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.

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.

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.

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.

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.

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.

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.

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.

Double-edged role of radiotherapy in patients with pulmonary large-cell neuroendocrine carcinoma.

Purpose: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is classified as non-small-cell lung cancer, but has characteristics similar to small-cell lung cancer. This study was performed to evaluate the effect of surgery and radiotherapy on patients with LCNEC. Materials and Methods: We analyzed 1,619 patients with stage I-III LCNEC, identified from the Surveillance, Epidemiology, and End Results database, diagnosed from 2000 to 2013. The Kaplan-Meier analysis and the Cox proportional hazard model were used to study patient prognosis. Results: Overall, 869 (53.7%) stage I LCNEC patients, 203 (12.5%) stage II patients, and 547 (33.8%) stage III patients were included in the analysis. Various surgery types were all associated with higher overall survival (OS) and lung cancer-specific survival (LCSS) than no surgery, with the following HRs: 0.334 (OS) and 0.279 (LCSS) for lobectomy, 0.468 (OS) and 0.416 (LCSS) for partial/wedge/segmental resection, and 0.593 (OS) and 0.522 (LCSS) for pneumonectomy (all p < 0.05). OS and LCSS of stage I and II LCNEC patients were not improved by radiotherapy (stage I: OS p = 0.719, LCSS p = 0.557; stage II: OS p = 0.136, LCSS p = 0.697). However, in stage III patients, radiotherapy significantly improved both OS and LCSS (p < 0.001). Following multivariate analysis, increased age, male patients, radiotherapy and diagnosed at stage II or III were all independent risk factors for LCNEC (all p < 0.05). Conclusion: Lobectomy had the best outcome for OS and LCSS in stage I-II LCNEC. For stage III LCNEC patients, radiotherapy can significantly improve survival time. However, in LCNEC patients undergoing surgery, radiotherapy may reduce survival time.

Regulation of response to radiotherapy by ß-arrestin1 in Non-small cell lung cancer.

ß-arrestin1 serves as scaffold proteins participating in multiple signaling pathways. However, there were few researches focusing on the impact of ß-arrestin1 on DNA damage response (DDR). Non-small cell lung cancer cell (NSCLC) lines were transfected with ß-arrestin1 plasmids or siRNA and received radiation treatment. MTT and colony formation assay were performed to assess the proliferation and viability of tumor cells. Flow cytometry was used to evaluate the impact of ß-arrestin1 on radiation-induced apoptosis. Western blotting was applied to detect protein expression in apoptosis, DDR, ERK and NF-kB pathways. We used qRT-PCR to test ATR, H2AX, ß-arrestin1 mRNA level in cancer tissues compared with para-carcinoma tissues. Co-IP was performed to evaluate the interaction between ß-arrestin1 and ATR or H2AX. Comet assay was used to detect DNA damage. ß-arrestin1 mRNA level co-related with ATR and H2AX levels in cancer tissues, and ß-arrestin1 bound to ATR and H2AX directly or indirectly. Overexpression of ß-arrestin1 enhanced the DNA damage response pathway activation and increase DNA damage and apoptosis. Interestingly, suppression of ß-arrestin1 inhibited cell proliferation and attenuated ERK and NF-kB pathways activation induced by radiation. Overexpression of ß-arrestin1 enhances DDR pathway activation induced by radiation, as well as downstream apoptosis, and depletion of ß-arrestin1 inhibits DDR pathway. Meanwhile ß-arrestin1 regulates cell proliferation by suppression of ERK and NF-kB pathways. Manipulation of ß-arrestin1 status modulates radiosensitivity for NSCLC.

Effects of postoperative non-steroidal anti-inflammatory drugs on long-term survival and recurrence of patients with non-small cell lung cancer.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve postoperative fever, surgery pain, and inflammation. In addition, NSAIDs have anticancer activity and may reduce the risk and mortality of several cancers. However, the association between postoperative NSAIDs and the clinical outcome of non-small cell lung cancer (NSCLC) patients with fever after surgery is not fully understood. We performed a retrospective study of NSCLC patients who underwent surgery between July 2011 and June 2012, aiming to evaluate the effect of postoperative NSAIDs on overall survival (OS) and progression-free survival (PFS). Differences in clinical data between the postoperative NSAIDs group and non-NSAIDs groups were analyzed by Chi-square tests. Kaplan-Meier curves method and Cox regression analysis were conducted for survival analysis. The primary and secondary endpoints were OS and PFS, respectively. This retrospective study included 347 NSCLC patients. There were no significant differences in the clinical characteristics between the NSAIDs group and non-NSAIDs group except for age (P = .024) and differential degree (P = .040). Administration of postoperative NSAIDs was related to longer OS (hazards ratio [HR] 0.528, 95% confidence interval [CI] 0.278-0.884, P = .006) and longer PFS (HR 0.557, 95% CI 0.317-0.841, P = .002) in the multivariate Cox regression model. Subgroup analysis showed statistically significant differences in elderly individuals, male subjects, low smoking index, poor differentiation, and non-adenocarcinoma subgroups, respectively. In conclusion, the administration of postoperative NSAIDs was related to longer OS and PFS in NSCLC patients with postoperative fever.

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.

Survival Outcomes for Patients with Surgical and Non-Surgical Treatments in Stages I-III Small-Cell Lung Cancer.

Objectives: Chemotherapy and radiation therapy are the standard treatments for patients with small-cell lung cancer (SCLC). However, recent studies suggest that patients with limited stage (I-III) SCLC may benefit from surgical treatment. This study was performed to evaluate the survival outcomes of surgery for stage I-III SCLC. Methods: This analysis used data from the Surveillance, Epidemiology, and End Results (SEER) database. All stage I-III (excluding N3 and Nx) SCLC patients received a diagnosis between 2004 and 2014. Overall survival (OS) and lung cancer-specific survival (LCSS) were determined by Kaplan-Meier analysis and compared using the log-rank test. A Cox proportional hazard model identified relevant survival variables. Results: A total of 4,780 histologically confirmed patients were identified from the SEER database, comprising 1,018 patients (21.3%) with stage I disease; 295 (6.2%) with stage II; and 3,467 (72.5%) with stage III disease. Among all of the patients, 520 had been treated with surgery, the majority (n = 344; 66.2%) of whom had stage I disease. The hazard ratio (HR) for OS and LCSS, in patients who underwent surgery, according to stage were as follows: OS, 0.369 and LCSS, 0.335 in stage I; OS, 0.549 and LCSS, 0.506 in stage II; and OS, 0.477 and LCSS, 0.456 in stage III (all p < 0.001). Patients who underwent surgery had significantly better OS, and lobectomy was associated with the best outcome. Conclusions: Surgical resection was associated with significantly improved OS outcomes and should be considered in the management of stage I-III SCLC.

Long-term outcomes of stage I NSCLC (≤3 cm) patients following segmentectomy are equivalent to lobectomy under analogous extent of lymph node removal: a PSM based analysis.

BACKGROUND: Segmentectomy has the advantage of less complications, but might have less lymph node sampling and higher risk of recurrence. We aimed to compare treatment outcome between two surgical options, and explore the effect of regional lymph node removal on the prognostic difference. METHODS: We retrospectively analyzed data of stage I non-small cell lung cancer (NSCLC) (≤3 cm in size) patients who underwent either segmentectomy, or lobectomy, collected from the Surveillance, Epidemiology and End Results (SEER) database, from 2003 to 2013. The primary endpoints were overall survival (OS) and lung cancer-specific survival (LCSS). We also collected data from Shandong Provincial Hospital as validation. RESULTS: Ultimately 1,156 patients treated by segmentectomy and 17,748 patients treated by lobectomy from SEER database were included in the analysis. Overall, segmentectomy was inferior to lobectomy in terms of OS [hazard ratio (HR): 1.316 (1.186-1.461), P<0.001] and LCSS [HR: 1.310 (1.142-1.504), P<0.001]. When the removal of regional lymph nodes (LN) was taken into consideration, no significant difference was found in OS and LCSS, in any Scope of Regional Lymph Node Surgery layer (0, 1-3, more than 3, and biopsy/sentinel layer, all P>0.05). After propensity score matching (PSM), there was no difference between segmentectomy and lobectomy in OS [HR: 1.081 (0.937-1.248), P=0.286] and LCSS [HR: 1.039 (0.861-1.253), P=0.692]. Only sex, age, histology, summary stage, differentiation, tumor size, and radiation still remained as independent prognostic factors for both OS and LCSS. For validation part, there was no significantly prognostic difference between lobectomy and sublobectomy group in overall (P=0.132) and each regional LN removed layer (0, 1-3, more than 3 layers: all P>0.05). CONCLUSIONS: Segmentectomy with proper lymph node resection or sampling could be a good alternative to lobectomy.

Subcellular localization of ß-arrestin1 and its prognostic value in lung adenocarcinoma.

ß-Arrestins play important roles in cancer progression, and the subcellular localization of ß-arrestin1 has been receiving increasingly more attention. Intriguingly, several studies, including some of our previous work, showed that the effects of ß-arrestin1 on outcomes of cancer patients were controversial.Specimens were obtained from 133 patients with lung adenocarcinoma. Immunohistochemistry was used to detect the expression of ß-arrestin1 and p300 in the collected tissues. The Kaplan-Meier analysis and Cox proportional hazards regression were used to examine the relationship between ß-arrestin1 and patient survival.We found no significant association between ß-arrestin1 and clinicopathological variables. The Kaplan-Meier plot showed that patients with high expression of ß-arrestin1 (especially in the nucleus) had a poorer overall survival (OS) and shorter disease-free survival (DFS) (P = .026, P = .015). Additionally, high p300 expression also resulted in worse OS (P = .039). Following the univariate analysis, high expressions of nuclear ß-arrestin1 and p300 were classed as poor prognostic factors for both OS (P = .016) and DFS (P = .025).The expression of ß-arrestin1 in the nucleus is associated with increased malignant tendency of lung adenocarcinoma, and the predictive value of ß-arrestin1 may be optimized by combining information about the expression of p300 acetyltransferase.

Loss of ß-arrestin-2 and Activation of CXCR2 Correlate with Lymph Node Metastasis in Non-small Cell Lung Cancer.

Background : Although ß-arrestin-2 (ß-arr2) and CXCR2 have been shown to affect various malignant tumors, their exact roles in lung cancer remain unclear. We investigated expression of ß-arr2 and CXCR2 in patients with non-small cell lung cancer (NSCLC) and their correlation with lymph node metastasis and prognosis. Methods : We reviewed medical records of 136 patients with NSCLC who underwent surgical resection, and assessed their specimens immunohistochemically for expression of ß-arr2 and CXCR2 in primary tumors and metastatic lymph nodes (MLNs), respectively. Results: High ß-arr2 expression was seen in 63 specimens (46.3%), and was significantly associated with male patients (P=0.011), squamous cell carcinoma (P=0.003), and lymph node metastasis (P<0.001). High CXCR2 expression was seen in 62 specimens (45.6%), and was significantly correlated only with lymph node metastasis (P<0.001). Expression of ß-arr2 was significantly lower at MLNs than at primary lesions (Z=-2.315; P=0.021; Wilcoxon signed-rank), whereas CXCR2 expression was significantly higher in MLNs than in primary lesions (Z=-3.712; P<0.001; Wilcoxon signed-rank). No relationship was seen between ß-arr2 and CXCR2 expression in primary lesions (r=-0.065, P=0.548; Spearman rank coefficient), but they were inversely related in MLNs (r=-0.263, P=0.012). Kaplan-Meier survival curve was shown that low ß-arr2 and high CXCR2 expressions was associated with poor survival (log-rank: χ2=5.926, P=0.015). Conclusions : ß-arr2 may promote lymph node metastasis in NSCLC by modulating CXCR2 activation.

Diagnostic and prognostic value of blood samples for KRAS mutation identification in lung cancer: a meta-analysis.

Circulating tumor DNA (ctDNA) and tumor cells (CTC) are novel approaches for identifying genomic alterations. Thus, we designed a meta-analysis to evaluate the diagnostic value and prognostic significance of a KRAS proto-oncogene, GTPase (KRAS) mutation for lung cancer patients. All included articles were from PubMed, EMBASE, Web of Science and Cochrane Library. Twelve articles that described 1,131 patients were reviewed. True positives (TP), false positives (FP), true negatives (TN), and false negatives (FN) were used to calculate pooled sensitivity, specificity, the positive likelihood ratio (PLR), the negative likelihood ratio (NLR), a diagnostic odds ratio (DOR), the area under the curve (AUC) and corresponding 95% confidence intervals (95% CI). PLR is calculated as sensitivity/(1-specificity) and NLR is (1- sensitivity)/specificity. DOR is a measured of diagnostic effectiveness (PLR/NLR). A survival analysis subgroup was also designed to evaluate prognostic significance. Pooled sensitivity, specificity, PLR, NLR, DOR and AUC were 0.79 (95% CI, 0.63-0.89), 0.93 (95% CI, 0.89-0.96), 12.13 (92% CI, 7.11-20.67), 0.22 (95% CI, 0.12-0.41), 54.82 (95% CI, 23.11-130.09), and 0.95 (95% CI, 0.93-0.96), respectively. KRAS mutation and wild-type hazard ratios for overall survival and progression-free survival were 1.37 (95% CI, 1.08-1.66), 1.46 (95% CI, 1.15-1.77) in blood samples, and 1.16 (95% CI, 1.03-1.28), 1.28 (95% CI, 1.09-1.46) in tumor tissue.

Prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma.

PURPOSE: Gastric carcinoma (GC) is a highly aggressive cancer and one of the leading causes of cancer-related deaths worldwide. Histopathological evaluation pertaining to invasiveness is likely to provide additional information in relation to patient outcome. In this study, we aimed to evaluate the prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma. MATERIALS AND METHODS: Hematoxylin and eosin-stained slides generated from 296 gastric adenocarcinoma patients with full clinical and pathological and follow-up information were systematically reviewed. The patients were grouped on the basis of tumor budding, single cell invasion, large cell invasion, mitotic count, and fibrosis. The association between histopathological parameters, different classification systems, and overall survival (OS) was statistically analyzed. RESULTS: Among the 296 cases that were analyzed, high-grade tumor budding was observed in 49.0% (145) of them. Single cell invasion and large cell invasion were observed in 62.8% (186) and 16.9% (50) of the cases, respectively. Following univariate analysis, patients with high-grade tumor budding had shorter OS than those with low-grade tumor budding (hazard ratio [HR]: 2.260, P<0.001). Similarly, the OS of patients with single cell invasion and large cell invasion was reduced (single cell invasion, HR: 3.553, P<0.001; large cell invasion, HR: 2.466, P<0.001). Following multivariate analysis, tumor budding and single cell invasion were observed to be independent risk factors for gastric adenocarcinoma (P<0.05). According to the Lauren classification, patients with intestinal-type adenocarcinoma had better outcomes than those with diffuse-type adenocarcinoma (HR: 2.563, P<0.001). CONCLUSION: Tumor budding and single cell invasion in gastric adenocarcinoma are associated with an unfavorable prognosis.

Nuclear overexpression of the overexpressed in lung cancer 1 predicts worse prognosis in gastric adenocarcinoma.

We have performed this retrospective study to elucidate whether elevated expression of the overexpressed in lung cancer 1 (OLC1) was related to the clinicopathological parameters and prognosis of patients with gastric adenocarcinoma. Additionally, different effects of various subcellular OLC1 expression on gastric adeno-carcinogenesis were focused on in our study. Both overall and subcellular expression of OLC1 was evaluated by immunohistochemistry(IHC) via tissue microarrays from total 393 samples. The Kaplan-Meier method and Cox's proportional hazard model were exerted to further explore the correlation between OLC1 and prognosis. Total overexpression of OLC1 was significantly associated with stage (P = 0.004) and differentiation (P = 0.009), and only the strong total expression could predict a poor prognosis (HR = 1.31, P = 0.04). There were significant associations found between nuclear overexpression and tumor invasion depth(P = 0.002), lymph node (P < 0.001), stage (P = 0.004), differentiation (P < 0.001) and smoking history (P = 0.045). Furthermore, over-expressed nuclear OLC1 protein could be an independent risk factor for gastric adenocarcinoma (univariate: HR = 1.43, P = 0.003; multivariate: HR = 1.39, P = 0.011). In general, both total and nuclear overexpression of OLC1 could be the signs of gastric adeno-carcinogenesis, which might be served as the biomarkers for diagnosis at an early stage, even at the onset of tumorigenesis. Rather than the total expression, nuclear overexpression of OLC1 was correlated with most clinicopathological parameters and could predict a poor overall survival as an independent factor for prognosis, which made it a more effective and sensitive biomarker for gastric adenocarcinoma.