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Malignant pleural mesothelioma (MPM) is a fatal thoracic malignancy, the epigenetics of which are poorly defined. We performed high-throughput methylation analysis covering 6,157 CpG islands in 20 MPMs and 20 lung adenocarcinomas. Newly identified genes were further analyzed in 50 MPMs and 56 adenocarcinomas via quantitative methylation-specific PCR. Targets of histone H3 lysine 27 trimethylation (H3K27me3) and genetic alterations were also assessed in MPM cells by chromatin immunoprecipitation arrays and comparative genomic hybridization arrays. An average of 387 genes (6.3%) and 544 genes (8.8%) were hypermethylated in MPM and adenocarcinoma, respectively. Hierarchical cluster analysis showed that the two malignancies have characteristic DNA methylation patterns, likely a result of different pathologic processes. In MPM, a separate subset of genes was silenced by H3K27me3 and could be reactivated by treatment with a histone deacetylase inhibitor alone. Integrated analysis of these epigenetic and genetic alterations revealed that only 11% of heterozygously deleted genes were affected by DNA methylation and/or H3K27me3 in MPMs. Among the DNA hypermethylated genes, three (TMEM30B, KAZALD1, and MAPK13) were specifically methylated only in MPM and could serve as potential diagnostic markers. Interestingly, a subset of MPM cases (4 cases, 20%) had very low levels of DNA methylation and substantially longer survival, suggesting that the epigenetic alterations are one mechanism affecting progression of this disease. Our findings show a characteristic epigenetic profile of MPM and uncover multiple distinct epigenetic abnormalities that lead to the silencing of tumor suppressor genes in MPM and could serve as diagnostic or prognostic targets. [Cancer Res 2009;69(23):9073–82]

Supplementary Figures 1-3, Tables 1-5 from Epigenetic Profiles Distinguish Malignant Pleural Mesothelioma from Lung Adenocarcinoma

Liver herniation is rare and sometimes difficult to differentiate from pleural or diaphragmatic tumor. A 64-year-old woman was admitted due to a mass-like shadow in the right lower lung field. Computed tomography, coronal view, showed a well-defined mass forming an acute angle with the right diaphragm, mimicking pleural tumor. Video-assisted thoracic surgery was performed, revealing herniated liver through one of the multiple diaphragmatic defects, which was repositioned into the abdominal cavity, and the diaphragmatic defect was repaired. The patient recovered well and was discharged on postoperative day 5.

Sphingolipids make up a family of molecules associated with an array of biological functions, including cell death and migration. Sphingolipids are often altered in cancer, though how these alterations lead to tumor formation and progression is largely unknown. Here, we analyzed non-small-cell lung cancer (NSCLC) specimens and cell lines and determined that ceramide synthase 6 (CERS6) is markedly overexpressed compared with controls. Elevated CERS6 expression was due in part to reduction of microRNA-101 (miR-101) and was associated with increased invasion and poor prognosis. CERS6 knockdown in NSCLC cells altered the ceramide profile, resulting in decreased cell migration and invasion in vitro, and decreased the frequency of RAC1-positive lamellipodia formation while CERS6 overexpression promoted it. In murine models, CERS6 knockdown in transplanted NSCLC cells attenuated lung metastasis. Furthermore, combined treatment with l-α-dimyristoylphosphatidylcholine liposome and the glucosylceramide synthase inhibitor D-PDMP induced cell death in association with ceramide accumulation and promoted cancer cell apoptosis and tumor regression in murine models. Together, these results indicate that CERS6-dependent ceramide synthesis and maintenance of ceramide in the cellular membrane are essential for lamellipodia formation and metastasis. Moreover, these results suggest that targeting this homeostasis has potential as a therapeutic strategy for CERS6-overexpressing NSCLC.

In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.

Aims Micronodular thymoma with lymphoid stroma (MNT) is an uncommon variant of thymoma, characterized by multiple small nodules consisting of type A thymoma-like cells, which are separated by abundant B lymphocytes. The aim of the study was to elucidate the pathogenesis of the stromal lymphoid hyperplasia, which is currently unclear. Methods and results We retrieved six cases of MNT, and immunohistochemically examined the number and distribution of Langerhans cells (LCs) and mature dendritic cells (DCs), and compared them with those in type A and type AB thymomas. Many LCs were present within the small tumour nests, but LCs were rarely seen in the stroma (75.5/HPF versus 6.1/HPF, P

The plasma D-dimer (D-dimer) level, a marker of hypercoagulation, has been reported to be associated with survival in several types of cancers. This retrospective study was conducted to evaluate the prognostic significance of the preoperative D-dimer level in patients with completely resected non-small cell lung cancer (NSCLC). A total of 237 completely resected NSCLC patients were included in this study. In addition to age, sex, the smoking status, etc., the association between the preoperative D-dimer level and survival was explored. The patients were divided into three groups according to the D-dimer level: group A (≤0.50 μg/ml, n = 76), group B (0.51–0.86 μg/ml, n = 79) and group C (>0.86 μg/ml, n = 82). The 5-year overall survival rate was 89.6 % (95 % confidence interval (CI) 77.7–95.3) for group A, 75.1 % (95 % CI 62.3–83.6) for group B and 60.1 % (95 % CI 46.8–71.1) for group C (P trend

Although 30-day mortality rate is adapted to evaluate perioperative mortality after surgery, whether 90-day mortality rate adequately evaluates perioperative mortality remains unknown. Therefore, we analyzed 30- and 90-day mortality rates after pulmonary resection in patients with primary lung cancer.A total of 2207 pulmonary resections for primary lung cancer performed between 1996 and 2010 at the Aichi Cancer Center Hospital were analyzed and divided into two groups of almost equal number: the early period group (1070 patients, 1996-2004) and the late period group (1137 patients, 2005-2010). Sixty-six and 34 patients died within a year during the early and late periods, respectively. The causes of death (recurrence, bleeding, sudden death, respiratory failure, and adverse event of chemotherapy), and 30- and 90-day mortality rates were investigated.The 30-/90-day mortality rates in the early and late period groups were 0.56/0.75 and 0.35/0.79 %, respectively. The postoperative survival days of 75 patients who died from recurrence within 1 year after pulmonary resection and 7 patients from bleeding or sudden death were more than 91 days and30 days, respectively. The median postoperative survival of patients who died from respiratory failure was 67 days (range 20-142 days) in the early period and 100 days (range 47-149 days) in the late period. In the late period, it was difficult to assess perioperative mortality of pulmonary complications with 30-day mortality.A risk assessment of perioperative mortality after pulmonary resection should be performed using the 30- and 90-day mortality.

Pulmonary nodules with ground-glass opacity (GGO) are frequently encountered; there is little consensus on appropriate monitoring of them. The purpose of this study was to clarify which baseline clinical and radiological characteristics were associated with growth of these nodules.We retrospectively studied patients with pulmonary nodules that met the following criteria: (1) lesion diameter of ≤3 cm, (2) GGO proportion of ≥50%, and (3) observation without treatment in the prior 6 months. Between 1999 and 2013, 120 pulmonary lesions in 67 patients fulfilled inclusion criteria. We evaluated changes in lesion size on serial computed tomography. Two endpoints, "time to 2-mm growth" and "incidence of 2-mm growth", were analyzed using Cox proportional hazards and logistic regression models, respectively.At the median observation period of 4.2 years, 34 lesions exhibited growth by ≥2 mm, whereas 86 remained unchanged. Smoking history and initial lesion diameter were statistically significant variables in both time-to-event and regression analyses. Hazard ratio (HR) for smoking history was 3.67 (P0.01). Compared with those ≤1 cm, HRs for 1.1-2 cm and 2.1-3 cm lesions were 2.23 (P=0.08) and 5.08 (P=0.04), respectively. Odds ratio (OR) for smoking history was 6.51 (P0.01); OR for lesion diameter of 1.1-3 cm (versus ≤1 cm) was 4.06 (P=0.02).Smoking history and initial lesion diameter are robustly associated with GGO growth. These results suggest that large GGOs, especially in smokers, warrant close follow-up to accurately monitor lesion growth.

Introduction: The presence of ground glass opacity (GGO) on high-resolution computed tomography (HRCT) is well known to be pathologically closely associated with adenocarcinoma in situ. Recently, measuring the tumor diameter including areas of GGO on HRCT has been reported to possibly overestimate the T status. The purpose of this study was to evaluate the significance of the tumor size measured eliminating the area of GGO on HRCT as a prognostic factor and to propose a refined TNM classification based on modified T descriptors. Methods: Four hundred seventy-five patients with clinical T1a-T2bN0M0 non-small-cell lung cancer underwent surgical resection. All tumors were reclassified based on the diameter measured eliminating the GGO area on HRCT according to the seventh TNM classification of lung cancer. We defined this new classification as modified T descriptors categorizing into five groups: mTis, mT1a, mT1b, mT2a, and mT2b. The overall survival rates of the patients in the current and modified staging groups were evaluated. Results: The 5-year survival rates were 88% and 82% in the patients with T1a and T1b tumors and 90% and 75% in the patients with mT1a and mT1b tumors, respectively. The differences in the survival rate of the patients classified by using mT1a and the other modified T descriptors were more clearly separated statistically than those of the patients classified by using the current T1a and other T descriptors. Conclusion: The modified T descriptors of the tumor size measured eliminating the GGO component on HRCT more clearly classified the prognoses of patients with early lung cancer than did the current T classification.

One reason for the poor outcomes of multimodality therapies, including macroscopic complete resection, in patients with malignant pleural mesothelioma (MPM) is the difficulty of correctly staging the disease, which can result in incomplete resection. The purpose of this study was to investigate the aspects of tumor infiltration to the port site and the usefulness of preoperative FDG PET/CT for diagnosing MPM. Between June 2007 and May 2013, 21 patients who underwent surgical treatment with curative intent for MPM that had been previously diagnosed on a video-assisted thoracic surgery (VATS) biopsy were included in this study. There were 17 males and four females, with a mean age of 63 years. The accumulation of FDG at the port site was observed in all nine patients with tumor infiltration to the port site, whereas this feature was not noted in 15 patients without tumor extension to the port site. There were more positive lymph node cases in the infiltration group than in the non-infiltration group (p = 0.02). No significant differences in survival were observed between the patients with and without tumor infiltration to the port site. FDG PET/CT is useful for detecting tumor infiltration of MPM to the port site and may help to prevent local recurrence, especially port site relapse, following macroscopic complete resection. However, this condition is related to tumor aggressiveness; therefore, performing careful staging and determining the appropriate treatment strategy are required in such patients.

We herein describe a surgical case of pulmonary involvement in Takayasu's arteritis with pulmonary infections of nontuberculous mycobacteria. A 24-year-old female was admitted to our hospital because of a recurrent fever, and contrast-enhanced computed tomography of the chest revealed the occlusion of the right pulmonary artery and cavitary lesions in the right lower lobe of the lung. A further examination of the neck revealed the occlusion of aortic branches, and the patient was diagnosed with Takayasu's arteritis. The cavitary lesions were diagnosed as nontuberculous mycobacteria disease according to the sputum culture result of Mycobacterium intracellulare. After antibiotic treatment for 6 months, the right pneumonectomy was performed with a good result. We should be aware of Takayasu's arteritis as a disease which can lead to the development of unexplained respiratory symptoms due to pulmonary artery involvement in young adults.

Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm arising from the mesothelial cells lining the parietal pleura and it exhibits poor prognosis. Although there has been significant progress in MPM treatment, development of more efficient therapeutic approaches is needed. BMAL1 is a core component of the circadian clock machinery and its constitutive overexpression in MPM has been reported. Here, we demonstrate that BMAL1 may serve as a molecular target for MPM. The majority of MPM cell lines and a subset of MPM clinical specimens expressed higher levels of BMAL1 compared to a nontumorigenic mesothelial cell line (MeT-5A) and normal parietal pleural specimens, respectively. A serum shock induced a rhythmical BMAL1 expression change in MeT-5A but not in ACC-MESO-1, suggesting that the circadian rhythm pathway is deregulated in MPM cells. BMAL1 knockdown suppressed proliferation and anchorage-dependent and independent clonal growth in two MPM cell lines (ACC-MESO-1 and H290) but not in MeT-5A. Notably, BMAL1 depletion resulted in cell cycle disruption with a substantial increase in apoptotic and polyploidy cell population in association with downregulation of Wee1, cyclin B and p21(WAF1/CIP1) and upregulation of cyclin E expression. BMAL1 knockdown induced mitotic catastrophe as denoted by disruption of cell cycle regulators and induction of drastic morphological changes including micronucleation and multiple nuclei in ACC-MESO-1 cells that expressed the highest level of BMAL1. Taken together, these findings indicate that BMAL1 has a critical role in MPM and could serve as an attractive therapeutic target for MPM.

Although inspiratory capacity (IC) is strongly associated with the disease severity of chronic obstructive pulmonary disease, there was no appropriate equation to compute predicted values for IC. Furthermore, whether assessment of IC can identify the risk of prolonged postoperative stay (PPS) in patients undergoing thoracic surgery also remains unclear. To evaluate whether %IC predicted, for which the new equation to compute the predicted values for IC was utilized, could be applied to identify the risk of PPS, we retrospectively analysed the cases of 412 patients who underwent thoracic surgery in Nagoya University Hospital. The multivariate analysis demonstrated that %IC predicted

肺活量や1秒量の対標準値を計算する際，BaldwinやBerglundの式などの欧米人を対象とした正常予測式がわが国でも広く用いられている．一方日本呼吸器学会肺生理専門委員会は2001年に日本人の正常予測式を提示している．今回実際の切除症例を用いて二つの方法で術後予測呼吸機能を比較してみたところ，肺活量も1秒量も日本人の正常予測式で算出した方が有意差をもって低く算出された．今後，標準式として日本人の正常予測式が導入されていく場合，従来よりも術後予測値が少なく計算されることを考慮して手術適応を検討する必要がある．

The role of ZEB1, a master epithelial-to-mesenchymal transition gene, in malignant pleural mesothelioma (MPM) is unclear.The expression of ZEB1, E-cadherin, vimentin, and epithelial cell adhesion molecule (EpCAM) in 18 MPM cell lines and a normal pleural mesothelial cell line MeT-5A was determined by quantitative real-time polymerase chain reaction and Western blot testing. RNA interference-mediated transient and/or stable knockdown of ZEB1 and EpCAM was performed. Microarray expression analysis was performed with a TORAY-3D gene chip. Growth was evaluated by colorimetric proliferation and colony formation assays. Luciferase reporter assay was performed to access the effects of ZEB1 knockdown on EpCAM promoter activity.Most MPM cell lines exhibited mesenchymal phenotype and expressed ZEB1. Transient ZEB1 knockdown suppressed growth in all four cell lines studied (ACC-MESO-1, H2052, Y-MESO-8A, Y-MESO-29) while stable ZEB1 knockdown suppressed growth only in Y-MESO-29. Genome-wide gene expression analysis revealed that EpCAM was the most prominently up-regulated gene by both transient and stable ZEB1 knockdown in ACC-MESO-1, with more marked up-regulation in stable knockdown. We hypothesized that EpCAM up-regulation counteracts the stable ZEB1 knockdown-induced growth inhibition in ACC-MESO-1. Transient EpCAM knockdown suppressed growth dramatically in ACC-MESO-1 cells expressing shZEB1 but only modestly in those expressing shGFP, supporting our hypothesis. Luciferase reporter assay showed that ZEB1 knockdown resulted in increased EpCAM promoter activity. EpCAM was also up-regulated in Y-MESO-29 expressing shZEB1, but this EpCAM up-regulation did not counteract ZEB1knockdown-induced growth suppression, suggesting that the counteracting effects of EpCAM may be cellular context dependent.RNA interference-mediated ZEB1 knockdown may be a promising therapeutic strategy for MPM, but one has to consider the possibility of diminished growth inhibitory effects of long-term ZEB1 knockdown, possibly as a result of EpCAM up-regulation and/or other gene expression changes resulting from ZEB1 knockdown.

症例は34歳，男性．来院の1週間前より咳嗽が出現し，3日前より発熱が出現していた．就寝中に喀血を認めたため当院救急外来を受診した．胸部単純CTにて右肺下葉に低濃度の腫瘤性病変と液体貯留を認め，肺化膿症と診断し緊急入院とした．翌日，原因検索目的に胸部造影CTを施行したところ，胸部下行大動脈より右肺下葉に流入する異常動脈を認め，肺分画症と診断した．感染を合併し肺化膿症となった分画肺が破綻して血胸・肺内出血を来たし，気道系への吸い込みにて喀血となったと考え，緊急に右肺下葉切除を施行した．手術所見から分画肺は正常胸膜と境界がなく，肺葉内肺分画症であった．また一部胸膜が裂けており肺内に凝血塊も認められた．肺分画症は胸部X線写真などで偶然発見されることが多いが，放置すると今回のような重篤な経過をたどる可能性があるため，無症状でも手術適応があると再認識した．

症例は35歳男性．検診の胸部X線写真にて異常を指摘され，他院を受診し胸部CTにて左肺門に約35mmの腫瘤が発見された．超音波気管支内視鏡下生検を施行するも悪性所見は得られず経過観察となっていたが，FDG-PETにて同部位に軽度集積を認め（SUVmax 2.63），悪性腫瘍も否定できないため当院に紹介された．Castleman病，肺カルチノイド，悪性リンパ腫，炎症性偽腫瘍などを疑い手術を施行した．術中迅速病理診断は，明らかな悪性所見を認めず，リンパ増殖性疾患と診断されたため，腫瘍切除術を施行した．最終病理診断はCastleman病であった．肺門部の孤立性腫瘤の鑑別は困難な場合が少なくないが，縦隔に次いで肺門リンパ節はCastleman病の好発部位であるため，当疾患も念頭に置く必要があると思われた．

Malignant pleural mesothelioma (MPM) is a fatal thoracic malignancy, the epigenetics of which are poorly defined. We performed high-throughput methylation analysis covering 6,157 CpG islands in 20 MPMs and 20 lung adenocarcinomas. Newly identified genes were further analyzed in 50 MPMs and 56 adenocarcinomas via quantitative methylation-specific PCR. Targets of histone H3 lysine 27 trimethylation (H3K27me3) and genetic alterations were also assessed in MPM cells by chromatin immunoprecipitation arrays and comparative genomic hybridization arrays. An average of 387 genes (6.3%) and 544 genes (8.8%) were hypermethylated in MPM and adenocarcinoma, respectively. Hierarchical cluster analysis showed that the two malignancies have characteristic DNA methylation patterns, likely a result of different pathologic processes. In MPM, a separate subset of genes was silenced by H3K27me3 and could be reactivated by treatment with a histone deacetylase inhibitor alone. Integrated analysis of these epigenetic and genetic alterations revealed that only 11% of heterozygously deleted genes were affected by DNA methylation and/or H3K27me3 in MPMs. Among the DNA hypermethylated genes, three (TMEM30B, KAZALD1, and MAPK13) were specifically methylated only in MPM and could serve as potential diagnostic markers. Interestingly, a subset of MPM cases (4 cases, 20%) had very low levels of DNA methylation and substantially longer survival, suggesting that the epigenetic alterations are one mechanism affecting progression of this disease. Our findings show a characteristic epigenetic profile of MPM and uncover multiple distinct epigenetic abnormalities that lead to the silencing of tumor suppressor genes in MPM and could serve as diagnostic or prognostic targets. [Cancer Res 2009;69(23):9073–82]

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm associated with asbestos exposure. Although expression and activation of receptor tyrosine kinases (RTKs), including MET, have been reported in most MPM, specific RTK inhibitors showed less than the expected response in MPM cells. To determine whether the lack of response of MET inhibitors was due to cooperation with other RTKs, we determined activation status of MET and other RTKs, including epidermal growth factor receptor (EGFR) family of 20 MPM cell lines, and tested whether dual RTK inhibition is an effective therapeutic strategy. We detected MET upregulation and phosphorylation (thus indicating activation) in 14 (70%) and 13 (65%) cell lines, but treatment with MET-specific inhibitors showed weak or modest effect of suppression in most of the cell lines. Phospho-RTK array analysis revealed that MET was simultaneously activated with other RTKs, including EGFR, ErbB2, ErbB3 and platelet-derived growth factor receptor-beta. Combination of MET and EGFR inhibitors triggered stronger inhibition on cell proliferation and invasion of MPM cells than that of each in vitro. These results indicated that coactivation of RTKs was essential in mesothelioma cell proliferation and/or survival, thus suggesting that simultaneous inhibition of RTKs may be a more effective strategy for the development of molecular target therapy for MPM.

The optimal extent of a combined resection in patients with lung cancer invading the chest wall remains controversial. To assess whether specific preoperative findings could lead to the precise evaluation of the depth of chest wall invasion and evade en-bloc resection of the chest wall in cases of tumor invasion limited to the parietal pleura, 132 patients with resected lung cancer involving the chest wall were retrospectively surveyed for the preoperative findings, surgical procedures, pathological results, and survival. A pathological examination of the resected specimens showed that 58 tumors had invaded only to the parietal pleura (shallow invasion) and 74 had involved the soft tissue or ribs (deep invasion). A multivariate analysis showed that preoperative CT findings of obvious tumor invasion beyond the parietal pleura (p = 0.005) and complaints of chest pain (p = 0.015) were independent indicators of deep invasion. In patients with lung cancer involving the chest wall, chest pain and/or invading on chest CT suggested that an en-bloc resection was a suitable surgical procedure, because 79% of those patients had deep invasion. On the other hand, in patients without chest pain and invasion on chest CT, an extrapleural approach was recommended at first based on the fact that 63% of them had shallow invasion. In practice, an extrapleural resection was performed in 40 cases and an en-bloc resection in 10 patients with shallow invasion. There was no significant difference in the survival between the two surgical procedures. Therefore, the CT findings of obvious tumor invasion beyond the parietal pleura and/or the presence of chest pain indicate the need to perform an en-bloc resection in patients with lung cancer involving the chest wall. However, in patients without these findings, an extrapleural approach could be initially attempted for chest wall resection, because an en-bloc resection had no survival benefit for patients with shallow invasion.

34歳，男性．左巨大気腫性肺嚢胞の切除目的に当院紹介となった．手術は右側臥位，左上肢は約120度の外転および外旋の肢位にて固定し，左前方腋窩開胸にて肺嚢胞切除術を施行，高度な癒着のために手術は4時間以上を要した．術後に左上肢の不全麻痺が出現，MRIにて腕神経叢の信号強度上昇を認め，神経症状と合わせて術中の肢位に起因する腕神経叢損傷と診断，ステロイド剤投与後に神経症状は徐々に軽快した．側臥位において腕神経叢損傷を回避するためには，上側の上肢を身体の前方で支持することが重要であり，過外転は避けることが望ましいと思われる．

症例は77歳，男性で，右B2原発の肺門型扁平上皮癌に対し右上葉管状切除術を行った．第6病日に発熱，呼吸困難，血痰が出現し，胸部X線写真にて右中葉に浸潤影を認めた．気管支鏡検査では中葉気管支は狭窄していたものの，気管支鏡の通過は可能であった．CTにて中葉の肺動静脈が全く造影されず，気管支の狭窄所見と合わせて血流障害を伴った肺捻転と診断，壊疽に陥っていた中葉を切除した．肺切除後の残肺捻転は早期診断が難しく，臨床症状，気管支鏡検査およびCT所見などを総合的に判断して，その可能性を検討することが重要である．特に捻転に伴う肺動静脈の血流障害の評価に造影CTは非常に有用であった．

Real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) with a dedicated EBUS bronchoscope has been reported as a minimally invasive and accurate method for sampling specimens from mediastinal and hilar lesions. Using this method, not only cytologic but also histologic specimens, which provide valuable information for a definitive diagnosis, can often be obtained. We report a case of an enlarged metastatic mediastinal lymph node from an unidentified primary papillary thyroid carcinoma that was accurately diagnosed by histological and immunohistochemical examination of tissue obtained by EBUS-TBNA.

Background and Objectives The distinction of primary lung from metastatic breast cancer is crucial in patients presenting with a solitary pulmonary nodule after mastectomy, because treatment strategies are completely different. Definitive diagnosis of these nodules, however, is often difficult. We assessed the feasibility of our diagnostic approach for these nodules and estimated the frequency of primary lung cancer occurrence in patients after mastectomy. Methods We evaluated solitary pulmonary nodules appearing in 48 patients after mastectomy. For histological examination, CT-guided needle aspiration biopsy (CT-NAB) or trans-bronchial lung biopsy (TBLB) was performed. Besides conventional morphopathological examination, differential diagnosis was performed by immunohistochemical examination and evaluation using a molecular marker (mammaglobin 1). Results Biopsy specimens were obtained using minimally invasive methods, namely CT-NAB and TBLB, in 91.7% of patients. From 48 patients, differential diagnosis was obtained by morphopathological methods alone in 32, and by immunohistochemical and molecular marker examination in the remaining 16. Final diagnosis was metastatic breast and primary lung cancer in 40 (83.3%) and 8 patients (16.7%), respectively. Conclusions Our results show the clinical feasibility of our stepwise approach to the differential diagnosis of primary lung cancer and breast cancer relapse presenting as a solitary nodule in patients after mastectomy. J. Surg. Oncol. 2008;98:510–514. © 2008 Wiley-Liss, Inc.

Objectives Immunological parameters and nutritional status influence the outcome of patients with malignant tumors. A prognostic nutritional index, calculated using serum albumin levels and peripheral lymphocyte count, has been used to assess prognosis for various cancers. This study aimed to investigate whether this prognostic nutritional index affects overall survival and the incidence of postoperative complications in patients with completely resected non-small cell lung cancer. Methods We retrospectively reviewed the medical records of 409 patients with non-small cell lung cancer who underwent complete resection between 2005 and 2007 at the Aichi Cancer Center. Results The 5-year survival rates of patients with high (≥50) and low (

症例は66歳, 女性. 2000年より後縦隔に7×5cmの嚢胞性病変の存在が指摘されていた. 2003年6月より発熱, 咳嗽を繰り返し, 同年10月31日に胸部CT上腫瘤内に鏡面形成が認められたため, 嚢胞内感染を伴う縦隔嚢胞の肺穿破を疑い手術を行った. 腫瘤は壁肥厚を認める単房性の嚢胞で, 炎症のため周囲との癒着が強固であった. 食道, 大動脈に接している壁の一部を残して嚢胞を右肺下葉の一部とともに摘出した. 嚢胞壁は炎症細胞の浸潤が著明で, 上皮の確認はできなかった. 病理学的には確定診断には至らないものの, 摘出組織に食物残渣様異物を認めたことと傍食道に存在していたことから, 食道嚢胞に炎症が発生し, それにより嚢胞の肺穿破が引き起こされたと考える.

Krüppel-like factor 6 (KLF6) is a ubiquitously expressed zinc finger transcriptional factor, which has been suggested to be a candidate tumor suppressor gene in prostate cancer and astrocytic glioma. Because KLF6 is located at chromosome 10p15, where non-small cell lung cancers (NSCLCs) also exhibit frequent allelic loss, we hypothesized that the inactivation of KLF6 is also involved in the development of NSCLC. To determine this, we performed mutational analysis for 105 NSCLCs, including 9 cell lines and 96 primary tumors, and Northern blot analysis for 74 NSCLCs, including the 9 cell lines and 65 primary tumors. Although somatic mutations were not detected in the coding sequence of KLF6, expression of KLF6 mRNA was down-regulated in the 9 cell lines and in 55 (85%) of the 65 primary tumors compared with normal lung tissue. Treatment of two cell lines expressing KLF6 at low levels with 5-azacytidine did not induce KLF6 expression, suggesting that KLF6 down-regulation is not due to promoter hypermethylation. We also performed loss of heterozygosity (LOH) analysis using the laser capture microdissection technique, and found that 21 of 62 (34%) informative samples had LOH in the KLF6 gene locus. Comparing the LOH status with mRNA expression of KLF6, we found that 14 of the 14 (100%) samples with LOH showed KLF6 down-regulation, and that even 23 of 31 (74%) samples without LOH also showed this down-regulation. We also studied the expression of the WAF1 gene, a possible downstream gene of KLF6, and detected simultaneous down-regulation of WAF1 and KLF6 mRNA in 6 of 9 (67%) cell lines and 48 of the 55 (87%) primary tumors, although there was not a significant association between loss of KLF6 and WAF1 expression. Furthermore, colony formation assay of two NSCLC cell lines (NCI-H1299 and NCI-H2009) induced a markedly reduced colony formation by KLF6 transfection, and Annexin V staining and terminal deoxynucleotidyl transferase-mediated nick end labeling assays revealed that KLF6 induced apoptosis. Our present studies demonstrated that KLF6 is frequently down-regulated in NSCLC and suppresses tumor growth via induction of apoptosis in NSCLC, which may suggest that KLF6 is a tumor suppressor for NSCLC.

誤嚥による肺内伏針に対して,胸腔鏡補助下に伏針のみを摘出しえた症例を経験したので文献的考察を加えて報告する.患者は37歳,女性.咳嗽と血痰を主訴に当院を受診し,胸部X線写真と胸部CTで左肺下葉に肺内伏針を認めた.気管支鏡下の摘出を試みたが,伏針はさらに奥に進んだため摘出困難となり胸腔鏡補助下の摘出を試みた.小開胸部からの触診にて左S9bの胸膜直下にまち針の頭を触知し,ハーモニックスカルペルを用いて臓側胸膜を切開した.露出したまち針の頭を把持鉗子にて牽引し摘出しえた.術後経過良好で第10病日に退院となった.

Beta-catenin is an essential element for the transcriptional activation of target genes in the Wnt signaling cascade and is also a cell adhesion molecule that couples with cadherins. Although plakoglobin (gamma-catenin), a closely related homologue of beta-catenin, is also known to be a cell adhesion molecule, its function as a transcriptional factor has not been revealed in detail. Using a human malignant mesothelioma cell line, NCI-H28, in which we have identified a homozygous deletion of the beta-catenin gene, we studied whether plakoglobin has a T-cell factor/lymphocyte enhancer factor (TCF/LEF) family-dependent transcriptional activity. Transfection with the wild-type plakoglobin expression vector induced accumulation of plakoglobin in the nucleus. Immunoprecipitation assay with cotransfection of plakoglobin and either TCF-4 or LEF-1 detected binding of plakoglobin to TCF-4 or LEF-1. Luciferase reporter assay demonstrated transcriptional activity of the wild-type plakoglobin when transfected with TCF/LEF, although plakoglobin showed less activity than beta-catenin. Exogenous plakoglobin was also shown to promote entrance of exogenous beta-catenin into the nuclei. Furthermore, small interfering RNA directed against plakoglobin suppressed expression of endogenous plakoglobin and its transcriptional activity, suggesting that endogenous plakoglobin has a weak transcriptional activity. These results suggest that plakoglobin can activate the Wnt signaling cascade directly without interaction of beta-catenin, and that plakoglobin has multiple functions as a transcriptional activator and a cell adhesion molecule like beta-catenin.

We have found that a malignant mesothelioma cell line, NCI-H28, had a chromosome 3p21.3 homozygous deletion containing the beta-catenin gene (CTNNB1), which suggested that the deletion of beta-catenin might have a growth advantage in the development of this tumor. To determine whether beta-catenin has a growth-inhibitory activity, we transfected wild-type beta-catenin, Ser37Cys mutant beta-catenin as an activated type, and C-terminus deletion mutant beta-catenin that lacks the transcription activity, into the NCI-H28 cells. A non-small cell lung cancer cell line, NCI-H1299, which expressed endogenous beta-catenin, was also studied. We tested the localization of exogenous beta-catenin in the NCI-H28 cells with immunofluorescence, and found that the wild-type beta-catenin and the C-terminus deletion mutant were more strongly expressed in the plasma membrane and cytoplasm than in the nucleus, while the Ser37Cys mutant was more in the nucleus than in the cytoplasm. By using luciferase-reporter assay, the beta-catenin/T-cell factor 4-mediated transactivity of the Ser37Cys mutant was shown to be higher than that of the wild-type beta-catenin in both cell lines. However, the transactivity of the C-terminus deletion mutant was strongly reduced in both. Colony formation of the NCI-H28 cells was reduced by 50% after transfection with the wild-type beta-catenin, and 60% with the Ser37Cys mutant, but only 20% with the C-terminus deletion mutant compared to the vector control. Inhibition of colony formation in NCI-H28 cells was because of apoptosis, manifested by positive staining of Annexin V and TUNEL assays in transfected cells. In contrast, when transfected with the wild-type beta-catenin, no significant reduction in colony formation was seen in beta-catenin wild-type NCI-H1299 cells. In conclusion, our data indicate that inactivation of beta-catenin by a 3p21.3 homozygous deletion might be a crucial event in the development of the mesothelioma NCI-H28 cells. Thus, while beta-catenin is well known to be a positive growth-stimulating factor for many human cancers, it can also act as a potential growth suppressor in some types of human cancer cells.

We established a new lung cancer cell line, designated Y-ML-1B, from a lung cancer of a 70-year-old Japanese man with leukocytosis and thrombocytosis. Before surgical resection, the white blood cell and platelet counts were elevated to 34,400/mm 3 and 668,000/mm 3 , respectively, and the granulocyte colony-stimulating factor (G-CSF) level in the serum was increased at 141 pg/mL. The primary tumor showed an undifferentiated morphology with large cells and induced extensive thickening of the pleura in the right hemithorax. The Y-ML-1B cells grow as a monolayer, with a doubling time of 19 hours, and are tumorigenic in nude mice, which showed a morphology similar to the primary tumor in xenografts. Analysis of the supernatant of cell culture medium of Y-ML-1B showed elevated levels of G-CSF and other cytokines such as interleukin (IL)-6, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF), consistent with the high levels detected in the patient's serum. Cytogenetic analysis revealed aneuploidy of greater than 56 in metaphases with many structural abnormalities. Mutation analysis of the tumor suppressor genes showed that Y-ML-1B is inactivated in TP53 and RASSF1A , but not in p14 ARF , p16 INK4A , or RB . Neither activating mutations of KRAS or NRAS nor amplification of MYC or MDM2 were detected. Y-ML-1B expressed N-cadherin but not E-cadherin. This newly established cell line might serve as a useful model for studying the molecular pathogenesis for large cell cancers of the lung which express high levels of cytokines.

Type AB thymomas are considered to be nonaggressive tumors, and the great majority are classified as Masaoka stage I or II. This report presents a case with Masaoka stage I and type AB thymoma, which metastasized to the brain 2 years 5 months after removal of the primary tumor. The original mediastinal lesion was adhesive but not invasive to the lung. The patient is now alive with multiple tiny pulmonary metastases 3 years after complete resection of the brain metastasis. Some reports of recurrent thymomas have suggested that the presence of peritumoral adherence to the adjacent structures might be a risk factor for recurrence in patients with such noninvasive thymomas. During the development of fibrosis which thus causes adhesion, the tumor may have an increased chance to metastasize because of the increased vessels and lymphatics.

Majority of cases of lung cancer are detected at an advanced stage; such patients are usually treated with chemotherapy and radiotherapy, and the prognosis is frequently poor. Surgical resection remains the only reliable curative method for the treatment of lung cancer, and combined resection of the primary tumor and involved neighboring structures is performed when possible in patients with locally advanced disease. In the TNM classification, tumors with direct extrapulmonary extension are subdivided based on the anatomic extent of disease and its potential for surgical treatment: T3 lesions with limited, circumscribed extension are thought to be potentially surgically resectable, whereas T4 tumors with extensive extension are considered unresectable. Although surgical treatment for T3 lesions is generally accepted, the outcome is frequently not satisfactory. On the other hand, advanced surgical techniques are now being applied for T4 lesions due to improvements in surgery and anesthesiology and progress in combined treatment modalities. In the present staging, T4N0–1M0 lesions are categorized as stage IIIA disease, and T4 tumors without mediastinal nodal metastasis are now considered to be potentially curable if complete resection is possible. This article reviews the modern surgical management of patients with lung cancer invading neighboring structures, including the chest wall, superior sulcus, diaphragm, tracheal carina, left atrium, superior vena cava, aorta and vertebrae. Furthermore, the surgical treatment of carcinomatous pleuritis, which was categorized as T4 disease in the previous TNM classification, is also assessed, and the role of surgical resection in cases of locally advanced lung cancer is discussed.

Spinal epidural hematoma (SEH) is rare but causes neurological disorders. Rapid diagnosis and treatment maximize neurological recovery. We present the case of SEH after lung cancer surgery under epidural and general anesthesia. A 64-year-old man underwent right upper lobectomy. Pulmonary embolism occurred on postoperative day 2. Anticoagulant therapy with fondaparinux and warfarin was started 2 hours after epidural catheter removal and he gradually recovered. On postoperative day 13, the level of prothrombin time-international normalized ratio reached 1.47 and fondaparinux administration was stopped. The next day, he developed back pain and paraplegia, and magnetic resonance imaging revealed a mass between Th4 and Th7 compressing the spinal cord. Emergency decompression laminectomy and hematoma evacuation were performed. After 2.5 months of rehabilitation, he regained almost all motor function and sensation. Late after epidural anesthesia, attention should be paid to possible SEH even though appropriate anticoagulant therapy had been initiated after epidural catheter removal.

A 63-year-old woman was referred to our hospital because screening had detected an anterior mediastinal tumor with a right aortic arch. She underwent typical total thymectomy via a median sternotomy but developed left recurrent laryngeal nerve (RLN) palsy postoperatively. The pathology examination revealed that the tumor was a stage I thymoma. This is the first report of a thymoma with a right aortic arch. The left RLN goes around the left ductus arteriosus, which connects the origin of the left subclavian artery to the left pulmonary artery. The RLN was likely to be injured in the neighborhood of the left ductus arteriosus when the tumor and thymus were dissected over the pulmonary artery. During operations for an anterior mediastinal tumor with a right aortic arch, we should be attentive to the location of the tumor, the left ductus arteriosus, and the left RLN.

A 49-year-old man was involved in a motor vehicle crash and was admitted to a local hospital. The following day, he was transferred to our hospital because of worsening dyspnea. Initial examination revealed no subcutaneous emphysema, and chest computed tomography (CT) demonstrated no mediastinal air. A left thoracentesis tube was placed for pneumothorax, which reduced the patient's respiratory distress. He had a persistent, productive cough, which worsened when he drank water. A repeat chest CT on the fifth hospital day revealed a tracheo-esophageal fistula. Bronchoscopy and esophagoscopy confirmed the diagnosis. He underwent repair of the trachea and esophagus. The ruptured membraneous portion of the trachea was closed with interrupted sutures and covered with pedicled pericardial flap. The perforated anterior esophageal wall was sutured in layers and reinforced with a fifth intercostal muscle flap. A gastrostomy tuve was placed for feeding access. Within 6 weeks, the patient recovered completely.

OBJECTIVES: The purpose of this study was to elucidate the detectability of recurrence and the prognostic significance of the serum carcinoembryonic antigen (CEA) levels in patients with completely resected non-small-cell lung cancer (NSCLC). METHODS: Five hundred and eighteen NSCLC patients who underwent complete resection at Aichi Cancer Center between April 2001 and March 2006 were enrolled in this study. The patient characteristics were as follows: the median age was 63 years; 331 tumours were classified as pathological stage I, 88 tumours were pathological stage II and 99 tumours were pathological stage III; 140 tumours were adenocarcinomas with epidermal growth factor receptor (EGFR) mutations, 268 tumours were adenocarcinomas with EGFR wild-type mutations and 110 tumours were other NSCLCs. The patients were divided into three groups: those with a normal CEA level before and 1–3 months after surgery (N group, n= 380), those with an elevated CEA level before surgery and a normal CEA level 1–3 months after surgery (HN group, n= 105) and those with an elevated CEA level 1–3 months after surgery regardless of the preoperative CEA level (H group, n= 33). The correlations between the changes in the serum CEA levels and the clinical outcomes were analysed. RESULTS: Recurrence developed in 122 patients (32%) in the N group, 49 patients (47%) in the HN group and 19 patients (58%) in the H group (P= 0.001). The sensitivity and specificity of an elevated serum CEA level during the follow-up period for detecting recurrence were 30 and 98% in the N group and 82 and 73% in the HN group, respectively. Twenty-seven asymptomatic recurrent tumours combined with an elevated serum CEA level were detected in the HN group. In the multivariate Cox regression analysis, the serum CEA level 1–3 months after surgery had prognostic value for overall survival. CONCLUSIONS: In completely resected NSCLC patients, measuring the serum CEA level during the follow-up period is useful in patients in whom an elevated level normalizes after surgery, and the serum CEA level 1–3 months after surgery is considered to have prognostic significance regarding survival.

It is often difficult to differentiate metachronous primary lung cancers from local pulmonary recurrences when the histopathological findings are similar. A 43-year-old man underwent right upper lobectomy with lymph node dissection for primary lung adenocarcinoma (p-T2aN0M0, stage IB). Fifteen years later, he developed a lung nodule in his right middle lobe. The tumor was preoperatively thought to be a metachronous second primary lung adenocarcinoma, and was surgically resected. Histopathological findings for both tumors were of poorly differentiated adenocarcinoma with mucus production. Both tumors also harbored the EML4 ( echinoderm microtubule-associated protein-like 4 )– ALK ( anaplastic lymphoma kinase ) fusion gene (variant 3a+b). Based on this molecular finding, the pulmonary nodule was considered to be a recurrence after very long latent period.

Histopathological diagnosis of thymic epithelial tumors according to the current World Health Organization classification is not adequately reproducible; however, most thoracic clinicians are unaware of this. We illustrate this problem in practical settings to raise clinician awareness. An expert pathologist specialized in thymic pathology and a trained general pathologist independently diagnosed 158 resected thymic epithelial tumors. Assuming that the expert’s diagnoses were more accurate, the two pathologists’ diagnoses were judged to be concordant when tumor subtypes (thymoma) or categories (thymic carcinoma and neuroendocrine tumor) were in agreement. The concordance rates for different thymoma subtypes were 75 % (3/4), 30 % (11/37), 100 % (17/17), 80 % (39/49), and 53 % (9/17) for types A, AB, B1, B2, and B3, respectively. Discordant cases of type AB thymoma were mainly diagnosed as type B1 or B2 by the general pathologist. Discordant cases of type B2 thymoma were diagnosed as type AB, B1, or B3, and discordant cases of type B3 thymoma were diagnosed as type A, B2, or carcinoma. Discordant cases of thymic carcinoma were diagnosed as type A or B3 thymoma. Investigation of the concordant and discordant cases suggested that reasonable discrepancies can occur because of the noncommittal categorical boundaries inherent in this classification. Thoracic clinicians should consider this potential problem in daily practice.