Shoji Hanada

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.

Primary Pulmonary Meningioma Presenting with Hemoptysis on Exertion

An 18-year-old woman presented with hemoptysis during long-distant running. A chest computed tomographic scan revealed a well-demarcated, round-shaped, solitary mass (3.0 cm in diameter) in the left pulmonary hilum. The bleeding was getting more often and a left upper lobectomy was carried out to avoid critical airway bleeding. A solid proliferation of short spindle cells with a remarkable whorl pattern was demonstrated histologically. Immunohistochemical studies showed positive for vimentin and S-100, and focally positive for epithelial membrane antigen. Primary pulmonary meningioma was thus diagnosed. The patient is well without recurrent disease 15 months after surgery.

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.

Inverted Intercostal Hernia of Soft Tissue Manifested as Slow-Growing Chest Wall Tumor After Thoracotomy

An 80-year-old woman had an asymptomatic chest wall tumor. She had undergone thoracotomy to treat a benign lesion 11 years previously. Chest computed tomography revealed a convex lens-shaped mass 7 cm in diameter in the chest wall. Positron emission tomography demonstrated mild accumulation of F-deoxyglucose. We performed an exploratory thoracotomy; however, no mass lesion was found. Therefore, we thought that the soft tissue of the back was drawn into the pleural cavity through the widened intercostal space during the previous thoracotomy. We simply aligned the ribs using heavy surgical sutures. The patient has experienced good recovery, with no recurrence since the surgery.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type arising in the pleura with pleural fibrous plaques in a lathe worker

Our patient was an 86-year-old man who had worked as a lathe operator for 40 years. He had no history of tuberculosis, pyothorax, or autoimmune disease. He had not been exposed to asbestos. He was asymptomatic, but an imaging study showed gradually increasing pleural plaques. A biopsy specimen of a pleural lesion showed sclerosis of the pleura and diffuse infiltration of small- to medium-sized B lymphocytes. Polymerase chain reaction-based analysis detected monoclonal rearrangement of immunoglobulin heavy-chain genes. Histologic diagnosis was extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma). The lymphoma was negative for Epstein-Barr virus. We report a rare case of a metal worker with MALT lymphoma arising in the pleura with pleural fibrous plaques. It is speculated that MALT lymphoma might develop in the background of pneumoconiosis. Inflammatory and/or immunologic reactions to metal particles might contribute to the oncogenesis of this tumor.

Transbronchial occlusion of a malignant bronchopleural fistula with cyanoacrylate glue.

A 73-year-old man who had undergone surgery for lingual cancer, followed by radiation therapy and chemotherapy, presented with severe dyspnea. A chest radiograph revealed a left tension pneumothorax. An immediate tube thoracostomy alleviated his dyspnea. A chest computed tomography scan showed multiple large cystic tumors in both lungs. Squamous cell carcinoma was cytologically proven in the pleural effusion. A malignant bronchopleural fistula due to a metastatic pulmonary tumor was diagnosed. Surgical interventions were tried twice. However, air leakage occurred when the rapidly recurring tumor caused bilateral pneumothoraces. Thus, bronchoscopic closure was conducted. A flexible video bronchoscope and a thin catheter were inserted into the targeted left bronchiolus. The lumen of the catheter was filled with water. Cyanoacrylate glue and lipiodol were mixed in 2 syringes, and the mixture was slowly injected and then flushed with water. As soon as the lipiodol accumulation was visualized by radiograph fluoroscopy, the air leakage stopped. Pleurodesis with the intrathoracic administration of OK-432 was added to both pleural cavities, and the left and right chest tubes were removed on the third and fifth days, respectively. The patient was discharged the following day. However, he died of the disease a month later.