Prognostic Indicator For Overall Survival Research Articles

RBMS3 is a tumor suppressor gene that acts as a favorable prognostic marker in lung squamous cell carcinoma.

Recent research indicates that RBMS3 may act as a tumor suppressor gene (TSG) in nasopharyngeal carcinoma (NPC) and esophageal squamous cell carcinoma (ESCC). It has been reported that RBMS3 directly binds to the promoter region of c-Myc in ESCC and that β-catenin from both whole cell extracts and nuclear fractionation was significantly downregulated in RBMS3-transfected NPC cells compared to control cells. The aim of this study was to evaluate the clinical significance of the RBMS3 gene expression in relation to the expression of Wnt pathway components in patients with lung squamous cell carcinoma (LSCC). RBMS3, c-Myc and cytoplasmic β-catenin were detected in 39.76, 56.63 and 89.16% of 83 LSCC samples by immunohistochemistry, respectively, in 83 primary LSCC samples. Semiquantitative reverse transcriptase-polymerase chain reaction and Western blotting demonstrated decreased RBMS3 mRNA and expression in 33.33% (10/30) and 36.67% (11/30) tumor tissues, respectively. Statistical correlation analysis showed RBMS3 to be negatively correlated with c-Myc (r=-0.384, p<0.001) and not correlated with cytoplasmic β-catenin in the LSCC samples. Multivariate Cox proportional hazards model analysis showed that the combined marker RBMS3/c-Myc was an independent prognostic indicator of overall survival (p=0.001; HR 3.470; IC 95%, 1.652-7.290), and c-Myc was a prognostic indicator of disease-free survival (p<0.001; HR 3.182; IC 95%, 1.961-8.920). RBMS3 is a novel TSG in LSCC, and its downregulation facilitates development and progression of LSCC. Therefore, it is suggested that Rbms3 as a tumor marker may play an important role in diagnosis of LSCC.

MiR-185-3p and miR-324-3p Predict Radiosensitivity of Nasopharyngeal Carcinoma and Modulate Cancer Cell Growth and Apoptosis by Targeting SMAD7.

BackgroundMiR-185-3p and miR-324-3p are 2 miRNAs that regulate nasopharyngeal carcinoma (NPC) radioresistance. This study tried to assess the clinical values of low miR-185-3p and low miR-324-3p expression in predicting response to radiotherapy (RT) and prognosis of NPC and to explore their new downstream targets.Material/MethodsWe recruited 80 patients with primary NPC. MiR-185-3p and miR-324-3p expression in the tumor tissues before and after RT or chemoradiotherapy (CRT) were determined. Overall survival and recurrence-free survival curves were estimated to assess the prognostic values of these 2 miRNAs. Their target was predicted using an online database and verified using dual luciferase assay, qRT-PCR, and Western blot analysis. In addition, the function of miR-185-3p/miR-324-3p-SMAD7 axis in NPC cells was investigated.ResultsThe expression of miR-185-3p and miR-324-3p was significantly reduced after RT in radioresistant but not in radiosensitive cases. Although miR-185-3p and miR-324-3p are not independent prognostic indicators of overall survival of NPC, their low expression is still associated with poor overall survival and recurrence-free survival. In addition, miR-185-3p and miR-324-3p can modulate growth and apoptosis of NPC cells, partly via SMAD7.ConclusionsCombined low miR-185-3p and miR-324-3p might be important markers for prediction of low response to RT/CRT and poor overall survival and recurrence-free survival. MiR-185-3p and miR-324-3p can modulate NPC cell growth and apoptosis, at least partly through targeting SMAD7.

Low RASSF6 expression in pancreatic ductal adenocarcinoma is associated with poor survival.

To analyze RASSF6 expression in pancreatic ductal adenocarcinoma (PDAC) and to determine whether RASSF6 has an independent prognostic value in PDAC. We studied RASSF6 expression in 96 histologically confirmed PDAC samples and 20 chronic pancreatitis specimens using immunohistochemistry and real-time quantitative reverse transcription-PCR. PDAC issues were then classified as RASSF6 strongly positive, weakly positive or negative. RASSF6 mRNA and protein expression in PDAC samples with strong positive staining was further evaluated using real-time PCR and Western blot analysis. Lastly, correlations between RASSF6 staining and patients' clinicopathological variables and outcomes were assessed. RASSF6 was negatively expressed in 51 (53.1%) PDAC samples, weakly positively expressed in 29 (30.2%) and strongly positively expressed in 16 (16.7%), while its expression was much higher in para-tumor tissues and chronic pancreatitis tissues. Positive relationships between RASSF6 expression and T-stage (P = 0.047) and perineural invasion (P = 0.026) were observed. The median survival time of strongly and weakly positive and negative RASSF6 staining groups was 33 mo, 15 mo and 11 mo, respectively. Cox multivariate analysis indicated that RASSF6 was an independent prognostic indicator of overall survival in patients with PDAC. A survival curve analysis revealed that increased RASSF6 expression was correlated with better overall survival (P = 0.009). RASSF6 expression is an independent biomarker of an unfavorable prognosis in patients with PDAC.

Annexin A2 plays a critical role in epithelial ovarian cancer.

This study aimed at investigating the potential role and prognostic significance of Annexin A2 in human epithelial ovarian cancer (EOC). Western blot was used to evaluate the expression of Annexin A2 in nine fresh EOC tissues, and immunohistochemical analysis was performed on formalin-fixed paraffin-embedded sections of 119 cases of ovarian cancers. Then, we used Fisher exact test to analyze the correlation between Annexin A2 and clinicopathological parameters. Starvation refeeding was used to detect the alteration of Annexin A2 in HO8910 cell cycle. Annexin A2 was overexpressed in carcinoma tissues compared with normal tissue, and the expression levels gradually increased from G1 to G3. Moreover, the staining of tissue microarray was consistent with the result we got from western blot, increasing from G1 to G3 gradually, and it was related to the Figo stage (P = 0.005), histologic grade (P = 0.002), ascite (P < 0.001), malignant tumor cells (P < 0.001), residual tumor size (P = 0.044), Ki-67 (P = 0.003). Kaplan-Meier analysis revealed that high Annexin A2 expression was significantly associated with poor prognoses of the patients (P < 0.001). Multivariate analysis demonstrated that Annexin A2 was an independent prognostic indicator for overall survival. Starvation refeeding indicated that Annexin A2 was related to EOC cell proliferation. We could hypothesize that Annexin A2 acted a critical role in EOC cell proliferation, and may be used as a potential and novel therapeutic target for EOC. These data suggest that Annexin A2 may promote the progression of EOC and be a therapeutic target for EOC therapy.

Extranodal NK T Lymphoma, Nasal Cell Type: A Retrospective Analysis of 25 Patients from an Academic Center

Background:Extranodal natural killer T (NK/T) -cell lymphoma, nasal-type, is a recognized entity within the WHO classification of lymphoid tumors. This neoplasm is a rare, and is well documented in East Asia. It is not commonly seen in the United States; however the overall prevalence and incidence of this lymphoma has started to increase. Due to its rare prevalence in the United States, a standardized chemotherapy regimen and a prognostic model have yet to be established in patients diagnosed with this lymphoma.Methods:In this retrospective study, we reviewed a total of 25 patients with a diagnosis of extranodal NK T cell lymphomas nasal type. Several variables were assessed including international prognostic index (IPI), performance status, regional lymph node involvement, bone marrow involvement, and proliferation index (high proliferation index defined as Ki67/MIB expression in > 50% cells). We assessed the clinical outcome using various treatment modalities over the last 2 decades.ResultsThe majority of the patients in this study were males 20 (80%). The median age of patients was 46 (20-72), and most patients were Hispanic (80%). Ann Arbor staging was performed and was noted as follows: stage I (12), stage II (5), stage III (3), and stage IV (5). Patient were risk stratified into IPI score and ECOG PS score: IPI score < 2 (17), IPI > 2 (8), ECOG < 2 (19) and ECOG >2 (6). Nine patients were treated with RCHOP + radiation (XRT) and 10 patients were treated with hyper CVAD therapy + XRT. Seven patients were treated with a non-anthracycline based approach: VIPD+ XRT (2), DEVIC + XRT (3), and SMILE+ XRT (2).The five year overall survival of this group was 38.4%. An IPI score > 2 was noted to have significant poor prognosis with a median survival of 15 months in comparison to 22 months (p< 0.001) for IPI < 2. Bulky cervical lymphadenopathy and bone marrow involvement at diagnosis were poor prognostic indicators of overall survival. Patients who presented with bulky cervical lymphadenopathy or evidence of bone marrow involvement at diagnosis were noted to have a median survival time of 12 months, as compared to no involvement had a median survival of 22 months ( p<0.001). A high proliferation index was also associated with a poor prognosis as well. Patients who were noted to have a high proliferation index had a median survival of 15 months as compared to 22 months in patients who were noted to have a low proliferation index (p< 0.001).Median survival in patients treated with RCHOP + XRT was noted be 12 months in comparison to patients with HYPER-CVAD+ XRT (24 months) and non-anthracycline approach (28 months) (p< 0.001). In addition, patients treated with RCHOP +XRT were noted to have increased incidence of disease progression comparison to patients treated with HYPERCVAD+ XRT and non-anthracycline based therapy +XRT (p< 0.0001) (Figure 1).Conclusions:In this retrospective analysis, we demonstrated that extra-nodal NK T cell, nasal type has a poor prognosis. Preliminary data from this study suggests hyperCVAD or a non-anthracycline based chemotherapy approach with concomitant radiation are superior to RCHOP with concomitant radiation. The results of this study also provided promising results for a prognostic model against this lymphoma in the future. These results underscore the need for further investigation for this lymphoma in the future. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Nutritional considerations in pediatric liver disease.

Within the last 60 years, pediatric hepatology has seen many advances in improvement in timely diagnosis and management of chronic liver disease and also in liver transplantation. Growth failure and malnutrition have always been important factors in the treatment of children with liver disease, specifically cholestatic liver diseases. The liver has a central function in nutrient metabolism, and the abnormalities seen in chronic liver disease result in nutritional and metabolic deficiencies. Nutritional needs are dependent on the type of liver disease, age of the patient, and whether the disease is acute or chronic. In the setting of acute liver disease, such as acute viral hepatitis, malnutrition is unusual; however, in fulminant liver failure, nutritional modifications are needed to manage hepatic encephalopathy. Chronic liver disease may be cholestatic or noncholestatic and in most instances is associated with malnutrition. Cholestatic injury to the liver reflects a diverse group of diseases, resulting from biliary obstruction, disorders of bile synthesis or transport, metabolic and endocrine disorders, infections, and toxic effects. The most common is biliary atresia, occurring in approximately 1 of 10,000 live births; it is the most common indication for liver transplantation in children. Patients have relatively progressive hepatic disease and, often, poor nutritional status, making preoperative management of malnutrition a challenge. Malnutrition is a negative prognostic indicator of overall survival, and the inability to improve nutritional status before surgery increases the risk of postoperative complications and mortality. Adequate nutrition allows for growth, improved immunologic status, and improved transplantation outcomes. Nutritional status in the setting of liver disease can be difficult to assess.Weight alone is not a sufficient marker for nutritional status, especially if the patient has ascites or organomegaly: fluid retention and a disproportionately large organ may result in substantial weight gain, whereas the overall nutritional status is actually poor. The ascites and organomegaly, as well as portal hypertension, can also contribute to poor oral tolerance, furthering the failure to gain appropriate weight for age and preventing the often needed catch-up weight gain. Although serial abdominal circumference measurement may aid in determining whether weight gain is secondary to ascites, it is an imprecise way of differentiating true weight gain from fluid gain. More accurate measures include triceps skinfolds and middle upper arm circumferencemeasurements, with standards for age available from the World Health Organization. These measurements, however, require calipers and training in proper technique. Peripheral edema is a potential cause of overestimation of both measures and if present needs to be considered. Both the child’s age and the specific disease affecting the liver contribute to the issues of nutrition and growth facing each patient. Assessment and support are key components of effective care, which is best performed by a team of physicians AUTHOR DISCLOSURE Drs Cameron and Kogan-Liberman have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

High levels of hepatitis B surface antigen are associated with poorer survival and early recurrence of hepatocellular carcinoma in patients with low hepatitis B viral loads.

Recurrence is a disastrous outcome in patients with hepatitis-related hepatocellular carcinoma (HCC) who have undergone curative resection, and little is known about whether high levels of hepatitis B surface antigen (HBsAg) increase the risk of HCC recurrence. This retrospective study included 1,360 HBsAg-positive postoperative HCC patients with hepatitis B viral (HBV) DNA levels < 2000 IU/mL, including 298 patients in a training cohort and 1,062 patients in a validation cohort. The prognostic value of the HBsAg level was evaluated using Cox regression and Kaplan-Meier analyses. We demonstrated that 1,000 IU/mL, but not 10 or 100 IU/mL, was a meaningful cutoff level for significantly discriminating these patients into an HBsAg(Low) group and an HBsAg(High) group based on correlations between the HBsAg level and liver cirrhosis (p = 0.028), tumor size (p = 0.039), and hepatitis B e antigen level (p < 0.001). The postoperative 1-, 3-, and 5-year overall survival (OS) rates of HCC patients in the HBsAg(Low) group were significantly higher than those of HCC patients in the HBsAg(High) group. Accordingly, the 5-year recurrence-free survival (RFS) rates of patients in the HBsAg(Low) group were markedly higher than those of HCC patients in the HBsAg(High) group. The HBsAg level was a prognostic indicator for OS (p = 0.014) and RFS (p = 0.01). HBsAg level is correlated with more aggressive tumor behavior and serves as a prognostic indicator in patients with surgically resected HCC with low HBV load.

Abstract 1956: The basic helix-loop-helix (bHLH) transcriptional factor ATOH8 promotes the stemness of breast cancer cells via Oct4 and Nanog

Abstract Breast cancer is the leading cause of cancer mortality in women with a high incidence of recurrence and eventual treatment failure. The last decade has yielded substantial evidence that cancer stem cells (CSCs) contribute to tumor relapse, metastasis and chemoresistance. CSCs are regulated by complex interactions with the components of the tumor microenvironment through networks of cytokines and growth factors, including the IL6-STAT3 signaling pathway. Although the IL6 signaling pathway has been extensively characterized, the network of effector genes and proteins that regulates the CSC population remains poorly understood. Here, we show that ATOH8 is a downstream effector of IL6-STAT3 signaling which promotes the stemness of breast cancer cells. ATOH8 is significantly increased after IL6 stimulation and can be directly regulated by STAT3. Ectopic expression of ATOH8 in 4T1 or T-47D cells is sufficient to increases the CSC sub-population and enhances tumorogenesis in mice. Mechanistically, ATOH8 promotes the expression of Oct3/4 and Nanog, key regulators of CSC renewed. Accordingly, Knock-down of ATOH8 in EMT6 or MDA-MB-231 cells is associated with decreased expression of Oct3/4 and Nanog and reduces the CSC sub-population. In patients, ATOH8 expression is a negative prognostic indicator for overall survival. Together, the results identify ATOH8 as a downstream effector of IL6-STAT3 signaling that compromises long-term surviving in breast cancer. Citation Format: Antao Chang, Yanan Chen, Wenzhi Shen, Ruifang Gao, Wei Zhou, Yunping Luo, Na Luo, Dwayne Stupack, Rong Xiang. The basic helix-loop-helix (bHLH) transcriptional factor ATOH8 promotes the stemness of breast cancer cells via Oct4 and Nanog. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1956. doi:10.1158/1538-7445.AM2014-1956

Comparative diagnostic and prognostic performances of the hematoxylin-eosin and phospho-histone H3 mitotic count and Ki-67 index in adrenocortical carcinoma

Mitotic count on hematoxylin and eosin slides is a fundamental morphological criterion in the diagnosis and grading of adrenocortical carcinoma in any scoring system employed. Moreover, it is the unique term strongly associated with patient's prognosis. Phospho-histone H3 is a mitosis-specific antibody, which was already proven to facilitate mitotic count in melanoma and other tumors. Therefore, a study was designed to assess the diagnostic and prognostic role of phospho-histone H3 in 52 adrenocortical carcinomas, comparing manual and computerized count to standard manual hematoxylin- and eosin-based method and Ki-67 index. Manual hematoxylin and eosin and phospho-histone H3 mitotic counts were highly correlated (r=0.9077, P<0.0001), better than computer-assisted phospho-histone H3 evaluations, and had an excellent inter-observer reproducibility at Bland-Altman analysis. Three of 15 cases having <5 mitotic figures per 50 high-power fields by standard count on hematoxylin and eosin gained the mitotic figure point of Weiss Score after a manual count on phospho-histone H3 slides. Traditional mitotic count confirmed to be a strong predictor of overall survival (P=0.0043), better than phospho-histone H3-based evaluation (P=0.051), but not as strong as the Ki-67 index (P<0.0001). The latter further segregated adrenocortical carcinomas into three prognostic groups, stratifying cases by low (<20%), intermediate (20–50%), and high (>50%) Ki-67 values. We conclude that (a) phospho-histone H3 staining is a useful diagnostic complementary tool to standard hematoxylin and eosin mitotic count, enabling optimal mitotic figure evaluation (including atypical mitotic figures) even in adrenocortical carcinomas with a low mitotic index and with a very high reproducibility; (b) Ki-67 proved to be the best prognostic indicator of overall survival, being superior to the mitotic index, irrespective of the method (standard on hematoxylin and eosin or phospho-histone H3-based) used to count mitotic figures.

Predicting survival in malignant pleural effusion: development and validation of the LENT prognostic score

BackgroundMalignant pleural effusion (MPE) causes debilitating breathlessness and predicting survival is challenging. This study aimed to obtain contemporary data on survival by underlying tumour type in patients with MPE, identify...

Combined expression of S100A4 and Annexin A2 predicts disease progression and overall survival in patients with urothelial carcinoma

ObjectivesTo determine the expression patterns and prognostic value of S100A4 and Annexin A2 for urothelial carcinoma of the urinary bladder. Methods and materialsImmunohistochemical staining for S100A4 and Annexin A2 was performed in 315 archived radical cystectomies and 63 normal specimens. The immunoreactivity of these proteins was correlated to evaluate their clinical significance as prognostic factors. ResultsProtein levels of S100A4 and Annexin A2 were up-regulated in urothelial carcinoma compared with adjacent nontumor tissues. The increased expressions of S100A4 and Annexin A2 were associated with invasion depth, lymph node metastasis, and distant metastasis (P<0.05). High expression of S100A4 correlated with expression of Annexin A2. These alterations in expression were also associated with greater risk of disease progression and decreased chance of carcinoma-specific survival. Further multivariate analysis suggested that expressions of S100A4 and Annexin A2 were independent prognostic indicators for overall survival in urothelial carcinoma. The patients with S100A4-positive/Annexin A2-positive carcinomas presented the lowest 5-year survival rate compared with the other 3 groups. ConclusionsS100A4 and Annexin A2 proteins could be useful prognostic markers to predict tumor progression and prognosis in urothelial carcinoma. The expression patterns of S100A4/Annexin A2 interaction correlated well with the pathologic stage, disease progression, and carcinoma-specific survival. This finding could aid in identifying more biologically aggressive carcinomas and thus patients who might benefit from more intensive adjuvant therapy.

Metastasis-Associated in Colon Cancer 1 Is a Novel Survival-Related Biomarker for Human Patients with Renal Pelvis Carcinoma

Metastasis-associated in colon cancer 1 (MACC1) has recently been identified as a novel independent prognostic indicator for metastasis occurrence, overall survival and cancer-free survival for patients with colon cancer and other solid tumors. In this study, we investigated the role of MACC1 in the development and progression of renal pelvis carcinoma, a form of upper tract urothelial carcinomas. MACC1 protein has been found in the cytoplasm as well as in the nucleus of the transitional epithelial cells of the normal renal pelvis in immunohistochemical (IHC) assays. Quantitative IHC examinations revealed that MACC1 abnormal abundance in cancerous tissues might represent a biological indicator clinically suggestive of tumor malignancy in the renal pelvis. Furthermore, investigation of the association of MACC1 protein levels with clinicopathological parameters in this study has suggested a correlation of MACC1 expression with tumor-node-metastasis stage and histopathological grade of patients with renal pelvis carcinoma, with elevated MACC1 protein levels frequently associated with higher aggressiveness of the disease. Moreover, both disease-free survival and overall survival for the patients in the high MACC1 expression group were significantly lower than those in the low expression group. Multivariate analysis with a Cox proportional-hazards model suggested that MACC1 is indeed an independent prognostic indicator of overall survival and cancer-free survival for patients with renal pelvis carcinoma. Thus, MACC1 may represent a promising prognostic biomarker candidate, as well as a potential therapeutic target for this disease.

Monitoring changes in circulating tumour cells as a prognostic indicator of overall survival and treatment response in patients with metastatic melanoma

BackgroundNew effective treatments for metastatic melanoma greatly improve survival in a proportion of patients. However biomarkers to identify patients that are more likely to benefit from a particular treatment are needed. We previously reported on a multimarker approach for the detection of heterogenous melanoma circulating tumour cells (CTCs). Here we evaluated the prognostic value of this multimarker quantification of CTCs and investigated whether changes in CTC levels during therapy can be used as a biomarker of treatment response and survival outcomes.MethodsCTCs were captured by targeting the melanoma associated markers MCSP and MCAM as well as the melanoma stem cell markers ABCB5 and CD271. CTCs were quantified in 27 metastatic melanoma patients treated by surgery or with vemurafenib, ipilimumab or dacarbazine. Patients were enrolled prospectively and CTC counts performed at baseline (prior to treatment), during and after treatment.ResultsBaseline CTC numbers were not found to be prognostic of overall survival nor of progression free survival. However, a low baseline CTC number was associated with a rapid response to vemurafenib therapy. A decrease in CTCs after treatment initiation was associated with response to treatment and prolonged overall survival in vemurafenib treated patients.ConclusionsMeasuring changes in CTC numbers during treatment is useful for monitoring therapy response in melanoma patients and for providing prognostic information relating to overall survival. Further studies with larger sample sizes are required to confirm the utility of CTC quantification as a companion diagnostic for metastatic melanoma treatment.

Overexpression of Dickkopf-1 predicts poor prognosis for patients with hepatocellular carcinoma after orthotopic liver transplantation by promoting cancer metastasis and recurrence.

Our previous data had shown that Dickkopf-1 (DKK1) combined with β-catenin was a novel prognostic predictor for hepatocellular carcinoma (HCC) patients. However, the role and mechanism of DKK1 in HCC recurrence or metastasis remain poorly understand. This study was to assess the role of DKK1 in tumor metastasis for patients with hepatocellular carcinoma after orthotopic liver transplantation (OLT). The expression of DKK1 protein was detected in hepatic cell lines, HCC cell lines, and HCC patients after OLT with different potential of metastasis. After DKK1 expression in the HCCLM3 cells was downregulated by siRNA-mediated approach, the role of DKK1 in cell invasion and metastasis was investigated. cDNA genechip was used to analyze the differential expressed genes related with DKK1 in two pairs of HCC cells. The prognostic significance of DKK1 was further assessed by Kaplan-Meier and Cox regression analyses in 148 HCC patients after OLT. The expression of DKK1 protein was higher in the high-invasive HCC cells and HCC patients of the disease recurrence group. With the downregulation of DKK1, HCCLM3 cells showed decreased aggressiveness in vitro and lower metastatic ability in vivo. DKK1 could regulate many genes involved in biological processes and pathways related with tumor progression. Furthermore, DKK1 overexpression correlated with tumor microvessel density in clinical HCC samples. Multivariate analysis revealed that DKK1 was an independent prognostic indicator for overall survival and cumulative recurrence in this cohort of HCC patients post-OLT. Collectively, overexpression of DKK1 was implicated in invasion/metastasis of HCC after OLT and DKK1 overexpression may be potential molecular therapeutic targets for liver cancer.

8:09 AM; Abstract No. 222 - Prognostic indicators of overall survival after resin-based Yttrium-90 radioembolization (Y90) therapy in patients who failed chemotherapy for metastatic colorectal cancer to liver

8:09 AM; Abstract No. 222 - Prognostic indicators of overall survival after resin-based Yttrium-90 radioembolization (Y90) therapy in patients who failed chemotherapy for metastatic colorectal cancer to liver

Gankyrin promotes tumor growth and metastasis through activation of IL-6/STAT3 signaling in human cholangiocarcinoma

Although gankyrin is involved in the tumorigenicity and metastasis of some malignancies, the role of gankyrin in cholangiocarcinoma (CCA) is unclear. In this study we investigated the expression of gankyrin in human CCA tissues and cell lines. The effects of gankyrin on CCA tumor growth and metastasis were determined both in vivo and in vitro. The results showed that gankyrin was overexpressed in CCA tissues and cell lines. Gankyrin expression was associated with CCA histological differentiation, TNM stage, and metastasis. The multivariate Cox analysis revealed that gankyrin was an independent prognostic indicator for overall survival. Gankyrin overexpression promoted CCA cell proliferation, migration, and invasion, while gankyrin knockdown inhibited CCA tumor growth, metastasis, and induced Rb-dependent senescence and G1 phase cell cycle arrest. Gankyrin increased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and promoted the nuclear translocation of p-STAT3. Suppression of STAT3 signaling by small interfering RNA (siRNA) or STAT3 inhibitor interfered with gankyrin-mediated carcinogenesis and metastasis, while interleukin (IL)-6, a known upstream activator of STAT3, could restore the proliferation and migration of gankyrin-silenced CCA cells. The IL-6 level was decreased by gankyrin knockdown, while increased by gankyrin overexpression. Gankyrin regulated IL-6 expression by way of facilitating the phosphorylation of Rb; meanwhile, rIL-6 treatment increased the expression of gankyrin, suggesting that IL-6 was regulated by a positive feedback loop involving gankyrin in CCA. In the xenograft experiments, gankyrin overexpression accelerated tumor formation and increased tumor weight, whereas gankyrin knockdown showed the opposite effects. The in vivo spontaneous metastasis assay revealed that gankyrin promoted CCA metastasis through IL-6/STAT3 signaling pathway. Gankyrin is crucial for CCA carcinogenesis and metastasis by activating IL-6/STAT3 signaling pathway through down-regulating Rb protein.

Tumor Infiltrating PD1-Positive Lymphocytes and the Expression of PD-L1 Predict Poor Prognosis of Soft Tissue Sarcomas

Recently, the possibility of PD1 pathway-targeted therapy has been extensively studied in various human malignant tumors. However, no previous study has investigated their potential application for soft-tissue sarcomas (STS). In this study, we evaluated the clinical impact of intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression in tumor cells in 105 cases of STS. Intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression were seen in 65% and 58% of STS, respectively. Both PD1-positivity and PD-L1 expression were significantly associated with advanced clinicopathological parameters such as higher clinical stage, presence of distant metastasis, higher histological grade, poor differentiation of tumor, and tumor necrosis. Moreover, both PD1-positivity and PD-L1 positivity were independent prognostic indicators of overall survival (OS) and event-free survival (EFS) of STS by multivariate analysis. In addition, the combined pattern of PD1- and PD-L1-positivity was also an independent prognostic indicator for OS and EFS by multivariate analysis. The patents with a PD1+/PD-L1+ pattern had the shortest survival time. In conclusion, this study is the first to demonstrate that the infiltration of PD1 positive lymphocytes and PD-L1 expression in STS cells could be used as novel prognostic indicators for STS. Moreover, the evaluation of PD1- and PD-L1-positivity in STS is also available as possible criteria for selection of patients suitable for PD1-based immunotherapy.

Epigenetic Inactivation of Heparan Sulfate (Glucosamine) 3-O-Sulfotransferase 2 in Lung Cancer and Its Role in Tumorigenesis

BackgroundThis study was aimed at investigating the functional significance of heparan sulfate (glucosamine) 3-O-sulfotransferase 2 (HS3ST2) hypermethylation in non-small cell lung cancer (NSCLC).Methodology/ Principal Findings HS3ST2 hypermethylation was characterized in six lung cancer cell lines, and its clinical significance was analyzed using 298 formalin-fixed paraffin-embedded tissues and 26 fresh-frozen tissues from 324 NSCLC patients. MS-HRM (methylation-specific high-resolution melting) and EpiTYPERTM assays showed substantial hypermethylation of CpG island at the promoter region of HS3ST2 in six lung cancer cell lines. The silenced gene was demethylated and re-expressed by treatment with 5-aza-2′-deoxycytidine (5-Aza-dC). A promoter assay also showed the core promoter activity of HS3ST2 was regulated by methylation. Exogenous expression of HS3ST2 in lung cancer cells H460 and H23 inhibited cell migration, invasion, cell proliferation and whereas knockdown of HS3ST2 in NHBE cells induced cell migration, invasion, and cell proliferation in vitro. A negative correlation was observed between mRNA and methylation levels of HS3ST2 in 26 fresh-frozen tumors tissues (ρ = -0.51, P = 0.009; Spearman’s rank correlation). HS3ST2 hypermethylation was found in 95 (32%) of 298 primary NSCLCs. Patients with HS3ST2 hypermethylation in 193 node-negative stage I-II NSCLCs with a median follow-up period of 5.8 years had poor overall survival (hazard ratio = 2.12, 95% confidence interval = 1.25–3.58, P = 0.005) compared to those without HS3ST2 hypermethylation, after adjusting for age, sex, tumor size, adjuvant therapy, recurrence, and differentiation.Conclusions/ SignificanceThe present study suggests that HS3ST2 hypermethylation may be an independent prognostic indicator for overall survival in node-negative stage I-II NSCLC.

Expression of nerve growth factor and heme oxygenase-1 predict poor survival of breast carcinoma patients

BackgroundNerve growth factor (NGF) is a neurotrophin and has been suggested to induce heme oxygenase-1 (HO1) expression. Although the role of HO1 in tumorigenesis remains controversial, recent evidence suggests NGF and HO1 as tumor-progressing factors. However, the correlative role of NGF and HO1 and their prognostic impact in breast carcinoma is unknown.MethodsWe investigated the expression and prognostic significance of the expression of NGF and HO1 in 145 cases of breast carcinoma.ResultsImmunohistochemical expression of NGF and HO1 was observed in 31% and 49% of breast carcinoma, respectively. The expression of NGF and HO1 significantly associated with each other, and both have a significant association with histologic grade, HER2 expression, and latent distant metastasis. The expression of NGF and HO1 predicted shorter overall survival of breast carcinoma by univariate and multivariate analysis. NGF expression was an independent prognostic indicator for relapse-free survival by multivariate analysis. The combined expression pattern of NGF and HO1 was also an independent prognostic indicator of overall survival and relapse-free survival. The patients with tumors expressing NGF had the shortest survival and the patients with tumor, which did not express NGF or HO1 showed the longest survival time.ConclusionsThis study has demonstrated that individual expression of NGF or HO1, and the combined NGF/HO1 expression pattern could be prognostic indicators for breast carcinoma patients.

Sorafenib for Egyptian patients with advanced hepatocellular carcinoma; single center experience

BackgroundAccording to the results of a number of phase 3 randomized studies, sorafenib is the only approved systemic therapy for advanced HCC; however the issue of high economic cost remains challenging; thus we have conducted this retrospective analysis of our HCC patients treated with sorafenib. MethodsHCC patients treated at Ain Shams University Hospitals, in the period between 2010 and 2012 were reviewed. Eligible patients were those who had received sorafenib for advanced HCC not eligible for or progressed after surgery or locoregional therapy. We investigated the impact of baseline clinicopathological factors (age, gender, child status, performance score, BCLC tumor stage, cause of chronic liver disease, median baseline alpha fetoprotein level and previous treatment received for HCC) on overall survival (OS) in an adjusted Cox regression model. Results41 patients were included in the analysis fulfilling the inclusion criteria. At a median follow up period of 13months, the median PFS for the whole group was 4months; the median OS for the whole group is 6.25months. Multivariate analysis identified three baseline characteristics that were prognostic indicators for overall survival: ECOG performance status (median OS for ECOG 1=7.01months and for ECOG 2=3.03months), Child–Pugh status (median OS for child A=12.04months and for child B=5.23months), and median baseline levels of alpha-fetoprotein. ConclusionsIn limited resource countries like Egypt, we suggest that the use of sorafenib for the treatment of advanced HCC cases should be restricted to a highly selected subgroup of patients with good performance and child A.