Kyukwang Chung

Serum AGR2 as an early diagnostic and postoperative prognostic biomarker of human lung adenocarcinoma

In the present study, the human orthologue of the secreted Xenopus laevis anterior gradient 2 (AGR2) protein was evaluated as a potential serum biomarker of lung adenocarcinoma. AGR2 protein levels were preoperatively measured in the serum of 111 primary lung adenocarcinoma patients and in 46 non-cancer controls with subsequent calculation of sensitivity and specificity in comparison with serum CEA levels. Correlations with clinicopathological variables were also assessed and survival analyses were performed according to the Kaplan-Meier method and differences determined with the log-rank test. The mean serum AGR2 level of lung adenocarcinoma patients in each stage, even Stage I, was significantly higher than in non-cancer controls (P < 0.001 for all stages, Mann-Whitney U test). The sensitivity was 65.8% (52.9% for stage IA), even higher than that of CEA, which was 45.0% (29.4% for stage IA), and the specificity was 87.0% according to the ROC curve (AUC=0.858). Positive serum AGR2 expression was significantly associated with the incidence of recurrence after surgery (P=0.025) and with a poor prognosis (P=0.037 for overall survival and P=0.004 for disease-free survival). Preoperative serum AGR2 might become a clinically useful biomarker for early detection, prediction of recurrence and prognosis with lung adenocarcinomas.

Myristoylated alanine-rich C-kinase substrate as a prognostic biomarker in human primary lung squamous cell carcinoma.

To identify novel biomarkers for the diagnosis and prognosis of human primary lung squamous cell carcinoma (SCC), we compared the spectrum of proteins expressed in SCC and in the adjacent non-cancer tissue, using QSTAR Elite liquid chromatography with tandem mass spectrometry (LC-MS/MS), coupled with iTRAQ technology. We identified 410 proteins differentially expressed in more than 75% of patients, and validated the expression of candidate target proteins by immunohistochemistry. Based on the results of LC-MS/MS, Ingenuity Pathway Analysis and immunohistochemical analyses, myristoylated alanine-rich C-kinase substrate (MARCKS) (upregulated 2.28-fold, p< 0.005) was selected as a potential biomarker of human lung SCC. In order to evaluate the association between patient prognosis and the expression of candidate biomarkers, univariate survival analysis was performed with disease-specific survival curves according to the Kaplan-Meier method, and differences in survival were assessed with the log-rank test. Immunohistochemical evaluation of MARCKS in 99 patients with lung SCC revealed a significant association between positive expression and poor prognosis compared with patients with negative expression (log-rank test; p=0.024). These results indicate that MARCKS may represent a potential biomarker for the prognosis of primary lung SCC.

Role of pulmonary resection in the diagnosis and treatment of limited-stage small cell lung cancer: revision of clinical diagnosis based on findings of resected specimen and its influence on survival

PurposeOur aims were to evaluate (1) the result of surgical treatment of limited-stage small cell lung cancer (SCLC) by examining long-term survival and prognostic factors, (2) the diagnostic role of surgery by comparing clinical and histopathological diagnoses and staging, and (3) the impact of preoperative diagnostic accuracy on survival.MethodsWe retrospectively reviewed the clinical profiles of 37 patients treated at our institution between January 1990 and December 2007 for SCLC diagnosed using surgical specimens.ResultsThe median follow-up period was 41.2 months, and the 5-year survival rate was 57.5%. Lobectomy or wider resection was performed alone in 33 cases and with mediastinal dissection in 29 cases. Fifteen patients did not receive chemotherapy. SCLC was diagnosed preoperatively or intraoperatively in 75% and non-SCLC in 25%. Clinical stage 1 disease was diagnosed in 29 patients; however, pathological stage 1 was seen in only 20. Patients at pathological stage 1 disease showed better survival than those at stage 2, but a similar result was not obtained in the case of clinical stage of the disease. Tumor size and nodal stage were the only significant factors influencing survival in a multivariate analysis. The adequacy of preoperative clinical diagnosis of tumor extensiveness, nodal involvement, and clinical stage did not significantly influence survival.ConclusionSurgery for limited-stage SCLC was associated with a favorable survival rate and provided important pathological information that can help predict survival. Accuracy of preoperative diagnoses showed no apparent impact on survival for surgically treated SCLC patients.

Sialyl Lewis X as a predictor of skip N2 metastasis in clinical stage IA non-small cell lung cancer

BackgroundRadical segmentectomy has been performed for small-sized non-small cell lung cancer (NSCLC). However, underestimation of mediastinal lymph node metastasis in the absence of hilar or interlobar metastasis (skip N2) affects surgical strategy. Our aim was to investigate preoperative and intraoperative predictors of skip N2 in clinical stage (c-stage) IA NSCLC.MethodsFrom 1998 to 2011, 279 patients (155 men and 124 women) with c-stage IA NSCLC (230 pN0, 17 pN1, 12 skip N2, 20 non-skip N2) underwent systematic lobectomy (R0 resection) at our institute. We compared preoperative serum concentrations of carcinoembryonic antigen, cytokeratin 19 fragment, sialyl Lewis X (SLX), and pre- and intraoperative clinicopathological features of pN0 and skip N2 patients. Receiver operator characteristic (ROC) curve analysis was performed to distinguish between the two patient groups.ResultsThe 5-year survival rate of skip N2 patients was 78.6%, higher than that of non-skip N2 patients (44.9%), and not significantly different than that of pN0 (86.7%) or pN1 patients (82.4%). The mean serum SLX concentration in skip N2 patients (28.0 U/ml) was elevated compared to that in pN0 patients (22.9 U/ml). In ROC analysis of SLX, the area under the curve was 0.710, and the optimal cut-off value was 21.4 U/ml (sensitivity, 91.7%; specificity, 51.7%). In multivariate analysis, SLX was an independent predictor of skip N2 in patients with c-stage IA NSCLC (odds ratio, 9.43; p = 0.006).ConclusionsSkip N2 metastasis is common in patients with c-stage IA NSCLC with high serum SLX, and lobectomy with complete dissection of hilar and mediastinal lymph nodes should remain the standard surgical procedure for these cases.

Complexin-2 (CPLX2) as a potential prognostic biomarker in human lung high grade neuroendocrine tumors.

The present study aimed to identify novel useful clinical biomarker of high grade lung neuroendocrine tumors (LNETs). Based on the results of QSTAR LC-MS/MS analysis, we selected complexin-2 (CPLX2) (upregulated 8.7-fold) as a potential biomarker in high grade human LNETs, and validated its expression immunohistochemically in comparison with non-small cell lung carcinomas (NSCLCs). CPLX2 was strongly positive in 16.3% of examined LNETs, but completely negative in all adjacent non-cancerous tissues and NSCLCs. Importantly, positive CPLX2 expression was associated with lymph vessel invasion (P=0.016), pathological stage (P=0.031), and poor disease-specific survival (P=0.004) of patients with LNETs. Preoperative serum CPLX2 level measured by ELISA was significantly elevated in high grade LNETs as compared with %NCs non-cancer controls (NCs) (P=0.002) and NSCLCs (P< 0.001). Receiver operating characteristic (ROC) curve analysis was used for separating high-grade LNET patients from NSCLC patients. The area under the ROC curve (AUC) was 0.825. The calculated optimal cut-off point for CPLX2 level in the serum was 17.8 pg/ml (Youden index=0.591), while sensitivity and specificity was 94.1% and 65.0%, respectively. CPLX2 is suggested as a novel potential clinically useful biomarker for the diagnosis, prognosis and adequate choice of therapy for patients with high grade LNETs.

Preoperative serum value of sialyl Lewis X predicts pathological nodal extension and survival in patients with surgically treated small cell lung cancer

We investigated various tumor markers in patients with surgically treated small cell lung cancer (SCLC) to identify the markers closely correlated to pathological staging and to predict survival by retrospective analyses.

Relationship between Perioperative N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) and Complications in Thoracic Surgery

Background: In cardiac surgery, the N-terminal pro-brain natriuretic peptide (NT-proBNP) level is reportedly correlated with the onset of postoperative complications. We examined the relationship between the NT-proBNP level and perioperative complications in thoracic surgery and elucidated the significance of NT-proBNP measurement. Methods: We evaluated 48 patients excluding hemodialysis patients who underwent lung resection from November 2015 to February 2016. NT-proBNP measurement was performed three times preoperatively on postoperative days 2 and 5. We examined the relationship between clinical background factors such as preoperative comorbidity and the development of postoperative complications. Based on established criteria for surgical complications (Clavien-Dindo classification), grade ≥ II was defined as a complications. We classified the patients into two groups (with or without complications) and compared and examined the background factors between the groups. Results: The study included 48 patients (33 male, 15 female) with an average age of 72 years (range, 35 - 86 years). Preoperative comorbidities included cardiovascular disease in five patients, diabetes mellitus in four, and chronic obstructive pulmonary disease in six. The average operation time was 163 (29 - 308) minutes, and the bleeding volume was 30 (10 - 620) ml. Early complications were confirmed in 11 patients, and late complications were confirmed in 7 patients. A high NT-proBNP level on postoperative day 5 was an independent risk factor for late complications. Conclusion: The perioperative NT-proBNP level is considered to be a predictor of complications. Its measurement is useful for predicting postoperative complications, and careful perioperative management is required for patients with high levels.

Pulmonary Resection for Lung Cancer Following Transcatheter Aortic Valve Implantation for Severe Aortic Valve Stenosis: A Case Report

An 82-year-old woman was referred to our hospital because of dyspnea on effort. Echocardiography revealed severe aortic valve stenosis (AS). Simultaneously, chest computed tomography (CT) revealed a 19-mm nodule in the lower lobe of the right lung, and bronchoscopic biopsy revealed adenocarcinoma. She underwent transcatheter aortic valve implantation (TAVI) for severe AS. Three weeks later, she underwent lower lobectomy of the right lung and mediastinal dissection for the lung cancer. Her postoperative course was good, and she was discharged 8 days postoperatively. In conclusion, we encountered a patient who successfully underwent pulmonary resection for lung cancer following TAVI for severe AS. We suggest that pulmonary resection following TAVI is an acceptable choice for lung cancer in patients with severe AS because of the lack of a need for cardiopulmonary bypass, the high safety and efficacy of two-stage therapy, and the short period between the two therapies.

Neoadjuvant chemotherapy and surgery for transdiaphragmatic liver invasion of primary lung cancer

A 75‐year‐old woman presented with intermittent dull abdominal pain, gradually exacerbating over eight months. Computed tomography demonstrated a large mass straddling both the right lower lobe of the lung and the right hepatic lobe. An 18‐fluoro‐2‐deoxy‐D‐glucose positron emission computed tomography scan (PET/CT) demonstrated high accumulation in the lesion and carinal lymph nodes. Transbronchial biopsy revealed squamous cell carcinoma; thus, primary lung cancer with transdiaphragmatic invasion into the liver was diagnosed. Chemotherapy with carboplatin (AUC = 5) on day one and weekly paclitaxel (70 mg/m2) doses were introduced for four courses. The size of the main tumor was reduced and the mediastinal lymph node accumulation disappeared in a subsequent PET/CT. Thus, en‐bloc radical resection of the lung tumor by right lower lobectomy with partial resection of invaded middle lobe and the diaphragm, subsegmentectomy of the liver, and standard mediastinal dissection were undertaken. The postoperative course was uneventful and the patient was discharged on day 30. Her nutrition status dramatically improved and she gained five kilograms of body weight in two months following the resection. The patient, however, then had a fall and suffered femur and multiple pelvic fractures and died of acute pneumonia five weeks after the femur fixation and 14 weeks after the lung surgery.