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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．

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．

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.

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.

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.

We herein report the cases of 3 patients with thymic epithelial tumours, including two thymomas and a carcinoma, where the tumours spontaneously regressed in size. The patients were all female ranging in age from 32 to 43 years. During 1 or 2 months without any treatment, the tumours regressed by 25–59% in size. The pleural effusion observed in 2 patients also disappeared during the same period. Pathological examinations revealed areas of necrosis or cystic changes within the two thymomas. Among the patients with thymic epithelial tumours, the existence of this rare disease entity must be recognized.

64歳男性.右肺門部原発の扁平上皮癌に対し, 右肺全摘術を施行した.横隔神経後方で上大静脈に沿って約5cm心膜を切開し, 心嚢内より肺動静脈を処理した.心膜切開部は, 直接縫合閉鎖し, 術後胸腔ドレーンは一5cmの陰圧をかけた.15時間後, 体位変換ととも心臓脱を発症, 蘇生を行いながら病室で緊急再開胸した.心臓は右胸腔内に脱出し, 著明に緊満しており, 心膜は縦方向に裂けていた.直ちに脱出心を用手的に還納し, パッチ閉鎖した.術後も不整脈・低血圧など循環管理に難渋し, 心電図でII, III, aVFでのST上昇・Q波の出現, 心筋シンチで右冠動脈領域の灌流欠損を認め, 心臓脱から右冠動脈起始部の絞拒をきたし心筋梗塞にいたったものど思われた.肺癌術時心膜の欠損はパッチ閉鎖を考慮するとともに, ドレーン管理・体位交換などの術後管理に対し, 細心の注意を払う必要がある.万一本症を合併した場合には不可逆的な心筋変化を来す前の早急な修復が不可欠である.

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.

Solitary fibrous tumour (SFT) is a mesenchymal neoplasm of subendothelial origin that can be found in all anatomical locations, but rarely in the lungs. A 71-year old female was referred to our hospital because of the increase in size of a solitary pulmonary mass. Chest contrast-enhanced dynamic computed tomography showed a well-circumscribed lobulated mass measuring 3.1×1.6 cm in the posterior segment of the right upper lobe of the lung. Positron emission tomography with 18F-fluorodeoxyglucose (FDG) demonstrated that the mass had high FDG uptake. A right upper lobectomy of the lung and mediastinal lymphadenectomy were performed. The tumour was pathologically diagnosed as an SFT. Seven months later, the patient was found to have brain metastases of the tumour, which led to dizziness. A craniotomy and successive radiosurgery with a gamma knife were performed for the metastatic tumours. She is still alive without evidence of disease 12 months after the treatment of the metastases. Pulmonary SFT seldom behaves aggressively, and only two previous cases of primary pulmonary SFT with brain metastases have been reported. Local therapy including surgery and radiotherapy against metastases from SFT could help improve the survival of such patients.

A total of 28 cases of idiopathic thrombocytopenic purpura (ITP) have been treated by splenectomy in the institute. We employed open splenectomy (OS) for 19 cases before 1992 and laparoscopic splenectomy (LS) for nine cases after 1993. In this study these two procedures were compared for various parameters. Surgical time was significantly shorter for OS than that for LS (126±52 vs 244±63 min., p=0.000141). Blood loss was less for OS than that for LS (322±264 vs 713±729ml). None of patients undergoing LS were converted to open surgery. Accessory spleen was found in four patients undergoing OS (21%) and in three patients undergoing LS (33%). Postoperative hospital stay was significantly longer for patients in the OS group than the othors (39.5±28.1 vs 10.0±3.0 days, p=0.00023). No significant difference was noted in the late efficacy rates of splenectomy, namely, efficacy rates for OS versus LS were “excellent”: 53.3% vs 44.4%; “effective”: 13.3% vs 33.3%; “slightly effective”: 20.0% vs 22.2%; and “ineffective”: 13.3% vs 0%, respectively. Compared with OS, LS required more surgical time, caused greater blood loss, had a comparable response rate and incidence of accessory spleen, and appeared to shorten the postoperative stay, decrease incisional discomfort, and provide better cosmetic results, especially in younger patients. Laparoscopic splenectomy is the preferable procedure for ITP.

Objectives In preoperative segmentectomy simulation for primary lung cancer, it is important to identify the intersegmental pulmonary veins and the relationship between them and the surgical safety margin. We have adopted a method that incorporates a virtual safety margin into three-dimensional computed tomography angiography images in order to plan adequate segmentectomy for lung cancer patients. In this study, we describe the new preoperative planning technique and review cases in which we performed segmentectomy based on its results. Methods We reviewed clinical, radiological, and pathological records and selected patients who underwent segmentectomy for a primary lung cancer lesion with a diameter of 2 cm or less. These segmentectomies were planned using preoperative three-dimensional computed tomography angiography with a virtual safety margin. Results A total of 17 primary lung cancers in 16 patients (11 male and 5 female, aged 52–82 years) were removed by segmentectomy, planned using the new technique. In 6 of 17 tumors (35%) were non-solid type adenocarcinomas, 3 tumors (18%) were partly solid type adenocarcinomas, 6 tumors (35%) were solid type adenocarcinomas and 2 tumors (12%) were squamous cell carcinomas. Pathological examination revealed no positive surgical margins and no lymph node metastases in any patients. Conclusions Three-dimensional computed tomography angiography with a virtual safety margin was able to non-invasively visualize the three-dimensional distances and the relationships between the primary tumor and intersegmental pulmonary veins. It was able to aid in the preoperative planning of a suitable segmentectomy procedure for patients with a primary lung cancer lesion of 2 cm or less in diameter.

An 1-year-old and 3-month-old girl was seen at another hospital because of vomiting. As consciousness disturbance was noticed, she was transferred to the Department of Pediatrics in our hospital. The body temperature exceeded 39°C and she fell into a deep coma. Anti-HSV antibody (IgM) was positive. Brain CT revealed an extensive low density area of the right hemisphere, which was enhanced by contrast medium. Dexamethasone and Acyclovir were started on the 3rd hospital day under a diagnosis of herpes encephalitis. On the 10th and 15th hospital days, massive tarry stool was found, and endoscopic examination showed coagula bulging from the pyloric ring. Therefore an emergency operation was performed. On entering the peritoneal cavity, coagula was seen scattered all over the abdomen. A perforated ulcer about 2cm in diameter was confirmed on the anterior wall from the bulbus to the 2nd portion of the duodenum, and was covered with coagula. After distal hemigastrectomy, reconstruction was performed with Billroth II. As it was thought immpossible to close the duodenal stump primarily, the jejunum was anastomosed to the duodenal stump with Roux-en-Y reconstruction. The postoperative course was uneventful. She was discharged from the hospital on the 93rd postoperative day.

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.

OBJECTIVES: Surgical resection is widely accepted as a beneficial treatment of pulmonary metastases originating from osteogenic and soft tissue sarcomas despite adequate validation. The factors associated with the selection of patients who receive pulmonary metastasectomy (PM) are controversial and not well known. In this study, we aimed to identify the prognostic factors associated with survival after treatment with PM and to disclose the candidates who profit from PM being performed on patients with osteogenic and soft tissue sarcomas. METHODS: We retrospectively reviewed the variables and survival outcomes in 52 consecutive patients who underwent PM to treat lung metastases originating from osteogenic and soft tissue malignancies from April 1996 to January 2011. Prognostic factors associated with overall survival after the first PM were evaluated using univariate and multivariate analyses. RESULTS: Fifty-eight PM procedures were performed in 52 patients as the first PM including 6 bilateral diseases. Wedge resection was the most frequently performed PM procedure (84%), and video-assisted thoracic surgery was introduced in 34 (59%). The median follow-up of the patients was 33 months and the 5-year survival rate after the first PM was 50.9%. Forty-eight (92%) patients underwent complete resection during the first PM. Thirty-three patients (62%) experienced relapse after the first PM. Among those patients, 20 received redo surgeries for pulmonary relapse, and the 5-year survival rate in this group was 49.7%. According to univariate analyses, the use of complete resection, the number of metastatic nodules (one or two) and the length of the disease-free interval prior to the first PM were each found to be significant favourable factors. According to a multivariate analysis, the use of complete resection and the number of metastatic nodules were both found to be independent prognostic factors associated with overall survival. Although our cohort included 15 patients with poor prognostic factors (29%), 5 patients who underwent redo surgery survived >22 months. CONCLUSIONS: The survival of those patients with one or two pulmonary nodules and those who underwent complete resection was favourable following the treatment of osteogenic and soft tissue sarcomas with PM. Redo surgery may also provide some survival benefit in patients with poor prognostic factors.

TIMELESS (TIM) is a mammalian homolog of a Drosophila circadian rhythm gene, but its circadian properties in mammals have yet to be determined. TIM appears to be essential for replication protection and genomic stability. Recently, the involvement of TIM in human malignancies has been reported; therefore, we investigated the role of TIM in lung cancer. Microarray expression analysis of lung cancer cell lines showed that TIM expression was elevated 3.7-fold (P < 0.001) in non-small cell lung cancer cell lines (n = 116) compared to normal lung controls (n = 59). In addition, small cell lung cancer cell lines (n = 29) expressed TIM at levels 2.2-fold (P < 0.001) higher than non-small cell lung cancer. Western blot analysis of 22 lung cancer cell lines revealed that all of them expressed TIM protein and that 20 cell lines (91%) expressed TIM protein at higher levels than a normal control line. Remarkably, immunohistochemistry of 30 surgically resected lung cancer specimens showed that all lung cancer specimens but no matched normal lung tissues were positive for TIM expression. Moreover, immunohistochemistry of surgically resected specimens from 88 consecutive patients showed that high TIM protein levels correlated with poor overall survival (P = 0.013). Mutation analysis for TIM in 23 lung cancer cell lines revealed no mutation. TIM knockdown suppressed proliferation and clonogenic growth, and induced apoptosis in H157 and H460 cells. Taken together, our findings suggest that TIM could be useful as a diagnostic and prognostic marker for lung cancer and targeting it would be of high therapeutic value for this disease.

Background Activated leukocyte cell adhesion molecule (ALCAM) has been shown to correlate with the prognosis of patients with various types of human malignancies. However, the relationship between ALCAM expression and progression of non–small-cell lung cancer (NSCLC) has not been investigated. This study was designed to clarify the prognostic impact of ALCAM expression of NSCLC cells. Materials and methods The study population consisted of 147 NSCLC patients who underwent complete resection. We performed immunohistochemical staining for ALCAM expression and correlated this to the clinicopathologic parameters and patient survival. The ALCAM expression in NSCLC cell lines was analyzed using quantitative reverse transcription–polymerase chain reaction and Western blot analyses. ALCAM knockdown in NSCLC cell lines was performed with lentivirus-mediated short hairpin RNA transduction. Results Positive membranous and cytoplasmic ALCAM expressions were detected in 66 (44.9%) and 57 (38.8%) patients, respectively. A significant association of high membranous ALCAM expression with shortened overall survival (OS) was found (P = 0.009). However, patients with cytoplasmic staining of ALCAM showed no significantly shortened OS (P = 0.723). Multivariate analyses showed that membranous expression was adverse prognostic factors for OS (hazard ratio, 2.11; P = 0.046). ALCAM knockdown with short hairpin RNA suppressed cell migration and invasion of NSCLC cell lines in vitro. Conclusions Strong membranous ALCAM expression is associated with a poor prognosis in patients with resected NSCLC, and overexpression of ALCAM causes malignant phenotypes of NSCLC.

特発性血小板減少性紫斑病 (以下, ITPと略記) の2例に対し腹腔鏡下脾摘術を施行したので報告する. 症例は63歳の男性と57歳の女性で, いずれも内科療法にて副作用の合併したITPの患者である. 手術: 体位を右斜め側臥位とし, 5本のトロッカーを挿入した. まず脾外側の腹膜を切開し, 脾結腸間膜を脾に沿って切離した. 次に胃脾間膜と膵脾間膜を脾に沿って徐々にEndo-Clip, Endo-Scissors, Endo-GIAを用いて脾臓を摘出した. 脾臓はEndo-pouchに収納し, 創を広げることなく砕いて腹腔より摘出した. 出血量は190mlと200mlで, 手術時間は3時間35分と3時間05分であった. ITPにおいて腹腔鏡下脾臓摘出術はステロイド療法に比べ, 副作用, 入院期間などはるかに優れており, 寛解率も良く, また疾患としても若い女性に多いことより美容的にも優れており, 治療方針として積極的に選択すべき方法と思われる.

Metaplastic thymoma is a rare primary thymic epithelial tumor. This report presents the 18F-FDG PET/CT appearance of a metaplastic thymoma developed in a 61-year-old female patient. The FDG uptake of the mediastinal mass showed a high maximum SUV, thus suggesting the possibility of thymic cancer. Surgical resection was performed for both a definitive diagnosis and treatment of the mediastinal tumor. A histological examination of the resected specimen revealed metaplastic thymoma. Although rare, thymoma should be carefully considered in the differential diagnosis in cases of mediastinal masses presenting with highly positive findings on 18F-FDG PET/CT to avoid any inappropriate patient management.

Solitary pulmonary nodules are sometimes detected by routine chest radiography. Although many of them are suspected to be benign tumors following noninvasive examinations including computed tomography and positron emission tomography, it is difficult to diagnose them accurately. This report presents a rare case of a solitary fibrous tumor located in the lung that could not be diagnosed preoperatively. More information must be accumulated concerning such rare cases of intrapulmonary solitary fibrous tumors.

Objectives: The increasing age of the population has raised the importance of determining the minimally required surgical treatment for elderly lung cancer patients. Despite a number of previous studies, the therapeutic impact of a radical mediastinal lymphadenectomy (RLA) associated with a pulmonary resection for lung cancer remains controversial. Herein, we investigated the impact of lymph node dissection on the overall survival for elderly lung cancer patients and assessed whether the non-performance of an RLA could be justified in the surgical treatment for these elderly patients. Methods: We analysed the data for 160 patients aged 70 years and older (113 males, 47 females) who underwent curative-intent surgery for non-small-cell lung cancer. They were divided into two groups, according to the method used for the intra-operative mediastinal lymph node dissection, the radical systematic lymphadenectomy (RLA, n = 76) and the non-radical lymphadenectomy (NLA, n = 94) groups.A Coxproportional hazardsmodel and the Kaplan—Meier methodwere usedfor the survival analyses.Propensity-based analyses were also used to reduce the effect of non-randomisation and possible bias in indication of treatment between the two groups. Results: RLAs had no protective effect on mortality; the hazard ratio for the RLA group in comparison to the NLA group was 0.97 (95% confidence interval (CI): 0.32— 2.89) in the multivariate analysis and 1.43 (95% CI: 0.42—4.91) in the propensity-based stratifying analysis. The 3-year survival probability was 81.3% (95% CI: 67.1—89.8) for the NLA group, which was marginally better than that of the RLA group (77.5% (95% CI: 63.3—86.8)). There was no significant difference in the overall survival between the two groups (p = 0.26). The 3-year survival probability of the NLA group at each quartile ofthe propensity scorealso tendedto bebetterthan thatoftheRLAgroup,whichdidnotshowany significantdifference.Conclusions:Therewas no survival benefit shown for RLA associated with pulmonary resections in the present cohort, even in the propensity-based analyses. Although some reports recommend a systematic mediastinal lymphadenectomy for proper staging and better survival, a pulmonary resection with nonperformance of radical lymphadenectomy could be an acceptable surgical treatment for the increasing number of elderly lung cancer patients. # 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Background Long-term postoperative pain in open thoracotomy patients could be related to injured intercostal nerves, and several methods have been devised to protect these nerves. Methods We retrospectively reviewed 184 consecutive patients who underwent posterolateral or anteroaxillary thoracotomy. Postoperative pain was routinely evaluated using an 11-point numerical pain rating scale (0 [no pain] to 10 [most severe pain]) at 1 to 2 weeks; 2 weeks to 1 month; and 1 to 2, 2 to 4, 4 to 6, 6 to 9, and 9 to 12 months after surgery. The following steps were considered to protect the intercostal nerves. During chest retraction, an intercostal muscle flap was harvested before using the retractor to prevent compression of the cranial intercostal nerve in posterolateral thoracotomy patients who needed buttressing of the bronchial stump. During closure, the thin space between the inferior edge of caudal rib and the intercostal neurovascular bundle was sutured to prevent strangulation of the intercostal nerve and vessels on the caudal side (edge closure technique). Subjects included 141 posterolateral and 43 anteroaxillary thoracotomies, 72 intercostal muscle flaps, and 87 conventional closures and 97 edge closures. Results During a year postoperatively, posterolateral thoracotomy patients experienced more pain (range, 1.2 to 4.6) than anteroaxillary thoracotomy patients (range, 1.1 to 3.7; p = 0.038 for all periods). Patients with the intercostal muscle flap tended to experience less pain than those without the flap during the first month postoperatively. The scores of patients having edge closure (range, 0.9 to 3.8) were significantly lower than those of patients undergoing conventional closure (range, 1.6 to 5.1; p Conclusions The edge closure technique, which preserved the caudal intercostal neurovascular bundle, successfully reduced pain.

Genome-wide array-based comparative genomic hybridization analysis of malignant pleural mesotheliomas (MPM) was carried out to identify regions that display DNA copy number alterations. Seventeen primary tumors and nine cell lines derived from 22 individuals were studied, some of them originating from the same patients. Regions of genomic aberrations observed in >20% of individuals were 1q, 5p, 7p, 8q24 and 20p with gains, and 1p36.33, 1p36.1, 1p21.3, 3p21.3, 4q22, 4q34-qter, 6q25, 9p21.3, 10p, 13q33.2, 14q32.13, 18q and 22q with losses. Two regions at 1p32.1 and 11q22 showed a high copy gain. The 1p32.1 region contained a protooncogene, JUN, and we further demonstrated overexpression of JUN with real-time polymerase chain reaction analysis. As MPM cell lines did not overexpress JUN, our findings suggested that induction of JUN expression was involved in the development of MPM cells in vivo, which also might result in gene amplification in a subset of MPM. Meanwhile, the most frequent alteration was the 9p21.3 deletion, which includes the p16INK4a/p14ARF locus. With polymerase chain reaction analysis, we determined the extent of the homozygous deletion regions of the p16INK4a/p14ARF locus in MPM cell lines, which indicated that the deletion regions varied among cell lines. Our results with array comparative genomic hybridization analysis provide new insights into the genetic background of MPM, and also give some clues to develop a new molecular target therapy for MPM. (Cancer Sci 2007; 98: 438–446)

Malignant pleural mesothelioma (MPM) is an asbestos-related malignancy that is highly resistant to current therapeutic modalities. We established four MPM cell lines (ACC-MESO-1, ACC-MESO-4, Y-MESO-8A and Y-MESO-8D) from Japanese patients, with the latter two from the same patient with biphasic-like characteristics of MPM, showing epithelial and sarcomatous phenotypes, respectively, in cell culture. These cells grew well in RPMI-1640 medium supplemented with 10% fetal bovine serum under 5% CO2. Mutation and expression analyses demonstrated that the tumor suppressor gene NF2, which is known to be one of the most frequently mutated in MPM, is mutated in ACC-MESO-1. We detected homozygous deletion of p16INK4A/p14ARF in all four MPM cell lines. However, mutations of other tumor suppressor genes, including TP53, and protooncogenes, including KRAS, NRAS, BRAF, EGFR and HER2, were not found in these cell lines. Polymerase chain reaction amplification of the simian virus 40 sequence did not detect any products. We also analyzed genetic alterations of six other MPM cell lines and confirmed frequent mutations of NF2 and p16INK4A/p14ARF. To characterize the biological differences between Y-MESO-8A and Y-MESO-8D, we carried out cDNA microarray analysis and detected genes that were differentially expressed in these two cell lines. Thus, our new MPM cell lines seem to be useful as new models for studying various aspects of the biology of human MPM as well as materials for the development of future therapies.