Epidermal Growth Factor Receptor Gene Amplification Predicts Worse Outcome in Patients With Surgically Resected Nonadenocarcinoma Lung Cancer.

PURPOSE: The aim of the present study was to examine the prognostic role of amplification and increased expression of the epidermal growth factor receptor (EGFR) gene in surgically resected non-adenocarcinoma of non-small cell lung cancer (NA-NSCLC). MATERIALS AND METHODS: The present retrospective study included 114 consecutive NA-NSCLC patients with available tumor tissue and survival data. EGFR gene copy number and protein expression were evaluated using fluorescent in situ hybridization (FISH) and immunohistochemistry in tissue microarray sections, respectively. RESULTS: Among 114 patients, 99 (86.8%) had squamous cell carcinoma histologic features. EGFR gene amplification and high polysomy (EGFR FISH+) were observed in 7.9% and 31.6% of cases, respectively. Patients with EGFR FISH+ had significantly shorter overall survival (P = .011). A multivariate model confirmed that patients with EGFR FISH+ had a significantly greater risk of death than EGFR FISH- patients after adjusting for pathologic stage, presence of pleural invasion, venous invasion, and surgical margins (hazard ratio, 1.36; 95% CI, 1.040 to 1.782; P = .025). EGFR protein expression by immunohistochemistry was not associated with overall survival in the same group. Neither EGFR gene amplification nor EGFR immunohistochemistry expression was associated with relapse-free survival. CONCLUSION: An increased EGFR gene copy number in surgically resected NA-NSCLC was associated with worse survival.

Long-Term Oncologic Outcomes, Opioid Use, and Complications after Esophageal Cancer Surgery.

Effective and adequate opioid use and prevention of postoperative complications are important for enhanced recovery after surgery. We examined the effects of postoperative opioid use and postoperative complications on overall survival and recurrence-free survival after esophageal cancer surgery. This retrospective cohort study analyzed the records of patients diagnosed with esophageal cancer who underwent the Ivor Lewis operation between January 2005 and December 2011. We collected data on total opioid use for 8 days postoperatively, as well as information on postoperative complications (Clavien-Dindo classification). One hundred and twenty-one patients were included in the final analysis. Total opioid use was not significantly associated with overall survival (p = 0.520) and recurrence-free survival (p = 0.818). In contrast, the hazard ratio of postoperative overall survival was significantly higher with respect to Clavien-Dindo classification 1-2 (hazard ratio: 2.009, p = 0.046), 3a-3b (hazard ratio: 5.759, p < 0.001), and 4a-5 (hazard ratio: 3.982, p = 0.020) complications compared to no complications. Additionally, the hazard ratio of the recurrence-free survival was significantly higher in class 1-2 complications (hazard ratio: 2.336, p = 0.028) compared to none. Our study demonstrates that postoperative opioid use is not associated with survival and recurrence-free survival after esophageal cancer surgery, while postoperative complications may increase the hazard ratio for survival and recurrence-free survival.

Magnesium sulphate improves pulmonary function after video-assisted thoracoscopic surgery: A randomised double-blind placebo-controlled study.

BACKGROUND: Reduced lung volumes are unavoidable after lung resection surgery. Magnesium sulphate (MgSO4) administration has been reported to reduce the requirement for neuromuscular blocking drugs and postoperative analgesics in surgical patients. OBJECTIVE: To investigate the effect of MgSO4 on pulmonary function after video-assisted thoracoscopic surgery (VATS). DESIGN: A randomised, double-blind, placebo-controlled trial. SETTING: A university tertiary care centre. PATIENTS: Sixty-six patients scheduled for pulmonary lobectomy or segmentectomy via VATS. INTERVENTION: Patients were allocated to one of two groups: the Mg (MgSO4 50 mg kg intravenously for 10 min, followed by a continuous infusion of 15 mg kg h during surgery) or the control (same volume of 0.9% saline). MAIN OUTCOME MEASURES: Pulmonary function tests [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and peak expiratory flow rate] were measured before surgery and at three time points after surgery (2, 24 and 48 h postoperatively) using a portable spirometer. Twelve months after surgery, pulmonary function test values were repeated at a regular outpatient follow-up visit. RESULTS: FEV1 at 24 (1.7 ±â€Š0.6 vs. 1.3 ±â€Š0.5 l, P = 0.033) and 48 h (1.7 ±â€Š0.6 vs. 1.4 ±â€Š0.5 l, P = 0.021) and FVC at 24 (2.0 ±â€Š0.8 vs. 1.6 ±â€Š0.6 l, P = 0.038) and 48 h (2.2 ±â€Š0.8 vs. 1.7 ±â€Š0.7 l, P = 0.008) after surgery were significantly greater in the Mg group. Patients in the Mg group required less rocuronium than those in the control group (64.2 ±â€Š19.9 vs. 74.9 ±â€Š20.3 mg, respectively; P = 0.041). Consumption of postoperative patient-controlled analgesia was also significantly less at 24 and 48 h after surgery in the Mg group (P = 0.022 and 0.015, respectively), although pain scores and rescue analgesics were comparable. Five patients in the control group were diagnosed with postoperative pneumonia using clinical and radiological criteria before discharge. FEV1 and FVC at 12 months after surgery were not different between the two groups. CONCLUSION: Intraoperative administration of MgSO4 improved pulmonary function and reduced the need for rocuronium and postoperative analgesics in patients who underwent VATS. TRIAL REGISTRATION: cris.nih.go.kr identifier: KCT0001410.

Radiologic Characteristics of Surgically Resected Non-Small Cell Lung Cancer With ALK Rearrangement or EGFR Mutations.

BACKGROUND: Radiogenomic features are predictive of anaplastic lymphoma kinase (ALK) rearrangement in surgically resected non-small cell lung cancer (NSCLC). METHODS: ALK rearrangement was screened by fluorescent in situ hybridization in 497 patients with resected NSCLC. Of these, 198 patients screened for both ALK and epidermal growth factor receptor (EGFR) mutation were enrolled. Clinicopathologic findings, survival after surgical procedure, computed tomographic (CT) features, and maximum standardized uptake value according to different genotypes were investigated with univariate and multivariate analyses. A receiver operating characteristic (ROC) curve analysis was performed to quantify the predictive value of these factors. RESULTS: The prevalence of ALK positivity in resected NSCLC was 5.0% (25 of 497). Patients with ALK rearrangement showed significant differences in terms of patient's age (p = 0.006 for ALK versus EGFR, and 0.04 for ALK versus wild type [WT]/WT, respectively), solid lesion (p = 0.0074 for ALK versus EGFR), degree of contrast enhancement (p = 0.0006 for ALK versus EGFR), and lesion margin (p = 0.0011 for ALK versus EGFR, and 0.0314 for ALK versus WT/WT, respectively) compared with EGFR mutant and WT/WT cohorts. Multivariate analysis revealed that young age, solid lesion, lobulated margin, and hypoattenuation at contrast-enhanced CT scan were independent predictors of ALK positivity (p = 0.027, 0.046, 0.001, 0.021, respectively). The area under the ROC curve of the predictive model was 0.832, which suggests good discrimination. CONCLUSIONS: ALK-rearranged lung cancer has characteristic clinical and imaging features compared with EGFR mutant or WT/WT cohorts. Our findings suggest that young age, lobulated margin, solid lesion, and hypoattenuation at contrast-enhanced CT scan are important predictors of ALK-rearranged lung cancer.

EML4-ALK fusion gene in Korean non-small cell lung cancer.

A fusion gene between echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic lymphoma kinase (ALK) has been identified in non-small cell lung cancers (NSCLCs). Although a few studies have evaluated EML4-ALK fusion genes in Korean NSCLCs, the prevalence of different EML4-ALK fusion variants has yet to be clearly assessed. Herein, we have examined the profiles of EML4-ALK fusion gene variants in Korean patients of NSCLCs. EML4-ALK fusion genes have been detected in 10 (6.0%) of 167 patients of NSCLCs and in 9 (7.4%) of 121 patients of adenocarcinoma. Of the 10 patients with fusion genes identified, 8 (80%) were E13;A20 (variant 1) and 2 (20%) were E6;A20, with an additional 33-bp sequence derived from intron 6 of EML4 (variant 3b). These results indicate that the profiles of EML4-ALK fusion gene variants in Korean patients of NSCLC may differ from those in other ethnic populations. Herein, we describe for the first time the profiles of EML4-ALK fusion variants of Korean patients with NSCLCs.

A preliminary study of protoporphyrin-IX as a potential candidate for identification of lung cancer cells using fluorescence microscopy.

OBJECTIVES: There is need for a cheap, sensitive, and specific method to identify and localize early stage lung cancer. In order to improve the sensitivity of fluorescent agents that exhibit selective tumor uptake that are used as population screening tools for the detection of early lung cancer, a number of porphyrins including protoporphyrin-IX (PpIX) were tested. We stained lung cancer cells using three different sample preparation schemes for fluorescence microscopy. METHODS: Lung tissues and sputum samples of nineteen patients were studied. Cells were collected on glass slides by touching tumor surfaces of surgically sectioned lung cancer tissue and normal regions of the lung during surgery. Filtered sputum cells were also collected. Cell-attached slides were stained with porphyrin using three different methods, including fixing (SM-1) prior to staining, and diluting porphyrin stock solutions in either RPMI-1640 medium (SM-2) or 100mM MES buffer (SM-3). RESULTS: Slides from normal lung tissue lacked fluorescent epithelial cells. Tumor slides containing typical lung cancer cells exhibited red fluorescence upon excitation through the soret band (400-450 nm) of porphyrin compounds. Tumor-selective staining was only observed on unfixed tumor slides that were incubated with PpIX in a RPMI-1640 culture medium (SM-3) used as a working solution for staining and washing. CONCLUSIONS: Protoporphyrin-IX is a potentially useful tumor-staining molecular agent for fluorescent location of cancer cell in sputum samples from lung cancer patients.

The impact of multiple metastatic nodal stations on survival in patients with resectable N1 and N2 nonsmall-cell lung cancer.

BACKGROUND: The aim of the study was to identify common prognostic factors in nonsmall-cell lung cancer (NSCLC) with N1 and N2 nodal involvement. METHODS: A retrospective review of NSCLC patients who underwent primary surgical resection without neoadjuvant chemotherapy was performed. In all, 280 patients were included in this study, and there were 132 patients with N1 disease (N1 group) and 148 patients with N2 disease (N2 group). The median follow-up period was 26 months, and complete follow-up was possible in 269 patients (96%). RESULTS: Lobectomy was performed in 194 patients (69%), bilobectomy was performed in 43 (15%), and pneumonectomy was performed in 43 (15%). Complete resection was possible in 273 patients (98%), and operative death occurred in 5 patients (2%). The overall and disease-free 5-year survival rates were 63% and 55%, respectively, in the N1 group, and 44% and 32%, respectively, in the N2 group (p < 0.05). The prognostic factors for overall survival in both the N1 and N2 groups were age and the number of metastatic nodal stations; however, N2 metastasis was not a significant prognostic factor in the multivariate analysis. The poor prognosis of the patients in the N2 group was due to the greater incidence of multiple node involvement in comparison with the N1 group (73% versus 15%; p < 0.05). CONCLUSIONS: Multiple metastatic nodal stations was the common prognostic factor in resectable NSCLC patients with nodal metastasis, and mediastinal nodal involvement was associated with a higher chance of multiple-station metastasis in this study.

Surgical treatment of malignant mediastinal nonseminomatous germ cell tumor.

BACKGROUND: The aim of this study was to evaluate the role of surgical treatment for mediastinal nonseminomatous germ cell tumors (MNSGCT) and identify the factors of long-term survival. METHODS: A retrospective review of the medical records of patients with primary MNSGCT who registered at our institute between 1988 and 2005 was performed. Of 29 patients who presented with primary MNSGCT, 21 patients (72.4%) underwent curative resection and were included in this study. RESULTS: All patients were male and symptomatic at presentation. Mean patient age was 24.4 years (range, 9 to 53 years). Three different regimens were used for preoperative chemotherapy, and 14 patients (66.7%) achieved partial response, 4 (19.0%) had stable disease, and 2 (9.5%) had progressive disease. Complete en bloc excision was possible in 16 patients (76.2%). The most common cause of incomplete resection was great vessel invasion (n = 3). Concomitantly resected organs were lung in 13 patients (61.9%) and superior vena cava in 5 (23.8%). Viable germ cell tumor was identified in pathology specimens in 12 (57.1%), total necrosis in 7 (33.3%), and remnant teratoma in 2 (9.5%). Five-year overall and disease-free survivals were 63.6% and 61.1%. Risk factors for poor overall survival by multivariate analysis were beta-human chorionic gonadotrophin (beta-HCG) elevation at initial diagnosis (p = 0.02) and incomplete resection (p = 0.002). CONCLUSIONS: Surgical resection of MNSGCT after chemotherapy showed favorable long-term survival. Complete resection should be performed to achieve long-term survival. An elevated beta-HCG level at initial diagnosis was associated with a poor prognosis despite multimodality therapy.

Diagnostic accuracy of CT-guided core biopsy of ground-glass opacity pulmonary lesions.

OBJECTIVE: The purpose of our study was to evaluate the accuracy of CT-guided percutaneous core biopsy of ground-glass opacity (GGO) pulmonary lesions. MATERIALS AND METHODS: The study included 50 patients (24 men, 26 women; age range, 43-78 years) who had a GGO pulmonary lesion and underwent CT-guided core biopsy. Diagnostic accuracy was compared between two groups according to lesion size (< 2 cm vs > or = 2 cm) and GGO component (> 90% vs 50-90%). Each case was reviewed for complications, including pneumothorax, thoracostomy tube insertion, and hemoptysis. RESULTS: Malignancy was finally diagnosed in 33 patients, including three who underwent repeated biopsies, with 33 true-positive and three false-negative findings for an overall sensitivity of 92% (33/36). A benign lesion was finally diagnosed in 10 patients with one false-positive result, for a specificity of 90%. Two benign lesions without confirmative diagnosis because of loss of follow-up and five nondiagnostic samples were excluded from the calculations of sensitivity, specificity, and diagnostic accuracy. The overall diagnostic accuracy was 91%, with a positive predictive value of 97% and a negative predictive value of 75%. Sensitivity and accuracy were not significantly different between the two groups of lesion size and GGO components (p = 0.0491). Ten (18%) patients had pneumothorax, with one (2%) requiring placement of a thoracostomy tube. Mild hemoptysis occurred in seven (13%) patients. CONCLUSION: CT-guided core biopsy of GGO lesions can yield high diagnostic accuracy and acceptable complication rates approaching those of solid lesions.

Clinical significance of a solitary ground-glass opacity (GGO) lesion of the lung detected by chest CT.

Ground-glass opacity (GGO) attracts attention because of the possibility of early lung cancer. However, some lesions are reduced in size or disappear at follow-up. This study was designed to explore the natural history of solitary GGO, to determine the prevalence of malignancy and to identify factors predictive of benignity or malignancy. Solitary and focal GGO lesions [pGGO (p=pure) and mGGO (m=mixed) based on the presence of a solid component] of less than 3 cm were included. Lesions of less than 1cm were followed up by chest HRCT 3 months later and lesions over 1cm were investigated by percutaneous needle biopsy (PCNB). One hundred and eighty-six patients (69 pGGO and 117 mGGO) were enrolled. Of the 69 pGGO lesions, 7 were diagnosed as pre-malignant or malignant lesions, 3 as benign lesions and 26 pGGO lesions (37.6%) were reduced or disappeared (transient lesions) at follow-up chest HRCT. The other 33 lesions showed no significant change during follow-up. Thus, the probability of malignancy in pGGO was 7/36 (19.4%). On the other hand, of the 117 mGGO lesions, 26 were found to be malignant, 3 were diagnosed as benign and 57 lesions (48.7%) were reduced or had disappeared at follow-up chest HRCT. The other 31 lesions showed no change during follow-up, and thus the probability of malignancy in mGGO was 26/86 (30.2%). A female sex and a spiculated mGGO border were found to be related with malignancy. However, a high blood eosinophil count was strongly associated with regressing or transient mGGO, suggesting that pulmonary infiltrate with eosinophilia (PIE) might have been responsible. We recommend short-term follow-up by chest HRCT be conducted for mGGO lesions in the presence of high eosinophilia--regardless of lesion size.

Aryl hydrocarbon receptor gene polymorphisms affect lung cancer risk.

To evaluate the role of genetic polymorphisms of AhR related to the carcinogen metabolism and cell proliferation, genotypes of three AhR polymorphisms Ex1+185A>G, IVS7+33T>G and Ex10+501G>A were determined in 616 lung cancer cases and 616 lung cancer-free controls. When the effect of each AhR allele on lung cancer risk was evaluated, any AhR genotype did not show the association with lung cancer risk. However, when haplotypes were composed of three AhR SNP sites, non-smokers with GGG haplotype (adjusted OR=1.7, 95% CI, 1.06-2.71) and smokers without GGG haplotype (adjusted OR=2.5, 95% CI, 1.64-3.74) showed significantly increased risk of lung cancer compared to non-smokers without GGG haplotype. Moreover, smokers with GGG haplotype showed the highest risk (adjusted OR=3.2, 95% CI, 2.10-4.74). Particularly, the synergistic effect between AhR haplotype and smoking was more apparent in squamous cell carcinoma (adjusted OR=6.1, 95% CI, 2.53-14.68). This result suggests that haplotypes of AhR gene play an important role in the development of lung cancer and there is a synergistic interaction between AhR gene and smoking for lung cancer risk.

Detection of lung cancer using MAGE A1-6 and SSX4 RT-PCR expression profiles in the bronchial wash fluid.

PURPOSE: Bronchial wash fluid may be a useful for detecting lung cancer. To increase the detection rates, we performed molecular analysis with using MAGE A1-6 and SSX4 RT-PCR on bronchial wash fluid specimens. MATERIALS AND METHODS: We obtained 57 lung cancer tissue specimens by bronchoscopic biopsy and 131 bronchial washes from 96 patients with lung cancer and 35 patients with benign lung diseases. The MAGE A1-6 and SSX4 gene expressions were investigated in the cancer tissue specimens and bronchial wash fluids. We evaluated the positive detection rates of these methods according to the cytology results and the clinical findings. RESULTS: For the cancer tissue specimens and the bronchial wash fluid, the positive detection rate of MAGE or SSX4 was 91.2% and 75.0%, respectively. Combined MAGE and SSX4 PCR and cytology tests showed an 83.3% detection rate for the bronchial wash fluid. From bronchial washes of patients with benign lung diseases, the positive rates of using MAGE or SSX4 was 11.4%. In the bronchial wash fluid of lung cancer patients, 66.7% of the peripheral cancers were detected by MAGE or SSX4, while examination with cytology did not detect any peripheral lung cancer. CONCLUSION: The application of both MAGE and SSX4 showed high sensitivity and specificity for the detection of lung cancer. Thus, MAGE and SSX4 RT-PCR may be effectively utilized as additional methods to improve detection of lung cancer with using bronchial wash fluids.