Overexpression of FADD and Bcl-XS proteins as novel prognostic biomarkers for surgically resected non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most widespread cancer with increasing morbidity and mortality. FAS-associated protein with death domain (FADD) is considered as an essential instrument in cell death, whereas Bcl-XS promotes apoptosis through inhibiting the activity of Bcl-2 and Bcl-XL. OBJECTIVE AND METHODS: We detected the expression of FADD and Bcl-XS in resected NSCLC tissues by immunohistochemistry, and investigated their association with clinicopathological characteristics and prognostic significance of NSCLC patients. RESULTS: Bcl-XS expression was significantly increased in well and moderate differentiated lung SCC (P= 0.004). Lung ADC patients with overexpression of FADD and lung SCC patients with low expression of Bcl-XS had importantly lower overall survival rates by Kaplan-Meier analysis (P= 0.033, P= 0.02, respectively). Multivariate analysis confirmed that elevated expression of FADD was an independent poor prognostic factor for patients with surgically resected lung ADC (P= 0.027) and increased expression of Bcl-XS was an independent good prognostic factor for patients with surgically resected lung SCC (P= 0.016)CONCLUSION: Elevated expression of FADD was identified as independent poor prognostic factor for patients with surgically resected lung ADC, however, increased expression of Bcl-XS was an independent good prognostic biomarker for patients with surgically resected lung SCC.

Multiple Primary Lung Cancers: A New Challenge in the Era of Precision Medicine.

With the widespread implementation of lung cancer screening, more and more patients are being diagnosed with multiple primary lung cancers (MPLCs). In the era of precision medicine, many controversies remain in differentiating MPLCs from intrapulmonary metastasis and the optimum treatment choice, especially in patients exhibiting similar histology. In this review, we summarize common diagnostic criteria and novel discrimination methods with a special emphasis on the emerging value of broad panel next-generation sequencing (NGS) for the diagnosis of MPLCs. We then discuss current advances regarding therapeutic approaches for MPLCs. Radical surgery is the main treatment modality, while stereotactic body radiotherapy (SBRT) is safe and feasible for early-stage MPLC patients with inoperable tumors. In addition, immunotherapy and targeted therapy, particularly epidermal growth factor receptor-tyrosine kinase inhibitors, are emerging therapeutic strategies that are still in their infancy. Characteristics of both genomic profiles and tumor microenvironment are currently being evaluated but warrant further exploration to facilitate the application of targeted systematic therapies in MPLC patients.

Elevated HSP90 associates with expression of HIF-1α and p-AKT and is predictive of poor prognosis in nasopharyngeal carcinoma.

AIMS: HSP90, as a molecular chaperone, has numerous substrate proteins, including HIF-1α and p-AKT, but the relationships among HSP90, HIF-1α and p-AKT have not been investigated in NPC. We examined and analysed the correlation between expression of HSP90, HIF-1α and p-AKT and clinicopathological features of NPC. METHODS: We collected 445 cases of NPC and 54 cases of non-cancerous nasopharyngeal epithelia tissues, detected expression of HSP90, HIF-1α and p-AKT proteins in these tissues by immunohistochemistry. RESULTS: The results indicated that overexpression of HSP90, HIF-1α and p-AKT in NPC was significantly higher than that in non-cancerous nasopharyngeal epithelia (P < 0.05). The overexpression of HIF-1α in primary NPC was significantly lower than that in matched lymph node metastatic NPC (P = 0.024) or recurrent NPC (P = 0.039). The overexpression of HSP90 (P < 0.001) and HIF-1α (P = 0.031) was evidently higher in late stage NPC. NPC patients with lymph node metastasis (LNM) had a higher overexpression rate of HSP90 (P < 0.001) than those without LNM. Increased HSP90 expression was positively associated with HIF-1α expression (r = 0.367, P < 0.001) and p-AKT (r = 0.142, P = 0.003) expression in NPC. Furthermore, HIF-1α was also related to p-AKT expression (r = 0.114, P = 0.017). The overall survival rate for NPC patients with up-regulated HSP90 was significantly lower than those with down-regulated HSP90 (P < 0.001), as was found with raised HIF-1α (P = 0.036) and increased p-AKT (P = 0.044). Multivariate Cox regression analysis further identified that HSP90 and HIF-1α were independent poor prognostic factors for NPC. CONCLUSIONS: Taken together, elevated HSP90 was associated with expression of HIF-1α and p-AKT in NPC. Furthermore, high expression of HSP90 and HIF-1α could be used as a novel independent poor prognostic biomarker for patients with NPC.

4EGI-1 induces apoptosis and enhances radiotherapy sensitivity in nasopharyngeal carcinoma cells via DR5 induction on 4E-BP1 dephosphorylation.

The eIF4F complex regulated by a various group of eIF4E-binding proteins (4E-BPs) can initial the protein synthesis. Small molecule compound 4EGI-1, an inhibitor of the cap-dependent translation initiation through disturbing the interaction between eIF4E and eIF4G which are main elements of the eIF4E complex, has been reported to suppress cell proliferation by inducing apoptosis in many types of cancer. And death receptor 5 (DR5) is a major component in the extrinsic apoptotic pathway. However, the correlation among 4EGI-1, DR5 and 4E-BPs have not been discovered in NPC now. Therefore, we intend to find out the effect of 4EGI-1 on the apoptosis process of NPC and the relationship among 4EGI-1, DR5 and 4E-BPs. Our results revealed a significant down regulation of DR5 expression in NPC tissues, which inversely correlated with lymph node metastasis status and clinical stages. Depressed DR5 expression was an independent biomarker for poor prognosis in NPC, and elevated DR5 expression showed longer overall survival time in 174 NPC patients. Besides, 4EGI-1 induced apoptosis in NPC cells through the DR5-caspase-8 axis on 4E-BP1 and eIF4E dephosphorylation exerting positive influence on their anti-tumor activities. The induction of DR5 also sensitized NPC cells to radiotherapy, and the SER was 1.195. These results establish the death receptor pathway as a novel anticancer mechanism of eIF4E/eIF4G interaction inhibitor in NPC.

Epidermal growth factor receptor mutation heterogeneity analysis of pulmonary sarcomatoid carcinoma successfully treated with erlotinib: A case report.

Pulmonary sarcomatoid carcinoma (PSC) is a rare histological subtype of non-small cell lung cancer, and the available studies on the response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is limited. In the present study, a 73-year-old female presented with a large mass in the lower right lung, which was diagnosed as a PSC on biopsy. An amplification-refractory mutation system (ARMS) test revealed that the patient possessed the wild-type EGFR gene, and the patient subsequently underwent radiotherapy (60 Gy) and four 21-day cycles of chemoradiotherapy (1,600 mg gemcitabine, days 1 and 8; 30 mg, cisplatin, days 1-3). Following radiotherapy and chemotherapy treatment, a CT scan revealed complete remission of the mass in the lower right lung, however, metastases were identified in the paraaortic lymph node, bilateral iliac fossa and the right gluteal region. Notably, an EGFR exon 21 L858R gene mutation was identified in the mass of the right gluteal metastasis. Therefore, treatment with erlotinib was initiated. The patient continued to experience progression-free survival for six months following the initiation of erlotinib therapy. However, multiple metastases were then identified, and all lesions possessed the wild-type EGFR gene, as identified by the ARMS test. The findings suggest that erlotinib is a viable therapeutic option for the treatment of PSC patients that possess an EGFR mutation. The spatio-temporal evolution of EGFR mutational heterogeneity in PSC may result in drug-resistance, which challenges EGFR-TKI therapy and EGFR gene mutation diagnosis.

Flot-2 Expression Correlates with EGFR Levels and Poor Prognosis in Surgically Resected Non-Small Cell Lung Cancer.

We previously reported that expression of Flotillin 2 (Flot-2), a protein isolated from caveolae/lipid raft domains, increased significantly in nasopharyngeal carcinoma (NPC) compared with normal tissues. Signal transduction through epidermal growth factor receptors (EGFR) and Flot-2 play an important role in cancer development, but their precise role in lung cancer has not been investigated. In this study, we have investigated the correlation between the expression of Flot-2 and EGFR, which increase significantly in non-small cell lung cancer (NSCLC) patients (n=352) compared with non-cancer tissues. Additionally, patients with advanced stages of NSCLC had higher positive expression of Flot-2 and EGFR than patients with early stages. NSCLC patients with increased expression of Flot-2 and EGFR had significantly less overall survival rates than patients with less expression of Flot-2 and EGFR. Taken together, our data suggest that increased expression of Flot-2 and EGFR in NSCLC patients is inversely proportional to the disease prognosis and that increased expression of Flot-2 associated with increased EGFR may serve as a biomarker to predict poor disease prognosis.

Effect of radiotherapy on moderate and severe thyroid associated ophthalmopathy: a double blind and self-controlled study.

OBJECTIVE: The effect of radiotherapy on moderate and severe Thyroid associated ophthalmopathy (TAO) was evaluated by various objective and quantitative indexes including T2 signal intensity ratios of orbital MRI inferior rectus and ipsilateral temporal muscle (T2SIR), extraocular muscles (EOM) volume, and the degree of exophthalmos using clinical research with prospective, randomized, double blind, self controlled. METHODS: The patients with TAO who in the moderate and severe active period and had similar double eyes condition in the Outpatient Department of Ophthalmology of Xiangya No. 2 Hospital of Central South University from 2011.2 to 2014.2 were selected as objects in this study. The related body check was finished after the research group was built. For the object, one eye of patient having random radiotherapy was chosen as the experimental eye. The other eye in the same patient with pseudo radiotherapy (merely known by operator, doctors in department of ophthalmology and patients were double blind) was selected as the control eye. The radiotherapy plan was made by the operator according to the CT results. The T2 signal intensity ratios of orbital MRI inferior rectus and ipsilateral temporal muscle (T2SIR), extraocular muscles (EOM) volume, and the exophthalmos degree was compared by MRI check to evaluate the effect of radiotherapy. RESULTS: The T2 signal intensity ratios of orbital MRI inferior rectus and ipsilateral temporal muscle (T2SIR), extraocular muscles (EOM) volume, and the exophthalmos degree between both eyes (experimental and control eyes) had significant differences and these data had statistical significance. CONCLUSIONS: The treatment of radiotherapy is effective for the TAO in the moderate and severe active period.

Fatty acid synthase-associated protein with death domain: a prognostic factor for survival in patients with nasopharyngeal carcinoma.

Fatty acid synthase-associated protein with death domain (FADD) is a key adaptor protein that bridges a death receptor (eg, death receptor 5) to caspase 8 to form the death-inducing signaling complex during apoptosis. The expression and prognostic impact of FADD in nasopharyngeal carcinoma (NPC) have not been well studied. This study focused on detecting FADD expression and analyzing its prognostic impact on NPC. FADD expression was assessed on pretreatment tumor tissues of 248 cases of NPC patients and 76 cases of noncancerous nasopharyngeal control tissue. The results showed that the positive percentage of FADD expression in NPC (63.7%, 158/248) was significantly higher than that in the noncancerous nasopharyngeal control tissues (28.9%, 22/76) (P < .0001). The positive expression of FADD in the NPC with cervical lymph node metastasis was significantly higher than those without lymph node metastasis (P = .009). Furthermore, FADD expression was more pronouncedly increased in metastatic NPC than the matched primary NPC tissues (P = .017). Both univariate and multivariate survival analysis indicated that increased FADD expression was significantly correlated inversely with overall survival in NPC patients (P = .003 and P = .007, respectively). Taken together, high expression of FADD may be an independent biomarker for poor prognosis in NPC.

Increased expression of IRS-1 is associated with lymph node metastasis in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southeast Asia, especially in Southern China, which is with characteristics of early cervical lymph node metastasis and high incidence rate of distant metastasis. Insulin receptor substrate 1 (IRS-1) is a signaling adapter protein that is encoded by the IRS-1 gene in humans, plays an important role in the development, progression, invasion and metastasis of tumors. The aim of the present study was to investigate the association between the expression of IRS-1 protein and clinicopathological characteristics in NPC by immunohistochemistry. The results showed that the expression level of IRS-1 was significant higher in NPC than that in the control nasopharyngeal epithelia (P = 0.042). The positive percentage of IRS-1 expression in NPC with lymph node metastasis was also significantly higher than those without lymph node metastasis (P = 0.008). Positive expression of IRS-1 was proved to be the independent predicted factor for lymph node metastasis of NPC (P = 0.025) regardless of age, gender, histological type and clinical stages by multivariate logistic regression analysis. In addition, results showed higher sensitivity and agreement rate of IRS-1 for predicting lymph node metastasis of NPC patients. Taken together, high expression of IRS-1 might be closely correlated with lymph node metastasis in NPC and positive expression of IRS-1 could be used as an independent biomarker for predicting lymph node metastasis of NPC.

Activation of Akt/mTOR pathway is associated with poor prognosis of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck region, which frequently occurs in Southeast Asia, especially in the south of China. It is known that the mammalian target of rapamycin (mTOR) pathway plays a central role in regulating cellular functions, including proliferation, growth, survival, mobility, and angiogenesis. Aberrant expression of the mTOR signaling pathway molecules has been found in many types of cancer. However, whether the alterations of p-Akt, p-p70S6K and p-4EBP1 protein expression are associated with clinicopathological features and prognostic implications in NPC have not been reported. The purposes of the present study are to investigate the association between the expression of p-Akt, p-p70S6K and p-4EBP1 proteins and clinicopathological features in NPC by immunohistochemistry. The results showed that the positive percentage of p-Akt, p-p70S6K and p-4EBP1 proteins expression in NPC (47.2%, 73.0% and 61.7%, respectively) was significantly higher than that in the non-cancerous nasopharyngeal control tissue (33.3%, 59.1% and 47.0%, respectively). There was a significantly higher positive expression of p-Akt in undifferentiated non-keratinizing nasopharyngeal carcinoma than that in differentiated non-keratinizing nasopharyngeal carcinoma (P = 0.014). Additionally, positive expression of p-p70S6K and p-4EBP1 proteins, and positive expression of either of p-Akt, p-p70S6K and p-4EBP1 were significantly correlated inversely with overall survival rates of NPC patients (P = 0.023, P = 0.033, P = 0.008, respectively). Spearman's rank correlation test showed that expression of p-Akt in NPC was significantly associated with expression of p-p70S6K (r = 0.263, P<0.001) and p-4EBP1(r = 0.284, P<0.001). Also there was an obviously positive association between expression of p-p70S6K and p-4EBP1 proteins in NPC (r = 0.286, P<0.001). Multivariate Cox regression analysis further identified positive expression of p-4EBP1 and p-p70S6K proteins were the independent poor prognostic factors for NPC (P = 0.043, P = 0.027, respectively). Taken together, high expression of p-p70S6K and p-4EBP1 proteins may act as valuable independent biomarkers to predict a poor prognosis of NPC.

Increased expression of flotillin-2 protein as a novel biomarker for lymph node metastasis in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southeast Asia, especially in Southern China. Flotillin-2 (Flot-2) is not only an important component of cellular membrane, but also involves in various cellular processes such as membrane trafficking, T cell and B cell activation, regulation of several signaling pathways associated with cell growth and malignant transformation, keeping structure and junction of epidermal cells and formation of filopodia. Although such molecular effects of Flot-2 have been reported, whether the expression of Flot-2 protein is associated with clinicopathologic implication for NPC has not been reported. The purpose of this research is to investigate the expression of Flot-2 protein in NPC and control nasopharyngeal epithelial tissues by immunohistochemistry and elucidate the association between the expression of Flot-2 protein and clinicopathological characteristics of NPC. The results showed that the positive percentage of Flot-2 expression in the NPC, nasopharyngeal epithelia with atypical hyperplasia and in the control nasopharyngeal mucosa epithelia was 88.8% (119/134), 76.9% (10/13) and 5.7% (5/88), respectively. There was significantly higher expression of Flot-2 protein in NPC and nasopharyngeal epithelia with atypical hyperplasia compared to the control nasopharyngeal mucosa epithelia (P<0.001, respectively). The positive percentage of Flot-2 protein expression in NPC patients with lymph node metastasis was significantly higher than those without lymph node metastasis. Increasing of Flot-2 expression was obviously correlated with clinical stages of NPC patients. The expression of Flot-2 was proved to be the independent predicted factor for lymph node metastasis by multivariate analysis. The sensitivity of Flot-2 for predicting lymph node metastasis of NPC patients was 93%. Taken together, our results suggest that the increased expression of Flot-2 protein is a novel higher sensitivity biomarker that can predict lymph node metastases in NPC.

Phosphorylated Mnk1 and eIF4E are associated with lymph node metastasis and poor prognosis of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southeast Asia, especially in Southern China. The phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) by MAP kinase-interacting kinases (Mnk) on Ser-209 promotes cellular proliferation, survival, malignant transformation and metastasis. However, whether the alterations of the expression of p-eIF4E and p-Mnk1 protein are associated with clinicopathologic/prognostic implication for NPC has not been reported. The purposes of the present study are to examine the expression of p-eIF4E and p-Mnk1 protein in NPC and non-cancerous nasopharyngeal epithelial tissues by immunohistochemistry and evaluate the association between the expression of p-eIF4E and p-Mnk1 protein and clinicopathological characteristics of NPC. The results showed that the positive percentage of p-Mnk1 and p-eIF4E proteins expression in NPC (83.5% and 75.4%, respectively) was significantly higher than that in non-cancerous nasopharyngeal epithelium (40.0% and 32.9%, respectively). The positive expression of p-eIF4E and p-Mnk1 in the NPC with cervical lymph node metastasis was significantly higher than those without lymph node metastasis. Additionally, p-eIF4E expression was more pronouncedly increased in metastatic NPC than the matched primary NPC. Increase of p-eIF4E and p-Mnk1 expression was significantly correlated inversely with overall survival. Spearman's rank correlation test further showed that expression of p-Mnk1 was strongly positive correlated with expression of p-eIF4E in NPC. The expression of p-Mnk1 and p-eIF4E in NPC was proved to be the independent prognostic factors regardless of lymph node metastasis, clinical stages and combination of radiotherapy and chemotherapy, histological type, age and gender by multivariate analysis. Taken together, high expression of p-Mnk1 and p-eIF4E might be novel valuable biomarkers to predict poor prognosis of NPC and therapeutic targets for developing the valid treatment strategies.

Aberrant expression of ß-catenin and E-cadherin is correlated with poor prognosis of nasopharyngeal cancer.

Nasopharyngeal carcinoma has a high incidence in southern China. The Wnt/ß-catenin signaling pathway plays a major role in cancer development and progression. Our current study aims to determine the clinical significance of the Wnt/ß-catenin pathway components such as ß-catenin, cyclooxygenase 2, cyclin D1, c-Myc, and E-cadherin in 148 nasopharyngeal carcinomas by immunohistochemistry. We found that nasopharyngeal carcinoma stage T3+T4 had significantly higher expression of ß-catenin, cyclooxygenase 2, cyclin D1, and c-Myc and lower expression of E-cadherin than nasopharyngeal carcinoma stage T1+T2 (P < .001, P < .05, respectively).There was significantly higher expression of ß-catenin (P = .001) and cyclooxygenase 2 (P = .003) and lower expression of E-cadherin (P = .001) in nasopharyngeal carcinoma with lymph node metastasis than in nasopharyngeal carcinoma without lymph node metastasis. The expression of ß-catenin in nasopharyngeal carcinoma was positively correlated with cyclooxygenase 2 (r = 0.458, P < .0001), cyclin D1 (r = 0.700, P < .0001), and c-Myc expression (r = 0.144, P = .006) but negatively correlated with E-cadherin expression (r = -0.601, P < .0001), respectively. The univariate analysis confirmed that overexpression of ß-catenin and cyclooxygenase 2 and decreased expression of E-cadherin were significantly correlated with disease-free survival (P < .01, P < .05, respectively). Overexpression of ß-catenin and cyclooxygenase 2 and reduced expression of E-cadherin significantly correlated with a poor prognosis (P = .005, P = .044, P = .019, respectively) by Kaplan-Meier survival curves and the log-rank test. Multivariate analysis indicated that high expression of ß-catenin and decreased expression of E-cadherin were independent prognostic factors (P = .002, P = .011, respectively) regardless of TNM stage and lymph node status. In conclusion, the aberrant high expression of ß-catenin and decreased expression of E-cadherin is associated with poor prognosis in nasopharyngeal carcinoma.

[Methylation status of RASSF1A and clinical efficacy of neoadjuvant therapy in patients with advanced epithelial ovarian cancer].

OBJECTIVE: To explore the relation between methylation status of RAS association domain family 1A (RASSF1A) in patients with advanced epithelial ovarian cancer and the clinical efficacy of cisplatin based neoadjuvant therapy. METHODS: Forty patients with advanced epithelial ovarian cancer were selected and the methylation status of RASSF1A was evaluated by methylation specific PCR (MSP). The clinical efficacy was compared between patients with different methylation statuses of RASSF1A. RESULTS: The response rate of 15 patients with methylation status in the promoter region was 26.6% and that of 25 patients without methylation status was 48.0%, with significant difference (P<0.05). CONCLUSION: The methylation status of RASSF1A can influence the clinical efficacy of neoadjuvant therapy in patients with advanced epithelial ovarian cancer.

[Expression profile of heat shock proteins in tissues and cells of lung adenocarcinoma].

OBJECTIVE: To observe the expression profile of heat shock proteins (HSPs) including HSP70, inducible HSP90 (HSP86) and aB-crystallin in cells and tissues of lung adenocarcinoma. METHODS: Western blotting and reverse transcriptional-polymerase chain reaction (RT-PCR) were performed to detect the expression of HSP70, HSP86 and aB-crystallin both in the protein and mRNA level respectively. RESULTS: Compared with normal lung tissue and human bronchial epithelium (HBE) cells, RT-PCR and Western blotting showed that the expression of HSP70, HSP86 and alphaB crystallin increased significantly in both the mRNA and protein level in the cancer tissue and A549 human lung adenocarcinoma cells. Among the 3 sub-families of HSPs, the expression of HSP70 mRNA and protein increased most in both the lung tissue of cancer and A549 human adenocarcinoma cell lines. CONCLUSION: The expression of HSPs is higher in the lung adenocarcinoma and A549 cells than that in the normal lung tissues and HBE cells. Among the HSP family, HSP70 is the most up-regulated member in the tissue and cells of lung adenocarcinoma.

[Therapeutic effect of whole body hyperthermia combined with chemotherapy in patients with advanced cancer].

OBJECTIVE: To determine the short-term efficacy and security of whole body hyperthermia (WBH) combined with chemotherapy for advanced cancer. METHODS: Different chemotherapy regimens were applied in 138 patients with advanced cancer. Among them, 68 patients (Group A) didn't receive any other therapies. The other 70 patients (Group B) received WBH together with chemotherapy. WBH was maintained at 40 degrees C approximately 42 degrees C for 50 approximately 60 min (once or twice every week and 4 times a cycle). RESULTS: In Group A, the rate of complete remission (CR) was 2.9%, partial remission (PR) was 36.8%, stable disease was 35.3%, progressive disease was 25.0%, the overall response rate (CR + PR) was 39.7%; while in Group B, the corresponding figures were 5.7%, 52.9%, 25.7%, 25.0%, and 58.6%, respectively. There was significant difference between the two groups (P < 0.05). The rates of III + IV gastrointestinal tract andmyelosuppression toxicities were 26.5% and 16.2% in Group A, while 27.1% and 18.6% in Group B. No significant difference was found. CONCLUSION: WBH combined with chemotherapy is efficient and safe for advanced cancer, and is worth generalizing extensively.