Therapeutic effect of anti CEACAM6 monoclonal antibody against lung adenocarcinoma by enhancing anoikis sensitivity.

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) plays a crucial role in tumorigenesis of lung cancer. However, the therapeutic potential for anti CEACAM6 monoclonal antibody (mAb) has only been limitedly explored. Here, we evaluate the therapeutic potential of naked anti CEACAM6 mAb against lung adenocarcinoma. Clone 8F5, recognizing B domain of CEACAM6, is established by immunizing A549 cells and screening for clones double positive for A549 and CEACAM6-Fc recombinant protein. We found that 85.7% of 70 resected lung adenocarcinoma tissue sections were positive for CEACAM6, whereas all squamous cell carcinoma examined were negative. A549 cells with high levels of CEACAM6 demonstrated more aggressive growth nature and showed increased paclitaxel chemosensitivity upon 8F5 binding. Treatment with 8F5 to A549 decreased cellular CEACAM6 expression and reversed anoikis resistance. 8F5 also decreased cellular status of Akt phosphorylation and increased apoptosis via caspase activation. In a mouse model of lung adenocarcinoma with xenotransplanted A549 cells, 8F5 treatment alone demonstrated 40% tumor growth inhibition. When combined with paclitaxel treatment, 8F5 markedly enhanced tumor growth inhibition, up to 80%. In summary, we demonstrate that anti CEACAM6 mAb is an effective therapeutic treatment for lung adenocarcinoma whose effect is further enhanced by combined treatment with paclitaxel.

Expression of cell cycle-related proteins, p16, p53 and p63 as important prognostic markers in gallbladder adenocarcinoma.

Gallbladder cancer, the most common biliary tract malignancy, is a highly malignant neoplasm. In the present work, we have analyzed the significance of cell cycle-related proteins to predict prognosis and to provide guidance for optimal therapeutic decision-making in patients with gallbladder adenocarcinoma. The expressions of p16, p21, p27, p53, p63, cyclin D1, bcl-2 and bcl-6 were examined in a tissue microarray constructed from 96 cases of gallbladder adenocarcinoma by immunohistochemistry and correlated with clinicopathologic prognostic factors. Expression of p16 was correlated with a low pT stage, adenoma background and good prognosis. Cases with p63 expression showed a higher T stage, more frequent perineural invasion and poor prognosis when compared to cases without p63 expression. Over-expression of p53 or loss of p53 was associated with poor tumor differentiation, frequent distant metastasis and low disease-specific survival rate. The expressions of p21, p27, bcl-2, bcl-6 and cyclin D1 were not significant prognostic factors for gallbladder adenocarcinoma. These results indicate that p16, p63 and p53 can be used as prognostic markers in gallbladder adenocarcinoma; especially p53 and p63 as poor prognostic markers and p16 as a favorable prognostic marker.

Multiple cardiac metastases from a nonfunctioning pancreatic neuroendocrine tumor.

Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms, which most commonly metastasize to the liver. However, intrathoracic metastases from pNETs are encountered infrequently. This report describes a case of nonfunctioning pNET with multiple cardiac metastases. A 56-year-old male presented with a palpable abdominal mass that showed progressive enlargement. Findings on computed tomography (CT) of the abdomen revealed two relatively well-marginated inhomogeneous low-attenuation masses, one in the head of the pancreas and the other in the tail. Multiple enhancing masses in the left pericardium with myocardial involvement were observed on chest CT and transthoracic echocardiography. Needle biopsies were performed on the mass in the tail of the pancreas and the left ventricular apical pericardium; histologic examination by hematoxylin and eosin morphology and immunohistochemical staining showed pNET in both. This is the first report of pNET with multiple cardiac metastases to previously undescribed metastatic sites.

Evaluation of Urine Cytology in Urothelial Carcinoma Patients: A Comparison of CellprepPlus® Liquid-Based Cytology and Conventional Smear.

BACKGROUND: Urine cytology is an important test in the screening of urothlelial neoplasms. The conventional smear (CS) method of testing urine samples has a low sensitivity, approximately 50% result accuracy for detecting urothelial carcinomas, while liquid-based cytology (LBC) has much improved diagnostic accuracy, sensitivity, and specificity. The aim of this study was to compare the morphologic features and diagnostic efficacy of CellprepPlus® LBC with those of CS for urine cytology. METHODS: A total of 713 cases of urine specimens collected from November 2009 to September 2010 were included. All specimens were divided equally for the preparation of CellprepPlus® LBC and CS for each case. RESULTS: CellprepPlus® revealed more cellularity, a cleaner background and better cytomorphologic features, but it showed a less intact architectural pattern compared to that of CS. Of the 88 histologically confirmed cases, the diagnostic sensitivity for CellprepPlus® was 50% and higher than the 37.5% for CS. The specificity of both preparations was 100%. CONCLUSIONS: The CellprepPlus® showed an improved quality of slides and provided better diagnostic accuracy, thus CellprepPlus® could be a first-line screening tool in urinary tract cytology.

EGFR mutation status in primary lung adenocarcinomas and corresponding metastatic lesions: discordance in pleural metastases.

UNLABELLED: We evaluated EGFR and KRAS mutations between 37 paired primary tumors and corresponding metastases in lung adenocarcinoma. A substantial discordance was found in EGFR mutation status between primary tumors and corresponding metastases including pleural metastases. Moreover, the responsiveness to EGFR tyrosine kinase inhibitors tend to be correlated with EGFR mutation status in metastatic lesions than in primary tumors. INTRODUCTION: The aim of this study was to compare epidermal growth factor receptor (EGFR) and KRAS mutations between primary tumors and corresponding metastases including pleural metastases in lung adenocarcinoma. METHODS: Thirty-seven paired primary lung adenocarcinomas and corresponding metastatic tumors were analyzed for EGFR and KRAS mutations. In addition, 21 pleural metastases including malignant pleural effusion or pleural biopsy were used in performing these mutation analyses. RESULTS: EGFR mutations were detected in 18 primary lung adenocarcinomas (48.6%) and in 16 corresponding metastases (43.2%). EGFR mutations showed a discordance rate of 16.2% (6 of 37 patients) between primary lung adenocarcinomas and corresponding metastases. Among 21 pleural metastases, 3 patients (14.3%) showed that the EGFR mutation was discordant. KRAS mutations were detected in one primary tumor and in two metastatic tumors. Eighteen patients were treated with EGFR tyrosine kinase inhibitors. One of seven patients who experienced partial response had EGFR mutations only in the metastasis, and two of seven patients who experienced progressive disease carried wild-type EGFR only in the metastasis. CONCLUSIONS: EGFR mutations were discordant between primary tumors and corresponding metastases in a significant portion of lung adenocarcinomas. Furthermore, these discordance was also observed in metastases to the pleura, the nearest metastatic site.

Characterization of Monoclonal Antibodies against Human Leukocyte Common Antigen (CD45).

BACKGROUND: The leukocyte common antigen (CD45) is a transmembrane-type protein tyrosine phosphatase that has five isoforms. METHODS: We generated seven murine mAbs against human CD45 by injecting cells from different origins, such as human thymocytes, PBMCs, and leukemic cell lines. By using various immunological methods including flow cytometry, immunohistochemistry, and immunoprecipitation, we evaluated the reactivity of those mAbs to CD45 of thymus as well as tonsil lysates. Furthermore, we transiently transfected COS-7 cells with each of gene constructs that express five human CD45 isoforms respectively, and examined the specificities of the mAbs against the transfected isoforms. RESULTS: In case of thymocytes, lymphocytes, and monocytes, all the seven mAbs demonstrated positive reactivities whereas none was reactive to erythrocytes and platelets. The majority of immune cells in formalin-fixed paraffin-embedded thymus and tonsil tissues displayed strong membranous immunoreactivity, and the main antigen was detected near 220 kDa in all cases. Among the mAbs, four mAbs (AP4, DN11, SHL-1, and P6) recognized a region commonly present in all the five isoforms. One mAb, YG27, recognized four isoforms (ABC, AB, BC, and O). Two mAbs, P1 and P14, recognized the isoforms that contain exon A encoded regions (ABC and AB). CONCLUSION: In this study, we confirmed that AP4, DN11, SHL-1, YG27 and P6, are mAbs reactive with the CD45 antigen whereas P1 and P14 are reactive with the CD45RA antigen.