Prognostic Factor In Lung Cancer Research Articles

Akciğer Kanseri Hastalarının Ölüm Risklerinin Zayıflık Modelleri ile Değerlendirilmesi

OBJECTIVE:The aim of this study is to investigate the prognostic factors of lung cancer by evaluating the most appropriate survival model with a selection criteria. MATERIAL AND METHODS:In the study, the data of 185 patients diagnosed with lung cancer from the Medical Oncology Outpatient Clinic of Mustafa Kemal University Faculty of Medicine were retrospectively obtained from the patient files. The frailty models with different distributions were used for evaluating the heterogeneity between patients. Model selections were made according to AIC and BIC criteria. RESULTS:The median survival time of patients with lung cancer in the study was 11 months (95% confidence interval 9.57-12.42). The best frailty models’ frailty distribution was lognormal and the basic hazard function distribution was loglogistic. The best model results showed that, the effect of the albumin variable on the risk of death of lung cancer patients was statistically significant (p = 0.018). CONCLUSIONS:Generally, environmental and genetic factors that affect the survival time of lung cancer patients can not be evaluated.Thus, the term of the frailty resulting from the heterogeneity of factors when assessing individuals influencing survival of patients with lung cancer should be taken into account.

Reactive Oxygen Species Modulator 1 is Associated with Poor Survival in Patients with Non-Small Cell Lung Cancer After Stereotactic Fractionated Radiosurgery: A Retrospective Pilot Study.

PurposeIt has been reported that the overexpression of reactive oxygen species modulator 1 (Romo1) is significantly associated with poor survival outcomes in patients with lung cancer who received surgical resection, conventional fractionated radiotherapy, and chemotherapy. In this study, we investigated whether Romo1 expression is associated with survival outcomes in patients with early-stage lung cancer who were treated with radiosurgery.MethodsRomo1 protein expression was evaluated and scored in the tumor tissue specimens of 40 patients with non-small cell lung cancer by immunohistochemistry. An optimal cut-off for Romo1 expression was determined and used to allocate patients to low or high Romo1 expression groups. Survival outcomes were compared between the two groups.ResultsRomo1 expression was significantly associated with distant metastasis-free survival. The 1- and 2-year distant metastasis-free survival rates were 96.4% and 92.6% in the low Romo1 expression group and 87.5% and 46.7% in the high Romo1 expression group (P=0.041), respectively. The overall, local recurrence-free, regional recurrence-free, and disease progression-free survival rates were higher in the low Romo1 expression group than the high Romo1 expression group. However, the differences were not statistically significant.ConclusionRomo1 overexpression is associated with poor distant metastasis-free survival in patients with non-small cell lung cancer treated with radiosurgery. Further, large-scale prospective studies are required to identify the clinical efficacy of Romo1 as a potential adverse prognostic factor in lung cancer.

Detecting tumor-infiltrating Forkhead box P3-positive T cells in the prognosis of lung adenocarcinoma: Possible role of clustering tumor interleukin-12 subunit alpha and transforming growth factor beta 1 expression.

While regulatory T cells (Tregs) are a poor prognostic factor for lung cancer, they may be detected as Forkhead box P3+ (FOXP3+) and cluster of differentiation (-CD) 4+ T cells by classifying FOXP3+CD4+ T cells into different subpopulations of CD4 cells. To classify clusters of tumor-infiltrating Tregs in lung adenocarcinoma based on the mRNA expression levels of interleukin-12 subunit alpha (IL12A) and transforming growth factor beta 1 (TGFB1) in tumor specimens. Seventy-nine patients with lung adenocarcinoma were evaluated in this study. Clinical data were obtained from the patients' medical records, while tumor tissue samples were preserved as formalin-fixed paraffin-embedded (FFPE) tissue specimens. Immunohistochemical staining for CD4, CD8 and FOXP3 was performed and stained cell counts were obtained under 5 high-power fields. cDNA was synthesized from total RNA extracted from FFPE tissue specimens and amplified with Taqman probes for FOXP3, IL12A, TGFB1, and the glyceraldehyde-3-phosphate dehydrogenase gene. Two clusters were identified: IL12AlowTGFB1low (Cluster 1: n = 44) and IL12AhighTGFB1high (Cluster 2: n = 39). Although no significant difference in the FOXP3+ cell/CD4+ cell ratio was observed between the 2 clusters (p = 0.921), the high FOXP3+/CD4+ cell ratio group showed a significantly poorer relapse-free survival rate than the low FOXP3+/CD4+ cell ratio group in Cluster 1 (p = 0.031). Although the results revealed no direct association between Tregs and prognosis according to each subtype, these results suggest that if a lung cancer specimen contains low levels of IL12A and TGFB1, the FOXP3+/CD4+ cell ratio is useful for predicting the prognosis of lung cancer.

Construction of a metastasis-associated ceRNA network reveals a prognostic signature in lung cancer

BackgroundLung cancer is the most common cancer worldwide, and metastasis is the leading cause of lung cancer related death. However, the molecular network involved in lung cancer metastasis remains incompletely described. Here, we aimed to construct a metastasis-associated ceRNA network and identify a lncRNA prognostic signature in lung cancer.MethodsRNA expression profiles were downloaded from The Cancer Genome Atlas (TCGA) database. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses and gene set enrichment analysis (GSEA) were performed to investigate the function of these genes. Using Cox regression analysis, we found that a 6 lncRNA signature may serve as a candidate prognostic factor in lung cancer. Finally, we used Transwell assays with lung cancer cell lines to verify that LINC01010 acts as a tumor suppressor.ResultsWe identified 1249 differentially expressed (DE) mRNAs, 440 DE lncRNAs and 26 DE miRNAs between nonmetastatic and metastatic lung cancer tissues. GO and KEGG analyses confirmed that the identified DE mRNAs are involved in lung cancer metastasis. Using bioinformatics tools, we constructed a metastasis-associated ceRNA network for lung cancer that includes 117 mRNAs, 23 lncRNAs and 22 miRNAs. We then identified a 6 lncRNA signature (LINC01287, SNAP25-AS1, LINC00470, AC104809.2, LINC00645 and LINC01010) that had the greatest prognostic value for lung cancer. Furthermore, we found that suppression of LINC01010 promoted lung cancer cell migration and invasion.ConclusionsThis study might provide insight into the identification of potential lncRNA biomarkers for diagnosis and prognosis in lung cancer.

Abstract D132: The association between Insurance and lung cancer survival: The relative contributions of sociodemographic, tumor, treatment, and neighborhood factors

Abstract Health insurance is associated with lung cancer treatment and survival. It remains unclear to what extent insurance-associated survival disparities are attributed to prognostic factors of lung cancer. Using the Surveillance, Epidemiology, and End Results dataset, we identified 127,784 patients (age<65) diagnosed with lung cancer between 2007 and 2016. Cox proportional hazards regression was used to compute hazard ratios (HRs) of lung cancer-specific mortality. Relative contributions of prognostic factors to survival disparities were quantified by percent changes in HRs with sequential adjustment for marital status, socioeconomic deprivation, rurality, cancer stage, size, histology, surgery, radiation therapy, and chemotherapy. Difference in differences analysis was performed to examine the associations between Medicaid expansion and changes in proportions of no insurance and early-stage diagnosis, and 2-year survival rates. Compared with privately insured counterparts, the risk of cancer-specific mortality was significantly increased in uninsured men (HR=1.51, 95% CI 1.47-1.56; 5-year absolute risk difference (ARD)=12.5%, 95% CI 11.6%-13.3%) in uninsured men, Medicaid men (HR=1.36, 95% CI 1.33-1.39; 5-year ARD=9.6%, 95% CI 9.0%-10.3%), uninsured women (HR=1.66, 95% CI 1.59-1.72; 5-year ARD=17.0%, 95% CI 15.8%-18.2%), and Medicaid women (HR=1.41, 95% CI 1.38-1.45; 5-year ARD=12.0%, 95% CI 11.2%-12.9%) after adjustment for age, race, and registries. Further adjustment for the aforementioned factors explained 63.7%-70.6% of survival disparities. Medicaid expansion was associated with a greater reduction in uninsured rates (2.0 percentage point (ppt), p<.0001), and a greater increase in the proportion of early-stage diagnosis (2.1 ppt, p<0.01) and 2-year survival (1.3 ppt, p=0.04) in men only, after adjustment for covariates. The study provided evidence for worse survival in uninsured and Medicaid lung cancer patients compared with privately insured counterparts, more than half of which were attributable to sociodemographic, tumor, treatment, and neighborhood factors. Medicaid expansion was associated with shift towards early-stage diagnosis and improvements in short-term survival in men with lung cancer. Citation Format: Ying Liu, Min Lian, Graham Colditz. The association between Insurance and lung cancer survival: The relative contributions of sociodemographic, tumor, treatment, and neighborhood factors [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D132.

Absolute Neutrophil Count and Mean Platelet Volume in the Blood as Biomarkers to Detect Lung Cancer.

Objective Inflammation plays an extremely considerable role in the development and progression of malignancies. Absolute neutrophil count (ANC) and mean platelet volume (MPV) in blood are associated with various inflammatory conditions and resulted in independent prognostic factors for lung cancer. However, whether ANC and MPV can be diagnostic markers for lung cancer remains unknown. This retrospective study investigated the roles of ANC and MPV, either alone or combined, in diagnosing lung cancer. Methods This study analyzed data from lung cancer patients and healthy individuals in Wuxi People's Hospital Affiliated with Nanjing Medical University. The Mann–Whitney U-test was performed to compare differences between lung cancer patients and healthy individuals. Spearman's correlation analysis was used to assess correlations. Receiver operating characteristic (ROC) curves were performed to determine diagnostic accuracy. Results 209 patients diagnosed with lung cancer and 236 healthy subjects were enrolled in this study. Levels of ANC and MPV increased in lung cancer patients compared with healthy individuals (P < 0.001). ANC had statistically significant negative weak correlation with albumin concentrations (r = ‐0.154, P = 0.026), and MPV had statistically significant negative weak correlation with total protein concentrations (r = ‐0.153, P = 0.027) in lung cancer patients. ANC and neutrophil-to-lymphocyte ratio had statistically significant positive correlation in both lung cancer patients (r = 0.756, P < 0.001) and healthy subjects (r = 0.639, P < 0.001). MPV and platelet-to-lymphocyte ratio had statistically significant negative weak correlation in both lung cancer patients (r = ‐0.242, P < 0.001) and healthy subjects (r = ‐0.325, P < 0.001). ANC had sensitivity (SEN) and specificity (SPE) of 0.512 and 0.809, respectively, and the area under the curve (AUC) with 95% confidence interval (95% CI) was 0.656 (0.603-0.710). SEN and SPE of MPV were 0.928 and 0.708, respectively, and the AUC (95% CI) was 0.913 (0.889-0.938). When ANC and MPV were combined, SEN and SPE became 0.842 and 0.835, respectively, and the AUC (95% CI) became 0.919 (0.895-0.943). Conclusions Compared with ANC or MPV alone, the combination of ANC and MPV can improve diagnostic ability to distinguish lung cancer patients from healthy subjects.

Prognostic factors of lung cancer in lymphoma survivors (the LuCiLyS study).

BackgroundSecond cancer is the leading cause of death in lymphoma survivors, with lung cancer representing the most common solid tumor. Limited information exists about the treatment and prognosis of second lung cancer following lymphoma. Herein, we evaluated the outcome and prognostic factors of Lung Cancer in Lymphoma Survivors (the LuCiLyS study) to improve the patient selection for lung cancer treatment.MethodsThis is a retrospective multicentre study including consecutive patients treated for lymphoma disease that subsequently developed non-small cell lung cancer (NSCLC). Data regarding lymphoma including age, symptoms, histology, disease stage, treatment received and lymphoma status at the time of lung cancer diagnosis, and data on lung carcinoma as age, smoking history, latency from lymphoma, symptoms, histology, disease stage, treatment received, and survival were evaluated to identify the significant prognostic factors for overall survival.ResultsOur study population included 164 patients, 145 of which underwent lung cancer resection. The median overall survival was 63 (range, 58–85) months, and the 5-year survival rate 54%. At univariable analysis no-active lymphoma (HR: 2.19; P=0.0152); early lymphoma stage (HR: 1.95; P=0.01); adenocarcinoma histology (HR: 0.59; P=0.0421); early lung cancer stage (HR: 3.18; P<0.0001); incidental diagnosis of lung cancer (HR: 1.71; P<0.0001); and lung cancer resection (HR: 2.79; P<0.0001) were favorable prognostic factors. At multivariable analysis, no-active lymphoma (HR: 2.68; P=0.004); early lung cancer stage (HR: 2.37; P<0.0001); incidental diagnosis of lung cancer (HR: 2.00; P<0.0001); and lung cancer resection (HR: 2.07; P<0.0001) remained favorable prognostic factors. Patients with non-active lymphoma (n=146) versus those with active lymphoma (n=18) at lung cancer diagnosis presented better median survival (64 vs. 37 months; HR: 2.4; P=0.02), but median lung cancer specific survival showed no significant difference (27 vs. 19 months; HR: 0.3; P=0.17).ConclusionsThe presence and/or a history of lymphoma should not be a contraindication to resection of lung cancer. Inclusion of lymphoma survivors in a lung cancer-screening program may lead to early detection of lung cancer, and improve the survival.

Outcomes of Surgically Treated Patients with Stage IIB Non-small Cell Lung Cancer, a Single Center Experience

Stage IIB lung cancers according to TNM8 staging include T1-2N1M0 and T3N0M0 groups. It has been emphasized that the most important prognostic factor of lung cancer is of tumor in many studies. In this study, we investigated the prognostic effect of some variables including tumor diameter, visceral pleural invasion, lymph node invasion, type of surgery, etc. in same tumorstage. After the approval of the local ethics committee, a total of 139 patients who were surgically treated for non-small-cell lung cancer in our department and whose pathological staging was reported as stage IIB were included in the study. The 15 patients were female and 124 were male, and the mean age was 61.5 (Range, 39–81; SD, 7.9). The overall survival and disease-free survival of patients were analyzed according to N1 presence, tumor diameter, histopathological type, visceral pleural invasion, age, and gender. The 5-year survival rate was 50.4%, and the 5-year diseases free survival rate was 54.9%. The survival of N1 (+) group was worse than the T3 group. Pneumonectomy, big tumor diameter, and squamous cell carcinoma histopathology were negative prognostic factors for survival, whereas visceral pleural invasion and adenocarcinoma histopathology were found as statistically significant to negative effect disease-free survival. Furthermore the 5-year survival rate of T2bN1M0 group was found worst than others. According to the TNM system adopted in 2016, the stage IIB lung cancers are a heterogeneous group, and as the survival studies related to this group increase, a separate tumor stage formation or separation of T2bN1 group from stage IIB may be considered.

MPDZ As a Novel Epigenetic Silenced Tumor Suppressor Inhibits Growth and Progression of Lung Cancer Through the Hippo-YAP Pathway

MPDZ is involved in signal transduction mediated by the formation of protein complexes. However, the expression regulation, clinical significance, potential function and mechanism of this gene in lung cancer remain unclear. Methylation status of MPDZ was measured by methylation-specific PCR and bisulfite genomic sequencing. Kaplan-Meier and Cox regression analyses were performed to identify the prognostic value of MPDZ. The tumor suppressing effects of MPDZ were determined in vitro and in vivo. The target molecules and signaling pathway that mediated the function of MPDZ were also identified. MPDZ methylation was identified in 61.2% of primary lung cancer tissues and most lung cancer cell lines but not in normal lung tissues. MPDZ expression was significantly downregulated in lung cancer tissues and negatively associated with DNA hypermethylation, and attenuated MPDZ expression predicted a poor outcome. Furthermore, MPDZ overexpression prominently dampened cell growth, migration and invasion of tumor cells. Conversely, MPDZ knockdown promoted cell proliferation, migration and invasion in vitro and in vivo. Importantly, MPDZ promotes tumor suppressor ability depends on the Hippo pathway-mediated repression of YAP. MPDZ activates the phosphorylation of YAP (Ser127) and inhibits YAP expression through interaction with MST1/LATS/YAP complex. Moreover, MPDZ deficiency promotes tumor metastasis and reduces the survival of MPDZ knock-out mice. We first identified and validated that MPDZ methylation and expression could be a good diagnostic marker and independent prognostic factor for lung cancer. MPDZ functions as a tumor suppressor by inhibiting cell proliferation, migration and invasion through regulating the Hippo-YAP signaling pathway. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (No. 81573179 and 81573114). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This study was approved by the Clinical Research Ethics Committee of the Third Military Medical University, and informed consent was obtained from all patients. All experimental animal procedures were approved by the Institutional Animal Care and Use Committee of Third Military Medical University, China.

Evaluation of the Cell Detachment Ratio on pH-responsive Chitosan as a Prognostic Factor in Lung Cancer

Evaluation of the Cell Detachment Ratio on pH-responsive Chitosan as a Prognostic Factor in Lung Cancer

P2.16-16 Calf Circumference Is Associated with Postoperative Outcomes in Lung Cancer Patients Who Underwent Surgery

Sarcopenia has gained considerable attention as a poor prognostic factor in lung cancer after surgical resection. Calf circumference (CC) is an easy-to-measure, non-invasive clinical indicator that reflects body muscle mass as well as subcutaneous fat. For this property, many studies have reported that CC is capable of screening sarcopenia, aside from the assessment of nutritional status. In this study, we investigated the association between CC and postoperative outcomes in lung cancer patients. Between 2007 and 2016, 873 lung cancer patients underwent surgery in our institution. Patients who received induction therapy (n=33), with a prior history of the disease that could affect the diameter of lower limb (n=5), and with missing data (n=17) were excluded in advance, leaving 818 patients for this retrospective analysis. CC was measured prior to surgery in the occasion of hospital admission. We chose 34 cm for men and 33 cm for women as the CC cutoff value for predicting low muscle mass, following the previous report in Japan (Kawakami R et al. Geriatr Gerontol Int.). The patient characteristics, operative factors, and surgical outcomes were examined to compare the groups. The Kaplan-Meier method was used to estimate long-term survival. The mean age of all patients was 67.9 years. There were 473 men and 345 women, and each of their average CC was 34.4 cm and 32.0 cm. In the smaller CC (s-CC) group (n=427), the average age and the female proportion were significantly higher, whereas BMI, %VC, %FEV1 and %DLco, in addition to the proportion of the other cancer history were significantly lower (P<0.01 each) compared with the other group (n=391). As for operative factors, there were no significant differences in surgical approach, type of resection, operation time and intraoperative bleeding, except that the ratio of systematic hilar and mediastinal lymph node dissection was lower (P<0.01) in the s-CC group. Though overall postoperative complications were equivalent (27.2% vs. 23.0%), complications grade 3 or higher were more frequent in the s-CC group (10.5% vs. 5.9%, P=0.02). The 5-year DFS (65.1% vs. 77.9%, P=0.01) and OS (77.9% vs. 81.7%, P=0.03) were significantly poorer in the s-CC group. The smaller CC was associated with severe postoperative complications and poor DFS and OS in patients with resected lung cancer. CC was useful for assessing sarcopenia and therefore predicting postoperative outcomes.

1990P - Leukocytosis as a negative prognostic factor in patients with lung cancer: Which subpopulation of leukocytes is responsible?

BackgroundLeukocytosis is common in patients with malignancies and might be a negative prognostic factor in lung cancer (LC). Leukocytes are, however, a heterogenous population of blood cells. Therefore, subpopulation of leukocytes responsible for this effect should be identified. It is presumed that neutrophilia and lymphocytopenia might be a negative factor in patients with lung cancer. MethodsLeukocyte, absolute neutrophil, lymphocyte, eosinophil, basophil and thrombocyte count were determined before beginning of treatment in patients with LC. Patients with recent bleeding, elevated CRP or treated with best-supportive care were excluded. The impact of leukocytosis, neutrophilia, lymphocytopenia, eosinophilia and basophilia on progression- free survival (PFS) was determined. Neutrophils to lymphocytes ratio (NLR) at various cut-offs were determined along with platelets to lymphocytes ratio (PLR) and their effect on PFS was assessed. Kaplan- Meier and Cox- regression statistical analysis were used. Results200 patients were examined in our retrospective study. Median PFS was 7.41 months. Leukocytosis and neutrophilia significantly worsened PFS in patients with LC [HR 0.5200, (95%CI 0.3684 to 0.7340), P<0.0001 and HR 0.5556 (95%CI 0.4068 to 0.7589) P=0.0001]. These results were confirmed in Cox- regression analysis (covariates: age, gender, stage). Lymphocytopenia, basophilia, eosinophilia and thrombocytosis had no impact on survival rates. Elevated NLR (cut- off 3.54) significantly worsened PFS in patients with LC [HR 0.6069 (95%CI 0.4475 to 0.8231), P=0.0013] even after adjustment to covariates (age, gender, stage). Elevated NLR at lower cut-offs (2.15 and 1.77) and elevated PLR (cut-off 123) did not affect the survival rate. ConclusionsNeutrophilia appears to be a negative prognostic factor in patients with LC. Impairment in other white blood cell lines does not affect PFS, however, significantly elevated NLR (≥ 3.54) seems to have detrimental effect on survival rates. Legal entity responsible for the studyFaculty Hospital Trencin, Department of Oncology. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

P1.14-22 SASH1, a Novel Prognostic and Predictive Factor for PARP Inhibitors in Lung Cancer

Genomic instability is a universal hallmark of all cancers. Many of the most commonly used chemotherapeutic agents target this genomic instability by directly damaging the DNA, which results in tumour cell death. Our previous work has revealed that loss of SASH1 is associated with impaired apoptosis and increased cellular proliferation. A new generation of drugs have been developed that target the DNA repair enzyme PARP to induce DNA damage and cell death. SASH1 (SAM and SH3 domain containing protein 1) has been described as a tumour suppressor and in support of this SASH1 mRNA levels are decreased in lung, breast, thyroid and colorectal cancers. Our data demonstrates that SASH1 functions in the repair of DNA damage and loss of SASH1 protein expression could be used as a companion diagnostic for PARP inhibitors. SASH1 IHC staining of lung cancer was correlated with patient survival. DNA damage repair was assessed following the depleted of SASH1 (siRNA). SASH1 protein levels in cell lines were correlated to PARP inhibitor sensitivity. A lung cancer tissue microarray (TMA) of 225 patients was assessed for SASH1 protein level. Low SASH1 levels were associated with an improved patient prognosis in adenocarcinoma on univariate analysis (p = 0.03). Analysis of DNA repair pathways demonstrated that SASH1 plays a role in homologous recombination (HR). Based on this observation, the impact of SASH1 expression on sensitivity to PARP inhibitors was explored. An inverse correlation between SASH1 levels and sensitivity to Olaparib was identified in lung cancer cell lines Figure 1 (R2 = 0.882). We subsequently analysed Olaparib sensitivity in a panel of SASH1 depleted lung cancer cells that demonstrated increased Olaparib sensitivity. Our results indicate that SASH1 protein expression is a prognostic factor in lung cancer, high levels being associated with a worse prognosis in adenocarcinoma. Low SASH1 expression is associated with loss of HR and has the potential to be a predictive biomarker for sensitivity to PARP inhibitors in this disease.

Plasma extracellular vesicle microRNAs for pulmonary ground-glass nodules

ABSTRACTIn this study, we evaluated the diagnostic value and molecular characteristics of plasma extracellular vesicles (EVs)-derived miRNAs for patients with solitary pulmonary nodules (SPNs), particularly ground-glass nodules (GGNs). This study was registered at www.clinicaltrials.gov under registration number NCT03230019. Small RNA sequencing was performed to assess plasma EVs miRNAs in 59 patients, including 12 patients with benign nodules (2017, training set). MiRNA profiles of 40 an additional individuals were sequenced (2018, validation set). Overall, 16 pure GGNs, 21 mixed GGNs, and 42 solid nodules were included, with paired post-operative plasma samples available for 20 patients. The target miRNA/reference miRNA ratio was used to construct a support vector machine (SVM) model. The SVM model with the best specificity showed 100% specificity in both the training and validation sets independently. The model with the best sensitivity showed 100% and 96.9% sensitivity in the training and validation sets, respectively. Principal component analysis revealed that pure GGN distributions were distinct from those of solid nodules, and mixed GGNs had a diffuse distribution. Among differentially expressed miRNAs, miR-500a-3p, miR-501-3p, and miR-502-3p were upregulated in tumor tissues and enhanced overall survival. The SVM classifier accurately distinguished malignant GGNs and benign nodules. The distinct profile characteristics of miRNAs provided insights into the feasibility of EVs miRNAs as prognostic factors in lung cancer.

R-spondin family members as novel biomarkers and prognostic factors in lung cancer.

The R-spondin (RSPO) family of secreted proteins consists of four members that have critical roles in embryonic development and organogenesis. However, the expression patterns and the exact roles of the individual RSPO family members in tumorigenesis and progression of lung cancer are unknown, particularly in non-small cell lung cancer, which accounts for 85% of all lung cancer cases. In the present study, data from the ONCOMINE database was used to compare the RNA expression levels of RSPOs in multiple different types of cancer with normal controls. The expression profiles of RSPOs in various types of cancer cell lines were subsequently compared based on data from the Broad Institute Cancer Cell Line Encyclopedia. Using the Kaplan-Meier plotter, the prognostic value of expression of the different RSPOs members was determined for different pathological subtypes of lung cancer. When compared with normal tissues, expression of RSPO1, RSPO2 and RSPO3 was significantly lower in patients with lung cancer. In the survival analysis, increased mRNA expression levels of RSPO1, RSPO2 and RSPO3 were associated with increased survival in patients with lung adenocarcinomas. These results suggest that RSPO1, RSPO2 and RSPO3 may serve as distinct biomarkers and prognostic factors in patients with lung cancer.

Mucin 21 is a key molecule involved in the incohesive growth pattern in lung adenocarcinoma

Decreased cell adhesion has been reported as a significant negative prognostic factor of lung cancer. However, the molecular mechanisms responsible for the cell incohesiveness in lung cancer have not yet been elucidated in detail. We herein describe a rare histological variant of lung adenocarcinoma consisting almost entirely of individual cancer cells spreading in alveolar spaces in an incohesive pattern. A whole exome analysis of this case showed no genomic abnormalities in CDH1 or other genes encoding cell adhesion molecules. However, whole mRNA sequencing revealed that this case had an extremely high expression level of mucin 21 (MUC21), a mucin molecule that was previously shown to inhibit cell‐cell and cell‐matrix adhesion. The strong membranous expression of MUC21 was found on cancer cells using mAbs recognizing different O‐glycosylated forms of MUC21. An immunohistochemical analysis of an unselected series of lung adenocarcinoma confirmed that the strong membranous expression of MUC21 correlated with incohesiveness. Thus, MUC21 could be a promising biomarker with potential diagnostic and therapeutic applications for lung adenocarcinoma showing cell incohesiveness.

Incidence, prognostic factors, and a nomogram of lung cancer with bone metastasis at initial diagnosis: a population-based study.

Bone is one of the common metastatic sites of lung cancer, and its prognosis is not optimistic. We performed a study to evaluate the incidence, survival, and prognostic factors of lung cancer with bone metastasis (LCBM) at initial diagnosis, and to develop a nomogram to predict its outcomes. We conducted a retrospective study choosing 13,541 patients with LCBM from the Surveillance, Epidemiology, and End Results (SEER) 18 registry database. An X-tile analysis provided the optimal age cutoff point. The incidence, overall survival, and prognosis of bone metastasis were evaluated according to the patient information, characteristics of the tumor, and therapy. We also used multivariable Cox regression to estimate mortality hazard ratios (HRs) among patients with LCBM, while a visual nomogram was established to judge the prognosis. The incidence of disease increased with age, but survival rates show the opposite trend. The median survival time was about 4 months. In addition, although the differences for patient race is not significant (P=0.445), White patients are prone to have bone metastases from lung cancer according to the incidence analysis. The difference for laterality is also not significant (P=0.534), while the factors of age, gender, the total number of sites, histological types, grade, tumor size, and treatment are significantly related to the outcome of patients with LCBM. Furthermore, our nomogram could predict the probability of surviving to the median survival time of the population with a c-index of 0.72. Age, characteristics of the tumor, and therapy should be considered for prediction of prognosis for patients with lung cancer bone metastasis. Putatively, the younger patients and the patients with chemotherapy and surgery may indicate improved survival.

Glucose-Regulated Protein 78 Signaling Regulates Hypoxia-Induced Epithelial-Mesenchymal Transition in A549 Cells.

Objective: Metastasis and therapeutic resistance are the major determinants of lung cancer progression and high mortality. Epithelial–mesenchymal transition (EMT) plays a key role in the metastasis and therapeutic resistance. Highly expressed glucose-regulated protein 78 (GRP78) is a poor prognostic factor in lung cancer and possibly correlated with EMT. This study aims to examine whether the up-regulation of GRP78 is involved in EMT in lung adenocarcinoma and explore the underlying downstream molecular pathways.Study Design: EMT was assessed by analysis of cell morphology and expression of EMT protein markers in A549 cells under normoxia, hypoxia and silencing GRP78 conditions. The expression levels of Smad2/3, Src, and MAPK (p38, ERK, and JNK) proteins were examined by Western blot analysis under hypoxia and treatments with phosphorylation inhibitors.Results: Under hypoxic conditions, the EMT morphology significantly changed and the GRP78 expression was significantly up-regulated in A549 cells compared with those in normoxia control. The expression and phosphorylation levels of smad2/3, Src, p38, ERK, and JNK were also upregulated. When GRP78 was silenced, EMT was inhibited, and the levels of phospho-smad2/3, phospho-Src, phospho-p38, phospho-ERK, and phospho-JNK were suppressed. When the activation of Smad2/3, Src, p38, ERK, and JNK was inhibited, EMT was also inhibited. The inhibition effect on EMT by these phosphorylation inhibitors was found to be weaker than that of GRP78 knockdown.Conclusions: Hypoxia-induced EMT in A549 cells is regulated by GRP78 signaling pathways. GRP78 promotes EMT by activating Smad2/3 and Src/MAPK pathways. Hence, GRP78 might be a potential target for treatment of lung adenocarcinoma.

Erratum: Clinical Characteristics and Prognostic Factors of Lung Cancer in Korea: A Pilot Study of Data from the Korean Nationwide Lung Cancer Registry.

This corrects the article on p. 118 in vol. 82, PMID: 29926550.

Combining data from TCGA and GEO databases and reverse transcription quantitative PCR validation to identify gene prognostic markers in lung cancer.

BackgroundThe aim of this study was to predict and explore the possible mechanism and clinical value of genetic markers in the development of lung cancer with a combined database to screen the prognostic genes of lung cancer.Materials and methodsCommon differential genes in two gene expression chips (GSE3268 and GSE10072 datasets) were investigated by collecting and calculating from Gene Expression Omnibus and The Cancer Genome Atlas databases using R language. Five markers of gene composition (ribonucleotide reductase regulatory subunit M2 [RRM2], trophoblast glycoprotein [TPBG], transmembrane protease serine 4[TMPRFF4], chloride intracellular channel 3 [CLIC3], and WNT inhibitory factor-1 [WIF1]) were found by the stepwise Cox regression function when we further screened combinations of gene models, which were more meaningful for prognosis. By analyzing the correlation between gene markers and clinicopathological parameters of lung cancer and its effect on prognosis, the TPBG gene was selected to analyze differential expression, its possible pathways and functions were predicted using gene set enrichment analysis (GSEA), and its protein interaction network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database; then, quantitative PCR and the Oncomine database were used to verify the expression differences of TPBG in lung cancer cells and tissues.ResultsThe expression levels of five genetic markers were correlated with survival prognosis, and the total survival time of the patients with high expression of the genetic markers was shorter than those with low expression (P<0.001). GSEA showed that these high-expression samples enriched the gene sets of cell adhesion, cytokine receptor interaction pathway, extracellular matrix receptor pathway, adhesion pathway, skeleton protein regulation, cancer pathway and TGF-β pathway.ConclusionThe high expression of five gene constituent markers is a poor prognostic factor in lung cancer and may serve as an effective biomarker for predicting metastasis and prognosis of patients with lung cancer.