A dramatic course after the resection of an SMARCA4-deficient undifferentiated tumour.

Thoracic SMARCA4-deficient undifferentiated tumours are ordinarily found as a huge mass with systemic metastasis, and the prognosis is poor. The potential of immunotherapy for these unresectable tumours has been reported. An asymptomatic 68-year-old man with a smoking history had a left lung mass without distant metastasis and underwent complete resection. Two months after surgery, with no adjuvant therapy, he developed multiple distant metastases with aphasia and died 4 months after surgery. Adjuvant treatment may be necessary with immune checkpoint inhibitors, with a closer follow-up to detect recurrence without symptoms.

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.

Carbon monoxide-releasing molecule-3 (CORM-3) offers protection in an in vitro model of compartment syndrome.

OBJECTIVE: Limb compartment syndrome (CS), a complication of trauma, results in muscle necrosis and cell death; ischemia and inflammation contribute to microvascular dysfunction and parenchymal injury. Carbon monoxide-releasing molecule-3 (CORM-3) has been shown to protect microvascular perfusion and reduce inflammation in animal models of CS. The purpose of the study was to test the effect of CORM-3 in human in vitro CS model, allowing exploration of the mechanism(s) of CO protection and potential development of pharmacologic treatment. METHODS: Confluent human vascular endothelial cells (HUVECs) were stimulated for 6 h with serum isolated from patients with CS. Intracellular oxidative stress (production of reactive oxygen species (ROS)) apoptosis, transendothelial resistance (TEER), polymorphonuclear leukocyte (PMN) activation and transmigration across the monolayer in response to the CS stimulus were assessed. All experiments were performed in the presence of CORM-3 (100 µM) or its inactive form, iCORM-3. RESULTS: CS serum induced a significant increase in ROS, apoptosis and endothelial monolayer breakdown; it also increased PMN superoxide production, leukocyte rolling and adhesion/transmigration. CORM-3 completely prevented CS-induced ROS production, apoptosis, PMN adhesion, rolling and transmigration, while improving monolayer integrity. CONCLUSION: CORM-3 offers potent anti-oxidant and anti-inflammatory effects, and may have a potential application to patients at risk of developing CS.

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

BACKGROUND: Radical 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. METHODS: From 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. RESULTS: The 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). CONCLUSIONS: Skip 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.

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.

Clinicopathological significance of combined analysis of cytokeratin19 expression and preoperative serum CYFRA21-1 levels in human lung squamous cell carcinoma.

BACKGROUND: To identify a useful biomarker for human lung squamous cell carcinoma (SCC), the expression of cytokeratin19 (CK19) in human SCC tissue was investigated. In addition, we examined the significance of CK19 expression levels by immunostaining and CYFRA21-1 levels in preoperative serum, and their correlation with the clinicopathologic features of human lung SCC. METHODS: To identify proteins in cancerous and non-cancerous tissues for the diagnosis and prognosis of SCC, QSTAR Elite LC-MS/MS was used. Immunostaining for CK19 was classified as either "CK19-strong" or "CK19-weak". Correlations between prognosis and both CK19 expression in tumor tissues and serum concentrations of CYFRA 21-1 were analyzed in 107 cases of lung SCC. RESULTS: The upregulation of CK19 in human squamous cell carcinoma tissues was observed by LCMS/MS. The weak expression of CK19, as determined by immunostaining intensity, was a significant predictor of poorer disease-specific survival (p = 0.032). The prognosis was significantly poorer for patients with weak CK19 immunostaining in tumor tissues and a high serum concentration of CYFRA21-1 compared with the other groups (p = 0.003). CONCLUSIONS: The combination of weak CK19 expression and high serum CYFRA21-1 levels is a predictor of poorer prognosis for patients with human lung SCC.

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.

Solitary bulky mediastinal lymph node metastasis from colon cancer.

A 75 year-old man underwent right hemicolectomy for colon cancer 3 yrs and 6 months ago, followed by chemotherapy with capecitabine. One year and 10 months later, solitary liver metastasis was resected. Five months later, a bulky mediastinal mass of 6 cm in diameter was detected by chest computed tomography and he was referred to our department. The tumor was successfully extirpated by videothoracoscopy-assisted right axillary approach. Histopathology disclosed poorly-differentiated tubular adenocarcinoma and diagnosed as metastatic mediastinal lymph node from the colon cancer. He was discharged on the day 5 and alive without disease 13 months after the mediastinal surgery.

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.

AGR2 as a potential biomarker of human lung adenocarcinoma.

BACKGROUND: The present study aimed to identify useful candidate biomarkers of lung adenocarcinoma for clinical diagnosis and treatment using proteomics technology. METHODS: We assessed frequently highly overexpressed proteins in 12 cases of lung adenocarcinoma compared with adjacent normal tissue samples by liquid chromatography tandem mass spectrometry (LC-MS/MS) coupled with isobaric tags for relative and absolute quantitation (iTRAQ) technology, and validated the expression of target proteins by immunohistochemistry in 268 lung adenocarcinoma cases. Protein expression and clinicopathological variables were compared statistically for the evaluation of novel biomarkers. RESULTS: One hundred seventy-seven proteins displaying significant quantitative changes compared with adjacent normal-appearing lung tissue were identified in more than 9 out of 12 lung adenocarcinoma patients. Based on the results of liquid chromatography tandem mass spectrometry, Ingenuity Pathway, and immunohistochemical analyses, anterior gradient homolog 2 (AGR2) (upregulated 9.9-fold) was selected as a potential biomarker of human lung adenocarcinoma. AGR2 was positive in 94% of lung adenocarcinoma patients. Negative AGR2 expression was associated with poor survival (p = 0.007). CONCLUSIONS: AGR2 is likely to become a biomarker for clinical applications.

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.

PURPOSE: Our 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. METHODS: We retrospectively reviewed the clinical profiles of 37 patients treated at our institution between January 1990 and December 2007 for SCLC diagnosed using surgical specimens. RESULTS: The 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. CONCLUSION: Surgery 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.

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

BACKGROUND AND OBJECTIVES: 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. METHODS: Reviewing database records between 1990 and 2007 revealed 36 patients with SCLC, that were grouped according to clinical and pathological stages. Receiver operating characteristic (ROC) curves were calculated for serum levels of various tumor makers to predict the pathological stage. The cut-off value was calculated from the ROC curve of the significant marker. Survival in patient groups divided by the new cut-off value was calculated. RESULTS: Serum levels of various tumor makers were not significantly different between the pathological stage groups, except for serum sialyl Lewis X (SLX). ROC curve of SLX was significantly correlated to pathological stages (P = 0.0136). The calculated SLX cut-off value was 25.1 U/ml, with 80% sensitivity and 70% specificity. Five-year survival of patients selected by this new cut-off was 82.5%, whereas that with the standard cut-off (38.0 U/ml) was 55.9%. CONCLUSIONS: Serum SLX values were associated with pathological stage and survival after surgery in SCLC patients.

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.