT was associated with improved outcomes in OMBC when added to systemic treatment, without significantly increasing toxicity. The prognostic factors identified to extend PFS and OS may help guide clinicians in selecting patients for LAT.

WS-LungNet A two-stage weakly-supervised lung cancer detection and diagnosis network.

Computer-aided lung cancer diagnosis (CAD) system on computed tomography (CT) helps radiologists guide preoperative planning and prognosis assessment. The flexibility and scalability of deep learning methods are limited in lung CAD. In essence, two significant challenges to be solved are (1) Label scarcity due to cost annotations of CT images by experienced domain experts, and (2) Label inconsistency between the observed nodule malignancy and the patients pathology evaluation. These two issues can be considered weak label problems. We address these issues in this paper by introducing a weakly-supervised lung cancer detection and diagnosis network (WS-LungNet), consisting of a semi-supervised computer-aided detection (Semi-CADe) that can segment 3D pulmonary nodules based on unlabeled data through adversarial learning to reduce label scarcity, as well as a cross-nodule attention computer-aided diagnosis (CNA-CADx) for evaluating malignancy at the patient level by modeling correlations between nodules via cross-attention mechanisms and thereby eliminating label inconsistency. Through extensive evaluations on the LIDC-IDRI public database, we show that our proposed method achieves 82.99% competition performance metric (CPM) on pulmonary nodule detection and 88.63% area under the curve (AUC) on lung cancer diagnosis. Extensive experiments demonstrate the advantage of WS-LungNet on nodule detection and malignancy evaluation tasks. Our promising results demonstrate the benefits and flexibility of the semi-supervised segmentation with adversarial learning and the nodule instance correlation learning with the attention mechanism. The results also suggest that making use of the unlabeled data and taking the relationship among nodules in a case into account are essential for lung cancer detection and diagnosis.

Targeting GSTP1 as Therapeutic Strategy against Lung Adenocarcinoma Stemness and Resistance to Tyrosine Kinase Inhibitors.

Glutathione S-transferase pi (GSTP1), a phase II detoxification enzyme, is known to be overexpressed and mediates chemotherapeutic resistance in lung cancer. However, whether GSTP1 supports cancer stem cells (CSCs) and the underlying mechanisms in lung adenocarcinoma (LUAD) remain largely unknown. This study unveiled that GSTP1 is upregulated in lung CSCs and supports tumor self-renewal, metastasis, and resistance to targeted tyrosine kinase inhibitors of LUAD both in vitro and in vivo. Mechanistically, CaMK2A (calciumcalmodulin-dependent protein kinase 2 isoform A)NRF2 (nuclear factor erythroid 2-related factor 2)GSTP1 is uncovered as a regulatory axis under hypoxia. CaMK2A increased GSTP1 expression through phosphorylating the Sersine558 residue of NRF2 and promoting its nuclear translocation, a novel mechanism for NRF2 activation apart from conventional oxidization-dependent activation. Upregulation of GSTP1 in turn suppressed reactive oxygen species levels and supported CSC phenotypes. Clinically, GSTP1 analyzed by immunohistochemistry is upregulated in a proportion of LUAD and serves as a prognostic marker for survival. Using patient-derived organoids from an ALK-translocated LUAD, the therapeutic potential of a specific GSTP1 inhibitor ezatiostat in combination treatment with the ALK inhibitor crizotinib is demonstrated. This study demonstrates GSTP1 to be a promising therapeutic target for long-term control of LUAD through targeting CSCs.

Elevated PAF1-RAD52 axis confers chemoresistance to human cancers.

Cisplatin- and gemcitabine-based chemotherapeutics represent a mainstay of cancer therapy for most solid tumors however, resistance limits their curative potential. Here, we identify RNA polymerase II-associated factor 1 (PAF1) as a common driver of cisplatin and gemcitabine resistance in human cancers (ovarian, lung, and pancreas). Mechanistically, cisplatin- and gemcitabine-resistant cells show enhanced DNA repair, which is inhibited by PAF1 silencing. We demonstrate an increased interaction of PAF1 with RAD52 in resistant cells. Targeting the PAF1 and RAD52 axis combined with cisplatin or gemcitabine strongly diminishes the survival potential of resistant cells. Overall, this study shows clinical evidence that the expression of PAF1 contributes to chemotherapy resistance and worse clinical outcome for lethal cancers.

Usefulness of pyruvate dehydrogenase-E1α expression to determine SUVmax cut-off value of

A more accurate cut-off value of maximum standardized uptake value (SUVmax) in

A case report of Indium lung with progressive emphysema and fibrosis underwent lung unilateral transplantation 20 years after the end of the exposure.

Indium lung is characterized by interstitial pneumonia andor emphysema which occurs in indium-tin oxide (ITO) workers. Indium lung is now known to progress after stopping exposure to ITO, but the long-term influences of ITO remain unclear. Forty seven years old, a never-smoker, who had been engaged in an ITO manufacturing process for 8 years. Emphysema was indicated by the medical check-up for ex-ITO workers, and he was diagnosed with indium lung. He underwent partial lung resections for pneumothorax two times, and obstructive pulmonary dysfunction had progressed through the years. He underwent right single lung transplant 20 years after ITO exposure. Pathologically, his lung showed severe distal acinar emphysema and honeycomb change. Fibrosis and destruction of the lung tissue significantly progressed compared to the previous partial resections. Scanning electron microscopy combined with energy dispersive spectroscopy revealed that the deposited particles contained indium and tin. After the transplantation, his respiratory function was improved. In this case, ITO resided in the lung tissue for 20 years, and lung tissue destruction kept progressing. Careful medical follow-up is recommended for ITO-workers even if they are asymptomatic.

Single-center study of different treatment for advanced or unresectable angiosarcoma patients.

Expert consensus on icotinib as adjuvant therapy for non-small cell lung cancer.

Clinical studies have established the clinical application of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) adjuvant targeted therapy. Compared with chemotherapy, the high efficiency and low toxicity of targeted therapy increases the survival benefit of patients. Icotinib was the first EGFR-TKI with independent intellectual property rights in China and the third EGFR-TKI to be marketed in the world. In order to summarize the experience of icotinib and other EGFR-TKIs in the adjuvant treatment of non-small cell lung cancer and further standardize and guide the clinical application of icotinib, experts from the China International Exchange and Promotive Association for Medical and Health Care and the Guangdong Association of Thoracic Diseases have organized an expert consensus on the adjuvant treatment of non-small cell lung cancer with icotinib, which is expected to provide clinicians with evidence-based medical evidences for postoperative targeted drug using. 临床研究奠定了表皮生长因子受体酪氨酸激酶抑制剂(EGFR－TKI)辅助靶向治疗的临床应用地位。与化疗比较，靶向药高效低不良反应的特点为患者增加了生存获益。埃克替尼是中国第1个拥有自主知识产权、也是全球第3个上市的EGFR－TKI。2021年6月埃克替尼获得批准用于ⅡⅢA期EGFR敏感突变非小细胞肺癌术后辅助治疗适应证，同年获得中国临床肿瘤学会指南Ⅰ级推荐，成为全球第1个获批术后辅助医保适应证并有指南推荐的第一代EGFR－TKI。为了总结目前埃克替尼及其他EGFR－TKIs辅助治疗非小细胞肺癌的用药经验，进一步规范、指导埃克替尼的临床应用，由中国医疗保健国际交流促进会、广东省胸部疾病学会组织专家编写了埃克替尼术后辅助治疗非小细胞肺癌的专家共识，期待能为临床医师提供术后靶向用药的循证医学证据。.

Clinical practice guideline for stage Ⅳ primary lung cancer in China (2023 edition).

Primary lung cancer is the most common malignant disease and the leading cause of cancer death in China, with an estimated 828 thousand incident cases and 657 thousand deaths in 2016. Due to the absence of effective early screening methods, most patients with lung cancer are in stage Ⅳ when diagnosed. Multi-disciplinary treatment based on systemic therapy is the treatment principle for patients with stage Ⅳ lung cancer, chemotherapy is the cornerstone of stage Ⅳ lung cancer, but its efficacy is unsatisfactory. In recent years, with the rapid development of molecular targeted therapy and immunotherapy, the treatment concept has continuously changed and treatment outcome for patients has also been greatly improved. In order to update the progress in the treatment of stage Ⅳ lung cancer worldwide timely, and further improve the level of standardized diagnosis and treatment of stage Ⅳ lung cancer in China, Chinese Association for Clinical Oncologists and Medical Oncology Branch of Chinese International Exchange and Promotion Association for Medical and Healthcare organized experts to compose Clinical Practice Guideline for Stage Ⅳ Primary Lung Cancer in China (2023 edition) . 原发性肺癌是中国发病率和死亡率最高的恶性肿瘤，2016年中国肺癌新发病例约82.8万例，死亡病例约65.7万例。由于缺乏有效的早期发现手段，导致大部分肺癌患者就诊时已是Ⅳ期。以全身治疗为主的综合治疗是Ⅳ期肺癌患者的治疗原则，化疗是治疗Ⅳ期肺癌的基石，但疗效不佳。近年来，随着分子靶向治疗、免疫治疗的飞速发展，Ⅳ期肺癌的治疗理念在不断发生变化，患者的治疗效果得到了很大改善。为了及时反映国内外Ⅳ期肺癌治疗的新进展，进一步提高中国Ⅳ期肺癌的规范化诊疗水平，中国医师协会肿瘤医师分会和中国医疗保健国际交流促进会肿瘤内科分会组织专家编写了《Ⅳ期原发性肺癌中国治疗指南(2023年版)》。.

Uptake of invitations to a lung health check offering low-dose CT lung cancer screening among an ethnically and socioeconomically diverse population at risk of lung cancer in the UK (SUMMIT) a prospective, longitudinal cohort study.

Lung cancer screening with low-dose CT reduces lung cancer mortality, but screening requires equitable uptake from candidates at high risk of lung cancer across ethnic and socioeconomic groups that are under-represented in clinical studies. We aimed to assess the uptake of invitations to a lung health check offering low-dose CT lung cancer screening in an ethnically and socioeconomically diverse cohort at high risk of lung cancer. In this multicentre, prospective, longitudinal cohort study (SUMMIT), individuals aged 55-77 years with a history of smoking in the past 20 years were identified via National Health Service England primary care records at practices in northeast and north-central London, UK, using electronic searches. Eligible individuals were invited by letter to a lung health check offering lung cancer screening at one of four hospital sites, with non-responders re-invited after 4 months. Individuals were excluded if they had dementia or metastatic cancer, were receiving palliative care or were housebound, or declined research participation. The proportion of individuals invited who responded to the lung health check invitation by telephone was used to measure uptake. We used univariable and multivariable logistic regression analyses to estimate associations between uptake of a lung health check invitation and re-invitation of non-responders, adjusted for sex, age, ethnicity, smoking, and deprivation score. This study was registered prospectively with ClinicalTrials.gov, NCT03934866. Between March 20 and Dec 12, 2019, the records of 2 333 488 individuals from 251 primary care practices across northeast and north-central London were screened for eligibility 1 974 919 (84·6%) individuals were outside the eligible age range, 7578 (2·1%) had pre-existing medical conditions, and 11 962 (3·3%) had opted out of particpation in research and thus were not invited. 95 297 individuals were eligible for invitation, of whom 29 545 (31·0%) responded. Due to the COVID-19 pandemic, re-invitation letters were sent to only a subsample of 4594 non-responders, of whom 642 (14·0%) responded. Overall, uptake was lower among men than among women (odds ratio OR 0·91 95% CI 0·88-0·94 p<0·0001), and higher among older age groups (1·48 1·42-1·54 among those aged 65-69 years vs those aged 55-59 years p<0·0001), groups with less deprivation (1·89 1·76-2·04 for the most vs the least deprived areas p<0·0001), individuals of Asian ethnicity (1·14 1·09-1·20 vs White ethnicity p<0·0001), and individuals who were former smokers (1·89 1·83-1·95 vs current smokers p<0·0001). When ethnicity was subdivided into 16 groups, uptake was lower among individuals of other White ethnicity than among those with White British ethnicity (0·86 0·83-0·90), whereas uptake was higher among Chinese, Indian, and other Asian ethnicities than among those with White British ethnicity (1·33 1·13-1·56 for Chinese ethnicity 1·29 1·19-1·40 for Indian ethnicity and 1·19 1·08-1·31 for other Asian ethnicity). Inviting eligible adults for lung health checks in areas of socioeconomic and ethnic diversity should achieve favourable participation in lung cancer screening overall, but inequalities by smoking, deprivation, and ethnicity persist. Reminder and re-invitation strategies should be used to increase uptake and the equity of response. GRAIL.

Associations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes in KEYNOTE-042 Pembrolizumab Versus Chemotherapy For Advanced PD-L1 Positive NSCLC.

We evaluated whether tissue tumor mutational burden (tTMB) and STK11, KEAP1, and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand-1 (PD-L1)‒positive (tumor proportion score TPS ≥1%) advancedmetastatic NSCLC without EGFRALK alterations in the phase 3 KEYNOTE-042 trial (ClinicalTrials.gov, NCT02220894). This retrospective exploratory analysis assessed prevalence of tTMB and STK11, KEAP1, and KRAS mutations determined by whole-exome sequencing (WES) of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mutationsexome. 345793 patients (43.5%) had tTMB ≥175 mutationsexome and 448793 (56.5%) patients had tTMB <175 mutationsexome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved OS, progression-free survival (PFS) among patients receiving pembrolizumab (Wald test, one-sided P<0.001) but not those receiving chemotherapy (Wald test, two-sided P>0.05). tTMB ≥175 mutationsexome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutationsexome was not (OS HR, 0.62 95% CI, 0.48‒0.80 and 1.09 95% CI, 0.88‒1.36 PFS 0.75 0.59‒0.95 and 1.27 1.04‒1.55, respectively). Improved OS (HR 95% CI) for pembrolizumab versus chemotherapy was observed regardless of STK11 (STK11 mutant (n33) 0.37 0.16‒0.86, STK11 wild-type (n396) 0.83 0.65‒1.05) KEAP1 (KEAP1 mutant (n64) 0.75 0.42‒1.35, KEAP1 wild-type (n365) 0.78 0.61‒0.99), or KRAS (KRAS mutant (n69) 0.42 0.22‒0.81 KRAS wild-type (n232 0.86 0.63‒1.18) mutation status. TTMB with a cutpoint of ≥175 mutationsexome is a potential predictive biomarker for pembrolizumab monotherapy for advancedmetastatic PD-L1 TPS ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11, KEAP1, or KRAS mutation status.

Pulmonary delivery of spray-dried Nisin ZP antimicrobial peptide for non-small cell lung cancer (NSCLC) treatment.

Nisin ZP is an antimicrobial peptide (AMP) produced by the bacterium Lactococcus lactis, and we have previously demonstrated anticancer activity in NSCLC (A549) cells. In this study, we formulated a nisin ZP dry powder (NZSD) using a spray dryer to facilitate inhaled delivery for the treatment of NSCLC. Nisin ZP was spray-dried with mannitol, l-leucine, and trehalose in a ratio of 751510 using Büchi mini spray-dryer B-290 in different drug loadings (10, 20, and 30% ww). NZSD powder revealed a good powder yield of >55% ww with ≤3 % ww moisture content and high nisin ZP drug loading for all the peptide ratios. The NZSD powder particles were irregularly shaped with corrugated morphology. The presence of an endothermic peak in DSC thermograms and attenuated crystalline peaks in PXRD diffractograms confirmed the semi-crystalline powder nature of NZSD. The anticancer activity of nisin ZP was maintained after fabricating it into NZSD powder and showed a similar inhibitory concentration to free nisin ZP. Stability studies indicated that NZSD powders were stable for three months at 4 and 25 ℃ with more than 90% drug content and semi-crystalline nature, as confirmed by DSC and PXRD. Aerosolization studies performed using NGI indicated an aerodynamic diameter (MMAD) within the desired range (1-5 µm) and a high fine particle fraction (FPF > 75%) for all peptide ratios, suggesting powder deposition in the lungs respiratory airways. In conclusion, a dry powder of nisin ZP was formulated using a spray dryer with enhanced storage stability and suitable for inhaled delivery.

Risk Factors for Death Among Veterans Following Acute Kidney Injury.

Acute kidney injury is prevalent among hospitalized veterans, and associated with increased risk of death following discharge. However, risk factors for death following acute kidney injury have not been well defined. We developed a mortality prediction model using Veterans Health Administration data. This retrospective cohort study included inpatients from 2013 through 2018 with a creatinine increase of ≥0.3 mgdL. We evaluated 45 variables for inclusion in our final model, with a primary outcome of 1-year mortality. Bootstrap sampling with replacement was used to identify variables selected in >60% of models using stepwise selection. Best sub-sets regression using Akaike information criteria was used to identify the best-fitting parsimonious model. A total of 182,683 patients were included, and 38,940 (21.3%) died within 1 year of discharge. The 10-variable model to predict mortality included age, chronic lung disease, cancer within 5 years, unexplained weight loss, dementia, congestive heart failure, hematocrit, blood urea nitrogen, bilirubin, and albumin. Notably, acute kidney injury stage, chronic kidney disease, discharge creatinine, and proteinuria were not selected for inclusion. C-statistics in the primary validation cohorts were 0.77 for the final parsimonious model, compared with 0.52 for acute kidney injury stage alone. We identified risk factors for long-term mortality following acute kidney injury. Our 10-variable model did not include traditional renal variables, suggesting that non-kidney factors contribute to the risk of death more than measures of kidney disease in this population, a finding that may have implications for post-acute kidney injury care.

Early-Stage Primary Lung Neuroendocrine Tumors Treated with Stereotactic Body Radiotherapy A Multi-Institution Experience.

Current guidelines recommend surgery as standard of care for primary lung neuroendocrine tumor (LNET). Given that LNET is a rare clinical entity, there is a lack of literature regarding treatment of LNET with stereotactic body radiotherapy (SBRT). We hypothesized that SBRT could lead to effective locoregional tumor control and long-term outcomes. We retrospectively reviewed 48 tumors in 46 patients from 11 institutions with a histologically confirmed diagnosis of LNET, treated with primary radiotherapy. Data was collected for patients treated nonoperatively with primary radiotherapy between 2006-2020. Patient records were reviewed for lesion characteristics and clinical risk factors. Kaplan-Meier analysis, log-rank tests and Cox multivariate models were used to compare outcomes. Median age at treatment was 71 years and mean tumor size was 2 cm. Thirty-two lesions were typical carcinoid histology, 7 were atypical, and 9 were indeterminate. The most common SBRT fractionation schedule was 50-60 Gy in 5 daily fractions. Overall survival at 3, 6, and 9 years was 64%, 43%, and 26%, respectively. Progression-free survival at 3, 6, and 9 years was 88%, 78%, and 78%, respectively. Local control at 3, 6, and 9 years was 97%, 91%, and 91%, respectively. There was one regional recurrence in a paraesophageal lymph node. No grade 3 or higher toxicity was identified. This is the largest series evaluating outcomes in patients with LNET treated with SBRT. This treatment is well tolerated, provides excellent locoregional control, and should be offered as an alternative to surgical resection for patients with early-stage LNET, particularly those who may not be ideal surgical candidates.

Is your kid actin out A series of six patients with inherited ARPC1B deficiency and review of the literature.

Hereditary ARPC1B deficiency is characterized clinically by ear, skin, and lung infections, bleeding, eczema, food allergy, asthma, skin vasculitis, colitis, arthritis, short stature, and lymphadenopathy. We aimed to describe the clinical, laboratory, and genetic features of six additional patients from four Mexican families. We performed exome sequencing in available patients of four families with suspected actinopathy, collected their data from medical records, and reviewed the literature for other reports of patients with ARPC1B deficiency. Six patients from 4 families were included. All had recurrent infections, mainly bacterial pneumonia, and cellulitis. 67% had eczema, while 50% had food allergies, failure to thrive, hepatomegaly, and bleeding. Eosinophilia was found in all, with 84% thrombocytopenia, 67% abnormal-size platelets, and anemia. Serum levels of IgG, IgA, and IgE were highly increased in most IgM was normal or low. T cells were decreased in 67% of patients, while B and NK cells were increased in half the patients. Two of the four probands had compound heterozygous variants. One patient was successfully transplanted. We identified 28 other patients whose most prevalent features were eczema, recurrent infections, failure to thrive, bleeding, diarrhea, allergies, vasculitis, eosinophilia, platelet abnormalities, high IgEIgA, low T cells, and high B cells. ARPC1B deficiency has a variable and heterogeneous clinical spectrum, expanded by these cases to include keloid scars and Epstein-Barr virus chronic hepatitis. A novel deletion in exon 8 is shared by three unrelated families and might be the result of a founder effect.

Expecting more the case for incorporating fertility services into comprehensive sickle cell disease care.

Assisted reproductive technologies (ART) are not yet systematically available to people with sickle cell disease or their parents. Fertility care for these groups requires addressing sickle cell disease-associated infertility risks, fertility preservation options, pregnancy possibilities and outcomes, and, when needed, infertility treatment. People with a chance of having a child with sickle cell disease can use in-vitro fertilisation with preimplantation genetic testing to conceive a child unaffected by sickle cell disease. Also, parents of children with sickle cell disease can use this technology to identify embryos to become potential future matched sibling donors for stem cell transplant. In the USA, disparities in fertility care for the sickle cell disease community are especially stark. Universal screening of newborn babies identifies sickle cell disease and sickle cell trait, guidelines direct preconception genetic carrier screening, and standard-of-care fertility preserving options exist. However, potentially transformative treatments and cures for patients with sickle cell disease are not used due to iatrogenic infertility concerns. In diversely resourced care settings, obstacles to providing fertility care to people affected by sickle cell disease persist. In this Viewpoint, we contend that fertility care should be incorporated into the comprehensive care model for sickle cell disease, supporting alignment of treatment goals with reproductive life plans and delivering on the promise of individualised high-quality care for people with sickle cell disease and their families. We consider the obligation to provide fertility care in light of medical evidence, with acknowledgment of formidable obstacles to optimising care, and powerful historical and ethical considerations.

Roxadustat and its failure A comparative dynamic study.

Roxadustat, a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase domain 2 (HIF-PHD2) has been recently overruled by the American Food and Drug Administration (FDA) in Phase 3 clinical trials. This study provides insights into the dynamics of Roxadustat with PHD2 and proposes two FDA-approved drugs Pemetrexed and Valrubicin to treat chronic kidney disease (CKD). Role of chemical scaffolds such as synthetic pyrimidine-based antifolate is found critical for PHD2 inhibitory activity, which is concurrent with the experimental findings for stimulating Endogenous erythropoietin (EPO) gene expression. Furthermore, Fe

The additional diagnostic value of virtual bronchoscopy navigation in patients with pulmonary nodules - The NAVIGATOR study.

The number of solitary pulmonary nodules to be evaluated is expected to increase and therefore we need to improve diagnostic and therapeutic tools to approach these nodules. To prevent patients from futile invasive procedures and receiving treatment without histological confirmation of cancer, we evaluated the value of virtual bronchoscopy navigation to obtain a diagnosis of the solitary pulmonary nodule in a real-world clinical setting. In the NAVIGATOR single center, prospective, observational cohort study patients underwent a virtual bronchoscopy navigation procedure with or without guide sheet tunnelling to assess a solitary pulmonary nodule. Nodules were considered not accessible if a diagnosis could not be obtained by either by CT-guided transthoracic biopsy or conventional bronchoscopy. Between February 2021 and January 2022 35 patients underwent the virtual bronchoscopy navigation procedure. The overall diagnostic yield was 77% and was dependent on size of the nodule and chosen path, with highest yield in lesions with an airway path. Adverse events were few and manageable. Virtual bronchoscopy navigation with or without sheet tunnelling is a new technique with a good diagnostic yield, also in patients in whom previously performed procedures failed to establish a diagnosis andor alternative procedures are considered not feasible based on expected yield andor safety. Preventing futile or more invasive procedures like surgery or transthoracic punctures with a higher complication rate is beneficial for patients, and allowed treatment adaptation in two-third of the analyzed patient population.

Prognostic impact of lymph node spreading pattern in N2 NSCLC patients.

One-third of non-small cell lung cancer (NSCLC) patients are diagnosed with locally advanced disease. Long-term survival in stage IIIAB-N2 remains poor this may also be due to lymph node spreading pattern. Therefore, we compared the overall survival of stage IIIAB-N2 patients with superior mediastinal lymph nodes (SML) with infracarinal- or inferior mediastinal lymph nodes (IML) and with multilevel disease (MLD). One-, three-and five-year survival rates were measured. Kaplan-Meier curves and Cox proportional hazards model assessed survival and were used to identify prognostic factors. We reviewed data of stage IIIAB-N2 patients (n 129) who underwent surgery for NSCLC between 2012 and 2020. Patients with SML (n 62) were compared to ILM (n 37) and MLD (n 30). SML patients showed significantly better one- (SML 95.2% vs. IML 78.6% vs. MLD 69.4%, p 0.03), three- (78.8% vs. 27.7 vs. 13.3% p <0.001) and five-year (61.1% vs. 17.1 vs. 3% p < 0.001) survival rates, than IML and MLD patients. Kaplan-Meier curves showed prolonged overall survival for SML patients (log-rank SML, ILM, MLD p < 0.0001). This study showed significantly better long-term survival of SML patients than IML and MLD patients. The long-term survival of ILM and MLD patients was equally poor.

Exclusion of Patients with Autoimmune Disease in Lung Cancer Clinical Trials.

The exclusion of patients with autoimmune disease has been a topic of cancer immunotherapy trial. This study aims to find recent trends in exclusion of autoimmune disease. Using the website clinicaltrials.gov, we searched for clinical trials that were initiated in 2012 or later and enrolled patients with lung cancer who were treated with PD-1PD-L1 therapy. Only trials including US locations were analyzed. A total of 198 trials met screening criteria in this study. There were 68 trials which had complete exclusion of any autoimmune disease in patients. In addition, 13 trials excluded active autoimmune disease and 87 trials excluded active autoimmune disease requiring treatment. The remaining 37 trials had undefined exclusion. Studies that had larger enrollment of patients with autoimmune diseases were largely in industry. The complete exclusion of patients with autoimmune diseases has decreased recently. Exclusion of patients with active autoimmune disease requiring treatment was one of the common exclusion criteria found. Strict exclusion of patients with autoimmune diseases has been decreasing over the years.

The Predictive Value of ERCC1, RRM1, and Thymidylate Synthase in Advanced Malignant Pleural Mesothelioma Patients Treated with Platinum-Based Chemotherapy.

A rare yet severe neoplasia called malignant pleural mesothelioma (MPM) typically manifests itself in advanced stages. Despite some improvements in the treatment of patients with MPM, this malignancy continues to have a detrimental prognosis . The primary goal of the present study was to assess the associatin between ERCC1, RRM1, and thymidylate synthase (TS) expression and disease outcome in patients with malignant pleural mesothelioma (MPM) treated with either pemetrexed plus cisplatin or gemcitabine plus cisplatin. This prospective cohort study was done on ninety-one advanced MPM patients. The patients received either pemetrexed plus platinum (55 of 91) or gemcitabine plus platinum chemotherapy (36 of 91). Tissue biopsy was taken at time of diagnosis. Immunohistochemistry was used to assess the levels of ERCC1, RRM1, and TS transcription in tissue biopsies (paraffin embedded). Based on the findings, 70% of patients with low expression of TS had low expression of ERCC1, and 68% of patients with high expression of TS had high expression of ERCC1, suggesting a significat association between ERCC1 expression and TS expression (p0.005). However, there was no relation between ERCC1 and RRM1 expression patterns (p 0.296). In patients underwen platinum-based theraphy (n 91), a significant correlation was detected between low ERCC1 median High-scoring and longer progression time (TTP9.6 v 5.3 monthsP< .001) or overall survival (OS) (OS18.1 v 9.1 months P<0.001). A significant correlation was found between low TS protein expression and longer time progression (TTP 11.8 v 5.4 months P< .001) or OS (OS 19.8 v 8.5 months P <0.001) in patients undergoing pemetrexed plus platinum chemotherapy (n 55). Low RRM1 expression was accompanied by high progression free survival (TTP 10.6 v 3.8 months) and OS (OS 20.6 v 8.6 months) in patients receiving gemcitabine plus platinum chemotherapy. Based on the multivariate test results, the independent variables significantly affecting OS were tumor stage (HR 2.3 95% CI 1.1-4.9 p 0.021) and ERCC1 (HR 2.7 95% CI 1.7-4.3 p < 0.001). Decreased TS protein expression can be indicative of greater responsivness to pemtrexed and of longer TTP and OS in individuals with advanced MPM (locally progressed or metastatic) who are receiving pemetrexed-based chemotheraphy. Low ERCC1 expressions in individuals with advanced MPM can predict increased PFS and OS, as well as a better responsivness to platinum-based chemotherapy. In patients with progressed MPM receiving gemcitabine plus cisplatin chemotherapy, lower RRM1 expression was associated with a better prognosis, longer PFS, and longer OS.

A Primary Epithelioid Angiosarcoma Arising in a Bilharzial Urinary Bladder A Reappraisal and Case Report.

Angiosarcoma (AS) of the urinary bladder is a very rare and aggressive malignancy with a dismal outcome. Here, we report a primary epithelioid angiosarcoma (EAS) of the urinary bladder in a forty-nine-year-old male patient who presented with severe hematuria. Cystoscopic examination revealed hemorrhagic ulcerated bladder mucosa but no definite mass lesions. Intractable hematuria raised the initial clinical impression of idiopathic hemorrhagic cystitis. Analysis of the cystoscopic biopsy revealed features of old bilharzial cystitis, markedly atypical epithelioid endothelial cells arranged as primitive anastomosing vascular structures and expressing vascular markers. The diagnosis of EAS was established. The patient developed intractable severe hematuria, and a radical cystoprostatectomy was performed. The patient was started on chemotherapy but suddenly developed widespread distant metastasis (liver, lung, suprarenal glands, and lymph nodes) and succumbed to death two months after the surgery. To the best of these authors knowledge, we presented the first report of primary EAS arising in a bilharzial bladder. The relevant studies were discussed.

Targeted next-generation sequencing for the detection of cancer-associated somatic mutations in adenomyosis.

Adenomyosis is a condition characterised by the invasion of endometrial tissues into the uterine myometrium, the molecular pathogenesis of which remains incompletely elucidated. Lesion profiling with next-generation sequencing (NGS) can lead to the identification of previously unanticipated causative genes and the detection of therapeutically actionable genetic changes. Using an NGS panel that included 275 cancer susceptibility genes, this study examined the occurrence and frequency of somatic mutations in adenomyotic tissue specimens collected from 17 women. Extracted DNA was enriched using targeted formalin-fixed paraffin-embedded tissue cores prior to the identification of lesion-specific variants. The results revealed that

Network analysis of large-scale ImmGen and Tabula Muris datasets highlights metabolic diversity of tissue mononuclear phagocytes.

The diversity of mononuclear phagocyte (MNP) subpopulations across tissues is one of the key physiological characteristics of the immune system. Here, we focus on understanding the metabolic variability of MNPs through metabolic network analysis applied to three large-scale transcriptional datasets we introduce (1) an ImmGen MNP open-source dataset of 337 samples across 26 tissues (2) a myeloid subset of ImmGen Phase I dataset (202 MNP samples) and (3) a myeloid mouse single-cell RNA sequencing (scRNA-seq) dataset (51,364 cells) assembled based on Tabula Muris Senis. To analyze such large-scale datasets, we develop a network-based computational approach, genes and metabolites (GAM) clustering, for unbiased identification of the key metabolic subnetworks based on transcriptional profiles. We define 9 metabolic subnetworks that encapsulate the metabolic differences within MNP from 38 different tissues. Obtained modules reveal that cholesterol synthesis appears particularly active within the migratory dendritic cells, while glutathione synthesis is essential for cysteinyl leukotriene production by peritoneal and lung macrophages.

EGFR inhibitor-induced folliculitis decalvans a case series and management guidelines.

Epidermal growth factor receptor (EGFR) is one of therapeutic targets in oncology for solid tumors originating from epithelial tissue, such as non-small-cell lung carcinoma (NSCLC) and breast cancer. EGFR inhibitors used in cancer treatment may cause a broad spectrum of dose-dependent cutaneous adverse events, including acneiform papulopustular rash, nail and hair disturbances, xerosis, and mucositis. The pathogenesis of the EGFR inhibitor-induced adverse reactions originates from disturbances in keratinocyte differentiation, cytokine secretion, and neutrophil chemotaxis. One of the rare, yet distressing adverse events may be folliculitis decalvans, a progressive neutrophil-driven scarring alopecia with hair tufts formation resembling dolls hair. Early diagnosis and introduction of treatment are crucial for disease prognosis since a long course of the disease leads to decreased quality of life. Here, we review the literature cases of EGFR inhibitor-induced folliculitis decalvans and provide guidance on management and prevention of this condition in oncologic patients. Furthermore, we report the first afatinib-associated folliculitis decalvans in three female patients with NSCLC.

Assessment of survival outcomes among lung cancer patients at the National and Referral Hospital in Kenya.

Lung cancer has a low overall survival rate linked to late diagnosis and metastasis. Unfortunately, comprehensive data within the African continent are limited due to the lack of a registry, low public awareness of lung cancer, financial constraints, and inadequate screening and treatment facilities. In addition, there was a lack of conclusive data in our setting. Therefore, this study aimed to assess survival outcomes among lung cancer patients at Kenyatta National Hospital. A hospital-based retrospective cohort study was performed to examine the survival outcomes of 151 lung cancer patients. All eligible lung cancer patients diagnosed and treated in the facility between January 1, 2018, and December 31, 2020, were included. The patients were retrospectively followed from the date of primary cancer diagnosis until death or the last follow-up period. The Statistical Package for the Social Sciences (SPSS) version 20.0 statistical software was used to enter and analyze the data. Kaplan-Meier survival and Cox regression analysis were employed to determine median survival and predictors of mortality, respectively. The mean and median follow-time was 18.2 and 17.5 months, respectively. Most (98%) of the patients had non-small cell lung cancer. The 2-year survival rate was 66.7%, with 59.6% of patients having developed distant metastasis during the follow-up, while 25.1% were deceased. The median cancer-specific survival time among the study population was 18.0 ± 3.40 months. Cox regression analyses showed that patients with distant metastasis had five times more risk of dying (AHR 4.74, 95% CI 2.1-10.8, p < 0.001) than patients without distant metastasis. The overall two-year survival rate of lung cancer patients at the Kenyatta National Hospital was 66.7%, with most patients developed distant metastasis during the follow-up period. Distant metastasis was the only significant predictor of mortality among lung cancer patients in our setting.

Feasibility and effectiveness of segmentectomy versus wedge resection for clinical stage I non-small cell lung cancer.

With recent improvements in surgical techniques for segmentectomy, we hypothesized that segmentectomy is feasible and more effective than wedge resection for non-small cell lung cancer (NSCLC). We compared perioperative and oncological outcomes for segmentectomy and wedge resection. We performed a retrospective analysis of 720 patients who underwent sublobar resection (segmentectomy, 479 wedge resection, 241) for clinical stage 0 or I NSCLC from January 2017 to June 2020. An adequate surgical margin was defined as a surgical margin distance of ≥ 2 cm or ≥ the total tumour size. Recurrence-free survival (RFS) was estimated using the Kaplan-Meier method for clinical stage IA. There was no significant difference in the rate of major (grade ≥ III) complications between segmentectomy (1.7%) and wedge resection (1.2%) (P 0.76). The probability of obtaining adequate surgical margins was significantly higher with segmentectomy (71.4%) versus wedge resection (59.5%) (P 0.002), and the difference was especially prominent for clinical stage IA2 (75.3% vs 56.9% P 0.012). Among patients with clinical stage IA, segmentectomy significantly improved the RFS compared with wedge resection (hazard ratio 2.7 95% confidence interval 1.60-4.61 log-rank P < 0.001). Subgroup analysis based on tumour status revealed that segmentectomy had a better RFS in clinical stage IA2 (P < 0.001) and in pure-solid tumors (P 0.022) than wedge resection. We demonstrate that segmentectomy is a feasible procedure with comparable safety outcomes and better surgical margins and cancer control than wedge resection, particularly for clinical stage IA2 NSCLC.

Comparison of the prognosis of symptomatic cerebral infarction and pulmonary embolism in patients with advanced non-small cell lung cancer.

Lung cancer patients face a high risk of thromboembolism (TE), which is considered to be a poor prognostic factor. However, the impact of symptomatic cerebral infarction (CI) and pulmonary embolism (PE) on the prognosis of advanced non-small cell lung cancer (NSCLC) patients is not fully understood. We retrospectively identified 46 patients with advanced NSCLC who developed symptomatic CI or PE at five hospitals in Japan between January 2010 and December 2019. Prognosis and biomarker levels after incident CI and PE were investigated. Of the 46 patients, 36 developed symptomatic CI, and 10 developed symptomatic PE. The median follow-up duration after incident CI and PE was 18.2 months. Although the proportion of Common Terminology Criteria for Adverse Events grade 4 tended to be higher in patients with PE than in those with CI (30% vs. 11%, p 0.16), the overall survival (OS) after incident TE tended to be worse in patients with CI than in those with PE (median 2.3 months vs. 9.1 months, log-rank test p 0.17). Multivariate analysis showed that OS after CI was worse in patients with high D-dimer (DD) levels than in those with low DD levels at the time of incident CI (median 1.3 months vs. 8.3 months, log-rank p < 0.001). This retrospective study demonstrated that the prognosis of patients tended to be poorer after CI than after PE. The DD levels at the time of incident CI might be a promising predictor of clinical outcomes in advanced NSCLC patients who develop CI.

Comparison of the sensitivity of different criteria to select lung cancer patients for screening in a cohort of German patients.

Trials of CT-based screening for lung cancer have shown a mortality advantage for screening in North America and Europe. Before introducing a nationwide lung cancer screening program in Germany, it is important to assess the criteria used in international trials in the German population. We used data from 3623 lung cancer patients from the data warehouse of the German Center for Lung Research (DZL). We compared the sensitivity of the following lung cancer screening criteria overall and stratified by age and histology the National Lung Screening Trial (NLST), the Danish Lung Cancer Screening Trial (DLCST), the 2013 and 2021 US Preventive Services Task Force (USPSTF), and an adapted version of the Prostate, Lung, Colorectal, and Ovarian no race model (adapted PLCOm2012) with 6-year risk thresholds of 1.0%6 year and 1.7%6 year. Overall, the adapted PLCOm2012 model (1%6 years), selected the highest proportion of lung cancer patients for screening (72.4%), followed by the 2021 USPSTF (70.0%), the adapted PLCOm2012 (1.7%6 year) (57.4%), the 2013 USPTF (57.0%), DLCST criteria (48.7%), and the NLST (48.5%). The adapted PLCOm2012 risk model (1.0%6 year) had the highest sensitivity for all histological types except for small-cell and large-cell carcinomas (non-significant), whereas the 2021 USPTF selected a higher proportion of patients. The sensitivity levels were higher in males than in females. Using a risk-based selection score resulted in higher sensitivities compared to criteria using dichotomized age and smoking history. However, gender disparities were apparent in all studied eligibility criteria. In light of increasing lung cancer incidences in women, all selection criteria should be reviewed for ways to close this gender gap, especially when implementing a large-scale lung cancer screening program.

Clear cell stromal tumor of the lung with multinucleated giant cells a report of a case with YAP1-TFE3 fusion.

Clear cell (hemangioblastoma-like) stromal tumor of the lung (CCSTL) is a rare pulmonary neoplasm. Recently, 9 cases of CCSTL harboring the YAP1-TFE3 gene fusion have been described, and it has been suggested that this aberration could be a characteristic feature of this tumor. We here report another case of CCSTL in a 57-year-old male, which presented as a solitary lung nodule 45 mm in the greatest dimension. Microscopically, the tumor consisted of epithelioid to spindled cells with mild-to-moderate nuclear atypia, finely granular or vesicular chromatin, and small nucleoli. Nuclear indentations were a common finding. There were up to 3 mitoses per 10 HPF. The cytoplasm was slightly eosinophilic or clear. Scattered non-tumor large multinucleated cells were present. Immunohistochemically, the tumor cells showed diffuse positivity for TFE3, CD10, vimentin, and IFITM1. Other markers examined were negative, and the expression of lineage-specific markers was not found. NGS analysis revealed a fusion transcript of the YAP1 and TFE3 genes, and a pathogenic variant of the MUTYH gene. Our finding supports the recent data suggesting that CCSTL represents a distinct entity characterized by the recurrent YAP1-TFE3 fusion.

Disseminated cryptococcal infection with pulmonary involvement presenting as diffuse cavitary nodules in an immunocompromised patient a case report.

Disseminated cryptococcal infection is especially prone to occur in immunosuppressed hosts. We herein report the case of an immunosuppressed girl with disseminated cryptococcal infection in whom pulmonary cryptococcosis (PC) presented as diffuse cavitary pulmonary nodules, a finding which has rarely been reported. A 16-year-old immunocompromised girl presented with fever and a non-productive cough. A chest computed tomography (CT) scan revealed diffuse pulmonary nodules with cavities. Subsequent results were consistent with disseminated cryptococcosis with Cryptococcus identified in her blood, bone marrow and cerebrospinal fluid cultures. Thus, the patient was diagnosed with disseminated cryptococcal infection with PC, cryptococcus meningitis, cryptococcus osteomyelitis and cryptococcus sepsis. After antifungal treatment, the patient demonstrated both clinical and chest radiological improvement. The atypical clinical manifestations of a disseminated cryptococcal infection and the rare manner of chest CT findings of PC reported in our case are easy to misdiagnose. It is necessary to carry out a thorough search for a definitive diagnosis using various methods.

Lipid biomarkers that reflect postoperative recurrence risk in lung cancer patients who smoke a case-control study.

The risk of postoperative recurrence is higher in lung cancer patients who smoke than non-smokers. However, objective evaluation of the postoperative recurrence risk is difficult using conventional pathological prognostic factors because of their lack of reproducibility. Consequently, novel objective biomarkers that reflect postoperative risk in lung cancer patients who smoke must be identified. Because cigarette smoking and oncogenesis alter lipid metabolism in lung tissue, we hypothesized that the lipid profiles in lung cancer tissues are influenced by cigarette smoking and can reflect the postoperative recurrence risk in smoking lung cancer patients. This study aimed to identify lipid biomarkers that reflect the smoking status and the postoperative recurrence risk. Primary tumor tissues of lung adenocarcinoma (ADC) (n 26) and squamous cell carcinoma (SQCC) (n 18) obtained from surgery were assigned to subgroups according to the patients smoking status. The ADC cohort was divided into never smoker and smoker groups, while the SQCC cohort was divided into moderate smoker and heavy smoker groups. Extracted lipids from the tumor tissues were subjected to liquid chromatography-tandem mass spectrometry analysis. Lipids that were influenced by smoking status and reflected postoperative recurrence and pathological prognostic factors were screened. Two and 12 lipid peaks in the ADC and SQCC cohorts showed a significant positive correlation with the Brinkman index, respectively. Among them, in the ADC cohort, a higher lipid level consisted of three phosphatidylcholine (PC) isomers, PC (140182), PC (161161), and PC (160162), was associated with a shorter recurrence free period (RFP) and a greater likelihoods of progressed T-factor (≥ pT2) and pleural invasion. In the SQCC cohort, a lower mz 736.5276 level was associated with shorter RFP and greater likelihood of recurrence. From our data, we propose three PC isomers, PC (140182), PC (161161), and PC (160162), and a lipid peak of mz 736.5276 as novel candidate biomarkers for postoperative recurrence risk in lung ADC and SQCC patients who are smokers.

Identifying molecular targets of Aspiletrein-derived steroidal saponins in lung cancer using network pharmacology and molecular docking-based assessments.

Lung cancer is one of the leading cancers and causes of cancer-related deaths worldwide. Due to its high prevalence and mortality rate, its clinical management remains a significant challenge. Previously, the in vitro anticancer activity of Aspiletrein A, a steroid and a saponin from Aspidistra letreae, against non-small cell lung cancer (NSCLC) cells was reported. However, the anticancer molecular mechanism of other Aspiletreins from A. letreae remains unknown. Using in silico network pharmacology approaches, the targets of Aspiletreins were predicted using the Swiss Target Prediction database. In addition, key mediators in NSCLC were obtained from the Genetic databases. The compound-target interacting networks were constructed using the STRING database and Cytoscape, uncovering potential targets, including STAT3, VEGFA, HSP90AA1, FGF2, and IL2. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that several pathways were highly relevant to cancer pathogenesis. Additionally, molecular docking and molecular dynamic analyses revealed the interaction between key identified targets and Aspiletreins, including hydrogen bonding and Van der Waals interaction. This study provides potential targets of Aspiletreins in NSCLC, and its approach of integrating network pharmacology, bioinformatics, and molecular docking is a powerful tool for investigating the mechanism of new drug targets on a specific disease.

Monocarboxylate transporter 4 involves in energy metabolism and drug sensitivity in hypoxia.

Metabolic reprogramming of cancer cells is a potential target for cancer therapy. It is also known that a hypoxic environment, one of the tumor microenvironments, can alter the energy metabolism from oxidative phosphorylation to glycolysis. However, the relationship between hypoxia and drug sensitivity, which targets energy metabolism, is not well known. In this study, A549 cells, a cell line derived from lung adenocarcinoma, were evaluated under normoxia and hypoxia for the sensitivity of reagents targeting oxidative phosphorylation (metformin) and glycolysis (α-cyano-4-hydroxycinnamic acid CHC). The results showed that a hypoxic environment increased the expression levels of monocarboxylate transporter (MCT) 4 and hypoxia-induced factor-1α (HIF-1α), whereas MCT1 and MCT2 expression did not vary between normoxia and hypoxia. Furthermore, the evaluation of the ATP production ratio indicated that glycolysis was enhanced under hypoxic conditions. It was then found that the sensitivity to metformin decreased while that to CHC increased under hypoxia. To elucidate this mechanism, MCT4 and HIF-1α were knocked down and the expression level of MCT4 was significantly decreased under both conditions. In contrast, the expression of HIF-1α was decreased by HIF-1α knockdown and increased by MCT4 knockdown. In addition, changes in metformin and CHC sensitivity under hypoxia were eliminated by the knockdown of MCT4 and HIF-1α, suggesting that MCT4 is involved in the phenomenon described above. In conclusion, it was shown that the sensitivity of reagents targeting energy metabolism is dependent on their microenvironment. As MCT4 is involved in some of these mechanisms, we hypothesized that MCT4 could be an important target molecule for cancer therapy.

Discordance between clinical and pathologic staging and the timeliness of care of non-small cell lung cancer patients diagnosed with operable tumors.

This study was performed to evaluate concordance between clinical and pathologic staging of non-small cell lung cancer (NSCLC) in our hospital network. We retrospectively reviewed records of 417 patients with NSCLC who received curative surgery and whose pathology was evaluated in our hospital between 2016 and 2021. Cytology, tissue pathology, and associated clinical, surgical, and imaging information were retrieved from hospital digital records. The cohort included 214 female and 203 male patients aged 20.6-85.8 years. Median times among staging computed tomography and surgery (105 days interquartile range (IQR) 77.0-143.0), positron emission tomography and surgery (78.5 days IQR 56.0-109.0), and endobronchial ultrasound-guided transbronchial needle aspiration and surgery (59 days IQR 42-94) indicated that Australian guidelines of <42 days between original referral and commencement of treatment were not being met in the majority of cases. Discordance between clinical TNM (cTNM) and pathologic TNM staging was 25.9%, including 18.4% cases that were clinically understaged and two patients with undetected stage IVA disease. cTNM understaging was significantly associated with time between the final staging investigation and surgery (p .023), pleural (p < .05) and vessel (p < .05) invasion, and diagnosis of high-grade adenocarcinoma (p .001). Discordance between clinical and pathologic staging of NSCLC is associated with tumor histopathologic characteristics and treatment delays. Although tumor factors that lead to discordant staging cannot be controlled, reduced time to surgery may have resulted in better outcomes for some patients in this potentially curable lung cancer cohort.

Percentage Up to Date With Chest Computed Tomography Among Those Eligible for Lung Cancer Screening.

Authors aimed to calculate the percentage up-to-date with testing in the context of lung cancer screening across 5 healthcare systems and evaluate differences according to patient and health system characteristics. Lung cancer screening‒eligible individuals receiving care within the 5 systems in the Population-based Research to Optimize the Screening Process Lung consortium from October 1, 2018 to September 30, 2019 were included in analyses. Data collection was completed on June 15, 2021 final analyses were completed on April 1, 2022. Chest computed tomography scans and patient characteristics were obtained through electronic health records and used to calculate the percentage completing a chest computed tomography scan in the previous 12 months (considered up-to-date). The association of patient and healthcare system factors with being up-to-date was evaluated with adjusted prevalence ratios and 95% CIs using log-binomial regression models. There were 29,417 individuals eligible for lung cancer screening as of September 30, 2019 8,333 (28.3%) were up-to-date with testing. Those aged 65-74 years (prevalence ratio1.19 CI1.15, 1.24, versus ages 55-64), those with chronic obstructive pulmonary disease (prevalence ratio2.05 CI1.98, 2.13), and those in higher SES census tracts (prevalence ratio1.22 CI1.16, 1.30, highest quintile versus lowest) were more likely to be up-to-date. Currently smoking (prevalence ratio0.91 CI0.88, 0.95), having a BMI ≥30 kgm The percentage up-to-date with testing among those eligible for lung cancer screening is well below up-to-date estimates for other types of cancer screening, and disparities in lung cancer screening participation remain.

Paraneoplastic Lambert-Eaton myasthenic syndrome a diagnostic challenge.

Lambert-Eaton myasthenic syndrome (LEMS) is a rare neuromuscular junction disorder. Underlying small cell lung cancer is found in more than half of patients. Proximal muscle weakness, autonomic features and areflexia are typical manifestations. However, LEMS is often misdiagnosed. We report a rare case of paraneoplastic LEMS, identified amid admission due to a different diagnosis. Our patient was initially admitted due to aspiration pneumonia. Further investigation revealed clinical and electrophysiological manifestations of LEMS. High clinical suspicion and early diagnostic workup were paramount in the patient outcome. Nevertheless, paraneoplastic aetiology was difficult to confirm and revealed itself a difficult challenge. Clinical awareness is crucial to diagnose LEMS and urge cancer screening and early treatment.

Safety and Effectiveness of Percutaneous Image-Guided Thermal Ablation of Juxta-cardiac Lung Tumors.

To evaluate the safety and effectiveness of percutaneous image-guided thermal ablation (IGTA) for juxta-cardiac lung tumors. This bi-institutional retrospective cohort study included 23 consecutive patients (13 57% males, mean age 55±18 years) with 30 juxta-cardiac lung tumors located ≤10 mm from the pericardium treated with 28 IGTA sessions (25 cryoablations, three microwave ablations) between 42008-82022. The primary outcome was any adverse cardiac event within 90 days post ablation. Secondary outcomes included non-cardiac adverse events, local tumor progression-free survival (LT-PFS), and the cumulative incidence of local tumor progression with death as a competing risk. Two tumors treated without curative intent or follow-up imaging were considered in the safety analysis but not in the progression analysis. The median imaging follow-up was 22 months (interquartile range IQR 10-53 months). Primary technical success was achieved in 25 (89%) ablations. No adverse cardiac events attributable to IGTA occurred. One patient experienced a phrenic nerve injury. The median LT-PFS was 59 months (IQR 32-73 months). At 1-, 3-, and 5-years, LT-PFS was 90% (95% confidence interval CI 78%-100%), 74% (CI 53%-100%), and 45% (CI 20%-97%) and cumulative incidence of local tumor progression was 4.3% (CI 0.29%-19%), 11% (CI 1.6%-30%), and 26% (CI 3.3%-58%). IGTA is safe and effective for lung tumors located ≤10 mm from the pericardium. No adverse cardiac events were not observed within 90 days following ablation.

Inter- and intrafractional 4D dose accumulation for evaluating ΔNTCP robustness in lung cancer.

Model-based selection of proton therapy patients relies on a predefined reduction in normal tissue complication probability (NTCP) with respect to photon therapy. The decision is necessarily made based on the treatment plan, but NTCP can be affected when the delivered treatment deviates from the plan due to delivery inaccuracies. Especially for proton therapy of lung cancer, this can be important because of tissue density changes and, with pencil beam scanning, the interplay effect between the proton beam and breathing motion. In this work, we verified whether the expected benefit of proton therapy is retained despite delivery inaccuracies by reconstructing the delivered treatment using log-file based dose reconstruction and inter- and intrafractional accumulation. Additionally, the importance of two uncertain parameters for treatment reconstruction, namely deformable image registration (DIR) algorithm and αβ ratio, was assessed. The expected benefit or proton therapy was confirmed in 97% of all studied cases, despite regular differences up to 2 percent point (p.p.) NTCP between the delivered and planned treatments. The choice of DIR algorithm affected NTCP up to 1.6 p.p., an order of magnitude higher than the effect of αβ ratio. For the patient population and treatment technique employed, the predicted clinical benefit for patients selected for proton therapy was confirmed for 97.0% percent of all cases, although the NTCP based proton selection was subject to 2 p.p. variations due to delivery inaccuracies.

We aimed to assess if radiation dose escalation to either the whole primary tumour, or to an Patients with inoperable, stage II-III NSCLC were randomised (11) to receive dose-escalated radiotherapy to the whole primary tumour or a PET-defined subvolume, in 24 fractions. The primary endpoint was freedom from local failure (FFLF), assessed by central review of CT-imaging. A phase II pick-the-winner design (alpha 0.05 beta 0.80) was applied to detect a 15 % increase in FFLF at 1-year. govNCT01024829. 150 patients were enrolled. 54 patients were randomised to the whole tumour group and 53 to the PET-subvolume group. The trial was closed early due to slow accrual. Median dosefraction to the boosted volume was 3.30 Gy in the whole tumour group, and 3.50 Gy in the PET-subvolume group. The 1-year FFLF rate was 97 % (95 %CI 91-100) in whole tumour group, and 91 % (95 %CI 82-100) in the PET-subvolume group. Acute grade ≥ 3 adverse events occurred in 23 (43 %) and 20 (38 %) patients, and late grade ≥ 3 in 12 (22 %) and 17 (32 %), respectively. Grade 5 events occurred in 19 (18 %) patients in total, of which before disease progression in 4 (7 %) in the whole tumour group, and 5 (9 %) in the PET-subvolume group. Both strategies met the primary objective to improve local control with 1-year rates. However, both strategies led to unexpected high rates of grade 5 toxicity. Dose differentiation, improved patient selection and better sparing of central structures are proposed to improve dose-escalation strategies.

Visualization of tumor hypoxia and re-oxygenation after stereotactic body radiation therapy in early peripheral lung cancer A prospective study.

In this study, fluoromisonidazole positron emission tomography (F-MISO PETCT) was used to evaluate tumor hypoxia and re-oxygenation in patients with lung tumors treated with stereotactic body radiation therapy (SBRT). Patients with T1-2 N0 lung cancer were included in this study. The prescribed dose was 48-52 Gy in four fractions. F-MISO PETCT was performed twice, before SBRT and 1-3 days after the first irradiation. The maximum standardized uptake value (SUVmax) and tumormuscle ratio (TMR) were evaluated as indicators of hypoxia. The threshold for hypoxia was defined as a TMR of 1.30 or more. Between 2016 and 2021, 15 patients were included. Pre-treatment tumor hypoxia was observed in nine tumors (60 %). TMR in all six tumors without pre-treatment hypoxia rose after single high-dose irradiation. In contrast, TMR in six of nine tumors with pre-treatment hypoxia dropped after irradiation, suggesting re-oxygenation. Although no local recurrence was noted, regional andor distant relapses were seen in four patients (27 %). Of these, three had tumors with abnormal F-MISO uptake. The remaining patient had a tumor without signs of hypoxia on pre-treatment PETCT. The 2-year progression free survival of patients with tumors with and without pre-treatment hypoxia were 30 % and 63 %, respectively (p 0.319). Tumor hypoxia reduced after single high-dose irradiation. Tumor with F-MISO uptake seems to be an unfavorable prognostic factor in lung SBRT.

External validation of the SORG machine learning algorithms for predicting 90-day and 1-year survival of patients with lung cancer-derived spine metastases--a recent bi-center cohort from China.

The survival prediction of lung cancer-derived spinal metastases is often underestimated by several scores. The SORG machine learning (ML) algorithm is considered a promising tool to predict the risk of 90-day and 1-year mortality in patients with spinal metastases, but not been externally validated for lung cancer. This study aimed to externally validate the SORG ML algorithms on lung cancer-derived spinal metastases patients from two large-volume, tertiary medical centers between 2018 and 2021. Retrospective, cohort study PATIENT SAMPLE Patients aged 18 years or older at two tertiary medical centers in China are treated surgically for spinal metastasis. Mortality within 90 days of surgery, mortality within 1 year of surgery METHODS The baseline characteristics were compared between the development cohort and our validation cohort. Discrimination (receiver operating curve), calibration (calibration plot, intercept, and slope), the overall performance (Brier score), and decision curve analysis was used to assess the overall performance of the SORG ML algorithms. This study included 150 patients with lung cancer-derived spinal metastases from two medical centers in China. Ninety-day and 1-year mortality rates were 12.9% (19147) and 51.3% (60117), respectively. Lung Cancer with targeted therapies had the lowest Hazard Ratio (HR0.490), showing an optimal protecting factor. The AUC of the SORG ML algorithm for 90-day mortality prediction in lung cancer-derived spinal metastases is 0.714. While the AUC for 1-year mortality prediction is 0.832(95CI%, 0.758-0.906). The algorithm for 1-year mortality was well-calibrated with an intercept of 0.13 and a calibration slope of 1.00. However, the 90-day mortality prediction was underestimated with an intercept of 0.60 and a slope of 0.37. The SORG ML algorithms for 1-year mortality showed a greater net benefit than the treats all or no patients strategies. In the latest cohort of lung cancer-derived spinal metastases in China, the SORG algorithms for predicting 1-year mortality performed well on external validation. However, 90-day mortality was underestimated. The algorithm should be further validated by single primary tumor-derived metastasis treated with the latest comprehensive treatment in diverse populations.

Multifunctional gold nanorods in low-temperature photothermal interactions for combined tumor starvation and RNA interference therapy.

Collateral damage to healthy tissue, uneven heat distribution, inflammatory diseases, and tumor metastasis induction hinder the translation of high-temperature photothermal therapy (PTT) from bench to practical clinical applications. In this report, a multifunctional gold nanorod (GNR)-based nanosystem was designed by attaching siRNA against B7-H3 (B7-H3si), glucose oxidase (GOx), and hyaluronic acid (HA) for efficient low-temperature PTT. Herein, GOx can not only exhaust glucose to induce starvation therapy but also reduce the heat shock protein (HSP), realizing the ablation of tumors without damage to healthy tissues. Evidence shows that B7-H3, a type I transmembrane glycoprotein molecule, plays essential roles in growth, metastasis, and drug resistance. By initiating the downregulation of B7-H3 by siRNA, siRNA-GOxGNRHA NPs may promote the effectiveness of treatment. By targeting cluster of differentiation 44 (CD44) and depleting B7-H3 and HSPs sequentially, siRNA-GOxGNRHA NPs showed 12.9-fold higher lung distribution than siRNA-GOxGNR NPs. Furthermore, 50% of A549-bearing mice in the siRNA-GOxGNR NPs group survived over 50 days. Overall, this low-temperature phototherapeutic nanosystem provides an appropriate strategy for eliminating cancer with high treatment effectiveness and minimal systemic toxicity. STATEMENT OF SIGNIFICANCE To realize efficient tumor ablation under mild low-temperature (42-45 ℃) and RNA interference simultaneously, here we developed a multifunctional gold nanorod (GNR)-based nanosystem (siRNA-GOxGNRHA NPs). This nanoplatform can significantly inhibit tumor cell proliferation and induce cell apoptosis by downregulation of HSP90α, HSP70, B7-H3, p-AKT, and p-ERK and upregulation of cleaved caspase-9 at mild low-temperature due to its superior tumor homing ability and the combined effect of photothermal effect, glucose deprivation-initiated tumor starvation, and B7-H3 gene silence effect. It is believed that this multifunctional low-temperature photothermal nanosystem with efficient and specific anticancer properties, shows a potential application in clinical tumor treatment.

Phase I Study of Single-Agent Anti-Programmed Death-1 (MDX-1106) in Refractory Solid Tumors Safety, Clinical Activity, Pharmacodynamics, and Immunologic Correlates.

Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This phase I study sought to determine the safety and tolerability of anti-PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity, pharmacodynamics, and immunologic correlates. Thirty-nine patients with advanced metastatic melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer, non-small-cell lung cancer (NSCLC), or renal cell carcinoma (RCC) received a single intravenous infusion of anti-PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3, 1, 3, or 10 mgkg, followed by a 15-patient expansion cohort at 10 mgkg. Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy. Anti-PD-1 was well tolerated one serious adverse event, inflammatory colitis, was observed in a patient with melanoma who received five doses at 1 mgkg. One durable complete response (CRC) and two partial responses (PRs melanoma, RCC) were seen. Two additional patients (melanoma, NSCLC) had significant lesional tumor regressions not meeting PR criteria. The serum half-life of anti-PD-1 was 12 to 20 days. However, pharmacodynamics indicated a sustained mean occupancy of > 70% of PD-1 molecules on circulating T cells ≥ 2 months following infusion, regardless of dose. In nine patients examined, tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment. Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity. Exploration of alternative dosing regimens and combinatorial therapies with vaccines, targeted therapies, andor other checkpoint inhibitors is warranted.

A rare case of canalicular adenoma in the parotid gland Highlighting diagnostic limitations of fine-needle aspiration.

Canalicular adenoma is a rare, benign tumor of primarily salivary gland origin that presents mostly in the upper lip. However, there are only six reports in the English literature detailing canalicular adenoma of the parotid gland, none of which discuss discrepancy between preoperative cytology and surgical pathology. In this report, we present a rare case of parotid gland canalicular adenoma where preoperative ultrasound-guided fine-needle aspiration (USFNA) suggested malignancy. The patient was treated with deep lobe parotidectomy due to the FNA results and her multiple comorbidities. However, her tumor may have been treated with observation alone if canalicular adenoma had been suspected prior to surgery. A 59-year-old female with a history of heart and lung disease presented with a 1.6 cm well defined, enhancing lesion involving the superficial portion of the right parotid gland. This lesion was incidentally noted on CT angiography (CTA) of the neck and chest. The well-defined characteristics of this lesion on CT imaging suggested benign neoplasm. However, USFNA results were suggestive of a malignant parotid lesion. The patient subsequently underwent right deep lobe parotidectomy with facial nerve dissection and superficial musculoaponeurotic system (SMAS) rotational flap reconstruction. Surgical pathology and immunohistochemistry yielded a final diagnosis of benign canalicular adenoma. USFNA diagnosis of CA is extremely difficult due to its low-grade neoplastic cells mimicking neoplastic cells in other benign and malignant tumors of the head and neck. FNA remains a useful tool for assessing malignancy risk, but the results always have some level of uncertainty and do not provide sufficient detail. Therefore, FNA results should be interpreted in concert with imaging and patients medical history. Cytopathologists can also report salivary gland FNA results in a more uniform and detailed manner by utilizing the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC).

Synergistic effect of cucurbitacin E and myricetin on Anti-Non-Small cell lung cancer Molecular mechanism and therapeutic potential.

Non-small cell lung cancer (NSCLC) is associated with extremely high morbidity and mortality rates worldwide. Citrullus colocynthis (L.) Schrad, widely distributed in Asian and African countries, is used to treat cancers in traditional Uyghur medicine. The combination of Cucurbitacin E (CuE) and Myricetin (Myr) of C. colocynthis could treat NSCLC by targeting autophagy. The potential anti-cancer components (CuE and Myr) of C. colocynthis were identified using in-silico methods and further in vitro explored the anti-NSCLC properties of the combination of CuE and Myr. Network pharmacology and molecular docking were used to identify potential therapeutic compounds of C. colocynthis for the treatment of NSCLC. In A549 cells, the anti-cancer activities and synergy of CuE and Myr were studied using CompuSyn, their mechanism behind autophagy regulation was determined by western blotting and immunofluorescence staining. CuMy-12 (CuE 0.5 µM, Myr 20 µM), a combination of CuE and Myr from C. colocynthis, inhibited A549 cell proliferation and colony formation, and induced apoptosis and cell cycle arrest in the G0G1 phase, exhibiting a synergistic effect. Furthermore, CuMy-12 inhibited autophagy and activation of the PI3KAKTmTOR signaling pathway, which was characterized by a decrease in Beclin 1, AKT, and phospho-AKT proteins. CuMy-12 can be considered a natural candidate with anticancer activity for autophagy-based regulation, but mechanistic and clinical studies are required to validate its potential.

Radiologic and histopathologic features of hydrogel sealant after lung resection in participants of a prospective randomized clinical trial.

To summarize imaging and histopathologic characteristics of hydrogel sealant (plug) in lung parenchyma and assess their correlation with time since deployment of sealant. Among a total of 208 participants randomized to the hydrogel sealant arm of a lung biopsy prospective randomized clinical trial, 51 underwent resection of the biopsied lesion. In 34 participants sealant material was present on histopathologic sections (n 22), or they had cross-sectional imaging of chest between biopsy and resection (n 23) or they had both imaging and histopathology (n 11). Histopathologic and imaging findings were described. The association of these findings with time since sealant deployment was evaluated using the Wilcoxon rank sum test. The mean time since sealant deployment for histopathology was 45.7 days (median 36, range 14-181) and for imaging studies was 99 days (median 32, range 4-527). The sealant was infiltrated by inflammatory cells in 20 (91%) participants. The main general histopathologic pattern of sealant was foamy in 12 (57%) and mesh in 8 (38%) participants. Imaging appearance of sealant was serpiginous in 18 (60%), linear in 10 (33%) or lobulated in 2 (6.7%) participants. In 2 participants the sealant was hypermetabolic with no histopathologic evidence of tumor. No correlation was found between time since sealant deployment and imaging or histopathologic appearances. Hydrogel sealant appears as a serpiginous, linear, or lobulated opacity on cross-sectional imaging which can be metabolically active. It is associated with an inflammatory reaction with a foamy or mesh general pattern on histopathological assessment. No correlation was found between time since sealant deployment and imaging or histopathologic appearances.

Does the presence of a micropapillary component predict worse prognosis in pathological stage IA lung adenocarcinoma

Considerable evidence has verified that the micropapillary pattern is significantly associated with worse prognosis in pulmonary adenocarcinoma. However, whether the presence of a micropapillary component in pathological stage IA lung adenocarcinoma is also related to worse prognosis remains unclear up to now. The aim of this meta-analysis was to identify the prognostic role of presence of a micropapillary component in pathological stage IA lung adenocarcinoma patients. Relevant studies were searched from the PubMed, EMBASE, Web of Science and CNKI databases and reviewed. The primary and secondary outcomes were the recurrence risk and long-term survival including the overall survival (OS) and disease-free survival (DFS), respectively. All statistical analysis were conducted by STATA 12.0 software. A total of 5257 lung adenocarcinoma patients at the pathological stage IA from ten retrospective studies were enrolled. The recurrence rates in pathological stage IA lung adenocarcinoma patients with and without the a micropapillary component were 32% 95% confidence interval (CI) 20%- 44% and 7% (95% CI 4%-10%) separately and pooled results indicated that presence of a micropapillary component was an obvious risk factor for recurrence odds ratio (OR) 3.41, 95% CI 2.80-4.16, P＜0.001. Besides, the presence of a micropapillary component was significantly related to poorer OS hazard ratio (HR) 2.44, 95% CI 1.28-4.68, P 0.007 and DFS (HR2.60, 95% CI 1.63-4.16, P＜0.001). Subgroup analysis focusing on invasive adenocarcinoma manifested consistent results. In pathological stage IA lung adenocarcinoma, the presence of a micropapillary component predicts obviously higher recurrence risk and worse prognosis even after focusing on invasive adenocarcinoma. However, more prospective high-quality studies are still needed to verify our findings.

TPGS decorated NLC shift gefitinib from portal absorption into lymphatic delivery Intracellular trafficking, biodistribution and bioavailability studies.

Lymphatic drug delivery (LDD) is an attractive option for the prevention and treatment of cancer metastasis. This study aims to develop TPGS decorated nanostructure lipid carrier gefitinib loaded (TPGS-NLC-GEF). Biocompatibility and cytotoxicity were studied using erythrocytes and A549 cell lines. Furthermore, cellular uptake of the prepared TPGS-NLC was studied using 5-carboxyfluorescein (5-CF). Pharmacokinetic, biodistribution, and chylomicron-block flow studies were performed using male Wister Albino rats to investigate the influence of TPGS-NLC on plasma concentration-time profile, organ deposition, and LDD of GEF. The present results indicated that the prepared TPGS-NLC and TPGS-NLC-GEF formulation had a particle size range of 268 and 288 nm with a negative zeta-potential value of - 29.3 and - 26.5 mV, respectively. The in-vitro release showed burst drug release followed by sustained release. In addition, the biosafety in the term of the hemocompatibility study showed that the prepared formulation was safe at the therapeutic level. Additionally, an in-vitro cytotoxicity study showed that the TPGS-NLC was able to enhance the activity of GEF against the A549 cell line. The cellular uptake study showed the ability of TPGS-NLC to enhance 5-CF internalization by 12.6-fold compared to the 5-CF solution. Furthermore, the in-vivo study showed that TPGS-NLC was able to enhance GEF bioavailability (1.5-fold) through lymphatic system which was confirmed via the indirect chylomicron-block flow method. The tissue distribution study showed the ability of lipid nanoparticles to enhance lung drug deposition by 5.8-fold compared to a GEF suspension. This study concluded that GEF-NLC-GEF is an encouraging approach for the treatment of metastatic lung cancer through lymphatic delivery, enhanced bioavailability, and reduced systemic toxicity.

A Case of Pneumocystis jirovecci in a Patient with Non-Small Cell Lung Cancer Treated with Immunotherapy.

Immune checkpoint inhibitors have become the standard of care in the management of metastatic non-small cell lung cancer (NSCLC) and are associated with improved outcomes when compared to traditional chemotherapy regimens. However, they present with their own unique set of immune-related side effects. One immune-related adverse effect that can arise is pneumonitis, where patients present with dyspnea with nonspecific radiologic findings, making it challenging to differentiate from other etiologies causing dyspnea. We present a case of a 58-year-old woman with NSCLC previously treated with immunotherapy, who presented with shortness of breath. She was initially thought to have immune-related pneumonitis and was treated with immunosuppressive therapy. After several days of treatment, bronchoscopy demonstrated a positive polymerase chain reaction (PCR) for Pneumocystis jirovecii (PJP) after an initial negative direct fluorescent antibody (DFA). The patient was started on appropriate management for PJP and no further immunosuppressive therapy was given.

Differential effects of WRAP53 transcript variants on non-small cell lung cancer cell behaviors.

The WD40-encoding RNA antisense to p53 (WRAP53) is an antisense gene of TP53 with three transcriptional start sites producing three transcript variants involved in the progression of non-small cell lung cancer. However, the mechanism by which these different transcript variants regulate non-small cell lung cancer cell behaviors is to be elucidated. Two non-small cell lung cancer cell lines, A549 cells with wild-type p53 and H1975 with mutated p53, were transfected with WRAP53-1α and WRAP53-1β siRNA. The biological effects were assessed via colony formation, cell viability, apoptosis, cell cycle, wound healing and cell invasion assays, as well as immunoblotting. Knockdown of WRAP53-1α increased the mRNA and protein levels of p53 suppressed colony formation and proliferation of A549 cells but promoted them in H1975 cells increased the proportion of cells in the G0G1 phase in A549 cells but decreased that in H1975 cells and suppressed migration and invasion in A549 cells but not in H1975 cells. Conversely, knockdown of WRAP53-1β had no effect on p53 expression promoted the growth of A549 cells but not of H1975 cells decreased the proportion of cells in the G0G1 phase in A549 cells but not in H1975 cells and promoted migration and invasion in A549 cells but not in H1975 cells. Knockdown of both WRAP53-1α and WRAP53-1β promoted apoptosis in A549 cells but not in H1975 cells. WRAP53 transcript variants exerted different functions in non-small cell lung cancer cells and regulated non-small cell lung cancer cell behaviors depending on the p53 expression.

Correlation between metastatic patterns and age in patients with metastatic primary liver cancer A population-based study.

Primary liver cancer is usually diagnosed at advanced stages with distant metastasis, underlying the high metastatic rate and mortality in patients. This study aimed to analyse the metastatic patterns and prognosis of primary liver cancer, and its relationship with age and several other factors, such as histological variants, TNM stage, and grade. We included data from 5274 patients from the Surveillance, Epidemiology, and End Results (SEER) database of the American National Cancer Institute diagnosed with primary liver cancer with metastatic disease between 2010 and 2015. The correlation between the metastatic patterns of primary liver cancer and age was evaluated. The hazard ratio (HR) and 95% confidence intervals (CI) for overall survival were calculated by applying univariate Cox analysis, while the correlation between the metastatic patterns and age was analysed by applying multivariate Cox analysis. We also plotted Kaplan-Meier curves to illustrate the correlation between overall survival (OS) and various factors. Several factors were associated with poorer prognosis, including age>60 years, histologic type of spindle cell variant, higher grade, no surgery, tumour size ≥ 1 cm, and lung metastasis. The rate of metastasis increased with age. Older patients (> 50 years) were prone to bone metastasis, while less likely to have lung metastasis compared with younger patients (< 50 years). Patients with lung metastasis had a higher risk of being diagnosed with metastasis in other locations. Furthermore, surgery significantly reduced mortality and primary site surgery in particular, mitigated the risk of bone and lung metastases. Our study shows the correlation of prognosis and metastatic patterns with age and several other factors. The findings can hopefully provide knowledge that will allow a better diagnosis and management of elderly patients with primary liver cancer.

Carcinoembryonic Antigen-Related Cell Adhesion Molecule Type 5 Receptor-Targeted Fluorescent Intraoperative Molecular Imaging Tracer for Lung Cancer A Nonrandomized Controlled Trial.

Localization of subcentimeter ground glass opacities during minimally invasive thoracoscopic lung cancer resections is a significant challenge in thoracic oncology. Intraoperative molecular imaging has emerged as a potential solution, but the availability of suitable fluorescence agents is a limiting factor. To evaluate the suitability of SGM-101, a carcinoembryonic antigen-related cell adhesion molecule type 5 (CEACAM5) receptor-targeted near-infrared fluorochrome, for molecular imaging-guided lung cancer resections, because glycoprotein is expressed in more than 80% of adenocarcinomas. For this nonrandomized, proof-of-principal, phase 1 controlled trial, patients were divided into 2 groups between August 1, 2020, and January 31, 2022. Patients with known CEACAM5-positive gastrointestinal tumors suggestive of lung metastasis were selected as proof-of-principle positive controls. The investigative group included patients with lung nodules suggestive of primary lung malignant neoplasms. Patients 18 years or older without significant comorbidities that precluded surgical exploration with suspicious pulmonary nodules requiring surgical biopsy were included in the study. SGM-101 (10 mg) was infused up to 5 days before index operation, and pulmonary nodules were imaged using a near-infrared camera system with a dedicated thoracoscope. SGM-101 localization to pulmonary nodules and its correlation with CEACAM5 glycoprotein expression by the tumor as quantified by tumor and normal pulmonary parenchymal fluorescence. Ten patients (5 per group 5 male and 5 female median IQR age, 66 58-69 years) with 14 total lesions (median range lesion size, 0.91 0.90-2.00 cm) were enrolled in the study. In the control group of 4 patients (1 patient did not undergo surgical resection because of abnormal preoperative cardiac clearance findings that were not deemed related to SGM-101 infusion), the mean (SD) lesion size was 1.33 (0.48) cm, 2 patients had elevated serum CEA markers, and 2 patients had normal serum CEA levels. Of the 4 patients who underwent surgical intervention, those with 2 and 3 tissue CEACAM5 expression had excellent tumor fluorescence, with a mean (SD) tumor to background ratio of 3.11 (0.45). In the patient cohort, the mean (SD) lesion size was 0.68 (0.22) cm, and no elevations in serum CEA levels were found. Lack of SGM-101 fluorescence was associated with benign lesions and with lack of CEACAM5 staining. This in-human proof-of-principle nonrandomized controlled trial demonstrated SGM-101 localization to CEACAM5-positive tumors with the detection of real-time near-infrared fluorescence in situ, ex vivo, and by immunofluorescence microscopy. These findings suggest that SGM-101 is a safe, receptor-specific, and feasible intraoperative molecular imaging fluorochrome that should be further evaluated in randomized clinical trials. ClinicalTrials.gov identifier NCT04315467.

A molecular phenotypic map of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare understudied cancer associated with exposure to asbestos. So far, MPM patients have benefited marginally from the genomics medicine revolution due to the limited size or breadth of existing molecular studies. In the context of the MESOMICS project, we have performed the most comprehensive molecular characterization of MPM to date, with the underlying dataset made of the largest whole-genome sequencing series yet reported, together with transcriptome sequencing and methylation arrays for 120 MPM patients. We first provide comprehensive quality controls for all samples, of both raw and processed data. Due to the difficulty in collecting specimens from such rare tumors, a part of the cohort does not include matched normal material. We provide a detailed analysis of data processing of these tumor-only samples, showing that all somatic alteration calls match very stringent criteria of precision and recall. Finally, integrating our data with previously published multiomic MPM datasets (n 374 in total), we provide an extensive molecular phenotype map of MPM based on the multitask theory. The generated map can be interactively explored and interrogated on the UCSC TumorMap portal (httpstumormap.ucsc.edupRCGMESOMICSMPMArchetypes ). This new high-quality MPM multiomics dataset, together with the state-of-art bioinformatics and interactive visualization tools we provide, will support the development of precision medicine in MPM that is particularly challenging to implement in rare cancers due to limited molecular studies.

Cip2a induces arginine biosynthesis and promotes tumor progression in non-small cell lung cancer.

Cancerous inhibitor of protein phosphatase 2A (Cip2a) is an oncoprotein, playing important roles in tumor progression. However, the underlying mechanisms by which Cip2a promotes tumor aggressiveness in NSCLC remain to be further investigated. In this study, we found that Cip2a expression is elevated in NSCLC and correlates with poor prognosis. Knockdown of Cip2a significantly reduced the ability of cell proliferation, invasion, and metastasis of NSCLC both in vitro and in vivo. Furthermore, we found that Cip2a promotes tumor progression partly by inducing arginine biosynthesis, and knockdown of Cip2a exhibited a significantly increased sensitivity to arginine deprivation and mTOR inhibition. In addition, we found that p53 mutants in NSCLC cells increased Cip2a expression by inhibiting the activity of wild-type p53. Our findings provide new insights into the mechanisms of Cip2a in promoting tumor progression and suggest that Cip2a represents a potential therapeutic target for treating NSCLC.

Choriocarcinoma masquerading as lumbar spinal tumor Case report and literature review.

Choriocarcinoma is a highly invasive gestational trophoblastic neoplasm, usually metastasis to lung and brain, but occurrence of choriocarcinoma following spontaneous abortion presenting as a vertebral tumor is extremely rare, to the best of our knowledge. Because of the poor diagnosis and high malignancy, the low progression-free survival follows up. We here are reporting a case of choriocarcinoma that presented with vertebral tumor induced paralysis of limbs and incontinence of urine. Combined with the childbearing history, high β-human chorionic gonadotrophinin levels, and imaging examination, a clinical diagnosis was made exactly. Till the pathological results after the operation of lumbar spinal canal tumorectomy, the diagnosis was exactly clear. After performing the laminectomy, the fierce bleeding follows up, just did the temporary limited decompression. Because of the vertebral artery embolization, lumbar spinal canal tumorectomy, spinal canal and root canal decompression, subdural decompression and hematoma removal were performed. After performing the operation and chemotherapy timely and positively, the patient lost consciousness and died due to the pulmonary embolism at last. This is the first case report describing choriocarcinoma with metastases to the spine amongst Chinese population as well. Early metastasis is one of the marked tendencies of choriocarcinoma, but spine metastasis and the related spinal oppressional symptoms were found instead of vaginal bleeding in this case, which is indeed rare.

Comparative study of the genomic landscape and tumor microenvironment among large cell carcinoma of the lung, large cell neuroendocrine of the lung, and small cell lung cancer.

Deciphering the genomic profiles and tumor microenvironment (TME) in large cell carcinomas of the lung (LCC), large cell neuroendocrine of the lung (LCNEC), and small cell lung cancer (SCLC) might contribute to a better understanding of lung cancer and then improve outcomes. Ten LCC patients, 12 LCNEC patients, and 18 SCLC patients were enrolled. Targeted next-generation sequencing was used to investigate the genomic profiles of LCC, LCNEC, and SCLC. Tumor-infiltrating lymphocytes (TILs) within cancer cell nests and in cancer stroma were counted separately. Precise 60% of LCNEC patients harbored classical non-small cell lung cancer driver alterations, occurring in BRAF, KRAS, ROS1, and RET. More than 70% of SCLC patients harbored TP53-RB1 co-alterations. Moreover, 88.9%, 40%, and 77.8% of LCC, LCNEC, and SCLC cases had a high tumor mutation burden level with more than 7 mutationsMb. Furthermore, high index of CD68 CD163 (TILs within cancer cell nests TILs within cancer cell nests and in cancer stroma, P .041, 548 days vs not reached) and CD163 TILs (P .041, 548 days vs not reached) predicted a shorter OS in SCLC. Our findings revealed the distinct genomic profiles and TME contexture among LCC, LCNEC, and SCLC. Our findings suggest that stratifying LCNECSCLC patients based on TME contexture might help clinical disease management.

Lung and bone metastases patterns in osteosarcoma Chemotherapy improves overall survival.

Osteosarcoma (OS) is a malignant tumor originating from the mesenchymal tissue. Simultaneous reports of lung and bone metastases (BM) in OS are rare in the literature. A total of 353 new cases of lung metastases (LM), 93 new cases of BM, and 59 new cases of LM and BM were diagnosed in the Surveillance, Epidemiology and End Results (SEER) database from 2010 to 2019. Univariate and multivariate logistic regression analyses were used to identify risk factors for LM andor BM, and Cox regression analyses were performed to identify the prognostic factors for LM andor BM. Kaplan-Meier (K-M) curves and log-rank tests were used to analyze the overall survival of patients with LM andor BM. LM was diagnosed in 353 patients. Female sex, tumor size >100 mm, telangiectatic OS type, central OS type, N1 stage, other locations, BM, surgical treatments, radiotherapy and chemotherapy were significantly correlated with LM. 93 patients were diagnosed with BM. 25 to 59 years old, T1 stage, presence of LM, liver metastases, radiotherapy, and surgical treatments were significantly correlated with the BM. 59 patients were diagnosed with LM and BM. The chondroblastic OS type, small cell OS type, T1 stage, N1 stage, other locations, liver metastases, radiotherapy, and surgical treatments were significantly correlated with LM and BM. Metastases, radiotherapy, and surgery at the primary site were significantly associated with LM andor BM. Chemotherapy at the primary site has been shown to be effective in improving the survival rate of LM andor BM. Of the OS patients with LM, 61.47% died, and older age, BM, no surgery, and no chemotherapy were harmful to survival. 72.04% of OS patients with BM died, and N1 stage, no surgery, and no chemotherapy were harmful for survival. 69.49% of OS patients with LM and BM died, and older age and no chemotherapy were harmful for survival.

Small cell lung cancer transformation after EGFR-TKIs treatment in lung adenocarcinoma A case report and literatures review.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are commonly used in the treatment of advanced non-small cell lung cancer. However, patients will inevitably develop resistance to EGFR-TKIs in the long-term treatment process. In this paper, we report a case of small cell lung cancer transformation after EGFR-TKIs treatment in lung adenocarcinoma. We summarize the characteristics of this case and the treatment after transformation, and emphasized the repeat biopsy and dynamic monitoring its genetic mutation was necessary. A 75-years-old man with no smoking history was admitted to our hospital with repeated cough and expectoration for 1 month and chest enhancement computed tomography showed paracbronchial soft tissue mass in the lower lobe of the left lung, which was considered to be central lung cancer. The first pathological analysis of lung biopsy confirmed left lung adenocarcinoma and clinical stage was T3N3M1 IVA. In June 2021, the second bronchoscopic biopsy was performed, and pathology showed small cell neuroendocrine carcinoma in the left lung. Gefitinib was given to patients when the first next generation sequence test showed EGFR L858 mutation. When the second next generation sequence test revealed EGFR T790M mutation, the patient received with osimertinib. The patient got 2 cycles chemotherapy of etoposide plus netaplatin when diagnosed with small cell lung cancer. Progression-free survival was only 8 months after gefitinib treatment. Moreover, the patient was insensitive to Oxitinib, and the disease progressed after 2 months of treatment with Oxitinib. Finally, he died of severe infection and hepatic failure after a diagnosis of small cell lung cancer. Our case highlights that if a patient has rapid disease progression, increase of serum neuron-specific enolase, and TP53 and Rb1 inactivation during EGFR-TKIs treatment, we should be alert to the pathological type transformation to small cell lung cancer.

Comparative effectiveness of pegfilgrastim biosimilars vs originator for prevention of febrile neutropenia A retrospective cohort study.

Absolute and relative risk estimation in the presence of outcome ascertainment gaps and competing risks.

Incomplete coverage by cancer registries can lead to an underreporting of cancers and a resulting bias in risk estimates. When registries are defined by geographic region, gaps in observation can arise for individuals who reside outside of or migrate from the total registry catchment area. Moreover, the exact periods of non-observation for an individual may be unknown due to intermittent reporting of residential histories. The motivating example for this work is the U.S. Radiologic Technologist (USRT) study which ascertained cancer outcomes for a national cohort through 43 stateregional registries similar gaps in outcome ascertainment can appear in other registry or electronic health record- based cohort studies. We propose a two-step procedure for estimating relative and absolute risk in these settings. First, using a mover stayer model fitted to individuals known residential history, we obtain individual posterior probabilities of residing outside the registry catchment area each year. Second, we incorporate these probabilities in the survival data likelihood for competing risks to account for unobserved events. We assess the performance of the proposed method in extensive simulation studies. Compared to several simple alternative approaches, the proposed method reduces bias and improves efficiency. Finally, we apply the proposed method to a study of first primary lung cancers in the USRT cohort.