[Nail Penetrating Injury of the Sternum].

A 48-year-old male was transported to the emergency room with a dirty rusty nail stuck in his chest. Three-dimensional computed tomography (3D-CT) scan revealed that the nail had penetrated the sternum and its tip was close to the left innominate vein. Emergency surgery was performed to avoid severe infections and major vascular injury. The nail was easily removed. We cleansed and debrided the wound which remained open to prevent infection, and was closed on post-operative day 3.

Functional differences between wild-type and mutant-type BRCA1-associated protein 1 tumor suppressor against malignant mesothelioma cells.

Malignant mesothelioma (MM) shows inactivation of the BRCA1-associated protein 1 (BAP1) gene. In this study, we found BAP1 mutations in 5 (26%) of the 19 cell lines that we established from Japanese MM patients, and examined functional differences between the WT and mutant BAP1. First, we studied the subcellular localization of BAP1, demonstrating that the WT primarily resides in the nucleus and that the mutant BAP1 is found in the cytoplasm of the cells. Transduction of the WT BAP1 vector into MM cells with homozygous deletion at the BAP1 3' side resulted in both inhibition of cell proliferation and anchorage-independent cell growth, whereas BAP1 mutants of a missense or C-terminal truncated form showed impaired growth inhibitory effects. Next, we studied how BAP1 is involved in MM cell survival after irradiation (IR), which causes DNA damage. After IR, we found that both WT and mutant BAP1 were similarly phosphorylated and phospho-BAP1 localized mainly in the nucleus. Interestingly, BRCA1 proteins were decreased in the MM cells with BAP1 deletion, and transduction of the mutants as well as WT BAP1 increased BRCA1 proteins, suggesting that BAP1 may promote DNA repair partly through stabilizing BRCA1. Furthermore, using the MM cells with BAP1 deletion, we found that WT BAP1, and even a missense mutant, conferred a higher survival rate after IR compared to the control vector. Our results suggested that, whereas WT BAP1 suppresses MM cell proliferation and restores cell survival after IR damage, some mutant BAP1 may also moderately retain these functions.

Micronodular thymoma with lymphoid stroma: an immunohistochemical study of the distribution of Langerhans cells and mature dendritic cells in six patients.

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 < 0.0001). In contrast, mature DCs were present mainly in the surrounding stroma rather than within the tumour nodules (63.5/HPF versus 6.0/HPF, P < 0.0001), forming clusters with mature T lymphocytes adjacent to lymphoid follicles. In large nodules, as well as in type A and type AB thymomas, a few scattered LCs and DCs were identified. All patients were still alive and well. CONCLUSIONS: Our results suggest that LCs take up tumour antigens and migrate to the stroma, where they mature and form clusters with T lymphocytes to activate them, resulting in lymphoid follicle formation. The favourable clinical behaviour may be attributable to the immune response induced by LCs.

The ABO blood group is an independent prognostic factor in patients with resected non-small cell lung cancer.

BACKGROUND: The ABO blood group is reported to be associated with the incidence and patient survival for several types of malignancies. We conducted a retrospective study to evaluate the prognostic significance of the ABO blood group in patients with resected non-small cell lung cancer (NSCLC). METHODS: A total of 333 patients (218 men and 115 women) with resected NSCLC were included in this study. In addition to age, sex, smoking status, preoperative serum carcinoembryonic antigen (CEA) level, operative procedure, histology of tumors, pathological stage (p-stage), and adjuvant therapy, the association between the ABO blood group and survival was explored. RESULTS: The 5-year overall and disease-free survival rates were 83.0% and 71.6% for blood group O, 67.2% and 62.3% for blood group A, 68.8% and 68.8% for blood group B and 69.2% and 65.3% for blood group AB, respectively. A multivariate analysis for overall survival showed the ABO blood group (group A vs. group O: HR 2.47, group AB vs. group O: HR 3.62) to be an independent significant prognostic factor, in addition to age, sex, smoking status, p-stage, and serum CEA level. A multivariate analysis for disease-free survival also showed the ABO blood group to be an independent significant prognostic factor. CONCLUSIONS: The ABO blood group is an independent prognostic factor in patients with resected NSCLC. Studies of other larger cohorts are therefore needed to confirm the relationship between the ABO blood group and the prognosis among patients with resected NSCLC.

Preoperative plasma D-dimer level is an independent prognostic factor in patients with completely resected non-small cell lung cancer.

PURPOSE: 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). METHODS: 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. RESULTS: 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 <0.001). A multivariate survival analysis showed that the D-dimer level (group B vs. group A HR 4.25, group C vs. group A HR 4.11) was an independent significant prognostic factor, in addition to age, sex, the pathological stage and the serum carcinoembryonic antigen level. CONCLUSIONS: The preoperative D-dimer level is an independent prognostic factor in patients with completely resected NSCLC.

Membranous expression of activated leukocyte cell adhesion molecule contributes to poor prognosis and malignant phenotypes of non-small-cell lung cancer.

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.

The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma.

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

[Feasibility and response of gemcitabine and carboplatin biweekly combination chemotherapy for patients with postoperative recurrence non-small cell lung cancer].

BACKGROUND: In advanced non-small cell lung cancer(NSCLC), the standard treatment is chemotherapy with platinum doublet. Gemcitabine (GEM)is one of the major drugs administered in combination with platinum. We studied the feasibility and response of GEM and Carboplatin(CBDCA)biweekly combination chemotherapy for patients with / postoperative recurrence NSCLC. METHOD: Patients received GEM(1,000 mg/m(2))over 30 minutes and CBDCA(AUC =3)over 60 minutes intravenously on day 1 biweekly. Response was evaluated with RECIST. RESULT: Between April 2005 and December 2006 thirteen patients with PS 0 or 1 were entered in the study. All patients received 4 or more cycles. Eight patients received 8 cycles. Of them, only two patients required dose-reduction for hematologic toxicity. / Grade 3/4 hematologic or non-hematologic toxicities and more than grade 2 thrombocytopenia did not occur in any patients. The overall response rate was 20%. SD was seen in 6 patients. CONCLUSION: GEM and CBDCA biweekly combination chemotherapy is a well-tolerated regimen with promising activity against NSCLC.

The contact length between the tumor contour and the lung on computed tomography is a risk factor for pleural recurrence after complete resection of thymoma.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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 < 0.001), although the TDs were not significantly different between the two groups. The multivariate analysis indicated that CLTL was only a risk factor for PR (p = 0.046). CONCLUSION: The CLTL was significantly associated with the PR after complete resection of thymoma.

FDG PET/CT is useful for detecting infiltration to the port site in patients with malignant pleural mesothelioma.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Surgical management of locally advanced lung cancer.

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.

Therapeutic surgery without a definitive diagnosis can be an option in selected patients with suspected lung cancer.

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.

RASSF3 downregulation increases malignant phenotypes of non-small cell lung cancer.

BACKGROUND: Ras-Association Family1A (RASSF1A) is a well-established tumor suppressor. Ten RASSF homologues comprise this family, and each member is considered a tumor suppressor. RASSF3 is one of the RASSF family members, but its function has not yet been clarified. Recently, we found that RASSF3 interacts with MDM2 and facilitates its ubiquitination, which induces apoptosis through p53 stabilization. However, the role of RASSF3 in human malignancies remains largely unknown. PATIENTS AND METHODS: Ninety-five non-small cell lung cancer (NSCLC) patients from Nagoya University Hospital and 45 NSCLC patients from Aichi Cancer Center Hospital underwent pulmonary resection at each hospital, and lung cancer and corresponding non-cancerous lung tissues were collected. The expression levels of RASSF3 were analyzed using quantitative real-time reverse transcription PCR. We performed statistical analysis to investigate the correlation with RASSF3 expression and the clinicopathological characteristics. We also transfected RASSF3-siRNA into NSCLC cells, and performed motility assays to evaluate the influence on migration ability. RESULTS: RASSF3 expression levels were downregulated in 125 of a total 140 NSCLCs. In a multivariate logistic regression analysis, the low RASSF3 expression group below the median value was independently correlated with progressive phenotypes (lymph node metastasis and pleural invasion), non-adenocarcinoma histology and wild-type epidermal growth factor receptor (EGFR) status. In motility assays, RASSF3-knockdown NSCLC cells increased the migration rate compared to the control cells. CONCLUSIONS: We found that the expression levels of RASSF3 were frequently downregulated in NSCLCs. Downregulation of RASSF3 strongly correlated with the progressive phenotypes of NSCLCs and EGFR wild-type status. In vitro studies also suggested that RASSF3 downregulation increases migration ability of lung cancer cells. Together, our findings indicate RASSF3 is a candidate tumor suppressor gene of NSCLCs.

Prognostic impact of tumor size eliminating the ground glass opacity component: modified clinical T descriptors of the tumor, node, metastasis classification of lung cancer.

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.

Pulmonary metastasectomy for osteogenic and soft tissue sarcoma: who really benefits from surgical treatment?

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.

Multilocular thymic cyst associated with thymoma: a clinicopathologic study of 20 cases with an emphasis on the pathogenesis of cyst formation.

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.

Activated leukocyte cell-adhesion molecule (ALCAM) promotes malignant phenotypes of malignant mesothelioma.

INTRODUCTION: Cell-adhesion molecules play important roles involving the malignant phenotypes of human cancer cells. However, detailed characteristics of aberrant expression status of cell-adhesion molecules in malignant mesothelioma (MM) cells and their possible biological roles for MM malignancy remain poorly understood. METHODS: DNA microarray analysis was employed to identify aberrantly expressing genes using 20 MM cell lines. Activated leukocyte cell-adhesion molecule (ALCAM) expression in MM cell lines was analyzed with quantitative reverse transcription-polymerase chain reaction and Western blot analyses in 47 primary MM specimens with immunohistochemistry. ALCAM knockdown in MM cell lines was performed with lentivirus-mediated short hairpin RNA (shRNA) transduction. Purified soluble ALCAM (sALCAM) protein was used for in vitro experiments, whereas MM cell lines infected with the sALCAM-expressing lentivirus were tested for tumorigenicity in vivo. RESULTS: ALCAM, a member of the immunoglobulin superfamily, was detected as one of the most highly upregulated genes among 103 cell-adhesion molecules with microarray analysis. Elevated expression levels of ALCAM messenger RNA and protein were detected in all 20 cell lines. Positive staining of ALCAM was detected in 26 of 47 MM specimens (55%) with immunohistochemistry. ALCAM knockdown with shRNA suppressed cell migration and invasion of MM cell lines. Purified sALCAM protein impaired the migration and invasion of MM cells in vitro, and the infection of sALCAM-expressing virus into MM cells significantly prolonged survival periods of MM-transplanted nude mice in vivo. CONCLUSION: Our study suggests that overexpression of ALCAM contributes to tumor progression in MM and that ALCAM might be a potential therapeutic target of MM.

LATS2 is a tumor suppressor gene of malignant mesothelioma.

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.

Effect of selective lymph node dissection based on patterns of lobe-specific lymph node metastases on patient outcome in patients with resectable non-small cell lung cancer: a large-scale retrospective cohort study applying a propensity score.

OBJECTIVE: Lobectomy with systematic complete mediastinal lymph node dissection is standard surgical treatment for localized non-small cell lung cancer. However, selective mediastinal lymph node dissection based on lobe-specific metastases (selective dissection) has often been performed. This study was designed to evaluate the validity of the selective lymph node dissection. METHODS: From 1995 through 2003, 625 patients in our hospital had surgery for complete mediastinal lymph node dissection and 147 for selective dissection. We evaluated whether selective dissection adversely affected overall survival. To minimize possible biases due to confounding by treatment indication, we performed a retrospective cohort analysis by applying a propensity score. The propensity score was calculated by logistic regression based on 15 factors available that were potentially associated with treatment indication. Patients were divided into 4 groups according to quartile, and comparison between selective dissection and complete mediastinal lymph node dissection was made using propensity score quartile-stratified Cox proportional hazard models. RESULTS: Comparison of baseline characteristics between patients having selective dissection and patients having complete mediastinal lymph node dissection according to propensity score quartile supported comparability of the 2 groups. The 5-year overall survival rates were 76.0% for selective dissection versus 71.9% for complete mediastinal lymph node dissection. The 5-year survival probabilities stratified by propensity score quartile consistently showed no marked difference. In multivariate models, there was no significant difference between the 2 groups (hazard ratio = 1.17, P = .500) as also seen in the analysis without propensity score (hazard ratio = 1.06; 95% confidence interval, 0.68-1.64; P = .810). Therefore, selective dissection showed no significant impact on poor survival compared with complete mediastinal lymph node dissection. CONCLUSIONS: Selective lymph node dissection did not worsen the survival of patients with non-small cell lung cancer.

Serum carcinoembryonic antigen level as a surrogate marker for the evaluation of tumor response to chemotherapy in nonsmall cell lung cancer.

PURPOSE: Carcinoembryonic antigen (CEA) is a tumor marker widely used for nonsmall cell lung cancer (NSCLC). The aim of this study was to evaluate changes in serum CEA levels as a surrogate marker for tumor response to chemotherapy in NSCLC. METHODS: From 1995 through 2005, we retrospectively analyzed 24 NSCLC patients who had high serum CEA levels (>5 ng/ml) and who received chemotherapy followed by surgery. We compared serum CEA levels with tumor response, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) or World Health Organization (WHO) criteria, as well as with histological response. RESULTS: Serum CEA levels after chemotherapy significantly decreased in patients who achieved partial response, defined by RECIST or WHO criteria (p = 0.004 and p = 0.008, respectively), when compared with the CEA levels before chemotherapy. In contrast, there was no significant difference in CEA levels in patients with either stable disease or no response to chemotherapy. They decreased significantly, however, in patients in whom less than one-third of tumor cells was viable by pathological examination, but not in patients in whom more than a third was viable (p = 0.008). Using the receiver-operating characteristic (ROC) curve analysis, we found that a 60% reduction of CEA levels was an appropriate cutoff value in predicting a good response to chemotherapy. When the value was set at that level, the sensitivity of CEA for RECIST was 82%, and the specificity was 69%. CONCLUSION: Serum CEA concentration was a useful surrogate marker for the evaluation of tumor response to chemotherapy and seemed to be comparable with RECIST in NSCLC patients who had elevated CEA levels prior to treatment.