Mingyon Mun

EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset

A subset of lung cancers harbors a small inversion within chromosome 2p, giving rise to a transforming fusion gene, EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene), which encodes an activated tyrosine kinase. We have earlier examined the presence of EML4-ALK by multiplex reverse transcription-polymerase chain reaction in 363 specimens of lung cancer, identifying 11 adenocarcinoma cases featuring the fusion gene. In this study, we clinicopathologically examined the characteristics of the EML4-ALK-positive cases, including the mutation status of EGFR, KRAS, and TP53, and whether they were of thyroid transcription factor-1 (TTF-1) cell lineage or not. Of 11 patients, 4 (36%) with EML4-ALK-positive lung adenocarcinomas who were below 50 years of age were affected by these diseases, as compared with 12 of 242 patients (5.0%) with EML4-ALK-negative lung adenocarcinomas (P=0.00038). EML4-ALK-positive lung adenocarcinomas were characterized by less-differentiated grade (P=0.0082) and acinar-predominant structure (P<0.0001) in histology. Furthermore, the presence of EML4-ALK appears to be mutually exclusive for EGFR and KRAS mutations (P=0.00018), whereas coexisting with TP53 mutations at a low frequency (1/11=9.1%), and correlating with non- or light smoking (P=0.040), in line with the TTF-1 immunoreactivity. Thus, EML4-ALK-positive tumors may form a distinct entity among lung adenocarcinomas, characterized by young onset, acinar histology, no or rare mutations in EGFR, KRAS, and TP53, and a TTF-1 cell lineage, all in agreement with the prevalence in non- or light smokers.

Video-assisted thoracic surgery for clinical stage I lung cancer in octogenarians.

BACKGROUND The purpose of this retrospective study was to investigate the value of video-assisted thoracic surgery (VATS) for clinical stage I lung cancer in octogenarians. METHODS From April 1999 to December 2006, 55 consecutive patients aged older than 80 years with clinical stage I lung cancer underwent VATS pulmonary resection. We reviewed preoperative and perioperative data, morbidity, and mortality occurring within 30 days or before discharge, and long-term survival. RESULTS There were 35 men and 20 women with a mean age of 82.7 years (range, 80 to 89 years). The surgical procedures using VATS comprised 37 lobectomies, one bilobectomy, and 17 sublobar resections (7 segmentectomies, 10 wedge resections). Two lobectomies (3.6%) were converted to thoracotomy due to bleeding. The cancer was adenocarcinoma in 38 patients (62.3%), squamous cell carcinoma in 12 (19.7%), bronchioloalveolar carcinoma in 3 (4.9%), large-cell neuroendocrine carcinoma in 3 (4.9%), and others in 4 (6.6%). Postoperative complications occurred in 14 patients (25.6%), including bacterial pneumonia in 4 (7.3%), mild arterial arrhythmia in 3 (5.6%), air leak lasting more than 7 days in 3 (5.6%), pulmonary dysfunction that needed oxygen therapy in 2 (3.6%), aggressive interstitial pneumonia in 1 (1.8%), and six other minor complications. There were two operative deaths (3.6%), one due to bacterial pneumonia on postoperative day 132, and another due to aggressive interstitial pneumonia on postoperative day 105. Median hospital stay was 8.0 days. Median follow-up was 49 months. The actuarial survival rate of the 55 patients was 76.4% at 3 years and 65.9% at 5 years. CONCLUSIONS With appropriate selection of patients and procedures, VATS can be safely used for lung cancer in octogenarians with good prognostic results.

The clinicopathological features associated with skip N2 metastases in patients with clinical stage IA non-small-cell lung cancer

OBJECTIVES Understanding the clinicopathological features of patients with skip N2 metastases (SN2) in clinical early stage lung cancer is important for surgical planning and other treatment considerations; however, the factors associated with SN2 are unclear. This study aimed to investigate the clinicopathological features associated with SN2 in patients with clinical stage IA (cIA) non-small-cell lung cancer (NSCLC). METHODS We retrospectively studied patients with cIA NSCLC who underwent pulmonary resection (at least lobectomy) and extensive lymphadenectomy (more than ND2a-1) at our institution between January 2004 and December 2010. We investigated the following factors for their association with SN2: age; sex; tumour marker (carcinoembryonic antigen); tumour size on computed tomography (CT), evaluated with a lung-window (LW) and a mediastinal-window (MW) setting; pathology, with or without adenocarcinoma; differentiation; visceral pleural invasion (VPI) and vascular/lymphatic invasion. RESULTS In total, 422 patients were enrolled, with the following pathological node (pN) statuses: 331 pN0 (78.4%), 39 pN1 (9.3%) and 52 pN2 (12.3%). There were 21 (23.1%) SN2 cases among the patients with nodal metastases. When the cut-off level was defined as a receiver operating characteristic curve with MW (11.5 mm), the sensitivity and specificity of SN2 was 95.2% and 42.9%, respectively. VPI was a statistically independent relevant factor for SN2 in both the patients with cIA and in those with nodal involvement. The VPI classification comprised 59 PL-0 (64.8%), 12 PL-1 (13.2%) and 20 PL-2 (22.0%) with nodal metastases, and there was a significant difference between the three groups (P = 0.03) according to SN2 frequency. There was no difference between VPI 1 and 2 (P = 0.27). CONCLUSIONS In conclusion, our study suggests that the incidence of SN2 is significantly associated with VPI in patients with cIA NSCLC. Although MW (>11.5 mm) had a low specificity in the assessment of SN2, it had a high sensitivity, suggesting the possibility of a superior benefit compared with LW. Standard hilar and mediastinal lymph node dissection should be required in patients with suspicious VPI and MW (>11.5 mm) on preoperative CT.

RAS mutation is a prognostic biomarker in colorectal cancer patients with metastasectomy.

Studies have demonstrated a relationship between clinical outcomes after curative resection for colorectal cancer (CRC) and gene mutations of the EGFR pathway; however, no studies have examined metastatic CRC (mCRC) patients with metastasectomy. The aim of this study was to evaluate the relationship between gene mutations of EGFR pathway and clinical outcomes after metastasectomy in mCRC patients. A total of 1,053 patients histopathologically confirmed CRC received a genotyping test for the EGFR pathway from February 2012 to October 2013. Detailed information was obtained through review of medical records. Gene mutations of EGFR pathway were analyzed by Luminex assay. Overall survival (OS) and recurrence free survival were estimated by the Kaplan‐Meier method and the log‐rank test was used to compare the survival outcomes by gene mutation status. A total of 132 patients received metastasectomy. The frequencies of KRAS exon 2, KRAS exon 3.4, NRAS, BRAF, and PIK3CA mutations were 38.6% (51/132), 3.6% (5/132), 5.1% (7/132), 5.1% (7/132), and 8.7% (12/132), respectively. With a median follow‐up of 84.1 months (57.2—NA) for a survivor, the 4‐year OS rate was 65.6% for mCRC with RAS mutation, and 81.3% for mCRC with wild‐type RAS (p < 0.05). We observed a statistically significant correlation for only the RAS mutation and OS. In multivariate analysis, RAS mutation and liver metastasis were independent factors for shorter OS. There were no significant differences between gene mutations of EGFR pathway and recurrence free survival. RAS mutation in mCRC metastasectomy patients was associated with shorter overall survival.

Locoregional Control of Thoracoscopic Lobectomy With Selective Lymphadenectomy for Lung Cancer

BACKGROUND In this retrospective study, we review our experience with video-assisted thoracic surgery (VATS) lobectomy with selective lymphadenectomy for clinical stage I lung cancer and report the long-term results. METHODS From April 1999 to December 2006, 355 patients with clinical stage I lung cancer underwent a VATS lobectomy. The perioperative data, morbidity, mortality, and long-term survival of each patient were reviewed. RESULTS A thoracoscopic lobectomy was performed successfully in 348 patients (T1 N0, 237 patients; T2 N0, 111 patients), and a selective lymphadenectomy was performed in 268. Seven procedures (2.0%) were uneventfully converted to a thoracotomy and were excluded. The median operation time was 192 minutes, and the median blood loss was 100 mL. The median postoperative stay was 6 days. There were no intraoperative deaths; 2 patients died within 30 days of operation (mortality; 0.6%); 1 died of bacterial pneumonia and the other of postoperative interstitial pneumonia exacerbation. Postoperative complications occurred in 54 patients (16% morbidity). Major complications included prolonged air leak (3.7%), bacterial pneumonia (3.4%), and mild arrhythmia (3.4%). Pathologic upstaging was noted in 67 patients (19%). At a median follow-up of 43 months, total recurrence occurred in 66 cases (26 locoregional and 40 distant). The locoregional recurrence rate was 0.021 per person per year. The overall and 5-year locoregional recurrence-free survival rates were 78.5% and 76.6%, respectively. CONCLUSIONS Our findings suggest that performing VATS lobectomy with selective lymphadenectomy for clinical stage I lung cancer is safe and results in acceptable locoregional control.

High expression of programmed cell death 1 ligand 1 in lung adenocarcinoma is a poor prognostic factor particularly in smokers and wild-type epidermal growth-factor receptor cases

A clinical implication of programmed cell death 1 ligand 1 (PD‐L1) expression in lung adenocarcinoma has not been well established. We evaluated PD‐L1 expression immunohistochemically on 296 surgically resected lung adenocarcinomas to investigate a clinical implication of PD‐L1 expression especially in terms of smoking history and epidermal growth‐factor receptor (EGFR) mutation status. Patients were classified into high‐ and low‐PD‐L1 expression groups. The high‐expression group (n = 107) showed a significantly higher proportion of smokers and poor differentiation compared with the low‐expression group (n = 189). Survival analysis showed that the prognosis of the high‐expression group was worse in overall survival than that of the low‐expression group (3‐year overall survival 85 vs. 94%, P = 0.005). Stratified survival analyses showed that the prognoses of the high‐expression group were worse than those of the low‐expression group in both strata of smokers and wild‐type EGFR (P = 0.009 and P = 0.007, respectively). We found that high PD‐L1 expression was a poor prognostic factor in the smokers or the patients with wild‐type EGFR, whereas it was not the case in those who never smoked or those with EGFR mutation, implying the importance of adenocarcinoma driver mutations and etiology.

Thoracoscopic removal of middle mediastinal schwannoma originating from recurrent nerve.

Schwannomas of the left recurrent nerve are rare and there is no agreement on how to manage them without causing recurrent nerve dysfunction. We present a 63-year-old male with unspecific clinical symptoms in whom a middle mediastinal mass with a diameter of 5 cm was found incidentally. At thoracoscopic surgery,we found that the encapsulated tumor originated from left recurrent nerve and we performed tumor enucleation without sacrificing the recurrent nerve. The patient did experience postoperative hoarseness and vocal cord paralysis even though we preserved the recurrent nerve. To our knowledge, thoracoscopic removal of a left recurrent nerve schwannoma has not been reported in the literature before.

Pulmonary adenocarcinoma in situ: analyses of a large series with reference to smoking, driver mutations, and receptor tyrosine kinase pathway activation.

Lung adenocarcinomas in situ (AISs) often occur in individuals who have never smoked, although smoking is one of the main causes of lung cancer. To characterize AIS and, in particular, determine how AIS might be related to smoking, we collected a large number of AIS cases and examined clinicopathologic features, EGFR and KRAS mutation status, and activation status of receptor tyrosine kinase downstream signal pathways, including pAkt, pERK, and pStat3, using immunohistochemistry. We identified 110 AISs (36 smokers and 74 nonsmokers) among 1549 adenocarcinomas resected surgically during 1995 to 2010. Between the AIS of smokers and nonsmokers, only the sex ratio was significantly different; all the other clinicopathologic factors including TTF-1 and driver mutations were not significantly different: EGFR and KRAS mutation rates (smokers:nonsmokers) were 61:58 (%) (P=0.7) and 6.1:1.4 (%) (P=0.2), respectively, whereas, in invasive adenocarcinomas, the rates were 41:69 (%) (P<0.001) and 9.4:2.3 (%) (P<0.04), respectively. For pAkt and pERK, around 40% to 50% of AISs were positive, and for pStat3, >80% were positive, with no significant differences between smokers and nonsmokers with AIS. Mucinous AIS (n=8) rarely harbored KRAS mutations and expressed significantly less pStat3 (P<0.001) than nonmucinous AIS. Taken together, AIS occurs predominantly in female individuals and nonsmokers. However, characteristics of AIS arising in smokers and nonsmokers were similar in terms of cell lineage, driver mutations, and receptor tyrosine kinase pathway activation. Our results suggest that smoking is not a major cause of AIS. Rather, smoking may play a role in progression of AIS to invasive adenocarcinoma with AIS features.

Prognostic Significance of Tumor Size of Small Lung Adenocarcinomas Evaluated with Mediastinal Window Settings on Computed Tomography

Background We aimed to clarify that the size of the lung adenocarcinoma evaluated using mediastinal window on computed tomography is an important and useful modality for predicting invasiveness, lymph node metastasis and prognosis in small adenocarcinoma. Methods We evaluated 176 patients with small lung adenocarcinomas (diameter, 1–3 cm) who underwent standard surgical resection. Tumours were examined using computed tomography with thin section conditions (1.25 mm thick on high-resolution computed tomography) with tumour dimensions evaluated under two settings: lung window and mediastinal window. We also determined the patient age, gender, preoperative nodal status, tumour size, tumour disappearance ratio, preoperative serum carcinoembryonic antigen levels and pathological status (lymphatic vessel, vascular vessel or pleural invasion). Recurrence-free survival was used for prognosis. Results Lung window, mediastinal window, tumour disappearance ratio and preoperative nodal status were significant predictive factors for recurrence-free survival in univariate analyses. Areas under the receiver operator curves for recurrence were 0.76, 0.73 and 0.65 for mediastinal window, tumour disappearance ratio and lung window, respectively. Lung window, mediastinal window, tumour disappearance ratio, preoperative serum carcinoembryonic antigen levels and preoperative nodal status were significant predictive factors for lymph node metastasis in univariate analyses; areas under the receiver operator curves were 0.61, 0.76, 0.72 and 0.66, for lung window, mediastinal window, tumour disappearance ratio and preoperative serum carcinoembryonic antigen levels, respectively. Lung window, mediastinal window, tumour disappearance ratio, preoperative serum carcinoembryonic antigen levels and preoperative nodal status were significant factors for lymphatic vessel, vascular vessel or pleural invasion in univariate analyses; areas under the receiver operator curves were 0.60, 0.81, 0.81 and 0.65 for lung window, mediastinal window, tumour disappearance ratio and preoperative serum carcinoembryonic antigen levels, respectively. Conclusions According to the univariate analyses including a logistic regression and ROCs performed for variables with p-values of <0.05 on univariate analyses, our results suggest that measuring tumour size using mediastinal window on high-resolution computed tomography is a simple and useful preoperative prognosis modality in small adenocarcinoma.

Prognostic significance of CpG island methylator phenotype in surgically resected small cell lung carcinoma

Methylation is closely involved in the development of various carcinomas. However, few datasets are available for small cell lung cancer (SCLC) due to the scarcity of fresh tumor samples. The aim of the present study is to clarify relationships between clinicopathological features and results of the comprehensive genome‐wide methylation profile of SCLC. We investigated the genome‐wide DNA methylation status of 28 tumor and 13 normal lung tissues, and gene expression profiling of 25 SCLC tissues. Following unsupervised hierarchical clustering and non‐negative matrix factorization, gene ontology analysis was performed. Clustering of SCLC led to the important identification of a CpG island methylator phenotype (CIMP) of the tumor, with a significantly poorer prognosis (P = 0.002). Multivariate analyses revealed that postoperative chemotherapy and non‐CIMP were significantly good prognostic factors. Ontology analyses suggested that the extrinsic apoptosis pathway was suppressed, including TNFRSF1A, TNFRSF10A and TRADD in CIMP tumors. Here we revealed that CIMP was an important prognostic factor for resected SCLC. Delineation of this phenotype may also be useful for the development of novel apoptosis‐related chemotherapeutic agents for treatment of the aggressive tumor.