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Supplementary Table 2 from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

Supplementary Figure 2 from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

Supplementary Figure 3 from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

Supplementary Figure 1 from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

Supplementary Materials and Methods from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

Supplementary Table 1 from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

Supplementary Figure Legends 1-3 from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

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

IntroductionThoracoscopic surgery is performed for refractory or recurrent primary spontaneous pneumothorax (PSP). To reduce postoperative recurrence, additional treatment is occasionally adopted during surgery after bulla resection. However, the most effective method has not been fully elucidated. Furthermore, the preference for additional treatment varies among countries, and its efficacy in preventing recurrence must be evaluated based on settings tailored for the conditions of a specific country. The number of registries collecting detailed data about PSP surgery is limited. Therefore, to address this issue, a prospective multicentre observational study was performed.Methods and analysisThis multicentre, prospective, observational study will enrol 450 participants aged between 16 and 40 years who initially underwent PSP surgery. Data about demographic characteristics, disease and family history, surgical details, and CT scan findings will be collected. Follow-up must be conducted until 3 years after surgery or in the event of recurrence, whichever came first. Patients without recurrence will undergo annual follow-up until 3 years after surgery. The primary outcome is the rate of recurrence within 2 years after surgery. A multivariate analysis will be performed to compare the efficacy of different surgical options. Then, adverse outcomes correlated with various treatments and the feasibility of treatment methods will be compared.Ethics and disseminationThis study was approved by the local ethics committee of all participating centres. The findings will be available in 2025, and they can be used as a basis for clinical decision-making regarding appropriate options for the initial PSP surgery.Trial registration numberNCT04758143.

Purpose: Metastasis to the lungs arising from biliary tract carcinoma (BTC) is extremely rare, and the patient characteristics and prognosis are not well known. We aimed to identify the imaging findings of pulmonary metastases originating from BTC and the eligible indications for surgical treatment. Methods: Fifteen patients who underwent pulmonary resection for metastases originating from BTC were retrospectively analyzed. Results: The primary sites included cholangiocarcinoma (n = 12) and gallbladder carcinoma (n = 3), and all cases were histologically diagnosed as well to moderately differentiated adenocarcinomas. The median disease-free interval between resection for the primary site and the detection of pulmonary metastasis was 30 months (range 0–144 months). Nine patients had a single lesion, and six had multiple lesions. As features of pulmonary lesions on thin-section computed tomography (CT), many appeared as solid nodules with smooth margins, whereas six lesions were concomitant with spiculation or pleural indentation, three with air bronchogram or ground-glass attenuation, and one with intra-tumoral cavity, and six cases with solitary pulmonary lesion were diagnosed as primary lung cancer before metastasectomy. The 3-year survival rate in the 11 patients who underwent complete metastasectomy was 45%. A disease-free interval of more than 3 years (p = 0.03) and single lesion (p, ファイル公開：2020/11/01

Sphingolipids constitute a class of bio‐reactive molecules that transmit signals and exhibit a variety of physical properties in various cell types, though their functions in cancer pathogenesis have yet to be elucidated. Analyses of gene expression profiles of clinical specimens and a panel of cell lines revealed that the ceramide synthase gene CERS6 was overexpressed in non–small‐cell lung cancer (NSCLC) tissues, while elevated expression was shown to be associated with poor prognosis and lymph node metastasis. NSCLC profile and in vitro luciferase analysis results suggested that CERS6 overexpression is promoted, at least in part, by reduced miR‐101 expression. Under a reduced CERS6 expression condition, the ceramide profile became altered, which was determined to be associated with decreased cell migration and invasion activities in vitro. Furthermore, CERS6 knockdown suppressed RAC1‐positive lamellipodia/ruffling formation and attenuated lung metastasis efficiency in mice, while forced expression of CERS6 resulted in an opposite phenotype in examined cell lines. Based on these findings, we consider that ceramide synthesis by CERS6 has important roles in lung cancer migration and metastasis.

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.

We adopted a bilateral approach to complete robotic extended thymectomy with the excision of the pericardial fat tissue from both sides and analyzed the initial outcomes. The patient cart was docked first from the left shoulder side. After dissection of the thymus and right pericardial fat tissue, the cart was temporarily rolled out, and the bed was rotated approximately 90° clockwise. The cart was then re-docked from the right-side shoulder, and extended thymectomy was performed via the left-side approach. The outcomes were compared with four cases of unilateral approach performed for mediastinal tumor in the same term. Four patients with myasthenia gravis (two of whom had stage I thymoma) underwent extended thymectomy by the bilateral approach. The mean operative time was 288 min, and the console time was 146 min in the right side and 67 min in the left side. The resected thymus and surrounding adipose tissue were almost symmetrical, in contrast with those obtained via the unilateral approach. No remarkable events were noted. Bilateral extended thymectomy for myasthenia gravis patients was safe and reasonable based on the initial outcomes.

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.

Background Previously, it has been shown that using a fixed ratio of FEV1/FVC of 0.7 to classify airway obstruction could not predict survival outcomes in lung cancer patients undergoing thoracic surgery. We demonstrated that use of the lower limit of normal (LLN) of FEV1/FVC may allow better risk stratification for postoperative outcomes in patients with chronic obstructive pulmonary disease (COPD) patients. Nevertheless, it remained unclear whether survival outcomes in this population could be predicted by LLN-defined airway obstruction. Objective To evaluate the clinical relevance of LLN-defined airway obstruction to survival outcomes. Methods The clinical relevance of LLN-defined airway obstruction was analyzed and compared in 699 subjects, using Kaplan–Meier curves and the log-rank test. A Cox regression model was used to explore prognostic risk factors. Results One hundred-and-seventy-eight subjects were assigned to the below-LLN group, in which airflow obstruction determined by the FEV1/FVC ratio was below the LLN. Five hundred-and-twenty-one subjects were assigned to the above-LLN group. The below-LLN group had a worse overall survival (OS) and disease-free survival (DFS) than the above-LLN group. The diffusing capacity of the lung for carbon monoxide and the ratio of the inspiratory capacity divided to the total lung capacity were independent risk factors for OS and DFS. Conclusions A standardized assessment of LLN-defined airway obstruction may allow risk stratification for survival likelihood in lung cancer patients who undergo thoracic surgery.

Patients with lung cancer should be treated according to histological subtype because of the disparities in tumor aggressiveness and treatment responses. It is important to re-evaluate the clinicopathological features of the two major subtypes of lung cancer, adenocarcinoma (AD) and squamous cell carcinoma (SQ). We retrospectively analyzed data on the clinicopathological features and outcomes of 2059 patients with pulmonary AD and pulmonary SQ who had undergone complete resection at Nagoya University Hospital and Aichi Cancer Center between 1995 and 2012. The cohort consisted of 1587 patients with AD (77 %) and 472 with SQ (23 %). Female gender, no history of smoking, and small tumor size were distinct characteristics of AD patients, and a higher age was a characteristic of SQ patients (p

Among the perioperative findings which included patient characteristics and imaging, surgical, and pathological findings of the tumor, the risk factors for pleural recurrence (PR) after complete resection of thymoma were explored. Fifty-three patients with Masaoka stage I to III thymoma who underwent complete resection, and five patients with stage IVa disease accompanied with pleural dissemination were analyzed. In these cohorts, the patients were divided into a non-recurrence (NR) group, PR group and stage IVa group. The maximum tumor diameter (TD) and the contact length between the tumor contour and the lung (CLTL) were measured at the maximum section of the tumor on axial computed tomography. A multivariate analysis including gender, age, TD, CLTL, tumor adhesion to the lung, Masaoka stage, and WHO histological type was performed to estimate risk factors for PR. The median follow-up period was 76.9 months. PR developed in six patients. The mean TDs were 44 mm in the NR group, 62 mm in the PR group and 73 mm in the stage IVa group, respectively. The mean CLTLs were 47, 90 and 96 mm, respectively. The CLTLs of the PR group were significantly longer than those of the NR group (p

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

OBJECTIVES With the recent improvements in the diagnostic accuracy of radiographic modalities, it might be an option to perform therapeutic surgery without a definitive diagnosis for selected patients with suspected lung cancer based on the findings of diagnostic imaging. METHODS Between April 2008 and December 2012, all nodules without a definitive diagnosis were classified into five categories according to the probability of lung cancer based on the diagnostic imaging: Category 1 (Benign), Category 2 (Probably benign), Category 3 (Intermediate), Category 4 (Suspected malignancy) and Category 5 (Highly suggestive of malignancy). In this study, the 232 surgical candidates for suspected clinical stage I lung cancer without a preoperative definitive diagnosis were considered to be Category 3 (n = 29), Category 4 (n = 46) and Category 5 (n = 157). Eighty-two patients (72% of Category 3, 46% of Category 4 and 25% of Category 5) had an intraoperative diagnosis during surgery, whereas the remaining 150 patients did not. The final pathological diagnosis and surgical outcomes were analysed. RESULTS The final pathological diagnosis of the 232 suspicious nodules revealed 214 lung cancers (52% of Category 3, 93% of Category 4 and 99% of Category 5). Wedge resection was performed for all seven benign tumours. In the multiple regression analysis, intraoperative diagnosis was a significant factor for the length of the operation. In the multivariate logistic regression analysis, the length of the operation was a significant factor predicting both the postoperative morbidity and a prolonged hospital stay. CONCLUSIONS Based on a careful clinical decision made using the current diagnostic imaging strategies, patients with a high probability of lung cancer are good candidates for therapeutic surgery, even without a preoperative or intraoperative definitive diagnosis.

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

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.

Thymoma is often associated with autoimmune diseases or endocrine disorders. We hereby report a rare case of invasive thymoma associated with autoimmune enteropathy, which was well managed by oral steroid treatment.

Multilocular thymic cysts (MTCs) are considered to be acquired lesions associated with various inflammatory conditions and/or malignant tumors. MTCs associated with thymomas are rare, with only 11 cases having been reported. On reviewing 110 consecutive patients with thymomas, we found 20 cases of MTCs. The patients included 18 men and 2 women aged 32 to 65 years (median 52 y). Eleven of the patients were symptomatic, and 6 presented with symptoms associated with inflammation. Computed tomography images were available for 11 patients, and cystic lesions were identified in 4 patients. The histologic subtypes of thymoma observed were: 3 tumors of type AB, 4 tumors of type B1, 9 tumors of type B2, and 4 tumors of type B3. In addition, 2 tumors were in advanced stages. Multilocular cystic structures accompanied by acute and chronic inflammation were observed in the remnant thymic tissues. Immunohistochemically, CK13 was diffusely expressed in the inner surface cells lining the cysts, whereas CK5/6 and p63 were primarily expressed in the basal cells of the cysts. D2-40 was weakly expressed in a small number of basal epithelial cells. The immunohistochemical profiles of the cysts were similar to those of Hassall corpuscles of normal thymi. A clinical follow-up showed that 15 patients continued to be alive without any evidence of disease, 1 patient with tumor recurrence continued to be alive, and 3 patients had died of other diseases. Our results suggest that MTCs associated with thymomas are not as uncommon as thought and may develop from the promotion of differentiation of increased numbers of epithelial cells into Hassall corpuscles by inflammatory processes. Our data also suggest a better clinical behavior for patients with thymomas accompanied by MTCs than patients with thymomas unaccompanied by those cysts, although further investigation is needed.

Positron emission tomography using [(18)F]-fluoro-2-deoxy-D-glucose ((18)F-FDG-PET) plays an important role in many oncological settings. In this study, we assessed the utility of (18)F-FDG PET-CT for predicting the histologic type and stage of thymic epithelial tumours.We retrospectively analyzed 58 patients with thymic epithelial tumours who underwent PET-CT before treatment and investigated the relationship between the histologic type based on the World Health Organization classification and the maximum standardized uptake value (SUV(max)) of each tumour. We also analyzed the relationship between the Masaoka tumour stage and the SUV(max).The study included 31 males and 27 females, ranging in age from 25 to 80 years (median: 62 years). The tumour histology of 44 tumours was thymoma and that of the remaining tumours was thymic carcinoma, including 11 squamous cell carcinomas and 3 carcinoids. The Masaoka tumour stage was as follows: Stage I in 8, Stage II in 24, Stage III in 18 and Stage IV in 8 patients. The patients were divided into three groups according to a simplified histologic classification: low-risk thymomas (types A, AB and B1, n = 23), high-risk thymomas (types B2 and B3, n = 21) and thymic carcinomas (n = 14). The SUV(max) of the thymic carcinoma group was significantly higher than those of the low-risk thymoma and high-risk thymoma groups (P0.001, respectively). No significant differences between the low-risk thymoma and high-risk thymoma groups were observed (P = 0.204). The SUV(max) of Stages III and IV thymomas showed a higher trend toward Stages I and II thymomas (P = 0.060).PET-CT is a useful modality for predicting the histologic type and tumour stage of thymic epithelial tumours.

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．

Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. We carried out genome-wide array-based comparative genomic hybridization analysis with 14 MM cell lines. Three cell lines showed overlapping homozygous deletion at chromosome 13q12, which harbored the LATS2 (large tumor suppressor homolog 2) gene. With 6 other MM cell lines and 25 MM tumors, we found 10 inactivating homozygous deletions or mutations of LATS2 among 45 MMs. LATS2 encodes a serine/threonine kinase, a component of the Hippo tumor-suppressive signaling pathway, and we transduced LATS2 in MM cells with its mutation. Transduction of LATS2 inactivated oncoprotein YAP, a transcriptional coactivator, via phosphorylation, and inhibited MM cell growth. We also analyzed LATS2 immunohistochemically and found that 13 of 45 MM tumors had low expression of LATS2. Because NF2 is genetically mutated in 40% to 50% of MM, our data indicate that Hippo pathway dysregulation is frequent in MM cells with inactivation of LATS2 or an upstream regulator of this pathway, Merlin, which is encoded by NF2. Thus, our results suggest that the inactivation of LATS2 is one of the key mechanisms for constitutive activation of YAP, which induces deregulation of MM cell proliferation. Cancer Res; 71(3); 873–83. ©2011 AACR.

A 61-year-old male was admitted to our hospital complaining of bloody sputum. A chest roentgenogram revealed a clearly demarcated mass located in the anterior mediastinum. Positron emission tomography revealed abnormal accumulation of (18)F-fluorodeoxy glucose only in the anterior mediastinal tumor. A computed tomography-guided needle aspiration biopsy was performed, and the tumor was diagnosed as a malignant melanoma. Although the skin, eyeballs, oral cavity, nasal cavity, etc., were closely evaluated, no other lesion of malignant melanoma was detected except the mediastinal tumor. Hence, this tumor was diagnosed as a primary malignant melanoma. We performed total thymectomy, including the tumor, and combined resection of the adhesive bilateral lungs, pericardium and left brachiocephalic vein. Because the tumor was histologically surrounded by thymus tissue, we diagnosed it as a primary mediastinal malignant melanoma that originated in the thymus. Although the patient's postoperative course was uneventful, he complained of back pain 5 months after the operation. Multiple bone metastases were found, and he received chemotherapy and radiotherapy, and is currently alive with disease 14 months after the primary treatment.

症例は16歳男性，検診の胸部X線で異常陰影を指摘された．胸部CTにおいて前縦隔に径7cm大の腫瘤と左上葉に径1cm大の結節を認めたため，手術にて双方を摘出した．病理組織学的所見としては，内腔が一層の内皮細胞で覆われた大小の拡大した血管腔の集簇から構成されており，縦隔と肺に発生した海綿状血管腫と診断された．胸部領域の海綿状血管腫は稀であり，縦隔と肺の同時発生の報告は極めて稀と考えられる．

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.

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．

We previously reported the results of bacterial artificial chromosome array comprehensive genomic hybridization of malignant pleural mesotheliomas (MPMs), including two cases with high-level amplification in the 11q22 locus. In this study, we found that the YAP1 gene encoding a transcriptional coactivator was localized in this amplified region and overexpressed in both cases, suggesting it as a candidate oncogene in this region. We analyzed the involvement of YAP1 in MPM proliferation, as well as its functional and physical interaction with Merlin encoded by the neurofibromatosis type 2 (NF2) tumor suppressor gene, which is frequently mutated in MPMs. YAP1-RNA interference suppressed growth of a mesothelioma cell line NCI-H290 with NF2 homozygous deletion, probably through cell-cycle arrest and apoptosis induction, whereas YAP1 transfection promoted the growth of MeT-5A, an immortalized mesothelial cell line. We also found that the introduction of NF2 into NCI-H290 induced phosphorylation at serine 127 of YAP1, which was accompanied by reduction of nuclear localization of YAP1, whereas nuclear localization of a YAP1 S 127A mutant was not affected. Furthermore, results of immunoprecipitation and in vitro pull-down assays indicated a physical interaction between Merlin and YAP1. These results suggest that YAP1 is involved in mesothelial cell growth and that the transcriptional coactivator activity of YAP1 is functionally inhibited by Merlin through the induction of phosphorylation and cytoplasmic retention of YAP1. This is the first report of negative regulatory signaling from Merlin to YAP1 in mammalian cells. Future studies of transcriptional targets of YAP1 in MPMs may shed light on the molecular mechanisms of MPM development and lead to new therapeutic strategies.

金沢大学がん研究所分子標的がん医療研究開発センター, Lysophosphatidic acid (LPA) is one of the simplest natural phospholipids. This phospholipid is recognized as an extracellular potent lipid mediator with diverse effects on various cells. Although LPA is shown to stimulate proliferation and motility via LPA receptors, LPA1 and LPA2, in several cancer cell lines, the role of LPA and LPA receptors for malignant pleural mesothelioma (MPM) has been unknown. MPM is an aggressive malignancy with a poor prognosis and the incidence is increasing and is expected to increase further for another 10-20 years worldwide. Therefore, the development of novel effective therapies is needed urgently. In this study, we investigated the effect of LPA on the proliferation and motility of MPM cells. We found that all 12 cell lines and four clinical samples of MPM expressed LPA1, and some of them expressed LPA2, LPA3, LPA4 and LPA5. LPA stimulated the proliferation and motility of MPM cells in a dose-dependent manner. Moreover, LPA-induced proliferation was inhibited by Ki16425, an inhibitor of LPA1, and small interfering RNA against LPA1, but not LPA2. Interestingly, LPA-induced motility was inhibited by small interfering RNA against LPA2, but not LPA1, unlike a number of previous reports. These results indicate that LPA is a critical factor on proliferation though LPA1, and on motility though LPA2 in MPM cells. Therefore, LPA and LPA receptors, LPA2 as well as LPA1, represent potential therapeutic targets for patients with MPM. © 2008 Japanese Cancer Association.

ポリエステル繊維の難燃加工処理工程からの排出源廃水及びその工場の最終廃水中の難燃剤ヘキサブロモシクロドデカン(HBCD)のγ線照射，γ線照射/生物処理による分解除去を検討した。HBCD廃液のγ線照射前後のHBCD濃度，分解率，更に有機物の指標としてのTOC，COD，BOD，また分解生成物である臭化物イオンの濃度を測定した。結果として，100kGyの線量で最終廃水中のHBCDが72.5％分解除去され，またその他の有機物もほとんど分解除去され，更に生物処理と組み合わせることで，HBCDが98％分解除去されることを明らかにした。

Identification of a homozygous deletion in cancer cells provides strong evidence for the location of a tumor suppressor gene (TSG). We analyzed the 2p24 homozygous deletion of a non-small-cell lung cancer (NSCLC) cell line, NCI-H2882, and found that the deletion size was 3.7 Mbp. Since RhoB, which has been suggested to be a candidate TSG, was located in this region, we analyzed RhoB for alterations in NSCLC. Although we found no mutations in 48 cell lines including 20 NSCLCs, a loss of heterozygosity (LOH) analysis in 128 primary NSCLCs showed that 25 of 62 informative samples had LOH at the RhoB locus. Northern blot analysis of 28 cell lines (including 15 NSCLCs) indicated that RhoB expression was downregulated in 27. We analyzed RhoB expression in 112 primary NSCLCs with immunohistochemistry and found no or a weak RhoB expression in 33 (42%) of 78 adenocarcinomas, whereas we found it in 29 (94%) of 31 squamous cell carcinomas. No or a weak expression of RhoB was more frequently observed in poorly- or moderately-differentiated adenocarcinomas than in well-differentiated ones (p = 0.0014). Furthermore, no or a weak expression of RhoB indicated a tendency to poor patient prognosis. Although hypermethylation was not found at the promoter region, the RhoB expression in NSCLC cell lines was induced by histone deacetylase inhibition, suggesting that RhoB downregulation may be due to histone modification. The present study demonstrates that RhoB expression is frequently downregulated in NSCLCs by multiple mechanisms, suggesting that RhoB is a candidate TSG for NSCLC.

Accidents involving of large vehicles such as buses and trucks are often caused by rollovers. Roll motions affects dynamics of large vehicles more than that of passenger cars because of their high center-of-gravity heights. In this paper, a 4-ton truck is used as an experiment vehicle in order to determine its plane and roll motion characteristics. Every experiment is conducted for two different load conditions in order to simulate the realistic operating condition of a truck, and the effects of the vehicle's load on its motions are determined. The results from both static and dynamic experiments are compared to see if the vehicle's reaction in actual driving differs from that of a static vehicle. Also, simple mathematical models are used to determine the relationship between the plane and roll motions of the vehicle.

In this paper, a three-degree-of-freedom model is employed for computer simulation to determine the relationship between the planar and roll motions of a large-size vehicle, so that the roll motion could be eventually predicted to prevent the vehicle from going dynamically unstable. Factors such as the varying center of gravity height and roll steer are also taken into consideration. An experiment is conducted using an actual truck with and without load to investigate its effect on the dynamics of the vehicle.

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.