Low alanine aminotransferase levels are independently associated with mortality risk in patients with atrial fibrillation.

Extremely low alanine aminotransferase (ALT) may reflect aging, frailty, sarcopenia, and malnutrition in several cardiovascular diseases, but the association between low ALT and patient characteristics, cardiovascular and all-cause mortality is not well investigated in the population with atrial fibrillation. We conducted a post hoc analysis of a prospective, observational multicenter study. Patients with nonvalvular AF in the SAKURA AF Registry (n = 3156) were classified into 3 tertiles according to baseline ALT: first (ALT ≤ 15 U/L, n = 1098), second (15 < ALT < 23 U/L, n = 1055), and third (ALT ≥ 23 U/L, n = 1003). The first tertile had an older age; lower body mass index (BMI); higher prevalence of heart failure; and lower hemoglobin, total cholesterol, and triglycerides (all P < 0.05). During median 39.2 months follow-up, the first tertile had significantly higher incidences of cardiovascular and all-cause mortality (log-rank P < 0.001). Lower ALT was significantly associated with the incidence of cardiovascular and all-cause mortality, even after adjusting for clinically relevant factors (P < 0.05). Low ALT may reflect aging, sarcopenia, and malnutrition and be independently associated with a high risk of all-cause mortality in patients with AF.

Gastrointestinal Bleeding From Oral Anticoagulant Therapy Among Japanese Patients With Atrial Fibrillation Identified From the SAKURA Atrial Fibrillation Registry.

BACKGROUND: In the Japanese clinical setting, the prevalence, potential cofounders of gastrointestinal (GI) bleeding from anticoagulant therapy, including direct oral anticoagulants (DOACs) and warfarin, and prognosis after GI bleeding are unclear.Methods and Results:We examined about GI bleeding from anticoagulant therapy using data from the SAKURA AF Registry, a prospective multicenter registry in Japan. Among 3,237 enrollees, 48.8% (n=1,561) were warfarin users and 51.2% (n=1,676) DOAC users. GI bleeding was identified in 68 patients (2.1%). No incidental differences in GI bleeding were observed between the DOAC and warfarin users (32 [1.9%] patients [0.67 events per 100 person-years] vs. 36 [2.3%] patients [0.75 events per 100 person-years], respectively; P=0.43). Multivariate Cox proportional hazard model analysis revealed that creatinine (hazard ratio [HR] 1.379, 95% confidence interval [CI] 1.091-1.743 P=0.007) and hemoglobin (HR 0.814, 95% CI 0.705-0.941, P=0.005) remained independent determinants of GI bleeding. Patients experiencing GI bleeding events had a higher risk of all-cause death (18%) than those without GI bleeding (6%) (P=0.045). CONCLUSIONS: GI bleeding was strongly associated with anemia and renal impairment. Patients experiencing GI bleeding had higher risk for all-cause death than those without GI bleeding.

Impact of the Fibrosis-4 Index on Risk Stratification of Cardiovascular Events and Mortality in Patients with Atrial Fibrillation: Findings from a Japanese Multicenter Registry.

BACKGROUND: Liver diseases drive the development and progression of atrial fibrillation (AF). The Fibrosis-4 (FIB4) index is a non-invasive scoring method for detecting liver fibrosis, but the prognostic impact of using it for AF patients is still unknown. Herein, we evaluated using the FIB4 index as a risk assessment tool for cardiovascular events and mortality in patients with AF. METHODS: We performed a post-hoc analysis of a prospective, observational multicenter study. A total of 3067 patients enrolled in a multicenter Japanese registry were grouped as first tertile (FIB4 index < 1.75, n = 1022), second tertile (1.75 ≤ FIB4 index < 2.51, n = 1022), and third tertile (FIB4 index ≥ 2.51, n = 1023). RESULTS: The third tertile had statistically significant results: older age, lower body mass index, increased heart failure prevalence, and lower clearances of hemoglobin and creatinine (all p < 0.05). During the follow-up period, incidences of major bleeding, cardiovascular events, and all-cause mortality were significantly higher for the third tertile (all p < 0.05). After multivariate adjustment, the third tertile associated independently with cardiovascular events (HR 1.72; 95% CI 1.31-2.25) and all-cause mortality (HR 1.43; 95% CI 1.06-1.95). Adding the FIB4 index to a baseline model with CHA2DS2-VASc score improved the prediction of cardiovascular events and all-cause mortality, as shown by the significant increase in the C-statistic (all p < 0.05), net reclassification improvement (all p < 0.001), and integrated discrimination improvement (all p < 0.001). A FIB4 index ≥ 2.51 most strongly associated with cardiovascular events and all-cause mortality in AF patients with high CHADS2 scores (all p < 0.001). CONCLUSIONS: The FIB4 index is independently associated with risks of cardiovascular events and all-cause mortality in AF patients.

University hospitals, general hospitals, private clinics: Place-based differences in patient characteristics and outcomes of AF-A SAKURA AF Registry Substudy.

BACKGROUND: Relations between characteristics and outcomes of patients in Japan with atrial fibrillation (AF) and the type of medical facility providing their outpatient care are unclear. METHODS AND RESULTS: We compared patient characteristics and outcomes between 2 university hospitals (n=1178), 20 general hospitals (n=1308), and 41 private clinics (n=751) (follow-up: 39.3 months) in the prospective SAKURA AF Registry. Private clinic patients were significantly older than university hospital and general hospital patients (73.4±9.2 vs. 70.3±9.8 and 72.6±8.9 years; p<0.001), and these patients' CHADS2 scores were significantly lower than general hospital, but higher than university hospital patients (1.8±1.1 vs. 2.0±1.2 and 1.6±1.1; p<0.001). The Kaplan-Meier incidences of stroke/systemic embolism (SE) (1.72 vs. 1.58 vs. 0.84 events per 100 patient-years; p=0.120), a cardiovascular event (4.09 vs. 2.44 vs. 1.40; p<0.001), and death were higher (2.39 vs. 2.21 vs. 1.24; p=0.015) for university and general hospital patients than for private clinic patients; the incidences of major bleeding were equivalent (1.78 vs. 1.33 vs. 1.16; p=0.273). After multivariate adjustments, this trend persisted. CONCLUSIONS: Adverse clinical events at small to large hospitals appear to be higher than those at private clinics, suggesting that careful attention for preventing stroke/SE and cardiovascular events should be paid to patients at a university or general hospital.

Adverse clinical events in Japanese atrial fibrillation patients with and without coronary artery disease-findings from the SAKURA AF Registry.

Background: Although atrial fibrillation (AF) and coronary artery disease (CAD) are increasing in prevalence in Japan, real-world data regarding clinical outcomes in Japanese AF patients with CAD are limited.Methods: The SAKURA AF Registry is a prospective multi-center registry created to investigate outcomes of oral anticoagulant (OAC) use in Japanese AF patients. A study was conducted involving 3237 enrollees from 63 Tokyo-area institutions who were followed up for a median of 39.3 months. Clinical adverse events were compared between the patients accompanied with (n = 312) and without CAD (n = 2925).Results: The incidence of cardiovascular events and all-cause mortality rates were significantly higher among patients with CAD than among those without CAD (5.98 vs 2.52 events per 100 patient-years, respectively, p < 0.001; 3.27 vs 1.94 deaths per 100 patient-years, respectively, p = 0.012), but there was no difference in strokes/transient ischemic attacks or systemic embolisms (1.70 vs 1.34). After a multivariate adjustment, CAD remained a risk factor for cardiovascular events (hazard ratio [HR] = 1.57, 95% confidence interval [CI] = 1.08-2.25, p = 0.018). Among CAD patients, the propensity score-adjusted risk for major bleeding was significantly decreased among direct oral anticoagulant (DOAC) users in comparison to that among warfarin users (HR = 0.29, 95% CI = 0.07-0.94, p = 0.04), but other adverse clinical events did not differ significantly between these two groups.Conclusions: CAD did not appear to be a major determinant of strokes/TIAs, major bleeding, or all-cause mortality, but appeared to increase the risk of cardiovascular events in Japanese AF patients. The risk of major bleeding in CAD patients appeared to decrease when a DOAC rather than warfarin was administered. The data suggested that patients with AF and concomitant CAD require careful management and follow-up to reduce cardiovascular risks, and DOACs may be a better choice over warfarin when considering the risk of major bleeding.

Oral anticoagulant use and clinical outcomes in elderly Japanese patients: findings from the SAKURA AF Registry.

Direct-acting oral anticoagulants (DOACs) are widely used in aged Japanese patients with atrial fibrillation (AF), but outcome data for such patients are limited. We compared outcomes between 1895 (58.5%) patients aged < 75 years (non-elderly), 1078 (33.3%) 75-84 years (elderly) and 264 (8.2%) ≥ 85 years (very elderly) enrolled in a prospective multicenter registry. Kaplan-Meier analysis (median follow-up: 39.3 months) revealed a significantly high incidence of stroke/systemic embolism (SE) among the very elderly relative to that among the non-elderly or elderly (3.2 vs. 1.2 and 1.5 events per 100 patient-years, p < 0.001). Major bleeding in the non-elderly group was significantly infrequent relative to that among the elderly or very elderly group (1.1 vs. 1.6 vs. 1.8 events, p = 0.033). After multivariate adjustment, the stroke/SE incidence was comparable between DOAC and warfarin users, regardless of age, but major bleeding decreased significantly among very elderly DOAC users (adjusted HR 0.220, 95% CI 0.042-0.920). The greater increasing incidence of stroke/SE than major bleeding as patients age suggests that stroke prevention should outweigh the bleeding risk when anticoagulants are being considered for aged patients. Our data indicated that DOACs can be a therapeutic option for stroke prevention in very elderly patients.

Clinical Outcomes of Off-Label Dosing of Direct Oral Anticoagulant Therapy Among Japanese Patients With Atrial Fibrillation Identified From the SAKURA AF Registry.

BACKGROUND: Off-label dosing of direct oral anticoagulants (DOACs) is encountered clinically among patients with atrial fibrillation (AF), although data on the clinical outcomes of over- and under-dosing are lacking in Japan. Methods and Results: We examined the clinical outcomes of off-label DOAC dosing using the SAKURA AF Registry, a prospective multicenter registry in Japan. Among 3,237 enrollees, 1,676 under any of the 4 DOAC regimens were followed up for a median of 39.3 months: 746 (45.0%), appropriate standard-dose; 477 (28.7%), appropriate low-dose; 66 (4.0%), over-dose; and 369 (22.2%) under-dose. Compared with the standard-dose group, patients in the under- and over-dose groups were significantly older and had a higher stroke risk. After multivariate adjustment, stroke/systemic embolism (SE) and death events were equivalent between the standard- and under-dose groups, but major bleeding events tended to be lower in the under-dose group (hazard ratio [HR] 0.474, P=0.0739). Composite events (stroke/SE, major bleeding, or death) were higher in the over-dose than in the standard-dose group (HR 2.714, P=0.0081). CONCLUSIONS: Clinical outcomes were not worse for under-dose than for standard-dose users among patients with different backgrounds. Over-dose users, however, were at higher risk for all clinical events and required careful follow-up. Further studies are needed to clarify the safety and effectiveness of off-label DOAC dosing in Japan.

Different determinants of vascular and nonvascular deaths in patients with atrial fibrillation: A SAKURA AF Registry substudy.

BACKGROUND: The incidence and causes of death among patients in Japan treated for atrial fibrillation (AF), a major determinant of strokes and death, with direct oral anticoagulants (DOACs) are unclear. This study's aim was two-fold: to compare the incidence and causes of death between DOAC and warfarin users in Japan and to identify the factors associated with vascular and nonvascular death in the Japanese AF population. METHODS: The study was based on the SAKURA AF registry, in which clinical events were tracked in 3267 enrollees from 63 institutions for 2-4 years. Enrollees included warfarin users (n=1577) and users of any of 4 DOACs (n=1690). The incidence, cause, and major determinants of death were analyzed. RESULTS: During a median 39.3-month follow-up, 200 patients died, with most succumbing to cardiac death (25%), malignancies (21%), or respiratory infections (20%). There was no significant difference in deaths from any cause between warfarin and DOAC users (108 vs. 92 patients, p=0.34). An age ≥75 years was found to be a major determinant of death, but the relative risk (vs. <75 years) was greater for nonvascular death (hazard ratio: 2.85 and 4.97 for age 75-84 and ≥85 years, respectively) than vascular death (2.14 and 2.98 for 75-84 and ≥85 years, respectively). Heart failure, renal dysfunction, and the type of institution were major determinants of vascular death, and a male sex, weight <50kg, and anemia were major determinants of nonvascular death. CONCLUSIONS: The results of our AF registry-based study, in which two thirds of the enrolled patients succumbed to cardiac death, malignancies, or respiratory infections within 2- 4 years and use of DOACs rather than warfarin did not reduce the mortality, indicated that a management of AF that includes prophylaxis for vascular and nonvascular events in addition to strokes is warranted.

Three-Year Clinical Outcomes Associated With Warfarin vs. Direct Oral Anticoagulant Use Among Japanese Patients With Atrial Fibrillation　- Findings From the SAKURA AF Registry.

BACKGROUND: Although direct oral anticoagulants (DOACs) are widely used in Japanese patients with atrial fibrillation (AF), large-scale investigations into their use, with suitable follow-up times and rates, are lacking. Methods and Results: The SAKURA AF Registry is a prospective multicenter registry created to investigate therapeutic outcomes of oral anticoagulant (OAC) use in Japanese AF patients. We conducted a study involving 3,237 enrollees from 63 institutions in the Tokyo area being treated with any of 4 DOACs (n=1,676) or warfarin (n=1,561) and followed-up for a median of 39.3 months (range 28.5-43.6 months). Analyses of 1- and 2-year follow-up data available for 3,157 (97.5%) and 2,952 (91.2%) patients, respectively, showed no significant differences in rates of stroke or systemic embolism (SE), major bleeding, and all-cause mortality for DOAC vs. warfarin users (1.2 vs. 1.8%/year, 0.5 vs. 1.2%/year, and 2.1 vs. 1.7%/year, respectively). Under propensity score matching, the incidence of stroke or SE (P=0.679) and all-cause death (P=0.864) remained equivalent, but the incidence of major bleeding was significantly lower (P=0.014) among DOAC than warfarin users. CONCLUSIONS: A high follow-up rate allowed us to obtain reliable data on the status of OAC use and therapeutic outcomes among AF patients in Japan. Warfarin and DOACs appear to yield equivalent 3-year stroke and all-cause mortality rates, but DOACs appear to reduce the risk of major bleeding.

Current use of direct oral anticoagulants for atrial fibrillation in Japan: Findings from the SAKURA AF Registry.

BACKGROUND: Large-scale investigations on the use of oral anticoagulants including direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) have not included Japanese patients. METHODS: We established the multicenter SAKURA AF Registry to support prospective observational research on the status of anticoagulation treatment, especially with DOAC, for AF in Japan. We enrolled 3266 AF patients treated with warfarin (n=1577) or any of 4 DOACs (n=1689) from 63 institutions (2 cardiovascular centers, 13 affiliated hospitals or community hospitals, and 48 private clinics) in the Tokyo area. RESULTS: We conducted our first analysis of the registry data, and although we found equivalent mean age between the DOAC and warfarin users (71.8±9.5 vs. 72.3±9.4 years, p=0.2117), we found a slightly lower risk of stroke (CHADS2 score of 0 or 1 [46.9% vs. 39.4%, p<0.0001]) and significantly better creatinine clearance in DOAC users (70.4±27 vs. 65.6±25.7 mL/min, p<0.0001). Importantly, we documented under-dosing in 32% of warfarin users and inappropriate-low-dosing in 19.7-27.6% of DOAC users. CONCLUSIONS: Our initial analysis of the SAKURA AF Registry data clarified the real-world use of anticoagulants, which includes DOACs and warfarin in Japan. The DOAC users were at a lower risk for stroke than the warfarin users. In 20-30% of DOAC users, the dose was inappropriately reduced.

Arterial blood gases predict long-term prognosis in stage I non-small cell lung cancer patients.

BACKGROUND: Preoperative hypercapnia and hypoxemia are reportedly risk factors for postoperative complications. This study aimed to establish the long-term survival risk associated with abnormal preoperative arterial blood gases (ABGs) in patients with non-small cell lung cancer (NSCLC). METHODS: This study involved 414 patients with stage I NSCLC who underwent lobectomy/bilobectomy with mediastinal lymph node dissection. The patients were divided into groups with normal (n = 269) and abnormal (n = 145) ABGs. RESULTS: The patients in the normal ABG group (median age 67 years) were significantly younger than those in the abnormal ABG group (median age 70 years). There were no significant differences between the groups in gender, performance status, pathological stage, histology, postoperative complications, or preoperative comorbidity, except for chronic obstructive pulmonary disease/pulmonary fibrosis. The 3-, 5- and 10-year survival rates in the normal and abnormal ABG groups were 87, 77 and 56, and 78, 63 and 42%, respectively (p = 0.006). According to multivariate analysis, age, gender, performance status, non-adenocarcinoma, differentiation of resected tumor, pathological stage, any prior tumor and abnormal ABGs (risk ratio, 1.61) were independent prognostic factors. CONCLUSIONS: Abnormal ABGs predict long-term survival risk in patients with NSCLC, which is important for planning therapeutic strategies.

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.

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.

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.

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.

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.

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.

Lobectomy for indeterminate lung tumors with a strong suspicion of lung cancer.

Wedge resection for tissue diagnosis of indeterminate lung tumors that is strongly suspected of being lung cancer, is sometimes difficult, and lobectomy, followed by a thorough pathological examination, is required. In the present report, four cases are presented, and the following indications, which have never been discussed before, are recommended for lobectomy without a pre-resectional diagnosis. First, where larger tumors are involved, and lobectomy is expected to result in a more favorable patient status and second, where the lesions are deeply located near major pulmonary vessels, or the patient is not a candidate for wedge resection or segmental resection. In each case, tolerance to surgery and detailed, informed consent for potentially complete resection are mandatory.

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.