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Background: Epithelial-mesenchymal transition plays a crucial role in cancer progression and is a significant prognosticator for postoperative survival in patients with lung cancer. Predicting epithelial-mesenchymal transition preoperatively using computed tomography may help to determine the optimal surgical strategy., Methods: We performed an immunohistochemical analysis of E-cadherin and vimentin expressions using tumor specimens from resected primary lung adenocarcinoma and classified the results into 3 subgroups according to the expressions: epithelial, intermediate, and mesenchymal. The intermediate and mesenchymal groups were classified as the epithelial-mesenchymal transition conversion group. We analyzed the association between epithelial-mesenchymal transition and radiologic characteristics, especially computed tomographic features., Results: The epithelial-mesenchymal transition conversion group comprised 162 patients (49.1%). Computed tomography revealed that tumors with epithelial-mesenchymal transition conversion showed a high consolidation/tumor ratio compared with those without conversion. Univariate analysis demonstrated that tumors with epithelial-mesenchymal transition were significantly associated with bronchial and/or vascular convergence (P < .001) and notching (P = .028). When the cutoff value for the consolidation/tumor ratio was set by the receiver operating characteristic curve, independent predictive factors for epithelial-mesenchymal transition by multivariate analysis were high ratio (>0.7946; P < .001) and the presence of convergence (P = .05). Tumors with a high consolidation/tumor ratio and convergence had a 4-fold higher odds ratio for epithelial-mesenchymal transition, and patients had significantly poorer survival., Conclusions: Convergence and a high consolidation/tumor ratio were independently associated with epithelial-mesenchymal transition conversion. These preoperative radiologic results will help to predict epithelial-mesenchymal transition conversion in lung adenocarcinoma., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Preoperative skeletal muscle loss was reported to be associated with a postoperative poor prognosis in non-small cell lung cancer (NSCLC) patients. The aim of this study was to elucidate the relationship between the change in skeletal muscle mass after surgery and the postoperative outcomes in NSCLC patients., Methods: The data were analyzed for 204 NSCLC patients who had undergone curative lung resection and whose preoperative and postoperative (1-year) computed tomographic images were available. The skeletal muscle area (SMA) at the 12th thoracic vertebra level was used. Postoperative/preoperative ratio was defined as postoperative normalized SMA (cm 2 /m 2 ) divided by preoperative normalized SMA. The cutoff value was set to a postoperative/preoperative ratio of 0.9. The neutrophil-lymphocyte ratio, the platelet-lymphocyte ratio, modified Glasgow prognostic score, and prognostic nutritional index were used to estimate change in the nutritional status., Results: There were 70 patients (34.3%) classified into the SMA-decreased group. Low body mass index was significantly associated with the SMA-decreased patients (P = .019). The SMA-decreased status was an independent prognostic factor for poor overall survival (P < .001) and disease-free survival (P = .001). The SMA-decreased status was significantly associated with the postoperative exacerbation of the neutrophil-lymphocyte ratio (P = .009), platelet-lymphocyte ratio (P = .026), modified Glasgow prognostic score (P = .003), and prognostic nutritional index (P = .013)., Conclusions: Skeletal muscle loss after surgery is significantly associated with poor postoperative outcomes in NSCLC patients. Further studies investigating the clinical impact of postoperative nutritional intervention are needed., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: We investigated the utility of the clinical T factor of the 8th edition of the TNM classification, which newly defines the consolidation size of the tumor, as a valuable predictor of pathologic lymph node metastasis (pN+) and the prognosis., Methods: We retrospectively reviewed 825 patients with surgically resected cN0 M0 non-small cell lung cancer of any T stage, focusing on the tumor's total size (7th edition) and consolidation size (8th edition) and examined pN+ and the prognosis., Results: No pN+ cases in the 7th or 8th edition groups had a tumor size of less than 1 cm, and in those sized 1 to 3 cm, the frequency of pN+ in the 7th and 8th edition groups was 10.3% and 13.4%, respectively. The frequency of pN+ in tumors without ground glass opacity (GGO-) was 5.5-times higher than that of tumors with GGO (GGO+). The frequency of pN+ in the GGO+ 8th edition group was twice that in the GGO+ 7th edition group. The frequency of pN+ in the GGO- 7th edition group was 4-times higher than that of the GGO+ 7th edition group. A multivariate analysis revealed that total size exceeding 2 cm, consolidation size exceeding 2 cm, and GGO- were significant predictors of a pN+ status, indicating that a consolidation size of more than 2 cm was a stronger predictor than a total size of more than 2 cm., Conclusions: A consolidation size of more than 2 cm and GGO- were predictors of pN+, and the clinical T factor of the 8th Edition was a stronger predictor of the pN+ status than that of the 7th edition., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The epithelial-mesenchymal transition (EMT) describes the process through which cells lose epithelial characteristics and gain a mesenchymal phenotype. The EMT contributes to tumor invasion and cancer progression, and is associated with metastasis and poor survival of patients with non-small-cell lung cancer. However, little is known about the relationships between the EMT and the clinicopathologic characteristics of patients with stage IA lung adenocarcinoma., Patients and Methods: We conducted immunohistochemical analysis of the expression of the EMT markers E-cadherin and vimentin of specimens acquired from 183 consecutive patients with stage IA lung adenocarcinoma. The clinicopathologic significance of the association of the EMT status with E-cadherin and vimentin expression was analyzed after propensity score matching., Results: E-cadherin and vimentin were detected in 68.3% and 18.6% of stage IA lung adenocarcinomas, respectively. The presence of cells with EMT conversion was associated with older patient age. A propensity score-matched cohort (128 patients) was used for further analyses. Computed tomography revealed that tumors with EMT conversion showed solid-dominant nodules compared to those without conversion. Survival analysis after propensity score matching showed that the EMT correlated with poor disease-free survival (hazard ratio = 2.57, P = .0451) and overall survival (hazard ratio = 4.23, P = .0471). Multivariate analysis revealed that the EMT was an independent predictor of shorter disease-free survival., Conclusion: The EMT was a significant predictor of poor prognosis of patients with stage IA lung adenocarcinoma. The EMT status may serve as an indicator for administering adjuvant therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Although high-mobility group box-1 (HMGB1), which is a nuclear protein, was reported to enhance the allogeneic responses in transplantation, the effect of HMGB1 on bronchiolitis obliterans syndrome (BOS) is unknown., Methods: A murine heterotopic tracheal transplantation model was used. Protein concentrations of HMGB1, interferon-γ (IFN-γ), interleukin (IL)-10, and IL-17 were analyzed in the isografts, allografts, controls, and HMGB1-neutralizing antibody administered allografts (n = 6; Days 1, 3, 5, 7, 14, 21, and 28). The luminal fibrous occlusion was analyzed (n = 6; Days 7, 14, 21, and 28). Infiltrating CD8 and CD4 T lymphocytes around the allografts and serum levels of IFN-γ and IL-10 were evaluated (n = 6; Day 7)., Results: The HMGB1 levels in the allografts were significantly increased compared with the isografts at Day 7. HMGB1 blockade did not change the IL-17 level, but decreased the IFN-γ/IL-10 ratio in the early phase (Days 5 and 7) and significantly improved the fibrous occlusion in the late phase (Days 14, 21, and 28). HMGB1 blockade significantly suppressed the CD8 T lymphocytes infiltration and decreased the serum IFN-γ/IL-10 ratio compared with the control at Day 7., Conclusions: HMGB1 may be a trigger of the BOS pathogenesis and candidate target for the treatment of the disease., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Enhancer of zeste homolog 2 (EZH2) is reported to be involved in lung cancer pathogenesis via the epigenetic regulation of various genes. Recently, EZH2 was shown to control mechanisms of adaptive resistance to immunotherapy in melanoma; however, the association between EZH2 and programmed death-ligand 1 (PD-L1), which reflects the tumor microenvironment, remains poorly understood., Methods: A total of 428 patients with resected lung adenocarcinoma were analyzed for their EZH2 and PD-L1 expression by immunohistochemistry and evaluated to determine the association between the EZH2 and PD-L1 expression., Results: Among 428 patients, the EZH2 expression was identified in 219 (51.2%) patients, while the PD-L1 expression was observed in 88 (20.6%) patients. The recurrence-free and overall survival were significantly shorter in patients with the EZH2 expression than in those without it. A multivariate analysis showed that EZH2 remained an independent prognosticator for recurrence-free and overall survival. Patients with the EZH2-positive lung adenocarcinoma exhibited a significantly higher expression of PD-L1 than did those without it. A logistic regression analysis with backward elimination revealed that the presence of lymphatic and vessel invasion and PD-L1 positivity were independently associated with the EZH2 expression, while age over 70 years, the presence of vessel invasion, wild-type epidermal growth factor receptor, and EZH2 positivity were significantly associated with the PD-L1 expression., Conclusions: EZH2-expressing lung adenocarcinomas were shown to express the PD-L1 protein more frequently than were nonexpressing lesions. This study provides the first evidence of a possible association between the EZH2 and PD-L1 expression in patients with resected lung adenocarcinoma., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Spread through air spaces (STAS) is a recently recognized invasive pattern of lung cancer defined by the World Health Organization as micropapillary clusters, solid nests, or single cells spreading within air spaces beyond the edge of the main tumor. Although STAS has been shown to be a significant prognosticator for the postoperative survival in early-stage lung cancer treated with limited resection, its prognostic impact on the survival in completely resected adenocarcinomas with lymph node metastasis remains unclear., Patients and Methods: STAS was assessed in a total of 63 adenocarcinomas with lymph node metastasis in patients who underwent complete resection. STAS was defined as tumor cells within air spaces in the lung parenchyma beyond the edge of the main tumor. We evaluated the association between STAS and the clinicopathologic characteristics and the postoperative survival., Results: Among 63 patients, 31 (49.2%) and 32 (50.8%) had disease that was pathologically positive for N1 and N2, respectively. STAS was observed in 45 patients (73.0%) and was not significantly associated with any clinicopathologic characteristics. Patients with the STAS had significantly shorter recurrence-free survival (RFS) but not overall survival than those without STAS (P = .04 and P = .35, respectively). The 5-year RFS in patients with and without STAS was 25.1% and 56.7%, respectively. According to a multivariate analysis, positivity for STAS remained an independent prognostic parameter for RFS (hazard ratio = 3.09; 95% confidence interval, 1.47-7.16; P < .01)., Conclusion: STAS was predictive of a poor RFS in completely resected adenocarcinomas with lymph node metastasis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: "Spread through air spaces" (STAS) is a recently described invasive pattern of lung cancer that spreads within air spaces beyond the edge of the main tumor. In the current study, we investigated the significance of STAS in patients with pathologic stage I adenocarcinoma., Methods: We assessed STAS in a total of 276 patients with resected pathologic stage I adenocarcinoma. STAS was classified as either no STAS, low STAS (1-4 single cells or clusters of STAS), or high STAS (≥5 single cells or clusters of STAS) using a 20x objective and a 10x ocular lens. We evaluated the association between STAS and the clinicopathologic characteristics and postoperative survivals., Results: Among 276 patients, 123 (44.6%), 48 (17.4%), and 105 (38.0%) were classified as having no, low, and high STAS, respectively. The positivity for STAS was significantly associated with larger radiologic tumor diameter (p = 0.008), higher consolidation/tumor ratio (p < 0.001), higher maximum standard uptake value (p < 0.001), pathologically larger tumor size (p = 0.004), pleural invasion (p = 0.027), and histologically invasive type (p < 0.001); whereas STAS was not significantly associated with epidermal growth factor receptor mutations or programmed death ligand-1 expression (p = 0.129 and p = 0.872, respectively). Patients with STAS had significantly shorter recurrence-free and overall survival than patients without STAS (p < 0.001 and p = 0.002, respectively). According to a multivariate analysis, positivity for STAS remained an independent prognostic factor for both recurrence-free survival and overall survival., Conclusions: Spread through air spaces was associated with clinicopathologically invasive features and was predictive of worse survival., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: The programmed death ligand 1(PD-L1)/programmed cell death protein 1 (PD-1) pathway is one of the most important checkpoint pathways for mediating tumor-induced immune suppression through T-cell exhaustion. Recently, targeted therapies using monoclonal antibodies against components of this pathway have been shown to reduce tumor burden in patients with non-small cell lung cancer (NSCLC). However, the prognostic significance of PD-L1 expression is controversial and the precise mechanisms of PD-L1 gene activation in lung cancer have yet to be clarified., Methods: We investigated copy number alterations (CNAs) in the PD-L1 gene by real-time PCR in 94 surgically resected lung cancer samples to find possible associations between PD-L1 CNA and lung cancer biology. Janus kinase 2 gene (JAK2) CNA and its influence on the PD-L1/PD-1 pathway were also assessed., Results: Five samples were shown to have PD-L1 gene amplification, whereas 89 samples did not. The patients with PD-L1 amplification had worse prognoses than did those without PD-L1 amplification. Genetic amplification of the PD-L1 gene was correlated with JAK2 gene amplification. The lung cancer cell line HCC4006 was found to harbor both JAK2 and PD-L1 amplification. Flow cytometry analyses revealed the level of PD-L1 protein expression to be higher in HCC4006 cells than in other NSCLC cell lines. Expression of the PD-L1 protein was significantly reduced by the JAK2 inhibitor TG-101348 and the signal transducer and activator of transcription 3 (STAT-3) inhibitor BP-1-102, but not by the STAT1 inhibitor fludarabine., Conclusions: Our data suggest that expression of PD-L1 protein is upregulated by the simultaneous amplification of the PD-L1 and JAK2 genes through JAK-STAT signaling in NCSLC., (Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Thymoma patients with no prior history of myasthenia gravis (MG) occasionally have MG after thymectomy. This study aimed to identify risk factors for developing postthymectomy MG., Methods: We retrospectively reviewed the characteristics and clinical outcomes of thymoma patients without preoperative MG who underwent a thymectomy at our institute., Results: Of the 229 thymoma patients who underwent surgery from 1991 to 2011, 123 had no history of MG. The serum of all patients was analyzed for acetylcholine receptor antibodies (AchR-Ab), and 33 patients had detectable levels (greater than 0.2 nmol/L). Ten seropositive patients had MG develop postoperatively within 3 to 2,859 days, whereas 90 seronegative patients did not. Univariate analysis showed that a positive result for serum AchR-Ab (p < 0.001), type B1/B2/B3 thymoma histology (p = 0.025), and incomplete resection (p = 0.008) were risk factors for the development of MG. In patients with post-thymectomy MG, the AchR-Ab levels at the onset of MG were significantly higher than the preoperative levels (p = 0.036). The analysis of the 33 antibody-positive patients showed a significant correlation between antibody levels and the onset of disease (p = 0.003). The analysis of 12 patients with incomplete resection revealed that perioperative chemotherapy or radiotherapy reduced the risk of development of MG (p = 0.009)., Conclusions: A positive result for serum AchR-Ab, type B1/B2/B3 thymoma histology, and incomplete resection were considered risk factors for the development of postthymectomy MG. Preoperative levels of serum AchR-Ab should be examined in all thymoma patients. Perioperative chemotherapy or radiotherapy for the patients with incomplete resection might reduce the risk of MG development., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Patterns of intrapulmonary metastasis, particularly metastasis outside tumor-bearing segments, were investigated in lung cancer patients to address the rationale for segmentectomy., Methods: In a consecutive series of patients who underwent resection of two or more pulmonary segments for primary lung cancer, intrapulmonary spread patterns, such as segmental/intersegmental node metastasis and pulmonary parenchymal metastasis, were pathologically examined., Results: Eligible 244 lesions included 167 adenocarcinomas, 66 squamous cell carcinomas, and 11 large cell carcinomas. Pathologic stages included 0 to IA (n=111), IB (n=56), IIA (n=31), IIB (n=20), IIIA (n=23), and IIIB to IV (n=3); and N1 (n=26) and N2 (n=22). Intrapulmonary spread was observed in 24 cases (9.8%). Of these, metastasis outside tumor-bearing segments was only observed in 4 cases (1.6%), and such cancer spread was more frequently seen in cases with extrapulmonary (hilar to mediastinal) nodal metastasis (7.9%) than in cases without extrapulmonary metastasis (0.5%; p=0.01). Metastasis outside tumor-bearing segments was not observed in 64 tumors with pure or mixed ground glass opacity features on computed tomography. Although tumor location (peripheral or central/intermediate) was not related to the incidence of metastasis outside tumor-bearing segments, intrapulmonary spread was observed in only 1 of 52 peripheral small (≤20 mm) tumors., Conclusions: Metastasis outside tumor-bearing segments is rarely observed in cases with tumors (1) without extrapulmonary nodal metastasis and (2) with ground glass opacity or peripheral small (≤20 mm) features., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Malignant pleural mesothelioma is a highly aggressive cancer with poor prognosis. We have previously demonstrated that regulatory T cells (Treg) depletion can impact tumor microenvironment when combined with chemotherapy. The aim of this study is to analyze the impact of Treg depletion on tumor cell repopulation during cycles of chemotherapy in a murine mesothelioma model., Methods: Tumor-bearing mice were treated with chemotherapy once weekly to mimic clinical settings and with PC61 to cause Treg depletion after each cycle of chemotherapy. Tumor cell repopulation was evaluated by BrdU labeling index with immunohistochemistry and flow cytometry, and Ki67 gene expression was determined by real-time reverse-transcribed polymerase chain reaction. The proportion of CD4+ CD25+Foxp3+ Tregs, CD4+, and CD8+ T cells in the tumor, spleen, draining lymph node, and peripheral blood from tumor-bearing mice was determined by using flow cytometry, and gene expression of activated T-cell-related cytokines was quantified by enzyme-linked immunosorbent assay and reverse-transcribed polymerase chain reaction., Results: Tumor growth delay was achieved by cisplatin followed by PC61 or cyclophosphamide. The BrdU labeling index indicated that tumor cell repopulation between cycles of cisplatin was significantly inhibited by PC61. The CD4+CD25+Foxp3+ Tregs in tumor and lymphoid organs were almost completely depleted, whereas the CD4+ or CD8+ T cells did not change. PC61 after chemotherapy resulted in an increase of gene expression of interferon-γ, granzyme B, perforin, and IP-10, thus leading to tumor cell lysis in cytotoxic lymphocyte assay. Nevertheless, cell killing induced by cyclophosphamide combined with cisplatin was due to cytotoxicity rather than specific immune response., Conclusion: Treg depletion between cycles of chemotherapy could improve the outcome of mesothelioma. Nevertheless, this effect seems limited, and more effective approaches need to be developed.

We describe a rare case of a giant thymoma that developed in the right thoracic cavity, and seemed to originate from the visceral pleura. We believe that there have been few reports of thymoma developing from such an unusual origin.