Desquamation of the subpleural lung parenchyma caused by empyema after pulmonary embolism: A case report.

Subpleural peripheral lung regions are mainly nourished by pulmonary arteries. Herein, we report a case in which pleural infection after pulmonary embolism caused circulation failure in the subpleural lung parenchyma (SLP) and massive desquamation of the SLP.

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.

Intensity of SLX predicts distance of tumor spread through alveolar spaces in stage I lung adenocarcinoma.

BACKGROUND: Tumor spread through alveolar spaces (STAS) is a recently described invasive pattern associated with the prognosis and recurrence of lung adenocarcinoma. This study was performed to determine whether the presence and distance of STAS can be predicted by the immunohistochemical intensity of SLX, a well-known cell adhesion protein. METHODS: In total, 245 patients with pathological stage I lung adenocarcinoma who underwent lobectomy with radical mediastinal lymph node dissection were identified from 1998 to 2012. Recurrence-free survival (RFS) was compared between patients stratified by STAS and the immunohistochemical intensity of SLX in the main tumor. Patients were divided into three groups based on the intensity of SLX staining: high (n = 108), moderate (n = 48), and low (n = 89). RESULTS: STAS was observed in 71 patients (29.0%). Patients with STAS had significantly poorer five-year RFS (67.1%) than those without STAS (84.8%). Although no relationship was observed between the existence of STAS and SLX intensity, the distance between STAS cells and the main tumor was significantly shorter in the moderate group (median 0.9 mm, range: 0.2-1.2 mm) than in the other two groups (median 1.2 mm, range: 0.4-5.0 mm). The five-year RFS rates in the high, moderate, and low groups were 80.0%, 96.0%, and 75.8%, respectively. Multivariate analysis revealed that pathological stage, lymphatic/vascular invasion, and SLX intensity were independent predictors of recurrence. CONCLUSION: SLX staining cannot predict the presence of STAS; however, it can predict the distance between STAS and the main tumor in stage I lung adenocarcinoma.

Correction to: Positive correlation between sarcopenia and elevation of neutrophil/lymphocyte ratio in pathological stage IIIA (N2-positive) non-small cell lung cancer patients.

In the original publication of the article, the title was incorrectly published as "Positive correlation between sarcopenia and elevation of neutrophil/lymphocyte ratio in pathological stage.

Rapid Progression of Tracheoesophageal Fistula Caused by Immunotherapy Administered after Tracheal Stent Placement.

Development of a tracheoesophageal fistula (TEF) is a serious complication of treatment for esophageal or lung cancer, especially following radiation therapy. However, development of a TEF as a complication of chemotherapy or tracheal stenting after surgical debulking is quite uncommon. We herein report a rare case involving a patient with advanced adenocarcinoma invading the mediastinum who rapidly developed a TEF after placement of a tracheal stent and administration of nivolumab immunotherapy. A 55-year-old heavy ex-smoker was diagnosed with lung adenocarcinoma with mediastinal invasion. Nine months after first-line therapy (chemotherapy and radiation therapy), he underwent treatment with nivolumab (3 mg/kg) as fourth-line therapy. Two weeks after the first dose, he underwent mechanical debulking of the tumor with tracheal stenting because of the rapid development of paraesophageal lymph node swelling and severe tracheal stenosis. He received a second dose of nivolumab 2 weeks later; however, imaging studies 12 days after this second dose revealed a huge fistula between the upper trachea and esophagus through a metastatic lymph node. Neither an additional stent nor replacement of the stent was considered because of the fistula site expansion and suffocation risk. Despite further treatment, the patient died of his primary disease 2 months later. Our findings will be of great interest to the readers, especially those involved in the clinical treatment of patients with advanced lung cancer treated by immunotherapy. The knowledge of potentially devastating TEF formation in the presence of transmural tracheal metastasis/invasion will allow clinicians to provide the best possible care for their patients.

Positive correlation between sarcopenia and elevation of neutrophil/lymphocyte ratio in pathological stage IIIA (N2-positive) non-small cell lung cancer patients.

OBJECTIVE: Surgical indication in stage IIIA (N2) non-small cell lung cancer is still controversial. Hence, there is a need for the identification of predictors of the postoperative outcome in these patients. Although sarcopenia is expected to be a novel predictor of postoperative outcome in these patients, the underlying clinical features of sarcopenia have not been well investigated. Elevation of neutrophil/lymphocyte ratio indicates cancer-associated inflammation and depression of anticancer immunity. We analyzed the influence of sarcopenia on postoperative prognosis, and investigated the relationship between sarcopenia and neutrophil/lymphocyte ratio in patients with stage IIIA (N2) non-small cell lung cancer. METHODS: We retrospectively investigated 69 patients with stage IIIA (N2) non-small cell lung cancer. We used the L3 muscle index as a clinical measurement of sarcopenia, and divided patients into the sarcopenic (n = 21) and the non-sarcopenic group (n = 48). We then investigated the effect of sarcopenia on postoperative prognosis, and evaluated the correlation between sarcopenia and neutrophil/lymphocyte ratio. RESULTS: This study included 47 males and 22 females. Univariate analysis revealed that sarcopenia, performance status, and serum cytokeratin-19 fragment level were predictors of poor prognosis; multivariate analysis revealed that performance status and sarcopenia were independent predictors of poor prognosis. The presence of sarcopenia was significantly correlated with neutrophil/lymphocyte ratio elevation. CONCLUSIONS: Sarcopenia is a novel predictor of poor prognosis in patients with stage IIIA (N2) non-small cell lung cancer. Neutrophil/lymphocyte ratio elevation might be the reason for poor prognosis in sarcopenic patients.

Pirfenidone suppresses polarization to M2 phenotype macrophages and the fibrogenic activity of rat lung fibroblasts.

Pirfenidone is a representative medication to treat interstitial pulmonary fibrosis. Researchers reported pirfenidone (>100 µg/ml) significantly suppressed fibroblast growth in vitro. However, clinically, the maximum concentration of pirfenidone in the blood is approximately 10 µg/ml. We hypothesized there might be an additional mechanism of pirfenidone to fibroblasts indirectly. Macrophages are known to control the activation of fibroblasts via the regulation of inflammatory M1 and suppressive M2 polarization. The aim of this study was to investigate the effects of pirfenidone on alveolar macrophage polarization. Rat alveolar macrophages (NR8383) were stimulated in vitro with lipopolysaccharide (LPS) + interferon (IFN)-γ, or interleukin (IL)-4 + IL-13. Expression of M1 and M2 markers and supernatant's levels of TGF-ß1 were assessed after pirfenidone treatment (0-100 µg/ml). Treatment with LPS + INF-γ or IL-4 + IL-13 significantly increased the expression of M1 and M2 markers, respectively. In macrophage polarization assays, pirfenidone significantly reduced the expression of M2 markers at concentrations greater than 10 µg/ml but had no effect on the expression of M1 markers. At these concentrations, pirfenidone significantly reduced TGF-ß1 levels in NR8383 culture supernatants. In rat lung fibroblasts treated with NR8383 culture supernatants, pirfenidone significantly suppressed proliferation, and the collagen mRNA and protein levels. In conclusion, our results demonstrated that pirfenidone suppressed polarization to M2 macrophages at clinically relevant concentrations and suppressed the rat lung fibroblasts fibrogenic activity.

Neutrophil-lymphocyte ratio predicts recurrence in patients with resected stage 1 non-small cell lung cancer.

BACKGROUND: The aim was to determine the prognostic value of the neutrophil-lymphocyte ratio (NLR) in patients with completely resected stage 1 non-small cell lung cancer (NSCLC). METHODS: The study enrolled 382 NSCLC patients, and an optimal NLR cutoff value was determined by ROC analysis. Patients were divided by preoperative NLR into low (< 1.5, n = 99), intermediate (1.5 ≤ NLR < 3.5, n = 245), and high (NLR ≥ 3.5, n = 38) value groups. Serum diacron-reactive oxygen metabolites (d-ROMs) were assayed in 33 consecutive patients and used as an indicator of oxidative stress. RESULTS: The mean NLR in patients with high d-ROMs (> 300 U.CARR, n = 16) was 1.72 ± 0.67, which was significantly higher than that in patients with low d-ROMs (1.41 ± 0.39, n = 17; P = 0.018). The 3-, 5- and 10-year survival rates in the three NLR groups were 92, 77, and 59% (low); 82, 70, and 50% (intermediate); and 76, 58, and 32% (high) (P = 0.034). The 1-, 3- and 5-year recurrence-free survival rates in the three groups were 98, 90, and 86% (low), 91, 77, and 74% (intermediate); and 92, 77, and 68% (high) (P = 0.033). Multivariate analysis found that although NLR was not predictive of overall survival, high NLR was an independent risk factor of recurrence (hazard ratio: 2.03, 95% confidence interval: 1.17-3.79, P = 0.011) as were as age, pathological stage, tumor differentiation, and lymph-vascular invasion. CONCLUSIONS: A low preoperative NLR predicted good prognosis, and was associated with low systemic inflammation status in patients with stage 1 NSCLC. It may be helpful when considering intervals of routine follow-up or choice of adjuvant therapy.

Impact of multiple malignancies on surgical outcomes in patients with 1 cm or smaller non-small cell lung cancer.

BACKGROUND: Because most patients with small-sized non-small cell lung cancer (NSCLC) are asymptomatic, their lesions are detected by cancer screenings or routine checkups for other diseases. Incidences of multiple malignancies have been reported to be 27% in patients with stage I-III NSCLC. Some patients have treatment histories for other malignancies, and their small-sized NSCLC was incidentally detected during follow-up. There is no established report regarding the influence of multiple malignancies on small-sized NSCLC prognosis. Therefore, we investigated the correlation between multiple malignancies and surgical outcomes in patients with small-sized NSCLC. METHODS: In total, 44 patients underwent definitive pulmonary resection for NSCLC of 1 cm or smaller between January 2003 and December 2012. Tumor size was measured by macroscopic findings of the resected specimens, and we then retrospectively investigated their clinical courses. RESULTS: One patient had hemoptysis symptoms, whereas 43 patients were asymptomatic; among them, NSCLC was detected by examinations for other diseases in 31 patients and by cancer screening in 12 patients. In total, 20 patients (45%) had multiple malignancies. The median follow-up period was 68 months. One patient had a recurrence from current NSCLC. No patients died of current NSCLC. The overall 5-year survival rate was 90% for all patients. Patients with multiple malignancies had significantly poorer prognoses compared with those without multiple malignancies (P = 0.016). However, patients with treatment intervals of more than 5 years had prognoses equivalent to those of patients without multiple malignancies (P = 0.829). Only the presence of multiple malignancies was a significantly poor prognostic factor in univariate and multivariate analyses. CONCLUSION: NSCLC of 1 cm or smaller showed good prognoses. The presence of multiple malignancies was a significantly poor prognostic factor, and short treatment intervals also correlated with poor prognosis.

Carbon monoxide-releasing molecule, CORM-3, modulates alveolar macrophage M1/M2 phenotype in vitro.

Alveolar macrophages are key contributors to both the promotion and resolution of inflammation in the lung and are categorized into pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. The change in M1/M2 balance has been reported in various pulmonary diseases and is a target for therapeutic intervention. The aim of this study was to assess the modulation of M1/M2 phenotype in alveolar macrophages by water-soluble carbon monoxide-releasing molecule-3 (CORM-3). Rat alveolar macrophages (AM) (NR8383) in culture were stimulated with LPS (5 ng/ml)/IFN-γ (10 U/ml) or IL-4 (10 ng/ml)/IL-13 (10 ng/ml) to induce M1 and M2 phenotypes, respectively. Expression of M1 phenotype markers, iNOS and TNF-α, and M2 phenotype markers, CD206 and Ym-1, was assessed by western blotting after 1, 3, 6, or 24 h in the absence or presence of CORM-3 (0.15 mM) treatment. Inactive CORM-3 (iCORM-3) was used as a control. Treatment of naïve (unstimulated) AM with CORM-3 promoted progression of the M2 phenotype as evidenced by the increased expression of CD206 (at 1 h; 1.8-fold) and Ym-1 (at 3 h; 1.9-fold), respectively. Surprisingly, CORM-3 treatment also upregulated the expression of iNOS protein as assessed 6 h following stimulation of AM with CORM-3 (2.6-fold). On the contrary, CORM-3 effectively reduced LPS/IFN-γ-induced expression of iNOS protein (0.6-fold); however, it had no effect on TNF-α expression. Finally, CORM-3 acutely (1-3 h) upregulated CD206 (1.4-fold) and Ym-1 (1.6-fold) levels in IL-4-/IL-13-treated (M2-stimulus) macrophages. These findings indicate that CORM-3 modulates macrophage M1 and M2 phenotypes in vitro with respect to continuous suppression of iNOS expression in M1-polarized macrophages and transient (early-phase) upregulation of CD206 and Ym-1 proteins in M2-polarized macrophages.

Attenuation of Bleomycin-Induced Pulmonary Fibrosis in Rats with S-Allyl Cysteine.

Pulmonary fibrosis is a complex disease with high mortality and morbidity. As there are currently no effective treatments, development of new strategies is essential for improving therapeutic outcomes. S-allyl cysteine (SAC) is a constituent of aged garlic extract that has demonstrated efficacy as an antioxidant and anti-inflammatory agent. The current study examines the effects of SAC on pulmonary fibrosis induced by a single intratracheal instillation of bleomycin (2.5 mg/kg). SAC was administered to rats as 0.15% SAC-containing diet from seven days prior to instillation up until the conclusion of the experiment (14 days post-instillation). SAC significantly reduced collagen mRNA expression and protein deposition (33.3 ± 2.7 µg/mg and 28.2 ± 2.1 µg/mg tissue in vehicle- and SAC-treated rats, respectively), and decreased fibrotic area, as assessed histologically. In the rats' lungs, SAC also attenuated the increased expression of transforming growth factor-ß1 (TGF-ß1), a central regulator of myofibroblast recruitment, activation, and differentiation. While bleomycin instillation increased the number of myofibroblasts within the lung mesenchymal area, this change was significantly reduced by SAC treatment. SAC may exert efficacy as an anti-fibrotic by attenuating myofibroblast differentiation through TGF-ß1-mediated fibroproliferative processes. Thus, our results indicate SAC may be useful for the prevention or treatment of pulmonary fibrosis.

Sarcopenia is a novel poor prognostic factor in male patients with pathological Stage I non-small cell lung cancer.

OBJECTIVES: Sarcopenia is the progressive loss of muscle mass and strength, and has a risk of adverse outcomes such as disability, poor quality of life and death. As prognosis depends not only on disease aggressiveness, but also on a patient's physical condition, sarcopenia can predict survival in patients with various cancer types. However, its effects on postoperative prognosis in patients with localized non-small cell lung cancers (NSCLC) have never been reported. METHODS: We retrospectively investigated 215 male patients with pathological Stage I NSCLC. L3 muscle index is defined as the cross-section area of muscle at the third lumbar vertebra level, normalized for height, and is a clinical measurement of sarcopenia. We then investigated the effect of preoperative sarcopenia on their postoperative prognosis. RESULTS: Our 215 subjects included 30 patients with sarcopenia. Sarcopenia was significantly associated with body mass index, nutritional condition, serum CYFRA 21-1 level and pathological stage, but not with preoperative respiratory function or performance status. Frequency of postoperative complications, length of postoperative hospital stay, thoracic drainage period or causes of death were not correlated with the presence of sarcopenia. The sarcopenia group had a significantly shorter median overall survival (32 months) than the no-sarcopenia group. CONCLUSION: Sarcopenia might not affect short-term outcomes in patients with early-stage lung cancer. Sarcopenia was a predictor of poor prognosis in male patients with Stage I NSCLC. As sarcopenic patients with NSCLC patients are at risk for significantly worse outcomes, their treatments require careful planning, even for those with Stage I disease.

Prognostic value of the frequency of vascular invasion in stage I non-small cell lung cancer.

OBJECTIVES: There is no standard pathological method for determining vessel invasion in lung cancer. Herein, we examine whether vessel invasion can be accurately assessed using hematoxylin-eosin staining alone, and investigate the prognostic impact of the presence and frequency of vessel invasion in lung cancer. METHODS: Vessel invasion was assessed by hematoxylin-eosin, Victoria blue, and D2-40 in 251 completely resected stage I non-small cell lung cancer patients. Vessel invasion was classified into 3 grades according to the number of invaded vessels. RESULTS: Using hematoxylin-eosin and Victoria blue, vascular invasion was detected in 27 (10.8 %) and 75 (29.9 %) of patients, respectively. Lymphatic permeation was detected in 126 (50.2 %) and 70 (27.9 %) of patients using hematoxylin-eosin and D2-40 staining. Hematoxylin-eosin staining did not accurately detect a high frequency of vessel invasion; only 5 and 21.7 % of high-frequency vascular invasion and lymphatic permeation cases diagnosed with Victoria blue and D2-40 were detected. Multivariate analysis based on elastic stain and immunostaining indicated that plural invasion, a high frequency of vascular invasion (hazard ratio 4.00), and a high frequency of lymphatic permeation (hazard ratio 2.30) were independent predictors of cancer recurrence within 3 years. Likewise, an age ≥70 years, male, and a high frequency of vascular invasion (hazard ratio 3.41) were independent predictors of overall survival. CONCLUSIONS: Vascular invasion should be confirmed by elastic stains, and the frequency, not but the presence, of vascular invasion is a powerful independent prognostic factor in completely resected stage I non-small cell lung cancer patients.

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.

Clinical Significance of Perioperative Blood Coagulation Factor XIII in Pulmonary Resections.

Background This study evaluated the clinical significance of perioperative levels of plasma blood coagulation factor XlII in patients undergoing pulmonary resection. Methods The study involved 27 patients with ≥2day prolonged air leakage after pulmonary resection. The 27 pulmonary resection procedures comprised 25 lobectomies, 1 segmentectomy, and 1 partial resection. The preoperative and 5-day postoperative blood coagulation factor XIII levels were measured. Results Perioperative changes in the blood coagulation factor XlII levels showed no significant correlation with the preoperative hemoglobin Aic levels. The mean postoperative blood coagulation factor XIII level was 78.2±15.7% in patients with postoperative total protein levels of <6.6 g/dL, and 102.1±19.7% in patients with postoperative total protein levels of ≥6.6 g/dL (p=0.018). The mean drainage duration was 8.3 ±2.7 days in patients with postoperative blood coagulation factor XIII levels of ≤70% and 5.3 2.3 days in patients with levels of >70% (p=0.017). Conclusions Low blood coagulation factor XIII levels may be associated with prolonged air leakage and thereby exogenous blood coagulation factor XIII may lead to shorter drain placement durations in patients undergoing thoracic surgery, particularly patients with a poor nutritional status.

Clinical Significance of Multiple Pulmonary Metastasectomy for Hepatocellular Carcinoma.

BACKGROUND: The lung is the most common site of extrahepatic metastasis from hepatocellular carcinoma (HCC). The aim of this study was to evaluate the significance and long-term outcomes of pulmonary metastasectomy for HCC, especially in patients with multiple nodules or repeated pulmonary recurrence. METHODS: We retrospectively analyzed 19 patients who underwent pulmonary metastasectomy for HCC at our institution from 1993 to 2013. RESULTS: No in-hospital mortality occurred. The 19 patients included 14 men. The median age was 61 (range 20-76) years. Eight patients (42 %) had single pulmonary metastatic lesions, whereas 4 (21 %) had >10 lesions. Median follow-up after pulmonary metastasectomy was 23.1 (6.3-230) months. Twelve patients died, and the cause of death was HCC progression in nine. The 1-, 3-, 5-, and 10-year overall survival rates after pulmonary metastasectomy were 89, 48, 48, and 21 %, respectively. Seven patients developed pulmonary recurrence after initial pulmonary metastasectomy. Five of the seven underwent repeat metastasectomy, with a median survival time of 65 months, and 2- and 3-year survival rates of 100 and 67 %, respectively. The 2- and 3-year survival rates in the four patients with >10 pulmonary nodules were 75 and 50 %, respectively. CONCLUSIONS: Surgical resection is a safe and effective treatment in selected patients with pulmonary metastasis from HCC, even in those with multiple nodules. Repeated locoregional therapy for lung recurrence might help to improve survival in these patients.

Clinical value of exogenous factor XIII for prolonged air leak following pulmonary lobectomy: a case control study.

BACKGROUND: We examined the effect of exogenous factor XIII (FXIII) concentrate in patients with prolonged air leak (PAL) after pulmonary lobectomy for non-small cell lung cancer. METHODS: We performed a retrospective analysis of 297 patients who underwent pulmonary lobectomy between July 2007 and March 2014: 90 had an air leak on the first postoperative day, which resolved spontaneously within 5 days in 53 cases (SR group). FXIII concentrate was administered to the remaining 37 patients (PAL group) for 5 days. This group was subdivided into those in whom the air leak resolved during FXIII treatment (EF group) and those who needed additional intervention (inEF group). The clinical and perioperative characteristics of the groups were compared. RESULTS: Although plasma FXIII activity did not differ significantly between the SR and PAL groups before surgery or on the fifth postoperative day, the proportional perioperative fall in FXIII activity was significantly greater in the SR group (33%) than the PAL group (22%, p = 0.044) and inEF group (14%, p = 0.048). On the fifth postoperative day, FXIII activity was significantly lower in the EF group than in the inEF group (74% versus 91%, p = 0.030). The optimal cut-off point for postoperative plasma FXIII activity to distinguish between the EF and inEF groups was 86%. CONCLUSIONS: Insufficient plasma FXIII consumption and lower postoperative FXIII activity may play a role in the resolution of PAL, and exogenous FXIII concentrate may be an effective, safe and non-invasive treatment.

Pulmonary sequestration presenting elevated CA19-9 and CA125 with ovarian cysts.

A 41-year-old woman was evaluated because of elevated serum levels of the tumor markers CA19-9 and CA125. Whole-body examination revealed an intralobar pulmonary sequestration in the right lower lobe and bilateral cystic ovarian tumors (right: 20 mm, left: 60 mm in diameter, respectively). The left ovarian cyst was resected and diagnosed as an endometrioma. The right ovarian cyst was preserved because of its small size. However, the tumor marker levels remained elevated postoperatively. S10 segmentectomy of the right lung was subsequently performed. Immunohistochemical examination of the sequestrated lung demonstrated positive staining for CA19-9 in the bronchial and alveolar epithelia and mucus. After the pulmonary resection, the CA19-9 and CA125 levels decreased to their normal ranges.

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.

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.