Multiparameter analysis using cell cycle biomarkers for small-size lung adenocarcinoma: prognostic implications

Cell cycle-related molecules play crucial roles in maintaining genomic stability, and can also serve as biomarkers of cell cycle phase distribution at the same time. In this study, we used multiparameter analysis of various biomarkers to investigate their utility for the evaluation of tumor proliferation activities and the prognosis of patients with small-size lung adenocarcinoma. We performed immunohistochemical analysis using five cell cycle-related biomarkers (MCM7, Ki-67, Geminin, Aurora A and H3S10ph) for 102 surgically resected small-size lung adenocarcinomas. We classified them into three phenotypes based on the dominant cell cycle phase distribution of the tumor cell population, and evaluated whether these phenotypes were associated with clinicopathological factors and survival. Phenotype I (MCM7-negative tumors; n=56) was correlated with high or moderate differentiation and reduced local invasiveness (pleural and lymphovascular invasion) compared with phenotype II (MCM7-, Ki-67- and Geminin-positive tumors; n=23) and phenotype III (MCM7-, Aurora A- and H3S10ph-positive tumors; n=17). Five-year survival rates of phenotypes I, II and III were 89.8, 55.4 and 38.6%, respectively, with a significant difference between them (p<0.01). Multivariate analysis revealed that phenotypes II and III were independent prognostic factors in the 79 patients with stage I lung adenocarcinoma. Multiparameter analysis using cell cycle biomarkers for small-size lung adenocarcinoma provided novel insights into the cell cycle phase distribution of dynamic tumor cell populations in?vivo; it may be possible to evaluate tumor proliferation activities and patient prognosis more precisely if this analytical procedure is used.     

Direct Comparison of 3 PCR Methods in Detecting EGFR Mutations in Patients with Advanced Non-Small-Cell Lung Cancer

BackgroundEpidermal growth factor receptor (EGFR) mutations are predictive of response to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. Several methods have been used to detect EGFR mutations; however, it is not clear which is the most suitable for use in the clinic. In this study, we directly compare the clinical sensitivity and specificity of 3 PCR methods.Patients and MethodsWe compared the 3 PCR methods (mutant-enriched PCR, PNA-LNA PCR, and PCR clamp) in patients with advanced NSCLC. A patient who showed sensitive mutations by at least 1 PCR method was treated with gefitinib. A patient who showed no sensitive mutations was treated with chemotherapy with cytotoxic agents.ResultsFifty patients with advanced NSCLC previously untreated with EGFR-TKIs were enrolled in this trial. Seventeen patients were harboring EGFR mutations, 5 of whom showed discrepancies between the results of different PCR methods. All 5 patients responded to gefitinib. All patients harboring EGFR mutations received gefitinib treatment and 21 of 33 EGFR-mutation-negative patients received chemotherapy with cytotoxic agents. Median progression-free survival of the gefitinib group and the chemotherapy group were 8.2 and 5.9 months, respectively.ConclusionWe considered that all the discrepancies might be false negatives because the patients responded to gefitinib. To clarify the reason for the false negatives of each PCR method, and establish the clinical sensitivity and specificity of each PCR method, a large prospective clinical trial is warranted.     

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.     

Fucosylated haptoglobin is a novel type of cancer biomarker linked to the prognosis after an operation in colorectal cancer

BACKGROUND:

Fucosylation is a crucial oligosaccharide modification in cancer and inflammation. Total cellular proteins of cancer cells and the sera of patients with cancer both show increased fucosylation levels. Certain kinds of fucosylated proteins can be applied as novel cancer biomarkers in glyco‐proteomic analyses. We previously identified fucosylated haptoglobin (Fuc‐Hpt) as a serologic marker for pancreatic cancer, and recently developed a lectin‐antibody enzyme‐linked immunosorbent assay system for quantifying Fuc‐Hpt. In the present study, we investigated the clinical outcome of Fuc‐Hpt levels in patients with colorectal cancer (CRC), and examined the mechanisms underlying Fut‐Hpt production using a murine tumor transplantation model.

METHODS:

The relationship between Fuc‐Hpt levels and clinical parameters was investigated in 77 patients with CRC, all of whom underwent primary resection. Serum Fuc‐Hpt levels were examined in athymic nude mice injected with colon cancer cell lines that lacked fucosylation.

RESULTS:

Fuc‐Hpt levels were significantly associated with overall and relapse‐free survival, distant metastasis, clinical stage, and curability. Multivariate analysis revealed that distant metastasis was an independent factor for increased Fuc‐Hpt levels. The combination of Fuc‐Hpt and CEA might be a better serologic marker to predict prognosis. Fuc‐Hpt levels were higher in mice with direct injection of tumor cells into the spleen than in those injected subcutaneously.

CONCLUSIONS:

Fuc‐Hpt might be a useful marker for the prognosis of CRC. Fuc‐Hpt could be produced by the tissue surrounding tumor cells, which might be the mechanism underlying Fuc‐Hpt elevation associated with distant metastasis. Cancer 2012;118: 3036–43. © 2011 American Cancer Society.     

Collision Tumors of Gastric Adenocarcinoma and Mucosa-associated Lymphoid Tissue Lymphoma

A 65-year-old woman with a history of treatment for splenic marginal zone B-cell lymphoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma underwent esophagogastroduodenoscopy. A reddish elevated lesion was found in the fundus of the stomach. On image-enhanced endoscopy, several findings, such as glandular structures of varying sizes suggesting well-differentiated adenocarcinoma, pruned blood vessels, and dilated blood vessels in deeper mucosa suggesting MALT lymphoma, were observed. The final pathological diagnosis after surgical resection was collision tumors of well-differentiated adenocarcinoma and MALT lymphoma. The features of both tumors could be observed simultaneously with image-enhanced endoscopy.     

A case report of advanced gastric cancer with peritoneal dissemination effectively treated by combination chemotherapy of S-1 and docetaxel

The present patient was a 69-year-old male diagnosed as gastric cancer with peritoneal dissemination by staging laparoscopy. He was treated with chemotherapy using S-1 (120 mg/body/day) and docetaxel (70 mg/body/day 1) administered for 2 weeks, followed by one drug-free week in three-week courses. After 4 courses of treatment, the primary tumor regressed, but only slightly. Because of an adverse event, we continued with a lower dose. After 4 more courses of treatment, the primary tumor and dissemination were undetectable on abdominal CT scan but were endoscopically detected. The patient has been followed on an outpatient basis without surgical treatment for 2 years.