Survival after initial lung metastasectomy for metastatic colorectal cancer in the modern chemotherapeutic era.

BACKGROUND: A clear survival benefit has been reported for lung metastasectomy for colorectal cancer, and several clinicopathological prognostic factors have been proposed in the past. However, clinical advances, such as chemotherapy and radiographic imaging, should have improved patient outcome and may have altered prognosticators. This study aimed to assess patient survival and determine prognostic factors for survival and recurrence in patients who underwent initial lung metastasectomy for colorectal cancer in the modern clinical era. METHODS: Clinicopathological data and outcomes of 59 patients who underwent curative initial lung metastasectomy for colorectal cancer from 2004 to 2012 at a single institution in Japan were retrospectively investigated. Survival was estimated using the Kaplan - Meier method, and Cox proportional hazards regression models were used to estimate the prognostic impacts of each variable in univariate and multivariate analysis. RESULTS: The 5-years overall and disease-free survival rates were 54.3 and 40.6%, respectively. A disease-free interval < 24 months after colorectal cancer resection (P = 0.004) and a serum carcinoembryonic antigen ≥ 5.0 ng/mL before initial lung metastasectomy (P = 0.015) were independent predictors for poor overall survival. Moreover, the disease-free interval after colorectal cancer resection < 24 months (P = 0.010) and a colorectal cancer with N2 stage disease (P = 0.018) were independently associated with poor disease-free survival. On the other hand, the number of lung metastasis was not identified as a poor prognostic factor for both overall and disease-free survival. CONCLUSIONS: Our findings demonstrated similar or slightly better overall survival, and substantially favorable disease-free survival as compared with past reports. Poor prognostic factors for overall survival appeared not to differ from those of past studies, although this modern series did not determine the number of lung metastasis as a poor prognostic factor, which should be investigated in future studies. Moreover, initial lung metastasectomy is not expected to be a curable treatment for patients with both a short disease-free survival after colorectal cancer resection and colorectal cancers with N2 stage disease.

Mucinous cystic tumor with CK20 and CDX2 expression of the thymus: Is this a benign counterpart of adenocarcinoma of the thymus, enteric type?

Primary thymic adenocarcinoma is extremely rare. Moreover, thymic pure epithelial benign neoplasms are extremely rare. We encountered a cystic tumor almost purely composed of goblet cell-like mucus-producing cells of the thymus. A mass lesion of the mediastinum was detected in a 54-year-old man. The gross specimen presented a unilocular cystic lesion containing abundant mucin, measuring 8 × 5.5 × 4.5 cm. Microscopic examination revealed a cystic tumor consisting of bland mucus-producing cells resembling goblet cells and forming tiny daughter cysts within the dense fibrous capsule. No destructive growth or infiltration into surrounding thymic tissue was observed. Papillary growth was found in a small focus. Immunohistochemically, tumor cells were positive for cytokeratin 20 and caudal type homobox 2, which are representative markers of enteric differentiation. The patient has been well without any recurrence for approximately ten years after the operation. Thus, the tumor should be regarded as a mucinous cystic tumor in the thymus. Very recently, thymic adenocarcinoma with enteric differentiation was proposed as a novel subtype of thymic carcinoma. This case could be regarded as a benign counterpart of adenocarcinoma of the thymus, enteric type. A further follow-up study is required to confirm the exact biological behavior of this tumor.

Soluble form of the MDA5 protein in human sera.

Viral double-stranded RNA (dsRNA) is sensed by toll-like receptor 3 (TLR3) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), including melanoma differentiation-associated gene 5 (MDA5). MDA5 recognizes the genome of dsRNA viruses and replication intermediates of single-stranded RNA viruses. MDA5 also plays an important role in the development of autoimmune diseases, such as Aicardi-Goutieres syndrome and type I diabetes. Patients with dermatomyositis with serum MDA5 autoantibodies (anti-CADM-140) are known to have a high risk of developing rapidly progressive interstitial lung disease and poor prognosis. However, there have been no reports on the soluble form of MDA5 in human serum. In the present study, we generated in-house monoclonal antibodies (mAbs) against human MDA5. We then performed immunohistochemical analysis and sensitive sandwich immunoassays to detect the MDA5 protein using two different mAbs (clones H27 and H46). As per the immunohistochemical analysis, the MDA5 protein was moderately expressed in the alveolar epithelia of normal lungs and was strongly expressed in the cytoplasm of lymphoid cells in the tonsils and acinar cells of the pancreas. Interestingly, soluble MDA5 protein was detectable in the serum, but not in the urine, of healthy donors. Soluble MDA5 protein was also detectable in the serum of patients with dermatomyositis. Immunoblot analysis showed that human cells expressed a 120 kDa MDA5 protein, while the 60 kDa MDA5 protein increased in the supernatant of peripheral mononuclear cells within 15 min after MDA5 agonist/double-strand RNA stimulation. Hydrogen deuterium exchange mass spectrometry revealed that an anti-MDA5 mAb (clone H46) bound to the epitope (415QILENSLLNL424) derived from the helicase domain of MDA5. These results indicate that a soluble MDA5 protein containing the helicase domain of MDA5 could be rapidly released from the cytoplasm of tissues after RNA stimulation.

Cone-Beam Computed Tomography-Guided Marking of Small Pulmonary Nodules with Surgical Clips.

BACKGROUND: Preoperative computed tomography-guided marking can help identify small non-palpable pulmonary nodules during surgery. However, this technique is associated with the risk of air embolism. We retrospectively evaluated whether small pulmonary nodules could be intraoperatively localized using cone-beam computed tomography (CBCT). METHODS: A hybrid operating room permitting stable lateral positioning and scanning from the pulmonary apex to the base was used in all patients. CBCT images were obtained using a 10-s protocol with 180º rotation of the C-arm flat panel detector around the patient. Clips were placed on the visceral pleura to help guide pulmonary nodule localization. Partial pulmonary resection was performed using video-assisted thoracoscopic surgery at the predicted nodule site. RESULTS: Between July 2013 and June 2019, 132 patients with 145 lesions underwent this procedure at our center. The detection rate of lesions on CBCT was 100%. The pathological diagnoses were primary lung cancer, metastatic pulmonary tumors, and benign lesions. The average consolidation-to-tumor ratio was 0.65 for all nodules, with ratios of 0.33, 0.96, and 0.70 for primary lung cancer, metastatic pulmonary tumors, and benign lesions, respectively. No complications related to this localization method were observed. CONCLUSIONS: CBCT-guided intraoperative localization is safe and feasible for non-palpable small pulmonary nodules. This technique may eliminate the risk of serious complications such as air embolism.

Endobronchial cryptococcosis with bronchial stenosis in a patient with severe asthma treated with inhaled corticosteroids: A case report.

Cryptococcosis typically manifests as pulmonary lesions, with endobronchial lesions occurring rarely. Inhaled corticosteroids (ICS) may be a risk factor for cryptococcosis of the larynx but not of the bronchi. Here, we report a case involving a 73-year-old Japanese man who developed endobronchial cryptococcosis during ICS treatment for asthma. Chest computed tomography showed right mainstem bronchial stenosis and asthma control worsening when he received adequate asthma treatments. Bronchoscopy revealed multiple elevated lesions with white slough from the trachea to the right mainstem bronchus and the right mainstem bronchus lumen entrance narrowing. Bronchial lavage culture revealed Cryptococcus neoformans. Combination treatment with the antifungal agent, mepolizumab, and bronchodilation surgery successfully controlled cryptococcosis and asthma. Attention should be paid to central airway lesions during ICS treatment for uncontrolled asthma.

Effectiveness of the Gerdq Questionnaire for Diagnosing Gastroesophageal Reflux Disease After Esophagectomy for Esophageal Cancer.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common complication after esophagectomy with gastric tube reconstruction. The GerdQ questionnaire was developed for diagnosing GERD in primary care patients. Its effectiveness in patients after esophagectomy remains unknown. In this study, we evaluated the usefulness of the GerdQ questionnaire for diagnosing GERD after esophagectomy for esophageal cancer. MATERIALS AND METHODS: A total of 124 patients with esophageal cancer underwent right transthoracic esophagectomy with gastric tube reconstruction between January 2010 and December 2016. Esophagogastroduodenoscopy and 24-hour esophageal pH-metry were performed at 1 month, 1 year, and 2 years postoperatively. The GerdQ questionnaire was administered at the same postoperative time points. We assessed any correlation between the GerdQ scores and the endoscopy and pH-metry findings. RESULTS: The incidence rates of GERD at 1 month, 1 year and 2 years post-surgery were 31.6%, 46.9%, and 49.2%, respectively. The GerdQ questionnaire showed 77% sensitivity and 56% specificity for diagnosing GERD at 2 years after esophagectomy when the cutoff point was 7. However, the optimal cutoff points were different at each postoperative time, and the scores showed some imbalance between sensitivity and specificity. Regurgitation may be a useful indicator, as the frequency of regurgitation was significantly higher in patients with GERD than in patients without GERD at 1 year (P = 0.046) and 2 years postoperatively (P = 0.048). CONCLUSION: The GerdQ questionnaire is not a useful diagnostic tool for GERD in patients who have undergone esophagectomy for esophageal cancer.

Utility of non-contrast-enhanced magnetic resonance imaging in predicting preoperative clinical stage and prognosis in patients with thymic epithelial tumor.

PURPOSE: The purpose of this study was to find useful imaging features on non-contrast-enhanced magnetic resonance imaging (MRI) that can divide patients with thymic epithelial tumor (TET) into clinical stage I-II and III-IV groups under assumption that contrast media are contraindicated. MATERIALS AND METHODS: This retrospective study included 106 patients (median age, 60 years; range, 27-82 years; 62 women) with surgically resected TET who underwent MRI between August 1986 and July 2015. All cases were classified according to the 2015 WHO classification and staged using the eighth edition of the TNM system. Two radiologists independently evaluated 14 categories of MRI findings; the findings in patients with stage I-II were compared with those of patients with stage III-IV using a logistic regression model. Disease-specific survival associated with significant findings was calculated using the Kaplan-Meier method. RESULTS: Univariate analysis showed that stage III-IV patients were more likely to have tumors with an irregular contour, heterogeneity on T1WI, low-signal intensity on T2WI, irregular border with lung, findings of great vessel invasion (GVI) (hereafter, GVI sign), pericardial thickening/nodule, and lymphadenopathy (all, P < 0.01). On multivariable analysis, only two findings, irregular border between tumor and lung (odds ratio [OR], 272.8; 95% CI 26.6-2794.1; P < 0.001) and positive GVI sign (OR, 49.3; 95% CI 4.5-539.8; P = 0.001) remained statistically significant. Patients with one or both features had significantly worse survival (log-rank test, P < 0.001). CONCLUSION: For patients with TET who are unable to receive contrast for preoperative staging, the two image findings of an irregular border between tumor and lung and the positive GVI sign on non-contrast-enhanced MRI could be helpful in determining stage III-IV disease which is associated with a worse survival.

[Combinatorial Vancomycin and Piperacillin/Tazobactam Results in Elevated Vancomycin Trough Concentration and Acute Kidney Injury: A Case Report].

In the hospital, antibiotics are widely used to treat infections. We report a case of acute kidney injury (AKI) caused by an antibiotic drug combination. A 30-year-old Japanese male presented with lung metastases, pneumothorax, empyema, and methicillin-resistant Staphylococcus aureus (MRSA) infection. The patient received a combination of vancomycin and piperacillin/tazobactam, which resulted in elevated vancomycin trough concentration and subsequently in AKI. Renal function was restored upon vancomycin and piperacillin/tazobactam cessation. Though this patient had AKI most likely due to the combined use of two agents as has been reported in many cases, vancomycin trough concentration showed an unexpected abnormal increase when halting vancomycin treatment. This is the first report indicating a drug-drug interaction between vancomycin and piperacillin/tazobactam with unexpected abnormal vancomycin trough concentration, leading to AKI, additionally we think that there was a situation that he stressed against the kidney by a history of medications caused renal dysfunction and co-administration. We suggest that when using vancomycin in combination with piperacillin/tazobactam, the trough concentration of vancomycin must be confirmed simultaneously with renal function and evaluation, and that the combination of these two drugs should be minimized.

Bronchial mucoepidermoid carcinoma, recurrent asthmatic symptoms, and pneumonia presenting in pregnancy.

We report the case of a 37-year-old pregnant Japanese woman (34th week of gestation) with a left main bronchus mucoepidermoid carcinoma. She had left lower lung pneumonia episodes for eight weeks that had been associated with bronchial asthma. Bronchoscopy revealed a membranous endobronchial tumour obstructing most of the left main bronchus. We delivered the baby without any problems by caesarean section, followed by tumour cauterization using a rigid bronchoscope under general anaesthesia. After that, we performed a sleeve resection of the main left bronchus. At one-year follow-up, the patient was disease-free and her baby was growing well.

Temporary airway stenting for giant anterior mediastinal tumor biopsy: Two case reports.

INTRODUCTION: When the management of an anterior mediastinal tumor requires general anesthesia, airway narrowing and obstruction may occur secondary to muscle relaxation. PRESENTATION OF CASES: Two men (ages, 15 and 36 years) presented with a giant anterior mediastinal tumor and central airway obstruction. We used Dumon stents to effectively secure the airway in both patients. After chemotherapy, stent removal was safely performed in each case because the tumor was substantially smaller. DISCUSSION: Dumon stents effectively secured the airway. These stents were easily removed after chemotherapy without severe complications. CONCLUSION: Temporary stenting is useful in patients with a giant anterior mediastinal tumor who require general anesthesia.

Exon 19 of EGFR mutation in relation to the CA-repeat polymorphism in intron 1.

Epidermal growth factor receptor (EGFR) mutations in lung cancer enhance tyrosine kinase activity and increase sensitivity to the EGFR tyrosine kinase inhibitor, gefitinib. Mutation analysis of the EGFR gene is therefore indispensable for predicting gefitinib response. We investigated a CA-repeat polymorphism in the EGFR gene related to EGFR mutations. Because an increasing number of CA-repeats at intron 1 of the EGFR gene has been reported to reduce transcription activity, we examined the relationship between EGFR mutations and this CA-repeat polymorphism. EGFR mutations at exon 19 were closely associated with shorter CA-repeat length in the shorter allele, but this was not the case for EGFR mutations at exons 18 or 21. Increased intrinsic EGFR mRNA expression in non-cancerous lung tissues from lung adenocarcinoma patients was also significantly associated with shorter CA-repeat length. A higher frequency of EGFR mutations at exon 19 was associated with shorter CA-repeat length only in patients with high levels of EGFR mRNA expression. To determine the phenotypes of cells possessing shorter CA-repeats, an in vitro study using human bronchial epithelial cells with different CA-repeat lengths was performed; more rapid cell growth and activated EGF/EGFR signaling were found more often in the cells having both shorter CA-repeats and increased EGFR mRNA expression. These results suggest that CA-repeat length in the EGFR gene may be a genetic factor related to cancer in the case of EGFR mutations at exon 19. The mechanism likely involves enhanced intrinsic expression of EGFR mRNA and activated EGF/EGFR signaling that accompany shorter CA-repeats.

Surgical resection of extramedullary haematopoiesis in the posterior mediastinum.

Extramedullary haematopoiesis is a rare disease that is usually associated with haematologic disorders such as thalassemia, myelodysplastic syndrome, and hereditary spherocytosis. It frequently occurs in the liver, spleen, and lymph nodes. Rarely, it occurs in the posterior mediastinum. We report the case of a 59-year-old man with lateral posterior mediastinal masses that were incidentally detected during treatment for hereditary spherocytosis. We performed video-assisted thoracic surgery to confirm the diagnosis and differentiate the masses from neurogenic tumours and other posterior mediastinal diseases. The pathological findings were consistent with intrathoracic extramedullary haematopoiesis. Although extramedullary haematopoiesis can be managed without interventions, surgery may be required in some cases. In such cases, video-assisted thoracoscopic surgery is advised because it is a useful and less invasive procedure.

Lung function in the late postoperative phase and influencing factors in patients undergoing pulmonary lobectomy.

BACKGROUND: Lung function in the late postoperative phase after pulmonary lobectomy is insufficiently characterized. This study aimed to appraise lung function in the late postoperative phase according to vital capacity (VC) and forced expiratory volume in 1 second (FEV1) in patients who underwent pulmonary lobectomy. METHODS: Pre- and postoperative VC and FEV1 were reviewed in 112 patients who underwent pulmonary lobectomy. Postoperative lung volume was assessed >1 year after surgery. Postoperative decreases in VC and FEV1 were compared with preoperative predicted values among patients who underwent resection of specific lobe. Determinants effecting a decrease in lung function were also investigated. RESULTS: A mean postoperative decreased VC of 10.5%±1.8% was recorded in patients who underwent right upper lobectomy (RU), 7.2%±1.5% for right middle lobectomy (RM), 14.3%±2.3% for right lower lobectomy (RL), 16.6%±3.0% for left upper lobectomy (LU), and 14.7%±2.5% for left lower lobectomy (LL). Corresponding FEV1 values were 14.8%±1.8% for RU, 11.9%±4.0% for RM, 14.9%±2.3% for RL, 17.9%±2.9% for LU, and 15.1%±2.4% for LL. The actual decreasing rate of VC was overestimated in patients who underwent RU, RL, LU, and LL. In contrast, FEV1 was overestimated only in patients who underwent RL and LL. Patients with chronic obstructive pulmonary disease (COPD) exhibited significantly better preservation of FEV1. CONCLUSIONS: Patients scheduled for RL and LL, or those with COPD, appeared to exhibit preserved lung function in the late postoperative phase after pulmonary lobectomy.

Periostin Expression in Non-Small Cell Lung Cancer: Clinical Significance.

Periostin is an extracellular matrix N-glycoprotein that is a major constituent of the desmoplastic stroma around solid tumors. Periostin promotes tumor invasion and metastasis via epithelial-mesenchymal transition. The aims of this study were to evaluate periostin expression immunohistochemically and quantitatively in patients with non-small cell lung cancer (NSCLC) and to assess any associations with clinical features and prognosis. A total of 184 specimens of NSCLC tissue were investigated, including 134 adenocarcinomas, 39 squamous cell carcinomas, and 11 other histologic subtypes. The intra-tumoral periostin expression area in each captured field was calculated using the image processing integration software WinROOF. The mean periostin expression score was classified as high or low by the median value of its expression area. Univariate analysis demonstrated that gender, tumor size, T status, N status, stage, histologic type, smoking habits, percent vital capacity, 1% forced expiratory volume, and pleural invasion were each significantly associated with periostin scores. Multivariate analysis revealed that high periostin expression score was an independent prognostic factor significantly associated with decreased cancer-specific survival (HR, 3.65; 95% CI, 1.04-12.84; P=0.0439). We concluded that intratumoral periostin expression was an independent prognostic factor for NSCLC.

Mutation profile of EGFR gene detected by denaturing high-performance liquid chromatography in Japanese lung cancer patients.

PURPOSE: EGFR mutations in lung cancer increase sensitivity to an EGFR tyrosine kinase inhibitor, gefitinib. Mutation analysis of EGFR is essential for prediction of gefitinib response and avoidance of the coincidental severe side effects for the unresponsive population. The purpose of the present study is to apply DHPLC as a screening system of detection of EGFR mutations for large scaled population. METHODS: EGFR mutations were detected by both DHPLC procedure and direct sequencing using lung cancer tissue samples obtained from 97 patients (81 surgical specimens and 16 pleural effusions of non-resectable lung cancer patients). RESULTS: DHPLC analysis detected EGFR mutations in 5 h as opposed to 18 h by direct sequencing for ten samples, and it costs eightfold more expensive by direct sequencing than DHPLC. In addition, DHPLC analysis was sixfold more sensitive than sequencing analysis for detection of the point mutation of exon 21, L858R. Using this system, EGFR mutations in exons 18, 19 and 21 were found in 34 of 97 patients (36%). Thirteen of the 15 patients with exon 21 mutations (87%) were female non-smokers, who were diagnosed with adenocarcinomas with the feature of BAC. Eight of the 18 patients with exon 19 mutations (44%) were 7 male and 1 female current or former smokers, and BAC feature was observed in 61% (8/18). CONCLUSION: DHPLC analysis for screening followed by sequencing analysis appears to be more sensitive and accurate, as well as easier and faster. In addition, these results suggest different mutagenesis and carcinogenesis pathways for mutations.

Prognostic impact of GATA binding protein-3 expression in primary lung adenocarcinoma.

GATA binding protein-3 (GATA3) is a transcription factor that regulates cell differentiation and maintenance in some types of normal cells. This study aimed to investigate the association between GATA3 expression and primary lung adenocarcinoma and to clarify the clinical significance of GATA3 expression in lung adenocarcinoma. Immunohistochemical GATA3 expression was evaluated using completely resected lung adenocarcinoma samples from 95 cases. GATA3 immunohistochemical staining was performed and scored. Associations between clinicopathological factors and GATA3 expression were analyzed by using the χ2 test and Fisher exact test. The Kaplan-Meier method was used to analyze overall survival (OS) and disease-free survival (DFS). Forty-nine cases expressed high levels of GATA3, which were associated with lymphatic invasion (P=.003). In univariate and multivariate analyses, vascular invasion (P<.001) and high GATA3 expression (P=.023) were identified as independent risk factors for OS. Higher pathological stages (P=.012), vascular invasion (P=.010), and high GATA3 expression (P=.009) were identified as independent risk factors for DFS. The high GATA3 expression group exhibited statistically worse OS (P=.031) and DFS (P=.011) than the low-expression group based on the Kaplan-Meier curves. In resected lung adenocarcinoma, high GATA3 expression is associated with poorer prognosis for both OS and DFS. Therefore, the immunohistochemical evaluation of GATA3 represents a potentially useful prognostic tool for postoperative patients.

Predicting exercise capacity after lobectomy by single photon emission computed tomography and computed tomography.

OBJECTIVES: This study compared the prediction of postoperative exercise capacity by employing lung perfusion scintigraphy images obtained with single photon emission computed tomography together with computed tomography (SPECT/CT) versus the common method of counting subsegments (SC method). METHODS: In 18 patients scheduled for lobectomy, predicted postoperative maximum oxygen uptake per kilogram body weight ([Formula: see text]) was calculated by the SPECT/CT and SC methods. Correlations were examined between the [Formula: see text] predicted by SPECT/CT or the SC method, and the actual [Formula: see text] measured at 2 weeks (mean 15.4 ± 1.5 days) and 1 month (mean 29.1 ± 0.75 days) after surgery to determine whether SPECT/CT was more accurate than SC for predicting postoperative exercise capacity. RESULTS: There was a significant positive correlation between the [Formula: see text] predicted by SPECT/CT and the actual value at 2 weeks (r = 0.802, p < 0.0001) or 1 month (r = 0.770, p < 0.0001). There was also a significant positive correlation between the [Formula: see text] predicted by SC and the actual value at 2 weeks (r = 0.785, p < 0.0001) or 1 month (r = 0.784, p < 0.0001). CONCLUSIONS: This study showed that both SPECT/CT and the SC method were useful for predicting postoperative [Formula: see text] in the clinical setting.

Experimental validation of talc pleurodesis for carcinomatous pleuritis in an animal model.

OBJECTIVE: This study was performed to evaluate the change of pleural cavity by talc pleurodesis for carcinomatous pleuritis in an animal model. METHODS: Models of malignant pleuritis were produced by an intra-venous injection of lung adenocarcinoma cells to male BALB/c nude mice at 6 weeks of age. Two weeks after the injection, either talc or saline was injected into the left thoracic cavity and the mice were further observed for 4 weeks. Six weeks after the injection, they were killed and the occurrence of lung cancer, amount of pleural effusion, and histological change of the pleural cavity were examined and compared between the two groups with or without talc administration. RESULTS: Talc administration caused a significant reduction in pleural effusion with no increase of pleural adhesion. Talc administration resulted in marked pleural thickening compared to saline treatment. The vascular architecture and its area did not differ between the two groups. CONCLUSION: Talc pleurodesis to reduce pleural effusion is valid for carcinomatous pleuritis, potentially through an acceleration of pleural thickening.

Prognostic Value of Programmed Death Ligand 1 and Programmed Death 1 Expression in Thymic Carcinoma.

PURPOSE: The immune checkpoint of the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway is believed to play an important role in evasion of host antitumor immune surveillance in various malignancies; however, little is known about its role in thymic carcinoma. This study investigated PD-1/PD-L1 expression and its association with clinicopathologic features, the expression of immune-related proteins in tumor-infiltrating lymphocytes (TIL), and patient prognosis. EXPERIMENTAL DESIGN: PD-L1 and PD-1 expression was evaluated by IHC in 25 thymic carcinoma tissue specimens. Copy number alterations of the PD-L1 gene in 11 cases were assessed in formalin-fixed, paraffin-embedded material using qRT-PCR. RESULTS: Compared with normal subjects, 3 thymic carcinoma patients showed an increase in PD-L1 copy number, whereas 8 did not. PD-L1 was significantly overexpressed in cases with copy number gain as compared with normal cases. High PD-L1 expression was associated with higher disease-free and overall survival rates as compared to cases with low expression. Prognostic analysis revealed low PD-L1 expression and high number of PD-1(+) TILs as significant predictors of poor survival, together with Masaoka-Koga stage IVa/IVb disease and incomplete resection. In the quantitative analysis of TILs, PD-L1 expression correlated proportionally with the number of infiltrating CTLs. CONCLUSIONS: Here, for the first time, we report that PD-L1 and PD-1 expression might be useful prognostic predictors in thymic carcinoma. Further studies are expected to substantiate the prognostic value of PD-L1 and PD-1 expression, and the potential efficacy of targeting the PD-1/PD-L1 pathway in thymic carcinoma via immunotherapy. Clin Cancer Res; 22(18); 4727-34. ©2016 AACR.

Clinicopathologic and Prognostic Implications of Programmed Death Ligand 1 Expression in Thymoma.

BACKGROUND: Programmed death ligand 1 (PD-L1) has been reported to be expressed in various malignancies and is considered to be a prognostic factor and an immunotherapeutic target. The aim of this study was to characterize PD-L1 expression in thymoma and determine statistical associations between this expression and clinical features. METHODS: We reviewed formalin-fixed, paraffin-embedded tissue specimens from 82 thymoma cases accumulated at Kurume University, the majority of which achieved surgical complete resection. Expression of PD-L1 was evaluated by immunohistochemistry. Statistical associations between PD-L1 expression and clinicopathologic features were evaluated by using χ(2) test and Fisher's exact test. Disease-free survival and overall survival curves were established by the Kaplan-Meier method and compared using a log-rank test. Predictive factors for disease-free survival after complete resection were analyzed by using a Cox proportional hazards model in univariate and multivariate analysis. RESULTS: Overall, 44 thymoma cases (54%) revealed high PD-L1 expression. High PD-L1 expression was statistically associated with Masaoka stage III/IV disease (p = 0.043) and World Health Organization type B2 or B3 thymoma (p = 0.044). Disease-free survival after complete resection in high PD-L1 expression was significantly worse than that in low PD-L1 expression (p = 0.021), although there was no significant difference in overall survival (p = 0.957). Multivariate analysis also revealed high PD-L1 expression as an independent risk factor for recurrence (p = 0.008). CONCLUSIONS: Characterization of PD-L1 expression in thymoma should enable more effective clinical approaches, including prognostic stratification of patients and potential use of anti-PD-L1 antibody immunotherapy.