Podoplanin promotes progression of malignant pleural mesothelioma by regulating motility and focus formation.

Malignant pleural mesothelioma (MPM) is characterized by dissemination and aggressive growth in the thoracic cavity. Podoplanin (PDPN) is an established diagnostic marker for MPM, but the function of PDPN in MPM is not fully understood. The purpose of this study was to determine the pathogenetic function of PDPN in MPM. Forty-seven of 52 tumors (90%) from Japanese patients with MPM and 3/6 (50%) MPM cell lines tested positive for PDPN. Knocking down PDPN in PDPN-high expressing MPM cells resulted in decreased cell motility. In contrast, overexpression of PDPN in PDPN-low expressing MPM cells enhanced cell motility. PDPN stimulated motility was mediated by activation of the RhoA/ROCK pathway. Moreover, knocking down PDPN with short hairpin (sh) RNA in PDPN-high expressing MPM cells resulted in decreased development of a thoracic tumor in mice with severe combined immune deficiency (SCID). In sharp contrast, transfection of PDPN in PDPN-low expressing MPM cells resulted in an increase in the number of Ki-67-positive proliferating tumor cells and it promoted progression of a thoracic tumor in SCID mice. Interestingly, PDPN promoted focus formation in vitro, and a low level of E-cadherin expression and YAP1 activation was observed in PDPN-high MPM tumors. These findings indicate that PDPN is a diagnostic marker as well as a pathogenetic regulator that promotes MPM progression by increasing cell motility and inducing focus formation. Therefore, PDPN might be a pathogenetic determinant of MPM dissemination and aggressive growth and may thus be an ideal therapeutic target.

Therapeutic activity of glycoengineered anti-GM2 antibodies against malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive neoplasm that arises from the pleural, pericardial, or peritoneal lining. Although surgery, chemotherapy, radiotherapy, and combinations of these therapies are used to treat MPM, the median survival of such patients is dismal. Therefore, there is a compelling need to develop novel therapeutics with different modes of action. Ganglioside GM2 is a glycolipid that has been shown to be overexpressed in various types of cancer. However, there are no published reports regarding the use of GM2 as a potential therapeutic target in cases of MPM. In this study, we evaluated the efficacy of the anti-GM2 antibody BIW-8962 as an anti-MPM therapeutic using in vitro and in vivo assays. Consequently, the GM2 expression in the MPM cell lines was confirmed using flow cytometry. In addition, eight of 11 cell lines were GM2-positive (73%), although the GM2 expression was variable. BIW-8962 showed a significant antibody-dependent cellular cytotoxicity activity against the GM2-expressing MPM cell line MSTO-211H, the effect of which depended on the antibody concentration and effector/target ratio. In an in vivo orthotropic mouse model using MSTO-211H cells, BIW-8962 significantly decreased the incidence and size of tumors. Additionally, the GM2 expression was confirmed in the MPM clinical specimens. Fifty-eight percent of the MPM tumors were positive for GM2, with individual variation in the intensity and frequency of staining. These data suggest that anti-GM2 antibodies may become a therapeutic option for MPM patients.

Significant relationship between the extent of pleural plaques and pulmonary asbestos body concentration in lung cancer patients with occupational asbestos exposure.

BACKGROUND: The aim of this study was to elucidate whether there is a relationship between the extent of pleural plaques and pulmonary asbestos body concentration (PABC). METHODS: The subjects were 207 lung cancer patients with occupational asbestos exposure. We determined the plaque extent by findings on chest images using our own criteria. PABCs were measured in resected or autopsy lung specimens. RESULTS: There was a significant relationship between plaque extent and PABC. Seventy-five percent of the patients determined to have extensive plaques based on our criteria had a PABC of ≥5,000 asbestos bodies per gram of dry lung tissue, which is one of the certification criteria of lung cancer caused by asbestos for workers' compensation in Japan. CONCLUSIONS: In lung cancer patients, the plaque extent had a significant positive relationship with the PABC. The plaque extent would be useful as a proxy for PABC for lung cancer compensation purposes.

[Chronic eosinophilic pneumonia presenting as a solitary nodule, suspicious of lung cancer;report of a case].

A 70-year-old man was followed up at the surgery department of our hospital after colon polypectomy. It was pointed out that the level of carcinoembryonic antigen(CEA) was high at blood test. Chest computed tomography (CT) showed small nodule close to the pulmonary vein in the right lower lobe (S6-S10), 15 mm in size, in September 2011. Fluorodeoxyglucose-positron emission tomography( FDG-PET)/CT scanning revealed a positive reaction in the right lower lobe lesion. He was introduced to our department. The video-assisted thoracoscopic surgery (VATS) was performed to establish diagnosis and treat. Histopathological examination showed no malignancy and chronic eosinophilic pneumonia(CEP).In a case of the solitary lung nodule patient with the past history of asthma or the atopic disease, CEP should be included in the differential diagnosis.

Pleural mesothelioma instigates tumor-associated fibroblasts to promote progression via a malignant cytokine network.

The tumor microenvironment is crucial to the progression of various malignancies. Malignant pleural mesothelioma (MPM), which originates from the pleura, grows aggressively in the thoracic cavity. Here we describe an orthotopic implantation SCID mouse model of MPM and demonstrate that α-SMA-positive fibroblast-like cells accumulate in the tumors produced by the human MPM cell lines MSTO-211H and Y-Meso-14. We assessed the interaction between MPM cells and their microenvironments, focusing on tumor-associated fibroblasts. MSTO-211H and Y-Meso-14 cells produced fibroblast growth factor-2 (FGF-2) and/or platelet-derived growth factor-AA (PDGF-AA); they also enhanced growth, migration, and production of hepatocyte growth factor (HGF) by human lung fibroblast MRC-5 cells. MRC-5 cells stimulated HGF-mediated growth and migration of MSTO-211H and Y-Meso-14 cells in an in vitro coculture system. In the orthotopic model, tumor formation by MSTO-211H and Y-Meso-14 cells was significantly inhibited by TSU-68, an inhibitor of FGF, VEGF, and PDGF receptors; imatinib, an inhibitor of PDGF receptors; and NK4, an antagonist of HGF. Histological analyses of clinical specimens from 51 MPM patients revealed considerable tumor-associated fibroblasts infiltration and expression of HGF, together with FGF-2 or PDGF-AA, in tumors. These findings indicate that MPM instigates tumor-associated fibroblasts, promoting tumor progression via a malignant cytokine network. Regulation of this cytokine network may be therapeutically useful for controlling MPM.

[Minute pulmonary meningothelial-like nodules （MPMNs） incidentally detected at surgical biopsy for ground-glass opacity（ GGO）].

A 75-year-old woman was followed up at the urology department of our hospital after left nephrectomy for renal cell carcinoma. Chest computed tomography (CT) showed ground-glass opacity in the right lower lobe( S6), 6 mm in size, in December 2010. 3 months later, the tumor was enlarged and she was introduced to our department. Wedge resection was performed to establish giagnosis. Pathological diagnosis was atypical adenomatous hyperplasia( AAH) and many small spindle-shaped cell nests were found at the same tissue. Immunohistochemically, this nest was shown to be minute pulmonary meningothelial-like nodules(MPMNs). MPMNs are asymptomatic small pulmonary nodules incidentally found during pathologic evaluation of pulmonary specimens. Combinations of MPMNs with adenocarcinoma or AAH have been reported, and the genetic relation of MPMNs and AAH is suggested.

Retrolaminar Block Versus Paravertebral Block for Pain Relief After Less-Invasive Lung Surgery: A Randomized, Non-Inferiority Controlled Trial.

Introduction A retrolaminar block (RLB) is a modified paravertebral technique with a local anesthetic injected at the retrolaminar site. The aim of this non-inferiority, parallel-group, prospective, and randomized study was to compare the analgesic efficacy of the paravertebral block (PVB) and RLB after lung surgery. Methods Eligible subjects were patients aged more than 20 years, with American Society of Anesthesiologists physical status Ⅰ or II, who were scheduled to undergo video-assisted thoracoscopic surgery (VATS) or limited thoracotomy because of lung disease. Patients were randomly allocated to receive either a PVB or RLB using a computer-generated sequence and sealed opaque envelopes. The PVB and RLB were induced by injecting 20 mL of 0.50% ropivacaine and 40 mL 0.25% ropivacaine, respectively. As the primary outcome variable, we considered the area under the curve (AUC) of the postoperative pain intensity using the trapezoidal method. Pain intensity was assessed using an 11-point numerical rating scale (NRS). We converted the NRS (0-10) into the visual analog scale (VAS) (0-100 mm) proportionally. We compared the AUC of the converted NRS (AUC-cNRS) on coughing between one and two hours after the operation. The non-inferiority margin was set at 25 mm × h in the AUC-cNRS. Patients and nurses were blinded to group assignments. Secondary outcomes included time to perform the block, NRS for pain intensity at rest and on coughing at one, two, four, 24, and 48 hours after the operation, the incidence of postoperative nausea and vomiting, time to first morphine use after the operation, and cumulative morphine consumption at 24 and 48 hours after the operation. Results In each group, 25 patients were randomized and analyzed. No significant difference in the AUC-cNRS was noted between the groups (P = 0.117). The mean difference in the AUC-cNRS (group RLB minus group PVB) was 13.42 mm × h, 95% confidence interval, -3.48 to 30.32 mm × h. However, when patients with unexpectedly extended skin incision were excluded from the analysis, the AUC-cNRS of group RLB was significantly higher as compared to group PVB (P = 0.0388). The time to perform the block was longer in PVB as compared to the RLB group (P < 0.0001). No significant differences were noted in the remaining secondary outcomes. Conclusion The non-inferiority of RLB as compared to PVB was not confirmed. Though RLB has the advantage of a shorter time to perform, RLB is not recommended for patients undergoing VATS or limited thoracotomy because of lack of efficacy as compared to PVB.

A case of cardiac amyloidosis incidentally detected by bone scintigraphy.

A 73-year-old man with lung cancer underwent bone scintigraphy for disease staging. Diffuse myocardial technetium hydroxymethylene diphosphonate (99mTc-HMDP) uptake was incidentally found. A diagnosis of amyloid transthyretin (ATTR) cardiac amyloidosis was suspected, although the patient had no symptoms at this time. Single-photon emission computed tomography (SPECT) showed particularly strong uptake in the ventricular septum. Cardiac magnetic resonance imaging (CMR) showed widespread subendocardial and partly transmural enhancement of the left ventricular myocardium on delayed postcontrast T1-weighted images. These findings were consistent with ATTR cardiac amyloidosis. 18F-FDG uptake in the left ventricle wall was observed on PET/CT. He was finally diagnosed with ATTR by endomyocardial biopsy. There are two major subtypes of cardiac amyloidosis: ATTR amyloidosis and amyloid light-chain (AL) amyloidosis. Endomyocardial biopsy is the gold standard for diagnosis. Recently, however, several reports have shown that bone scintigraphy using a 99mTc-labelled bone-seeking agent can detect ATTR cardiac amyloidosis and differentiate it from AL amyloidosis. Bone scintigraphy may play an important role in the detection and differentiation of ATTR cardiac amyloidosis.

[A phase I study of intraperitoneal plus intravenous paclitaxel against gastric cancer with peritoneal dissemination (HGCG 0301)].

The safety of the intraperitoneal (ip) plus intravenous (iv) paclitaxel against gastric cancer with peritoneal dissemination was evaluated on a phase I dose escalation trial. Patients were treated with ip paclitaxel administered in 500 ml of normal saline before closing the abdomen, using the following dose levels: level 1, 50 mg/m(2); level 2, 60 mg/m(2); level 3, 70 mg/m(2); and level 4, 80 mg/m(2), followed by iv infusion of the same doses of paclitaxel on days 14 and 21. Twelve patients were enrolled in this study: 7 underwent reduction surgery,while 5 had only a laparotomy. ip therapy was well tolerated, and did not bring about any postoperative complications even in patients who underwent gastrectomy. Although multiple NCI/CTC grade 1 toxicities and grade 2 anemia (4 of six patients at dose levels 2 and 3) were observed, there was no dose-limiting toxicity. The overall median survival time was 316 days, and that for patients who underwent gastrectomy was 413 days. Paclitaxel at a dose of 80 mg/m(2) can be delivered by the operative ip route with acceptable toxicity profile.

Akt Kinase-Interacting Protein 1 Signals through CREB to Drive Diffuse Malignant Mesothelioma.

Diffuse malignant mesothelioma (DMM) is a tumor of serosal membranes with propensity for progressive local disease. Because current treatment options are largely ineffective, novel therapeutic strategies based on molecular mechanisms and the disease characteristics are needed to improve the outcomes of patients with this disease. Akt kinase interacting protein 1 (Aki1; Freud-1/CC2D1A) is a scaffold protein for the PI3K-PDK1-Akt signaling module that helps determine receptor signal selectivity for EGFR. Aki1 has been suggested as a therapeutic target, but its potential has yet to be evaluated in a tumor setting. Here, we report evidence supporting its definition as a therapeutic target in DMM. In cell-based assays, Aki1 silencing decreased cell viability and caused cell-cycle arrest of multiple DMM cell lines via effects on the PKA-CREB1 signaling pathway. Blocking CREB activity phenocopied Aki1 silencing. Clinically, Aki1 was expressed in most human DMM specimens where its expression correlated with phosphorylated CREB1. Notably, Aki1 siRNA potently blocked tumor growth in an orthotopic implantation model of DMM when administered directly into the pleural cavity of tumor-bearing mice. Our findings suggest an important role for the Aki1-CREB axis in DMM pathogenesis and provide a preclinical rationale to target Aki1 by intrathoracic therapy in locally advanced tumors.

Pulmonary metastasectomy for 165 patients with colorectal carcinoma: A prognostic assessment.

OBJECTIVE: The purpose of this study was to analyze our entire experience with pulmonary resection for metastatic colorectal carcinoma to determine prognostic factors and critically evaluate the potential role of extended metastasectomy. METHODS: We analyzed the postoperative survival of 165 patients who underwent curative pulmonary surgery at eight institutions in the Kansai region of western Japan (Kansai Clinical Oncology Group) from 1990 to 2000. RESULTS: Overall survivals at 5 and 10 years were 39.6% and 37.2%, respectively. Cumulative survival of patients who underwent simultaneous bilateral metastasectomy was significantly lower than that of the patients who underwent unilateral metastasectomy or sequential bilateral metastasectomy (P =.048). Five-year survival was 53.6% for patients without hilar or mediastinal lymph node metastasis, versus 6.2% at 4 years for patients with metastases (P <.001). Five-year survival of patients with a prethoracotomy carcinoembryonic antigen level less than 10 ng/mL was 42.7%, versus 15.1% at 4 years for patients with a carcinoembryonic antigen level 10 ng/mL or greater (P <.0001). Twenty-one patients underwent a second or third thoracotomy for recurrent colorectal carcinoma. Overall 5-year survival from the date of the second thoracotomy was 52.1%. The 34.1% 10-year survival for the 26 patients with hepatic metastasis resected before thoracotomy did not differ significantly from that of patients without hepatic metastases (P =.38). CONCLUSIONS: The status of the hilar or mediastinal lymph nodes and prethoracotomy carcinoembryonic antigen level were significant independent prognostic factors. Patients with pulmonary metastases potentially benefit from pulmonary metastasectomy even when there is a history of solitary liver metastasis. Careful follow-up is warranted, because patients with recurrent pulmonary metastases can undergo repeat thoracotomy with acceptable long-term survival. Simultaneous bilateral metastasectomy confers no survival benefit. Prospective studies may determine the significance of this type of pulmonary metastasectomy.

Snail expression is associated with a poor prognosis in malignant pleural mesotheliomas.

BACKGROUND: Malignant pleural mesotheliomas (MPMs) are aggressive tumors with a poor prognosis. We aimed to clarify the mechanisms of epithelial-to-mesenchymal transition (EMT) in MPMs by analyzing the expressions of EMT-associated transcription factors and E-cadherin in relation to tumor proliferation rates and patient survival. METHODS: One hundred nine patients with MPMs were investigated. Among these patients, there were 61 epithelioid tumors, 21 sarcomatoid tumors, 20 biphasic tumors, and 7 desmoplastic tumors. Immunohistochemical analyses were performed to evaluate the expressions of Snail, ZEB1, Twist, E-cadherin, and the Ki-67 proliferation index. RESULTS: The expressions of Snail and ZEB1 were significantly higher in the nonepithelioid tumors than in the epithelioid tumors (p<0.0001 and p=0.0051, respectively). Furthermore, the E-cadherin expression was significantly lower in the Snail-high tumors than in the Snail-low tumors (p=0.0423). The E-cadherin expression was significantly lower in the nonepithelioid tumors than in the epithelioid tumors (p=0.0126). The Ki-67 proliferation index was significantly higher in the nonepithelioid tumors than in the epithelioid tumors (p=0.025). Patient survival was significantly lower in patients with Snail-high MPMs than in those with Snail-low MPMs (p=0.0016), especially in patients with nonepithelioid tumors (p=0.0089). The multivariate analysis also demonstrated that nuclear Snail expression was a significant predictor of poor prognosis in patients with MPMs (p=0.0142). CONCLUSIONS: The Snail expression is associated with EMT and a poor prognosis in MPMs. Snail could be a potential molecular target for the treatment of patients with MPMs.

Intratumoral Wnt2B expression affects tumor proliferation and survival in malignant pleural mesothelioma patients.

Malignant pleural mesothelioma (MPM) is an aggressive thoracic tumor with a poor prognosis. We performed a comprehensive clinical study on the intratumoral expression of Wnt1, Wnt2B and Wnt5A in MPM. One hundred and seven MPM patients were investigated. Immunohistochemistry was performed to evaluate the intratumoral expression of Wnt1, Wnt2B, Wnt5A, survivin and c-Myc, and the Ki-67 proliferation index. The apoptotic index was evaluated by the TUNEL method. Among the 107 MPMs, 23 MPMs (21.5%) were Wnt1-high tumors, 72 MPMs (67.3%) were Wnt2B-high tumors and 54 MPMs (50.5%) were Wnt5A-high tumors. There was no correlation among the levels of Wnt expression. The percentage of Wnt2B-positive tumors was significantly higher compared to that of the other Wnts (p<0.0001). Furthermore, intratumoral Wnt2B expression significantly correlated with the expression of survivin (p<0.001) and c-Myc (p<0.001). Regarding tumor biology, the Ki-67 proliferation index was significantly higher in the Wnt2B-high tumors than in the Wnt2B-low tumors (p=0.0438). In addition, the overall survival was significantly lower in patients with Wnt2B-high tumors than in those with Wnt2B-low tumors (p=0.0238). A Cox multivariate analysis also demonstrated the Wnt2B status to be a significant prognostic factor in MPM patients (p=0.0042). Intratumoral Wnt2B expression was associated with the expression of survivin and c-Myc, tumor proliferation and patient survival in MPM. Wnt2B is a potential molecular target for the treatment of Wnt2B-overexpressing MPMs.