independent prognostic marker

HCC patients with low DLC1 expression had lower disease-free and 5-year survival rates than those with high DLC1 expression as determined using the Kaplan-Meier method (Fig. 5). Univariate Cox regression analysis also identified that clinical variables including gender, tumor number, maximal tumor size, HBV infection, tumor differ- entiation, TNM stage and portal vein invasion and dissem- ination were all positively correlated with overall survival. Furthermore, to evaluate the potential of DLC1 expression as an independent prognostic marker for overall survival of HCC, multivariate Cox regression analyses were per- formed. While the others failed to demonstrate inde- pendence, DLC1 expression (HR: 2.234, 95 % CI: 0.937–4.148, p < 0.001), tumor differentiation (HR: 3.769, 95 % CI: 1.925–6.989, P = 0.003), and portal vein invasion and dissemination (HR: 1.341,95 % CI: 0.843– 2.631, p < 0.001) may play a role in predicting the over- all survival in HCC (p < 0.05).

This is to certify that the dissertation entitled “SERUM FERRITIN –AN INDEPENDENT PROGNOSTIC MARKER IN PREDICTING EARLY MORTALITY IN ADVANCED LIVER DISEASE” is a bonafide work done by Dr. SHUJAATH ASIF.M at Madras Medical College, Chennai in partial fulfilment of the university rules and regulations for award of D.M., Degree in Medical Gastroenterology (Branch-IV) under my guidance and supervision during the academic year 2011 -2014.

In conclusion, the present study a) confirms in two independent data sets, that KCNJ3 is upregulated in breast carcinomas when compared to normal breast tissue, b) shows that increased KCNJ3 expression is significantly associated with estrogen receptor positive breast cancer subtypes, c) highlights that increased KCNJ3 is an independent prognostic marker conferring worse overall and disease free survival probabilities to estrogen receptor positive breast cancer patients, and d) demonstrates that KCNJ3 upregulation might be involved in conferring higher self-renewal capacity to cancer cells. Future studies are required to elucidate the mechanisms that lead to KCNJ3 upregulation in ER positive breast cancer, to unveil its involvement in invasion and metastasis and to evaluate its potential as drugable target.

Interestingly, IM TM expression was prominent in the overt DIC group and had good correlation with other coagulation markers. Of note, IM TM expression was found to be an independent prognostic marker for DIC, which has been the focus of this study. Other phenoty- pic changes of the monocytes also showed differences between the overt and non-overt DIC, such as the lower TF expression of CMs in the overt DIC group. TF expression of CM was significant in multivariate analy- sis, but the correlations with other coagulation markers were weak and the differences between the survivor/ non-survivor groups were minimal, and this needs to be studied further. When the survivors and non-survivors were compared, the percentage of CM was lower and TM expression on CMs and IMs was higher in the non- survivors. The TM expression on CM was significant in the univariate analysis but was not found to be an inde- pendent prognostic factor. In addition, the TM and TF expressions of DMs were higher than those of the IMs, but the mean differences of the TM and TF expressions of DMs between survivors and non-survivor were not significant and the phenotype of DMs was not found to be significant in multivariate analysis. These findings support the clinical relevance and importance of TM rather than TF expression in IMs.

ZNF331 is frequently methylated in human primary CRC, and methylation of ZNF331 is a poor prognostic marker Methylation of ZNF331 was detected by MSP in primary CRC samples and normal colorectal mucosa. ZNF331 was methylated in 67.1% (98/146) of primary CRC and 0% (0/10) of normal colorectal mucosa (Fig. 2a). Methylation of ZNF331 was significantly associated with tumor size (p < 0.05, Table 2), while no association was found between ZNF331 methylation and gender, age, tumor differenti- ation, lymphatic metastasis, tumor location, and TNM stages (all p > 0.05, Table 2). KRAS and BRAF mutation was detected in 30.15% (41/136) and 2.94% (4/136) of pri- mary CRC. No association was found between ZNF331 methylation and KRAS or BRAF mutations (all p > 0.05, Table 3). CIMP-high was detected in 11.03% (15/136) of primary CRC. The methylation frequency of four markers (RUNX3, CACNA1G, IGF2, and MLH1) is 10.29% (14/ 136), 21.32% (29/136), 25% (34/136), and 15.44% (21/136).

Another related mechanism-based assay used to assess metastasis risk is measurement of TMEM density [9]. TMEM counts performed in a small case control study of 30 pairs of invasive breast cancer patients in which half of them (30) developed distant metastasis, while another 30 patients did not. TMEM counts were signifi- cantly higher in the patient group that developed distant metastasis compared to the patient group that had only localized breast tumor ( P = 0.00006), independent of other clinicopathologic variables [9]. Roughly, the risk of distant metastases doubled as for every 10 TMEMs mea- sured in the area of patient tissue analyzed. Expression of Mena INV , but not Mena 11a, correlates with TMEM density supporting the hypothesis that Mena11a is not Table 1 Clinicopathological characteristics of Yale cohorts

Tumor specimens (2 independent cohorts with a total of 352 HCCs) were randomly collected after curative resection from February 2005 to November 2006 and from January 1999 to December 2003 respectively, in the Liver Cancer Institute, Zhongshan Hospital, Shanghai, China. The patient enrollment criteria and postsurgical patient surveillance were similar to those specified in our previous reports [8]. Simply put, patients who were enrolled into this research, must fulfill the following criteria 1) definitive HCC diagnosis and stage by pathology on the basis of International Union Against Cancer Tumor Node Metastasis Classification System(7th edition); 2) no prior anticancer treatment; 3) surgical resection with cut surface being freed from cancer by histological examination; 4) availability of complete clinicopathologic and follow-up

All statistical analyses were performed using SPSS 19.0. The chi-square test was used to analyze the relationship between the expres- sion of Flot-2 protein and the clinicopathologi- cal characteristics and prognostic factors in OSCC. Kaplan-Meier analysis was performed for overall survival curves and statistical signifi- cance was assessed using the log-rank test. Overall survival was defined as the time from the treatment initiation (diagnosis) to the data of death. To identify whether expression of Flot- 2 protein is an independent prognostic factor of overall survival for OSCC, the multivariate anal- ysis using the Cox proportional hazard regres- sion model was performed. All P values were based on the two-sided statistical analysis and P-value less than 0.05 was considered to be statistically significant.

exceedingly relevant in the clinical practice. The specifi- city and sensitivity of IHC staining for CUBN in cohorts of tumor tissue has provided an example of a novel diag- nostic biomarker for RCC. Although extended studies regarding the expression pattern in additional tumors of relevance for differential diagnostics, e.g. adrenal gland tumors and other forms of clear cell cancer, are required to establish the usefulness of CUBN staining in clinical routine, the presented results indicate that this marker could be used for difficult cases where a diagnosis of RCC needs to be confirmed.

This was the first paper that studied the NAT10 expression in HCC and its correlation with dis- ease prognosis. In summary, the NAT10 protein was frequently over-expressed in HCC, parti- cularly in the nuclei. The elevation of NAT10 expression might contribute to the tumorigen- esis and cancer development. Therefore NAT10 could be a promising marker for the diagnosis and prognosis of HCC. Further researches on other types of tumors are necessary for a more comprehensive understanding of NAT10 in can- cer development.

Zinc finger and BTB domain-containing 20 (ZBTB20) is a new BTB/POZ-domain gene and a member of the POK family of transcriptional repressors. Notably, the role of ZBTB20 and its underlying mechanisms involved in hepatocarcinogenesis are poorly investigated. In this study, the expression of ZBTB20 was significantly overexpressed in hepatocellular carcinoma (HCC) tissues. The positive expression of ZBTB20 was associated with large tumor size, high Edmondson-Steiner grading and advanced tumor-node-metastasis (TNM) tumor stage. Additionally, HCC patients with positive expression of ZBTB20 had a poorer 5-year survival. Multivariate analyses revealed that ZBTB20 overexpression was an independent prognostic factor for HCC. Gain- and loss-of-function experiments demonstrated that ZBTB20 promoted HCC cell viability, proliferation, tumorigenicity, and cell cycle progression. Mechanistically, Cyclin D1 and Cyclin E were increased, while p21 and p27 were decreased by ZBTB20 in HCC cells. FoxO1 was inversely correlated with ZBTB20 protein expression in the same cohort of HCC specimens. We further revealed that FoxO1 was transcriptionally repressed by ZBTB20 in HCC. Moreover, restoration of FoxO1 expression partially abrogated ZBTB20-induced HCC cell proliferation and growth entry in vitro and in vivo. Collectively, these results indicate that ZBTB20 may serve as a prognostic marker and promotes tumor growth of HCC via transcriptionally repressing FoxO1.

Although HMGB1, HMGB2 and HMGB3 are homologous genes in which their amino acid sequence exhibits 80% homology, and both HMGB1 and HMGB2 are potential oncogenes [12], the role of HMGB3 in cancer is still unclear. Until now, limited studies have been done to evaluate the relationship between HMGB3 expression and cancer progression, such as breast [11], gastric [13] and non-small-cell lung cancer (NSCLC) [14]. Although HMGB3 may play an important role in carcinogenesis, there is no report on its role in tumorigenesis and progression of esophageal carcinoma. To explore the exact role of HMGB3 in ESCC, we investigated whether the expression of HMGB3 protein is different between tumor tissues and normal tissues, whether HMGB3 has any role in the development and progression of ESCC, and whether HMGB3 is a prognostic factor in ESCC after curative surgical treatment.

Abstract: Objectives: Peroxiredoxin 4 (Prx 4) is a newly emerging antioxidant protein that has been studied in several human cancers. Recently, it was revealed that Prx 4 is highly expressed in human lung cancer and is needed for the promotion of lung cancer progression in vitro. However, there are no clinical data regarding the association of Prx 4 and prognosis in lung cancer. Materials and methods: The Prx 4 expression state as a prognostic indicator was assessed by immunohistochemical staining in 142 patients with stage II non-small cell lung cancer (NSCLC) who had undergone curative surgery between 2006 and 2010. The association between the degree of Prx 4 expression and several clinicopathologic parameters was then evaluated by statistical analyses. Results: The degree of Prx 4 expression was associated with histology and recurrence in the overall NSCLC patient group, with the proportion of patients with positive Prx 4 expression significantly higher for the adenocarcinoma subtype (39/70, 56%) than the squamous cell carcinoma subtype (23/72, 32%) (P = 0.004). However, when subgroup analyses according to histo- pathology were performed in terms of recurrence, positive Prx 4 expression was significantly correlated with higher recurrence rates (P = 0.003) and shorter disease-free survival (DFS) (P = 0.003, hazard ratio = 3.910) in patients with squamous cell carcinoma. In contrast, no meaningful relationship was observed between the level of Prx 4 ex- pression and DFS in the adenocarcinoma subgroup. Conclusion: Positive Prx 4 expression is significantly correlated with recurrence and shorter DFS in patients with early-stage lung squamous cell carcinoma.

Background: Mucin-1 (MUC1, CD227), more widely known as CA15-3, is an abundantly expressed epithelial cell surface antigen and has evolved to be the most predictive serum tumour marker in breast cancer. PankoMab-GEX ™ , which is currently being evaluated for its therapeutic efficacy in a phase IIb clinical trial, is a glyco-optimized anti-MUC1 antibody specifically recognizing a tumour-associated MUC1 epitope (TA-MUC1). The current study aimed to analyse the immunoreactivity of PankoMabGEX ™ and its correlation with established clinico-pathological variables including 10-year and overall survival in a large cohort of breast cancer patients.

C-terminal binding protein 2 (CtBP2) is a transcriptional co-repressor that promotes cancer cell migration and invasion by inhibiting multiple tumor suppressor genes that contribute to cell mobility and adhesion. In this investigation, we showed thatCtBP2 expression was increased significantly in HCC tissues when compared to matched normal adjacent liver tissues. We also showed that CtBP2 expression is associated with worse HCC patient prognosis after liver resection. CtBP2 over- expression induced epithelial-mesenchymal transition (EMT) in Huh7 cells and, correspondingly, silencing CtBP2 suppressed EMT in MHCC97H cells. ChIP assays revealed that GLI1 increased CtBP2 transcription by directly binding its promoter. Furthermore, interaction of CtBP2 and Snail Family Zinc Finger 1 (SNAI1), both of which were found to be positively regulated by GLI1, was confirmed by Co-IP assay. SNAI1 knockdown revealed that SNAI1 was essential for CtBP2 induction of the EMT phenotype of HCC cells, and CtBP2 knockdown reversed GLI1-SNAI1 driven EMT in Huh7 cells. Finally, in vivo experiments demonstrated that enhanced CtBP2expression promoted HCC xenograft growth and induced EMT. In conclusion, CtBP2 may serve as a prognostic marker for post liver resection HCC and may play a role during GLI1- driven EMT as a transcriptional co-repressor of SNAI1.

Second, we compared different prognostic risk scores from different predictive models by calculating receiver operating characteristic (ROC) curves analysis. In statistics, a curve is a graphical plot that illustrates the performance of a binary classifiersystem as its discrimination threshold is varied. The curve is created by plotting the true positive rate against the false positive rate at various threshold settings. The ROC curve is thus the sensitivity as a function of fall-out. In this study, ROC was used to test the overall prognostic accuracy of TrxR, AFP and other serum biomarkers and results were reported as area under the curve (AUC). To test whether the TrxR levels improves score performance, we considered the nested models with TrxR, AFP and Hs-CRP as compared with those markers only.

to unfavorable outcome according to our alternative clinical endpoints, which represent the four hallmarks (local, local invasive, occult systemic and metastatic) of tumor growth and dissemination in prostate cancer (Figure 3). More than 70% of patients without 12p deletion had either local or local invasive disease while this fraction decreased to 53% in patients with 12p deletion (p < 0.0001, Figure 3a). A separate analysis of low grade (Gleason ≤ 3 + 4 = 7) and high grade (Gleason ≥ 4 + 3 = 7) cancers revealed that the prognostic impact of 12p deletions was particularly strong in low-grade cancers (p = 0.0029) while it largely disappeared in high grade tumors (p = 0.1032, Figure 3b–3c). In a multivariate analysis including the established prognostic predictors pT stage, Gleason grade, nodal

aid recovery or repair of stalled replication forks to enhance survival of tumor cells [11]. Therefore, it can be assumed that alterations in Cdc7/Dbf4 protein activity during tumorigenesis may have important consequences for tumor cell survival, underlining the potential of Cdc7 as an anticancer target. High expression of Cdc7 protein correlates with poor prognosis in patients with diffuse large B-cell lymphoma and is a marker of resistance to DNA-damaging agents in oral squamous cell carcinoma [9, 8]. Preclinical data show that Cdc7 is a novel and promising target for tumor-cell killing, as has been shown with different inhibitors [12–15]. Little is known about the prevalence and significance of Cdc7 in colorectal cancer. To study the potential role of Cdc7 in CRC a tissue microarray containing 1.800 tumor samples with clinical follow-up data was analyzed. Our data suggest that Cdc7 overexpression may point out a small but significant subset of immunohistochemically p53-positive CRC that could benefit from anti-Cdc7 treatment.

prediction and post-treatment monitoring has not been available. 3,4 Traditional detection methods are less reliable for ADC due to anterior lesions associated with ADC that are located in deep side depressions of the transformation region of the cervix, making it dif fi cult to obtain effective specimens. 5,6 Compared to SCC, ADC has usually larger tumor volumes, earlier local invasion and rapid lymph node metastasis. The malignant behavior of ADC is extremely strong, it has the capability of long-distance transmission, is resistant to radiotherapy and systemic chemotherapy and has a particularly poor prognosis. 7,8 In previous literature, there have been many efforts to enhance the clinicopatho- logical assessment of the predictive prognostic factor of ADC, 2,9-11 such as International Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis (LNM), stromal invasion, differentiation and tumor size. However, the above studies mainly focused on postopera- tive predictive prognostic factors, lacking preoperative intervention and assessment. Currently, multiple serum tumor-markers have been described as possible preopera- tive factors for the screening and monitoring of the clinical course of primary gynecological carcinoma. 12 – 14 Earlier studies found that serum carbohydrate antigen 125 (CA125) is an independent prognostic marker for patients with ADC and elevated serum carcinoembryonic antigen (CEA) levels were signi fi cantly associated with the presence of lymph node metastasis in ADC. 15,16 Unfortunately, their roles in early ADC disease have not been de fi ned. In addition, other routinely tested tumor markers, such as squamous cell carcinoma antigen (SCC-Ag), alpha-fetoprotein (AFP), carbohydrate antigen 153 (CA153) and carbohydrate antigen 199 (CA199) have been investigated to correlate with prognosis in human malignancies, 10,17-19 but there is no evidence that they are associated with the prognosis of early stage ADC. Moreover, recent studies con fi rmed that the combination of CEA and CA125 could predict prognosis in gastric cancer, pancreatic cancer and breast cancers, but its utility for early-stage ADC has not been identi fi ed. 20 – 22 Our research aimed to resolve these unanswered questions.

Our study cohort was too small to allow a meaningful multivariate analysis. We thus could not determine whether copeptin is an independent prognostic marker that yields additional information beyond that derivable from other known prognostic factors such as GCS and hematoma volume (both of which are correlated with the copeptin level). These associations were expected since GCS and hematoma volume are strong outcome predic- tors. It has been shown in a larger cohort in patients with ischemic stroke on the other hand that copeptin is a very strong independent prognostic marker (i.e., independent of age, lesion size, glucose, WBC, CRP and clinical sever- ity on admission) for functional outcome and mortality. Thus it is possible that in a larger cohort copeptin might