A successful trimodality therapy for difficult-to-diagnose primary mediastinal dedifferentiated liposarcoma, which originated from the perihilar fat and invaded the right lungs.

A 40-year-old man with high fever, hemoptysis, and fatigue showed a 10-cm mass in the middle and lower lobes of the right lung on computed tomography. Histological examination of transbronchial biopsy specimens showed sheets of small round tumor cells and mild staining for CD99. Primary Ewing sarcoma was suspected, and a trimodality therapy consisting of chemotherapy, intensity-modulated radiation therapy, and right pneumonectomy with surrounding tissue resection was performed. In surgical specimens, negative outcome of NKX2.2 in immunostaining and EWSR1 rearrangement in fluorescence in situ hybridization did not support the diagnosis of Ewing sarcoma. Positive immunostaining for MDM2 and CDK4 led to a diagnosis of dedifferentiated liposarcoma, which probably originated from an adipose tissue of the right perihilar mediastinum, and then invaded the lungs. The postoperative course was uneventful, without recurrence for more than 16 months.

Uniportal video-assisted thoracic surgery and perioperative pirfenidone for lung cancer and idiopathic pulmonary fibrosis: a case report.

Patients with idiopathic pulmonary fibrosis (IPF) occasionally experience acute exacerbations after surgery for lung cancer. Several recent studies have revealed a prophylactic effect of perioperative pirfenidone treatment on postoperative acute exacerbations of IPF in patients with lung cancer. A 75-year-old woman consulted with her pulmonologist because of an IPF shadow detected by follow-up chest computed tomography 2 months after surgical treatment of biliary cancer. Another 7 months later, chest computed tomography showed a 23- × 14-mm nodule located in the right lower lobe with high accumulation of fluorodeoxyglucose detected by positron emission tomography, resulting in a radiological diagnosis of primary lung cancer with IPF. We administered perioperative pirfenidone treatment followed by right lower lobectomy using uniportal video-assisted thoracoscopic surgery after attaining a pathological diagnosis of adenocarcinoma. The patient developed no acute exacerbations of IPF during the postoperative period, and she had no recurrence of lung cancer for 15 months after surgery. We successfully used a combination of perioperative antifibrotic medication and minimally invasive surgery after lung cancer surgery in a patient with IPF.

Role of leukotriene B4 12-hydroxydehydrogenase in α-galactosylceramide-pulsed dendritic cell therapy for non-small cell lung cancer.

Invariant natural killer T (iNKT) cells exhibit potent antitumor effects upon activation by recognizing a specific glycolipid antigen. We previously performed phase I-II clinical studies to utilize iNKT cells using α-galactosylceramide-pulsed dendritic cells and identified leukotriene B4 12-hydroxydehydrogenase (LTB4DH) as a biomarker highly expressed in T cells derived from non-small cell lung cancer (NSCLC) patients who showed prolonged survival in respond to the iNKT cell immunotherapy. Because LTB4DH expression correlated with prolonged survival of NSCLC patients, we considered LTB4DH to play a role in iNKT cell immunotherapy. We herein demonstrate that the overexpression of LTB4DH in CD4+ or CD8+ T cells increases interferon-γ production and tumoricidal activity in the presence of prostaglandin E2. Moreover, the expression of granzyme a, granzyme b, and perforin mRNA was increased in LTB4DH-overexpressing cells.

Chylopericardium following thoracoscopic resection of a mediastinal cyst: A case report.

INTRODUCTION: Thoracic duct cysts are very rare, and diagnosis is often difficult. We report a rare case of chylopericardium following thoracic duct cyst resection. There are no established guidelines on the management of such cases. We reviewed the literature on postoperative complications after thoracic duct cyst resection, and conducted the first thorough review of the etiology and management of chylopericardium in surgical cases. PRESENTATION OF CASE: A 54-year-old male presented with cardiac tamponade due to chylopericardium. He had undergone resection of a thoracic duct cyst 2 years previously, which was complicated by postoperative chylothorax. Chyle accumulation resolved with conservative treatment. DISCUSSION: Chylothorax is a frequent complication following thoracic duct cyst resection, especially in cases where no intraoperative diagnosis is reached. Diagnosis may be difficult due to anomalous location of the cyst, as in our case. Chylopericardium is rarely reported, and may have occurred in our case because of prior pleurodesis. Chyle accumulation can reportedly be managed with diet restrictions in over half of reported cases, especially in cases of lung or mediastinal tumor resection. CONCLUSION: The most important points highlighted by this rare case of chylopericardium secondary to thoracic duct cyst resection are: 1) pedicles should be ligated in cyst resections, regardless of location; 2) careful assessment in the initial surgery may help identify the point of leakage; 3) low-fat diet is the first choice in the initial management of postoperative chylopericardium, but surgical repair may be considered in cases with no response after>2 weeks of conservative treatment.

HCV T Cell Receptor Chain Modifications to Enhance Expression, Pairing, and Antigen Recognition in T Cells for Adoptive Transfer.

T cell receptor (TCR)-gene-modified T cells for adoptive cell transfer can mediate objective clinical responses in melanoma and other malignancies. When introducing a second TCR, mispairing between the endogenous and introduced α and ß TCR chains limits expression of the introduced TCR, which can result in impaired efficacy or off-target reactivity and autoimmunity. One approach to promote proper TCR chain pairing involves modifications of the introduced TCR genes: introducing a disulfide bridge, substituting murine for human constant regions, codon optimization, TCR chain leucine zipper fusions, and a single-chain TCR. We have introduced these modifications into our hepatitis C virus (HCV) reactive TCR and utilize a marker gene, CD34t, which allows us to directly compare transduction efficiency with TCR expression and T cell function. Our results reveal that of the TCRs tested, T cells expressing the murine Cß2 TCR or leucine zipper TCR have the highest levels of expression and the highest percentage of lytic and interferon-γ (IFN-γ)-producing T cells. Our studies give us a better understanding of how TCR modifications impact TCR expression and T cell function that may allow for optimization of TCR-modified T cells for adoptive cell transfer to treat patients with malignancies.

Does segmentectomy really preserve the pulmonary function better than lobectomy for patients with early-stage lung cancer?

PURPOSE: Recently, segmentectomy has been considered as an alternative to lobectomy in early peripheral non-small lung cancer (NSCLC); however, controversy has remained regarding the long-term functional advantage after segmentectomy. The aim of this study was to analyze the postoperative lung function after segmentectomy and lobectomy for non-small cell lung cancer. METHODS: Patients with p-T1aN0M0 NSCLC who had undergone segmentectomy (n = 37) or lobectomy (n = 33) were retrospectively analyzed. The ratios of postoperative to preoperative forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were defined as the recovery rates. The radiological lung volume and weight were evaluated before and more than 6 months after surgery, and the postoperative values were compared with the predicted values that were calculated from the preoperative values, subtracting the resected lobes or segments. RESULTS: The clinical characteristics, including the preoperative lung function showed no significant differences between the groups. No statistical differences were recognized in the trend lines for recovery ratios of FVC and FEV1.0 (P = 0.96 and P = 0.33). The recovery ratios for radiologic lung volume and weight showed no significant differences (P = 0.46 and P = 0.22). The postoperative lung volume and weight were almost the same as the predicted values after segmentectomy, whereas those after lobectomy were significantly higher than the predicted values. CONCLUSIONS: No functional advantage for segmentectomy was observed during long-term follow-up, possibly due to compensatory lung growth after lobectomy.

Impact of free tumor clusters on prognosis after resection of pulmonary adenocarcinoma.

OBJECTIVE: Pulmonary adenocarcinoma with a micropapillary component (MPC) has aggressive malignant behavior even if resectable. The aim of this study was to determine clinicopathologic features of patients who underwent surgery for pulmonary adenocarcinoma harboring MPCs, with particular focus on coexistent free tumor clusters (FTCs). METHODS: We retrospectively reviewed 444 patients with pulmonary adenocarcinoma who underwent surgery from March 2007 to July 2013. An MPC was defined as a >5% micropapillary pattern. We also defined FTCs to be a group of more than 3 small clusters containing <20 nonintegrated micropapillary tumor cells that were spreading within air spaces, >3 mm apart from the main tumor. The clinicopathologic characteristics of patients with and without FTCs were retrospectively investigated in MPC-positive patients. RESULTS: MPCs were identified in 67 patients (15.1%), 31 of whom (46.3%) were positive for FTCs. The distance between the furthest edge of FTCs and main tumors did not exceed the diameter of the main tumor in each case (average, 7.3 mm). Locoregional recurrences were frequently observed in FTC-positive patients. FTC-positive patients experienced a significantly lower 5-year recurrence-free survival rate compared with FTC-negative/MPC-positive patients (20.4% vs 52.2%, P < .001). Recurrence-free survival of FTC-negative and -positive patients was equivalent to that of patients with p-T2 and p-T3 MPC-negative adenocarcinoma, respectively. CONCLUSIONS: Coexistence of FTCs resulted in a further negative impact on postoperative prognosis among MPC-positive adenocarcinomas and should be considered for upstaging the p-T factor and during evaluation of surgical margins.

Strategies to genetically engineer T cells for cancer immunotherapy.

Immunotherapy is one of the most promising and innovative approaches to treat cancer, viral infections, and other immune-modulated diseases. Adoptive immunotherapy using gene-modified T cells is an exciting and rapidly evolving field. Exploiting knowledge of basic T cell biology and immune cell receptor function has fostered innovative approaches to modify immune cell function. Highly translatable clinical technologies have been developed to redirect T cell specificity by introducing designed receptors. The ability to engineer T cells to manifest desired phenotypes and functions is now a thrilling reality. In this review, we focus on outlining different varieties of genetically engineered T cells, their respective advantages and disadvantages as tools for immunotherapy, and their promise and drawbacks in the clinic.

Is left upper lobectomy for lung cancer a risk factor for cerebral infarction?

PURPOSE: Cerebral infarction is a rare complication of lung resection that can result in severe sequelae. Our aim was to investigate the characteristics of patients who suffer from cerebral infarction after surgery for lung cancer. METHODS: We retrospectively reviewed all patients who underwent resection of at least a single lobe for lung cancer at our institution between January 2008 and October 2013. We compared the patients who presented with cerebral infarction with those patients who did not within 30 days of surgery. RESULTS: A total of 562 patients underwent surgery, with five males and one female subsequently experiencing cerebral infarction. Five patients underwent left upper lobectomy and one underwent left lower lobectomy. Patient age, sex, body mass index, smoking index, and operative time were not significantly different between the six patients with postoperative cerebral infarction and the other 556 patients; only the type of operative procedure was significantly different (p < 0.001). Contrast-enhanced computed tomography revealed thrombosis in the stump of the left superior pulmonary vein in patients with postoperative cerebral infarction. CONCLUSIONS: Cerebral infarction occurs at a high frequency in patients who undergo left upper lobectomy for lung cancer. Thrombosis in the left superior pulmonary-vein stump might cause cerebral infarction.

Risk factors predictive of atrial fibrillation after lung cancer surgery.

Postoperative atrial fibrillation (POAF), the most frequent arrhythmia after pulmonary resection, is a cause of both morbidity and mortality. Being able to predict the risk of POAF before surgery would help us evaluate the surgical risk and plan prophylaxis. We investigated the reported preoperative risk factors associated with the incidence of POAF and found that the recommended predictive factors were quite variable. Therefore, we evaluated the previously reported preoperative risk factors for POAF using our institutional data. We discuss our findings in this short review. Male gender, resected lung volume, brain natriuretic peptide (BNP), and left ventricular early transmitral velocity/mitral annular early diastolic velocity (E/e') calculated by echocardiography were suggested as independent predictors for POAF, but the predictive values of each individual parameter were not high. The lack of definitive predictors for POAF warrants further investigations by gathering the reported knowledge, to establish an effective preoperative examination strategy.

Late recurrence of a tumor of Ewing's sarcoma family of tumors: report of a case.

A 27-year-old female presented with a history of a right chest wall tumor at 3 years of age. At that time, the tumor was surgically resected and diagnosed as Ewing's sarcoma (EWS), and postoperative chemoradiotherapy was administered. The patient remained disease-free for 25 years. At age 27, chest computed tomography revealed a mass adjacent to the anterolateral thoracic wall. After surgery, the diagnosis was primitive neuroectodermal tumor (PNET). She died of the disease 10 months later. PNET and EWS were integrated into a single item in the 2002 WHO classification; thus, they are considered clinically and pathologically identical. The morphologic, immunohistochemical, and molecular biological characteristics of both specimens showed that the second tumor was a local recurrence of Ewing's sarcoma family of tumors (ESFT). Our case is the longest duration local recurrence reported. Long-term recurrences of ESFT and patients with recurrent ESFT have a poor prognosis; thus, long-term follow-up is necessary.

[Corrigendum] Aberrant methylation of CXCL12 in non-small cell lung cancer is associated with an unfavorable prognosis.

The PCR panels presented in Figs. 1 and 2 are incorrect. The authors provide the correct figures below. These changes do not affect the interpretation or conclusions of this work. The authors regret this error. [the original article was published in the International Journal of Oncology 33: 113-119, 2008 DOI: 10.3892/ijo.33.1.113]

Experience with perioperative pirfenidone for lung cancer surgery in patients with idiopathic pulmonary fibrosis.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a progressive diffuse lung disease associated with an increased risk of lung cancer. Patients with IPF sometimes develop a life-threatening acute exacerbation of IPF (AE-IPF) after lung cancer surgery. In this retrospective study, pirfenidone, an antifibrotic agent, was perioperatively administered to IPF patients with lung cancer with the aim of preventing postoperative AE-IPF, and the feasibility and clinical outcomes were investigated. METHODS: Twelve IPF patients with concomitant lung cancer who received perioperative pirfenidone treatment (PPT) for lung cancer surgery were retrospectively investigated. Sixteen IPF patients undergoing lung cancer surgery without PPT were analyzed as historical controls. RESULTS: Compared to the controls, the PPT patients had a more severely impaired preoperative pulmonary function and a larger number of limited pulmonary resections. There was a significant preoperative decrease in the serum KL-6 levels of the PPT patients. No severe pirfenidone-related complications or IPF-related events occurred in the PPT patients, while six control patients developed AE-IPF (P = 0.0167). A quantitative histopathological evaluation of resected lung specimens found that tissue changes associated with IPF were significantly fewer in the PPT patients (P = 0.021). CONCLUSIONS: PPT is a feasible perioperative treatment for IPF patients with lung cancer. Its effectiveness in preventing postoperative AE-IPF thus warrants prospective verification.

Accumulation of activated invariant natural killer T cells in the tumor microenvironment after α-galactosylceramide-pulsed antigen presenting cells.

PURPOSE: The intravenous administration of α-Galactosylceramide (α-GalCer)-pulsed antigen presenting cells (APCs) is well tolerated and the increased IFN-γ producing cells in the peripheral blood after the treatment appeared to be associated with prolonged survival. An exploratory study protocol was designed with the preoperative administration of α-GalCer-pulsed APCs to clarify the mechanisms of these findings, while especially focusing on the precise tumor site. METHODS: Patients with operable advanced lung cancer received an intravenous injection of α-GalCer-pulsed APCs before surgery. The resected lung and tumor infiltrating lymphocytes (TILs) as well as peripheral blood mononuclear cells were collected and the invariant NKT (iNKT) cell-specific immune responses were analyzed. RESULTS: Four patients completed the study protocol. We observed a significant increase in iNKT cell numbers in the TILs and augmented IFN-γ production by the α-GalCer-stimulated TILs. CONCLUSION: The administration of α-GalCer-pulsed APCs successfully induced the dramatic infiltration and activation of iNKT cells in the tumor microenvironment.

Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy.

Vα24 natural killer T (NKT) cells have potent anti-tumor activity. We performed a phase II clinical study in patients with head and neck squamous cell carcinoma (HNSCC) using ex vivo expanded Vα24 NKT cells and α-galactosylceramide (αGalCer; KRN7000)-pulsed antigen-presenting cells (APCs) to investigate the efficacy and induction of NKT cell-specific immune responses. The subjects were 10 patients with locally recurrent and operable HNSCC. One course of nasal submucosal administration of αGalCer-pulsed APCs and intra-arterial infusion of activated NKT cells via tumor-feeding arteries was given before salvage surgery. Anti-tumor effects, NKT cell-specific immune responses in extirpated cancer tissue and peripheral blood, safety, and pathological effects were evaluated. Five cases achieved objective tumor regression. The number of NKT cells increased in cancer tissues in 7 cases and was associated with tumor regression. The combination therapy induced NKT cell-specific immune responses in cancer tissues that were associated with beneficial clinical effects.

A set of genes associated with the interferon-γ response of lung cancer patients undergoing α-galactosylceramide-pulsed dendritic cell therapy.

Invariant natural killer T (iNKT) cells possess potent antitumor effects after activation with a specific glycolipid antigen, α-galactosylceramide (αGalCer). A phase I-II clinical study of αGalCer-pulsed dendritic cells (DC) to activate endogenous iNKT cells was previously performed in patients with non-small-cell lung cancer (NSCLC). In this clinical trial, the patients with increased interferon-γ (IFN-γ) production (>two-fold) in PBMC after the DC treatment (good responder group) experienced a prolonged overall survival time in comparison with the poor responder group. We extended the previous study and performed a microarray-based gene expression analysis using peripheral blood CD56(+) cells and CD56(-) CD3(+) T cells from patients enrolled in the above-mentioned clinical study. We sought to identify any biomarkers associated with the immune responses in this immunotherapy trial. Six patient samples corresponding to three subjects in the good responder group and three subjects in the poor responder group were included in the microarray analysis. Genes differentially expressed between pre-treatment and post-treatment samples were selected for analysis. Subsequently, genes that were only expressed in the good responder group or poor responder group were chosen. After these procedures, four selected genes were quantified by reverse transcriptase-polymerase chain reaction in another eight patient samples, and two genes, LTB4DH and DPYSL3, were confirmed to be candidate genes for the predictor of a good immune response. The expression profile of these two genes may be associated with the responsiveness of IFN-γ production after αGalCer-pulsed DC treatment.

Molecular characterization of chronic obstructive pulmonary disease-related non-small cell lung cancer through aberrant methylation and alterations of EGFR signaling.

BACKGROUND: The aim of this study was to evaluate the molecular influence of chronic obstructive pulmonary diseases (COPD) on the pathogenesis of non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The methylation profiles of 12 genes, and the epidermal growth factor receptor (EGFR) and KRAS mutations were determined for samples from 229 NSCLC patients. In addition, protein expression of EGFR and HER2 in 116 NSCLCs was analyzed based on the presence or absence of COPD. RESULTS: IL-12Rbeta2 and Wif-1 methylation and HER2 overexpression were more frequent events in the COPD group. Eighty nonmalignant lung tissues had no correlation with any molecular changes between the COPD and the non-COPD group. EGFR mutation was significantly higher in the non-COPD group, while EGFR expression was inversely correlated with %FEV1.0. In the COPD group, unmethylated SPARC and sFRP-2 genes or a negative CpG island methylator phenotype (CIMP) was a negative prognostic factor, while methylation of p16(INK4A) and WNT antagonist genes was a negative prognostic factor in the non-COPD group. CONCLUSIONS: Novel characteristics of COPD-related NSCLC were identified by examination of methylation profiles and alterations of EGFR signaling. In consideration of the high sensitivity to smoking in patients with COPD, NSCLC with COPD might be a distinct population of smoke-related NSCLC, the genetic profile of which is quite different from non-COPD NSCLC.

A phase I-II study of alpha-galactosylceramide-pulsed IL-2/GM-CSF-cultured peripheral blood mononuclear cells in patients with advanced and recurrent non-small cell lung cancer.

To evaluate the safety, immune responses, and antitumor responses after the administration of alpha-galactosylceramide (alphaGalCer) KRN7000-pulsed PBMC cultured with IL-2 and GM-CSF (IL-2/GM-CSF-cultured PBMCs), a phase I-II study in patients with non-small cell lung cancer was conducted. Patients with advanced non-small cell lung cancer or recurrent lung cancer refractory to the standard therapy were eligible. alphaGalCer-pulsed IL-2/GM-CSF-cultured PBMCs (1 x 10(9)/m(2)) were i.v. administered four times. Immune responses were monitored weekly. Twenty-three patients were enrolled in this study and 17 cases (73.9%) completed. No severe adverse event related to the treatment was observed. After the injection of alphaGalCer-pulsed IL-2/GM-CSF-cultured PBMCs, an increased number of IFN-gamma-producing cells in the peripheral blood were detected in 10 patients (58.8%). Five cases remained as stable disease, and the remaining 12 cases were evaluated as progressive disease. The estimated median survival time (MST) of the 17 cases was 18.6 mo (range, 3.8 to 36.3 mo). Ten patients who displayed increased IFN-gamma-producing cells (> or =2-fold) showed prolonged MST (31.9 mo; range, 14.5 to 36.3 mo) as compared with poor-responder patients (n = 7) MST (9.7 mo; range, 3.8 to 25.0 mo) (log-rank test, p = 0.0015). The administration of alphaGalCer-pulsed IL-2/GM-CSF-cultured PBMCs was well tolerated and was accompanied by the successful induction of NKT cell-dependent immune responses. The increased IFN-gamma-producing cells that result from alphaGalCer stimulation in PBMCs were significantly associated with prolonged MST. These results are encouraging and warrant further evaluation for survival benefit of this immunotherapy.

Prostaglandin E2 receptor 2 overexpression in squamous cell carcinoma of the lung correlates with p16INK4A methylation and an unfavorable prognosis.

Several studies have described p16INK4A and prostaglandin E2 (PGE2) co-alterations in various solid tumors, including non-small cell lung cancer (NSCLC). In this study, we examined the correlation between PGE2 receptor 2 (EP2) expression and p16INK4A methylation in NSCLC, and the association with clinicopathological features and prognostic significance. We retrospectively reviewed 88 NSCLC patients who underwent resection from July 1993 to May 1997. The tumors included 43 adenocarcinomas, 39 squamous cell carcinomas, and 6 large cell carcinomas. EP2 expression was determined by immunostaining, and p16INK4A methylation was analyzed by methylation specific PCR. EP2 was overexpressed in 44% of NSCLC patients, 61% of adenocarcinoma cases, 28% of squamous cell carcinoma cases, and 33% of large cell carcinoma cases. EP2 expression positively correlated with lymph node metastasis (P=0.034), especially in patients with squamous cell carcinoma (P<0.009). Methylation of p16INK4A was detected in 34% of NSCLC patients, 23% of adenocarcinoma cases, 44% of squamous cell carcinoma cases, and 50% of large cell carcinoma cases. In patients with squamous cell carcinoma, EP2 overexpression correlated with poor prognosis with a relative risk of 2.4 (confidence interval 2.1-51.8, P<0.003), and positively correlated with p16INK4A methylation (P<0.024). Adenocarcinoma patients with p16INK4A methylation had poor prognosis with a relative risk of 2.4 (confidence interval 1.8-69.7, P<0.009), but this was not correlated with EP2 expression. In conclusion, EP2 overexpression was common in NSCLCs, especially in adenocarcinomas. Synchronous alteration of p16INK4A and EP2 may accelerate progression of squamous cell carcinomas. These two alterations may differentially affect pathogenesis among subtypes of NSCLC.