BACKGROUND: Currently, lung cancer is one of the malignant tumors with a high morbidity and mortality all over the world. However, the exact mechanisms underlying lung cancer progression remain unclear. The tumor necrosis factor receptor associated factor (TRAF) family members are cytoplasmic adaptor proteins, which function as both adaptor proteins and ubiquitin ligases to regulate diverse receptor signalings, leading to the activation of nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK) and interferon regulatory factor (IRF) signaling. The aim of this study was to investigate the expression of TRAFs in different tissues and cancer types, as well as its mRNA expression, protein expression, prognostic significance and functional enrichment analysis in non-small cell lung cancer (NSCLC), in order to provide new strategies for the diagnosis and treatment of NSCLC. METHODS: RNA sequencing data from the The Genotype-Tissue Expression database was used to analyze the expression patterns of TRAF family members in different human tissues. RNA sequencing data from the Cancer Cell Line Encyclopedia database was used to analyze the expression patterns of TRAF family members in different types of cancer cell lines. RNA sequencing data from the The Cancer Genome Atlas (TCGA) database was used to analyze the mRNA levels of TRAF family members across different types of human cancers. Immunohistochemistry (IHC) analyses from HPA database were used to analyze the TRAF protein levels in NSCLC [lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC)]. Overall survival analysis was performed by Log-rank test using original data from Kaplan-Meier Plotter database to evaluate the correlation between TRAF expressions and prognosis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed on the TRAF family-related genes using RNA sequencing data from the TCGA database for NSCLC. The correlation between the expression levels of TRAF family members and the tumor immune microenvironment was analyzed using the ESTIMATE algorithm based on RNA sequencing data from the TCGA database. RESULTS: The TRAF family members exhibited significant tissue-specific expression heterogeneity. TRAF2, TRAF3, TRAF6 and TRAF7 were widely expressed in most tissues, while the expressions of TRAF1, TRAF4 and TRAF5 were restricted to specific tissues. The expressions of TRAF family members were highly specific among different types of cancer cell lines. In mRNA database of LUAD and LUSC, the expressions of TRAF2, TRAF4, TRAF5 and TRAF7 were significantly upregulated; while TRAF6 did the opposite; moveover, TRAF1 and TRAF3 only displayed a significant upregulation in LUAD and LUSC, respectively. Except for TRAF3, TRAF4 and TRAF7, other TRAF proteins displayed an obviously deeper IHC staining in LUAD and LUSC tissues compared with normal tissues. Additionally, patients with higher expression levels of TRAF2, TRAF4 and TRAF7 had shorter overall survival; while patients with higher expression levels of TRAF3, TRAF5 and TRAF6 had significantly longer overall survival; however, no significant difference had been observed between TRAF1 expression and the overall survival. TRAF family members differentially regulated multiple pathways, including NF-κB, immune response, cell adhesion and RNA splicing. The expression levels of TRAF family members were closely associated with immune cell infiltration and stromal cell content in the tumor immune microenvironment, with varying positive and negative correlations among different members. CONCLUSIONS TRAF family members exhibit highly specific expression differences across different tissues and cancer types. Most TRAF proteins exhibit upregulation at both mRNA and protein levels in NSCLC, whereas, only upregulated expressions of TRAF2, TRAF4 and TRAF7 predict worse prognosis. The TRAF family members regulate processes such as inflammation, immunity, adhesion and splicing, and influence the tumor immune microenvironment.
Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Lung Neoplasms/mortality* ; Prognosis ; Gene Expression Regulation, Neoplastic ; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/metabolism*

BACKGROUND: The purpose of this study is to compare the survival time of non-small cell lung cancer (NSCLC) patients with different organ metastasis. Among all cancers, the morbidity and mortality of lung cancer is the highest worldwide, which may caused by local recurrence and distant metastasis, and the location of metastasis may predict the prognosis of patients. METHODS: A total of 117,542 patients with NSCLC diagnosed between 2010 and 2014 were enrolled from Surveillance, Epidemiology, and End Result (SEER) databases, and the relationship between distant metastasis and survival time was retrospectively analyzed. RESULTS: Of all the 117,542 patients diagnosed with non-small cell lung cancer, 42,071 (35.8%) patients had different degrees of distant metastasis during their medical history, including 26,932 single organ metastases and 15,139 multiple organ metastases, accounting for 64.0% and 36.0% of the metastatic patients respectively. Compared with patients with no metastasis, whose median survival time was 21 months, the median survival time of patients with metastases was 7 months (lung), 6 months (brain), 5 months (bone), 4 months (liver), and 3 months (multiple organ) respectively, and the difference was significant (P<0.001, except liver vs multiple organ P=0.650); Most patients with NSCLC (88.4%) eventually died of lung cancer. CONCLUSIONS Distant metastasis of NSCLC patients indicates poor prognosis. In NSCLC patients with single organ metastasis, the prognosis of lung metastasis is the best, and liver metastasis is the worst, and multiple organ metastasis is worse than single organ metastasis.
Aged ; Aged, 80 and over ; Bone Neoplasms ; mortality ; secondary ; Brain Neoplasms ; mortality ; secondary ; Carcinoma, Non-Small-Cell Lung ; mortality ; pathology ; Female ; Humans ; Liver Neoplasms ; mortality ; secondary ; Lung Neoplasms ; mortality ; pathology ; Male ; Middle Aged ; Neoplasm Metastasis ; Neoplasm Staging ; Prognosis ; Retrospective Studies

BACKGROUND: Currently, there is no consensus on the follow-up strategy (follow-up time interval and content) of non-small cell lung cancer (NSCLC) in the world, and the relevant clinical evidence is also very limited. In this study, we aimed to summarize the recurrence/metastasis sites and timings of stage I NSCLC patients based on their follow-up data, aiming to provide a basis of follow-up time interval and content for this group of patients. METHODS: We retrospectively analyzed the 416 stage I NSCLC patients that underwent continuous anatomic lobectomy between Jan. 2000 to Oct. 2013 in our prospective lung cancer database. According to the recurrence/metastasis sites and timings, the long term follow-up time interval and content were explored. RESULTS: The 5-yr disease free survival (DFS) and overall survival (OS) in the whole group were 82.4% and 85.4%, respectively. There were 76 cases (18.3%) had recurrence/metastasis during follow-up, among which the most frequent site was pulmonary metastasis (21 cases, 5.0%), followed by brain metastasis (20 cases, 4.8%), bone metastasis (12 cases, 2.9%), and mediastinal lymph node metastasis (12 cases, 2.9%). Among the factors that could influence recurrence/metastasis, patients with pT2a suffered from a higher recurrence/metastasis rate compared to patients with pT1 (P=0.006), with 5-yr DFS being 73.8% and 87.3%, respectively (P=0.002), and the 5-yr OS being 77.7% and 90.3%, respectively (P=0.011). CONCLUSIONS The commonest recurrence/metastasis sites of stage I NSCLC after anatomic lobectomy are lung, brain and mediastinal lymph nodes, the risk of recurrence/metastasis within 2 years were equal to that between 3 years and 5 years. The follow-up frequencies and content within 2 years could be adjusted according to T stages.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Non-Small-Cell Lung ; mortality ; pathology ; surgery ; Female ; Follow-Up Studies ; Humans ; Lung Neoplasms ; mortality ; pathology ; surgery ; Lymph Nodes ; surgery ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Staging ; Pneumonectomy ; Prospective Studies ; Retrospective Studies ; Young Adult

BACKGROUND: Recently, the detectable rate of ground-glass opacity (GGO ) was significantly increased, a appropriate diagnosis before clinic treatment tends to be important for patients with GGO lesions. The aim of this study is to validate the ability of the mean computed tomography (m-CT) value to predict tumor invasiveness, and compared with other measurements such as Max CT value, GGO size, solid size of GGO and C/T ratio (consolid/tumor ratio, C/T) to find out the best measurement to predict tumor invasiveness. METHODS: A retrospective study was conducted of 129 patients who recieved lobectomy and were pathological confirmed as atypical adenomatous pyperplasia (AAH) or clinical stage Ia lung cance in our center between January 2012 and December 2013. Of those 129 patients, the number of patients of AAH, AIS, AIS and invasive adenocarcinoma were 43, 26, 17 and 43, respectively. We defined AAH and AIS as noninvasive cancer (NC), MIA and invasive adenocarcinoma were categorized as invasive cancer(IC). We used receiver operating characteristic (ROC) curve analysis to compare the ability to predict tumor invasiveness between m-CT value, consolidation/tumor ratio, tumor size and solid size of tumor. Multiple logistic regression analyses were performed to determine the independent variables for prediction of pathologic more invasive lung cancer. RESULTS: 129 patients were enrolled in our study (59 male and 70 female), the patients were a median age of (62.0±8.6) years (range, 44 to 82 years). The two groups were similar in terms of age, sex, differentiation (P>0.05). ROC curve analysis was performed to determine the appropriate cutoff value and area under the cure (AUC). The cutoff value of solid tumor size, tumor size, C/T ratio, m-CT value and Max CT value were 9.4 mm, 15.3 mm, 47.5%, -469.0 HU and -35.0 HU, respectively. The AUC of those variate were 0.89, 0.79, 0.82, 0.90, 0.85, respectively. When compared the clinical and radiologic data between two groups, we found the IC group was strongly associated with a high m-CT value, high Max CT value, high C/T ratio and large tumor size. Gender, solid tumor size, tumor size, C/T ratio, m-CT value and MaxCT value were selected factor for multivariate analysis, when using the preoperatively determined variables to predict the tumor invasiveness, revealed that tumor size, C/T ratio, m-CT value and Max CT value were independent predictive factors of IC. CONCLUSIONS The musurements of Max CT value, GGO size, solid size of GGO and C/T ratio were significantly correlated with tumor invasiveness, and the evaluation of m-CT value is most useful musurement in predicting more invasive lung cancer.
Adenocarcinoma ; diagnosis ; diagnostic imaging ; mortality ; pathology ; Adult ; Aged ; Female ; Humans ; Lung Neoplasms ; diagnosis ; diagnostic imaging ; mortality ; pathology ; Male ; Middle Aged ; Neoplasm Invasiveness ; Neoplasm Staging ; ROC Curve ; Retrospective Studies ; Tomography, X-Ray Computed ; methods

BACKGROUND: Surgery was not standard-of-care of patients with advanced lung cancer. However, a serial of retrospective studies demonstrated that thoracic dissemination (M1a) patients could benefit from contraindicated surgery. After non-standard treatment, how should these patients choose following treatment approaches? Herein, we conducted this retrospective study to explore subsequent optimal treatment approaches. METHODS: Different therapeutic approaches were evaluated by comparing progression-free survival (PFS), overall survival (OS), time to treatment interval (TTI) using the Kaplan-Meier method and Log-rank test. A Cox proportional hazards regression model was used for multivariate analysis. RESULTS: 141 eligible were enrolled. The median PFS of chemotherapy group, targeted therapy group and observation group were 14.7, 41.0 and 31.0 months, respectively (95%CI: 19.01-26.01; P<0.001). There was no significantly statistically difference between median PFS of targeted group and observation group (P=0.006). The median OS were 39.0, 42.6 and 38.1 months (95%CI: 32.47-45.33; P=0.478). The median PFS and OS of TTI<3 months and TTI ≥3 months were 15.2 months versus 31.0 months (95%CI: 19.01-26.06; P<0.001) and 41.7 months versus 38.7 months (95%CI: 32.47-45.33; P=0.714). Multivariate analyses revealed gender (P=0.027), lymph node status (P=0.036) and initial therapy (P<0.001) were independent prognostic factors for PFS. CONCLUSIONS Observation did not shorten survival of thoracic dissemination patients with lung adenocarcinoma or squamous carcinoma, therefore, it could be an favorable option. But prospective randomized controlled study was needed to confirm its validity.
Adenocarcinoma ; drug therapy ; mortality ; pathology ; surgery ; Adenocarcinoma of Lung ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Carcinoma, Squamous Cell ; drug therapy ; mortality ; pathology ; surgery ; Disease-Free Survival ; Female ; Humans ; Lung Neoplasms ; drug therapy ; mortality ; pathology ; surgery ; Male ; Middle Aged ; Neoplasm Staging ; Retrospective Studies ; Young Adult

BACKGROUND: Small cell lung cancer (SCLC) is highly malignant and prone to bone marrow metastasis in early stage, but its related reports are limited. This study analyzed the clinical feature, laboratory examination, treatment and prognosis of SCLC patients with bone marrow metastasis. METHODS: The clinical data of 26 SCLC patients with bone marrow metastasis were analyzed retrospectively. Prognostic factors were evaluated. RESULTS: The median age of 26 patients was 57 years and the median time from diagnosis of SCLC to confirmed bone marrow metastases was 8 d. Most patients (96.2%) were accompanied by other organ metastases. The most common laboratory abnormalities were elevated lactate dehydrogenase in 19 cases (73.1%), thrombocytopenia and elevated alkaline phosphatase respectively in 11 cases (42.3%) and anemia in 7 cases (26.9%). Twenty patients had received chemotherapy and the remaining 6 patients had not. Of this group, 16 patients received at least 2 cycles of chemotherapy after the diagnosis of bone marrow metastasis. The median survival time was 15.7 wk (0.1 wk-82.9 wk) after diagnosis of bone marrow metastasis. The survival of patients with chemotherapy was significantly better than that of those without chemotherapy (χ²=33.768, P<0.001). Multivariate analysis showed that no chemotherapy was independent poor prognostic factors (P<0.05). CONCLUSIONS The SCLC patients with bone marrow metastasis have short survival, whereas chemotherapy can extend the survival of patients.
Aged ; Bone Marrow ; pathology ; Bone Marrow Neoplasms ; mortality ; pathology ; secondary ; Female ; Humans ; Lung Neoplasms ; pathology ; Male ; Middle Aged ; Neoplasm Metastasis ; Retrospective Studies ; Small Cell Lung Carcinoma ; pathology

Recently, genetic variants in the WNT signaling pathway have been reported to affect the survival outcome of Caucasian patients with early stage non-small cell lung cancer (NSCLC). We therefore attempted to determine whether these same WNT signaling pathway gene variants had similar impacts on the survival outcome of NSCLC patients in a Korean population. A total of 761 patients with stages I-IIIA NSCLC were enrolled in this study. Eight variants of WNT pathway genes were genotyped and their association with overall survival and disease-free survival were analyzed. None of the eight variants were significantly associated with overall survival or disease-free survival. There were no differences in survival outcome after stratifying the subjects according to age, gender, smoking status, and histological type. These results suggest that genetic variants in the WNT signaling pathway may not affect the survival outcome of NSCLC in a Korean population.
Aged ; Asian Continental Ancestry Group/*genetics ; Carcinoma, Non-Small-Cell Lung/*genetics/mortality/pathology ; Demography ; Disease-Free Survival ; Female ; Genotype ; Humans ; Kaplan-Meier Estimate ; Lung Neoplasms/*genetics/mortality/pathology ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Republic of Korea ; Smoking ; Wnt Signaling Pathway/*genetics

Hypoxia-inducible factor-1 alpha (HIF-1α) plays a vital role in the initiation, evaluation and prognosis in lung cancer. The prognostic value of HIF-1α reported in diverse study remains disputable. Accordingly, a meta-analysis was implemented to further understand the prognostic role of HIF-1α in lung cancer. The relationship between HIF-1α and the clinicopathological characteristics and prognosis of lung cancer were investigated by a meta-analysis. PubMed and Embase were searched from their inception to January 2015 for observational studies. Fixed-effects or random-effects meta-analyses were used to calculate odds ratios and 95% confidence intervals of different comparisons. A total of 20 studies met the criteria. The results showed that HIF-1α expression in lung cancer tissues was significantly higher than that in normal lung tissues. Expression of HIF-1α in patients with squamous cell carcinoma was significantly higher than that of patients with adenocarcinomas. Similarly, non-small cell lung cancer (NSCLC) patients had higher HIF-1α expression than small cell lung cancer (SCLC) patients. Moreover, lymph node metastasized tissues had higher HIF-1α expression than non-lymph node metastasized tissues. A high level HIF-1α expression was well correlated with the expression of vascular endothelial growth factor and epidermal growth factor receptor in the NSCLC. Notably, NSCLC or SCLC patients with positive HIF-1α expression in tumor tissues had lower overall survival rate than patients with negative HIF-1α expression. It was suggested that HIF-1α expression may be a prognostic biomarker and a potential therapeutic target for lung cancer.
Adenocarcinoma ; diagnosis ; genetics ; mortality ; pathology ; Biomarkers, Tumor ; genetics ; metabolism ; Carcinoma, Non-Small-Cell Lung ; diagnosis ; genetics ; mortality ; pathology ; Carcinoma, Squamous Cell ; diagnosis ; genetics ; mortality ; pathology ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; genetics ; metabolism ; Lung Neoplasms ; diagnosis ; genetics ; mortality ; pathology ; Lymphatic Metastasis ; Neoplasm Grading ; Neoplasm Staging ; Odds Ratio ; Prognosis ; Receptor, Epidermal Growth Factor ; genetics ; metabolism ; Survival Analysis ; Vascular Endothelial Growth Factor A ; genetics ; metabolism

OBJECTIVEThe aim of this study was to analyze the clinical features and prognostic factors in patients with brain metastasis from colorectal cancer (CRC).

METHODSClinical materials of 45 colorectal cancer patients who developed brain metastasis were collected, and the data and follow-up data of those patients were retrospectively analyzed.

RESULTSMost brain metastases were from rectal cancer (64.4%), and 80.0% of the 45 cases had extracranial metastases. The most common extracranial metastatic site was the lung (57.8%), followed by the liver (35.6%). All the brain metastases in patients with liver metastases were supratentorial, while in contrast, 44.8% of the patients without liver metastasis had subtentorial metastasis, showing a significant difference between them (P<0.05). The interval time from diagnosis of CRC to the development of brain metastases in case of Dukes D stage was 12.0 months, significantly shorter than that in the cases of Dukes A stage (24.0 months), B (36.0 months) and C (29.0 months) (P<0.05). The interval time was also shorter in the patients who developed extracranial metastasis within one year than those more than one year (12.0 months vs. 38.0 months)( P<0.05). The median survival time of patients with brain metastasis from colorectal was 6.0 months, with a 1-year survival rate of 21.1% and 2-year survival rate of 3.3% only. Univariate analysis showed that the median survival of patients with a KPS score of ≥70 was 8.0 months, significantly higher than 2.0 months in those with a KPS score of <70 (P<0.05). The median survival of patients with one or two brain metastases was 8.0 months, significantly higher than 4.0 months of those with >2 brain metastases (P<0.05). The median survival time after diagnosis of brain metastasis was 4.0 months for those who received monotherapy (only steroids, only chemotherapy or only radiotherapy), significantly shorter than 10.0 months of patients who received chemoradiotherapy, and 12.0 months of those who underwent surgery (P<0.05). Comparing each two differently treated groups, the survival time of surgery combined with chemotherapy or radiotherapy group was significantly different from that of all of other groups (P<0.05). The median survival time of chemoradiotherapy group was longer than that of monotherapy, but the difference was not significant (P>0.05). Multivariate analysis showed that brain metastases >2 and treatment modality type are independent prognostic factors for survival.

CONCLUSIONSPatients initially diagnosed with a Dukes D stage primary colorectal tumor and occurrence of extracranial metastasis (especially, pulmonary metastasis) within one year are associated to an increased risk of brain metastases and have a shorter survival time. Most brain metastases in patients with liver metastases are supratentorial, while many patients without liver metastasis have subtentorial metastasis. Brain metastases >2 and the type of treatment modality are independent prognostic factors for survival. The prognosis of patients who received chemoradiotherapy is better than those treated only with chemotherapy or radiotherapy. Some subsets of patients may benefit from surgery plus chemotherapy/radiotherapy.

Brain Neoplasms ; mortality ; secondary ; therapy ; Chemoradiotherapy ; Colorectal Neoplasms ; Humans ; Liver Neoplasms ; secondary ; Lung Neoplasms ; secondary ; Neoplasm Staging ; Prognosis ; Rectal Neoplasms ; pathology ; Retrospective Studies ; Survival Rate ; Time Factors

PURPOSE: Patients with non-small cell lung cancer (NSCLC) and simultaneously having brain metastases at the initial diagnosis, presenting symptoms related brain metastasis, survived shorter duration and showed poor quality of life. We analyzed our experiences on surgical treatment of brain metastasis in patients with NSCLC. MATERIALS AND METHODS: We performed a single-center, retrospective review of 36 patients with NSCLC and synchronous brain metastases between April 2006 and December 2011. Patients were categorized according to the presence of neurological symptoms and having a brain surgery. As a result, 14 patients did not show neurological symptoms and 22 patients presented neurological symptoms. Symptomatic 22 patients were divided into two groups according to undergoing brain surgery (neurosurgery group; n=11, non-neurosurgery group; n=11). We analyzed overall surgery (OS), intracranial progression-free survival (PFS), and quality of life. RESULTS: Survival analysis showed there was no difference between patients with neurosurgery (OS, 12.1 months) and non-neurosurgery (OS, 10.2 months; p=0.550). Likewise for intracranial PFS, there was no significant difference between patients with neurosurgery (PFS, 6.3 months) and non-neurosurgery (PFS, 5.3 months; p=0.666). Reliable neurological one month follow up by the Medical Research Council neurological function evaluation scale were performed in symptomatic 22 patients. The scale improved in eight (73%) patients in the neurosurgery group, but only in three (27%) patients in the non-neurosurgery group (p=0.0495). CONCLUSION: Patients with NSCLC and synchronous brain metastases, presenting neurological symptoms showed no survival benefit from neurosurgical resection, although quality of life was improved due to early control of neurological symptoms.
Adult ; Aged ; Aged, 80 and over ; Brain Neoplasms/physiopathology/*secondary/*surgery ; Carcinoma, Non-Small-Cell Lung/mortality/*pathology ; Demography ; Disease-Free Survival ; Female ; Follow-Up Studies ; Humans ; Kaplan-Meier Estimate ; Lung Neoplasms/*pathology ; Male ; Middle Aged ; Treatment Outcome