Prognostic impact of soluble PD-L1 derived from tumor-associated macrophages in non-small-cell lung cancer.

Programmed cell death-ligand 1 (PD-L1) on tumor cells can be degraded to soluble form (sPD-L1) and enter circulation, however, the clinical significances of sPD-L1 in peripheral blood remains to be elucidated in non-small-cell lung cancer (NSCLC). We monitored plasma sPD-L1 levels during perioperative periods and evaluated PD-L1-positive cells in tumor tissues in patients with operable NSCLC. Then the correlation between preoperative plasma sPD-L1 levels and relapse-free survival (RFS) was analyzed retrospectively. In patients who underwent radical surgery (n = 61), plasma sPD-L1 levels (median; 63.5 pg/mL) significantly increased 1 month after surgery (72.2 pg/mL, P < 0.001). The combined score of PD-L1-positive cells including tumor cells and tumor-associated macrophages (TAMs) was significantly associated with preoperative plasma sPD-L1 levels. In patients with high levels of preoperative plasma sPD-L1, the probability of 5-year RFS was significantly poor for patients with low PD-L1 expression intensity of tumor cells (tcPD-L1) compared with those with high tcPD-L1 (33.3% vs. 87.5%, respectively, P = 0.016; 95% CI, 0.013-0.964). In former group, PD-L1-positive TAMs were markedly infiltrating compared with those from latter group (246.4 vs. 76.6 counts/mm2, respectively, P = 0.003). In NSCLC, plasma sPD-L1 can reflect the accumulation of PD-L1-posotive TAMs, not just PD-L1-positive tumor cells. In patients with high levels of preoperative plasma sPD-L1, the prognoses after surgery depends on which PD-L1-positive cells, tumor cells or TAMs, are the primary source of the sPD-L1. Thus, measuring both plasma sPD-L1 levels and PD-L1 expression status of tumor cells and TAMs is of benefit for assessment of postoperative prognosis in operable NSCLC.

Oncogenic epidermal growth factor receptor signal-induced histone deacetylation suppresses chemokine gene expression in human lung adenocarcinoma.

Epidermal growth factor receptor (EGFR)-mutated (mt) lung adenocarcinoma (LA) is refractory to immune checkpoint inhibitors (ICIs). However, the mechanisms have not been fully elucidated. CD8+ T cell infiltration was significantly lower in EGFR-mt than in EGFR-wild-type LA, which was associated with suppression of chemokine expression. Since this T cell-deserted tumor microenvironment may lead to the refractoriness of ICIs against EGFR-mt LA, we investigated the mechanism by focusing on the regulation of chemokine expression. The expression of C-X-C motif ligand (CXCL) 9, 10 and 11, which constitute a gene cluster on chromosome 4, was suppressed under EGFR signaling. The assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) revealed open chromatin peaks near this gene cluster following EGFR-tyrosine kinase inhibitor (TKI) treatment. The histone deacetylase (HDAC) inhibitor recovered the expression of CXCL9, 10 and 11 in EGFR-mt LA. Nuclear HDAC activity, as well as histone H3 deacetylation, were dependent on oncogenic EGFR signaling. Furthermore, the Cleavage Under Targets and Tagmentation (CUT & Tag) assay revealed a histone H3K27 acetylation peak at 15 kb upstream of CXCL11 after treatment with EGFR-TKI, which corresponded to one of the open chromatin peaks detected by ATAC-seq. The data suggest that EGFR-HDAC axis mediates silencing of the chemokine gene cluster through chromatin conformational change, which might be relevant to the ICI resistance by creating T cell-deserted tumor microenvironment. Targeting this axis may develop a new therapeutic strategy to overcome the ICI resistance of EGFR-mt LA.

Biphasic prognostic significance of PD-L1 expression status in patients with early- and locally advanced-stage non-small cell lung cancer.

Programmed cell death-ligand 1 (PD-L1) expression on tumor cells is induced by interferon-gamma, suggesting the induction of an anti-tumor immune response. In turn, binding of PD-L1 to programmed cell death 1 (PD-1) triggers an immune checkpoint pathway that contributes to tumor growth. Though it remains to be elucidated, the clinical significance of PD-L1 expression might vary with tumor progression in non-small-cell lung cancer (NSCLC). Immunohistochemical analysis of PD-L1 was done in tumor specimens from patients who underwent radical surgery for stage I-IIIA NSCLC (n = 228). Tumor PD-L1 expression intensity was semi-quantitatively scored and its correlation with various clinicopathological features and postoperative relapse-free survival (RFS) was assessed relative to pathological stage. In stage I, postoperative RFS was significantly prolonged in patients with a high PD-L1 score compared with a low PD-L1 score, exhibiting 5-year relapse-free probabilities of 94.1% and 75.1%, respectively (P = 0.031). A multivariate analysis revealed that a high PD-L1 score was a prognostic factor of longer postoperative RFS (hazard ratio: 0.111, P = 0.033). Conversely, in stages II and IIIA, patients with a high PD-L1 score tended to suffer from postoperative tumor recurrence. In early-stage NSCLC, high tumor PD-L1 expression status represents a biomarker to predict good prognosis after radical surgery and may reflect the induction of an antitumor immune response. However, in locally advanced stage NSCLC, tumor PD-L1 expression status may reflect the execution of an immune checkpoint pathway and predicts the incidence of postoperative tumor recurrence.

Clinical significance of PD-L1-positive cancer-associated fibroblasts in pN0M0 non-small cell lung cancer.

OBJECTIVES: Cancer-associated fibroblasts (CAFs) are a dominant cell type in tumor stroma and support the generation of pro-tumorigenic microenvironment. CAFs have frequent opportunities to interact with immune cells infiltrating the tumor stroma, but the process remains to be determined. In this study, we focused on immune checkpoint mechanism. We also examined the induction of programmed cell death-ligand 1 (PD-L1) on CAFs by immune cell, and the clinical significance of PD-L1-expressed CAFs in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: CAFs were isolated from human NSCLC tissues, and PD-L1 expression levels in CAFs were analyzed by real-time polymerase chain reaction and flow-cytometry. Following immunohistochemical analysis of PD-L1 in surgically resected pN0M0 NSCLC (n = 125, including 88 invasive adenocarcinomas and 37 squamous cell carcinomas), the correlation of PD-L1-positive CAFs with clinicopathological features was investigated. RESULTS: PD-L1 mRNA and protein expression on CAFs was upregulated by exogenously supplemented interferon-gamma (IFN-γ) and downregulated through the depletion of IFN-γ. PD-L1 expression on CAFs was upregulated by co-culture with activated lymphocytes releasing IFN-γ. Immunohistochemistry revealed that PD-L1-positive CAFs were observed in 31 cases (24.8%). Postoperative relapse-free survival was significantly prolonged in patients with PD-L1-positive CAFs as compared with those with PD-L1-negative CAFs, with 5-year relapse-free probabilities of 84.5% and 66.3%, respectively (P = 0.031). Multivariate analysis revealed that PD-L1 expression on CAFs was an independent prognostic factor of longer relapse-free survival after surgery (hazard ratio: 3.225, P = 0.027). CONCLUSION: PD-L1 expression on CAFs is reversibly regulated by environmental stimuli including IFN-γ from activated lymphocytes. In the non-metastatic NSCLC, PD-L1 expression on CAFs suggests the induction of anti-tumor immune responses, contributing to better prognosis after surgery.

Predictive importance of galectin-3 for recurrence of non-small cell lung cancer.

OBJECTIVE: The predictive importance of galectin-3 in non-small cell lung cancer (NSCLC) has not been elucidated. We examined whether galectin-3 could serve as a predictor for tumor recurrence in NSCLC. METHODS: In 42 consecutive patients with NSCLC who underwent radical resection, galectin-3 expression in tumor cells was examined by immunohistochemistry. Galectin-3 levels in serum were assessed before surgery and 1 month after surgery by enzyme-linked immunosorbent assays. RESULTS: Higher expression of galectin-3 in tumor cells was associated significantly with lymphatic invasion (p = 0.049) and tumor recurrence (p = 0.001). The Kaplan-Meier curves for relapse-free survival after radical resection showed that patients with high expression of galectin-3 had significantly shorter relapse-free survival than those with low expression of galectin-3 (p < 0.001). The serum level of galectin-3 was not reduced after radical resection, and there was no significant correlation between the serum level of galectin-3 and recurrence. CONCLUSIONS: Galectin-3 expression in tumor cells could serve as a predictive factor for recurrence, but serum level of galectin-3 is not useful for predicting NSCLC recurrence.

Chylothorax secondary to a pleuroperitoneal communication and chylous ascites after pancreatic resection.

To the best of our knowledge, there have been no previous reports of chylothorax developing after pancreatectomy, although chylous ascites can occur. In patients with a pleuroperitoneal communication, ascitic fluid can flow into the thoracic cavity through a small hole in the diaphragm. A 70-year-old woman underwent total pancreatectomy and was referred to our department for treatment of right chylothorax after removal of her abdominal drainage tubes. An occult pleuroperitoneal communication was detected, and the portion of the diaphragm containing a diaphragmatic fistula was resected using a surgical stapler. After surgery, the chylothorax resolved, but chylous ascites developed. We speculated that this was a rare case of chylous ascites that flowed into the thoracic cavity through a diaphragmatic fistula after a pancreatic resection. When a patient develops chylothorax after an abdominal operation, the combination of a pleuroperitoneal communication and chylous ascites must be considered.

Hypoxia­induced galectin­3 enhances RhoA function to activate the motility of tumor cells in non­small cell lung cancer.

Galectin­3 plays crucial roles in tumor progression. However, in non­small cell lung cancer (NSCLC), it remains unclear whether the hypoxic tumor microenvironment enhances galectin­3­induced cell motility. We investigated galectin­3 expression in NSCLC cells under hypoxia, and the possible molecular mechanisms by which galectin­3 influences tumor aggressiveness. Galectin­3 levels in NSCLC cell lines under hypoxia were assessed using reverse transcription PCR and western blotting. To clarify the role of endogenous galectin­3, the effect of galectin­3 knockdown in NSCLC cells was investigated using scratch and invasion assays. The expression and clinicopathological significance of galectin­3 in 57 patients with pN0M0 invasive pulmonary adenocarcinoma were investigated by immunohistochemistry. Both mRNA and protein levels of galectin­3 in the NSCLC cell lines A549 and LK­2 were upregulated by hypoxia. As revealed by scratch and invasion assays, the cell migratory and invasive activities were significantly increased under hypoxia, but were reduced by galectin­3 knockdown. Notably, addition of galectin­3 to the media did not improve the cell motility impaired by galectin­3 knockdown. To clarify the role of endogenous galectin­3 in the enhancement of tumor cell motility under hypoxia, we focused on the function of RhoA. RhoA level in the plasma membrane, but not in the cytoplasm, was increased under hypoxia and decreased by galectin­3 knockdown. RhoA activity was significantly enhanced under hypoxia and effectively inhibited by galectin­3 knockdown. In patients with pN0M0 invasive pulmonary adenocarcinoma, higher galectin­3 expression on tumor cells was significantly associated with tumor cell invasion into microvessels and tumor recurrence after surgery. These data demonstrate that in NSCLC cells under hypoxia, upregulated galectin­3 levels increase the localization of RhoA to the plasma membrane, thus enhancing RhoA activity, which is associated with aggressive cell motility. In pN0M0 invasive pulmonary adenocarcinoma, galectin­3 is a potential biomarker for predicting tumor recurrence after radical surgery.

Continuous quantitative measurement of the main bronchial dimensions and lung density in the lateral position by four-dimensional dynamic-ventilation CT in smokers and COPD patients.

PURPOSE: The purpose of this study was to measure changes in lung density and airway dimension in smokers in the lateral position using four-dimensional dynamic-ventilation computed tomography (CT) during free breathing and to evaluate their correlations with spirometric values. MATERIALS AND METHODS: Preoperative pleural adhesion assessments included dynamic-ventilation CT of 42 smokers (including 22 patients with COPD) in the lateral position, with the unoperated lung beneath (dependent lung). The scanned lungs' mean lung density (MLD) and the bilateral main bronchi's luminal areas (Ai) were measured automatically (13-18 continuous image frames, 0.35 seconds/frame). Calculations included cross-correlation coefficients (CCCs) between the MLD and Ai time curves, and correlations between the quantitative measurements and spirometric values were evaluated by using Spearman's rank coefficient. RESULTS: The ΔMLD1.05 (from the peak inspiration frame to the third expiratory frame, 1.05 seconds later) in the nondependent lung negatively correlated with FEV1/FVC (r=-0.417, P<0.01), suggesting that large expiratory movement of the nondependent lung would compensate limited expiratory movement of the dependent lung due to COPD. The ΔAi1.05 negatively correlated with the FEV1/FVC predicted in both the lungs (r=-0.465 and -0.311, P<0.05), suggesting that early expiratory collapses of the main bronchi indicate severe airflow limitation. The CCC correlated with FEV1/FVC in the dependent lung (r=-0.474, P<0.01), suggesting that reduced synchrony between the proximal airway and lung occurs in patients with severe airflow limitation. CONCLUSION: In COPD patients, in the lateral position, the following abnormal dynamic-ventilation CT findings are associated with airflow limitation: enhanced complementary ventilation in the nondependent lung, early expiratory airway collapses, and reduced synchrony between airway and lung movements in the dependent lung.

Diagnosis of thoracic endometriosis with immunohistochemistry.

BACKGROUND: Pathological and immunohistochemical features of thoracic endometriosis are not well understood. In the present study, we retrospectively analyzed the clinical and pathological diagnostic characteristics of 55 female pneumothorax cases. METHODS: This study was a retrospective observation of 55 women aged from 8 to 62 years old who underwent surgery for pneumothorax from November 2001 through January 2018. Immunohistochemistry for estrogen receptor (ER), progesterone receptor (PR), and CD10 was performed for all cases. As controls, we analyzed resected specimens of spontaneous pneumothorax in men who received surgery. RESULTS: Of 55 cases, endometrial stroma and glands by Hematoxylin-Eosin (HE) stain was found in only one case. Thirty-seven cases (67.3%) were ER- and PR-positive in stromal bland spindle cells of the lung. The remaining 18 cases (32.7%) were ER-, PR-, and CD10-negative. The ER- and PR-positive specimens could be further classified according to 2 staining patterns: 'scattered pattern' and 'aggregated pattern'. Thirty-three cases (60.0%) were scattered and four cases (7.3%) were aggregated pattern. Only the aggregated pattern specimens exhibited positive staining for CD10. As the scattered pattern was also found in men, we only diagnosed the aggregated pattern cases as endometriosis. CONCLUSIONS: A diagnosis of thoracic endometriosis is simple when both endometrial stroma and gland are present. In cases of endometriosis with stroma only, a further classification of "aggregated pattern", in which immunohistochemistry is ER-, PR- and CD10-positive might be necessary for diagnosis.

Blocking the FSTL1-DIP2A Axis Improves Anti-tumor Immunity.

Immune dysfunction is a strong factor in the resistance of cancer to treatment. Blocking immune checkpoint pathways is a promising approach to improve anti-tumor immunity, but the clinical efficacies are still limited. We previously identified follistatin-like 1 (FSTL1) as a determinant of immune dysfunction mediated by mesenchymal stromal/stem cells (MSCs) and immunoregulatory cells. Here, we demonstrate that blocking FSTL1 but not immune checkpoint pathways significantly suppresses cancer progression and metastasis in several mouse tumor models with increased MSCs. Expression of DIP2A (the receptor of FSTL1) in tumor cells is critical for FSTL1-induced immunoresistance. FSTL1/DIP2A co-positivity in tumor tissues correlates with poor prognosis in NSCLC patients. Thus, breaking the FSTL1-DIP2A axis may be a useful strategy for successfully inducing anti-tumor immunity.

A risk score to predict postoperative complications after lobectomy in elderly lung cancer patients.

OBJECTIVE: In elderly patients with lung cancer, the presumed fear of postoperative complications has resulted in the delivery of limited resection. Surgical decision-making for such patients would become easier if clinicians could predict who is at high risk of postoperative complications. The purpose of this study is to propose a scoring system to predict the risk of postoperative complications for elderly patients with lung cancer. METHODS: We reviewed patients aged 75 years or older who underwent lobectomy for lung cancer at a single hospital (n = 199). A multivariable logistic regression model was utilized to determine risk factors for postoperative complications. RESULTS: Six risk factors for postoperative complications were identified, and we derived a risk score by assigning weights to these factors based on their odds ratios, as follows: Risk score = 7 × (performance status of 2) + 6 × (coronary artery disease) + 3 × (a history of cerebrovascular accident) + 2 × (restrictive ventilatory impairment) + 1 × (male sex) + 1 × (interstitial pneumonia). The postoperative complication rates in patients with risk scores of 0, 1-2, 3-5, 6-8, and 9-14 were 19, 29, 56, 68, and 90%, respectively. CONCLUSIONS: The proposed risk score was able to predict the incidence of postoperative complications. The risk score can be used to identify high-risk patients and to select proper treatment strategies.

Preoperative assessment of pleural adhesion by Four-Dimensional Ultra-Low-Dose Computed Tomography (4D-ULDCT) with Adaptive Iterative Dose Reduction using Three-Dimensional processing (AIDR-3D).

PURPOSE: To assess the feasibility of Four-Dimensional Ultra-Low-Dose Computed Tomography (4D-ULDCT) for distinguishing pleural aspects with localized pleural adhesion (LPA) from those without. METHODS: Twenty-seven patients underwent 4D-ULDCT during a single respiration with a 16cm-coverage of the body axis. The presence and severity of LPA was confirmed by their intraoperative thoracoscopic findings. A point on the pleura and a corresponding point on the outer edge of the costal bone were placed in identical axial planes at end-inspiration. The distance of the two points (PCD), traced by automatic tracking functions respectively, was calculated at each respiratory phase. The maximal and average change amounts in PCD (PCDMCA and PCDACA) were compared among 110 measurement points (MPs) without LPA, 16MPs with mild LPA and 10MPs with severe LPA in upper lung field cranial to the bronchial bifurcation (ULF), and 150MPs without LPA, 17MPs with mild LPA and 9MPs with severe LPA in lower lung field caudal to the bronchial bifurcation (LLF) using the Mann-Whitney U test. RESULTS: In the LLF, PCDACA as well as PCDMCA demonstrated a significant difference among non-LPA, mild LPA and severe LPA (18.1±9.2, 12.3±6.2 and 5.0±3.3mm) (p<0.05). Also in the ULF, PCDACA showed a significant difference among three conditions (9.2±5.5, 5.7±2.8 and 2.2±0.4mm, respectively) (p<0.05), whereas PCDMCA for mild LPA was similar to that for non-LPA (12.3±5.9 and 17.5±11.0mm). CONCLUSIONS: Four D-ULDCT could be a useful non-invasive preoperative assessment modality for the detection of the presence or severity of LPA.

The mechanism of de novo expression of programmed cell death-ligand 1 in squamous cell carcinoma of the lung.

Immune checkpoint mechanisms such as the programmed cell death-ligand 1-programmed cell death 1 (PD­L1-PD­1) axis are utilized by tumor cells to evade the cytotoxicity of effector immune cells. However, environmental factors responsible for the expression of PD­L1 on tumor cells remain to be fully elucidated. We hypothesized that an immunological interaction with tumor-infiltrating CD8+ lymphocytes (CD8+ TILs) would contribute to PD­L1 expression in tumor cells. To verify this hypothesis, we examined the effect of interferon-γ (IFN-γ), a cytokine secreted by CD8+ TILs, on PD­L1 expression in pulmonary squamous cell carcinomas in vitro. We also evaluated the expression of PD­L1 and major histocompatibility complex (MHC) class I molecules on tumor cells and CD8+ TILs in squamous cell carcinomas of the lung (n=77) by immunohistochemistry. IFN-γ upregulated PD­L1 expression on pulmonary squamous carcinoma cells, and the reaction was reversible. In cases where which MHC class I molecule-positive tumor cells were dominant (n=72, 93.5%), cases in which PD­L1-positive tumor cells were dominant (PD­L1+ tumor cell­dominant cases; n=45) were more frequently observed than PD­L1-negative tumor cell­dominant cases (n=27) (P=0.006). The number of CD8+ TILs was significantly higher in PD­L1+ tumor cell­dominant cases compared with PD­L1- tumor cell­dominant cases (P=0.005). These data suggest that the de novo expression of PD­L1 on tumor cells is upregulated by IFN-γ secreted from CD8+ TILs upon recognition of the tumor cells with an MHC class I molecule.

Decrease in performance status after lobectomy mean poor prognosis in elderly lung cancer patients.

BACKGROUND: Surgery remains the best treatment for obtaining cure in patients with resectable lung cancer, regardless of age. In elderly patients, however, the presumed fear of decreased performance status (PS) after lobectomy has resulted in the delivery of sub-optimal cancer surgery. Surgical decision making for such patients would become easier if post-lobectomy survival benefits and changes in PS were well defined. METHODS: We reviewed patients aged 75 years or older who received lobectomy for non-small cell lung cancer (NSCLC) at our hospital between January 2004 and December 2014. Eastern Cooperative Oncology Group PS was preoperatively and postoperatively assessed in 137 patients. Patients were classified into 2 groups based on the change in PS: in Group 1, postoperative and preoperative PS were the same; in group 2, postoperative PS was less than preoperative PS. We compared the characteristics of patients in groups 1 and 2. RESULTS: Overall 5-year survival was 47.4% in group 1 and 0% in group 2 (P<0.001). History of cardiac ischemia (P=0.001) and squamous cell carcinoma (P=0.015) were identified as significant predictors of reduced postoperative PS. CONCLUSIONS: Our results show that maintenance of PS after lobectomy is expected to be associated with a good prognosis. However, reduction of PS after lobectomy indicates an extremely poor prognosis in elderly patients with lung cancer. History of cardiac ischemia and squamous cell carcinoma are possible risk factors for decreasing PS. Thus, careful patient evaluation and selection are needed when deciding whether to use lobectomy in clinical practice.

Clinical outcome of posterior fixation surgery in patients with vertebral metastasis of lung cancer.

Vertebral metastasis of non-small-cell lung cancer (NSCLC) often leads to neurological paralysis, with deterioration of the patients' activities of daily living (ADL). Surgical treatments for the symptoms are unlikely to be recommended due to the poor prognosis of patients with advanced NSCLC. The aim of the present study was to retrospectively evaluate the clinical outcome of posterior spinal fixation surgery in patients with neurological paralysis resulting from vertebral metastasis of NSCLC. Between April, 2007 and March, 2012, 4 patients (3 men and 1 woman; median age, 56.5 years) underwent fixation surgery at the Shiga University of Medical Science Hospital (Otsu, Japan). The mean preoperative Tokuhashi and Tomita scores of the patients were high (8.25 and 7.0, respectively). However, the Frankel grade functional score and performance status of the patients improved following fixation surgery, after which all patients received chemoradiotherapy. Postoperatively, the median paralysis-free time was 41 months (range, 17-42 months) and the median survival time was 42.5 months (range, 22-43 months). According to the functional scores, the patients had a poor prognosis, which may have been a contraindication for fixation surgery. In these cases, however, surgical treatment improved the patients' ADL and increased the likelihood of receiving anticancer therapy, contributing to the prolongation of survival. Therefore, fixation surgery may be beneficial for patients with neurological paralysis following vertebral metastasis of advanced NSCLC.

Simultaneous resection of pulmonary tumor following cardiovascular surgery.

BACKGROUND: A pulmonary tumor is occasionally detected on a chest computed tomography (CT) scan before cardiovascular surgery. PURPOSE: In this study, we examined clinical courses of patients who had undergone the simultaneous resection of a pulmonary tumor following cardiovascular surgery. METHODS: From 2008 to 2013, 18 patients (13 men and 5 women) with a median age of 69.8 years underwent the wedge pulmonary resection for a lung tumor through a median thoracotomy following cardiovascular surgery in our hospital. Cardiovascular surgeries consisted of off-pump coronary artery bypass grafting (CABG) in six patients, aortic valve replacement and/or mitral valve plasty in 10 patients, total arch replacement in 10 patients and descending aorta replacement in 10 patients. RESULTS: No complications associated with pulmonary resections were observed. Pathological examination revealed that 15 patients (83.3%) were diagnosed with lung cancers including 13 adenocarcinomas and two squamous cell carcinomas, with the clinical stages of 1A in 13 patients, 2A in one patient and 2B in one patient. Among them, five patients received the radical pulmonary resection subsequently, whereas 10 patients were unable to receive it due to their poor cardiopulmonary function. Kaplan-Meier analysis of patients with lung cancer revealed that the 5-year survival rate and progression-free survival (PFS) rate after 3 years from the surgery were 46.2% and 73.8%, respectively. CONCLUSION: The simultaneous resection of pulmonary tumor following cardiovascular surgery is safely performed, and is useful for the pathological diagnosis of the tumor. Further studies are warranted, however, this procedure may contribute to controlling the progression of lung cancer in patients with cardiovascular disease with comorbidities.

Scoring of PD-L1 expression intensity on pulmonary adenocarcinomas and the correlations with clinicopathological factors.

INTRODUCTION: The contribution of programmed cell death ligand-1 (PD-L1) immune checkpoint molecule toward progression of non-small cell lung cancer (NSCLC) has not yet been elucidated, in part, because of lack of a standardised method to evaluate PD-L1 expression. In this study, we developed a novel method for the evaluation of PD-L1 expression on NSCLC cells and examined its correlation with clinicopathological characteristics. METHODS: After immunohistochemical examination of PD-L1 expression for surgically resected pulmonary adenocarcinomas (n=106), based on the findings that PD-L1 are consistently expressed on alveolar macrophages, PD-L1 staining intensity of tumour cells was classified into four levels relative to PD-L1 staining intensity in alveolar macrophages; PD-L1 expression scores (range, 0-300) were semiquantitatively assessed. An analysis of statistical association between PD-L1 expression score and clinicopathological characteristics was performed. RESULTS: Almost all of the alveolar macrophages in the specimens were moderately to strongly stained with PD-L1, serving as an internal positive control in the immunohistochemistry of PD-L1. PD-L1 expression score (median, 52.3) was significantly higher in tumours with G2/3 differentiation than in those with G1 (p=0.022) and higher in those with lymphatic invasion than in those without invasion (p=0.032). Postoperative relapse-free survival was significantly shorter in patients with a high PD-L1 expression score than in those with low PD-L1 expression score (p=0.035). Smoking habits, histological subtype, and epidermal growth factor receptor mutation status were not associated with PD-L1 expression score. CONCLUSIONS: Given the heterogeneous distribution of PD-L1 expression in pulmonary adenocarcinoma cells, the scoring of PD-L1 expression on tumour cells relative to that in alveolar macrophages appears to be a valid indicator of PD-L1 status of patients with pulmonary adenocarcinomas, demonstrating a significant correlation with several factors associated with tumour progression.

[Resection of double bronchogenic cysts within the anterior mediastinum; report of a case].

We reported a case of surgically resected double bronchogenic cysts within the anterior mediastinum. An anterior mediastinal tumor had been found at medical examination 6 years ago in a 66-year-old man, but has been followed up without treatment. After the treatment of another disease, he was referred to our hospital for evaluation of the mediastinal tumor. A chest computed tomography showed 2 anterior mediastinal nodules. Nodules in the thymus were resected with video-assisted thoracic surgery. The tumors were both pathologically diagnosed as bronchogenic cysts.

Single-trocar thoracoscopy under local anesthesia for pleural space infection.

OBJECTIVE: The role of single-trocar thoracoscopy for complicated parapneumonic effusion (CPE) and pleural empyema is not established as yet. The aim of this study was to report our experience and analyze the efficacy and safety of debridement by single-trocar thoracoscopy for the patients with CPE and multiloculated empyema. METHODS: We performed a retrospective study reviewing the medical records of the patients treated parapneumonic effusion and multiloculated empyema by single-trocar thoracoscopy under local anesthesia at our department from January 2000 to December 2012. RESULTS: A total 29 patients with CPE and multiloculated empyema were treated by single-trocar thoracoscopy. As the staging of pleural infection, class 5 and class 7 by Light classification were 21 and 8 patients, respectively. The onset of the symptom was on average 13.9 ± 11.7 days before the procedure. This procedure was successful in 23 of 29 patients (79.3%) without further operation under general anesthesia. Complication occurred in 1 case of 29 patients (3.4%). Six patients required subsequently the operation under general anesthesia, and one of the 6 patients died to multiple organ failure caused by sepsis. A microbiological diagnosis could be made in fifteen patients (51.7%). CONCLUSIONS: Debridement by single-trocar thoracoscopy can be an acceptable approach as the first-line procedure in patients with CPE and empyema. This procedure can provide not only appropriate and expeditious treatment but also information of pleural cavity to decide indication for thoracotomy under general anesthesia.

Mucinous bronchioloalveolar carcinoma with K-ras mutation arising in type 1 congenital cystic adenomatoid malformation: a case report with review of the literature.

Congenital cystic adenomatoid malformation (CCAM) of the lung is a rare hamartomatous cystic lesion, characterized by the presence of large cysts, which are histopathologically lined by pseudostratified ciliated cells. It has been recognized that rare cases of type 1 CCAM show malignant transformation, usually bronchioloalveolar carcinoma (BAC) or adenocarcinoma. Herein, we describe a case of BAC arising in type 1 CCAM with K-ras mutation. A 9-year-old Japanese girl presented with fever. Computed tomography demonstrated large cystic lesions in her right lower lung. Histopathological study of the resected specimen revealed multiple cysts, which were lined by pseudostratified ciliated cells, and occasionally interspersed with mucous cells without atypia. A small focus of proliferation of columnar cells showing lepidic growth pattern was present. These columnar cells had abundant mucin in the cytoplasm and mildly to moderately enlarged nuclei. Accordingly, a diagnosis of BAC arising in type 1 CCAM was made. Polymerase chain reaction analysis revealed K-ras mutation at codon 12 in the BAC component. The presence of mucous cell/goblet cell hyperplasia and atypical adenomatous hyperplasia is a well known phenomenon in type 1 CCAM. A recent study clearly demonstrated K-ras mutation in these lesions, which are thought to be precursors of BAC. Therefore, the concept of malignant transformation in the sequence from type 1 CCAM to mucous cell hyperplasia to atypical adenomatous hyperplasia to BAC and invasive adenocarcinoma due to K-ras mutation has been proposed. Careful histopathological analysis is important for evaluation of malignant lesions in type 1 CCAM.