The Analysis of Erlotinib on Brain Metastases in Patients with Non-small-cell Lung Cancer

Background and objective Brain metastases are common in non-small-cell lung cancer (NSCLC) and the prognosis is poor. Erlotinib is a specific inhibitor of the epidermal growth factor receptor-associated tyrosine kinase (EGFRTKI), which has been gradually used in the treatment for advanced NSCLC. The aim of this study is to evaluate the antitumor efficacy and its relevant factors of erlotinib in NSCLC patients with brain metastases. Methods The clinical data of 30 NSCLC patients with brain metastases were reviewed retrospectively. All of them were treated with erlotinib, given orally 150mg daily. These patients discontinued administration of erlotinib until disease progression, death or intolerable side effects. Results In terms of intracranial lesions, partial response (PR) was observed in 2 patients (6.7%), with stable disease (SD) in 17 patients (56.7%), for overall disease control rate (DCR) of 63.4%. As for systemic disease, PR was observed in 2 patients (6.7%), with SD in 5 patients (16.7%), for overall DCR of 23.4%. There was no statistical difference in DCR among different subtypes of age, gender, smoking history, histology, PS score, the number of brain metastases, the onset of brain metastases, chemotherapy, brain radiotherapy and side effects. The median time to disease progression (MTTP) and median survival time (MST) was 2.4 months and 7.7 months respectively. The 1 and 2 year survival rate was 38.4% and 15.2%. The univariate analysis showed that the survival time was related to the patients’ PS score, smoking history, brain radiotherapy and chemotherapy. The multivariate analysis indicated that brain radiotherapy was the independent prognostic factor and the relationship between the survival time and smoking history was near to statistical significance. Conclusion The patients receiving brain radiotherapy may have better survival benefit. Non-smokers have a trend to survive longer than smokers. Erlotinib may be effective on brain metastases in NSCLC patients and appears to be a possible new treatment option

Survival Analysis of 1,742 Patients with Stage IV Non-small Cell Lung Cancer

Background and objective At present non-small cell lung cancer (NSCLC) is still the leading cause of death induced by cancer. The aim of this study is to investigate the prognostic factors of advanced NSCLC. Methods Total 1,742 cases of stage IV NSCLC data from Jan 4, 2000 to Dec 25, 2008 in Shanghai Chest Hospital were collected, confirmed by pathological examinations. Analysis was made to observe the impact of treatment on prognosis in gender, age, smoking history, pathology, classification, clinical TNM stage. Survival rate, survival difference were evaluated by Kaplan-Meire method and Logrank test respectively. The prognosis were analyzed by Cox multivariate regression. Results The median survival time of 1,742 patients was 10.0 months (9.5 months-10.5 months). One, two, three, four, and five-year survival rates were 44%, 22%, 13%, 9%, 6% respectively. The median survivals of single or multiple metastasis were 11 months vs 7 months (P < 0.001). Survival time were different in metastasic organs, with the median survival time as follows: lung for about 12 months (11.0 months-12.9 months), bone for 9 months (8.3 months-9.6 months), brain for 8 months (6.8 months-9.1 months), liver, adrenal gland, distannt lymph node metastasis for 5 months (3.8 months-6.1 months), and subcutaneous for 3 months (1.7 months-4.3 months). The median survival times of adenocarcinoma (n=1,086, 62%) and squamous cell carcinoma cases (n=305, 17.5%) were 12 months vs 8 months (P < 0.001). The median survival time of chemotherapy and best supportive care were 11 months vs 6 months (P < 0.001); the median survival times of with and without radiotherapy were 11 months vs 9 months (P=0.017). Conclusion Gender, age, gross type, pathological type, clinical T stage, N stage, numbers of metastatic organ, smoking history, treatment of advanced non-small cell lung cancer were independent prognostic factors

Correlations between IGF-IR Expression and Clinicopathological Factors and Prognosis in Patients with Lung Adenocarcinoma

Background and objective The incidence of lung adenocarcinoma increases rapidly, and IGF-IR is the key mediator of several growth factors signal transduction, therefore it plays an important role in the proliferation and differentiation of cancer cell. The aim of this study is to detect the expression of IGF-IR in lung adenocarcinoma and to evaluate its implication for the clinicopathological factors and prognosis of patients with this disease. Methods The IGF-IR expression was detected by immunohistochemical staining. Correlations between IGF-IR expression with clinicopathological factors were analyzed using the Chi-squared test. The Kaplan-Meier method was used to calculate the overall patient survival rate, and the difference in survival curves was evaluated using a Log-rank test. Univariate and multivariate analysis was carried out using the Cox proportional-hazard model. Results In 126 cases of tumor sections tested, IGF-IR were detected in 89 cases. Statistical analysis revealed that the IGF-IR expression was related to tumor size and T stage, while there were no relations between IGFIR expression and age, gender, smoking, pathological stages, and differentiation. Cox analysis indicated that metastasis and chemotherapy efficacy were the prognostic factors in these patients, while IGF-IR expression was not the independent prognostic factor. Conclusion The IGF-IR expression is related to tumor size and T stage, while there is no relation between IGF-IR expression and prognosis

Clinical Observation of Erlotinib in the Treatment of Advanced Non-small Cell Lung Cancer: A Report of 92 Eases

Background and objective Erlotinib, a selective inhibitor of epidermal growth factor receptor tyrosine kinase, has been approved effective in local advanced or metastatic non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the efficacy and safety of erlotinib for the treatment of advanced NSCLC. Methods Ninety-two patients with advanced NSCLC who had failed or not tolerated or refused chemotherapy received 150 mg oral doses of erlotinib once daily until the disease progression or intolerable toxicity. Results Among the 92 NSCLC patients, 2 patient got complete response (2.2%), 22 partial response (23.9%), 48 stable disease (52.2%) and 20 progressive disease (21.7%). The overall response rate and the disease controlled rate of erlotinib was 26.1% (24/92) and 78.3% (72/92), respectively. The response rate of erlotinib were significantly higher in rash and ECOG 0-1 than no rash and ECOG ≥ 2. The disease controlled rate of erlotinib was significantly higher in female and non-smokers than male and smokers (P < 0.05). The response rate of erlotinib did not show significant differences within pathological type or previous treatment. The most common side effects were rash and diarrhea with 84.8% and 31.5%, respectively, but usually were mild. Conclusion Erlotinib is effective and safe in the treatment of advanced NSCLC patients

The Value of Autofluorescence Bronchoscopy Combined with White Light Bronchoscopy Compared with White Light Alone in the Diagnosis of Intraepithelial Neoplasia and Invasive Lung Cancer: A Meta-Analysis

ObjectiveTo compare the accuracy of autofluorescence bronchoscopy (AFB) combined with white light bronchoscopy (WLB) versus WLB alone in the diagnosis of lung cancer.MethodsThe Ovid, PubMed, and Google Scholar databases from January 1990 to October 2010 were searched. Two reviewers independently assessed the quality of the trials and extracted data. The relative risk for sensitivity and specificity on a per-lesion basis of AFB + WLB versus WLB alone to detect intraepithelial neoplasia and invasive cancer were pooled by Review Manager.ResultsTwenty-one studies involving 3266 patients were ultimately analyzed. The pool relative sensitivity on a per-lesion basis of AFB + WLB versus WLB alone to detect intraepithelial neoplasia and invasive cancer was 2.04 (95% confidence interval [CI] 1.72–2.42) and 1.15 (95% CI 1.05–1.26), respectively. The pool relative specificity on a per-lesion basis of AFB + WLB versus WLB alone was 0.65 (95% CI 0.59–0.73).ConclusionsAlthough the specificity of AFB + WLB is lower than WLB alone, AFB + WLB seems to significantly improve the sensitivity to detect intraepithelial neoplasia. However, this advantage over WLB alone seems much less in detecting invasive lung cancer

Epithelial Neoplasia Coincides with Exacerbated Injury and Fibrotic Response in the Lungs of \u3cem\u3eGprc5a\u3c/em\u3e-Knockout Mice Following Silica Exposure

Exposure to crystalline silica is suggested to increase the risk for a variety of lung diseases, including fibrosis and lung cancer. However, epidemiological evidences for the exposure-risk relationship are ambiguous and conflicting, and experimental study from a reliable animal model to explore the relationship is lacking. We reasoned that a mouse model that is sensitive to both lung injury and tumorigenesis would be appropriate to evaluate the exposure-risk relationship. Previously, we showed that, Gprc5a-/- mice are susceptible to both lung tumorigenesis and endotoxin-induced acute lung injury. In this study, we investigated the biological consequences in Gprc5a-/- mouse model following silica exposure. Intra-tracheal administration of fine silica particles in Gprc5a-/- mice resulted in more severe lung injury and pulmonary inflammation than in wild-type mice. Moreover, an enhanced fibrogenic response, including EMT-like characteristics, was induced in the lungs of Gprc5a-/- mice compared to those from wild-type ones. Importantly, increased hyperplasia or neoplasia coincided with silica-induced tissue injury and fibrogenic response in lungs from Gprc5a-/- mice. Consistently, expression of MMP9, TGFβ1 and EGFR was significantly increased in lungs from silica-treated Gprc5a-/- mice compared to those untreated or wild-type ones. These results suggest that, the process of tissue repair coincides with tissue damages; whereas persistent tissue damages leads to abnormal repair or neoplasia. Thus, silica-induced pulmonary inflammation and injury contribute to increased neoplasia development in lungs from Gprc5a-/- mouse model

Autopalmitoylation of TEAD Proteins Regulates Transcriptional Output of Hippo Pathway

TEA domain (TEAD) transcription factors bind to the co-activator YAP/TAZ, and regulate the transcriptional output of Hippo pathway, playing critical roles in organ size control and tumorigenesis. Protein S-palmitoylation attaches fatty acid (palmitate) to cysteine residues, and regulates protein trafficking, membrane localization and signaling activities. Using activity-based chemical probes, we discovered that human TEADs possess intrinsic palmitoylating enzyme-like activities, and undergo autopalmitoylation at evolutionarily conserved cysteine residues under physiological conditions. We determined the crystal structures of lipid-bound TEADs, and found that the lipid chain of palmitate inserts into a conserved deep hydrophobic pocket. Strikingly, palmitoylation is required for TEAD’s binding to YAP/TAZ, but dispensable for the binding to Vgll4 tumor suppressor. In addition, palmitoylation does not alter TEAD’s localization. Moreover, TEAD palmitoylation-deficient mutants impaired TAZ-mediated muscle differentiation in vitro, and Yorkie-mediated tissue overgrowth in Drosophila in vivo. Our study directly linked autopalmitoylation to the transcriptional regulation of Hippo pathway