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Chromatin CKAP2, a New Proliferation Marker, as Independent Prognostic Indicator in Breast Cancer  [PDF]
Han-Seong Kim, Jae-Soo Koh, Yong-Bock Choi, Jungsil Ro, Hyun-Kyoung Kim, Mi-Kyung Kim, Byung-Ho Nam, Kyung-Tae Kim, Vishal Chandra, Hye-Sil Seol, Woo-Chul Noh, Eun-Kyu Kim, Joobae Park, Chang-Dae Bae, Kyeong-Man Hong
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098160
Abstract: Background The level of proliferation activity is a strong prognostic or predictive indicator in breast cancer, but its optimal measurement is still in debate, necessitating new proliferation markers. In the present study, the prognostic significance of the CKAP2-positive cell count (CPCC), a new proliferation marker, was evaluated, and the results were compared with those for the mitotic activity index (MAI). Methods This study included 375 early-stage breast cancer samples collected from two institutions between 2000 and 2006. Immunohistochemical staining was performed using a CKAP2 monoclonal antibody. Cox proportional hazard regression models were fitted to determine the association between the CPCC and relapse-free survival (RFS) amongst three groups formed on the basis of the CPCC or MAI value: groups 2 and 3 showing the middle and highest values, respectively, and group 1 the lowest. Results After adjustment for age, T stage, N stage, HER2 status, estrogen receptor status, progesterone receptor status, institution, and year of surgical resection, the CPCC was associated with a significantly worse RFS {hazard ratio [HR] = 4.10 (95% CI: 1.64–10.29) for group 2; HR = 4.35 (95% CI: 2.04–10.35) for group 3}. Moreover, its prognostic significance was similar to or higher than that based on the MAI {HR = 2.05 (95% CI: 0.94–4.65) for group 2; HR = 2.35 (95% CI: 1.09–5.10) for group 3}. In subgroup analyses, the CPCC showed a prognostic significance in the luminal A and triple-negative subgroups, but not in the HER2-positive subgroup. Conclusions Chromatin CKAP2 is an independent prognostic marker for RFS in early-stage breast cancer, and could potentially replace the MAI in clinical evaluation of proliferation activity. Additionally, our study results suggest that the prognostic significance of proliferation activity differs among the various subgroups of breast cancer.
Thrombomodulin phenotype of a distinct monocyte subtype is an independent prognostic marker for disseminated intravascular coagulation
Sang Hwang, Ji-Eun Kim, Kyou-Sup Han, Hyun Kim
Critical Care , 2011, DOI: 10.1186/cc10139
Abstract: In total, 98 patients suspected of having DIC were enrolled. The subtypes of circulating monocytes were identified using CD14 and CD16 and the thrombomodulin and TF expression in each subtype, expressed as mean fluorescence intensity, was measured by flow cytometry. Plasma level of tissue factor was measured by ELISA. In cultures of microbead-selected, CD14-positive peripheral monocytes, lipopolysaccharide (LPS)- or interleukin-10-induced expression profiles were analyzed, using flow cytometry.The proportion of monocyte subtypes did not significantly differ between the overt and non-overt DIC groups. The IM thrombomodulin expression level was prominent in the overt DIC group and was well correlated with other coagulation markers. Of note, IM thrombomodulin expression was found to be an independent prognostic marker in multivariate Cox regression analysis. In addition, in vitro culture of peripheral monocytes showed that LPS stimulation upregulated thrombomodulin expression and TF expression in distinct populations of monocytes.These findings suggest that the IM thrombomodulin phenotype is a potential independent prognostic marker for DIC, and that thrombomodulin-induced upregulation of monocytes is a vestige of the physiological defense mechanism against hypercoagulopathy.Thrombomodulin (TM) is a transmembrane glycoprotein that blocks the interaction between thrombin and procoagulant protein substrates and acts as a vascular endothelial cell receptor for thrombin to activate protein C. Activated protein C inactivates factors Va and VIIIa and inhibits further thrombin generation and thus plays an important role in the anticoagulant state of the endothelium [1]. Tissue factor (TF) is an essential cofactor for the initiation of the extrinsic coagulation pathway. TF complexes with factors VII and VIIa and activates factors IX and X, and these activated factors contribute to the generation of thrombin on cell surfaces [2].Disseminated intravascular coagulation (DIC) is c
Decreased Expression of SATB2: A Novel Independent Prognostic Marker of Worse Outcome in Laryngeal Carcinoma Patients  [PDF]
Tian-Run Liu, Li-Hua Xu, An-Kui Yang, Qian Zhong, Ming Song, Man-Zhi Li, Li-Juan Hu, Fu-Jin Chen, Ze-Dong Hu, Ping Han, Mu-Sheng Zeng
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040704
Abstract: Background To investigate the expression and role of special AT-rich sequence-binding protein-2 (SATB2) in laryngeal squamous cell carcinoma (LSCC) tissue and cell line (HEp2), and to evaluate the clinical and prognostic significance of SATB2 protein in patients with LSCC. Methods The expression of SATB2 was examined in LSCC tissue and HEp2 cells by Western-blotting, Real-time PCR and immunohistochemical staining. Cell growth curve assay and colony formation assay were used to verify the effect of SATB2 on the proliferation and tumor progression ability of HEp2 cells. Tumor formation assay in nude mice was used to analyze the effect of SATB2 on the tumorigenicity of HEp2 cells. Results The status of SATB2 protein in carcinoma tissues is much lower than that in paracarcinoma tissues. The overall survival of the patients with high SATB2 expression was significantly higher than the low SATB2 expression group. Lower or negative SATB2 expression was significantly correlated with advanced clinical staging, histological grade and tumor recurrence. In vitro experiments demonstrated that over-expression of SATB2 in HEp2 cells inhibited cell proliferation and tumor progression ability, and down-regulation of SATB2 showed the opposite effects. Over-expression of SATB2 repressed the tumorigenicity of HEp2 cells by in vivo experiments. Moreover, multivariate analysis suggested that SATB2 expression might be an independent prognostic indicator for the survival of LSCC patients after curative surgery. Conclusions SATB2 might involve in the development and progression of LSCC as a tumor suppressor, and thereby may be a valuable prognostic marker for LSCC patients.
Lymphangiogenesis in Regional Lymph Nodes Is an Independent Prognostic Marker in Rectal Cancer Patients after Neoadjuvant Treatment  [PDF]
Christiane Jakob, Daniela E. Aust, Birgit Liebscher, Gustavo B. Baretton, Kaustubh Datta, Michael H. Muders
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027402
Abstract: One of the major prognostic factors in rectal cancer is lymph node metastasis. The formation of lymph node metastases is dependent on the existence of a premetastatic niche. An important factor preceding metastasis are lymph vessels which are located in the lymph node. Accordingly, the occurrence of intranodal lymphangiogenesis is thought to indicate distant metastasis and worse prognosis. To evaluate the significance of lymph node lymphangiogenesis, we studied formalin fixed, paraffin embedded adenocarcinomas and regional lymph nodes of 203 rectal cancer patients who were treated with neoadjuvant radiochemotherapy and consecutive curative surgery with cancer free surgical margins (R0). Regional lymph node lymph vessels were detected by immunohistochemistry for podoplanin (D2-40). Our results show that the presence of lymphatic vessels in regional lymph nodes significantly affects the disease-free survival in univariate and multivariate analyses. In contrast, there was no correlation between peritumoral or intratumoral lymph vessel density and prognosis. Indeed, our study demonstrates the importance of lymphangiogenesis in regional lymph nodes after neoadjuvant radiochemotherapy and consecutive surgery as an independent prognostic marker. Staining for intranodal lymphangiogenesis and methods of intravital imaging of lymphangiogenesis and lymphatic flow may be a useful strategy to predict long-term outcome in rectal cancer patients. Furthermore, addition of VEGF-blocking agents to standardized neoadjuvant treatment schemes might be indicated in advanced rectal cancer.
FBXW7 Acts as an Independent Prognostic Marker and Inhibits Tumor Growth in Human Osteosarcoma  [PDF]
Zhanchun Li,Jie Xiao,Kongzu Hu,Gang Wang,Maoqiang Li,Jidong Zhang,Guangqi Cheng
International Journal of Molecular Sciences , 2015, DOI: 10.3390/ijms16022294
Abstract: F-box and WD repeat domain-containing 7 (FBXW7) is a potent tumor suppressor in human cancers including breast cancer, colorectal cancer, gastric cancer and hepatocellular carcinoma. In this study, we found that the expressions of FBXW7 protein and mRNA levels in osteosarcoma (OS) cases were significantly lower than those in normal bone tissues. Clinical analysis indicated that FBXW7 was expressed at lower levels in OS patients with advanced clinical stage, high T classification and poor histological differentiation. Furthermore, we demonstrated that high expression of FBXW7 was correlated with a better 5-year survival of OS patients. Multivariate Cox regression analysis indicated that FBXW7 was an independent prognostic marker in OS. Our in vitro studies showed that FBXW7 overexpression inhibited cell cycle transition and cell proliferation, and promoted apoptosis in both U2OS and MG-63 cells. In a nude mouse xenograft model, FBXW7 overexpression slowed down tumor growth by inducing apoptosis and growth arrest. Mechanistically, FBXW7 inversely regulated oncoprotein c-Myc and cyclin E levels in both U2OS and MG-63 cells. Together these findings suggest that FBXW7 may serve as a prognostic biomarker and inhibit tumor progression by inducing apoptosis and growth arrest in OS.
Bax expression measured by AQUAnalysis is an independent prognostic marker in oral squamous cell carcinoma  [cached]
Bose Pinaki,Klimowicz Alexander C,Kornaga Elizabeth,Petrillo Stephanie K
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-332
Abstract: Background Resistance to apoptosis is a hallmark of cancer and proteins regulating apoptosis have been proposed as prognostic markers in several malignancies. However, the prognostic impact of apoptotic markers has not been consistently demonstrated in oral squamous cell carcinoma (OSCC). This inconsistency in reported associations between apoptotic proteins and prognosis can be partly attributed to the intrinsic low resolution and misclassification associated with manual, semi-quantitative methods of biomarker expression measurement. The aim of this study was to examine the association between apoptosis-regulating proteins and clinical outcomes in oral squamous cell carcinoma (OSCC) using the quantitative fluorescence immunohistochemistry (IHC) based AQUAnalysis technique. Methods Sixty-nine OSCC patients diagnosed between 1998–2005 in Calgary, Alberta, Canada were included in the study. Clinical data were obtained from the Alberta Cancer Registry and chart review. Tissue microarrays (TMAs) were assembled from triplicate cores of formalin-fixed paraffin embedded pre-treatment tumour tissue. Bax, Bcl-2 and Bcl-XL protein expression was quantified using fluorescent IHC and AQUA technology in normal oral cavity squamous epithelium (OCSE) and OSCC tumour samples. Survival was analyzed using Kaplan-Meier plots and the Cox proportional hazard model. Results Bax expression was predominantly nuclear in OCSE and almost exclusively cytoplasmic in OSCC. No similar differences in localization were observed for Bcl-2 or Bcl-XL. Only Bax expression associated with disease-specific survival (DSS), with 5-year survival estimates of 85.7% for high Bax versus 50.3% for low Bax (p = 0.006), in univariate analysis. High Bax expression was also significantly associated with elevated Ki67 expression, indicating that increased proliferation might lead to an improved response to radiotherapy in patients with elevated Bax expression. In multivariate analyses, Bax protein expression remained an independent predictor of DSS in OSCC [HR 0.241 (0.078-0.745), p = 0.013]. Conclusions The AQUA technique used in our study eliminates observer bias and provides reliable and reproducible estimates for biomarker expression. AQUA also provides essential measures of quality control that cannot be achieved with manual biomarker scoring techniques. Our results support the use of Bax protein expression as a prognostic marker in conjunction with other clinico-pathological variables when designing personalized treatment strategies for OSCC patients.
Mammaglobin B is an independent prognostic marker in epithelial ovarian cancer and its expression is associated with reduced risk of disease recurrence
Renata A Tassi, Stefano Calza, Antonella Ravaggi, Eliana Bignotti, Franco E Odicino, Germana Tognon, Carla Donzelli, Marcella Falchetti, Elisa Rossi, Paola Todeschini, Chiara Romani, Elisabetta Bandiera, Laura Zanotti, Sergio Pecorelli, Alessandro D Santin
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-253
Abstract: MGB-2 expression was evaluated by quantitative real time-PCR in fresh-frozen tissue biopsies and was validated by immunohistochemistry in matched formalin fixed-paraffin embedded tissue samples derived from a total of 106 EOC patients and 27 controls. MGB-2 expression was then associated with the clinicopathologic features of the tumors and was correlated with clinical outcome.MGB-2 expression was found significantly elevated in EOC compared to normal ovarian controls, both at mRNA and protein level. A good correlation was detected between MGB-2 expression data obtained by the two different techniques. MGB-2 expressing tumors were significantly associated with several clinicopathologic characteristics defining a less aggressive tumor behavior. Univariate survival analysis revealed a decreased risk for cancer-related death, recurrence and disease progression in MGB-2-expressing patients (p < 0.05). Moreover, multivariate analysis indicated that high expression levels of MGB-2 transcript (HR = 0.25, 95%, 0.08–0.75, p = 0.014) as well as positive immunostaining for the protein (HR = 0.41, 95%CI, 0.17–0.99, p = 0.048) had an independent prognostic value for disease-free survival.This is the first report documenting that MGB-2 expression characterizes less aggressive forms of EOC and is correlated with a favorable outcome. These findings suggest that the determination of MGB-2, especially at molecular level, in EOC tissue obtained after primary surgery can provide additional prognostic information about the risk of recurrence.Epithelial ovarian cancer (EOC) accounts for the majority of ovarian malignancies and is estimated to be the third most common malignancy of the female genital tract and the first leading cause of death from gynecological cancer in the US in 2008 [1]. The paucity of disease specific symptoms and the lack of effective clinical markers contribute to the high mortality rate of EOC. Although primary surgical cytoreduction and standard care, based on fir
Transglutaminase 2 as an independent prognostic marker for survival of patients with non-adenocarcinoma subtype of non-small cell lung cancer
Chang-Min Choi, Se-Jin Jang, Seong-Yeol Park, Yong-Bock Choi, Jae-Heon Jeong, Dae-Seok Kim, Hyun-Kyoung Kim, Kang-Seo Park, Byung-Ho Nam, Hyeong-Ryul Kim, Korean Thoracic Oncology Research Group (KTORG), Soo-Youl Kim, Kyeong-Man Hong
Molecular Cancer , 2011, DOI: 10.1186/1476-4598-10-119
Abstract: The significance of TGase 2 expression as an invasive/migratory factor was addressed by in vitro assays employing down-regulation of TGase 2. TGase 2 expression as a prognostic indicator was assessed in 429 Korean patients with early-stage non-small cell lung cancer (NSCLC) by immunohistochemical staining.TGase 2 expression increased the invasive and migratory properties of NSCLC cells in vitro, which might be related to the induction of MMP-9. In the analysis of the immunohistochemical staining, TGase 2 expression in tumors was significantly correlated with recurrence in NSCLC (p = 0.005) or in the non-adenocarcinoma subtype (p = 0.031). Additionally, a multivariate analysis also showed a significant correlation between strong TGase 2 expression and shorter disease-free survival (DFS) in NSCLC (p = 0.029 and HR = 1.554) and in the non-adenocarcinoma subtype (p = 0.030 and HR = 2.184). However, the correlation in the adenocarcinoma subtype was not significant.TGase 2 expression was significantly correlated with recurrence and shorter DFS in NSCLC, especially in the non-adenocarcinoma subtype including squamous cell carcinoma.Lung cancer is the leading cause of cancer-related death, accounting for approximately 29% of all cases (Cancer Stat Fact Sheets, http://www.seer.cancer.gov webcite); approximately 85% of lung cancer cases are non-small cell lung cancer (NSCLC). There are several different subtypes of NSCLC, among which are adenocarcinoma and squamous cell cancer. Currently, the NSCLC subtypes are regarded as a single disease, however, the adenocarcinoma and non-adenocarcinoma subtypes are regarded as being separate entities, owing to their different responses to recently developed agents such as pemetrexed, gefitinib, bevaciuzumab, and crizotinib, which are more effective in adenocarcinoma [1-3]. Accordingly, identification of the molecular differences between these tumor types will have a significant impact on the design of novel therapies that can improve tre
Prognostic Value of Mitotic Index and Bcl2 Expression in Male Breast Cancer  [PDF]
Miangela M. Lacle, Carmen van der Pol, Arjen Witkamp, Elsken van der Wall, Paul J. van Diest
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060138
Abstract: The incidence of male breast cancer (MBC) is rising. Current treatment regimens for MBC are extrapolated from female breast cancer (FBC), based on the assumption that FBC prognostic features and therapeutic targets can be extrapolated to MBC. However, there is yet little evidence that prognostic features that have been developed and established in FBC are applicable to MBC as well. In a recent study on FBC, a combination of mitotic index and Bcl2 expression proved to be of strong prognostic value. Previous papers on Bcl2 expression in MBC were equivocal, and the prognostic value of Bcl2 combined with mitotic index has not been studied in MBC. The aim of the present study was therefore to investigate the prognostic value of Bcl2 in combination with mitotic index in MBC. Immunohistochemical staining for Bcl2 was performed on tissue microarrays of a total of 151 male breast cancer cases. Mitotic index was scored. The prognostic value of Bcl2 expression and Bcl2/mitotic index combinations was evaluated studying their correlations with clinicopathologic features and their prediction of survival. The vast majority of MBC (94%) showed Bcl2 expression, more frequently than previously described for FBC. Bcl2 expression had no significant associations with clinicopathologic features such as tumor size, mitotic count and grade. In univariate survival analysis, Bcl2 had no prognostic value, and showed no additional prognostic value to tumor size and histological grade in Cox regression. In addition, the Bcl2/mitotic index combination as opposed to FBC did not predict survival in MBC. In conclusion, Bcl2 expression is common in MBC, but is not associated with major clinicopathologic features and, in contrast to FBC, does not seem to have prognostic value, also when combined with mitotic index.
Lymphatic vessel invasion detected by the endothelial lymphatic marker D2-40 (podoplanin) is predictive of regional lymph node status and an independent prognostic factor in patients with resected esophageal cancer  [cached]
Miros?aw Koz?owski,Wojciech Naumnik,Jacek Nikliński,Robert Milewski
Folia Histochemica et Cytobiologica , 2011, DOI: 10.5603/4148
Abstract: The discovery of markers to lymphatic endothelial cells and the development of novel antibodies to these markers have brought increasing attention to the lymphatics and progress in the understanding of lymphangiogenesis and cancer metastasis. In this study, we investigate the presence of lymphatic vessel invasion (LVI) detected by D2-40 immunohistochemical staining in resected esophageal cancer and correlated with clinicopathologic data and patient survival. Sixty nine patients, who had a primary resection of esophageal cancer, were analyzed by univariate and multivariate logistic regression, and univariate and multivariate survival analysis. The total rate of LVI was 72% (50/69). Positive LVI was significantly correlated with lymph node metastasis (p < 0.001), tumor size (p < 0.001), histological grading (p = 0.017), tumor depth (p = 0.001), and stage (p < 0.001). Multivariate logistic analysis identified LVI (p = 0.036) as a predictor of regional lymph node metastasis. On univariate survival analysis, patients with LVI had a significantly shorter disease-free survival, cancer-specific survival and overall survival. Multivariate analysis proved that LVI diagnosed by D2-40 is an independent prognostic factor of both disease-free survival (p = 0.04) and overall survival (p = 0.032) in resected esophageal cancer. These results show that LVI assessment identifies patients at high risk for regional lymph node metastasis and that LVI is an independent prognostic factor in patients with esophageal cancer. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 1, pp. 90–97)
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