Sook-Whan Sung

High MET Gene Copy Number Leads to Shorter Survival in Patients with Non-small Cell Lung Cancer

Introduction: Activation of MET, either by increased gene copy number (GCN) or mutation, has been detected in various cancers. We investigate the clinicopathologic features of MET gene copy in nonsmall cell lung cancer (NSCLC). Methods: Tumor tissues were obtained from 180 resected NSCLCs, including 97 squamous cell carcinomas (SCCs) and 72 adenocarcinomas. No patient received epidermal growth factor receptor (EGFR)-targeted therapy. EGFR and MET GCNs were studied using fluorescence in situ hybridization (FISH) and were estimated according to the University of Colorado Cancer Center (UCCC) criteria. For MET, we also assessed GCNs using the Cappuzzo system. Results: FISH-positive MET was observed in 16.7% using the UCCC criteria; specifically, amplification was seen in 3.9% and high polysomy in 12.8%. FISH-positive MET status was significantly correlated with FISH-positive EGFR (p = 0.003). In the Cappuzzo system, high MET GCN (mean, ≥5 copies/cell) was found in 6.7% and also associated with FISH-positive EGFR (p = 0.031). MET gene copy status was not associated with gender, smoking history, histology, or stage. However, true MET amplification was more frequent in patients with SCC than in those with adenocarcinoma. FISH-positive MET status predicted worse survival in patients with NSCLC at advanced stages (p = 0.034) and in patients with SCC (p = 0.028). In multivariate analyses, increased MET GCN was significantly associated with shorter survival in patients with SCC, as analyzed using both the UCCC and Cappuzzo criteria (p = 0.019 and 0.008). Conclusions: Our results suggest that increased MET GCN would be an independent poor prognostic factor in SCC of the lung.

Epidermal Growth Factor Receptor Mutation and Pathologic-Radiologic Correlation Between Multiple Lung Nodules with Ground-Glass Opacity Differentiates Multicentric Origin from Intrapulmonary Spread

Introduction: No standard guidelines detailing recommendations for the selection and treatment for multiple lung nodules with ground-glass opacity (GGO) have been established. For treatment decision, we analyzed epidermal growth factor receptor (EGFR)/K-ras somatic aberrations and pathologic-radiologic correlation in multiple lung nodules presented as GGO to differentiate multifocal lesions from intrapulmonary spread. Methods: Twenty-four patients with multiple lung nodules presented as GGO were identified to investigate somatic mutations of EGFR (exon 18–21) and K-ras (codons 2, 13, and 61). This series included 18 atypical adenomatous hyperplasias (AAH), 15 bronchioloalveolar carcinomas (BAC), and 23 adenocarcinomas (ADC) obtained from 24 patients. Results: High frequency of discordant EGFR mutations (17 of 24, 70.8%) could discriminate tumor clonality (18 of 24, 75%) of multiple lung neoplastic nodules presented as GGO. EGFR mutations were common in AAH (38.9%), BAC (46.7%), and ADC (39.1%). In case 4, AAH and BAC had different mutational changes, and in case 10, the BAC lesion contains EGFR mutation that is not in the invasive ADC. In case 17, the BAC had more mutational changes than the carcinoma. The pure GGO appearance in the radiologic examination corresponded preinvasive pathologic change. Conclusions: This study showed that synchronous BAC and/or ADC can have different EGFR or K-ras mutational profiles suggesting these lesions arise as independent events rather than intrapulmonary spread or systemic metastasis. This has significant implication in staging and treatment. These findings might be a clue to establish guidelines of the multiple neoplastic lung nodules with GGO.

The prognostic significance of ERCC1, BRCA1, XRCC1, and βIII-tubulin expression in patients with non-small cell lung cancer treated by platinum- and taxane-based neoadjuvant chemotherapy and surgical resection

OBJECTIVESnThe DNA repair pathway and isotype composition of beta-tubulin are known to be associated with resistance to platinum- and taxane-based chemotherapy, respectively. The aim of this study was to identify the clinical significance of excision repair cross-complementation 1 (ERCC1), breast cancer susceptibility gene 1 (BRCA1), X-ray repair cross-complementation 1 (XRCC1) and betaIII-tubulin on the chemotherapy response and overall survival in patients with non-small cell lung cancer (NSCLC) who received neoadjuvant chemotherapy.nnnMETHODSnProtein expression profiles were evaluated by immunohistochemistry on surgical specimens of 82 NSCLC patients who underwent platinum- and taxane-based neoadjuvant chemotherapy. The expression levels of proteins were measured semi-quantitatively and the correlation with tumor responses, pathologic cell death rate and survival were evaluated.nnnRESULTSnThere were 73 (89.0%) clinical stage III patients. Lobectomy, bilobectomy, and pneumonectomy were performed in 54 (65.0%), 11 (13.4%), and 17 (20.7%) patients, respectively. There was no correlation between clinical response and protein expression. The expression levels of ERCC1, BRCA1, and XRCC1 increased proportionally to the cell death rate (p<0.05); however, betaIII-tubulin expression did not correlate with cell viability. Multivariate analysis demonstrated that early pathologic stage, adjuvant chemotherapy, high ERCC1 and low betaIII-tubulin expression were good prognostic factors for overall survival (p<0.05).nnnCONCLUSIONSnThe inverse correlation between DNA repair proteins and cell viability suggests that these protein expression levels can be markers for chemotherapy responsiveness. However, only ERCC1 and betaIII-tubulin were prognostic factors after platinum- and taxane-based neoadjuvant chemotherapy following surgical resection.

Protein overexpression and gene amplification of epidermal growth factor receptor in nonsmall cell lung carcinomas: Comparison of four commercially available antibodies by immunohistochemistry and fluorescence in situ hybridization study.

Epidermal growth factor receptor (EGFR) overexpression in nonsmall cell lung carcinomas (NSCLC) is variable ranging from 19% to 89% and its prognostic value remains controversial. We tried to investigate (1) EGFR protein expression using four different antibodies, (2) the correlation between protein overexpression and EGFR gene amplification, and (3) the correlation between EGFR genetic status and clinicopathologic features in NSCLC. We examined EGFR protein expression using four different antibodies including Zymed EGFR kit (Clone 31G7), Dako EGFR pharmDx kit (Clone 2-18C9), Dako (Clone H11) and Novocastra (Clone EGFR 113) by immunohistochemical analysis. The protein overexpression was compared to gene amplification status by fluorescence in situ hybridization (FISH). EGFR protein overexpression was observed in 56% of tumors with Zymed EGFR kit, in 51% with Dako EGFR pharmDx kit, in 5% with Dako and in 18% with Novocastra (p=0.010). Both Zymed and Dako pharmDx kit were more sensitive than the Dako test (clone H11) and Novocastra clone EGFR 113. EGFR overexpression was more prominent in squamous cell carcinomas (SCC) than adenocarcinomas (ADC) (71% vs. 48%, p=0.001 with Zymed, 61% vs. 45%, p=0.011 with Dako pharmDx kit; respectively). EGFR FISH-positivity as represented by high polysomy and gene amplification was observed in 45% of the NSCLC patients. Protein expression levels significantly correlated with the gene copy number per tumor cell (p<0.001). Our data showed a higher percentage of positive cells detected by Zymed and Dako pharmDx tests. The EGFR protein overexpression rate varied from 4% to 72% according to different antibody clones and histologic types. EGFR protein expression detected by Zymed and Dako pharmDx was significantly associated with a high EGFR gene copy number.

CD24, a Novel Cancer Biomarker, Predicting Disease-Free Survival of Non-small Cell Lung Carcinomas: A Retrospective Study of Prognostic Factor Analysis from the Viewpoint of Forthcoming (Seventh) New TNM Classification

Introduction: Metastasis-associated protein CD24 has been identified as a new prognostic factor and stem cell marker in the human neoplasm. However, the importance of the CD24 in non-small cell lung carcinomas (NSCLCs) has not been elucidated well. Methods: We evaluated CD24 expression in 267 consecutive cases of NSCLC by immunohistochemistry using a tissue microarray technique and correlated with clinicopathologic parameters including forthcoming (seventh) new tumor node metastasis classification. Results: CD24-high expression was demonstrated in 87 of 267 (33%) and was associated with adenocarcinoma (ADC) histology than in squamous cell carcinoma histology (64 of 165 [39%] vs. 20 of 88 [23%]; p = 0.023). Patients with CD24-high tumors tended to have a higher risk of disease progression (p < 0.001) and cancer-related death (p = 0.002). Multivariate analysis proved CD24-high expression as independent prognostic factors of disease progression and cancer-related death (p = 0.002, hazard ratio = 1.78, 95% confidence interval = 1.23–2.58 and p = 0.017, hazard ratio = 1.93, 95% confidence interval =1.13–3.31). CD24-high expression had a tendency to correlate with new pathologic stage (p-stage) (p = 0.089) rather than old p-stage (p = 0.253). Performance status and new p-stage, regardless of the tumor histology, were identified as consistent independent prognostic factors of disease progression and cancer-related death. However, age was related to a significantly shorter cancer-specific survival in ADC only. Conclusions: CD24 expression in NSCLC is associated with ADC histology and disease progression and cancer-related death, indicative of aggressive tumor behavior. Performance status and new p-stage, to a lesser extent, age correlated with progression-free survival and cancer-specific survival, regardless of tumor histology.

The Impact of Multiple Metastatic Nodal Stations on Survival in Patients With Resectable N1 and N2 Nonsmall-Cell Lung Cancer

BACKGROUNDnThe aim of the study was to identify common prognostic factors in nonsmall-cell lung cancer (NSCLC) with N1 and N2 nodal involvement.nnnMETHODSnA 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%).nnnRESULTSnLobectomy 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).nnnCONCLUSIONSnMultiple 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

BACKGROUNDnThe 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.nnnMETHODSnA 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.nnnRESULTSnAll 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).nnnCONCLUSIONSnSurgical 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.

Additional mechanical pleurodesis after thoracoscopic wedge resection and covering procedure for primary spontaneous pneumothorax

BackgroundAdditional mechanical pleurodesis for the treatment of primary spontaneous pneumothorax (PSP) is believed to reduce the recurrence of PSP, and a covering procedure with absorbable mesh also shows comparable results. This study was conducted to determine whether additional mechanical pleurodesis would be effective in reducing recurrence after thoracoscopic wedge resection and covering procedure.Materials and methodsBetween May 2003 and August 2005, 99 patients underwent thoracoscopic bullectomy with staple line covering with absorbable cellulose mesh and fibrin glue followed by an additional mechanical pleurodesis. These patients were compared with 98 patients who underwent thoracoscopic bullectomy with staple line coverage alone.ResultsThe additional mechanical pleurodesis group had findings comparable to those of the coverage group for duration of postoperative chest drainage, length of hospital stay, and complication rate. After median follow-up of 29.2xa0months, postoperative recurrence occurred in four patients (4.0%).ConclusionsAdditional mechanical pleurodesis after covering procedure is also effective in decreasing postoperative recurrence of PSP.

Differences in the Expression Profiles of Excision Repair Crosscomplementation Group 1, X-Ray Repair Crosscomplementation Group 1, and βIII-Tubulin Between Primary Non-small Cell Lung Cancer and Metastatic Lymph Nodes and the Significance in Mid-Term Survival

Introduction: This study aimed to compare the expression profiles of excision repair crosscomplementation group 1 (ERCC1), x-ray repair crosscomplementation group 1 (XRCC1), and &bgr;III-tubulin between patients with primary non-small cell lung cancer (NSCLC) and those with metastatic lymph nodes and to identify the prognostic significance of each chemotherapy resistance protein. Materials: Those who met the inclusion criteria were patients (1) with NSCLC, (2) with metastatic lymph nodes (N1 or N2), and (3) who underwent surgical resection followed by platinum-based adjuvant chemotherapy. A total of 82 patients were included in the study. The expression profile of each protein was evaluated by immunohistochemistry and compared according to tumor location. Results: The mean age of the patients was 57.5 ± 8.4 years. There were 30 N1 and 52 N2 patients. ERCC1 expression was upregulated in 55% and downregulated in 8% of metastatic lymph nodes, when compared with primary tumors (p < 0.05). XRCC1 was also upregulated in 56% and downregulated in 6% (p < 0.05). However, &bgr;III-tubulin was upregulated in 12% and downregulated in 45% of patients (p < 0.05). &bgr;III-tubulin expression in metastatic lymph nodes was greater in patients with adenocarcinoma than other cell types. Upregulation of ERCC1 in metastatic lymph nodes was a poor prognostic factor in N1 patients but not in N2 patients. Conclusions: Significant changes in the expression profile of each protein were observed in metastatic lymph nodes. The resistance protein-guided treatment should be performed after integrative interpretation of expression profiles of each protein in both primary and metastatic sites.

Surgical management of the esophageal leiomyoma: lessons from a retrospective review

Esophageal leiomyoma is the most common benign tumor of the esophagus. Although enucleation via thoracotomy has been considered standard treatment, minimally invasive surgery is increasingly used for the treatment of this disease. We analyzed our surgical outcomes by comparing thoracotomy and the thoracoscopic approach. A retrospective review was performed of patients who underwent surgical resection of esophageal leiomyomas at the Seoul National University Hospital. Between 1982 and 2005, 63 patients were identified (male, n= 39; female, n= 24) at a mean age of 44.5 years. Thirty-two patients (51%) were symptomatic. Forty-five patients underwent thoracotomy, and 18 patients were resected using thoracoscopy. There was no mortality. The mean length of hospital stay was 10.3 days in the open group and 8.0 days in thoracoscopy group. Intraoperative mucosal repair was required in eight patients. Preoperative endoscopic mucosal biopsy within 1 month was identified as a risk factor for mucosal injury. Among the 11 patients with tumors less than 1.5u2003cm in size, thoracoscopic resection was attempted on four patients, and three out of the four cases required conversions to thoracotomy. Minimally invasive surgery for esophageal leiomyoma can be performed with good results. Our results suggest that the thoracoscopic approach should be considered as a standard surgical method for the treatment of esophageal leiomyoma. However, in cases of small tumors less than 1.5u2003cm in size, localization of the tumor may be difficult, and if asymptomatic, a regular monitoring should be considered as an alternative approach in such small tumors.