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Real-World Outcomes and Treatments Patterns Prior and after the Introduction of First-Line Immunotherapy for the Treatment of Metastatic Non-Small Cell Lung Cancer.

This study provides insights into the treatment use and outcomes of metastatic non-small cell lung cancer (NSCLC) patients in a real-world setting prior to and after the availability of immuno-oncology (IO) regimens in the first line (1L). Metastatic NSCLC patients, who initiated systemic 1L anticancer treatment from 2014 to 2020, were identified from health records. Patients were grouped into Pre-1L IO and Post-1L IO, according to the availability of pembrolizumab 1L monotherapy at the date of initiating 1L systemic anticancer treatment. Patient characteristics, treatment patterns and outcomes were assessed by the cohort. Overall survival (OS) and real-world progression-free survival (rwPFS) were calculated using the Kaplan-Meier method. The most common 1L treatment was platinum-based chemotherapy regimens in both groups (≥46%), followed by single-agent chemotherapy (27.0%) in Pre-1L IO and pembrolizumab (26.0%) in Post-1L IO. Median OS was 6.2 (95% CI 5.5-7.4) in Pre- and 8.9 months (95% CI 7.5-10.6) in Post-1L IO, while rwPFS was 3.7 (95% CI 3.3-4.2) and 4.7 months (95% CI 3.9-5.7), respectively. Even if a small proportion of patients received a 1L IO, the data showed an improved survival outcomes in the Post-1L IO group.

Lung Adenocarcinoma Cell Sensitivity to Chemotherapies A Spotlight on Lipid Droplets and

To explore the relationship between cancer cell SREBF1 expression, lipid droplets (LDs) formation, and the sensitivity to chemotherapies, we cultured lung adenocarcinoma cells H1299 (with LD) and H1563 (without LD) in a serum-free basal medium (BM) or neutrophil degranulation products containing medium (NDM), and tested cell responses to cisplatin and etoposide. By using the DESeq2 Bioconductor package, we detected 674 differentially expressed genes (DEGs) associated with NDMBM differences between two cell lines, many of these genes were associated with the regulation of sterol and cholesterol biosynthesis processes. Specifically,

A Scoping Review to Assess Adherence to and Clinical Outcomes of Wearable Devices in the Cancer Population.

The use of wearable devices (WDs) in healthcare monitoring and management has attracted increasing attention. A major problem is patients adherence and acceptance of WDs given that they are already experiencing a disease burden and treatment side effects. This scoping review explored the use of wrist-worn devices in the cancer population, with a special focus on adherence and clinical outcomes. Relevant articles focusing on the use of WDs in cancer care management were retrieved from PubMed, Scopus, and Embase from 1 January 2017 to 3 March 2022. Studies were independently screened and relevant information was extracted. We identified 752 studies, of which 38 met our inclusion criteria. Studies focused on mixed, breast, colorectal, lung, gastric, urothelial, skin, liver, and blood cancers. Adherence to WDs varied from 60% to 100%. The highest adherence was reported in the 12-week studies. Most studies focused on physical activity, sleep analysis, and heart vital signs. Of the 10 studies that described patient-reported outcomes using questionnaires and personal interviews, 8 indicated a positive correlation between the patient-reported and wearable outcomes. The definitions of the outcome measures and adherence varied across the studies. A better understanding of the intervention standards in terms of the clinical outcomes could improve adherence to wearables.

Transcriptome Analysis of Human Endogenous Retroviruses at Locus-Specific Resolution in Non-Small Cell Lung Cancer.

Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer deaths worldwide. Among its subtypes, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are the most common, accounting for more than 85% of lung cancer diagnoses. Despite the incredible efforts and recent advances in lung cancer treatments, patients affected by this condition still have a poor prognosis. Therefore, novel diagnostic biomarkers are needed. Recently, a class of transposable elements called human endogenous retroviruses (HERVs) has been found to be implicated in cancer development and later employed as novel biomarkers for several tumor types. In this study, we first ever characterized the expression of HERVs at genomic locus-specific resolution in both LUAD and LUSC cohorts available in The Cancer Genome Atlas (TCGA). Precisely, (i) we profiled the expression of HERVs in TCGA-LUAD and TCGA-LUSC cohorts (ii) we identified the dysregulated HERVs in both lung cancer subtypes (iii) we evaluated the impact of the dysregulated HERVs on signaling pathways using neural network-based predictions and (iv) we assessed their association with overall survival (OS) and relapse-free survival (RFS). In conclusion, we believe this study may help elucidate another layer of dysregulation that occurs in lung cancer involving HERVs, paving the way for identifying novel lung cancer biomarkers.

Emerging Role of Noncoding RNAs in EGFR TKI-Resistant Lung Cancer.

Lung cancer accounts for the majority of malignancy-related mortalities worldwide. The introduction of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has revolutionized the treatment and significantly improved the overall survival (OS) of lung cancer. Nevertheless, almost all

Farnesoid X Receptor Overexpression Decreases the Migration, Invasion and Angiogenesis of Human Bladder Cancers via AMPK Activation and Cholesterol Biosynthesis Inhibition.

Bladder cancer is one of the most prevailing cancers worldwide. Although treatments for urothelial carcinoma have improved, the rate of recurrence observed in the clinic is still high. The aim of this study was to evaluate whether cholesterol biosynthesis is involved in the effect of Farnesoid X Receptor (FXR) on bladder cancers. FXR overexpression contributed to activation of 5 AMP-activated protein kinase (AMPK) and decreased cholesterol levels. FXR overexpression reduced cholesterol biosynthesis and secretion by downregulating Sterol Regulatory Element Binding Protein 2 (SREBP2) and 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR) expression. In addition, an AMPK inhibitor, dorsomorphin, reversed the inhibition of migration, invasion and angiogenesis by FXR overexpression. In a metastatic xenograft animal study, FXR overexpression suppressed bladder cancer lung metastasis by decreasing matrix metalloproteinase-2 (MMP2), SREBP2 and HMGCR expression. Moreover, FXR overexpression combined with atorvastatin treatment further enhanced the downregulation of the migratory, adhesive, invasive and angiogenic properties in human urothelial carcinoma. In clinical observations, statin administration was associated with better survival rates of early-stage bladder cancer patients. Our results may provide guidance for improving therapeutic strategies for the treatment of urothelial carcinoma.

Erlotinib is a highly specific and reversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), but resistance inevitably develops as the disease progresses. Erlotinib resistance and cancer stem cells (CSCs) are poor factors hindering the prognosis of patients with lung adenocarcinoma (LUAD). Although studies have shown that erlotinib resistance and CSCs can jointly promote cancer development, the mechanism is currently unclear. Here, we investigated the potential biomarker and molecular mechanism of erlotinib resistance and cancer stemness in LUAD. An erlotinib resistance model based on four genes was constructed from The Cancer Genome Atlas (TCGA), the GEO database, the Cancer Cell Line Encyclopedia (CCLE), and the Genomics of Drug Sensitivity in Cancer (GDSC). Through multiple bioinformatic analyses,

No Impact of PolySia-NCAM Expression on Treatment Response in Neuroendocrine Neoplasms of the Lung.

Polysialic acids (abbr. polySia) are found on numerous tumors, including neuroendocrine lung tumors. They have previously been shown to impact metastatic potential, as they can influence the signaling and adhesion properties of neuronal cell adhesion molecules (abbr. NCAM) and other cell adhesion molecules. Therefore, the aim of this small pilot study was to analyze whether there was a correlation between polySia-NCAM expression and specific clinical or histopathologic characteristics, and if polySia-NCAM expression had an impact on treatment response, disease progression and prognosis of lung neuroendocrine neoplasms. This work was based on an analysis of 28 digitized patient records and corresponding patient samples. The response to therapy was radiologically determined at the time of diagnosis and at certain intervals during therapy following the current RECIST1.1 and volumetric sphere calculation. To analyze whether polySia-NCAM expression had prognostic relevance, polySia-NCAM-positive and -negative cases were compared in a Kaplan-Meier survival analysis. A majority of 78.6% lung neuroendocrine neoplasms showed a strong staining signal for polySia-NCAM. There was a significant correlation between expression and histopathological grade ( PolySia-NCAM expression was more common in high-grade compared to low-grade neuroendocrine neoplasms of the lung however, this small pilot study failed to show an association between polySia-NCAM expression and response to therapy.

SPP1 Derived from Macrophages Is Associated with a Worse Clinical Course and Chemo-Resistance in Lung Adenocarcinoma.

Osteopontin, also called secreted phosphoprotein 1 (SPP1), is a multifunctional secreted phosphorylated glycoprotein. SPP1 is also expressed in tumor cells, and many studies demonstrated that a high level of circulating SPP1 is correlated with a poor prognosis in various cancers. SPP1 is expressed not only by tumor cells but also by stromal cells, such as macrophages. However, there have been no studies distinguishing the SPP1 expression of cancer cells and tumor-associated macrophages (TAMs). Thus, in this study, we tried to accurately evaluate the SPP1 expression status on cancer cells and TAMs separately in patients with non-small cell lung cancer by using double immunohistochemistry. We demonstrated that high SPP1 expression on TAMs predicted a poor prognosis in lung adenocarcinoma patients. Additionally, we investigated the expression mechanisms related to SPP1 using human-monocyte-derived macrophages and revealed that the SPP1 expression level increased in macrophage differentiation mediated by granulocyte-macrophage colony-stimulating factor. Furthermore, SPP1 contributed to anti-cancer drug resistance in lung cancer cell lines. In conclusion, SPP1 production on TAMs predicted a poor prognosis in lung adenocarcinoma patients, and TAM-derived SPP1s involvement in the chemo-resistance of cancer cells was suggested.

Assessment of a Large-Scale Unbiased Malignant Pleural Effusion Proteomics Study of a Real-Life Cohort.

Pleural effusion (PE) is common in advanced-stage lung cancer patients and is related to poor prognosis. Identification of cancer cells is the standard method for the diagnosis of a malignant PE (MPE). However, it only has moderate sensitivity. Thus, more sensitive diagnostic tools are urgently needed. The present study aimed to discover potential protein targets to distinguish malignant pleural effusion (MPE) from other non-malignant pathologies. We have collected PE from 97 patients to explore PE proteomes by applying state-of-the-art liquid chromatography-mass spectrometry (LC-MS) to identify potential biomarkers that correlate with immunohistochemistry assessment of tumor biopsy or with survival data. Functional analyses were performed to elucidate functional differences in PE proteins in malignant and benign samples. Results were integrated into a clinical risk prediction model to identify likely malignant cases. Sensitivity, specificity, and negative predictive value were calculated. In total, 1689 individual proteins were identified by MS-based proteomics analysis of the 97 PE samples, of which 35 were diagnosed as malignant. A comparison between MPE and benign PE (BPE) identified 58 differential regulated proteins after correction of the This study demonstrated a partial least squares regression model with an area under the curve of 98 and an accuracy of 0.92 when evaluated on the holdout test data set. Furthermore, highly significant survival markers were identified (e.g., PSME1 with a log-rank of 1.68 × 10

Benefits from Adjuvant Chemotherapy in Patients with Resected Non-Small Cell Lung Cancer Possibility of Stratification by Gene Amplification of

Surgical treatment is the best curative treatment option for patients with non-small cell lung cancer (NSCLC), but some patients have recurrence beyond the surgical margin even after receiving curative surgery. Therefore, therapies with anti-cancer agents also play an important role perioperatively. In this paper, we review the current status of adjuvant chemotherapy in NSCLC and describe promising perioperative therapies, including molecularly targeted therapies and immune checkpoint inhibitors. Previously reported biomarkers of adjuvant chemotherapy for NSCLC are discussed along with their limitations. Adjuvant chemotherapy after resective surgery was most effective in patients with metastatic lesions located just outside the surgical margin in addition, these metastatic lesions were the most sensitive to adjuvant chemotherapy. Thus, the first step in predicting patients who have sensitivity to adjuvant therapies is to perform a qualified evaluation of metastatic ability using markers such as actinin-4 (ACTN4). In this review, we discuss the potential use of biomarkers in patient stratification for effective adjuvant chemotherapy and, in particular, the use of ACTN4 as a possible biomarker for NSCLC.

Define the Two Molecular Subtypes of Epithelioid Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a fatal disease of respiratory system. Despite the availability of invasive biomarkers with promising results, there are still significant diagnostic and therapeutic challenges in the treatment of MPM. One of three main mesothelioma cell types, epithelioid mesothelioma makes up approximately 70% of all mesothelioma cases. Different observational findings are under process, but the molecular heterogeneity and pathogenesis of epithelioid malignant pleural mesothelioma (eMPM) are still not well understood. Through molecular analysis, expression profiling data were used to determine the possibility and optimal number of eMPM molecular subtypes. Next, clinicopathological characteristics and different molecular pathways of each subtype were analyzed to prospect the clinical applications and advanced mechanisms of eMPM. In this study, we identified two distinct epithelioid malignant pleural mesothelioma subtypes with distinct gene expression patterns. Subtype I eMPMs were involved in steroid hormone biosynthesis, porphyrin and chlorophyll metabolism, and drug metabolism, while subtype II eMPMs were involved in rational metabolism, tyrosine metabolism, and chemical carcinogenesis pathways. Additionally, we identified potential subtype-specific therapeutic targets, including CCNE1, EPHA3, RNF43, ROS1, and RSPO2 for subtype I and CDKN2A and RET for subtype II. Considering the need for potent diagnostic and therapeutic biomarkers for eMPM, we are anticipating that our findings will help both in exploring underlying mechanisms in the development of eMPM and in designing targeted therapy for eMPM.

Effects of Cigarette Smoke on Adipose and Skeletal Muscle Tissue In Vivo and In Vitro Studies.

Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro models. Mice were exposed to cigarette smoke or air for 72 days and the pre-adipose cell line 3T3-L1 was utilized as an in vitro model. Cigarette smoke exposure decreased body weight, and the proportional loss in fat mass was more pronounced than the lean mass loss. Cigarette smoke exposure reduced adipocyte size and increased adipocyte numbers. Adipose macrophage numbers and associated cytokine levels, including interleukin-1β, interleukine-6 and tumor necrosis factor-α were elevated in smoke-exposed mice. Muscle strength and protein synthesis signaling were decreased after smoke exposure however, muscle mass was not changed. In vitro studies demonstrated that lipolysis and fatty acid oxidation were upregulated in cigarette smoke-exposed pre-adipocytes. In conclusion, cigarette smoke exposure induces a loss of whole-body fat mass and adipose atrophy, which is likely due to enhanced lipolysis.

Prognostic Profiling of the EMT-Associated and Immunity-Related LncRNAs in Lung Squamous Cell Carcinomas.

Lung squamous cell carcinoma (Lung SCC) is associated with metastatic disease, resulting in poor clinical prognosis and a low survival rate. The aberrant epithelial-mesenchymal transition (EMT) and long non-coding RNA (LncRNA) are critical attributors to tumor metastasis and invasiveness in Lung SCC. The present study divided lncRNAs into two subtypes, C1 and C2 (Cluster 1 and Cluster 2), according to the correlation of EMT activity within the public TCGA and GEO databases. Subsequently, the differential clinical characteristics, mutations, molecular pathways and immune cell deconvolution between C1 and C2 were evaluated. Lastly, we further identified three key lncRNAs (DNM3OS, MAGI2-AS3 and LINC01094) that were associated with EMT and, at the same time, prognostic for the clinical outcomes of Lung SCC patients. Our study may provide a new paradigm of metastasis-associated biomarkers for predicting the prognosis of Lung SCC.

Liquid Biopsy Analysis as a Tool for TKI-Based Treatment in Non-Small Cell Lung Cancer.

The treatment of non-small cell lung cancer (NSCLC) has recently evolved with the introduction of targeted therapy based on the use of tyrosine kinase inhibitors (TKIs) in patients with certain gene alterations, including

From Molecular Mechanisms to Therapeutics Understanding MicroRNA-21 in Cancer.

MicroRNAs (miRNAs) are small noncoding RNAs that play an important role in regulating gene expression at a posttranscriptional level. As one of the first discovered oncogenic miRNAs, microRNA-21 (miR-21) has been highlighted for its critical role in cancers, such as glioblastoma, pancreatic adenocarcinoma, non-small cell lung cancer, and many others. MiR-21 targets many vital components in a wide range of cancers and acts on various cellular processes ranging from cancer stemness to cell death. Expression of miR-21 is elevated within cancer tissues and circulating miR-21 is readily detectable in biofluids, making it valuable as a cancer biomarker with significant potential for use in diagnosis and prognosis. Advances in RNA-based therapeutics have revealed additional avenues by which miR-21 can be utilized as a promising target in cancer. The purpose of this review is to outline the roles of miR-21 as a key modulator in various cancers and its potential as a therapeutic target.

Targeting HSP90 as a Novel Therapy for Cancer Mechanistic Insights and Translational Relevance.

Heat shock protein (HSP90), a highly conserved molecular chaperon, is indispensable for the maturation of newly synthesized poly-peptides and provides a shelter for the turnover of misfolded or denatured proteins. In cancers, the client proteins of HSP90 extend to the entire process of oncogenesis that are associated with all hallmarks of cancer. Accumulating evidence has demonstrated that the client proteins are guided for proteasomal degradation when their complexes with HSP90 are disrupted. Accordingly, HSP90 and its co-chaperones have emerged as viable targets for the development of cancer therapeutics. Consequently, a number of natural products and their analogs targeting HSP90 have been identified. They have shown a strong inhibitory effect on various cancer types through different mechanisms. The inhibitors act by directly binding to either HSP90 or its co-chaperonesclient proteins. Several HSP90 inhibitors-such as geldanamycin and its derivatives, gamitrinib and shepherdin-are under clinical evaluation with promising results. Here, we review the subcellular localization of HSP90, its corresponding mechanism of action in the malignant phenotypes, and the recent progress on the development of HSP90 inhibitors. Hopefully, this comprehensive review will shed light on the translational potential of HSP90 inhibitors as novel cancer therapeutics.

The Ni(II)-Binding Activity of the Intrinsically Disordered Region of Human NDRG1, a Protein Involved in Cancer Development.

Nickel exposure is associated with tumors of the respiratory tract such as lung and nasal cancers, acting through still-uncharacterized mechanisms. Understanding the molecular basis of nickel-induced carcinogenesis requires unraveling the mode and the effects of Ni(II) binding to its intracellular targets. A possible Ni(II)-binding protein and a potential focus for cancer treatment is

Role of WTAP in Cancer From Mechanisms to the Therapeutic Potential.

Wilms tumor 1-associating protein (WTAP) is required for N

Network Dynamics Caused by Genomic Alteration Determine the Therapeutic Response to FGFR Inhibitors for Lung Cancer.

Recently, FGFR inhibitors have been highlighted as promising targeted drugs due to the high prevalence of FGFR1 amplification in cancer patients. Although various potential biomarkers for FGFR inhibitors have been suggested, their functional effects have been shown to be limited due to the complexity of the cancer signaling network and the heterogenous genomic conditions of patients. To overcome such limitations, we have reconstructed a lung cancer network model by integrating a cell line genomic database and analyzing the model in order to understand the underlying mechanism of heterogeneous drug responses. Here, we identify novel genomic context-specific candidates that can increase the efficacy of FGFR inhibitors. Furthermore, we suggest optimal targets that can induce more effective therapeutic responses than that of FGFR inhibitors in each of the FGFR-resistant lung cancer cells through computational simulations at a system level. Our findings provide new insights into the regulatory mechanism of differential responses to FGFR inhibitors for optimal therapeutic strategies in lung cancer.

Integrating Expression Data-Based Deep Neural Network Models with Biological Networks to Identify Regulatory Modules for Lung Adenocarcinoma.

Lung adenocarcinoma is the most common type of primary lung cancer, but the regulatory mechanisms during carcinogenesis remain unclear. The identification of regulatory modules for lung adenocarcinoma has become one of the hotspots of bioinformatics. In this paper, multiple deep neural network (DNN) models were constructed using the expression data to identify regulatory modules for lung adenocarcinoma in biological networks. First, the mRNAs, lncRNAs and miRNAs with significant differences in the expression levels between tumor and non-tumor tissues were obtained. MRNA DNN models were established and optimized to mine candidate mRNAs that significantly contributed to the DNN models and were in the center of an interaction network. Another DNN model was then constructed and potential ceRNAs were screened out based on the contribution of each RNA to the model. Finally, three modules comprised of miRNAs and their regulated mRNAs and lncRNAs with the same regulation direction were identified as regulatory modules that regulated the initiation of lung adenocarcinoma through ceRNAs relationships. They were validated by literature and functional enrichment analysis. The effectiveness of these regulatory modules was evaluated in an independent lung adenocarcinoma dataset. Regulatory modules for lung adenocarcinoma identified in this study provided a reference for regulatory mechanisms during carcinogenesis.

Bone Marrow Endothelial Cells Increase Prostate Cancer Cell Apoptosis in 3D Triculture Model of Reactive Stroma.

The bone marrow tumor microenvironment (BMTE) is a complex network of cells, extracellular matrix, and sequestered signaling factors that initially act as a hostile environment for disseminating tumor cells (DTCs) from the cancerous prostate. Three-dimensional (3D) culture systems offer an opportunity to better model these complex interactions in reactive stroma, providing contextual behaviors for cancer cells, stromal cells, and endothelial cells. Using a new system designed for the triculture of osteoblastic prostate cancer (PCa) cells, stromal cells, and microvascular endothelial cells, we uncovered a context-specific pro-apoptotic effect of endothelial cells of the bone marrow different from those derived from the lung or dermis. The paracrine nature of this effect was demonstrated by observations that conditioned medium from bone marrow endothelial cells, but not from dermal or lung endothelial cells, led to PCa cell death in microtumors grown in 3D BMTE-simulating hydrogels. Analysis of the phosphoproteome by reverse phase protein analysis (RPPA) of PCa cells treated with conditioned media from different endothelial cells identified the differential regulation of pathways involved in proliferation, cell cycle regulation, and apoptosis. The findings from the RPPA were validated by western blotting for representative signaling factors identified, including forkhead box M1 (FOXM1 proliferation factor), pRb (cell cycle regulator), and SmacDIABLO (pro-apoptosis) among treatment conditions. The 3D model presented here thus presents an accurate model to study the influence of the reactive BMTE, including stromal and endothelial cells, on the adaptive behaviors of cancer cells modeling DTCs at sites of bone metastasis. These findings in 3D culture systems can lead to a better understanding of the real-time interactions among cells present in reactive stroma than is possible using animal models.

Modeling lung diseases using reversibly immortalized mouse pulmonary alveolar type 2 cells (imPAC2).

A healthy alveolar epithelium is critical to the gas exchange function of the lungs. As the major cell type of alveolar epithelium, alveolar type 2 (AT2) cells play a critical role in maintaining pulmonary homeostasis by serving as alveolar progenitors during lung injury, inflammation, and repair. Dysregulation of AT2 cells may lead to the development of acute and chronic lung diseases and cancer. The lack of clinically relevant AT2 cell models hampers our ability to understand pulmonary diseases. Here, we sought to establish reversibly immortalized mouse pulmonary alveolar type 2 cells (imPAC2) and investigate their potential in forming alveolar organoids to model pulmonary diseases. Primary mouse pulmonary alveolar cells (mPACs) were isolated and immortalized with a retroviral expression of SV40 Large T antigen (LTA). Cell proliferation and survival was assessed by crystal violet staining and WST-1 assays. Marker gene expression was assessed by qPCR, Western blotting, andor immunostaining. Alveolar organoids were generated by using matrigel. Ad-TGF-β1 was used to transiently express TGF-β1. Stable silencing β-catenin or overexpression of mutant KRAS and TP53 was accomplished by using retroviral vectors. Subcutaneous cell implantations were carried out in athymic nude mice. The retrieved tissue masses were subjected to H E histologic evaluation. We immortalized primary mPACs with SV40 LTA to yield the imPACs that were non-tumorigenic and maintained long-term proliferative activity that was reversible by FLP-mediated removal of SV40 LTA. The EpCAM

MIR99AHG inhibits EMT in pulmonary fibrosis via the miR-136-5pUSP4ACE2 axis.

Long non-coding RNAs (lncRNAs) are closely related to the occurrence and development of cancer. Abnormally expressed lncRNA can be used as a diagnostic marker for cancer. In this study, we aim to investigate the clinical significance of MIR99AHG expression in lung adenocarcinoma (LUAD), and its biological roles in LUAD progression. The relative expression of MIR99AHG in LUAD tissues and cell lines was analyzed using public databases and RT-qPCR. The biological functions of MIR99AHG were investigated using a loss-of-function approach. The effect of MIR99AHG on lung fibrosis was assessed by scratch assay, invasion assay and lung fibrosis rat model. FISH, luciferase reporter assay and immunofluorescence were performed to elucidate the underlying molecular mechanisms. LncRNA MIR99AHG expression level was downregulated in LUAD tissues and cell lines. Low MIR99AHG levels were associated with poorer patient overall survival. Functional analysis showed that MIR99AHG is associated with the LUAD malignant phenotype in vitro and in vivo. Further mechanistic studies showed that, MIR99AHG functions as a competitive endogenous RNA (ceRNA) to antagonize miR-136-5p-mediated ubiquitin specific protease 4 (USP4) degradation, thereby unregulated the expression of angiotensin-converting enzyme 2 (ACE2), a downstream target gene of USP4, which in turn affected alveolar type II epithelial cell fibrosis and epithelial-mesenchymal transition (EMT). In summary, the MIR99AHGmiR-136-5pUSP4ACE2 signalling axis regulates lung fibrosis and EMT, thus inhibiting LUAD progression. This study showed that downregulated MIR99AHG leads to the development of pulmonary fibrosis. Therefore, overexpression of MIR99AHG may provide a new approach to preventing LUAD progression.

Comparative profiling of single-cell transcriptome reveals heterogeneity of tumor microenvironment between solid and acinar lung adenocarcinoma.

The diversity of histologic composition reflects the inter- and intra-tumor heterogeneity of lung adenocarcinomas (LUADs) macroscopically. Insights into the oncological characteristics and tumor microenvironment (TME) of different histologic subtypes of LUAD at the single-cell level can help identify potential therapeutic vulnerabilities and combinational approaches to improve the survival of LUAD patients. Through comparative profiling of cell communities defined by scRNA-seq data, we characterized the TME of LUAD samples of distinct histologic subtypes, with relevant results further confirmed in multiple bulk transcriptomic, proteomic datasets and an independent immunohistochemical validation cohort. We find that the hypoxic and acidic situation is the worst in the TME of solid LUADs compared to other histologic subtypes. Besides, the tumor metabolic preferences vary across histologic subtypes and may correspondingly impinge on the metabolism and function of immune cells. Remarkably, tumor cells from solid LUADs upregulate energy and substance metabolic activities, particularly the folate-mediated one-carbon metabolism and the key gene MTHFD2, which could serve as a potential therapeutic target. Additionally, ubiquitination modifications may also be involved in the progression of histologic patterns. Immunologically, solid LUADs are characterized by a predominance of exhausted T cells and immunosuppressive myeloid cells, where the hypoxic, acidified and nutrient-deprived TME has a non-negligible impact. Discrepancies in stromal cell function, evidenced by varying degrees of stromal remodeling and fibrosis, may also contribute to the specific immune phenotype of solid LUADs. Overall, our research proposes several potential entry points to improve the immunosuppressive TME of solid LUADs, thereby synergistically potentiating their immunotherapeutic efficacy, and may provide precise therapeutic strategies for LUAD patients of distinct histologic subtype constitution.

Clinical features and treatment outcome of lymphoepithelioma-like carcinoma from multiple primary sites a population-based, multicentre, real-world study.

Lymphoepithelioma-like carcinoma (LELC) is a rare and unique subtype of cancer that histologically resembles undifferentiated nasopharyngeal carcinoma (NPC). The population-based analysis of LELC and the optimal treatment remains unclear. This real-world, retrospective study investigated 770 patients with LELC for primary site, treatment, and survival outcomes from 2005 to 2019 from five cancer centres in China. The overall survival (OS) of different subgroups was appraised by log-rank tests and Kaplan-Meier analysis. Primary sites LELC included the lung (597 cases, 77.5%), salivary gland (115 cases, 14.9%), and others. The median progression-free survival (PFS) of LELC patients was 47.4 months. The median overall survival (OS) was not reached. The 5-year survival rate for LELC patients was 77.8%. Most patients in stages I and II received surgery. The majority of patients in stage III received surgery and radiotherapy. More than half of the patients in stage IV received chemotherapy. Among relapsed or metastatic cases receiving chemotherapy, patients who received immunotherapy at any time presented with a superior OS than those without immunotherapy (P < 0.0001, HR 0.39, 95% CI 0.25-0.63). Compared with the SEER database, patients with LELC had a better prognosis than NPC, with a 5-year overall survival of 77.3% vs. 56.8% (P < 0.001). Our data provide treatment patterns and outcomes for LELC from various primary sites. Randomized controlled studies are necessary to further define the standard of care for patients with LELC. Trial registration This clinical trial was registered at ClinicalTrials.gov (No. NCT04614818).

Hsa-microRNA-27b-3p inhibits hepatocellular carcinoma progression by inactivating transforming growth factor-activated kinase-binding protein 3nuclear factor kappa B signalling.

MicroRNAs (miRNAs) play crucial roles in the development of hepatocellular carcinoma (HCC). Hsa-microRNA-27b-3p (hsa-miR-27b) is involved in the formation and progression of various cancers, but its role and clinical value in HCC remain unclear. The expression of hsa-miR-27b in HCC was examined by quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH) assays of clinical samples. Cell Counting Kit-8 assays (CCK-8), 5-ethynyl-2-deoxyuridine (EdU) incorporation assays, Transwell assays, filamentous actin (F-actin) staining and western blot analyses were used to determine the effects of hsa-miR-27b on HCC cells in vitro. Subcutaneous xenograft and lung metastatic animal experiments were conducted to verify the role of hsa-miR-27b in HCC in vivo. In silico prediction, qRT-PCR, western blot, anti-Argonaute 2 (AGO2) RNA immunoprecipitation (RIP) and dual luciferase reporter assays were applied to identify the target genes of hsa-miR-27b. To detect the impacts of hsa-miR-27b on nuclear factor kappa B (NF-кB) signalling cascades mediated by transforming growth factor-activated kinase-binding protein 3 (TAB3), we performed qRT-PCR, western blot assays, immunofluorescence staining, immunohistochemistry (IHC) and dual-luciferase reporter assays. Recombinant oncolytic adenovirus (Onco The expression of hsa-miR-27b was lower in HCC than in adjacent non-tumourous tissues (ANTs), and the reduced expression of hsa-miR-27b was associated with worse outcomes in patients with HCC. Hsa-miR-27b significantly inhibited the proliferation, migration, invasion, subcutaneous tumour growth and lung metastasis of HCC cells. The suppression of hsa-miR-27b promoted the nuclear translocation of NF-κB by upregulating TAB3 expression. TAB3 was highly expressed in HCC compared with ANTs and was negatively correlated with the expression of hsa-miR-27b. The impaired cell proliferation, migration and invasion by hsa-miR-27b overexpression were recovered by ectopic expression of TAB3. Recombinant Onco By targeting TAB3, hsa-miR-27b acted as a tumour suppressor by inactivating the NF-кB pathway in HCC in vitro and in vivo, indicating its therapeutic value against HCC.

Conductive metal-organic framework based label-free electrochemical detection of circulating tumor DNA.

An ultrasensitive electrochemical biosensor was designed for the rapid label-free detection of circulating tumor DNA (ctDNA, EGFR 19 Dels for non-small cell lung cancer, NSCLC). We linked the highly conjugated tricatecholate, 2,3,6,7,10,11-hexahydroxytriphenylene (HHTP) with Ni(II) ions into the two-dimensional porous conductive metal-organic frameworks (MOFs), which is termed Ni-catecholates (Ni-CAT). Then, the AuNPsNi-catecholatescarbon blackpolarized pencil graphite electrode (AuNPsNi-CATCBPPGE) was obtained by electrodeposition of AuNPs on the surface of PPGE modified with Ni-CATCB composite materials. The AuNPsNi-CATCBPPGE were used for label-less detection of ctDNA, with a total detection time of only 30 min. Under optimal detection conditions, the AuNPsNi-CATCBPPGE sensor exhibited excellent detection performance with good linear response to ctDNA over a wide concentration range and the detection limit down to the femtomolar level. The sensor was applied to the determination of ctDNA in serum samples with high sensitivity. This simple, efficient, and expeditious method has practical value in liquid biopsy of ctDNA and has potential for development in early detection, treatment, and prognosis of tumors. Herein, an ultrasensitive electrochemical biosensor was designed for the rapid label-free detection of ctDNA (EGFR 19 Dels for non-small cell lung cancer, NSCLC). We linked the highly conjugated tricatecholate, 2,3,6,7,10,11-hexahydroxytriphenylene (HHTP) with Ni(II) ions into the two-dimensional porous conductive metal-organic frameworks (MOFs), which is termed as Ni-catecholates (Ni-CAT). Then, the AuNPsNi-catecholatescarbon blackpolarized pencil graphite electrode (AuNPsNi-CATCBPPGE) was obtained by electrodeposition of AuNPs on the surface of PPGE modified with Ni-CATCB composite materials. The AuNPsNi-CATCBPPGEs were used for label-less detection of ctDNA, with a total detection time of only 30 min. Under optimal detection conditions, the AuNPsNi-CATCBPPGE sensor exhibited excellent detection performance with good linear response to ctDNA in the concentration range of 1 × 10

Arctigenin impairs UBC12 enzyme activity and cullin neddylation to attenuate cancer cells.

Neddylation is a type of posttranslational protein modification that has been observed to be overactivated in various cancers. UBC12 is one of two key E2 enzymes in the neddylation pathway. Reports indicate that UBC12 deficiency may suppress lung cancer cells, such that UBC12 could play an important role in tumor progression. However, systematic studies regarding the expression profile of UBC12 in cancers and its relationship to cancer prognosis are lacking. In this study, we comprehensively analyzed UBC12 expression in diverse cancer types and found that UBC12 is markedly overexpressed in most cancers (1721), a symptom that negatively correlates with the survival rates of cancer patients, including gastric cancer. These results demonstrate the suitability of UBC12 as a potential target for cancer treatment. Currently, no effective inhibitor targeting UBC12 has been discovered. We screened a natural product library and found, for the first time, that arctigenin has been shown to significantly inhibit UBC12 enzyme activity and cullin neddylation. The inhibition of UBC12 enzyme activity was newly found to contribute to the effects of arctigenin on suppressing the malignant phenotypes of cancer cells. Furthermore, we performed proteomics analysis and found that arctigenin intervened with cullin downstream signaling pathways and substrates, such as the tumor suppressor PDCD4. In summary, these results demonstrate the importance of UBC12 as a potential therapeutic target for cancer treatment, and, for the first time, the suitability of arctigenin as a potential compound targeting UBC12 enzyme activity. Thus, these findings provide a new strategy for inhibiting neddylation-overactivated cancers.

Genomic landscape of pleural and peritoneal mesothelioma tumours.

Malignant pleural and peritoneal mesotheliomas are rare malignancies with unacceptable poor prognoses and limited treatment options. The genomic landscape is mainly characterised by the loss of tumour suppressor genes and mutations in DNA repair genes. Currently, data from next-generation sequencing (NGS) of mesothelioma tumours is restricted to a limited number of cases moreover, data comparing molecular features of mesothelioma from the pleural and peritoneal origin with NGS are lacking. We analysed 1113 pleural mesothelioma and 355 peritoneal mesothelioma samples. All tumours were sequenced with the FoundationOne® or FoundationOne®CDx assay for detection of substitutions, insertion-deletions, copy-number alterations and selected rearrangements in at least 324 cancer genes. This analysis revealed alterations in 19 genes with an overall prevalence of at least 2%. Alterations in BAP1, CDKN2A, CDKN2B, NF2, MTAP, TP53 and SETD2 occurred with a prevalence of at least 10%. Peritoneal, compared to pleural mesothelioma, was characterised by a lower prevalence of alterations in CDKN2A, CDKN2B and MTAP. Moreover, we could define four distinct subgroups according to alterations in BAP1 and CDKN2AB. Alterations in Hedgehog pathway-related genes (PTCH12 and SUFU) and Hippo pathway-related gene (NF2) as well as KRAS, EGFR, PDGFRAB, ERBB2 and FGFR3 were detected in both cohorts. Here, we report the molecular aberrations from the largest cohort of patients with mesothelioma. This analysis identified a proportion of patients with targetable alterations and suggests that molecular profiling can identify new treatment options for patients with mesothelioma.

Analyzing integrated network of methylation and gene expression profiles in lung squamous cell carcinoma.

Gene expression, DNA methylation, and their organizational relationships are commonly altered in lung squamous cell carcinoma (LUSC). To elucidate these complex interactions, we reconstructed a differentially expressed gene network and a differentially methylated cytosine (DMC) network by partial information decomposition and an inverse correlation algorithm, respectively. Then, we performed graph union to integrate the networks. Community detection and enrichment analysis of the integrated network revealed close interactions between the cell cycle, keratinization, immune system, and xenobiotic metabolism gene sets in LUSC. DMC analysis showed that hypomethylation targeted the gene sets responsible for cell cycle, keratinization, and NRF2 pathways. On the other hand, hypermethylated genes affected circulatory system development, the immune system, extracellular matrix organization, and cilium organization. By centrality measurement, we identified NCAPG2, PSMG3, and FADD as hub genes that were highly connected to other nodes and might play important roles in LUSC gene dysregulation. We also found that the genes with high betweenness centrality are more likely to affect patients survival than those with low betweenness centrality. These results showed that the integrated network analysis enabled us to obtain a global view of the interactions and regulations in LUSC.

The effect of paclitaxel plus carboplatin chemotherapy on subclinical cardiotoxicity in patients with non-small cell lung cancer A speckle tracking echocardiography-based study.

Although chemotherapy-induced cardiotoxicity is an emerging problem, limited information is available on the effects of chemotherapy on left ventricular (LV) mechanical functions in patients with non-small cell lung cancer (NSCLC). We aimed to explore chemotherapy-induced alterations in cardiac mechanical functions in patients with NSCLC using speckle tracking echocardiography (STE). Seventy-one patients with NSCLC and 34 age and sex matched control subjects were consecutively included. Based on their good performance status (Eastern Cooperative Oncology Group performance status), 39 patients were treated with paclitaxel plus carboplatin (PC) regimen and 32 patients were treated with vinorelbine plus cisplatin (VC) regimen. All patients and controls underwent conventional two-dimensional echocardiography and STE at baseline to assess their LV functions. The echocardiographic examinations of NSCLC patients were repeated after the chemotherapy regimens. None of the NSCLC patients developed any signs or symptoms of clinical heart failure during or after the chemotherapy. There were not any significant differences in LV ejection fraction between NSCLC patients and controls before and after chemotherapy. There were not any significant differences in baseline LV global longitudinal strain (GLS), radial strain (RS), and circumferential strain (CS) between NSCLC patients and controls. However, all LV GLS, RS and CS significantly decreased in patients treated with the PC regimen resulting in a significant difference compared to both VC group and controls while no significant decreases were observed in strain measures in VC group. Paclitaxel plus carboplatin, but not VC, may induce subclinical cardiotoxicity in patients with NSCLC, which may be detected by STE.

Advances in the treatment of postoperative recurrence of non-small cell lung cancer and their impact on survival in Asian patients.

We investigated the effect of tyrosine kinase inhibitors (TKIs) and immunotherapy on survival after postoperative recurrence of non-small cell lung cancer (NSCLC). This single-center retrospective study included patients with NSCLC who underwent lobectomy or more with complete pathological resection between 2008 and 2018 (N 2254). Median follow-up was 5.1 years. Survival trends and the effect of TKIsimmunotherapy were analyzed using Joinpoint (National Cancer Institute) and Cox regression. In 443 (19.7%) postoperative recurrences, median time to recurrence was 1.1 years epidermal growth factor receptor mutation (EGFR), 191 (43.1%) anaplastic lymphoma kinase rearrangement (ALK), 13 (2.9%) not detected or unknown (ND), 239 (54.0%). In multivariable analysis, age, time to recurrence, adenocarcinoma, symptomatic recurrence, any treatment for recurrence, use of the epidermal growth factor receptor TKI, use of the anaplastic lymphoma kinase TKI, and use of immunotherapy were significant prognostic factors. Survival was significantly better in the EGFRALK group than in the ND group (median, 4.7 vs 2.1 years P < .01). Between 2010 and 2018, 2-year postrecurrence survival improved significantly (annual percentage change APC, 4.2 95% CI, 1.5-7.0). In subset analyses, neither change in 2-year survival nor TKI use was significant over time in the EGFRALK group, but the ND group experienced significant improvement in 2-year survival (APC, 13.5 95% CI, 5.4-22.2) and increasing trend in immunotherapy use (APC, 23.0 95% CI, -5.9 to 60) after 2013. Survival after postoperative recurrence of NSCLC has improved significantly since 2010. Use of immunotherapy in patients without driver mutations may have contributed to that improvement. Prognosis in patients with driver mutations remains favorable with the TKIs introduced before the study period.

PSMA-directed imaging and therapy of salivary gland tumors a single-center retrospective study.

We analyzed the diagnostic performance of PSMA-PETCT as well as the dosimetry, efficacy, and safety of

Detecting multiple lesions of lung cancer-caused metastasis with bone scans using a self-defined object detection model based on SSD framework.

Unraveling phenotypic plasticity and evolution in small cell lung cancer.

Malignant cell populations in a tumor often exist in distinct phenotypic states. Deciphering tumor heterogeneity requires determining how many such unique states exist and what the biological traits associated with each are. Archetype analysis of SCLC transcriptomes reveals key phenotypic states in SCLC tumors and their patterns of evolution.

Diagnostic and prognostic role of pancreatic secretory granule membrane major glycoprotein 2 (GP2) immunohistochemistry A TMA study on 27,681 tumors.

Pancreatic secretory granule membrane major glycoprotein 2 (GP2) is a membrane component of zymogen granules which is abundantly secreted by pancreatic acinar cells. Because RNA based analyses suggest a strict limitation of GP2 expression to the pancreas in normal tissues, and a strong preference to pancreatic cancer among tumors, GP2 expression analysis might have diagnostic utility. To better understand the role of GP2 protein expression, GP2 was successfully analyzed in 27,965 tumor samples from 132 different tumor types and subtypes as well as 8 samples each of 76 different normal tissue types by immunohistochemistry in a tissue microarray format (TMA). GP2 immunostaining was seen in 14 of 16 (87.5 %) acinar cell carcinomas, 6 of 507 (1.2 %) ductal adenocarcinomas, and 3 of 99 neuroendocrine neoplasms of the pancreas (3.0 %). GP2 was also found in 23 extra-pancreatic tumor entities including several types of neuroendocrine neoplasms (14.3-58.8 %), prostatic adenocarcinomas (8.2-18.8 %), various other adenocarcinomas (0.1-7.7 %), and several categories of benign and malignant salivary gland tumors (2.3-3.1 %). A strong GP2 positivity was only seen in 6 tumor categories including 50 % of 16 pancreatic acinus cell carcinomas, 11.8 % of 17 neuroendocrine tumors of the lung, 1.3 % of 80 primary Gleason 4 4 % and 0.6 % of 181 recurrent prostate cancers, as well as 0.8 % of 133 adenocarcinomas of the lung. In a cohort of 14,747 prostate cancers with follow up data, GP2 immunostaining was strongly linked to advanced pT stage, high Gleason grade, lymph node metastasis, and recurrence free survival (p < 0.0001 each). The prognostic impact of GP2 positivity was independent of established parameters in TMPRSS2ERG fusion-negative cancers (p < 0.0001). In summary, our data show that GP2 is preferentially expressed in acinar cell carcinomas of the pancreas but the glycoprotein can - rarely - also be expressed in a variety of other tumor entities.

Outcomes for Children With Type II and Type III Pleuropulmonary Blastoma Following Chemotherapy A Report From the International PPB

Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Type II and type III PPB have historically been associated with a poor prognosis. Patients with known or suspected PPB were enrolled in the International PPB From 1987 to 2021, 314 children with centrally confirmed type II and type III PPB who received upfront chemotherapy were enrolled 132 children (75 with type II and 57 with type III) received IVADo chemotherapy. Adjusted analyses suggest improved overall survival for children treated with IVADo in comparison with historical controls with an estimated hazard ratio of 0.65 (95% CI, 0.39 to 1.08). Compared with localized disease, distant metastasis at diagnosis was associated with worse PPB event-free survival and overall survival with hazard ratio of 4.23 (95% CI, 2.42 to 7.38) and 4.69 (95% CI, 2.50 to 8.80), respectively. The use of IVADo in children with type II and type III PPB resulted in similar-to-improved outcomes compared with historical controls. Inferior outcomes with metastatic disease suggest the need for novel therapies. This large cohort of uniformly treated children with advanced PPB serves as a benchmark for future multicenter therapeutic studies for this rare pediatric tumor.

Social disparities in unplanned 30-day readmission rates after hospital discharge in patients with chronic health conditions A retrospective cohort study using patient level hospital administrative data linked to the population census in Switzerland.

Unplanned readmissions shortly after discharge from hospital are common in chronic diseases. The risk of readmission has been shown to be related both to hospital care, e.g., medical complications, and to patients resources and abilities to manage the chronic disease at home and to make appropriate use of outpatient medical care. Despite a growing body of evidence on social determinants of health and health behaviour, little is known about the impact of social and contextual factors on readmission rates. The objective of this study was to analyse possible effects of educational, financial and social resources of patients with different chronic health conditions on unplanned 30 day-readmission risks. The study made use of nationwide inpatient hospital data that was linked with Swiss census data. The sample included n 62,109 patients aged 25 and older, hospitalized between 2012 and 2016 for one of 12 selected chronic conditions. Multivariate logistic regressions analysis was performed. Our results point to a significant association between social factors and readmission rates for patients with chronic conditions. Patients with upper secondary education (OR 1.26, 95% CI 1.11, 1.44) and compulsory education (OR 1.51, 95% CI 1.31, 1.74) had higher readmission rates than those with tertiary education when taking into account demographic, social and health status factors. Having private or semi-private hospital insurance was associated with a lower risk for 30-day readmission compared to patients with mandatory insurance (OR 0.81, 95% CI 0.73, 0.90). We did not find a general effect of social resources, measured by living with others in a household, on readmission rates. The risk of readmission for patients with chronic conditions was also strongly predicted by type of chronic condition and by factors related to health status, such as previous hospitalizations before the index hospitalization (77%), number of comorbidities (15% higher probability per additional comorbidity) as well as particularly long hospitalizations (64%). Stratified analysis by type of chronic condition revealed differential effects of social factors on readmissions risks. Compulsory education was most strongly associated with higher odds for readmission among patients with lung cancer (142%), congestive heart failure (63%) and back problems (53%). We assume that low socioeconomic status among patients with chronic conditions increases the risk of unplanned 30-day readmission after hospitalisation due to factors related to their social situation (e.g., low health literacy, material deprivation, high social burden), which may negatively affect cooperation with care providers and adherence to recommended therapies as well as hamper active participation in the medical process and the development of a shared understanding of the disease and its cure. Higher levels of comorbidity in socially disadvantaged patients can also make appropriate self-management and use of outpatient care more difficult. Our findings suggest a need for increased preventive measures for disadvantaged populations groups to promote early detection of diseases and to remove financial or knowledge-based barriers to medical care. Socially disadvantaged patients should also be strengthened more in their individual and social resources for coping with illness.

Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function.

The Warburg effect, aerobic glycolysis, is a hallmark feature of cancer cells grown in culture. However, the relative roles of glycolysis and respiratory metabolism in supporting in vivo tumor growth and processes such as tumor dissemination and metastatic growth remain poorly understood, particularly on a systems level. Using a CRISPRi mini-library enriched for mitochondrial ribosomal protein and respiratory chain genes in multiple human lung cancer cell lines, we analyzed in vivo metabolic requirements in xenograft tumors grown in distinct anatomic contexts. While knockdown of mitochondrial ribosomal protein and respiratory chain genes (mito-respiratory genes) has little impact on growth in vitro, tumor cells depend heavily on these genes when grown in vivo as either flank or primary orthotopic lung tumor xenografts. In contrast, respiratory function is comparatively dispensable for metastatic tumor growth. RNA-Seq and metabolomics analysis of tumor cells expressing individual sgRNAs against mito-respiratory genes indicate overexpression of glycolytic genes and increased sensitivity of glycolytic inhibition compared to control when grown in vitro, but when grown in vivo as primary tumors these cells down-regulate glycolytic mechanisms. These studies demonstrate that discrete perturbations of mitochondrial respiratory chain function impact in vivo tumor growth in a context-specific manner with differential impacts on primary and metastatic tumors.

Response to osimertinib plus trametinib in a heavily treated epidermal growth factor receptor (EGFR)-positive NSCLC harboring a rare, acquired rapidly accelerated fibrosarcoma B-type (BRAF) p.D594N mutation a case report.

Heterogeneity in the acquired genetic cause of osimertinib resistance leads to difficulties in understanding and addressing molecular mechanisms of resistance in clinical practice. Recent studies and clinical cases established that altered BRAF could drive osimertinib resistance in an EGFR-independent manner. Herein, we present a case in which an EGFR-positive, MET-amplified nonsmall cell lung cancer (NSCLC) patient acquired BRAF p.D594N mutation on third-line osimertinib plus crizotinib and responded to seventh-line treatment with osimertinib plus MEK inhibitor trametinib. Disease control was maintained for 6 months. BRAF p.D594N is a kinase impaired mutation but leads to increased MEKERK signaling, which could activate the downstream signaling of EGFR and induce drug resistance. There has been preclinical evidence supporting dual inhibition of MEK and EGFR for overcoming this resistance. To the best of our knowledge, our case is the first to provide clinical evidence that trametinib plus osimertinib was effective for EGFR-mutant NSCLC patients with acquired BRAF p.D594N mutation. More supporting data and systematic validation studies are needed for comprehensive understanding of this therapy strategy and future applications.

23-hydroxybetulinic acid reduces tumorigenesis, metastasis and immunosuppression in a mouse model of hepatocellular carcinoma via disruption of the MAPK signaling pathway.

Hepatocellular carcinoma (HCC) shows recurrence and lung metastasis even after treatment. 23-hydroxybetulinic acid (23-HBA), a major active constituent of Pulsatilla chinensis, exhibits potent antitumor activities. We herein investigate the biological effect of 23-HBA on metastasis and immunosuppression in a mouse model of HCC. Microarray-based gene expression profiling was employed to identify the target genes of 23-HBA in the treatment of HCC. The effect of 23-HBA on the progression of HCC was evaluated by in-vitro cell function measurements along with in-vivo xenograft implantation, lung metastasis and CD11bGr1 staining experiments. The potential mechanism involving target signaling pathway was investigated by western blot analysis. Bioinformatics analysis revealed that matrix metalloproteinase 2 (MMP2) was a key target gene mediated by 23-HBA in HCC, whereas Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis demonstrated that MMP2 mainly affects the development and metastasis of HCC. 23-HBA significantly reduced cell malignant functions in vitro while delaying the HCC growth and metastasis in vivo. In addition, the number of myeloid-derived suppressor cells was shown to be reduced following administration of 23-HBA in mice. Mechanistic analysis indicated that these effects of 23-HBA during HCC were involved with the mitogen-activated protein kinase (MAPK) signaling pathway inactivation and resulted in decreased phosphorylation of both mitogen-activated protein kinases 12 and extracellular signal-regulated kinase 12. Our study reveals that 23-HBA acts as a tumor suppressor agent and suppresses HCC tumorigenesis, metastasis and immunosuppression via blockade of the MAPK signaling pathway, suggesting that 23-HBA may serve as a promising drug target to treat HCC.

Alveolar adenoma and coexisting atypical adenomatous hyperplasia a case report and literature review.

Alveolar adenoma is a rare tumour of the lung. It is typically found in asymptomatic adults as a peripheral or subplerual nodule on imaging examination. Microscopically, the tumour is composed of admixture of epithelial and mesenchymal component in variable sized cystic or alveolar structures. The tumour shows a benign nature. There have been no reported recurrences or metastases. Malignant transformation of alveolar adenoma and coexisting with lung carcinoma have been rarely described. In this article, we report a case of an alveolar adenoma and coexisting atypical adenomatous hyperplasia. This case, contributing to the limited numbers of cases described to date, illustrates the importance of awareness on the possibility of alveolar adenoma being associated with lung carcinoma and its precursor lesions especially when diagnosed by small biopsy specimens.

Pulmonary squamous cell carcinoma with a lepidic-pagetoid growth pattern.

We report a rare case of a peripheral squamous cell carcinoma (SCC) of the lung in which most of the tumor displayed a lepidic growth pattern. The tumor cells also appeared to grow along the alveolar walls between the overlying pneumocytes and underlying basement membrane, a form reminiscent of the pagetoid mode of spread. The neoplastic cells were positive for the squamous markers p63 and p40. TTF-1 and CK7 highlighted residual non-neoplastic pneumocytes, which either covered the lepidic tumor cells or lined pseudoglandular formations created by the filling of alveolar spaces by the tumor. CK7 also stained the tumor cells, albeit focally and weakly, a not uncommon finding in peripheral lung SCC. The tumor cells were negative for TTF-1 (clone 8G7G31), but did show focal weak reactivity with the less specific clone SPT24. The invasive area measured 2.5 mm while the overall size of the tumor including the lepidic-pagetoid component was 9.0 mm. Even though the invasive component was < 0.5 cm, the only option according to existing staging criteria was to stage it as pT1a. Since the current staging system does not account for the non-invasive lepidic component of pulmonary SCC, the increasing awareness of this variant may require its inclusion within the classification and pathological staging of lung carcinoma.

Cytoreductive Surgical Treatment of Pleural Mesothelioma in a Porcine Model Using Magnetic-Resonance-Guided Focused Ultrasound Surgery (MRgFUS) and Radiofrequency Ablation (RFA).

A combination of surgery and chemotherapy is the most effective treatment available for Malignant Pleural Mesothelioma (MPM). However, both cause significant collateral damage and cannot eliminate residual microscopic disease. This investigation aimed to compare and determine the feasibility of utilizing Radiofrequency Ablation (RFA) and Magnetic-Resonance-guided Focused Ultrasound Surgery (MRgFUS) as alternative treatments for MPM. A large animal tumor model was developed in 13 Yorkshire female pigs using the MSTO211H cell line. Two pigs were initially used to determine the cyclosporine dose required for immunosuppression and tumor development. Subsequently, 11 other pigs underwent tumor development. Of these 11, 2 died during cell inoculation. Small tumor masses and adhesions were present in the other 9, indicating mesothelioma development. Five pigs then received RFA treatment, and 4 pigs received MRgFUS treatment. Tumor model development and effect of the two treatments were examined using MRI and by necropsy. RFA and MRgFUS both successfully ablated approximately the same sized area in the same treatment time. This study demonstrates that RFA and MRgFUS are feasible for tumor debulking, and while MRgFUS requires more pretreatment planning compared to RFA, MRgFUS is a completely noninvasive procedure.

PD-L1 Over-Expression Varies in Different Subtypes of Lung Cancer Will This Affect Future Therapies

Programmed death-ligand (PD-L) 1 and 2 are ligands of programmed cell death 1 (PD-1) receptor. They are members of the B7CD28 ligand-receptor family and the most investigated inhibitory immune checkpoints at present. PD-L1 is the main effector in PD-1-reliant immunosuppression, as the PD-1PD-L pathway is a key regulator for T-cell activation. Activation of T-cells warrants the upregulation of PD-1 and production of cytokines which also upregulate PD-L1 expression, creating a positive feedback mechanism that has an important role in the prevention of tissue destruction and development of autoimmunity. In the context of inadequate immune response, the prolonged antigen stimulation leads to chronic PD-1 upregulation and T-cell exhaustion. In lung cancer patients, PD-L1 expression levels have been of special interest since patients with non-small cell lung cancer (NSCLC) demonstrate higher levels of expression and tend to respond more favorably to the evolving PD-1 and PD-L1 inhibitors. The Food and Drug Administration (FDA) has approved the PD-1 inhibitor, pembrolizumab, alone as front-line single-agent therapy instead of chemotherapy in patients with NSCLC and PD-L1 ≥1% expression and chemoimmunotherapy regimens are available for lower stage disease. The National Comprehensive Cancer Network (NCCN) guidelines also delineate treatment by low and high expression of PD-L1 in NSCLC. Thus, studying PD-L1 overexpression levels in the different histological subtypes of lung cancer can affect our approach to treating these patients. There is an evolving role of immunotherapy in the other sub-types of lung cancer, especially small cell lung cancer (SCLC). In addition, within the NSCLC category, squamous cell carcinomas and non-G12C KRAS mutant NSCLC have no specific targetable therapies to date. Therefore, assessment of the PD-L1 expression level among these subtypes of lung cancer is required, since lung cancer is one of the few malignances wherein PD-L1 expression levels is so crucial in determining the role of immunotherapy. In this study, we compared PD-L1 expression in lung cancer according to the histological subtype of the tumor.

Prediction of Total-Body and Partial-Body Exposures to Radiation Using Plasma Proteomic Expression Profiles.

There is a need to identify new biomarkers of radiation exposure for not only systemic total-body irradiation (TBI) but also to characterize partial-body irradiation and organ specific radiation injury. In the current study, we sought to develop novel biodosimetry models of radiation exposure using TBI and organ specific partial-body irradiation to only the brain, lung or gut using a multivariate proteomics approach. Subset panels of significantly altered proteins were selected to build predictive models of radiation exposure in a variety of sample cohort configurations relevant to practical field application of biodosimetry diagnostics during future radiological or nuclear event scenarios. Female C57BL6 mice, 8-15 weeks old, received a single total-body or partial-body dose of 2 or 8 Gy TBI or 2 or 8 Gy to only the lung or gut, or 2, 8 or 16 Gy to only the brain using a Pantak X-ray source. Plasma was collected by cardiac puncture at days 1, 3 and 7 postirradiation for total-body exposures and only the lung and brain exposures, and at days 3, 7 and 14 postirradiation for gut exposures. Plasma was then screened using the aptamer-based SOMAscan proteomic assay technology, for changes in expression of 1,310 protein analytes. A subset panel of protein biomarkers which demonstrated significant changes (P < 0.01) in expression after irradiation were used to build predictive models of radiation exposure using different sample cohorts. Model 1 compared controls vs. all pooled irradiated samples, which included TBI and all organ specific partial irradiation. Model 2 compared controls vs. TBI vs. partial irradiation (with all organ specific partial exposure pooled within the partial-irradiated group), and model 3 compared controls vs. each individual organ specific partial-body exposure separately (brain, gut and lung). Detectable values were obtained for all 1,310 proteins included in the SOMAscan assay for all samples. Each model algorithm built using a unique sample cohort was validated with a training set of samples and tested with a separate new sample series. Overall predictive accuracies of 89%, 78% and 55% resulted for models 1-3, respectively, representing novel predictive panels of radiation responsive proteomic biomarkers. Though relatively high overall predictive accuracies were achieved for models 1 and 2, all three models showed limited accuracy at differentiating between the controls and partial-irradiated body samples. In our study we were able to identify novel panels of radiation responsive proteins useful for predicting radiation exposure and to create predictive models of partial-body exposure including organ specific radiation exposures. This proof-of-concept study also illustrates the inherent physiological limitations of distinguishing between small-body exposures and the unirradiated using proteomic biomarkers of radiation exposure. As use of biodosimetry diagnostics in future mass casualty settings will be complicated by the heterogeneity of partial-body exposure received in the field, further work remains in adapting these diagnostic tools for practical use.

The Strong Anti-Tumor Effect of Smp24 in Lung Adenocarcinoma A549 Cells Depends on Its Induction of Mitochondrial Dysfunctions and ROS Accumulation.

Non-small cell lung cancer (NSCLC) is the leading cause of death in lung cancer due to its aggressiveness and rapid migration. The potent antitumor effect of Smp24, an antimicrobial peptide derived from Egyptian scorpion

Association of Sinoatrial Node Radiation Dose With Atrial Fibrillation and Mortality in Patients With Lung Cancer.

Atrial fibrillation (AF) can develop following thoracic irradiation. However, the critical cardiac substructure responsible for AF has not been properly studied. To describe the incidence of AF in patients with lung cancer and determine predictive cardiac dosimetric parameters. This retrospective cohort study was performed at a single referral center and included 239 patients diagnosed with limited-stage small cell lung cancer (SCLC) and 321 patients diagnosed with locally advanced non-small cell lung cancer (NSCLC) between August 2008 and December 2019 who were treated with definitive chemoradiotherapy. Radiation dose exposure to cardiac substructures, including the chambers, coronary arteries, and cardiac conduction nodes, were calculated for each patient. Main outcomes were AF and overall survival. Of the 239 and 321 patients with SCLC and NSCLC, the median (IQR) age was 68 (60-73) years and 67 (61-75) years, and 207 (86.6%) and 261 (81.3%) were men, respectively. At a median (IQR) follow-up time of 32.7 (22.1-56.6) months, 9 and 17 patients experienced new-onset AF in the SCLC and NSCLC cohorts, respectively. The maximum dose delivered to the sinoatrial node (SAN Dmax) exhibited the highest predictive value for prediction of AF. A higher SAN Dmax significantly predicted an increased risk of AF in patients with SCLC (adjusted hazard ratio aHR, 14.91 95% CI, 4.00-55.56 P < .001) and NSCLC (aHR, 15.67 95% CI, 2.08-118.20 P .008). However, SAN Dmax was not associated with non-AF cardiac events. Increased SAN Dmax was significantly associated with poor overall survival in patients with SCLC (aHR, 2.68 95% CI, 1.53-4.71 P < .001) and NSCLC (aHR, 1.97 95% CI, 1.45-2.68 P < .001). In this cohort study, results suggest that incidental irradiation of the SAN during chemoradiotherapy may be associated with the development of AF and increased mortality. This supports the need to minimize radiation dose exposure to the SAN during radiotherapy planning and to consider close follow-up for the early detection of AF in patients receiving thoracic irradiation.

Adoption of Extended-Interval Dosing of Single-Agent Pembrolizumab and Comparative Effectiveness vs Standard Dosing in Time-to-Treatment Discontinuation.

Extended-interval dosing of pembrolizumab (400 mg every 6 weeks) was approved by US Food and Drug Administration (FDA) in April 2020 as an alternative to standard-interval dosing (200 mg every 3 weeks). Extended-interval dosing may enhance access, alleviate patient and health system financial toxicity, and improve patient quality of life, particularly during the COVID-19 pandemic. Neither adoption nor effectiveness of extended interval in the US has been adequately described. To describe adoption of extended-interval dosing of pembrolizumab since its FDA approval and to measure its preliminary real-world effectiveness compared with standard-interval dosing. This was a retrospective cohort study that used data from the Veterans Health Administration (VHA), a US-based, nationwide single-payer health system. Participants were veterans who were prescribed single-agent pembrolizumab within the VHA between April 1, 2020, and July 1, 2021. Patients receiving combinations of pembrolizumab and cytotoxic chemotherapy or tyrosine kinase inhibitors were excluded. A subcohort of veterans with non-small cell lung cancer (NSCLC) was also identified using claims-based codes. Single-agent pembrolizumab at extended or standard intervals. The number and proportion of single-agent pembrolizumab prescriptions that were extended compared with standard interval. Effectiveness was described in terms of time-to-treatment discontinuation (TTD) and extended- to standard-interval pembrolizumab prescriptions were compared using Cox proportional hazards regression. A total of 835 veterans (mean age SD, 70.9 8.7 years 809 96.9% men) began single-agent pembrolizumab during the study period (all-diseases cohort), and of these, 234 (mean SD age, 71.6 7.3 years 225 96.2% men) had NSCLC (NSCLC cohort). Extended-interval adoption reached its steady state plateau of approximately 35% by January 2021 65% of participants who began standard-interval single-agent pembrolizumab received only standard-interval dosing during the treatment course. In analysis consistent with the intention-to-treat principle, no differences in TTD were observed between standard- and extended-interval dosing in either the all-diseases cohort (HR, 1.00 95% CI, 1.00-1.00) or the NSCLC cohort (HR, 1.00 95% CI, 1.00-1.00). This retrospective cohort study found that extended-interval dosing comprised a minority of single-agent pembrolizumab prescriptions despite the FDA approval and its potential health system and public health benefits. The findings support the TTD equivalence of standard- and extended-interval pembrolizumab across indications, complementing clinical pharmacology and single-arm clinical trial data in melanoma. This study provides further support for extended-interval pembrolizumab dosing.

Preclinical and Clinical Trial Results Using Talazoparib and Low-Dose Chemotherapy.

On the basis of preclinical data, we hypothesized that low doses of chemotherapy (10% of therapeutic doses) with full dose of a PARP inhibitor could have improved efficacy and tolerability. In this phase I dose-escalation study, patients with BRCA-normal advanced malignancies were assigned to either talazoparibtemozolomide or talazoparibirinotecan. Talazoparib was dose-escalated from 500 mcg to 1 mg daily before dose escalation of temozolomideirinotecan. The starting dose of temozolomide was 25 mgm2day orally on days 1 to 5 and irinotecan was 25 mgm2day intravenously on days 1 and 15. The primary objectives of this trial were safety and tolerability, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD). Of 40 patients enrolled, 18 (mean 7 prior therapies) were enrolled in talazoparib temozolomide and 22 in talazoparib irinotecan. DLTs were hematologic in both arms, but all hematologic adverse events resolved with either treatment interruption andor dose reductions of talazoparib. The MTDs were talazoparib 1 mg temozolomide 37.5 mgm2 and talazoparib 1 mg irinotecan 37.5 mgm2. There were four partial responses in the talazoparib temozolomide arm and five in the talazoparib irinotecan arm for a response rate of 23% (940). The pharmacokinetic profiles of talazoparib temozolomideirinotecan were similar to that of talazoparib monotherapy. Responses were seen independent of homologous recombination (HR) status and HR deficiency score. These results show that talazoparib with low-dose temozolomide or irinotecan is reasonably well tolerated and demonstrates clinical activity in a wide range of cancers. Randomized trials of talazoparib with or without low-dose chemotherapy are ongoing in small cell lung cancer and ovarian cancer.

Central nervous systemic efficacy of immune checkpoint inhibitors and concordance between intraextracranial response in non-small cell lung cancer patients with brain metastasis.

Immune checkpoint inhibitors (ICIs) markedly improve the clinical outcomes of advanced non-small-cell lung cancer (NSCLC). However, the intracranial efficacy of ICI is not well elucidated, and previous studies showed discordant outcomes of ICI between intracranial and extracranial diseases. We aimed to evaluate the clinical outcomes and the intracranial and extracranial response of patients with NSCLC and brain metastasis who were treated with ICI in the real-world setting. A total of 55 patients (median age, 63 years range 42-80 male, 78%) who had NSCLC with brain metastasis and treated with ICI monotherapy were retrospectively analyzed. We separately assessed the response rates of brain lesions and systemic lesions, and estimated the overall survival (OS) and progression-free survival (PFS). The median OS and overall PFS were 17.0 months (95% CI 10.3-25.6) and 3.19 months (95% CI 2.24-5.03), respectively. The intracranial objective response rate and disease control rate of ICI were 36 and 54%, respectively. Among the 44 patients who showed disease progression, only 32% (n 14) showed concordant outcomes and 9 patients (20%) showed opposing discordant outcomes. Eight patients continued ICI with local brain therapy after intracranial progression, and their median extracranial PFS and OS were 15 months (95% CI 5.0-not assessed NA) and 23.8 months (95% CI 14.7-NA), respectively. ICI monotherapy had a clinically meaningful intracranial efficacy in NSCLC patients with brain metastasis. Watchful waiting and close monitoring without local radiotherapy might be feasible in NSCLC patients with asymptomatic active brain metastasis.

Mutational Landscape and Expression of PD-L1 in Patients with Non-Small Cell Lung Cancer Harboring Genomic Alterations of the MET gene.

Mesenchymal-to-epithelial transition (MET) exon 14 skipping mutations and MET gene amplification occur in 3-5% of non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs) targeting MET alterations have shown promising results in these patients. The aim of this study was to describe the genomic profile, PD-L1 expression and clinicopathological features of MET dysregulated NSCLC. We identified 188 patients with advanced-stage NSCLC with data on MET expression by immunohistochemistry (IHC). IHC for PD-L1 expression was performed in 131 patient samples, and next-generation sequencing (NGS) analysis was performed in 109 patient samples. MET exon 14 skipping alterations were identified in 16 (14.7%) samples, MET amplifications with cut-off ≥4 copy number variations were identified in 11 (10.1%) samples, and an oncogenic MET mutation (MET p.D1228N) was identified in 1 (0.9%) sample. 1215 tumors (80.0%) harboring MET exon 14 alterations and 711 (63.6%) MET-amplified tumors expressed PD-L1 in ≥1% of tumor cells. Tumors harboring MET exon 14 skipping alterations expressed PD-L1 more frequently than MET wild-type IHC-positive tumors (p 0.045). Twenty-five percent of MET exon 14-altered cases and 33% of MET-amplified cases harbored potentially targetable oncogenic co-mutations in KRAS, BRAF, and EGFR. The most frequent co-occurring mutations in all MET-altered tumors were TP53, KRAS, BRAF, and CDK4. We demonstrated that MET exon 14 skipping alterations and MET amplification are not mutually exclusive to other oncogenic co-mutations, and report the association of genomic MET alterations with PD-L1 expression. Since genomic MET alterations are emerging targets requiring upfront treatment, optimal understanding of the co-mutational landscape for this patient population is needed.

Pharmacological interventions for preventing atrial fibrillation after lung surgery systematic review and meta-analysis.

Postoperative atrial fibrillationflutter (POAF) is one of the most common cardiac complications after lung surgery. We aimed to assess the safety and efficacy of pharmacological interventions for new-onset POAF prophylaxis in patients with lung cancer after lung surgery. PubMed, Embase, Web of Science, Scopus, and the Cochrane Library were searched to identify randomized controlled trials comparing the effects of pharmacological interventions to prevent POAF following lung surgery. A total number of 19 studies with 2,922 participants were included. Pharmacological interventions significantly reduced the incidence of POAF (odds ratio OR 0.36, 95% confidence interval 95% CI 0.26-0.52) while did not increase the incidence of severe pulmonary complications (OR 1.17, 95% CI 0.57-2.41) after lung surgery compared with placebousual care. Among different trials, beta-blockers appeared to be the most effective with an OR of 0.13 (95% CI, 0.07-0.27) and a number needed-to-treat (NNT) of 3.63 and was considered safe with no serious adverse events recorded. The risk of POAF decreased from 25.6 to 11.4% (P < 0.001) overall and from 34.2 to 6.7% (P < 0.001) with beta-blockers as monotherapy. Pharmacological interventions did not reduce the 30-day mortality (OR 0.89, 95% CI 0.43-1.84, I Current clinical evidence supports the effectiveness of pharmacological intervention with beta-blockers, amiodarone, magnesium sulfate, or calcium-channel blockers to reduce the incidence of POAF after lung surgery in patients with lung cancer. In the absence of contraindications, prophylaxis with beta-blockers seems to be the most effective of the treatments studied.

The long-term course of subsolid nodules and predictors of interval growth on chest CT a systematic review and meta-analysis.

To calculate the pooled incidence of interval growth after long-term follow-up and identify predictors of interval growth in subsolid nodules (SSNs) on chest CT. A search of MEDLINE (PubMed), Cochrane Library, Web of Science Core Collection, and Embase was performed on November 08, 2021, for relevant studies. Patient information, CT scanner, and SSN follow-up information were extracted from each included study. A random-effects model was applied along with subgroup and meta-regression analyses. Study quality was assessed by the Newcastle-Ottawa scale, and publication bias was assessed by Eggers test. Of the 6802 retrieved articles, 16 articles were included and analyzed, providing a total of 2898 available SSNs. The pooled incidence of growth in the 2898 SSNs was 22% (95% confidence interval CI, 15-29%). The pooled incidence of growth in the subgroup analysis of pure ground-glass nodules was 26% (95% CI 12-39%). The incidence of SSN growth after 2 or more years of stability was only 5% (95% CI 3-7%). An initially large SSN size was found to be the most frequent risk factor affecting the incidence of SSN growth and the time of growth. The pooled incidence of SSN growth was as high as 22%, with a 26% incidence reported for pure ground-glass nodules. Although the incidence of growth was only 5% after 2 or more years of stability, long-term follow-up is needed in certain cases. Moreover, the initial size of the SSN was the most frequent risk factor for growth. • Based on a meta-analysis of 2898 available subsolid nodules in the literature, the pooled incidence of growth was 22% for all subsolid nodules and 26% for pure ground-glass nodules. • After 2 or more years of stability on follow-up CT, the pooled incidence of subsolid nodule growth was only 5%. • Given the incidence of subsolid nodule growth, management of these lesions with long-term follow-up is preferred.

Rapid

α-Ketoglutarate is a key biomolecule involved in a number of metabolic pathways─most notably the TCA cycle. Abnormal α-ketoglutarate metabolism has also been linked with cancer. Here, isotopic labeling was employed to synthesize 1-

Expression of the cytokinesis regulator PRC1 results in p53-pathway activation in A549 cells but does not directly regulate gene expression in the nucleus.

Protein regulator of cytokinesis 1 (PRC1) is a microtubule-binding protein with essential roles in mitosis and cytokinesis. PRC1 is frequently overexpressed in cancer cells where it could contribute to chromosomal instability. Due to its nuclear localization in interphase, it has been speculated that PRC1 has additional functions that are involved in its pro-tumorigenic functions. In this study we investigated the potential nuclear functions of PRC1 in a lung cancer cell line. Genome wide expression profiling by RNA sequencing revealed that the expression of PRC1 results in activation of the p53 pathway and inhibition of the pro-proliferative E2F-dependent gene expression. A mutant of PRC1 that is unable to enter into the nucleus regulated the same gene sets as wildtype PRC1, suggesting that PRC1 has no nuclear-exclusive functions in A549 cells. Instead, induction of p53 by PRC1 correlates with multinucleation and depends on the localization of PRC1 to the midbody, suggesting that the induction of p53 is a consequence of overexpressed PRC1 to interfere with the normal function of PRC1 during cytokinesis. Activation of p53 by PRC1 results in cellular senescence but not in apoptosis. In conclusion, while PRC1 is frequently overexpressed in many cancers, the p53 pathways may initially protect cancer cells from the negative effects of PRC1 overexpression on cytokinesis. Because depletion of PRC1 also results in p53-pathway activation and senescence, levels of PRC1 need to be tightly regulated to allow unperturbed proliferation. Targeting the expression or function of PRC1 could create a therapeutic vulnerability for the treatment of cancer.

Rare surfactant-related variants in familial and sporadic pulmonary fibrosis.

The role of constitutional genetic defects in idiopathic pulmonary fibrosis (IPF) is increasingly appreciated. Monogenic disorders associated with IPF affect two pathways telomere maintenance, accounting for approximately 10% of all patients with IPF, and surfactant biology, responsible for 1%-3% of cases and often co-occurring with lung cancer. We examined the prevalence of rare variants in five surfactant-related genes, SFTPA1, SFPTA2, SFTPC, ABCA3, and NKX2-1, that were previously linked to lung disease in whole genome sequencing data from 431 patients with IPF. We identified functionally deleterious rare variants in SFTPA2 with a prevalence of 1.3% in individuals with and without a family history of IPF. All individuals had no personal history of lung cancer, but substantial bronchiolar metaplasia was noted on lung explants and biopsies. Five patients had novel missense variants in NKX2-1, but the contribution to disease is unclear. In general, patients were younger and had longer telomeres compared with the majority of patients with IPF suggesting that these features may be useful for identifying this subset of patients in the clinic. These data suggest that SFTPA2 variants may be more common in unselected IPF cohorts and may manifest in the absence of personalfamily history of lung cancer or IPF.

Polycomb Directed Cell Fate Decisions in Development and Cancer.

The polycomb group (PcG) proteins are a subset of transcription regulators highly conserved throughout evolution. Their principal role is to epigenetically modify chromatin landscapes and control the expression of master transcriptional programs to determine cellular identity. The two mayor PcG protein complexes that have been identified in mammals to date are Polycomb Repressive Complex 1 (PRC1) and 2 (PRC2). These protein complexes selectively repress gene expression via the induction of covalent post-translational histone modifications, promoting chromatin structure stabilization. PRC2 catalyzes the histone H3 methylation at lysine 27 (H3K27me123), inducing heterochromatin structures. This activity is controlled by the formation of a multi-subunit complex, which includes enhancer of zeste (EZH2), embryonic ectoderm development protein (EED), and suppressor of zeste 12 (SUZ12). This review will summarize the latest insights into how PRC2 in mammalian cells regulates transcription to orchestrate the temporal and tissue-specific expression of genes to determine cell identity and cell-fate decisions. We will specifically describe how PRC2 dysregulation in different cell types can promote phenotypic plasticity andor non-mutational epigenetic reprogramming, inducing the development of highly aggressive epithelial neuroendocrine carcinomas, including prostate, small cell lung, and Merkel cell cancer. With this, EZH2 has emerged as an important actionable therapeutic target in such cancers.

Acquired G2032R Resistance Mutation in ROS1 to Lorlatinib Therapy Detected with Liquid Biopsy.

Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK)receptor tyrosine kinase inhibitor (ROS1), demonstrated efficacy in ROS1 positive (ROS1) non-small cell lung cancer (NSCLC), although approval is currently limited to the treatment of ALK patients. However, lorlatinib-induced resistance mechanisms, and its efficacy against the resistance mutation G2032R in ROS1, respectively, have not yet been fully understood. Furthermore, concomitant tumor suppressor gene p53 (TP53) mutations occur in driver alteration positive NSCLC, but their prognostic contribution in the context of ROS1 inhibition remains unclear. Here we report a ROS1 NSCLC patient who developed an on target G2032R resistance mutation during second-line lorlatinib treatment, indicating the lack of activity of lorlatinib against ROS1 G2032R. The resistance mutation was detected in plasma-derived ctDNA, signifying the clinical utility of liquid biopsies.

Comparison of Efficacy and Safety of Taxanes Plus Platinum and Fluorouracil Plus Platinum in the First-Line Treatment of Esophageal Cancer A Systematic Review and Meta-Analysis.

Fluoropyrimidine plus platinum (FP) and taxanes plus platinum (TP) are standard treatments for esophageal cancer (EC). This systematic review and meta-analysis aim to explore the difference in the therapeutic effect and toxicity of FP and TP regimens in EC patients. PubMed, Embase, and Cochrane were fully searched and analyzed to find relevant articles on EC patients treated with FP and TP regimens up to 22 March 2022. Thirty-one studies, with a total of 3432 participants, were included in this review. The primary outcomes showed that the prognosis and therapeutic efficacy of TP groups were better than those of FP groups for the EC patients treated with definitive chemoradiotherapy treatment (3-year OS RR 1.25, 95% CI 1.08-1.44,

Association between Temporal Muscle Thickness and Overall Survival in Non-Small Cell Lung Cancer Patients with Brain Metastasis.

Temporal muscle thickness (TMT) has recently been suggested as a novel biomarker of sarcopenia in head and neck malignancies. However, few studies have evaluated TMT as a prognostic marker in patients with brain metastasis. This study investigated the association of TMT with overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastasis. The records of all NSCLC patients with brain metastasis between 2009 and 2018 at St. Vincents Hospital were reviewed retrospectively. A total of 221 patients met our eligibility criteria. In the group with TMT thicker than the median, OS was longer than the group with TMT thinner than the median (240 days versus 139 days,

The Tobacco Endgame-A New Paradigm for Smoking Cessation in Cancer Clinics.

Smoking cessation represents an untapped resource for cancer therapy. Many people who smoke and have cancer (tobacco-related or otherwise) struggle to quit and as a result, jeopardise response to treatment, recovery after surgery and long-term survival. Many health care practitioners working in cancer medicine feel undertrained, unprepared and unsupported to provide effective smoking cessation therapy. Many institutions and healthcare systems do provide smoking cessation programs, guidelines and referral pathways for cancer patients, but these may be unevenly applied. The growing body of evidence, from both retrospective and prospective clinical studies, confirms the benefit of smoking cessation and will provide much needed evidence for the best and most effective interventions in cancer clinics. In addition to reducing demand, helping cancer patients quit and treating addiction, a firm commitment to developing smoke free societies may transform cancer medicine in the future. While the Framework Convention for Tobacco Control (FCTC) has dominated global tobacco control for the last two decades, many jurisdictions are starting to develop plans to make their communities tobacco free, to introduce the tobacco endgame. Characterised by downward pressure on tobacco supply, limited sales, limited access and denormalization of smoking, these policies may radically change the milieu in which people with cancer receive treatment, in which health care practitioners refine skills and which may ultimately foster dramatic improvements in cancer outcomes.

Tobacco Use and Response to Immune Checkpoint Inhibitor Therapy in Non-Small Cell Lung Cancer.

Tobacco is a known risk factor for lung cancer, and continued tobacco use is associated with poorer outcomes across multiple lung cancer treatment modalities including surgery, chemotherapy and radiation therapy. Less is known about the association of tobacco use and outcomes with immune checkpoint inhibitors (ICIs), which are becoming an important part of the treatment landscape in lung cancer, both in metastatic and curative settings. We reviewed the literature on the association of tobacco and tumor biology as it relates to immunotherapy. We also reviewed the association of tobacco use on outcomes among phase III randomized clinical trials involving ICIs in non-small cell lung cancer (NSCLC). We identified that patients with a smoking history may have a greater benefit with ICI treatment compared to never smokers in both treatment-naïve (HR 0.82, 95% CI 0.69-0.97, vs. HR 1.06, 95% CI 0.81-1.38) and pre-treated (HR 0.79, 95% CI 0.70-0.90 vs. 1.03, 95% CI 0.74-1.43) settings. In trials where smoking status was further defined, ex-smokers appear to demonstrate greater benefit with ICI therapy compared to current smokers (HR 0.78, 95% CI 0.59-1.01 vs. 0.91, 95% CI 0.72-1.14). We conclude by offering our perspective on future directions in this area of research, including implementation of standardized collection and analysis of tobacco use in clinical trials involving ICI therapy in lung cancer and other disease sites, and also evaluating how tobacco may affect toxicities related to ICI therapy. Based on our review, we believe that a patients history of tobacco smoking does have a role to play in guiding treatment decision making in patients with lung cancer.

Neoadjuvant Immunotherapy Combined with Chemotherapy for Local Advanced Non-Small-Cell Lung Cancer in a Patient with a History of Breast Cancer A Case Report.

Durvalumab consolidation therapy is the standard treatment after concurrent chemoradiotherapy for patients with surgically unresectable stage IIIA (N2) non-small-cell lung cancer (NSCLC). Neoadjuvant therapy followed by surgery could reduce locoregional and distant recurrence and improve the survival rate for surgically resectable NSCLC. However, the value of neoadjuvant therapy in locally advanced potentially resectable NSCLC remains controversial. Herein, we report a locally advanced potentially resectable NSCLC case with a history of breast cancer who achieved a pathologic complete response (pCR) after preoperative treatment with pembrolizumab and chemotherapy. A 50-year-old woman developed squamous cell carcinoma (SCC) (left lower lobe of the lung, stage IIIA-N2) after two years of chemotherapy and anti-HER2 therapy following a diagnosis of HER2-overexpressing breast cancer. Surgical resection was attempted despite an MDT classification as unamenable to curative surgical resection. After two cycles of neoadjuvant chemotherapy combined with anti-PD1 immunotherapy, the tumor significantly shrank, then the patient underwent a left lower lobectomy. Complete resection with negative margins (R0 resection) was achieved in the patient. The patient experienced grade 1-2 adverse effects and no grade 3 or worse adverse effects occurred. Cardiotoxicity did not occur in the patient despite prior anti-HER2 treatment for breast cancer. Our case study contributes to the existing evidence on the feasibility, efficacy, and safety of neoadjuvant immunotherapy combined with chemotherapy in locally advanced unresectable NSCLC. Furthermore, future studies are needed to determine which patients can benefit from immunoadjuvant therapy and the duration and course of preoperative and postoperative immunotherapy.

The Efficacy and Safety of Celecoxib in Addition to Standard Cancer Therapy A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The purpose of this meta-analysis was to evaluate the efficacy and safety of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, in addition to standard anticancer therapy. Randomized controlled trials (RCTs) that evaluated the efficacy and safety of celecoxib-combined cancer therapy were systematically searched in PubMed and Embase databases. The endpoints were overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), objective response rate (ORR), disease control rate (DCR), pathological complete response (pCR), and adverse events (AEs). The results of 30 RCTs containing 9655 patients showed limited benefits in celecoxib-combined cancer therapy. However, celecoxib-combined palliative therapy prolonged PFS in epidermal growth factor receptor (EGFR) wild-type patients (HR 0.57, 95%CI 0.35-0.94). Moreover, despite a slight increase in thrombocytopenia (RR 1.35, 95%CI 1.08-1.69), there was no increase in other toxicities. Celecoxib combined with adjuvant therapy indicated a better OS (HR 0.850, 95%CI 0.725-0.996). Furthermore, celecoxib plus neoadjuvant therapy improved the ORR in standard cancer therapy, especially neoadjuvant therapy (overall RR 1.13, 95%CI 1.03-1.23 neoadjuvant therapy RR 1.25, 95%CI 1.09-1.44), but not pCR. Our study indicated that adding celecoxib to palliative therapy prolongs the PFS of EGFR wild-type patients, with good safety profiles. Celecoxib combined with adjuvant therapy prolongs OS, and celecoxib plus neoadjuvant therapy improves the ORR. Thus, celecoxib-combined cancer therapy may be a promising therapy strategy.

Preoperative Serum Triglyceride to High-Density Lipoprotein Cholesterol Ratio Can Predict Prognosis in Non-Small Cell Lung Cancer A Multicenter Retrospective Cohort Study.

Previously, research has reported associations of lipid and lipoprotein imbalances with carcinogenesis and cancer progression, so they have been considered as promising prognostic biomarkers for cancer in recent years. However, the correlation of preoperative serum triglyceride to high-density lipoprotein cholesterol ratio (TGHDL-C) with non-small cell lung carcinoma (NSCLC) prognosis remains under exploration. Here, the study investigated the prognostic function of TGHDL-C for NSCLC. The total combined group of this retrospective study enrolled 479 NSCLC patients from two tertiary referral hospitals, of which 223 patients were defined as the training group (Nanchang) and the remaining 256 were defined as the validation group (Wuhan). The cut-off of preoperative TGHDL-C was determined through ROC curve in the training group and verified in the validation and combined groups subsequently. With one Cox proportional hazards model and K-M survival curves, a survival analysis was conducted. In the training group, the optimal cut-off of TGHDL-C was 1.02. Furthermore, the data based on the training group revealed a greater, shorter, overall survival (OS) in patients having a high TGHDL-C (gt1.02) than those having low TGHDL-C (≤1.02). Meanwhile, in univariate and multivariate analysis, for prognostic OS among NSCLC patients, TGHDL-C acted as one independent factor. All the results above were confirmed in the validation and combined groups. NSCLC patients with a comparatively low preoperative serum TGHDL-C level had a correlation with well OS. TGHDL-C possibly acted as one novel, effective prognostic biomarker for NSCLC patients.

Long-Term Survival after Linac-Based Stereotactic Radiosurgery and Radiotherapy with a Micro-Multileaf Collimator for Brain Metastasis.

this study aimed to evaluate the prognostic factors associated with long-term survival after linear accelerator (linac)-based stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) with a micro-multileaf collimator for brain metastasis (BM). This single-center retrospective study included 226 consecutive patients with BM who were treated with linac-based SRS or fSRT with a micro-multileaf collimator between January 2011 and December 2018. Long-term survival (LTS) was defined as survival for more than 2 years after SRSfSRT. The tumors originated from the lung ( female sex, a favorable pre-treatment KPS score, and the absence of extracranial metastasis were associated with long-term survival in the current cohort of patients with BM.

Obesity in cases undergoing the surgical procedure of lung lobectomy risk or benefit

The aim of the study was to evaluate the effect of body mass index on patients short-term results following lung lobectomy. In this retrospective study, we compared the perioperative and short-term postoperative results of obese (BMI≥30 kgm2) versus non-obese patients (BMI<30 kgm2) who underwent anatomical lung resection for cancer. The two groups had the same distribution of input risk factors and the same ratio of surgical approaches (thoracoscopy vs. thoracotomy). The study included a total of 144 patients 48 obese and 96 non-obese patients. Both groups had the same ratio of thoracoscopic vs. thoracotomy approach (5050%), and were comparable in terms of demographics and clinical data. The g roups did not significantly differ in the frequency of perioperative or postoperative complications. Postoperative morbidity was higher among non-obese patients (34.4 vs. 27.1%), but this difference was not statistically significant (p0.053). Hospital stay was similar in both study groups (p0.100). Surgery time was significantly longer among obese patients (p0.133). Postoperative mortality was comparable between the study groups (p0.167). Obesity does not increase the frequency of perioperative and postoperative complications in patients after lung lobectomy. The slightly better results in obese patients suggest that obesity may have some protective role.

Need for accelerating tobacco control in India findings from the national cancer registry programme.

To describe the epidemiology of cancer in sites associated with tobacco use in India, according to recent findings from the National Cancer Registry Programme. The data on cancers in sites associated with tobacco use has been sourced from 28 population-based and 58 hospital-based cancer registries of the National Cancer Registry Programme in India. The data covering a period of 5 years (2012-2016) was taken up for analysis. The highest age-adjusted incidence rate (AAR) among males was reported in the Aizawl district in Mizoram (197.3 per 100 000). The AAR was the highest (121.1 per 100 000) in the Papumpare district in females. The top five leading sites were cancers of the lung (10.7%), mouth (8.7%), oesophagus (6%), tongue (6%) and stomach (5%) among males and cancer of the cervix (10.3%), lung (4.3%), oesophagus (3.3%), mouth (3.3%) and tongue (2.7%) in females. The highest significant increase in AAR, indicated by the annual percentage change was seen among males in Aurangabad (3.4) and females in Kamrup urban (2.4). Except for lung cancer, most patients with other cancer types among both genders presented to the health facility with a locoregional (spread to nearby lymph nodes) disease spread. It is projected that in 2025, there will be 694367 cases of cancers in the sites associated with tobacco use. Tobacco uses in either form and cancer in sites associated with tobacco use are an important matter of public health concern in India. Cancer registries play a crucial role in identifying populations with high cancer incidence in sites associated with tobacco use, monitoring the trends over time, and evaluating the impact of tobacco control measures.

Comprehensive molecular docking and dynamic simulations for drug repurposing of clinical drugs against multiple cancer kinase targets.

Drug repurposing is a method to identify novel therapeutic agents from the existing drugs and clinical compounds. In the present comprehensive work, molecular docking, virtual screening and dynamics simulations were carried out for ten cancer types viz breast, colon, central nervous system, leukaemia, melanoma, ovarian, prostate, renal and lung (non-small and small cell) against validated eighteen kinase targets. The study aims to understand the action of chemotherapy drugs mechanism through binding interactions against selected targets via comparative docking simulations with the state-art molecular modelling suits such as MOE, Cresset-Flare, AutoDock Vina, GOLD and GLIDE. Chemotherapeutic drugs (

Lung adenocarcinoma coexisting with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia manifesting as multiple pulmonary nodules A case report.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), a rare condition, is characterized by pathological proliferation of neuroendocrine cells. Some of them are localized to the airway mucosa, and others locally infiltrate to form tumorlets and nodules. Here, we present a patient with lung adenocarcinoma accompanied by DIPNECH, making the latter difficult to distinguish from multiple pulmonary metastases. The patient, a 72-year-old Japanese woman, was diagnosed as having stage IVA lung adenocarcinoma because she had multiple nodules in both lungs. Mutation of epidermal growth factor receptor gene having been found in the primary tumor, treatment with osimertinib was started. This resulted in shrinkage of the primary tumor, but not the multiple pulmonary nodules. To determine whether these lung nodules were indeed lung metastases, we performed right upper lobectomy with lymphadenectomy and wedge resection of the right lower lobe. On pathological examination, the primary tumor was diagnosed as invasive adenocarcinoma, whereas the multiple pulmonary nodules were diagnosed as DIPNECH manifesting as tumorlets. Therefore, the final diagnosis was stage IA1 lung adenocarcinoma accompanied by DINPECH. The patient had no recurrences 1 year after the operation without any additional treatment. This is a rare case of lung adenocarcinoma accompanied by DIPNECH presenting as multiple pulmonary nodules. DIPNECH should be included in the differential diagnosis of multiple pulmonary nodules.

Long-Term Treatment-Free Survival After Multimodal Therapy in a Patient with Stage IV Lung Adenocarcinoma.

We report the first case of a patient with non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE) who achieved disease- and treatment-free survival for nearly 10 years. A 50-year-old man was diagnosed with NSCLC with MPE and underwent chemotherapy and salvage thoracic surgery. The patient received chemotherapy with cisplatin, pemetrexed, and bevacizumab, and a partial response was achieved. After informed consent was obtained from the patient, right middle lobectomy was performed to achieve local tumor control. Postoperative adjuvant chemotherapy with pemetrexed and bevacizumab was discontinued after almost 1 year of chemotherapy due to side effects such as diarrhea and muscle weakness. The patient has survived without recurrence of lung cancer for more than 11 years after being diagnosed and nearly 10 years after discontinuing chemotherapy.

Self-assembled dipeptide based fluorescent nanoparticles as a platform for developing cellular imaging probes and targeted drug delivery chaperones.

Self-assembled peptide-based nanostructures, comprised of naturally occurring amino acids, display excellent biocompatibility, biodegradability, flexible responsiveness, and synthetic feasibility and can be customized for various biomedical applications. However, the lack of inherent optical properties of peptide-based nanoparticles is a limitation on their use as imaging probes or drug delivery vehicles. To overcome this impediment, we generated Boc protected tyrosine-tryptophan dipeptide-based nanoparticles (DPNPs) with structure rigidification by Zn(ii), which shifted the peptides intrinsic fluorescent properties from the ultraviolet to the visible range. These DPNPs are photostable, biocompatible and have visible fluorescence signals that allow for real-time monitoring of their entry into cells. We further show that two DPNPs (PS1-Zn and PS2-Zn) can encapsulate the chemotherapeutic drug doxorubicin (Dox) and facilitate intracellular drug delivery resulting in cancer cell killing actions comparable to the unencapsulated drug. Finally, we chemically modified our DPNPs with an aptamer directed toward the epithelial cell surface marker EPCAM, which improved Dox delivery to the lung cancer epithelial cell line A549. In contrast, the aptamer conjugated DPNPs failed to deliver Dox into the cardiomyocyte cell line AC16. Theoretically, this strategy could be employed

The Relationship Between Specific Age-Related Chronic Conditions of Comorbidity and Depression Scores Among Men in an Elderly Population A Cross-Sectional Study.

Objective There had been an observed increase in the prevalence of depression as well as many chronic conditions of comorbidity among the elderly population of Ireland above the age of 50. The relationship between different prominent conditions of comorbidity and depression scores amongst older adult men in Ireland was sought to be examined and explored. Methods A cross-sectional analysis of data from wave 1 of The Irish Longitudinal Study on Aging (TILDA) had been used for statistical analysis, which served to be the representative cohort study sample of elderly adults living in Ireland aged 50 and older. Summary statistics (cross-tabulation, t-test, analysis of varianceANOVA and odds ratio) were used to explore the relationship between depression scores and different conditions of comorbidity. Results Results were drawn from the three different tests conducted cross-tabulation, t-test, and analysis of varianceANOVA. Cross-tabulation served to provide the total population of men who suffered from depression (CES-D score ≥ 16), which totaled 123 (1.4%) of the entire 8,504 available candidates. Of the participants that met the criteria for having a significant risk of clinical depression along with an accompanying chronic illness odds ratio (OR) had been calculated. All but one of the conditions yielded a significant increase in OR between having a chronic condition and depression with the exception of chronic lung disease. Congestive heart failure demonstrated the highest OR of 4.40 (CI 95% 1.77-10.95), followed by arthritis, diabetes and cancer. Subsequent t-tests used to construct an ANOVA then illustrated the mean CES-D score for males suffering from one of the five concomitant illnesses selected (congestive heart failure, chronic lung disease, arthritis, cancer, and diabetes) as well as those free of the selected diseases of the study, with a total count of 2,117. All results had been deemed to be significant with p

Non-Small Cell Lung Cancer Presenting as a Mobile Left Atrial Mass.

Primary cardiac tumors are extremely rare and mostly metastatic in origin. The signs and symptoms depend on the location of the tumor rather than its histopathology and, rarely, may be the first presentation of the malignant disease. We report a 54-year-old woman diagnosed with non-small lung cancer with new-onset heart murmur and dyspnea on exertion as the first clinical manifestations.

The role of psychiatry in quality of life in young patients with non-small cell lung cancer.

Lung cancer is often seen in geriatric patients, with an age of onset of approximately 60 years. Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality in the United States and around the world. Young patients are rarely diagnosed with lung cancer, with less than 3.5% of patients presenting with this tumor at an age less than 45. In this paper, we examine NSCLC in young patients, between 18 and 35 years of age, which most commonly occurs in non-smokers and is characterized by a higher proportion of adenocarcinoma histology and advanced disease at presentation. These patients often present with metastasis involving one organ and they test positive for driver gene mutations including, but not limited to, epidermal growth factor receptor (EGFR), tyrosine kinase inhibitor (TKI) sensitive mutation and anaplastic lymphoma kinase (ALK). We addressed depression and anxiety and their effect on quality of life (QOL) and attempted to examine how improvement in QOL in these young patients could affect their course of illness and prognosis. We conducted a literature review using PubMed, Cochrane, and Google search. We concentrated our search on two elements, reviewing approximately 50 articles focusing on the driver mutations EGFR and ALK as well as genetic mapping of lung adenocarcinoma in patients aged 18-35 years old. We also conducted a review of approximately 30 articles focusing on quality of life in the context of anxiety and depression within this patient population. We have described a case of a 28-year-old male with new-onset metastatic lung adenocarcinoma that we had treated in our hospital. He was found to have mutations in EGFR and ALK rearrangement. We aimed to address his depression, anxiety, and poor QOL in the context of his diagnosis. Due to his presenting symptoms leading to the diagnosis of adjustment disorder, he was treated with pharmacotherapy as well as conventional therapy to improve his QOL. Due to the time required to identify mutations, our patient passed away before a more targeted treatment could be offered. It is important to fully explore the nature of the cancer, including mutation types. Our case demonstrates that the detection of the driver gene mutation EGFR andor ALK rearrangement could affect treatment and prognosis in this patient population. There are many studies available that highlight targeted therapies for these mutations as well as chemotherapy and radiation. Psychiatry has a significant role in improving quality of life in these patients, which could enhance their response to treatment and survival. Involving psychiatry early in the course results in lower rates of depression, anxiety and premature death.

Establishment and Validation of a Predictive Nomogram for Postoperative Survival of Stage I Non-Small Cell Lung Cancer.

Surgical procedure is the preferred option for people with early-stage non-small cell lung cancer (NSCLC), while nearly 30% of patients experienced metastatic or recurrent tumor after operation. The primary intention of this context is to summarize high-risk prognostic factors and set up a novel nomogram to predict the overall survival of individuals with stage I NSCLC after resection. Research objects, 10,218 patients with stage I NSCLC after operation from 2010 to 2015, were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Independent prognostic factors, confirmed by Cox regression analyses, were integrated into a nomogram, to predict the 3-and 5-year overall survival of these individuals. The model experienced internal validation of testing cohorts above and external validation crewed by 160 patients from China. Finally, the nomogram was evaluated through several verification methods such as concordance index (C-index), calibration plots and receiver operating characteristic curve (ROC). Multivariate analysis identified that age, gender, histologic type, differentiation class, type of operation, T stage and treatment were significant predictive factors for the survival of stage I NSCLC. Based on these factors, a nomogram was constructed to predict the 3- and 5-year overall survival of these individuals. Meanwhile, in the training set, this nomogram displayed excellent superiority over the TNM staging system with abroad application, especially in C-index (0.669 vs 0.580) and the AUC (the Area Under ROC Curve) for the 3- and 5-year survival (0.678 vs 0.582 0.650 vs 0.576). In the calibration curve, the curve representing predicted survival tended to align with the line representing actual survival as well. A nomogram was successfully created and verified to achieve the goal that made a rounded accurate prediction on the survival of postoperative I NSCLC patients in terms of the SEER database.

Pharmacological properties, molecular mechanisms and therapeutic potential of ginsenoside Rg3 as an antioxidant and anti-inflammatory agent.

Inflammation and oxidative stress lead to various acute or chronic diseases, including pneumonia, liver and kidney injury, cardiovascular and cerebrovascular diseases, metabolic diseases, and cancer. Ginseng is a well-known and widely used ethnic medicine in Asian countries, and ginsenoside Rg3 is a saponin isolated from

The Prominent Role of miR-942 in Carcinogenesis of Tumors.

As a family of short noncoding RNAs, MicroRNAs have been identified as possible biomarkers for cancer discovery and assist in therapy control due to their epigenetic involvement in gene expression and other cellular biological processes. In the present review, the evidence for reaching the clinical effect and the molecular mechanism of miR-942 in various kinds of cancer is amassed. Dysregulation of miR-942 amounts in different kinds of malignancies, as bladder cancer, esophageal squamous cell carcinoma, breast cancer, cervical cancer, gastric cancer, colorectal cancer, Kaposis sarcoma, melanoma, Hepatocellular carcinoma, nonsmall-cell lung cancer, oral squamous cell carcinoma, osteosarcoma, ovarian cancer, pancreatic ductal adenocarcinoma, renal cell carcinoma, and prostate cancer has stated a considerable increase or decrease in its level indicating its function as oncogene or tumor suppressor. MiR-942 is included in cell proliferation, migration, and invasion through cell cycle pathways, including pathways of transforming growth factor-beta signaling pathways, Wnt pathway, JAKSTAT pathway, PI3KAKT pathway, apoptosis pathway, hippo signaling pathway, lectin pathway, interferon-gamma signaling, signaling by G-protein coupled receptor, developmental genes, nuclear factor-kappa B pathway, Mesodermal commitment pathway, and T-cell receptor signaling in cancer. An important biomarker, MiR-942 is a potential candidate for prediction in several cancers. The present investigation introduced miR-942 as a prognostic marker for early discovery of tumor progression, metastasis, and development.

Association between trauma exposure and respiratory disease-A Mendelian randomization study.

Trauma is a well-known risk factor for many disease, but the effect of trauma on respiratory disease is unclarified. In the present study, we aimed to evaluate the association between trauma and respiratory disease. Using both United Kingdom biobank and Finnish biobank genome-wide association study data (GWAS), we performed a two-sample Mendelian randomization (MR) analysis to evaluate the relationship between trauma and respiratory disease. We used four methods including inverse-variance weighted (IVW), weighted median, Maximum likelihood, and MR-Egger in this MR analysis. The IVW MR was selected as the main method. We also performed multivariable Mendelian randomization (MVMR) to simultaneously assess the independent impact of trauma exposure on respiratory disease. In the main two-sample MR analysis, trauma exposure was significantly associated with increased risk of respiratory disease (OR 1.15, 95%CI 1.05-1.25). Besides, there was no heterogeneity and horizontal pleiotropy observed in the sensitivity analysis. After adjusting for pack years of smoking and body mass index (BMI), trauma exposure retained its association with respiratory disease (OR, 1.13, 95%CI, 1.04-1.23 adjusted by pack years of smoking and OR, 1.11, 95%CI, 1.04-1.18 adjusted by BMI). Our study discovered the association between trauma exposure and the increased risk of respiratory disease, suggesting the prevention and treatment with trauma to reduce the risk of respiratory disease.

Drug repurposing of ivermectin abrogates neutrophil extracellular traps and prevents melanoma metastasis.

Neutrophil extracellular traps (NETs) have recently been identified to play a crucial role in cancer metastasis. However, the therapeutic target in NETs of melanoma cancer metastasis is still unknown. In this work, we screened a collection of 231 small molecule compounds. We identified ivermectin (IVM), a widely used antiparasitic drug, significantly inhibits neutrophil extracellular traps (NETs) formation after cathepsin B (CTSB) treatment. In vivo, IVM treatment showed no effects of melanoma tumor growth, while the orthotopic melanoma to lung metastasis was significantly suppressed by IVM. Serum level of myeloperoxidase-DNA and neutrophil elastase-DNA were suppressed after IVM treatment. Tumor infiltrated myeloid-derived suppressor cells (MDSCs) were significantly suppressed while tumor infiltrated CD8T cells in lung was increased after IVM treatment in mouse melanoma model. Mechanistically, IVM targeted a pyroptotic driving factor gasdermin D (GSDMD), and exhibited a Kd of 267.96 nM by microscale thermophoresis (MST) assay. Furthermore, the direct interaction of IVM and GSDMD significantly suppressed GSDMD oligomerization, which are essential for GSDMD-dependent NETs formation. In vitro, treatment with CTSB in bone marrow neutrophils significantly promotes NETs formation, and the release of extracellular DNA was significantly suppressed by IVM pretreatment. Collectively, our results reveal that with the regulation role of IVM in neutrophils and NETs, IVM may potentially be used as a viable therapeutic approach for the treatment of melanoma cancer metastasis.

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The role of tumor-associated macrophages and soluble mediators in pulmonary metastatic melanoma.

Skin malignant melanoma is a highly aggressive skin tumor, which is also a major cause of skin cancer-related mortality. It can spread from a relatively small primary tumor and metastasize to multiple locations, including lymph nodes, lungs, liver, bone, and brain. Whats more metastatic melanoma is the main cause of its high mortality. Among all organs, the lung is one of the most common distant metastatic sites of melanoma, and the mortality rate of melanoma lung metastasis is also very high. Elucidating the mechanisms involved in the pulmonary metastasis of cutaneous melanoma will not only help to provide possible explanations for its etiology and progression but may also help to provide potential new therapeutic targets for its treatment. Increasing evidence suggests that tumor-associated macrophages (TAMs) play an important regulatory role in the migration and metastasis of various malignant tumors. Tumor-targeted therapy, targeting tumor-associated macrophages is thus attracting attention, particularly for advanced tumors and metastatic tumors. However, the relevant role of tumor-associated macrophages in cutaneous melanoma lung metastasis is still unclear. This review will present an overview of the origin, classification, polarization, recruitment, regulation and targeting treatment of tumor-associated macrophages, as well as the soluble mediators involved in these processes and a summary of their possible role in lung metastasis from cutaneous malignant melanoma. This review particularly aims to provide insight into mechanisms and potential therapeutic targets to readers, interested in pulmonary metastasis melanoma.

The Association Between Genetic Polymorphisms of Transporter Genes and Prognosis of Platinum-Based Chemotherapy in Lung Cancer Patients.

Platinum-based chemotherapy is the first-line treatment of lung cancer. However, different individual and genetic variation effect therapy for lung cancer. The purpose of this study was to evaluate the association between transport genes genetic polymorphisms and the prognosis of platinum-based chemotherapy in lung cancer patients. A series of 593 patients with treatment of platinum-based chemotherapy were recruited for this study. A total of 21 single-nucleotide polymorphisms in nine transporter genes were selected to investigate their associations with platinum-based chemotherapy prognosis. Patients with ABCG2 rs1448784 CC genotype had a significantly shorter PFS than CT or TT genotypes (Additive model HR 1.54, 95% CI 1.02-2.35, Genetic polymorphisms of rs1448784 in ABCG2 might be potential clinical marker for predicting the prognosis of lung cancer patients treated with platinum-based chemotherapy.

An esterase-activatable prodrug formulated liposome strategy potentiating the anticancer therapeutic efficacy and drug safety.

Liposomal nanomedicine represents a common and versatile carrier for the delivery of both lipophilic and hydrophilic drugs. However, the direct formulation of many chemotherapeutics into a liposomal system remains an enormous challenge. Using the topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN38) as a model drug, we combined lipophilic prodrug construction with subsequent integration into an exogenous liposomal scaffold to assemble a prodrug-formulated liposome for systemic administration. Reconstructing SN38 with lipid cholesterol

Chimeric nanoparticles for targeting mitochondria in cancer cells.

Mitochondrial dysfunction is implicated in myriad diseases, including cancer. Subsequently, targeting mitochondrial DNA (mt-DNA) in cancer cells has emerged as an unorthodox strategy for anti-cancer therapy. However, approaches targeting only one component of the mitochondrial central dogma can be evaded by cancer cells through various mechanisms. To address this, herein, we have engineered mitochondria-targeting cholesterol-based chimeric nanoparticles (mt-CNPs) consisting of cisplatin, camptothecin, and tigecycline, which can simultaneously impair mt-DNA, mitochondrial topoisomerase I (mt-Top1), and mitochondrial ribosomes. mt-CNPs were characterized as being positively charged, spherical in shape, and 187 nm in diameter. Confocal microscopy confirmed that mt-CNPs efficiently localized into the mitochondria of A549 lung cancer cells within 6 h, followed by mitochondrial morphology damage and the subsequent generation of reactive oxygen species (ROS). mt-CNPs showed remarkable cancer-cell killing abilities compared to free-drug combinations in A549 (lung), HeLa (cervical), and MCF7 (breast) cancer cells. These mitochondria-targeting lipidic chimeric nanoparticles could be explored further to impair multiple targets in mitochondria, helping researchers to gain an understanding of mitochondrial translational and transcriptional machinery and to develop new strategies for cancer therapy.

What are the similarities and differences in lung cancer symptom appraisal and help-seeking according to smoking status A qualitative study with lung cancer patients.

Lung cancer in never-smokers represents a growing proportion of patients. The relationship between smoking status, symptom appraisal and help-seeking behaviour is complex. Little is known about cancer symptom-related health behaviours according to smoking status. The aim of the study was to explore lung cancer patients experiences of a lung cancer diagnosis, identifying differences by smoking history. This was a qualitative study involving telephone interviews with 40 lung cancer patients (20 never smokers, 11 former smokers and 9 current smokers). We used framework analysis to analyse the data using the Common Sense Model of Illness Self-Regulation as a theoretical framework, developed after initial analysis. All patients were likely to delay seeking help for symptoms in primary care regardless of smoking history, but for different reasons. Smoking history was instrumental to how individuals perceived and responded to early symptoms of lung cancer. Differences in interpretation and coping responses to new symptoms seemed to be caused by the higher presence of comorbidities due to smoking, and perceptions of the current state of health. Individuals with a smoking history reported acting with urgency in seeking help and follow up, whereas patients who experienced low levels of concern were more easily reassured by clinicians, resulting in delays. Never and former smokers perceive, interpret, and respond to symptoms of lung cancer differently to smokers. However, few people attribute their lung symptoms to cancer initially, even with a smoking history. Interventions that drive increased urgency and vigilance in never smokers may be effective.

Economic burden in patients with anaplastic lymphoma kinase (

This observational study describes the real-world economic burden in patients with anaplastic lymphoma kinase ( Administrative claims data (Truven Health MarketScan® Commercial Claims and Encounters database and Medicare Supplemental and Coordination of Benefits database January 1, 2015-March 31, 2020) for adult patients with A total of 496 patients were eligible for analysis. Mean PPPM total healthcare costs were $21,961 for all patients receiving up to 1 year of a first-line ALK inhibitor. Patients were significantly more likely to have higher mean PPPM total costs if they had BM prior to first-line ALK inhibitor (vs. no BM odds ratio 1.11 95% confidence interval 1.02, 1.21 The economic burden in patients with

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Predicting nicotine metabolism across ancestries using genotypes.

There is a need to match characteristics of tobacco users with cessation treatments and risks of tobacco attributable diseases such as lung cancer. The rate in which the body metabolizes nicotine has proven an important predictor of these outcomes. Nicotine metabolism is primarily catalyzed by the enzyme cytochrone P450 (CYP2A6) and CYP2A6 activity can be measured as the ratio of two nicotine metabolites trans-3-hydroxycotinine to cotinine (NMR). Measurements of these metabolites are only possible in current tobacco users and vary by biofluid source, timing of collection, and protocols unfortunately, this has limited their use in clinical practice. The NMR depends highly on genetic variation near CYP2A6 on chromosome 19 as well as ancestry, environmental, and other genetic factors. Thus, we aimed to develop prediction models of nicotine metabolism using genotypes and basic individual characteristics (age, gender, height, and weight). We identified four multiethnic studies with nicotine metabolites and DNA samples. We constructed a 263 marker panel from filtering genome-wide association scans of the NMR in each study. We then applied seven machine learning techniques to train models of nicotine metabolism on the largest and most ancestrally diverse dataset (N2239). The models were then validated using the other three studies (total N1415). Using cross-validation, we found the correlations between the observed and predicted NMR ranged from 0.69 to 0.97 depending on the model. When predictions were averaged in an ensemble model, the correlation was 0.81. The ensemble model generalizes well in the validation studies across ancestries, despite differences in the measurements of NMR between studies, with correlations of 0.52 for African ancestry, 0.61 for Asian ancestry, and 0.46 for European ancestry. The most influential predictors of NMR identified in more than two models were rs56113850, rs11878604, and 21 other genetic variants near CYP2A6 as well as age and ancestry. We have developed an ensemble of seven models for predicting the NMR across ancestries from genotypes and age, gender and BMI. These models were validated using three datasets and associate with nicotine dosages. The knowledge of how an individual metabolizes nicotine could be used to help select the optimal path to reducing or quitting tobacco use, as well as, evaluating risks of tobacco use.

Deep learning-based tumor microenvironment segmentation is predictive of tumor mutations and patient survival in non-small-cell lung cancer.

Despite the fact that tumor microenvironment (TME) and gene mutations are the main determinants of progression of the deadliest cancer in the world - lung cancer, their interrelations are not well understood. Digital pathology data provides a unique insight into the spatial composition of the TME. Various spatial metrics and machine learning approaches were proposed for prediction of either patient survival or gene mutations from this data. Still, these approaches are limited in the scope of analyzed features and in their explainability, and as such fail to transfer to clinical practice. Here, we generated 23,199 image patches from 26 hematoxylin-and-eosin (HE)-stained lung cancer tissue sections and annotated them into 9 different tissue classes. Using this dataset, we trained a deep neural network ARA-CNN. Next, we applied the trained network to segment 467 lung cancer HE images from The Cancer Genome Atlas (TCGA) database. We used the segmented images to compute human-interpretable features reflecting the heterogeneous composition of the TME, and successfully utilized them to predict patient survival and cancer gene mutations. We achieved per-class AUC ranging from 0.72 to 0.99 for classifying tissue types in lung cancer with ARA-CNN. Machine learning models trained on the proposed human-interpretable features achieved a c-index of 0.723 in the task of survival prediction and AUC up to 73.5% for PDGFRB in the task of mutation classification. We presented a framework that accurately predicted survival and gene mutations in lung adenocarcinoma patients based on human-interpretable features extracted from HE slides. Our approach can provide important insights for designing novel cancer treatments, by linking the spatial structure of the TME in lung adenocarcinoma to gene mutations and patient survival. It can also expand our understanding of the effects that the TME has on tumor evolutionary processes. Our approach can be generalized to different cancer types to inform precision medicine strategies.

Identification of rs2736099 as a novel cis-regulatory variation for TERT and implications for tumorigenesis and cell proliferation.

Lung cancer is a malignant tumor with obvious genetic predisposition. Association studies have proposed that rs2853677, a SNP localizing at intron region of TERT (telomerase reverse transcriptase), is significantly associated with TERT expression, telomere length and eventually lung cancer risk. However, functional genomics work indicates that rs2853677 is not with the ability to alter gene expression. All these facts make us hypothesize that some other genetic variation(s) are in linkage disequilibrium (LD) with rs2853677 and influence TERT expression. LD pattern in rs2853677 nearby region was analyzed based on 1000 genomes data for three representative populations in the world and functional genomics research was performed for this locus. Only one SNP, rs2736099, is in strong LD with rs2853677 in East Asian. Dual-luciferase reporter assay verifies that rs2736099 can regulate gene expression and should be the causal SNP for this disease. Through chromosome conformation capture assay, it is disclosed that the enhancer surrounding rs2736099 can interact with TERT promoter. Through chromatin immunoprecipitation, the transcription factor SP1 (Sp1 transcription factor) is recognized for the chromatin segment spanning rs2736099. Our results provide the missing piece between genetic variation at this locus and lung cancer risk, which is also applied to tumorigenesis in other tissues and cell proliferation.

A Sonic Hedgehog Pathway Score to Predict the Outcome of Resected Non-Small Cell Lung Cancer Patients.

Mutations and deregulations in components of the Hedgehog (Hh) pathway have been associated with cancer onset and tumor growth in different malignancies, but their role in non-small cell lung cancer (NSCLC) remains unclear. This study aims to investigate the expression pattern of the main components of the Hh pathway in tumor and adjacent normal tissue biopsies of resected NSCLC patients. The relative expression of GLI1, PTCH1, SHH, and SMO was analyzed by quantitative polymerase chain reaction (PCR) in a cohort of 245 NSCLC patients. Results were validated in an independent cohort of NSCLC patients from The Cancer Genome Atlas (TCGA). We found that SMO and GLI1 were overexpressed in the tumor compared with normal-paired tissue, whereas PTCH1 and SHH were underexpressed. In addition, patients with higher expression levels of PTCH1 presented better outcomes. A gene expression score, called the Hedgehog Score, was calculated using a multivariable model including analyzed components of the Hh signaling pathway. NSCLC patients with a high Hedgehog Score had significantly shorter relapse-free survival (RFS) and overall survival (OS) than patients with a low score, especially at stage I of the disease. Similarly, patients in the adenocarcinoma (ADC) subcohort had shorter RFS and OS. Multivariate Cox analysis exhibited that the Hedgehog Score is an independent prognostic biomarker for OS in both the entire training cohort and the ADC subcohort. The Hedgehog Score was validated in an independent cohort of NSCLC patients from TCGA, which confirmed its prognostic value. Our results provide relevant prognostic data for NSCLC patients and support further studies on the Hh pathway.

Butorphanol inhibits angiogenesis and migration of hepatocellular carcinoma and regulates MAPK pathway.

Butorphanol, a synthetic opioid, exerts analgesic and anti-inflammatory effects against pathogenic diseases. Butorphanol repressed malignant behaviors of tumor cells. In this study, the role of butorphanol in hepatocellular carcinoma was evaluated. Firstly, hepatocellular carcinoma cells were treated with butorphanol. The results showed that butorphanol decreased cell viability of hepatocellular carcinoma cells. Cell proliferation and metastasis of hepatocellular carcinoma cells were inhibited by butorphanol. Secondly, butorphanol suppressed angiogenesis, and reduced phosphorylation levels of p38 and JNK in hepatocellular carcinoma cells. Thirdly, butorphanol reduced in vivo tumor growth of hepatocellular carcinoma in nude mice. Butorphanol reduced tumor micro-vascular density (MVD) and repressed lung metastasis. In conclusion, butorphanol exerted anti-angiogenic and anti-metastatic effects on hepatocellular carcinoma and induced inactivation of MAPKs signaling.

Fulminant Myocarditis for Non-small-cell Carcinoma of the Lung with Nivolumab and Ipilimumab Plus Chemotherapy A Case Report.

A 59-year-old man with a high level of antinuclear antibody received nivolumab and ipilimumab plus chemotherapy for lung cancer. Two weeks after the second course, he was admitted with a fever and severe fatigue. Laboratory studies showed elevated markers of myocardial damage, and a myocardial biopsy showed inflammatory cell infiltration, damaged myocardial fibers. Myocarditis was diagnosed as an immune-related adverse event (irAE), and high-dose corticosteroids were initiated. However, his cardiac function rapidly worsened, and he died on the fifth day after admission. There is no established treatment strategy for fulminant myocarditis as an irAE, and the further exploration of viable treatment strategies is required.

Immunotherapy in Advanced NSCLC Without Driver Mutations Available Therapeutic Alternatives After Progression and Future Treatment Options.

The treatment paradigm of non-small-cell lung cancer without oncogenic drivers has varied dramatically in recent years and is constantly evolving. Immune- checkpoint inhibitors have demonstrated unprecedented durable efficacy in a subset of these patients, so these drugs have become the standard of care in most cases. There are different ways to deliver these agents, such as monotherapy and combinations of immunotherapy or chemotherapy plus immunotherapy. Treatment selection is complicated by an absence of head-to-head comparisons in randomized trials because these agents have gained approval by demonstrating superiority to platinum-doublet chemotherapy alone. Unfortunately, most patients will progress and die from their disease despite advances. Furthermore, after progression on these agents, there is a lack of randomized controlled data to support further management, constituting an unmet need. This review discusses the therapeutic alternatives after progression, summarizes mechanisms of resistance and progression patterns, and describes the main approaches under clinical investigation in the field.

Non-small cell lung carcinomas with diffuse coexpression of TTF1 and p40 clinicopathological and genomic features of 14 rare biphenotypic tumours.

Thyroid transcription factor 1 (TTF1) and p40 are widely-utilized diagnostic markers of lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), respectively. Diffuse coexpression of TTF1 and p40 has been described in only rare case reports. In a multi-institutional study, we collected the largest cohort of these unusual tumours to-date (n 14), with the goal of elucidating their clinicopathological and genomic characteristics. Lung tumours with diffuse coexpression (labelling 50-100% tumour cells) of TTF1 clone 8G7G31 and p40 clone BC28 were identified. Detailed clinicopathological and immunohistochemical parameters were analyzed. Eight tumours were analyzed by next-generation sequencing (NGS) and the results were compared to those in > 9 K LUAD and > 1 K LUSC. All tumours with diffuse TTF1p40 coexpression were poorly differentiated non-small cell lung carcinomas (NSCLC), 42% of which had basaloid features. Some tumours exhibited focal keratinization (14%), napsin A andor mucicarmine labelling (46%) or both squamous and glandular features (7%). NGS revealed a uniquely high rate of FGFR1 amplifications (70%) compared to either LUAD (0.7%, P < 0.0001) or LUSC (11%, P 0.001). LUAD-type targetable driver alterations were identified in 38% of cases (one EGFR, two KRAS G12C). The tumours were clinically aggressive, exhibiting metastatic disease in most patients. Lung carcinomas with diffuse TTF1p40 coexpression represent poorly differentiated NSCLCs with frequent basaloid features, but some show evidence of focal squamous, glandular or dual differentiation with a distinctly high rate of FGFR1 amplifications. The presence of targetable LUAD-type alterations (EGFR, KRAS G12C) emphasizes the importance of molecular testing in these tumours.

Patients experiences with cancer care in Switzerland Results of a multicentre cross-sectional survey.

The objectives were to describe patients experiences of cancer care in Switzerland and explore the variation of these experiences by type of cancer. The Swiss Cancer Patient Experiences (SCAPE) study was a cross-sectional, multicentre survey conducted in 2018. Adult patients (n 7145) with breast, prostate, lung, colorectal, skin or haematological cancer from four large hospitals in French-speaking Switzerland were invited to complete a survey. Logistic regressions were used to assess whether experiences varied according to cancer type, adjusting for confounders. Of the 3121 persons who returned the survey (44% response rate), 2755 reporting an eligible cancer were included in the analyses. Participants average score for overall care was 8.5 out of a maximum score of 10. Higher rates of positive experiences were found for nurse consultations (94%), diagnostic tests (85%) and inpatient care (82%). Lower positive responses were reported for support for people with cancer (70%), treatment decisions (66%), diagnosis (65%) and home care (55%). We observed non-systematic differences in experiences of care by cancer type. This large study identified that cancer patient experiences can be improved in relation to communication, information and supportive care aspects. Improvement efforts should target these areas of care to enhance responsiveness of cancer care.

Cardiac Function Modifies the Impact of Heart Base Dose on Survival A Voxel-Wise Analysis of Patients With Lung Cancer From the PET-Plan Trial.

Heart dose has emerged as an independent predictor of overall survival in patients with NSCLC treated with radiotherapy. Several studies have identified the base of the heart as a region of enhanced dose sensitivity and a potential target for cardiac sparing. We present a dosimetric analysis of overall survival in the multicenter, randomized PET-Plan trial (NCT00697333) and for the first time include left ventricular ejection fraction (EF) at baseline as a metric of cardiac function. A total of 205 patients with inoperable stage II or III NSCLC treated with 60 to 72 Gy in 2 Gy fractions were included in this study. A voxel-wise image-based data mining methodology was used to identify anatomical regions where higher dose was significantly associated with worse overall survival. Univariable and multivariable Cox proportional hazards models tested the association of survival with dose to the identified region, established prognostic factors, and baseline cardiac function. A total of 172 patients remained after processing and censoring for follow-up. At 2-years posttreatment, a highly significant region was identified within the base of the heart (p < 0.005), centered on the origin of the left coronary artery and the region of the atrioventricular node. In multivariable analysis, the number of positron emission tomography-positive nodes (p 0.02, hazard ratio 1.13, 95% confidence interval 1.02-1.25) and mean dose to the cardiac subregion (p 0.02, hazard ratio 1.11 Gy This work validates previous image-based data mining studies by revealing a strong association between dose to the base of the heart and overall survival. For the first time, an interaction between baseline cardiac health and heart base dose was identified, potentially suggesting preexisting cardiac dysfunction exacerbates the impact of heart dose on survival.