Factors that Predict Clinical Benefit of EGFR TKI Therapy in Patients with EGFR Wild-Type Lung Adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancers have emerged as key predictive biomarkers in EGFR tyrosine kinase inhibitor (TKI) treatment. However, a few patients with wild-type EGFR also respond to EGFR TKIs. This study investigated the factors predicting successful EGFR TKI treatment in lung adenocarcinoma patients with wild-type EGFR. METHODS: We examined 66 patients diagnosed with lung adenocarcinoma carrying wide-type EGFR who were treated with EGFR TKIs. The EGFR gene copy number was assessed by silver in situ hybridization (SISH). We evaluated the clinical factors and EGFR gene copy numbers that are associated with a favorable clinical response to EGFR TKIs. RESULTS: The objective response rate was 12.1%, while the disease control rate was 40.9%. EGFR SISH analysis was feasible in 23 cases. Twelve patients tested EGFR SISH-positive, and 11 were EGFR SISH-negative, with no significant difference in tumor response and survival between EGFR SISH-positive and -negative patients. The overall median progression-free survival (PFS) and overall survival (OS) of 66 patients were 2.1 months and 9.7 months, respectively. Female sex and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 were independent predictors of PFS. ECOG PS 0-1 and a low tumor burden of extrathoracic metastasis were independent predictors of good OS. CONCLUSION: Factors such as good PS, female sex, and low tumor burden may predict favorable outcomes following EGFR TKI therapy in patients with EGFR wild-type lung adenocarcinoma. However, EGFR gene copy number was not predictive of survival.

Association between thyroid cancer and epidermal growth factor receptor mutation in female with nonsmall cell lung cancer.

BACKGROUND: The aim of this study was to investigate the association between epidermal growth factor receptor (EGFR) mutation and thyroid cancer in female patients with nonsmall-cell lung cancer (NSCLC). METHODS: In a retrospective study, we examined 835 female patients who were diagnosed with NSCLC and underwent an EGFR mutation test between June 2003 and August 2013. The associations of EGFR mutation with thyroid cancer and a family history of thyroid cancer were evaluated using logistic regression models. RESULTS: EGFR mutation was found in 378 of 835 patients. In addition to adenocarcinoma (P < 0.001), EGFR mutations were positively associated with a personal history of thyroid cancer (5.8% versus 2.6%; P = 0.020), while showing a trend toward inverse association with a personal history of nonthyroid cancer (5.8% vs. 9.0%; P = 0.086). Likewise, the incidence of EGFR mutations was associated with a family history of thyroid cancer (2.9% vs. 0.9%; P = 0.028), while showing a trend toward inverse association with a family history of nonthyroid cancer (27.8% vs. 33.7%; P = 0.066). Multivariate logistic regression showed that the incidence of EGFR mutations was different in women with thyroid or nonthyroid cancer (P = 0.035) and in women with a family history of thyroid or nonthyroid cancer (P = 0.023). CONCLUSIONS: Our data suggest that thyroid cancer and a family history of thyroid cancer are associated with EGFR-mutated NSCLC in female patients. The differences in the incidence of thyroid cancer and a family history of thyroid cancer by EGFR mutational status provide new insight into pathogenesis of this genetic change.

Pulmonary Metastasectomy in Adult Patients with Synovial Sarcoma: A Single-Center Experience.

BACKGROUND: This study assessed the efficacy of pulmonary metastasectomy for synovial sarcoma in adult patients. METHODS: Fifty patients, diagnosed with pulmonary metastasis from June 1990 to August 2010, were reviewed retrospectively. Twenty-eight patients underwent complete pulmonary metastasectomy, and their survival was evaluated. Age, sex, time to metastatic progression, laterality, number of tumors, size of largest nodule, and number of metastasectomies were analyzed as potential prognostic factors. RESULTS: In all, 29 patients underwent at least one pulmonary metastasectomy, and 51 resections were performed. One intraoperative mortality occurred, and the 5-year survival rate was 58.4%. Bilateral metastases and early metastatic progression were associated with poor survival in multivariate analyses. CONCLUSION: Surgical resection can be a good option for treating pulmonary metastasis in patients with synovial sarcoma. Repeated resection was feasible with low mortality and morbidity.

Epidermal growth factor receptor mutations and brain metastasis in patients with nonadenocarcinoma of the lung.

OBJECTIVE: This study explored the potential association between epidermal growth.factor receptor. (EGFR) mutation status and brain metastasis in patients with nonadenocarcinoma nonsmall cell lung cancer. (NSCLC). PATIENTS AND METHODS: We analyzed clinical data from 286 patients with nonadenocarcinoma NSCLC, who were tested for EGFR mutations and underwent brain magnetic resonance imaging at diagnosis. We examined the relationship between EGFR mutation and brain metastasis at initial presentation. RESULTS: Of the 286 patients, 20 patients (7.0%) had EGFR mutations. EGFR mutations were more frequent in younger patients (11.1% in patients =64 years vs. 3.3% in patients >64 years: P = 0.01), females (21.4% vs. 3.5% in males: P <0.001), never-smokers (25.0% vs. 3.4% in smokers: P < 0.001), and tumors with nonsquamous histology (25.0% vs. 4.1% in squamous histology: P < 0.001). At diagnosis, the frequency of EGFR mutations was significantly different in patients with metastasis to different sites (4.0% [no metastases] vs. 10.4% [extracranial metastases] vs. 40.0% [brain metastases], P < 0.001). The strong association between EGFR mutation and brain metastasis remained significant in multivariate analysis (adjusted odds ratio [OR] = 9.68, 95% confidence interval [CI] =2.32-40.45; P = 0.002). Associations were also found for EGFR mutation status with nonsquamous histology (adjusted OR = 4.46, 95% CI = 1.46-13.56; P = 0.008). CONCLUSION: This study indicates that the likelihood of nonadenocarcinoma patients having EGFR mutant tumors may differ according to brain metastasis and squamous cell histology.

Epidermal growth factor receptor mutations in female patients with postoperative recurrent non-small-cell lung cancer.

PURPOSE: We did this retrospective study to explore the association between epidermal growth factor receptor (EGFR) mutation and clinical features in postoperative recurrent female non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: We reviewed clinical data on 86 female patients who had postoperative recurrent disease between December 1992 and July 2007. The start of tyrosine kinase inhibitor therapy was treated as a censoring event. Corresponding surgical specimens of primary tumors were used to test for EGFR mutations. RESULTS: Thirty patients presented with local recurrence and distant recurrence was identified in 56. Thirty-four of the 86 patients (40%) harbored EGFR mutations. Patients with distant recurrence were more likely to have EGFR mutations than patients with local recurrence (48% versus 23%; P = 0.024). On multivariate analysis, distant recurrence was associated with a high frequency of EGFR mutations (OR, 3.3; P = 0.028). Survival analysis showed poor survival of patients with mutated EGFR (HR, 2.3; P = 0.017) or with non-adenocarcinoma histology (HR, 3.3; P = 0.001). CONCLUSION: The association between recurrence pattern and EGFR mutation status was suggested in recurrent female NSCLC patients. In addition, our data indicate unfavorable disease process of EGFR mutated tumors. Further studies need to be conducted to validate these findings.

Association between age at diagnosis and the presence of EGFR mutations in female patients with resected non-small cell lung cancer.

BACKGROUND: Our previous report showed an association between age and outcome in gefitinib-treated female patients with non-small cell lung cancer (NSCLC). Only limited numbers of molecular studies have been performed with respect to the presence of epidermal growth factor receptor (EGFR) mutations according to age. This retrospective study was performed to evaluate a possible association between age at the time diagnosis and the presence of EGFR mutations in female patients with NSCLC. METHODS: Tumor specimens were collected retrospectively from paraffin blocks of 98 female patients with primary NSCLC who underwent surgical resection between January 1992 and December 2002 at the Korea Cancer Center Hospital. To detect EGFR mutations, a Scorpion Amplified Refractory Mutation System was used. RESULTS: Most of the study population comprised never smokers (84%) and patients with adenocarcinoma (82%). The age at the time of diagnosis ranged from 34 to 74 years (median, 57 years). When the median age was used as a cutoff value, older patients were more likely to have EGFR mutations than younger patients (70 versus 39%; p = 0.004). After controlling for the effects of histology, smoking history, and stage, age remained a significant predictor for EGFR mutations (odds ratio, 4.03; 95% confidence interval, 1.61-10.09; p = 0.003). CONCLUSIONS: Our data suggest that age at the time of diagnosis in female patients with NSCLC may be associated with the frequency of EGFR mutations, a strong indicator for favorable outcomes.

Adenomyomatous hamartoma of lung mimicking benign mucinous tumor in fine needle aspiration biopsy: a case report.

BACKGROUND: Typical cytologic features of pulmonary hamartoma (PH) are usually smears of hyaline cartilage, fibrous tissue, smooth muscle, adipocytic components and respiratory epithelium. Cytologic features of adenomyomatous hamartoma, a special variant of PH, are not documented in the literature and are confused with epithelial neoplasm in the case of sparse stromal cellularity. CASE: A 59-year-old man presented with a solitary pulmonary nodule by chest radiograph at his routine health examination. Fine needle aspiration biopsy (FNAB) revealed numerous mucinous epithelial cells presenting predominantly in cohesive cellular sheets that suggested benign mucinous epithelial lesion. The patient underwent surgery for the tumor, and it was histologically proven to be an adenomyomatous hamartoma. CONCLUSION: An unusual type of PH could lead to misdiagnosis by FNAB in the case of few stromal components. This case demonstrates the wide spectrum of PH in FNAB and led us to consider PH as a differential diagnosis despite lack of chondromyxoid stromal components.

Volume-expanding complications after pneumonectomy: comparison of CT findings.

The purpose of this study was to assess and characterize the computed tomographic (CT) findings of various volume-expanding complications occurring in the postpneumonectomy space. Chest CT scans, obtained in 17 patients in whom plain chest radiographs had revealed shift of the mediastinum away from the surgical side after pneumonectomy for lung cancer, were retrospectively reviewed. Recurrent neoplasm (n=6) appeared as soft-tissue mass projecting into the postpneumonectomy space and/or enlarged mediastinal lymph nodes. Empyema (n=4) was manifested by smooth thickening of the residual pleura with or without thickening of the extrapleural tissues. Hemothorax (n=4) was characterized by amorphous material of high attenuation contained within the postpneumonectomy space. Chylothorax (n=2) presented no abnormal finding except for expansion of the postpneumonectomy space. The remaining one case showed only expansion of the postpneumonectomy space and it was normalized without any treatment, which was supposed to be transient pleural fluid collection of uncertain cause. When mediastinal shift away from the surgical side occurs on plain chest radiography following pneumonectomy, CT can be helpful in differentiating various volume-expanding complications providing characteristic features.

Postoperative adjuvant chemotherapy for stage I non-small cell lung cancer.

OBJECTIVE: Surgery constitutes the mainstay of treatment in stage I non-small cell lung cancer (NSCLC). However, a significant fraction of patients after surgical resection die mainly due to systemic relapse. Nonetheless, the best adjuvant treatment to improve survival and decrease relapse rate remains as an ever controversial issue. Therefore, we conducted a randomized trial to determine whether postoperative adjuvant chemotherapy is beneficial in prolonging survival and decreasing recurrence in patients with completely resected stage I NSCLC. METHODS: It was designed as a randomized, prospective two-armed study with surgery only (control group, 59 patients) versus surgery plus adjuvant MVP (mitomycin C, vinblastin and cisplatin) chemotherapy (study group, 59 patients). RESULTS: Data for all the patients were complete. Twenty-four patients in the control group and nine patients in the study group experienced tumor recurrence during the follow-up. Neither histological type nor surgical extent correlated with recurrence. However, the addition of adjuvant MVP chemotherapy could decrease the rate of recurrence and the incidence of cancer-related death after surgery in the patients of stage I NSCLC (P<0.05). We followed up at least 5 years, and the duration of mean follow-up was 7.3 years. The rates of the loco-regional and distant metastases were 3.4 and 40.7% in the control group, and 3.4 and 11.9% in the study group, respectively. The 5- and 10-year survival rates were 74.6 and 56.3% in the control group, and 81.4 and 65.0% in the study group, respectively (P=0.19, log-rank test). The 5- and 10-year disease-free survival rates were 64.8 and 54.8% in the control group, and 88.8 and 76.8% in the study group, respectively (P=0.002, log-rank test). CONCLUSIONS: Our results suggest that the addition of adjuvant MVP chemotherapy may reduce the incidence of distant metastasis and prolong the disease-free survival of the patients with stage I NSCLC after surgery.

Overexpression of Glut1 in lymphoid follicles correlates with false-positive (18)F-FDG PET results in lung cancer staging.

UNLABELLED: The evaluation of mediastinal lymph node involvement in non-small cell lung carcinoma (NSCLC) is very important for the selection of surgical candidates. PET using (18)F-FDG has remarkably improved mediastinal staging in NSCLC. However, false (18)F-FDG PET results remain a problem. This study was undertaken to identify histologic and immunohistochemical differences between cases showing false and true results of mediastinal lymph node involvement assessed by (18)F-FDG PET. METHODS: Preoperative (18)F-FDG PET examinations were performed on 62 patients with NSCLC, and mediastinal lymph node sampling was done at thoracotomy or mediastinoscopy. In 111 lymph nodes, the size, glucose transporter 1 (Glut1) expression, grade of follicular hyperplasia, and involved proportion of tumor were examined and compared with the (18)F-FDG PET findings. RESULTS: Lymphoid follicular cells were strongly positive for the expression of Glut1. The grade of follicular hyperplasia in false-positive lymph nodes was higher than that in true-negative nodes (P < 0.001). The Glut1 expression of metastatic tumors was higher in true-positive nodes than that in false-negative nodes (P < 0.001). Metastatic squamous cell carcinomas showed stronger Glut1 expression than adenocarcinomas and no false-negative results on (18)F-FDG PET. On the other hand, metastatic adenocarcinomas exhibited focal and weak Glut1 expression with frequent false-negative results. CONCLUSION: The results of this study indicate that (a). lymphoid follicular hyperplasia with Glut1 overexpression may have a causal relationship with high (18)F-FDG uptake of false-positive nodes and (b). the lower expression of Glut1 in metastatic tumors, such as adenocarcinomas, might be responsible for false-negative lymph nodes.

FDG-PET in Mediastinal Nodal Staging of Non-small Cell Lung Cancer: Correlation of False Results with Histopathologic Finding.

PURPOSE: Mediastinal staging of non-small cell lung cancer can be markedly improved by FDG-PET scan, but the problem of false staging of mediastinal nodes by PET scan in non-small cell lung cancer has not yet been overcome. The aim of this study was to identify the mechanism underlying the false staging of mediastinal nodes by FDG-PET in the case of non-small cell lung cancer. MATERIALS AND METHODS: To evaluate the factors determining the FDG uptake in mediastinal nodes, FDG-PET was performed preoperatively, and mediastinal dissection with pulmonary resection was performed in 62 patients with NSCLC. GLUT-1 expression was studied by immunohistochemistry of the mediastinal nodes (n=111, true positive 31, true negative 41, false positive 27, false negative 12) using the anti-GLUT-1 antibody. The size, percentage of tumor (tumor ratio), labeling index (rate of stained tumor), staining intensity of the tumor, level of follicular hyperplasia, and staining intensity of the follicle center in the mediastinal node were also studied. RESULTS: There was no significant difference in size among the 4 nodal groups (TP, TN, FP, FN), nor in the tumor ratio of the metastatic nodes between the TP and FN groups. The labeling index and staining intensity of the TP group were higher than those of the FN group (Mann-Whitney test, p=.001, p=.007) in the case of the metastatic nodes. The level of follicular hyperplasia of the FP group was higher than that of the TN group in the case of the non-metastatic nodes (p=.000). CONCLUSION: These results suggest that in mediastinal staging of non-small cell lung cancer by FDG-PET, the FN node is associated with low uptake of FDG due to low expression of GLUT-1, and that the FP node is associated with a high level of follicular hyperplasia as a result of there being a reactive change to an inflammatory and/or immune reaction. This is the first report on the mechanism underlying the false results that are sometimes obtained, and which constitute a major problem in the clinical application of FDG-PET to the mediastinal staging of non-small cell lung cancer.