A Clinicopathological and Prognostic Analysis of PD-L2 Expression in Surgically Resected Primary Lung Squamous Cell Carcinoma.

BACKGROUND: Immunotherapy targeting programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has shown dramatic therapeutic effects for lung squamous cell carcinoma (SCC), and PD-L1 expression has been shown not only to be a predictive biomarker for response to immunotherapy but also a prognostic factor for lung SCC. However, the clinical significance of programmed death-ligand 2 (PD-L2), another PD-1 ligand, remains unclear. Therefore, we analyzed PD-L2 expression by immunohistochemistry in surgically resected primary lung SCC. PATIENTS AND METHODS: PD-L1 and PD-L2 expression on tumor cells were analyzed in 211 primary lung SCC specimens by immunohistochemistry. Additionally, numbers of CD3+, CD4+, and CD8+ tumor-infiltrating lymphocytes were also examined. RESULTS: The rates of positive PD-L2 expression were 77.3% and 67.3% using 5% and 10% cut-off values, respectively. Low PD-L2 expression on tumor cells was statistically associated with histological type (non-keratinizing/keratinizing) and lymphatic invasion. PD-L2-positive patients had significantly longer postoperative survival time (log-rank test; p = 0.0170 at 5% cut-off and p = 0.0500 at 10% cut-off). Furthermore, survival analysis according to PD-L1 and PD-L2 expression revealed that PD-L1-positive and PD-L2-negative patients had the most unfavorable prognosis. CONCLUSIONS: PD-L2 protein expression was associated with prognosis in primary lung SCC patients. PD-L2 expression might be a potential biomarker for response to PD-1/PD-L1-targeted immunotherapy, which should be investigated in future studies.

Prognostic Significance of Expression of the Epithelial-Mesenchymal Transition-Related Factor Brachyury in Intrathoracic Lymphatic Spread of Non-Small Cell Lung Cancer.

BACKGROUND: Brachyury is a transcriptional regulator that plays important roles in epithelial mesenchymal transition (EMT) during development and has been reported to be essential for mesoderm formation in the early human embryo. We investigated Brachyury protein expression in hilar and mediastinal metastatic lymph nodes of non-small cell lung cancer patients and the prognostic significance of Brachyury expression at metastatic sites. METHODS: Expression of Brachyury in 115 surgically resected primary lung cancer and corresponding metastatic lymph node samples was evaluated by immunohistochemical staining. The relationships between Brachyury protein expression and the patient's clinicopathological factors and prognosis were analyzed. RESULTS: Brachyury expression in metastatic lymph nodes was significantly higher than that in the primary tumor (p = 0.012). Patients with high Brachyury expression in the metastatic lymph nodes had significantly poor prognoses (p = 0.0236) compared with patients with low expression. In addition, patients with larger differences in Brachyury expression between metastatic lymph nodes and the primary tumor had significantly poorer prognoses compared with patients with smaller differences (p = 0.0146). The Brachyury protein expression level in metastatic lymph nodes was significantly associated with the protein expression levels of other EMT-related factors (E-cadherin [inverse association], p = 0.0265; Slug, p = 0.029; and interleukin-8, p = 0.0135). CONCLUSIONS: High expression of Brachyury protein in metastatic carcinoma cells in the intrathoracic lymph nodes was associated with poor prognosis of lung cancer patients. Increased Brachyury expression during the metastatic process may confer further potential for invasion and metastasis of cancer cells.

Treatment of the postoperative recurrence of lung cancer in octogenarians.

PURPOSE: Guidelines for the treatment of postoperative recurrent lung cancer in octogenarians do not exist. In this study, we investigated the prognosis of patients with recurrence after the resection of lung cancer and discuss the management of recurrent tumors in octogenarians. METHODS: This study clinicopathologically evaluated 135 octogenarians who underwent resections for lung cancer at a single institution between 1992 and 2010. We retrospectively reviewed the clinical records of 37 patients with confirmed recurrence. The overall survival of the patients and the treatments used for postoperative recurrence were evaluated. RESULTS: Among 37 patients, six underwent intensive treatment, 14 underwent palliative treatment and 17 received supportive care only. The overall survival rates of the patients in the antitumor treatment groups tended to be associated with a better prognoses than those of the patients in the supportive care only group, but they did not exhibit significantly better prognoses at 1 year (p = 0.202). However, among the patients with a good performance status, the intensive treatment group tended to exhibit prolonged survival. Of the 37 patients with recurrent tumors, five (14%) died of other diseases. CONCLUSIONS: Antitumor treatment of postoperative recurrent lung cancer in octogenarians may not always improve the survival rate. However, carefully selecting patients for intensive therapy, such as those with a good performance status, may lead to longer survival rates after postoperative recurrence in octogenarians.

Expression of Brachyury gene is a significant prognostic factor for primary lung carcinoma.

BACKGROUND: The clinical significance of Brachyury expression and its relationship to epithelial-mesenchymal transition in primary lung carcinoma is unclear. METHODS: Expression of Brachyury mRNA was investigated in 104 surgically resected primary lung carcinoma tissues. Immunohistochemical analysis of Brachyury transcription factor, Slug, E-cadherin, IL-8, N-cadherin, and Ki67 was performed in 67 of 104 cases, and their expression was correlated to prognoses and clinicopathological factors. RESULTS: Brachyury mRNA expression in primary lung carcinoma tissues was a significant predictor of poor prognosis for 5-year disease-free survival and overall survival rates and was significantly correlated to vascular invasion, lymphatic permeation, histological grade, pathologic T stage, and pathologic N stage (P < 0.05). Brachyury mRNA expression was significantly inversely correlated to E-cadherin expression (P = 0.0252) and positively correlated to IL-8 protein (P = 0.0241) and to Slug protein (P = 0.0243) in adenocarcinoma tissues. CONCLUSIONS: A positive association between Brachyury and Slug and IL-8, and a negative association with E-cadherin may lead to invasiveness and metastasis in primary lung carcinoma. Brachyury mRNA expression is a significant predictor of poor prognosis in primary lung carcinoma.

Differences in the expression of epithelial-mesenchymal transition related molecules between primary tumors and pulmonary metastatic tumors in colorectal cancer.

PURPOSE: Epithelial-mesenchymal transition (EMT) is a key event in cancer metastasis. This study immunohistochemically examined the expression of EMT-related molecules in both primary colorectal cancer and pulmonary metastases, and analyzed the expression pattern. METHODS: Ten patients with colorectal cancer that underwent surgical resections for both the primary tumor and metastatic pulmonary tumors were included. The expression status of EMT-related molecules was examined using immunohistochemical staining. RESULTS: Nine of the 10 cases maintained the expression of both E-cadherin and ß-catenin in the primary site. The expression of E-cadherin and ß-catenin in the pulmonary metastatic site was preserved in 10 and 12 out of 15 metastatic lesions, respectively. The EMT-related transcription factor, Twist, was positively expressed in all 10 cases, Smad interacting protein 1 (Sip1) in 9, Snail in 4 and Slug in 3 of the primary sites. On the other hand, staining for Twist, Sip1 and Snail at the metastatic pulmonary site, was negative in all 10 cases. CONCLUSION: The expression of EMT-related transcription factors in metastatic pulmonary tumors from colorectal cancer decreased in comparison to the primary tumors. These findings suggested that the expression status of EMT-related transcription factors might play an important role in the implantation of metastatic foci.

[Chest surgery in patients with pulmonary metastasis from head and neck cancer].

There have been only a few reports about a surgical resection of pulmonary metastasis from malignant head and neck tumors. Here we reviewed the literatures concerning the surgical results of pulmonary metastasectomy from malignant head and neck tumors, and discussed the indication for surgery. The 5-year overall survival after a metastasectomy was approximately 50.0% including all the histological types of head and neck cancer. Limiting to the squamous cell carcinoma (SCC), the 5-year overall survival was approximately 30.0%. Of the head and neck SCCs, the oral cavity SCC such as SCC of the tongue showed an extremely poor survival after metastasectomy. A pulmonary metastasectomy of squamous cell carcinoma is thus justified with the exception of oral cavity origin. Both adenoid cystic carcinoma of salivary glands and thyroid cancer are of low malignant nature, and the progression after occurrence of distant metastases is also very slow. Therefore, the survival benefit by those pulmonary metastasectomy is not evident.

Surgical diagnosis and treatment of a solitary lung nodule of IgG4-related disease, mimicking primary lung carcinoma or metastatic lung tumour: A rare case.

INTRODUCTION: IgG4-related disease is a poorly understood immune disorder. Its features include tumour-like swelling of involved organs, lymphoplasmacytic infiltrate with IgG4 positive plasma cells. IgG4-related lung disease can manifest radiologically as various types of pulmonary abnormalities, including mass-like lesions and pleural effusion, and it may mimic malignant disease. PRESENTATION OF CASE: A 76-year-old man was found to have a 4-mm ground glass opacity in the left lower lobe of the lung on follow-up chest CT after surgery for colon carcinoma. This lesion gradually became consolidated and enlarged to 9 mm over about three years. We performed a video-assisted left basal segmentectomy for the purposes of both diagnosis and treatment. Pathological examination revealed lymphoplasmacytic infiltration, mainly with IgG4-positive plasma cells. DISCUSSION: A major characteristic of IgG4-related lung disease is multiple, small, bilateral, lung nodules and solid nodules reportedly being detected in almost all patients. However, solitary nodules are rare, being present in only 14 %. Moreover, this case shows extremely rare radiological findings in which a ground-glass opacity had gradually morphed into a solid nodule. It is difficult to differentiate IgG4-related lung nodules from other lung diseases, such as primary or metastatic lung tumours, standard interstitial pneumonia, organizing pneumonia. CONCLUSION: We have here presented a rare case of IgG4-related lung disease with a 3-year course, including detailed radiological findings. Surgery is very useful for both diagnosis and treatment of a small, solitary, deeply located, pulmonary nodule of IgG4-related lung disease.

Hypothyroidism With ACTH Deficiency During Pembrolizumab Therapy for Lung Cancer: Case Report and Literature Review.

BACKGROUND/AIM: Immune-checkpoint inhibitors have recently shown great promise in treating various cancers, but often cause immune-related adverse events (irAEs). Simultaneous drug-induced hypothyroidism and isolated adrenocorticotropic hormone (ACTH) deficiency are rare irAEs. This combination of irAEs is associated with paradoxical endocrine dysfunction characterized by large amounts of thyroid-stimulating hormone (TSH) and small amounts of ACTH in the anterior lobe of the pituitary. We herein report a case of hypothyroidism with isolated ACTH deficiency during pembrolizumab therapy for recurrent lung cancer. CASE REPORT: Our patient was a 66-year-old man with recurrence of squamous cell lung carcinoma. Four months after chemotherapy that included pembrolizumab, the patient presented with general fatigue and laboratory tests showed high concentrations of TSH with low concentrations of free-T4. He was diagnosed with hypothyroidism and levothyroxine was prescribed. His ACTH concentration was found to be low 1 week later when he developed an acute adrenal crisis with associated hyponatraemia. We then changed his diagnosis to concurrent hypothyroidism with isolated ACTH deficiency. His condition improved after 3 weeks of administration of cortisol. CONCLUSION: It is difficult to diagnose a concurrent paradoxical endocrine disorder, such as hypothyroidism with isolated ACTH deficiency, as in the present case. Physicians should pay attention to symptoms and laboratory data to identify various types of endocrine disorders as irAEs.

A unique method for repairing intraoperative pulmonary air leakage with both polyglycolic acid sheets and fibrin glue.

BACKGROUND: In the present study we present a unique maneuver, using both fibrin glue and polyglycolic acid (PGA) sheets, for repairing intraoperative pulmonary air leakage, and report our clinical results. METHODS: Based on the results from in vitro experiments, we retrospectively investigated the clinical effects of our method for repairing intraoperative pulmonary air leakage in 377 consecutive patients, who underwent a pulmonary resection for primary lung cancer or metastatic lung tumors from 2004 to 2009. From April 2004 through September 2007, repair of intraoperative pulmonary air leakage was performed in 204 patients using only fibrin glue. From October 2007 through December 2009, the repair was performed in 173 patients with a unique application of both fibrin glue and PGA sheets, i.e., (1) rubbing fibrin glue A solution, (2) applying a PGA sheet cut to an appropriate size, (3) rubbing fibrin glue B solution on the PGA sheet, and (4) reapplying fibrin glue A solution and rubbing. RESULTS: The mean duration of postoperative pleural drainage was significantly shorter in the latter time period when both fibrin glue and PGA sheets were used than in the former period when fibrin glue was used alone. The incidence of prolonged air leakage longer than 1 week was also significantly lower in the latter era than in the former era. CONCLUSION: Our unique application of both fibrin glue and PGA sheets for the intraoperative repair of pulmonary air leakage effectively resulted in a shortening of the duration of postoperative pleural drainage.

Non-small cell lung cancer in never smokers as a representative 'non-smoking-associated lung cancer': epidemiology and clinical features.

Recent interest in lung cancer without a history of tobacco smoking has led to the classification of a distinct disease entity of 'non-smoking-associated lung cancer'. In this review article, we have made an overview of the recent literature concerning both the epidemiology and clinical features of lung cancer in never smokers, and have brought 'non-smoking-associated lung cancer' into relief. The etiology of lung cancer in never smokers remains indefinite although many putative risk factors have been described including secondhand smoking, occupational exposures, pre-existing lung diseases, diet, estrogen exposure, etc. Non-small cell lung cancer (NSCLC) in never smokers is clinically characterized by an increased incidence in females and a higher occurrence of adenocarcinoma in comparison to NSCLC in ever smokers in both surgical patients and non-resectable advanced-stage patients. Furthermore, the prognosis of never-smoking NSCLC is better than that of smoking-related NSCLC in both surgical patients and non-resectable advanced-stage patients. Recently recognized novel gene mutations such as EGFR (epidermal growth factor receptor) mutations are largely limited to never smokers or light smokers, and the expression of this gene is responsible for the clinical efficacy of gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor. NSCLC with the EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion gene is also more likely to occur in never smokers and in those with adenocarcinoma histology, and is expected to benefit from ALK inhibitors. In consideration of the future increase in never-smoking NSCLC or 'non-smoking-associated lung cancer', both clinical trials and investigations are needed.

Assessing a clinical pathway to improve the quality of care in pulmonary resections.

PURPOSE: To evaluate the efficacy of the current clinical pathway for pulmonary resections. METHODS: This study examined variances from expected clinical pathway outcomes for pulmonary resections performed between 2005 and 2009. Data on a total of 383 patients were retrospectively analyzed. RESULTS: The median length of hospital stay (LOS) using the clinical pathway was 12 days (range: 1-188 days); the mean LOS was 15.5 days. The cost per day with use of the clinical pathway was 102 726 yen. Poor control of pain from intercostal neuralgia was the most frequently observed variance from expected outcomes. It affected 119 of 168 electronic clinical pathway patients (70.8%). The clinical pathway was terminated in 3.9% of patients (15/383) due to serious or life-threatening complications. CONCLUSIONS: This study showed the single institutional experience of the clinical pathway for pulmonary resections. These findings indicate a need to revise certain aspects of the pathway, based on data from our analysis of variances.

The influence of intracellular epidermal growth factor receptor (EGFR) signal activation on the outcome of EGFR tyrosine kinase inhibitor treatment for pulmonary adenocarcinoma.

PURPOSE: The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, exhibit up to a 70% response rate against non-small cell lung cancer (NSCLC) harboring somatic activating mutations of the EGFR gene (EGFR). The mechanism of intrinsic resistance of EGFR mutation-positive NSCLC against EGFR-TKIs is not known. The current study assesses the relationship between the molecular expression of EGFR signals and the response to gefitinib treatment in patients with pulmonary adenocarcinoma to elucidate the mechanism of intrinsic resistance to gefitinib. METHODS: The present study included 30 patients with pulmonary adenocarcinoma who were treated with gefitinib for a postoperative recurrence. The correlation between the response to gefitinib treatment and various clinical and molecular features was evaluated. RESULTS: EGFR mutations were detected in 20 (66.7%) of the 30 patients. The response to gefitinib treatment was a complete response in 1 case, partial response in 12 cases, stable disease in 4 cases, and progressive disease in 13 cases. Both univariate and multivariate analyses showed the presence of an EGFR mutation, and the expression of phospho-EGFR (p-EGFR) significantly correlated with a better response to gefitinib treatment. Ten of the 16 p-EGFR positive patients were disease controlled, but all 4 p-EGFR negative patients were intrinsically resistant to EGFR-TKIs (P = 0.025). Other factors including sex, smoking status, serum carcinoembryonic antigen and cytokeratin-19 fragment levels, EGFR, Met proto-oncogene, phospho-Met, and hepatocyte growth factor expression were not associated with the response to gefitinib treatment. CONCLUSION: These results suggest that, even if EGFR mutations were observed, a p-EGFR negative state might be a cause of intrinsic resistance to EGFR-TKIs.

Prognostic impact of local treatment against postoperative oligometastases in non-small cell lung cancer.

OBJECTIVES: In this study, we investigated prognostic factors associated with survival after distantly metastatic recurrence in surgically resected non-small cell lung cancer (NSCLC), and clarified the influence of local treatment on the prognosis for oligometastatic recurrence. METHODS: From 1994 through 2004, 418 consecutive patients with NSCLC underwent complete resection; 138 experienced a postoperative recurrence by December 2005. Of those, we reviewed 93 patients with only distant metastases for clinicopathological information, treatment modality, and survival. RESULTS: For the 93 patients with distant metastasis alone, the 2- and 5-year survival rates after recurrence were 43.9% and 38.7%, respectively. Of those patients, 44 first received local treatment, including radiotherapy in 31 and a surgical resection in 13. Their recurrent disease (oligometastases) was limited with the potential to be controlled with local treatment. The targeted metastatic organs were brain in 14 patients, bone in 14, lungs in 12, and other organs in 4. Significant prognostic factors for postrecurrence survival included adenocarcinoma histology, long disease-free interval (DFI) (1 year or longer), and the performance of local treatment for oligometastases. CONCLUSION: Local therapy such as radiotherapy and surgery, might be considered first-line treatment in patients with postoperative oligometastatic recurrence, especially those with a DFI ≥ 1 year.

Surgical treatment of Bochodalek hernia incarcerated into the extra-pleural space: A rare case report.

INTRODUCTION: Bochdalek hernias are a type of diaphragm hernia. Almost all occur in the neonatal period, only 5% of these hernias occurring in adults. We here present a rare case of adult Bochdalek hernia incarcerated in the extra-pleural space. PRESENTATION OF CASE: An asymptomatic 51-year-old man was admitted to our hospital for a detailed examination after an abnormality had been detected on a chest radiograph. Chest computed tomography (CT) examination revealed findings consistent with a left Bochdalek hernia, which we repaied surgically. Intraoperatively, retroperitoneal fatty tissue was found to be incarcerated in the extra-pleural space. Thus, surgical repair required dissection of the parietal pleura and excision of the incarcerated fatty tissues. DISCUSSION: The incarceration of the Bochdalek hernia in the extra-pleural space could not be identified on a preoperative chest CT examination. To the best of our knowledge, no reports of incarceration of a Bochdalek hernia in the extra-pleural space have been published; thus, this phenomenon is extremely rare. CONCLUSION: Surgical treatment of a Bochdalek hernia incarcerated in the extra-pleural space requires dissection of the parietal pleura and repair via a transthoracic approach.

Pulmonary metastasis presenting as a ground glass opacity-like lesion with a thin-walled cavity: A case report.

INTRODUCTION: Most of pulmonary metastases present as well-defined solid and round nodules. Here we report a case of a pulmonary metastasis presenting as a ground glass opacity (GGO)-like lesion with a thin-walled cavity and lymph node metastasis of tongue cancer. CASE PRESENTAION: A 22-year-old man was referred to our department for surgical diagnosis and treatment for a GGO-like pulmonary nodule with a thin-walled cavity in the right lower lobe. He had a history of surgical resection for tongue cancer. The size of the GGO-like lesion with a thin-walled cavity in the center gradually increased. A right lower lobectomy and hilar lymphadenectomy were performed. Postoperative pathology revealed the lesion as pulmonary metastasis and hilar lymph node metastasis of tongue cancer. DISCUSSION: Our case report of pulmonary metastasis of tongue cancer is rare from the viewpoint of pulmonary GGO-like lesions with a following thin-walled cavity and hilar lymph node metastasis. The positron emission tomography/computed tomography (PET/CT) examination was useful to show right hilar lymph node metastasis. CONCLUSION: It is important to make a differential diagnosis of from the pulmonary nodule in case of a GGO-like lesion with a thin-walled cavity.

Clinical and Prognostic Significance of the Epithelial-Mesenchymal Transition in Stage IA Lung Adenocarcinoma: A Propensity Score-Matched Analysis.

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.

Co-expression of IDO1 and PD-L1 in lung squamous cell carcinoma: Potential targets of novel combination therapy.

OBJECTIVES: Combination therapy with an inhibitor of indoleamine 2, 3-dioxygenase 1 (IDO1) and an agent targeting programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) is expected to be a novel and effective treatment option for various solid tumors including non-small cell lung cancer (NSCLC). Therefore, it is important to elucidate the clinical and pathological features of tumors with IDO1/PD-L1 co-expression and the association between IDO1/PD-L1 co-expression and efficacy of combination therapy in NSCLC patients. In this study, we examined the prognostic impact of IDO1/PD-L1 co-expression and its relationship with tumor-infiltrating lymphocytes (TILs) in primary lung squamous cell carcinoma (SCC). MATERIALS AND METHODS: The expression levels of IDO1, PD-L1, Ki-67, cluster of differentiation 3 (CD3), CD4, and CD8 in 202 patients with surgically resected primary lung SCC were evaluated by immunohistochemistry. RESULTS: Among 202 patients, 176 (87.1%) were positive for IDO1 expression, 106 (52.5%) were positive for PD-L1 expression, and 99 (49.0%) showed co-expression of IDO1/PD-L1 proteins. Fisher's exact test showed a significant association between IDO1 and PD-L1 tumor proportion scores (P = 0.0011). Kaplan-Meier curve showed that PD-L1 alone and co-expression of IDO1 and PD-L1 were significantly associated with shorter overall survival, but IDO1 alone was not (log rank test: P = 0.0122, P = 0.0303 and P = 0.5168, respectively). The Ki-67 labeling index was significantly higher in patients with co-expression of IDO1 and PD-L1 than in patients without co-expression (Student's t-test: P = 0.0005). Moreover, IDO1/PD-L1 co-expression was significantly associated with high CD3, CD4, and CD8 expression (Fisher's exact test: P = 0.0033, P = 0.0003, and P < 0.0001, respectively). CONCLUSIONS: IDO1 expression correlated to PD-L1 expression, and co-expression of IDO1 and PD-L1 may be important targets for immunotherapy in lung SCC.

Association of Low Body Mass Index With Poor Clinical Outcomes After Resection of Non-small Cell Lung Cancer.

BACKGROUND/AIM: This study was performed to evaluate the influence of the body mass index (BMI) on disease-free survival and overall survival (DFS and OS) in patients with resected non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Overall, 546 of 780 (70%) patients with stage I to III NSCLC who underwent surgical resection were randomly selected. The patients were subdivided into three groups: low BMI (<18.5 kg/m2), normal BMI (18.5 to <25.0 kg/m2), and high BMI (≥25.0 kg/m2). Cox proportional hazards regression analyses were performed to identify variables associated with survival. RESULTS: In all patients, a low BMI was an independent prognostic factor for both DFS and OS (p=0.0175 and p=0.0134, respectively). In patients with stage I, a low BMI was also an independent prognostic factor for both DFS and OS (p=0.0066 and p<0.0001, respectively). CONCLUSION: A low BMI was an independent prognostic factor after surgical resection of stage I NSCLC. Molecular targeted therapies, such as epidermal growth factor receptor inhibitors, anaplastic lymphoma kinase-tyrosine kinase inhibitors, and immune checkpoint inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-L1) pathway have greatly improved the clinical course for patients with non-small cell lung cancer (NSCLC), especially advanced-stage NSCLC (1-7). However, lung cancer remains the leading cause of cancer-related death worldwide (8). Even in patients with stage I to IIIA NSCLC, the clinical course is unsatisfactory despite the fact that surgical resection is the main treatment option (9). Therefore, it is important to identify useful, simple, and inexpensive prognostic markers in patients with resectable NSCLC.

Association between peripheral blood markers and immune-related factors on tumor cells in patients with resected primary lung adenocarcinoma.

We sought to identify peripheral blood markers associated with two immune-related factors-programmed cell death-ligand-2 (PD-L2) and indoleamine 2,3-dioxygenase-1 (IDO1)-that are expressed on tumor cells in primary lung adenocarcinoma (AD) specimens. We randomly selected 448 patients (70%) from 640 consecutive patients with resected stage I-III primary lung AD, who had been treated at that point with surgery alone. Expression of PD-L2 and IDO1 in these patients was assessed by immunohistochemistry, and evaluated with respect to peripheral blood markers measured before surgery, including white blood cells, absolute neutrophil count, absolute lymphocyte count, absolute monocyte count (AMC), absolute eosinophil count (AEC), serum C-reactive protein, and serum lactate dehydrogenase levels. Membrane PD-L2 expression and cytoplasmic IDO1 expression were defined by tumor proportion score (TPS); samples with TPS < 1% were considered negative. Logistic regression models were used to identify variables associated with the immune-related factors. Advanced stage (P = 0.0090), higher AMC (P = 0.0195), and higher AEC (P = 0.0015) were independent predictors of IDO1 expression. PD-L2 expression was not associated with any tested peripheral blood markers. Peripheral blood markers, especially AMC and AEC, could potential predict IDO1 expression in lung AD. This study should be replicated in another cohort; further efforts to explore other biomarkers that predict PD-L2 or IDO1 expression are also warranted.

The association and prognostic impact of enhancer of zeste homologue 2 expression and epithelial-mesenchymal transition in resected lung adenocarcinoma.

OBJECTIVES: Epithelial-mesenchymal transition (EMT) and the histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2) are important regulators of lung cancer progression and metastasis. Although recent studies support the correlation between EZH2 expression and EMT, no reports have investigated their association using immunohistochemistry or explored their prognostic impact on lung adenocarcinoma. The aim of this study was to elucidate the association between EZH2 and EMT, and their prognostic significance. METHODS: EZH2 and the EMT markers E-cadherin and Vimentin were examined by IHC in lung adenocarcinoma specimens that were resected from 2003-2012. Associations between EZH2 and EMT markers and their correlations with survival were analyzed. RESULTS: We enrolled 350 patients, approximately 70% of whom were diagnosed as pathological stage I. The rates of positive E-cadherin, Vimentin, and EZH2 expression were 60.3%, 21.4%, and 52.0%, respectively. There was a significant positive correlation between EZH2 and Vimentin expression (p = 0.008), and EZH2 scores were higher in the Mesenchymal group (p = 0.030). In multivariate analysis, EZH2 was an independent predictor of Vimentin expression, and vice versa. EMT and EZH2 overexpression were significantly correlated with poor disease-free and overall survival. Furthermore, the Epithelial group with high EZH2 expression had significantly worse disease-free and overall survival. Positive staining for EMT markers was unfavorable regarding disease-free survival among patients with low EZH2 expression. CONCLUSIONS: EMT and high EZH2 expression were associated with poor NSCLC prognoses. Vimentin is a key factor linking EMT and EZH2 in lung adenocarcinoma.