Severe megaloblastic anemia in a patient with advanced lung adenocarcinoma during treatment with erlotinib: a case report and literature review.

BACKGROUND: Erlotinib is a first-generation, tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) used for the treatment patients with NSCLC. Erlotinib is considered as a safe and effective treatment option, with generally good tolerance. Diarrhea and rash are the most common side effects, and more rare side effects appear in long-term real-world applications. Severe erlotinib related megaloblastic anemia is rare and remains unreported. This is the first case report of severe megaloblastic anemia in a patient with advanced lung adenocarcinoma with an EGFR L858R mutation treated with erlotinib. In this report, the clinical manifestations, diagnosis and treatment of erlotinib related severe megaloblastic anemia are described, and the possible pathogenesis and related treatment options are discussed. CASE DESCRIPTION: Herein, we present a 57- year-old non-smoking female diagnosed with metastatic lung adenocarcinoma harboring an EGFR L858R mutation, who had received erlotinib as the first-line therapy. After 44 weeks of treatment, the patient developed severe anemia. Anemia was manifested as megaloblastic anemia with elevated mean corpuscular volume and mean corpuscular hemoglobin. The total vitamin B12 level was below the detection limit of 50.00 pg /mL. Bone marrow smear suggested megaloblastic anemia. Her hematologic parameters were markedly recovered following the withdrawal of erlotinib and vitamin B12 supplement. As a result, the patient was diagnosed with erlotinib-associated megaloblastic anemia. CONCLUSIONS: This is the first case of severe megaloblastic anemia reported with erlotinib. Few of these hematologic adverse effects have been observed in studies on erlotinib, this case report highlights this possibility for long-term erlotinib administration. Close clinical and blood monitoring is recommended for patients receiving long-term TKI therapy.

An inflammation-related nomogram for predicting the survival of patients with non-small cell lung cancer after pulmonary lobectomy.

BACKGROUND: Emerging inflammatory response biomarkers are developed to predict the survival of patients with cancer, the aim of our study is to establish an inflammation-related nomogram based on the classical predictive biomarkers to predict the survivals of patients with non-small cell lung cancer (NSCLC). METHODS: Nine hundred and fifty-two NSCLC patients with lung cancer surgery performed were enrolled into this study. The cutoffs of inflammatory response biomarkers were determined by Receiver operating curve (ROC). Univariate and multivariate analysis were conducted to select independent prognostic factors to develop the nomogram. RESULTS: The median follow-up time was 40.0 months (range, 1 to 92 months). The neutrophil to lymphocyte ratio (cut-off: 3.10, HR:1.648, P = 0.045) was selected to establish the nomogram which could predict the 5-year OS probability. The C-index of nomogram was 0.72 and the 5-year OS calibration curve displayed an optimal agreement between the actual observed outcomes and the predictive results. CONCLUSIONS: Neutrophil to lymphocyte ratio was shown to be a valuable biomarker for predicting survival of patients with NSCLC. The addition of neutrophil to lymphocyte ratio could improve the accuracy and predictability of the nomogram in order to provide reference for clinicians to assess patient outcomes.

Loss of ß-arrestin1 expression predicts unfavorable prognosis for non-small cell lung cancer patients.

We aimed to study the expression status of ß-arrestin1 in non-small cell lung cancer (NSCLC) specimens and its clinicopathologic significance. The correlation between ß-arrestin1 and the tumor migration biomarker E-cadherin, as well as smoking index were studied. A total of 152 patients with NSCLC who undergone surgery were enrolled. Altogether, 88 lung squamous cell lung cancer (SCC) specimens and 64 adenocarcinoma (ADC) specimens were tested for immunohistochemistry. Patients' survival was analyzed by the Kaplan-Meier method. Univariate and multivariate analyses were performed to determine independent prognostic factors. Spearman rank correlation test was used to show data associations. For SCC patients, the expression of ß-arrestin1 was either lost (56 of 88, 63.6 %) or low (32 of 88, 36.4 %), which was significantly and negatively associated with E-cadherin expression (P = 0.017). The similar correlation existed between smoking index and ß-arrestin1 expression (P = 0.044). For ADC patients, the deletion of ß-arrestin1 expression was rare (4 of 64, 6.3 %). Loss of ß-arrestin1 expression indicated poorer survival for both SCC (P = 0.026) and ADC patients (P = 0.006). ß-arrestin1 expression was detected in the other ADC specimens but showed no significant correlation with survival. In SCC patients, the loss expression of ß-arrestin1 was frequently observed, and ß-arrestin1 expression was significantly correlated with the smoking index and E-cadherin expression, which all indicated ß-arrestin1's significant clinicopathologic role. However, ß-arrestin1 was expressed in most ADC patients, but its clinicopathologic role seemed to be obscure and might need further exploration.

Tumor-infiltrating neutrophils predict poor outcome in adenocarcinoma of the esophagogastric junction.

Tumor-infiltrating neutrophil (TIN) has been reported to be an independent predictor in multiple tumors, but its role in the development of adenocarcinoma of the esophagogastric junction (AEG) remains unclear. We conducted immunohistochemistry (IHC) to detect the expression of TIN in 113 consecutive patients with primary AEG. The prognostic value and its relationship with clinicopathological characteristics and Ki-67 (a proliferation-associated antigen) expression were analyzed. High level of TIN was related to poor outcome in AEG patients with a hazard ratio (HR) of 3.93 (95% confidence interval (CI) = 2.14-7.19, p < 0.001) in univariate analysis and a HR of 3.44 (95% CI = 1.85-6.37, p < 0.001) in multivariate analysis. In addition, TIN was positively correlated with Ki-67 expression (p = 0.008). Our study found that TIN expression was an independent unfavorable predictor in AEG. Furthermore, the relationship between TIN and Ki-67 indicated that TIN was associated with tumor proliferation, which might provide a potential mechanism for why TIN was related to poor outcome in AEG.

Co-expression of ß-arrestin1 and NF-кB is associated with cancer progression and poor prognosis in lung adenocarcinoma.

ß-arrestin1 and NF-κB have been demonstrated to be associated with tumorigenesis, tumor progression, and metastasis. Thus far, there is nevertheless little study about these two molecules in lung adenocarcinoma. The aim of this study was to investigate the correlation between ß-arrestin1 and NF-κB expression and the clinicopathological characteristics in lung adenocarcinoma. A total of 115 surgically resected lung adenocarcinoma patients were recruited for the study. Expression of ß-arrestin1 and p65 were detected by immunohistochemistry (IHC) in lung adenocarcinoma tissue samples. Nuclear expression of ß-arrestin1 and p65 were observed in 39.1 % (45/115) and 46.1 % (53/115) cases of lung adenocarcinoma, respectively. And high expression of ß-arrestin1 had negative prognostic impact for overall survival (OS) and disease-free survival (DFS) (p = 0.034 and p = 0.033). In addition, overexpression of p65 indicated a significantly poor OS and DFS than those of lower-expression (p = 0.038 and p = 0.041). Furthermore, co-expression of nuclear ß-arrestin1 and p65 correlated with poorer OS and DFS in lung adenocarcinoma patients. Multivariate analysis using the Cox regression model confirmed that co-expression of nuclear ß-arrestin1 and p65 was an independent prognostic factor for tumor progression (p = 0.008). In conclusion, these data indicated that co-expression of nuclear ß-arrestin1 and p65 was a novel predictor for worse prognosis in patients with lung adenocarcinoma.

Evaluation of Prognostic Nutritional Index in Patients Undergoing Radical Surgery with Nonsmall Cell Lung Cancer.

The prognostic nutritional index (PNI) has been reported to be a prognostic indicator in some malignant tumors. However, its prognostic value in nonsmall cell lung cancer (NSCLC) has not been fully investigated. A retrospective review of 1416 patients with NSCLC who underwent radical surgery between January 2006 and December 2011 was conducted. To obtain optimal cutoff levels of PNI, running log-rank statistics was applied. Survival was calculated by the Kaplan-Meier method. The prognostic significance of PNI, together with various clinicopathological factors, was evaluated by multivariate analysis. The optimal cutoff point for PNI was 52. The 1-, 3-, and 5-yr survival rates in patients with PNI of less than 52 were 80.0%, 61.3%, and 50.4%, respectively, and were significantly more unfavorable than those in patients with PNI 52 or higher (84.7%, 71.5%, and 60.3%, respectively, P < 0.001). Multivariate analysis suggested that gender (P = 0.026), age (P < 0.001), PNI (P = 0.005), differentiation (P = 0.024), pathology T category (P = 0.003), and pathology N category (P < 0.001) were revealed to be independent prognostic factors. Our results indicate that PNI is an independent predictor of survival for patients undergoing radical surgery with NSCLC.

ß-Arrestin-biased agonism as the central mechanism of action for insulin-like growth factor 1 receptor-targeting antibodies in Ewing's sarcoma.

Owing to its essential role in cancer, insulin-like growth factor type 1 receptor (IGF-1R)-targeted therapy is an exciting approach for cancer treatment. However, when translated into clinical trials, IGF-1R-specific antibodies did not fulfill expectations. Despite promising clinical responses in Ewing's sarcoma (ES) phase I/II trials, phase III trials were discouraging, requiring bedside-to-bench translation and functional reevaluation of the drugs. The anti-IGF-1R antibody figitumumab (CP-751,871; CP) was designed as an antagonist to prevent ligand-receptor interaction but, as with all anti-IGF-1R antibodies, it induces agonist-like receptor down-regulation. We explored this paradox in a panel of ES cell lines and found their sensitivity to CP was unaffected by presence of IGF-1, countering a ligand blocking mechanism. CP induced IGF-1R/ß-arrestin1 association with dual functional outcome: receptor ubiquitination and degradation and decrease in cell viability and ß-arrestin1-dependent ERK signaling activation. Controlled ß-arrestin1 suppression initially enhanced CP resistance. This effect was mitigated on further ß-arrestin1 decrease, due to loss of CP-induced ERK activation. Confirming this, the ERK1/2 inhibitor U0126 increased sensitivity to CP. Combined, these results reveal the mechanism of CP-induced receptor down-regulation and characteristics that functionally qualify a prototypical antagonist as an IGF-1R-biased agonist: ß-arrestin1 recruitment to IGF-1R as the underlying mechanism for ERK signaling activation and receptor down-regulation. We further confirmed the consequences of ß-arrestin1 regulation on cell sensitivity to CP and demonstrated a therapeutic strategy to enhance response. Defining and suppressing such biased signaling represents a practical therapeutic strategy to enhance response to anti-IGF-1R therapies.

Selective recruitment of G protein-coupled receptor kinases (GRKs) controls signaling of the insulin-like growth factor 1 receptor.

ß-Arrestins are multifunctional proteins that play central roles in G protein-coupled receptor (GPCR) trafficking and signaling. ß-Arrestin1 is also recruited to the insulin-like growth factor-1 receptor (IGF-1R), a receptor tyrosine kinase (RTK), mediating receptor degradation and signaling. Because GPCR phosphorylation by GPCR-kinases (GRKs) governs interactions of the receptors with ß-arrestins, we investigated the regulatory roles of the four widely expressed GRKs on IGF-1R signaling/degradation. By suppressing GRK expression with siRNA, we demonstrated that lowering GRK5/6 abolishes IGF1-mediated ERK and AKT activation, whereas GRK2 inhibition increases ERK activation and partially inhibits AKT signaling. Conversely, ß-arrestin-mediated ERK signaling is enhanced by overexpression of GRK6 and diminished by GRK2. Similarly, we demonstrated opposing effects of GRK2 and -6 on IGF-1R degradation: GRK2 decreases whereas GRK6 enhances ligand-induced degradation. GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting ß-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated ß-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R, and subsequent mutation analysis demonstrated clear effects on IGF-1R signaling and degradation, mirroring alterations by GRKs. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation, consistent with GRK isoform-specific serine phosphorylation. This study demonstrates distinct roles for GRK isoforms in IGF-1R signaling through ß-arrestin binding with divergent functional outcomes.

Prognostic role of Twist or Snail in various carcinomas: a systematic review and meta-analysis.

BACKGROUND: Twist and Snail are considered as key transcriptional repressors of E-cadherin tightly related to epithelial-to-mesenchymal transition (EMT) and cancer progression. Numerous studies have investigated the prognostic value of Twist and Snail. However, the published results were controversial or even opposite. Our article aimed to evaluate the prognostic role of Twist and Snail in patients with cancer. DESIGN: A comprehensive literature search of PubMed, Embase and Web of Science was conducted. Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were assessed to quantify the prognostic role. RESULTS: The pooled HR with 38 studies for Twist was 2·18 (95% CI: 1·77-2·68, I(2) = 69·8%, P = 0·000) and for Snail with 40 studies was 1·58 (95% CI: 1·33-1·87, I(2) = 70·0%, P = 0·000), suggesting high Twist/Snail expression predicted poor prognosis related to all clinical outcomes. For Twist, the pooled HR for overall survival (OS) was 2·07 (95% CI: 1·63-2·63, I(2) = 72·6%, P = 0·000) and for progression-free/recurrence-free/metastasis-free/disease-free/cancer-free survival (PFS/RFS/MFS/DFS/CFS) was 2·36 (95% CI: 1·76-3·17, I(2) = 65·0%, P = 0·000). For Snail, the pooled HR for OS was 1·63 (95% CI: 1·33-1·99, I(2) = 70·8%, P = 0·000) and for PFS/RFS/MFS/DFS/CFS was 1·54 (95% CI: 1·17-2·02, I(2) = 59·1%, P = 0·001). All of those results were suggesting that high Twist/Snail expression was associated with poor prognosis. Furthermore, when grouped into different types of cancers, the pooled HRs were also calculated for the subgroups. No publication bias was found except studies evaluating all clinical outcomes of Twist (P = 0·006 for Begg's test and 0·006 for Egger's test). CONCLUSIONS: Elevated Twist or Snail expression in tumour tissue indicated poor prognosis for cancer.

The adverse events profile of anti-IGF-1R monoclonal antibodies in cancer therapy.

AIM(S): Insulin-like growth factor-1 receptor (IGF-1R) targeted therapies have become one of the intriguing areas in anticancer drug development during the last decade. As one of these therapies, anti-IGF-1R monoclonal antibodies (mAbs) are also advancing further in development. Our purpose was to conduct a systematic review of the adverse events (AEs) caused by anti-IGF-1R monoclonal antibodies in cancer therapy. METHODS: We searched the term'IGF-1R monoclonal antibody' in the Pubmed database and found 389 related articles. After elaborate selection, 15 clinical studies that satisfied our criteria were then adopted for further analysis. We extracted all the useful information about the AEs of mAbs from the enrolled studies. Every kind of reported AE as well as corresponding incidences were summed up and calculated. We compared AE incidence differences in two age groups, and analyzed toxicities of mAbs used as a single agent or combined with chemotherapies. Finally, the differences of AE profiles between individual mAbs were also valued. RESULTS: AEs were more severe in the lower age group and 13 of 19 AE incidences in the single-agent group were significantly lower than in the combination group (P < 0.05). R1507 seemed to show a worse AE profile than cixutumumab and figitumumab. CONCLUSIONS: When anti-IGF-1R mAbs are used for cancer therapy, it is essential to choose the proper drug and combined chemotherapies to reduce AE occurrences. Also, administration of these mAbs to younger patients should be more carefully supervised. Furthermore, some more frequently observed AEs for specific mAb should be paid adequate attention.

Identification of the key DNA damage response genes for predicting immunotherapy and chemotherapy efficacy in lung adenocarcinoma based on bulk, single-cell RNA sequencing, and spatial transcriptomics.

BACKGROUND: Immune checkpoint inhibitors (ICI) plus chemotherapy is the preferred first-line treatment for advanced driver-negative lung adenocarcinoma (LUAD). The DNA damage response (DDR) is the main mechanism underlying chemotherapy resistance, and EGLN3 is a key DDR component. METHOD: We conducted an analysis utilizing TCGA and GEO databases employing multiple labels-WGCNA, DEGs, and prognostic assessments. Using bulk RNA-seq and scRNA-seq data, we isolated EGLN3 as the single crucial DDR gene. Spatial transcriptome analysis revealed the spatial differential distribution of EGLN3. TIDE/IPS scores and pRRophetic/oncoPredict R packages were used to predict resistance to ICI and chemotherapy drugs, respectively. RESULTS: EGLN3 was overexpressed in LUAD tissues (p < 0.001), with the high EGLN3 expression group exhibiting a poor prognosis (p = 0.00086, HR: 1.126 [1.039-1.22]). Spatial transcriptome analysis revealed EGLN3 overexpression in cancerous and hypoxic regions, positively correlating with DDR-related and TGF-ß pathways. Drug response predictions indicated EGLN3's resistance to the common chemotherapy drugs, including cisplatin (p = 6.1e-14), docetaxel (p = 1.1e-07), and paclitaxel (p = 4.2e-07). Furthermore, on analyzing the resistance mechanism, we found that EGLN3 regulated DDR-related pathways and induced chemotherapy resistance. Additionally, EGLN3 influenced TGF-ß signaling, Treg cells, and cancer-associated fibroblast cells, culminating in immunotherapy resistance. Moreover, validation using real-world data, such as GSE126044, GSE135222, and, IMvigor210, substantiated the response trends to immunotherapy and chemotherapy. CONCLUSIONS: EGLN3 emerges as a potential biomarker predicting lower response to both immunotherapy and chemotherapy, suggesting its promise as a therapeutic target in advanced LUAD.

Survival analysis and clinicopathological features of patients with stage IA lung adenocarcinoma.

Background: With the development of medical technology and change of life habits, early-stage lung adenocarcinoma (LUAD) has become more common. This study aimed to systematically analyzed clinicopathological factors associated to the overall survival (OS) of patients with Stage IA LUAD. Methods: A total of 5942 Stage IA LUAD patients were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier methods and log-rank tests were used to compare the differences in OS. A nomogram constructed based on the Cox regression was evaluated by Concordance index (C index), calibration curve, decision curve analysis (DCA) and area under curve (AUC). And 136 patients were recruited from Shandong Province Hospital for external validation. Results: Cox analysis regression indicated that 12 factors, such as Diagnosis to Treatment Interval (DTI) and Income Level, were independent prognostic factors and were included to establish the nomogram. The C-index of our novel model was 0.702, 0.724 and 0.872 in the training, internal and external validation cohorts, respectively. The 3-year and 5-year survival AUCs and calibration curves showed excellent agreement in each cohort. Some new factors in the SEER database, including DTI and Income Level, were firstly confirmed as independent prognostic factors of Stage IA LUAD patients. The distribution of these factors in the T1a, T1b, and T1c subgroups differed and had different effects on survival. Conclusion: We summarized 12 factors that affect prognosis and constructed a nomogram to predict OS of Stage IA LUAD patients who underwent operation. For the first time, new SEER database parameters, including DTI and Income Level, were proved to be survival-related.

Antitumor effect of embryonic stem cells in a non-small cell lung cancer model: antitumor factors and immune responses.

Research in recent years has revealed that embryonic stem cells (ESCs) could generate obvious antitumor effects in both vitro and vivo. In vitro, ESCs could secrete soluble factors that are capable of blocking cancer cells proliferation, moreover, embryonic microenvironments could effectively inhibit tumorigenesis and metastasis; while in vivo, administration of ESCs in tumor-bearing mice could generate significant antitumor effects by indirectly activating the antitumor immune system. In this study, non-small cell lung cancer cells (Lewis Lung Carcinoma cells, LLCs) and ESCs were co-injected together into mice, after that subcutaneous tumor growth was monitored, cellular and humoral immune responses were detected, and different control groups were set to compare the results in different conditions. Our results suggested that compared to be injected alone, ESCs co-injected with cancer cells could inhibit cancer cell growth more efficiently in vivo, with more CD8+ lymphocytes generated in both peripheral circulation and spleen, and with higher serum anticancer cytokine level (interleukin (IL)-2 and interferon (IFN)-γ). We conclude that the boosted antitumor effects induced by ESCs and cancer cells co-injection may be both the effects of antitumor factors secreted by ESCs and immune responses induced by ESCs in vivo.

Association of ERCC2/XPD polymorphisms and interaction with tobacco smoking in lung cancer susceptibility: a systemic review and meta-analysis.

The association of the two ERCC polymorphisms, Asp312Asn and Lys751Gln, with lung cancer risk remains controversial and inconclusive. To better evaluate the potential role of the two polymorphisms and interaction with tobacco smoking in lung cancer susceptibility presented in diverse populations, we have conducted a meta-analysis based on 26 studies from 24 publications which included analyses of Asp312Asn (7121 cases, 8962 controls) and Lys751Gln (8396 cases, 10510 controls) polymorphisms. Overall, significantly elevated lung cancer risk was associated with ERCC2 312Asn allele(homozygous model: OR=1.20[1.05-1.36], P=0.006; recessive model: OR=1.20[1.06-1.35], P=0.004) and 751Gln allele(homozygous model: OR=1.31[1.17-1.46], P<0.00001; heterozygous model: OR=1.11[1.04-1.19], P=0.003; recessive model: OR=1.23[1.11-1.37], P<0.0001; dominant model: OR=1.15[1.08-1.23], P<0.0001). In ethnic subgroup analyses, significantly increased risk was associated with ERCC2 312Asn allele for both Caucasians and Asians, and 751Gln allele for both Caucasians and Latino-Americans. When stratified by smoking status, significantly elevated risk of both polymorphisms for never-smokers was detected (dominant model, OR=1.46[1.09-1.95] and 1.57[1.19-2.08], P=0.01 and 0.002, respectively). In conclusion, this meta-analysis suggests that the two ERCC2 polymorphisms may contribute to lung cancer susceptibility serving as low-penetrance risk factors. Extremely large-scale evidence would be necessary to confirm the effects on ethnically specific populations and gene-environment interactions.

Prediction of prognosis, immunogenicity and efficacy of immunotherapy based on glutamine metabolism in lung adenocarcinoma.

Background: Glutamine (Gln) metabolism has been reported to play an essential role in cancer. However, a comprehensive analysis of its role in lung adenocarcinoma is still unavailable. This study established a novel system of quantification of Gln metabolism to predict the prognosis and immunotherapy efficacy in lung cancer. Further, the Gln metabolism in tumor microenvironment (TME) was characterized and the Gln metabolism-related genes were identified for targeted therapy. Methods: We comprehensively evaluated the patterns of Gln metabolism in 513 patients diagnosed with lung adenocarcinoma (LUAD) based on 73 Gln metabolism-related genes. Based on differentially expressed genes (DEGs), a risk model was constructed using Cox regression and Lasso regression analysis. The prognostic efficacy of the model was validated using an individual LUAD cohort form Shandong Provincial Hospital, an integrated LUAD cohort from GEO and pan-cancer cohorts from TCGA databases. Five independent immunotherapy cohorts were used to validate the model performance in predicting immunotherapy efficacy. Next, a series of single-cell sequencing analyses were used to characterize Gln metabolism in TME. Finally, single-cell sequencing analysis, transcriptome sequencing, and a series of in vitro experiments were used to explore the role of EPHB2 in LUAD. Results: Patients with LUAD were eventually divided into low- and high-risk groups. Patients in low-risk group were characterized by low levels of Gln metabolism, survival advantage, "hot" immune phenotype and benefit from immunotherapy. Compared with other cells, tumor cells in TME exhibited the most active Gln metabolism. Among immune cells, tumor-infiltrating T cells exhibited the most active levels of Gln metabolism, especially CD8 T cell exhaustion and Treg suppression. EPHB2, a key gene in the model, was shown to promote LUAD cell proliferation, invasion and migration, and regulated the Gln metabolic pathway. Finally, we found that EPHB2 was highly expressed in macrophages, especially M2 macrophages. It may be involved in the M2 polarization of macrophages and mediate the negative regulation of M2 macrophages in NK cells. Conclusion: This study revealed that the Gln metabolism-based model played a significant role in predicting prognosis and immunotherapy efficacy in lung cancer. We further characterized the Gln metabolism of TME and investigated the Gln metabolism-related gene EPHB2 to provide a theoretical framework for anti-tumor strategy targeting Gln metabolism.

Identification and Validation of a Three Pyroptosis-Related lncRNA Signature for Prognosis Prediction in Lung Adenocarcinoma.

Pyroptosis, defined as programmed cell death, results in the release of inflammatory mediators. Recent studies have revealed that pyroptosis plays essential roles in antitumor immunity and immunotherapy efficacy. Long noncoding RNAs (lncRNAs) are involved in a variety of biological behaviors in tumor cells, although the roles and mechanisms of lncRNAs in pyroptosis are rarely studied. Our study aimed to establish a novel pyroptosis-related lncRNA signature as a forecasting tool for predicting prognosis and ascertaining immune value. Based on lung adenocarcinoma (LUAD) patients from The Cancer Genome Atlas (TCGA), we performed Pearson's correlation analysis to identify pyroptosis-related lncRNAs. After differentially expressed gene analysis and univariate Cox regression analysis, we selected prognosis-related and differentially expressed lncRNAs. Finally, we performed multivariate Cox regression analysis to establish the three pyroptosis-related lncRNA signature. Kaplan-Meier (KM) survival analyses and receiver operating characteristic (ROC) curves indicated the excellent performance for predicting the prognosis of LUAD patients. At the same time, we applied multidimensional approaches to further explore the functional enrichment, tumor microenvironment (TME) landscape, and immunotherapy efficacy among the different risk groups. A nomogram was constructed by integrating risk scores and clinical characteristics, which was validated using calibrations and ROC curves. Three lncRNAs, namely, AC090559.1, AC034102.8, and AC026355.2, were involved in this signature and used to classify LUAD patients into low- and high-risk groups. Overall survival time (OS) was higher in the low-risk group than in the high-risk group, which was also validated in our LUAD cohort from Shandong Provincial Hospital. TME landscape analyses revealed that a higher abundance of infiltrating immune cells and a greater prevalence of immune-related events existed in the low-risk group. Meanwhile, higher expression of immune checkpoint (ICP) genes, higher immunophenoscore (IPSs), and greater T cell dysfunction in the low-risk group demonstrated a better response to immunotherapy than the high-risk group. Combined with predictions from the Tumor Immune Dysfunction and Exclusion (TIDE) website, we found that LUAD patients in the low-risk group significantly benefited from programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) immune checkpoint blockade (ICB) therapy compared with those in the high-risk group. Furthermore, drug susceptibility analysis identified potential sensitive chemotherapeutic drugs for each risk group. In this study, a novel three pyroptosis-related lncRNA signature was constructed, which could accurately predict the immunotherapy efficacy and prognosis in LUAD patients.

Prognostic analysis and clinical characteristics of dual primary lung cancer: a population study based on surveillance, epidemiology, and end results (SEER) database.

BACKGROUND: The peculiarity and the lack of clinical studies of dual primary lung cancer (DPLC) led to limited knowledge about its clinical characteristics and prognosis. This study performed a retrospective analysis to assess the prognostic factors and clinical characteristics of DPLC. METHODS: A total of 1419 DPLC patients from SEER were analyzed by univariate and multivariable Cox regression analyses. The independent prognostic factors were included to establish a nomogram. The accuracy and reliability of prognostic model were evaluated by C indexes, calibration plots, receiver operating characteristic (ROC) curves, decision curve analyses (DCA) and integrated discrimination improvement (IDI) scores. Chi-square test was used to assess the differences between DPLC and single primary lung cancer (SPLC) or synchronous DPLC (sDPLC) and metachronous DPLC (mDPLC). RESULTS: Cox regression analysis showed that age, sex, histological type, stage, lymph node (LN) metastasis, surgery, chemotherapy were independent prognostic factors, we included these factors to establish a nomogram. In the training cohort, the C index was 0.690, and the area under curves (AUC) of 3 and 5-year survival time were 0.720 and 0.723. The calibration plots in training cohort and validation cohort were in excellent agreement. DCA and IDI showed that the predictive effect of the novel prognostic model was better than the model based on 8th AJCC TNM system. Chi-square test indicated that DPLC and SPLC had statistical differences on pathological and clinical features. CONCLUSIONS: The clinical and pathological characteristics of DPLC were different from the SPLC. The nomogram could provide accurate and individualized survival predictions for DPLC.

Peripheral insertion of reverse-tapered and non-tapered central catheters (PICC) in patients receiving tumor chemotherapy.

Objective: The objective of the study is to investigate the effect of the reverse-tapered peripherally inserted central catheters (PICC) and the nontapered PICC in tumor chemotherapy. Materials and Methods: Retrospective January to May 2019, 110 subjects were collected in the study, including a group of 49 patients with the reverse-tapered PICC catheters. In the other group, 61 patients were implanted with the nontapered PICC catheters. The incidence of PICC catheter-related symptomatic thrombosis, the difficulty degree of catheterization, and the rate of bleeding at the puncture point 24 h after catheterization were compared between two groups. Results: The comparison of the difficulty of catheterization and the permeability rate at puncture point 24 h after catheterization between the two groups showed statistically significant differences (all P < 0.05). There was no significant difference in the incidence of symptomatic thrombosis associated with PICC catheters between the two groups (P > 0.05). Conclusion: The reverse-tapered PICC and the nontapered PICC catheters have similar safety performance in tumor chemotherapy; different design types of PICC were selected according to the treatment needs of patients.

Prognostic model of AU-rich genes predicting the prognosis of lung adenocarcinoma.

BACKGROUND: AU-rich elements (ARE) are vital cis-acting short sequences in the 3'UTR affecting mRNA stability and translation. The deregulation of ARE-mediated pathways can contribute to tumorigenesis and development. Consequently, ARE-genes are promising to predict prognosis of lung adenocarcinoma (LUAD) patients. METHODS: Differentially expressed ARE-genes between LUAD and adjacent tissues in TCGA were investigated by Wilcoxon test. LASSO and Cox regression analyses were performed to identify a prognostic genetic signature. The genetic signature was combined with clinicopathological features to establish a prognostic model. LUAD patients were divided into high- and low-risk groups by the model. Kaplan-Meier curve, Harrell's concordance index (C-index), calibration curves and decision curve analyses (DCA) were used to assess the model. Function enrichment analysis, immunity and tumor mutation analyses were performed to further explore the underlying molecular mechanisms. GEO data were used for external validation. RESULTS: Twelve prognostic genes were identified. The gene riskScore, age and stage were independent prognostic factors. The high-risk group had worse overall survival and was less sensitive to chemotherapy and radiotherapy (P < 0.01). C-index and calibration curves showed good performance on survival prediction in both TCGA (1, 3, 5-year ROC: 0.788, 0.776, 0.766) and the GSE13213 validation cohort (1, 3, 5-year ROC: 0.781, 0.811, 0.734). DCA showed the model had notable clinical net benefit. Furthermore, the high-risk group were enriched in cell cycle, DNA damage response, multiple oncological pathways and associated with higher PD-L1 expression, M1 macrophage infiltration. There was no significant difference in tumor mutation burden (TMB) between high- and low-risk groups. CONCLUSION: ARE-genes can reliably predict prognosis of LUAD and may become new therapeutic targets for LUAD.

Gender specific eRNA TBX5-AS1 as the immunological biomarker for male patients with lung squamous cell carcinoma in pan-cancer screening.

As an innate feature of human beings, gender differences have an influence on various biological phenotypes, yet it does not attract enough attention in genomics studies. The prognosis of multiple carcinomas usually exhibits a favorable ending for female patients, but the neglect of gender differences can cause serious bias in survival analysis. Enhancer RNAs (eRNAs) are mostly downstream of androgens or estrogen. The present study was aimed to screen eRNAs in patients with non-small-cell lung cancer. The findings revealed that eRNA TBX5-AS1 was expressed differently between female and male patients. Meanwhile, its prognostic significance appeared only in male patients with squamous cell carcinoma (SCC) type. The Gene Set Enrichment Analysis proved that the expression level of TBX5-AS1 increased following the activation of the androgen signaling pathway. In pan-cancer analysis, the prognostic prediction based on gender grouping obtained more meaningful results, and the synergy between TBX5-AS1 and its homologous target was more consistent. Furthermore, immunity variations between sexes prompted us to explore the role that TBX5-AS1 played in tumor microenvironment and immunotherapy. The robust evidence proved that male patients with high expression of TBX5-AS1 possessed a malignant immune microenvironment and urgently needed immune checkpoint inhibitor treatment. In conclusion, TBX5-AS1 may be one of the strongest candidates to predict prognosis for male patients with SCC and provide a reference for immunotherapy.