BioMed Research International: Oncology The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Prognostic Significance of Neutrophil to Lymphocyte Ratio, Lymphocyte to Monocyte Ratio, and Platelet to Lymphocyte Ratio in Patients with Nasopharyngeal Carcinoma Wed, 22 Feb 2017 11:43:09 +0000 The peripheral blood neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and platelet to lymphocyte ratio (PLR) have been reported to correlate with the prognosis of many malignancies. This study evaluated the prognostic value of pretreatment NLR, LMR, and PLR in nasopharyngeal carcinoma (NPC). A retrospective analysis of clinical and pathological data of 140 NPC patients without distant metastasis during initial treatment was conducted to identify correlations between NLR, LMR, and PLR and clinicopathological features, overall survival, and progression-free survival. Cox proportional hazard regression analysis was used to reveal the independent factors affecting the prognosis of NPC patients. NLR was associated with T staging, N staging, and overall clinical stage grouping of the NPC patients (). NLR ≥ 2.28, LMR < 2.26, and PLR ≥ 174 were significantly associated with a relatively short overall survival (). In addition, NLR ≥ 2.28 was significantly associated with a relatively short progression-free survival (). Cox proportional hazard regression analysis showed that NLR was an independent prognostic factor in NPC. Pretreatment NLR, LMR, and PLR might be a useful complement to TNM staging in the prognostic assessment of NPC patients. Aiying Lu, Haifeng Li, Yuming Zheng, Minzhong Tang, Jun Li, Huihui Wu, Weiming Zhong, Jianquan Gao, Ningjiang Ou, and Yonglin Cai Copyright © 2017 Aiying Lu et al. All rights reserved. Prognostic Role of the MicroRNA-200 Family in Various Carcinomas: A Systematic Review and Meta-Analysis Wed, 22 Feb 2017 09:54:18 +0000 Background/Aims. The miRNA-200 (miR-200) family may act as key inhibitors of epithelial-to-mesenchymal transition. However, the potential prognostic value of miR-200s in various human malignancies remains controversial. This meta-analysis analyzed the associations between miR-200 levels and survival outcomes in a variety of tumors. Methods. Eligible published studies were identified by searching the Embase, PubMed, CINAHL, and Google scholar databases. Patient clinical data were pooled, and pooled hazard ratios (HRs) with 95% confidence intervals (95% CI) were used to calculate the strength of this association. Results. The pooled HRs suggested that high tissue expression of miR-200 family members was associated with better survival (overall survival [OS]: HR = 0.70, 95% CI 0.54–0.91; progression-free survival [PFS]: HR = 0.63, 95% CI 0.52–0.76) in thirty-four eligible articles. In contrast, higher expression of circulating miR-200 members was significantly associated with poor clinical outcome (OS, HR = 1.68, 95% CI 1.15–2.46; PFS, HR = 2.62, 95% CI 1.68–4.07). Conclusion. The results from this meta-analysis suggest that miR-200 family members are potential prognostic biomarkers in patients with various carcinomas. To apply these findings in the clinic, large prospective studies are needed to validate the prognostic values of miR-200s in individual cancer types. Jung Soo Lee, Young-Ho Ahn, Hye Sung Won, Der Sheng Sun, Yeo Hyung Kim, and Yoon Ho Ko Copyright © 2017 Jung Soo Lee et al. All rights reserved. Hidden IgG Antibodies to the Tumor-Associated Thomsen-Friedenreich Antigen in Gastric Cancer Patients: Lectin Reactivity, Avidity, and Clinical Relevance Tue, 21 Feb 2017 00:00:00 +0000 Natural antibodies to the tumor-associated Thomsen-Friedenreich antigen (TF) are related to tumor immunosurveillance and cancer patients’ survival. Hidden IgG antibodies (HAbs) to TF, their lectin reactivity, avidity, and clinical relevance were studied. HAbs were present in cancer patients and controls. A decreased level of IgG HAbs was detected in cancer. The HAbs level positively correlated with the sialospecific SNA lectin binding in purified total IgG (tIgG) in donors and cancer patients, indicating that HAbs are higher sialylated. The avidity of anti-TF IgG in tIgG samples was lower in cancer patients () while no difference in the avidity of free anti-TF IgG was established. A negative correlation between the avidity of anti-TF IgG in tIgG and SNA binding in both groups was observed (). The HAbs level negatively correlated with the anti-TF IgG avidity in tIgG only in donors (). Changes in the level of HAbs and Abs avidity showed a rather good stage- and gender-dependent diagnostic accuracy. Cancer patients with a lower anti-TF IgG avidity in tIgG showed a benefit in survival. Thus the TF-specific HAbs represent a particular subset of anti-TF IgG that differ from free serum anti-TF IgG in SNA reactivity, avidity, diagnostic potential, and relation to survival. Oleg Kurtenkov and Kersti Klaamas Copyright © 2017 Oleg Kurtenkov and Kersti Klaamas. All rights reserved. Diagnostic and Therapeutic Biomarkers in Glioblastoma: Current Status and Future Perspectives Mon, 20 Feb 2017 14:10:31 +0000 Glioblastoma (GBM) is a primary neuroepithelial tumor of the central nervous system, characterized by an extremely aggressive clinical phenotype. Patients with GBM have a poor prognosis and only 3–5% of them survive for more than 5 years. The current GBM treatment standards include maximal resection followed by radiotherapy with concomitant and adjuvant therapies. Despite these aggressive therapeutic regimens, the majority of patients suffer recurrence due to molecular heterogeneity of GBM. Consequently, a number of potential diagnostic, prognostic, and predictive biomarkers have been investigated. Some of them, such as IDH mutations, 1p19q deletion, MGMT promoter methylation, and EGFRvIII amplification are frequently tested in routine clinical practice. With the development of sequencing technology, detailed characterization of GBM molecular signatures has facilitated a more personalized therapeutic approach and contributed to the development of a new generation of anti-GBM therapies such as molecular inhibitors targeting growth factor receptors, vaccines, antibody-based drug conjugates, and more recently inhibitors blocking the immune checkpoints. In this article, we review the exciting progress towards elucidating the potential of current and novel GBM biomarkers and discuss their implications for clinical practice. Wojciech Szopa, Thomas A. Burley, Gabriela Kramer-Marek, and Wojciech Kaspera Copyright © 2017 Wojciech Szopa et al. All rights reserved. Leptin-LepRb Expressed in Gastric Cancer Patients and Related to Cancer-Related Depression Mon, 20 Feb 2017 09:54:32 +0000 Depression is the most common psychiatric disorder among cancer patients. Studies have not only highlighted that leptin and its receptor (LepRb) are independent poor prognostic factors in gastric cancer (GC) patients but also shown that the leptin-LepRb is necessary for antidepressant-like behaviors. In this study, we examined the serum and tissue leptin-LepRb expression in GC patients. Enzyme-linked immunosorbent assay showed that depressive GC patients had significantly higher serum leptin-LepRb than healthy donors. Leptin-LepRb levels in GC tissues were also significantly higher than in matched paracarcinoma tissues using real-time RT-PCR. Moreover, we observed that both serum and tissue leptin-LepRb were significantly higher in depressive GC patients than those in nondepressive GC patients. Further, the patients with high tumor stage tend to have higher leptin-LepRb mRNA levels than that with low tumor stage. Together, our findings suggest that leptin-LepRb plays an important role in the pathogenesis and depression in GC. Leptin-LepRb therefore could be a potential diagnostic marker and therapeutic target in GC patients with depression. Yunbao Pan, Fuling Zhou, Chenyan He, Lingyun Hui, Tianhe Huang, and Yongchang Wei Copyright © 2017 Yunbao Pan et al. All rights reserved. SHISA3 Promoter Methylation Is a Potential Diagnostic and Prognostic Biomarker for Laryngeal Squamous Cell Carcinoma Thu, 16 Feb 2017 07:29:16 +0000 The purpose of this study was to evaluate the contribution of SHISA3 promoter methylation to laryngeal squamous cell carcinoma (LSCC). SHISA3 promoter methylation status and expression were determined using methylation-specific polymerase chain reaction (MSP) and quantitative real-time PCR (qRT-PCR) in 93 paired LSCC and adjacent normal tissues, respectively. Furthermore, the regulatory function of the SHISA3 promoter fragment was analyzed using a luciferase reporter assay. The results reveal that there is a significant increase in SHISA3 methylation in LSCC tissues compared with corresponding nontumor tissues . The qRT-PCR results show a significant association between SHISA3 methylation and expression in LSCC . In addition, the area under the receiver operating characteristic curve was 0.91. Consequently, a log-rank test and multivariate Cox analysis suggest that SHISA3 promoter hypermethylation is a predictor of poor overall survival for LSCC (log-rank P = 0.024; HR = 2.71; 95% CI = 1.024–7.177; P = 0.047). The results indicate that SHISA3 promoter hypermethylation might increase the risk of LSCC through regulation of gene expression and is a potential diagnostic and prognostic biomarker for LSCC. Zhisen Shen, Chongchang Zhou, Jinyun Li, Dong Ye, Hongxia Deng, Bin Cao, Wenjuan Hao, Lexi Lin, and Yuna Zhang Copyright © 2017 Zhisen Shen et al. All rights reserved. MicroRNA-Related Polymorphisms in PI3K/Akt/mTOR Pathway Genes Are Predictive of Limited-Disease Small Cell Lung Cancer Treatment Outcomes Thu, 09 Feb 2017 00:00:00 +0000 The phosphoinositide-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays an important role in cancer progression and treatment, including that of small cell lung cancer (SCLC), a disease with traditionally poor prognosis. Given the regulatory role of microRNA (miRNA) in gene expression, we examined the association of single nucleotide polymorphisms (SNPs) at miRNA-binding sites of genes in the mTOR pathway with the prognosis of patients with limited-disease SCLC. A retrospective study was conducted of 146 patients with limited-disease SCLC treated with chemoradiotherapy. Nine SNPs of six mTOR pathway genes were genotyped using blood samples. Cox proportional hazard regression modeling and recursive partitioning analysis were performed to identify SNPs significantly associated with overall survival. Three SNPs, MTOR: rs2536 (T>C), PIK3R1: rs3756668 (A>G), and PIK3R1: rs12755 (A>C), were associated with longer overall survival. Recursive partitioning analysis based on unfavorable genotype combinations of the rs2536 and rs3756668 SNPs classified patients into three risk subgroups and was internally validated with 1000 bootstrap samples. These findings suggest that miRNA-related polymorphisms in the PI3K/Akt/mTOR pathway may be valuable biomarkers to complement clinicopathological variables in predicting prognosis of limited-disease SCLC and to facilitate selection of patients likely to benefit from chemoradiotherapy. Wei Jiang, Wenjue Zhang, Lihong Wu, Lipin Liu, Yu Men, Jingbo Wang, Jun Liang, Zhouguang Hui, Zongmei Zhou, Nan Bi, and Luhua Wang Copyright © 2017 Wei Jiang et al. All rights reserved. Long Noncoding RNA PVT1 as a Novel Diagnostic Biomarker and Therapeutic Target for Melanoma Tue, 07 Feb 2017 09:53:19 +0000 Accumulating evidences indicated that plasmacytoma variant translocation 1 (PVT1) plays vital roles in several cancers. However, the expression, functions, and clinical values of PVT1 in melanoma are still unknown. In this study we measured the expression of PVT1 in clinical tissues and serum samples and explored the diagnostic value of PVT1 for melanoma and the effects of PVT1 on melanoma cell proliferation, cell cycle, and migration. Our results, combined with publicly available PVT1 expression data, revealed that PVT1 is upregulated in melanoma tissues compared with nonneoplastic nevi tissues. Serum PVT1 level is significantly increased in melanoma patients compared with age and gender-matched nonmelanoma controls with melanocytic nevus. Receiver operating characteristic curve analyses revealed that serum PVT1 level could sensitively discriminate melanoma patients from controls. Furthermore, serum PVT1 level indicted melanoma dynamics. Functional experiments showed that overexpression of PVT1 promotes melanoma cells proliferation, cell cycle progression, and migration, while depletion of PVT1 significantly inhibits melanoma cells proliferation, cell cycle progression, and migration. Collectively, our results indicate that PVT1 functions as an oncogene in melanoma and could be a potential diagnostic biomarker and therapeutic target for melanoma. Xiangjun Chen, Guozhen Gao, Sha Liu, Li Yu, Dexiong Yan, Xingwei Yao, Weijing Sun, Dezhi Han, and Hao Dong Copyright © 2017 Xiangjun Chen et al. All rights reserved. Primary Tumor Characteristics Are Important Prognostic Factors for Sorafenib-Treated Patients with Metastatic Renal Cell Carcinoma: A Retrospective Multicenter Study Tue, 07 Feb 2017 00:00:00 +0000 We aimed to identify prognostic factors associated with progression-free survival (PFS) and overall survival (OS) in metastatic renal cell carcinoma (mRCC) patients treated with sorafenib. We investigated 177 patients, including 116 who received sorafenib as first-line therapy, using the Cox regression model. During a median follow-up period of 19.2 months, the PFS and OS were 6.4 and 32.6 months among all patients and 7.4 months and undetermined for first-line sorafenib-treated patients, respectively. Clinical T3-4 stage (hazard ratio [HR] 2.56) and a primary tumor size >7 cm (HR 0.34) were significant prognostic factors for PFS among all patients, as were tumor size >7 cm (HR 0.12), collecting system invasion (HR 5.67), and tumor necrosis (HR 4.11) for OS (). In first-line sorafenib-treated patients, ≥4 metastatic lesions (HR 28.57), clinical T3-4 stage (HR 4.34), collecting system invasion (univariate analysis HR 2.11; multivariate analysis HR 0.07), lymphovascular invasion (HR 13.35), and tumor necrosis (HR 6.69) were significant prognosticators of PFS, as were bone metastasis (HR 5.49) and clinical T3-4 stages (HR 4.1) for OS (). Our study thus identified a number of primary tumor-related characteristics as important prognostic factors in sorafenib-treated mRCC patients. Sung Han Kim, Sohee Kim, Byung-Ho Nam, Sang Eun Lee, Choung-Soo Kim, Ill Young Seo, Tae Nam Kim, Sung-Hoo Hong, Tae Gyun Kwon, Seong Il Seo, Kwan Joong Joo, Kanghyon Song, Cheol Kwak, and Jinsoo Chung Copyright © 2017 Sung Han Kim et al. All rights reserved. Tissue Factor Pathway Inhibitor-1 Is a Valuable Marker for the Prediction of Deep Venous Thrombosis and Tumor Metastasis in Patients with Lung Cancer Thu, 26 Jan 2017 08:55:56 +0000 Activation of blood coagulation contributes to cancer progression. Tissue factor pathway inhibitor-1 (TFPI-1) is the main inhibitor of extrinsic coagulation pathway. The aim of this study is to assess the predicting significance of TFPI-1 for thrombotic complication and metastasis in lung cancer patients. Total of 188 non-small cell lung cancer (NSCLC) patients were included in this study. Plasma TFPI-1, D-dimer (D-D), antithrombin (AT), Fibrinogen (Fbg), and coagulating factor VIII activity (FVIII:C) were measured. In NSCLC patients, significantly decreased TFPI-1 and AT and increased D-D, Fbg, and FVIII:C levels were observed, and there was a significant correlation between TFPI-1 and other hemostatic parameters (, resp.). NSCLC patients with deep venous thrombosis (DVT) or metastasis had significantly lower TFPI-1 levels than those without DVT or metastasis (, resp.). Multivariate regression revealed that TFPI-1 acted as a predictor for DVT or tumor metastasis in NSCLC patients [OR: 4.15 or 3.28, , resp.]. The area under ROC curve of TFPI-1 was 0.905 (95% CI, 0.842~0.967) or 0.828 (95% CI, 0.742~0.915) for predicting DVT or metastasis (, resp.). The optimal point of TFPI-1 was 57.7 or 54.3 ng/mL for predicting DVT or metastasis, respectively. Combination of TFPI-1 and D-D measurements can improve the predicting power for DVT or metastasis in NSCLC patients. Our findings suggested that TFPI-1 was a valuable predictor of DVT and tumor metastasis in NSCLC patients. Xianming Fei, Huan Wang, Wufeng Yuan, Mingyi Wo, and Lei Jiang Copyright © 2017 Xianming Fei et al. All rights reserved. Miniature Dielectric Barrier Discharge Nonthermal Plasma Induces Apoptosis in Lung Cancer Cells and Inhibits Cell Migration Tue, 24 Jan 2017 07:52:07 +0000 Traditional cancer treatments like radiotherapy and chemotherapy have drawbacks and are not selective for killing only cancer cells. Nonthermal atmospheric pressure plasmas with dielectric barrier discharge (DBD) can be applied to living cells and tissues and have emerged as novel tools for localized cancer therapy. The purpose of this study was to investigate the different effects caused by miniature DBD (mDBD) plasma to A549 lung cancer cells. In this study, A549 lung cancer cells cultured in 12 well plates were treated with mDBD plasma for specified treatment times to assess the changes in the size of the area of cell detachment, the viability of attached or detached cells, and cell migration. Furthermore, we investigated an innovative mDBD plasma-based therapy for localized treatment of lung cancer cells through apoptotic induction. Our results indicate that plasma treatment for 120 sec causes apoptotic cell death in 35.8% of cells, while mDBD plasma treatment for 60 sec, 30 sec, or 15 sec causes apoptotic cell death in 20.5%, 14.1%, and 6.3% of the cell population, respectively. Additionally, we observed reduced A549 cell migration in response to mDBD plasma treatment. Thus, mDBD plasma system can be a viable platform for localized lung cancer therapy. Surya B. Karki, Eda Yildirim-Ayan, Kathryn M. Eisenmann, and Halim Ayan Copyright © 2017 Surya B. Karki et al. All rights reserved. Natural Products as Adjunctive Treatment for Pancreatic Cancer: Recent Trends and Advancements Mon, 23 Jan 2017 00:00:00 +0000 Pancreatic cancer is a type of common malignant tumors with high occurrence in the world. Most patients presented in clinic had pancreatic cancer at advanced stages. Furthermore, chemotherapy or radiotherapy had very limited success in treating pancreatic cancer. Complementary and alternative medicines, such as natural products/herbal medicines, represent exciting adjunctive therapies. In this review, we summarize the recent advances of using natural products/herbal medicines, such as Chinese herbal medicine, in combination with conventional chemotherapeutic agents to treat pancreatic cancer in preclinical and clinical trials. Qingxi Yue, Guogang Gao, Gangyong Zou, Haiqing Yu, and Xi Zheng Copyright © 2017 Qingxi Yue et al. All rights reserved. Scientific Evidence of Rice By-Products for Cancer Prevention: Chemopreventive Properties of Waste Products from Rice Milling on Carcinogenesis In Vitro and In Vivo Sun, 22 Jan 2017 11:45:55 +0000 Cancer is a significant global health concern affecting men and women worldwide. Although current chemopreventive drugs could inhibit the growth of cancer cells, they exert many adverse side effects. Dietary factor plays a crucial role in the management of cancers and has drawn the attention of researchers to be used as an option to combat this disease. Both in vitro and in vivo studies showed that rice and its by-products display encouraging results in the prevention of this disease. The mechanism of anticancer effect is suggested partly through potentiation of bioactive compounds like vitamin E, phytic acid, -aminobutyric acid (GABA), -oryzanol, and phenolics. Nevertheless, the bioactivity of rice and its by-products is still incompletely understood. In this review, we present the findings from a preclinical study both in in vitro and in animal experiments on the promising role of rice by-products with focus on cancer prevention. Bee Ling Tan and Mohd Esa Norhaizan Copyright © 2017 Bee Ling Tan and Mohd Esa Norhaizan. All rights reserved. RNA Sequencing Analysis Reveals Interactions between Breast Cancer or Melanoma Cells and the Tissue Microenvironment during Brain Metastasis Sun, 22 Jan 2017 00:00:00 +0000 Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non–small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanisms underlying the metastasis of cancer cells to the brain have remained unclear. Metastasizing cancer cells interact with their microenvironment in the brain to establish metastases. We have now developed mouse models of brain metastasis based on intracardiac injection of human breast cancer or melanoma cell lines, and we have performed RNA sequencing analysis to identify genes in mouse brain tissue and the human cancer cells whose expression is associated specifically with metastasis. We found that the expressions of the mouse genes Tph2, Sspo, Ptprq, and Pole as well as those of the human genes CXCR4, PLLP, TNFSF4, VCAM1, SLC8A2, and SLC7A11 were upregulated in brain tissue harboring metastases. Further characterization of such genes that contribute to the establishment of brain metastases may provide a basis for the development of new therapeutic strategies and consequent improvement in the prognosis of cancer patients. Ryo Sato, Teppei Nakano, Mari Hosonaga, Oltea Sampetrean, Ritsuko Harigai, Takashi Sasaki, Ikuko Koya, Hideyuki Okano, Jun Kudoh, Hideyuki Saya, and Yoshimi Arima Copyright © 2017 Ryo Sato et al. All rights reserved. Expression of Cadherin-17 Promotes Metastasis in a Highly Bone Marrow Metastatic Murine Breast Cancer Model Thu, 19 Jan 2017 07:29:31 +0000 We previously established 4T1E/M3 highly bone marrow metastatic mouse breast cancer cells through in vivo selection of 4T1 cells. But while the incidence of bone marrow metastasis of 4T1E/M3 cells was high (~80%) when injected intravenously to mice, it was rather low (~20%) when injected subcutaneously. Therefore, using 4T1E/M3 cells, we carried out further in vitro and in vivo selection steps to establish FP10SC2 cells, which show a very high incidence of metastasis to lungs (100%) and spines (85%) after subcutaneous injection into mice. qRT-PCR and western bolt analysis revealed that cadherin-17 gene and protein expression were higher in FP10SC2 cells than in parental 4T1E/M3 cells. In addition, immunostaining revealed the presence of cadherin-17 at sites of bone marrow and lung metastasis after subcutaneous injection of FP10SC2 cells into mice. Suppressing cadherin-17 expression in FP10SC2 cells using RNAi dramatically decreased the cells’ anchorage-independent growth and migration in vitro and their metastasis to lung and bone marrow in vivo. These findings suggest that cadherin-17 plays a crucial role in mediating breast cancer metastasis to bone marrow. Tomoko Okada, Atsushi Kurabayashi, Nobuyoshi Akimitsu, and Mutsuo Furihata Copyright © 2017 Tomoko Okada et al. All rights reserved. MiR-451 Promotes Cell Proliferation and Metastasis in Pancreatic Cancer through Targeting CAB39 Thu, 19 Jan 2017 00:00:00 +0000 Emerging evidence shows that microRNAs (miRNAs) play important roles in the regulation of various biological and pathologic processes in human cancers and the aberrant expression of miRNAs contributes to the tumor development. In this study, our findings indicate that miR-451 is significantly overexpressed in pancreatic cancer tissues and cell lines and elevated expression of miR-451 contributes to promoted cell viability (in vitro and in vivo). Moreover, overexpression of miR-451 is closely linked to poor prognosis and lymphatic metastasis. Inhibition of miR-451 dramatically suppresses cell viability and invasion, promotes cell apoptosis, and induces cell cycle arrest. Furthermore, miR-451 directly targets CAB39 and negatively regulates its expression and inhibition of CAB39 contributes to the promoted cell viability and invasion. Our findings improve our understanding of the function of miR-451 in the identification and therapy of pancreatic cancer. Rende Guo, Jianhua Gu, Zhibin Zhang, Yi Wang, and Chuan Gu Copyright © 2017 Rende Guo et al. All rights reserved. Andrographolide Inhibits Proliferation and Metastasis of SGC7901 Gastric Cancer Cells Wed, 18 Jan 2017 06:28:38 +0000 To explore the mechanisms by which andrographolide inhibits gastric cancer cell proliferation and metastasis, we employed the gastric cell line SGC7901 to investigate the anticancer effects of andrographolide. The cell survival ratio, cell migration and invasion, cell cycle, apoptosis, and matrix metalloproteinase activity were assessed. Moreover, western blotting and real-time PCR were used to examine the protein expression levels and the mRNA expression levels, respectively. The survival ratio of cells decreased with an increasing concentration of andrographolide in a dose-dependent manner. Consistent results were also obtained using an apoptosis assay, as detected by flow cytometry. The cell cycle was blocked at the G2/M2 phase by andrographolide treatment, and the proportion of cells arrested at G1/M was enhanced as the dose increased. Similarly, wound healing and Transwell assays showed reduced migration and invasion of the gastric cancer cells at various concentrations of andrographolide. Andrographolide can inhibit cell proliferation, invasion, and migration, block the cell cycle, and promote apoptosis in SGC7901 cells. The mechanisms may include upregulated expression of Timp-1/2, cyclin B1, p-Cdc2, Bax, and Bik and downregulated expression of MMP-2/9 and antiapoptosis protein Bcl-2. Lei Dai, Gang Wang, and Wensheng Pan Copyright © 2017 Lei Dai et al. All rights reserved. Antineoplastic Effects of Honokiol on Melanoma Tue, 17 Jan 2017 06:22:30 +0000 Honokiol, a plant lignan has been shown to have antineoplastic effects against nonmelanoma skin cancer developments in mice. In this study, antineoplastic effects of honokiol were investigated in malignant melanoma models. In vitro effects of honokiol treatment on SKMEL-2 and UACC-62 melanoma cells were evaluated by measuring the cell viability, proliferation, apoptosis, cell cycle analysis, and expressions of various proteins associated with cell cycle progression and apoptosis. For the in vivo study, male nude mice inoculated with SKMEL-2 or UACC-62 cells received injections of sesame oil or honokiol for two to seven weeks. In vitro honokiol treatment caused significant decrease in cell viability, proliferation, cell cycle arrest, increased apoptosis, and modulation of apoptotic and cell cycle regulatory proteins. Honokiol caused an accumulation of cells in the G2/M phase of the cell cycle in SKMEL-2 and G0/G1 phase in UACC-62 cells. An elevated level of caspases and PARP were observed in both cell lines treated with honokiol. A decrease in the expression of various cell cycle regulatory proteins was also observed in honokiol treated cells. Honokiol caused a significant reduction of tumor growth in SKMEL-2 and UACC-62 melanoma xenografts. These findings suggest that honokiol is a good candidate for further studies as a possible treatment for malignant melanoma. Ruth Guillermo-Lagae, Sreevidya Santha, Milton Thomas, Emily Zoelle, Jonathan Stevens, Radhey S. Kaushik, and Chandradhar Dwivedi Copyright © 2017 Ruth Guillermo-Lagae et al. All rights reserved. The lncRNA H19 Promotes Cell Proliferation by Competitively Binding to miR-200a and Derepressing β-Catenin Expression in Colorectal Cancer Tue, 10 Jan 2017 09:08:10 +0000 H19, a paternally imprinted noncoding RNA, has been found to be overexpressed in various cancers, including colorectal cancer (CRC), and may function as an oncogene. However, the mechanism by which H19 regulates CRC progression remains poorly understood. In this study, we aimed to assess H19 expression levels in CRC tissues, determine the effect of H19 on CRC proliferation, and explore the mechanism by which H19 regulates the proliferation of CRC. We measured H19 expression using qRT-PCR and analysed the effects of H19 on colon cancer cell proliferation via cell growth curve, cell viability assay, and colony formation assays. To elucidate the mechanism underlying these effects, we analysed the interactions between H19 and miRNAs and identified the target gene to which H19 and miRNA competitively bind using a series of molecular biological techniques. H19 expression was upregulated in CRC tissues compared with adjacent noncancerous tissues. H19 overexpression facilitated colon cancer cell proliferation, whereas H19 knockdown inhibited cell proliferation. miR-200a bound to H19 and inhibited its expression, thereby decreasing CRC cell proliferation. β-Catenin was identified as a target gene of miR-200a. H19 regulated β-catenin expression and activity by competitively binding to miR-200a. H19 promotes cell proliferation by competitively binding to miR-200a and derepressing β-catenin in CRC. Weiwei Yang, Ning Ning, and Xiaoming Jin Copyright © 2017 Weiwei Yang et al. All rights reserved. Bu-Zhong-Yi-Qi Decoction, the Water Extract of Chinese Traditional Herbal Medicine, Enhances Cisplatin Cytotoxicity in A549/DDP Cells through Induction of Apoptosis and Autophagy Thu, 05 Jan 2017 00:00:00 +0000 Cisplatin is one of the most active cytotoxic agents for non-small cell lung cancer (NSCLC) treatment. However, the development of cisplatin resistance is common. Bu-Zhong-Yi-Qi decoction (BZYQD), a Chinese traditional herbal medicine, is widely used for the enhancement of antitumor effect in other medications. In this study, we evaluated the effect and drug-resistance reversal mechanism of BZYQD combined with cisplatin on cisplatin-resistant A549/DDP cells. Our results showed that BZYQD exhibited direct cytotoxic and chemosensitizing effects. Cotreatment with BZYQD and cisplatin induced intrinsic apoptotic pathways which were measured by condensed nuclear chromatin, Annexin V/PI apoptosis assay, and apoptosis related proteins expression. In addition, cotreatment with BZYQD and cisplatin also activated autophagy, as indicated by an increase in LC3 puncta, classical autophagosomes and/or autolysosomes, and an accumulation of LC3-II and ATG7 protein. Finally, cotreatment with BZYQD and cisplatin resulted in the generation of ROS and scavenging ROS by NAC almost completely suppressing cell death. These results suggest that cotreatment with BZYQD and cisplatin might reverse cisplatin resistance by inducing ROS accumulation, which activates apoptosis and autophagy by oxidative stress. The combination of BZYQD and cisplatin may represent a novel approach in treatment for NSCLC and thus offer a new target for chemotherapy. Ning Yu, Ying Xiong, and Chun Wang Copyright © 2017 Ning Yu et al. All rights reserved. Interaction of MRE11 and Clinicopathologic Characteristics in Recurrence of Breast Cancer: Individual and Cumulated Receiver Operating Characteristic Analyses Wed, 04 Jan 2017 14:20:53 +0000 The interaction between the meiotic recombination 11 homolog A (MRE11) oncoprotein and breast cancer recurrence status remains unclear. The aim of this study was to assess the interaction between MRE11 and clinicopathologic variables in breast cancer. A dataset for 254 subjects with breast cancer (220 nonrecurrent and 34 recurrent) was used in individual and cumulated receiver operating characteristic (ROC) analyses of MRE11 and 12 clinicopathologic variables for predicting breast cancer recurrence. In individual ROC analysis, the area under curve (AUC) for each predictor of breast cancer recurrence was smaller than 0.7. In cumulated ROC analysis, however, the AUC value for each predictor improved. Ten relevant variables in breast cancer recurrence were used to find the optimal prognostic indicators. The presence of any six of the following ten variables had a high (79%) sensitivity and a high (70%) specificity for predicting breast cancer recurrence: tumor size ≥ 2.4 cm, tumor stage II/III, therapy other than hormone therapy, age ≥ 52 years, MRE11 positive cells > 50%, body mass index ≥ 24, lymph node metastasis, positivity for progesterone receptor, positivity for epidermal growth factor receptor, and negativity for estrogen receptor. In conclusion, this study revealed that these 10 clinicopathologic variables are the minimum discriminators needed for optimal discriminant effectiveness in predicting breast cancer recurrence. Cheng-Hong Yang, Sin-Hua Moi, Li-Yeh Chuang, Shyng-Shiou F. Yuan, Ming-Feng Hou, Yi-Chen Lee, and Hsueh-Wei Chang Copyright © 2017 Cheng-Hong Yang et al. All rights reserved. CT-Guided 125I Seed Interstitial Brachytherapy as a Salvage Treatment for Recurrent Spinal Metastases after External Beam Radiotherapy Mon, 26 Dec 2016 13:03:34 +0000 The aim of this study is to evaluate the feasibility, safety, and clinical efficacy of CT-guided 125I seed interstitial brachytherapy in patients with recurrent spinal metastases after external beam radiotherapy (EBRT). Between August 2003 and September 2015, 26 spinal metastatic lesions (24 patients) were reirradiated by this salvage therapy modality. Treatment for all patients was preplanned using a three-dimensional treatment planning system 3–5 days before 125I seed interstitial brachytherapy; dosimetry verification was performed immediately after seed implantation. Median actual was 99 Gy (range, 90–176), and spinal cord median was 39 Gy (range, 6–110). Median local control (LC) was 12 months (95% CI: 7.0–17.0). The 6- and 12-month LC rates were 52% and 40%, respectively. Median overall survival (OS) was 11 months (95% CI: 7.7–14.3); 6-month and 1-, 2-, and 3-year OS rates were 65%, 37%, 14%, and 9%, respectively. Pain-free survival ranged from 2 to 42 months (median, 6; 95% CI: 4.6–7.4). Treatment was well-tolerated, with no radiation-induced vertebral compression fractures or myelopathy reported. Reirradiation with CT-guided 125I seed interstitial brachytherapy appears to be feasible, safe, and effective as pain relief or salvage treatment for patients with recurrent spinal metastases after EBRT. Lihong Yao, Qianqian Cao, Junjie Wang, Jiwen Yang, Na Meng, Fuxin Guo, Yuliang Jiang, Suqing Tian, and Haitao Sun Copyright © 2016 Lihong Yao et al. All rights reserved. Basic Parameters of Blood Count as Prognostic Factors for Renal Cell Carcinoma Mon, 26 Dec 2016 10:18:42 +0000 Background. Renal cell carcinoma is the most common type of kidney cancer. Taking account of morbidity and mortality increase, it is evident that searching for independent prognostic factors is needed. Aim of the Study. The aim of the study was to analyze routinely performed blood parameters as potential prognostic factors for kidney cancer. Material and Methods. We have retrospectively reviewed the records of 230 patients treated for renal cell carcinoma in the years 2000–2006. Preoperative blood parameters, postoperative histopathological results, and staging and grading were performed. To estimate the risk of tumor recurrence and cancer specific mortality (CSM) within five years of follow-up, uni- and multivariate Cox and regression analyses were used. To assess the quality of classifiers and to search for the optimal cut-off point, the ROC curve was used. Results. T stage of the tumor metastasis is the most important risk factor for early recurrence and cancer specific mortality (). The preoperative platelet count (PLT) above 351 × 103/uL (95.3%; 55.1%) and AUC of 77% are negative prognostic factors and correlate with increased cancer specific mortality (CSM) during the five-year follow-up (). Increased risk of local recurrence was observed for PLT above 243.5 × 103/ul (59%; 88%) and AUC of 80% (). The opposite was observed in the mean platelets volume (MPV) for cancer specific mortality (CSM). The cut-off point for the MPV was 10.1 fl (75.4%; 55.1%) and for the AUC is of 68.1% (). Conclusions. Many analyzed parameters in univariate regressions reached statistical significance and could be considered as potential prognostic factors for ccRCC. In multivariate analysis, only T stage, platelet count (PLT), and mean platelet volume (MPV) correlated with CSM or recurrent ccRCC. Grzegorz Prokopowicz, Marcin Życzkowski, Krzysztof Nowakowski, Rafał Bogacki, Piotr Bryniarski, and Andrzej Paradysz Copyright © 2016 Grzegorz Prokopowicz et al. All rights reserved. Preoperative Chemotherapy for Gastric Cancer: Personal Interventions and Precision Medicine Sun, 25 Dec 2016 08:44:27 +0000 In spite of the declining incidence of gastric cancer (GC) in recent years, the mortality rate is still high. The asymptomatic nature and nonspecific clinical manifestations combined with the lack of efficient screening programs delay the diagnosis of GC. Therefore, the prevalence of advanced gastric cancer (AGC) has prompted the need for aggressive and intensive treatment options. Among the various treatment options for AGC, surgery is still the mainstay. However, the efficacy of surgery alone is not established. Results from multiple randomized controlled trials suggest that preoperative chemotherapy is promising intervention for the treatment and management of AGC. The main objective of neoadjuvant chemotherapy is to downstage or control micrometastasis in resectable tumor before surgery. On the other hand, conversion chemotherapy refers to surgical treatment aiming at R0 resection after chemotherapy for originally nonresectable or marginally resectable tumors. Nevertheless, preoperative chemoradiotherapy is considered beneficial for AGC patients. Over the last few decades, the combination of chemotherapy and targeted therapy prior to surgery demonstrated great results for the treatment of AGC. The rapid developments in genomics and proteomics have heralded the era of precision medicine. The combination of preoperative chemotherapy and precision medicine may enhance survival in AGC patients. Wei Xu, Maneesh K. Beeharry, Wentao Liu, Min Yan, and Zhenggang Zhu Copyright © 2016 Wei Xu et al. All rights reserved. Inhibitor of Nicotinamide Phosphoribosyltransferase Sensitizes Glioblastoma Cells to Temozolomide via Activating ROS/JNK Signaling Pathway Tue, 20 Dec 2016 07:10:56 +0000 Overcoming temozolomide (TMZ) resistance is a great challenge in glioblastoma (GBM) treatment. Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide and has a crucial role in cancer cell metabolism. In this study, we investigated whether FK866 and CHS828, two specific NAMPT inhibitors, could sensitize GBM cells to TMZ. Low doses of FK866 and CHS828 (5 nM and 10 nM, resp.) alone did not significantly decrease cell viability in U251-MG and T98 GBM cells. However, they significantly increased the antitumor action of TMZ in these cells. In U251-MG cells, administration of NAMPT inhibitors increased the TMZ (100 μM)-induced apoptosis and LDH release from GBM cells. NAMPT inhibitors remarkably enhanced the activities of caspase-1, caspase-3, and caspase-9. Moreover, NAMPT inhibitors increased reactive oxygen species (ROS) production and superoxide anion level but reduced the SOD activity and total antioxidative capacity in GBM cells. Treatment of NAMPT inhibitors increased phosphorylation of c-Jun and JNK. Administration of JNK inhibitor SP600125 or ROS scavenger tocopherol with TMZ and NAMPT inhibitors substantially attenuated the sensitization of NAMPT inhibitor on TMZ antitumor action. Our data indicate a potential value of NAMPT inhibitors in combined use with TMZ for GBM treatment. Jun Feng, Peng-Fei Yan, Hong-yang Zhao, Fang-Cheng Zhang, Wo-Hua Zhao, and Min Feng Copyright © 2016 Jun Feng et al. All rights reserved. miR-375 and miR-205 Regulate the Invasion and Migration of Laryngeal Squamous Cell Carcinoma Synergistically via AKT-Mediated EMT Mon, 19 Dec 2016 09:33:37 +0000 Previous studies have found that miR-375 and miR-205 were significantly dysregulated in laryngeal squamous cell carcinoma, which contributed to the invasion and migration of LSCC. However, the mechanisms of miR-375 and miR-205 regulating the invasion and migration of LSCC remain unknown. qRT-PCR was performed in 40 pairs of tissue samples to investigate the expression of miR-375 and miR-205 in LSCC and paracarcinoma tissues. To investigate whether or not miR-375 and miR-205 regulated the invasion and migration of LSCC synergistically via AKT-mediated epithelial-mesenchymal transition, miR-375 mimic and miR-205 inhibitor were transfected into SNU899 cells and miR-375 inhibitor and miR-205 mimic were transfected into SNU899 cells, respectively, with or without AKT inhibitor. Then the expressions of miR-375 and miR-205 were validated by qRT-PCR, cell migration and invasion were determined by wound healing assay and transwell invasive assay, and western blot analysis was performed to detect the expression of related proteins. Our results showed that miR-375 and miR-205 regulated the invasion and migration of LSCC via AKT-mediated EMT synergistically. In conclusion, our findings provided not only new information about the molecular mechanism of miRNAs regulating invasion and migration of LSCC, but also a theoretical principle for potential targeting therapy of laryngeal squamous carcinoma. Bin Wang, Kexing Lv, Weixiong Chen, Jing Zhao, Jie Luo, Jianhui Wu, Zenghong Li, Hao Qin, Thian-Sze Wong, Weiqiang Yang, Qing-Ling Fu, and Wenbin Lei Copyright © 2016 Bin Wang et al. All rights reserved. The Role of BRCA2 Mutation Status as Diagnostic, Predictive, and Prognosis Biomarker for Pancreatic Cancer Sun, 18 Dec 2016 11:16:40 +0000 Pancreatic cancer is one of the deadliest cancers worldwide, and life expectancy after diagnosis is often short. Most pancreatic tumours appear sporadically and have been highly related to habits such as cigarette smoking, high alcohol intake, high carbohydrate, and sugar consumption. Other observational studies have suggested the association between pancreatic cancer and exposure to arsenic, lead, or cadmium. Aside from these factors, chronic pancreatitis and diabetes have also come to be considered as risk factors for these kinds of tumours. Studies have found that 10% of pancreatic cancer cases arise from an inherited syndrome related to some genetic alterations. One of these alterations includes mutation in BRCA2 gene. BRCA2 mutations impair DNA damage response and homologous recombination by direct regulation of RAD51. In light of these findings that link genetic factors to tumour development, DNA damage agents have been proposed as target therapies for pancreatic cancer patients carrying BRCA2 mutations. Some of these drugs include platinum-based agents and PARP inhibitors. However, the acquired resistance to PARP inhibitors has created a need for new chemotherapeutic strategies to target BRCA2. The present systematic review collects and analyses the role of BRCA2 alterations to be used in early diagnosis of an inherited syndrome associated with familiar cancer and as a prognostic and predictive biomarker for the management of pancreatic cancer patients. Javier Martinez-Useros and Jesus Garcia-Foncillas Copyright © 2016 Javier Martinez-Useros and Jesus Garcia-Foncillas. All rights reserved. Pain Analysis in Patients with Pancreatic Carcinoma: Irreversible Electroporation versus Cryoablation Thu, 15 Dec 2016 13:21:08 +0000 The aim of this article is to evaluate and compare the postprocedure pain in patients with pancreatic carcinoma treated with irreversible electroporation (IRE) and cryoablation (CRYO). We compared 22 patients with 22 lesions in pancreas treated with IRE and 26 patients with 27 lesions treated with cryosurgery. All the patients in the two groups were under celiac plexus block (CPB) treatment to alleviate the postprocedure pain. A numerical rating scale (VAS) consisting of 11-point scales and the 24 h total hydromorphone use were recorded for the analysis of the pain level in the patients who underwent these two technologies separately. Other parameters, such as the complications and the ECOG performance status, were also noted. Statistical analysis was performed by Fisher’s exact test, the Chi-square test, and Student’s -test. All the pancreatic carcinoma patients in our study were reported to have postprocedure pain in the two groups. But there was no significant difference in the mean pain score (4.95 (IRE) versus 4.85 (CRYO); ) and 24 h total hydromorphone use (3.89 mg (IRE) versus 3.97 mg (CRYO); ). IRE is comparable to cryotherapy in the amount of pain that patients with pancreatic carcinoma experience. Jiannan Li, Shihou Sheng, Kai Zhang, and Tongjun Liu Copyright © 2016 Jiannan Li et al. All rights reserved. A Novel Assay for the Identification of NOTCH1 PEST Domain Mutations in Chronic Lymphocytic Leukemia Thu, 15 Dec 2016 11:31:28 +0000 Aims. To develop a fast and robust DNA-based assay to detect insertions and deletions mutations in exon 34 that encodes the PEST domain of NOTCH1 in order to evaluate patients with chronic lymphocytic leukemia (CLL). Methods. We designed a multiplexed allele-specific polymerase chain reaction (PCR) combined with a fragment analysis assay to detect specifically the mutation c.7544_7545delCT and possibly other insertions and deletions in exon 34 of NOTCH1. Results. We evaluated our assay in peripheral blood samples from two cohorts of patients with CLL. The frequency of NOTCH1 mutations was 8.4% in the first cohort of 71 unselected CLL patients. We then evaluated a second cohort of 26 CLL patients with known cytogenetic abnormalities that were enriched for patients with trisomy 12. NOTCH1 mutations were detected in 43.7% of the patients with trisomy 12. Conclusions. We have developed a fast and robust assay combining allele-specific PCR and fragment analysis able to detect NOTCH1 PEST domain insertions and deletions. Paulo Vidal Campregher, Roberta Cardoso Petroni, Nair Hideko Muto, Roberta Sitnik, Flavia Pereira de Carvalho, Nydia Strachman Bacal, Elvira Deolinda Rodrigues Pereira Velloso, Gislaine Borba Oliveira, João Renato Rebello Pinho, Davi Coe Torres, Marcela Braga Mansur, Rocio Hassan, Irene Gyongyvér Heidemarie Lorand-Metze, Carlos Sérgio Chiattone, Nelson Hamerschlak, and Cristovão Luis Pitangueira Mangueira Copyright © 2016 Paulo Vidal Campregher et al. All rights reserved. Retracted: Downregulation of MDR1 Gene by Cepharanthine Hydrochloride Is Related to the Activation of c-Jun/JNK in K562/ADR Cells Mon, 05 Dec 2016 06:11:49 +0000 BioMed Research International Copyright © 2016 BioMed Research International. All rights reserved. Aberrant Expression Profile of Long Noncoding RNA in Human Sinonasal Squamous Cell Carcinoma by Microarray Analysis Thu, 01 Dec 2016 08:03:57 +0000 Objectives. This study aimed to identify aberrantly expressed long noncoding RNAs (lncRNAs) profile of sinonasal squamous cell carcinoma (SSCC) and explore their potential functions. Methods. We investigated lncRNA and mRNA expression in SSCC and paired adjacent noncancerous tissues obtained from 6 patients with microarrays. Gene ontology (GO) analysis and pathway analysis were utilized to investigate the gene function. Gene signal-network and lncRNA-mRNA network were depicted. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to validate 5 lncRNAs in a second set of paired SSCC and adjacent noncancerous tissues obtained from 22 additional patients. Results. We identified significantly differentially expressed lncRNAs () and mRNAs () in SSCC relative to noncancerous tissues. The GO annotation indicated that there are some core gene products that may be attributed to the progress of SSCC. The pathway analysis identified many pathways associated with cancer. The results of lncRNA-mRNA network and gene signal-network implied some core lncRNAs/mRNAs might play important roles in SSCC pathogenesis. The results of qRT-PCR showed that all of the 5 lncRNAs were differentially expressed and consistent with the microarray results. Conclusion. Our study is the first screening and analysis of lncRNAs expression profile in SSCC and may offer new insights into pathogenesis of this disease. Ling-zhao Meng, Ju-gao Fang, Jing-wu Sun, Fan Yang, and Yong-xiang Wei Copyright © 2016 Ling-zhao Meng et al. All rights reserved. A Randomized Controlled Trial for the Effectiveness of Aromatherapy in Decreasing Salivary Gland Damage following Radioactive Iodine Therapy for Differentiated Thyroid Cancer Wed, 30 Nov 2016 13:52:04 +0000 Objective. The aim of this study was to investigate effects of aromatherapy in decreasing salivary gland damage for patients undergoing radioactive iodine (RAI) therapy with differentiated thyroid cancer (DTC). Materials and Methods. The subjects were 71 patients with DTC. They were divided into aromatherapy group (group A, ) and a control group (group B, ). We blended 1.0 mL of lemon and 0.5 mL of ginger essential oils. The patients in the inhalation aromatherapy group inhaled this blend oil and those in the control group inhaled distilled water as placebo for 10 min during admission. We statistically compared salivary gland function before and after treatment between groups A and B. Results. In comparison with group B, the rate of change of the accumulation rate was significantly higher in the parotid glands and submandibular glands of group A (). In comparison with group B, a significant increase in rate of secretion change before and after treatment was noted in the bilateral parotid glands in group A (). Conclusion. Because an amelioration of salivary gland function was observed in the present study, our results suggest the efficacy of aromatherapy in the prevention of treatment-related salivary gland disorder. This trial is registered with UMIN Clinical Trial Registry: UMIN000013968. Michihiro Nakayama, Atsutaka Okizaki, and Koji Takahashi Copyright © 2016 Michihiro Nakayama et al. All rights reserved. Clinically Meaningful Use of Blood Tumor Markers in Oncology Wed, 30 Nov 2016 09:58:09 +0000 Before the introduction of modern imaging techniques and the recent developments in molecular diagnosis, tumor markers (TMs) were among the few available diagnostic tools for the management of cancer patients. Easily obtained from serum or plasma samples, TMs are minimally invasive and convenient, and the associated costs are low. Single TMs were traditionally used but these have come under scrutiny due to their low sensitivity and specificity when used, for example, in a screening setting. However, recent research has shown superior performance using a combination of multiple TMs as a panel for assessment, or as part of validated algorithms that also incorporate other clinical factors. In addition, newer TMs have been discovered that have an increased sensitivity and specificity profile for defined malignancies. The aim of this review is to provide a concise overview of the appropriate uses of both traditional and newer TMs and their roles in diagnosis, prognosis, and the monitoring of patients in current clinical practice. We also look at the future direction of TMs and their integration with other diagnostic modalities and other emerging serum based biomarkers, such as circulating nucleic acids, to ultimately advance diagnostic performance and improve patient management. Stefan Holdenrieder, Lance Pagliaro, David Morgenstern, and Farshid Dayyani Copyright © 2016 Stefan Holdenrieder et al. All rights reserved. Tricholoma matsutake Aqueous Extract Induces Hepatocellular Carcinoma Cell Apoptosis via Caspase-Dependent Mitochondrial Pathway Mon, 28 Nov 2016 14:25:02 +0000 Tricholoma matsutake, one of widely accepted functional mushrooms, possesses various pharmacological activities, and its antitumor effect has become an important research point. Our study aims to evaluate the cytotoxicity activities of T. matsutake aqueous extract (TM) in HepG2 and SMMC-7721 cells. In in vitro experiments, TM strikingly reduced cell viability, promoted cell apoptosis, inhibited cell migration ability, induced excessive generation of ROS, and caused caspases cascade and mitochondrial membrane potential dissipation in hepatocellular carcinoma cells. In in vivo experiments, 14-day TM treatment strongly suppressed tumor growth in HepG2 and SMMC-7721-xenografted nude mice without influence on their body weights and liver function. Furthermore, TM increased the levels of cleaved poly-ADP-ribose polymerase (PARP), Bad, and Bax and reduced the expressions of B-cell lymphoma 2 (Bcl-2) in treated cells and tumor tissues. All aforementioned results suggest that caspase-dependent mitochondrial apoptotic pathways are involved in TM-mediated antihepatocellular carcinoma. Yanzhen Wang, Yiling Chen, Xinrui Zhang, Guangsheng Cai, Shengshu An, Xue Wang, Lirong Teng, and Di Wang Copyright © 2016 Yanzhen Wang et al. All rights reserved. Portal Vein Stenting Combined with Iodine-125 Seeds Endovascular Implantation Followed by Transcatheter Arterial Chemoembolization for Treatment of Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombus Thu, 24 Nov 2016 13:58:13 +0000 Aim was to assess the therapeutic value of portal vein stenting (PVS) combined with iodine-125 seed (125I seed) strand endovascular implantation followed by transcatheter arterial chemoembolization (TACE) for treating patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). This was a retrospective study of 34 patients aged 29–81 years, diagnosed HCC with PVTT, and treated with PVS combined with 125I seed strand endovascular implantation followed by TACE between January 2012 and August 2014. Survival, stent patency, technical success rate, complications related to the procedure, and adverse events were recorded. The technical success rate was 100%. No serious procedure-related adverse event was recorded. The median survival was 147 days. The cumulative survival rates and stent patency rates at 90, 180, and 360 days were 94.1%, 61.8%, and 32.4% and 97.1% (33/34), 76.9% (24/34), and 29.4% (10/34), respectively. PVS combined with 125I seed strand endovascular implantation followed by TACE is feasible for patients with HCC and PVTT. It resulted in appropriate survival and stent patency, with no procedure-related adverse effects. Jun-Hui Sun, Tanyang Zhou, Tongyin Zhu, Yuelin Zhang, Chunhui Nie, Jing Ai, Guanhui Zhou, Aibin Zhang, Meng-Jie Dong, Wei-Lin Wang, and Shu-Sen Zheng Copyright © 2016 Jun-Hui Sun et al. All rights reserved. Efficacy of External Beam Radiation-Based Treatment plus Locoregional Therapy for Hepatocellular Carcinoma Associated with Portal Vein Tumor Thrombosis Thu, 24 Nov 2016 13:31:01 +0000 Background. Portal vein tumor thrombosis (PVTT) is a common event in advanced hepatocellular carcinoma (HCC). The optimal treatment for these patients remains controversial. Methods. A retrospective review of 149 patients who had unresectable HCC associated with PVTT between January 2005 and December 2012 was performed. Outcomes related to external beam radiation-based treatment were measured, and clinicopathological features and parameters affecting prognosis were analyzed as well. Results. The radiotherapeutic response of PVTT was an important element that affected the overall treatment response of HCC. Serum α-fetoprotein < 400 ng/mL, the presence of a radiotherapeutic response on PVTT, and receiving additional locoregional therapy were significant prognostic factors affecting the survival of patients. Patients who had received additional locoregional therapy obtained a better outcome, and six of them were eventually able to undergo surgical management with curative intent. Conclusion. The outcome of HCC associated with PVTT remains pessimistic. In addition to the current recommended treatment using sorafenib, a combination of external beam radiotherapy targeting PVTT and locoregional therapy for intrahepatic HCC might be a promising strategy for patients who had unresectable HCC with PVTT. This approach could perhaps offer patients a favorable outcome as well as a possible cure with following surgical management. Ming-Yang Chen, Yu-Chao Wang, Tsung-Han Wu, Chen-Fang Lee, Ting-Jung Wu, Hong-Shiue Chou, Ngan-Ming Tsang, Kun-Ming Chan, and Wei-Chen Lee Copyright © 2016 Ming-Yang Chen et al. All rights reserved. EF24 Suppresses Invasion and Migration of Hepatocellular Carcinoma Cells In Vitro via Inhibiting the Phosphorylation of Src Wed, 23 Nov 2016 09:37:34 +0000 Diphenyl difluoroketone (EF24), a curcumin analog, is a promising anticancer compound that exerts its effects by inhibiting cell proliferation and inducing apoptosis. However, the efficacy of EF24 against cancer metastasis, particularly in hepatocellular carcinoma (HCC), remains elusive. In this study, the effect of EF24 on HCCLM-3 and HepG2 cell migration and invasion was detected by wound healing and transwell assay, respectively. The results revealed that EF24 suppressed the migration and invasion of both HCCLM-3 and HepG2 cells. Furthermore, EF24 treatment decreased the formation of filopodia on the cell surface and inhibited the phosphorylation of Src in both cell lines, which may help contribute towards understanding the mechanism underlying the suppressive effect of EF24 on HCC migration and invasion. Additionally, the expression of total- and phosphorylated-Src in primary HCC tissues and their paired lymph node metastatic tissues was detected, and phosphorylated-Src was found to be associated with HCC lymph node metastasis. The results of this study suggest that Src is a novel and promising therapeutic target in HCC and provide evidence to support the hypothesis that EF24 may be a useful therapeutic agent for the treatment of HCC. Ran Zhao, Lamtin Tin, Yuhua Zhang, Yiqi Wu, Yinji Jin, Xiaoming Jin, Fengmin Zhang, and Xiaobo Li Copyright © 2016 Ran Zhao et al. All rights reserved. Oxymatrine Inhibits Proliferation and Migration While Inducing Apoptosis in Human Glioblastoma Cells Sun, 13 Nov 2016 08:54:06 +0000 Oxymatrine (OMT), an alkaloid derived from the traditional Chinese medicine herb Sophora flavescens Aiton, has been shown to exhibit anticancer properties on various types of cancer cells. In this study, we investigate the anticancer properties of OMT on human glioblastoma (GBM) cells and evaluate their underlying mechanisms. MTT assays were performed and demonstrated that OMT significantly inhibits the proliferation of GBM cells. Flow cytometry suggested that OMT at a concentration of 10−5 M may induce apoptosis in U251 and A172 cells. Western blot analyses demonstrated a significant increase in the expression of Bax and caspase-3 and a significant decrease in expression of Bcl-2 in both U251 and A172 cells. Additionally, OMT was found by transwell and high-content screening assays to decrease the migratory ability of the evaluated GBM cells. These findings suggest that the antitumor effects of OMT may be the result of inhibition of cell proliferation and migration and the induction of apoptosis by regulating the expression of apoptosis-associated proteins. OMT may represent a novel anticancer therapy for the treatment of GBM. Feili Liu, Baocheng Wang, Jiajia Wang, Xiaozheng Ling, Qifeng Li, Wei Meng, and Jie Ma Copyright © 2016 Feili Liu et al. All rights reserved. Deregulated MicroRNAs in Biliary Tract Cancer: Functional Targets and Potential Biomarkers Wed, 09 Nov 2016 12:58:50 +0000 Biliary tract cancer (BTC) is still a fatal disease with very poor prognosis. The lack of reliable biomarkers for early diagnosis and of effective therapeutic targets is a major demanding problem in diagnosis and management of BTC. Due to the clinically silent and asymptomatic characteristics of the tumor, most patients are diagnosed at an already advanced stage allowing only for a palliative therapeutic approach. MicroRNAs are small noncoding RNAs well known to regulate various cellular functions and pathologic events including the formation and progression of cancer. Over the last years, several studies have shed light on the role of microRNAs in BTC, making them potentially attractive therapeutic targets and candidates as biomarkers. In this review, we will focus on the role of oncogenic and tumor suppressor microRNAs and their direct targets in BTC. Furthermore, we summarize and discuss data that evaluate the diagnostic power of deregulated microRNAs as possible future biomarkers for BTC. Christian Mayr, Marlena Beyreis, Andrej Wagner, Martin Pichler, Daniel Neureiter, and Tobias Kiesslich Copyright © 2016 Christian Mayr et al. All rights reserved. Long Noncoding RNA-LET Suppresses Tumor Growth and EMT in Lung Adenocarcinoma Tue, 08 Nov 2016 10:46:34 +0000 Recently, many studies showed that long noncoding RNAs (lncRNAs) are involved in tumor progression. It is reported that lncRNA-LET is downregulated and has antitumor effect on several types of cancer. This study focuses on the role of lncRNA-LET on lung adenocarcinoma (LAC) progression. RT-PCR results indicated that frequent downregulation of lncRNA-LET in LAC tissues was related to clinicopathologic factors. lncRNA-LET knockdown significantly promoted LAC cell proliferation, invasion, and migration while lncRNA-LET overexpression obviously inhibited LAC cell proliferation, invasion, and migration, indicating a tumor inhibition of lncRNA-LET in LAC progression. Besides, lncRNA-LET inhibited EMT and negatively regulated Wnt/β-catenin pathway in part. Our study suggests that lncRNA-LET exhibits an important tumor-suppressive effect on LAC progression by inhibiting EMT and Wnt/β-catenin pathway, which provides potential therapeutic targets for LAC. Bin Liu, Chun-Feng Pan, Zhi-Cheng He, Jun Wang, Peng-Li Wang, Teng Ma, Yang Xia, and Yi-Jiang Chen Copyright © 2016 Bin Liu et al. All rights reserved. Expression and Clinical Significance of the Novel Long Noncoding RNA ZNF674-AS1 in Human Hepatocellular Carcinoma Tue, 08 Nov 2016 08:34:14 +0000 Long noncoding RNAs (lncRNAs) play crucial roles in cancer occurrence and progression. However, the relationship between the expression levels of lncRNAs and the hepatocellular carcinoma (HCC) process is unclear. The goal of this study was to determine the expression level of ZNF674-AS1, a newly found lncRNA, in HCC and its clinical association. The expression of ZNF674-AS1 in 137 pairs of tumorous and adjacent normal tissues from patients with HCC was detected by quantitative real-time reverse transcription polymerase chain reaction. Additionally, the potential associations between its level in HCC tissue and clinicopathological features were analyzed. The expression of ZNF674-AS1 in the HCC cell lines HepG2, HCCLM3, SK-Hep1, HuH7, Hep3B, and MHCC97H was significantly downregulated compared with that in the normal liver cell line QSG-7701. The expression of ZNF674-AS1 was downregulated in 72% (99/137) of HCC tissues compared with that in paired adjacent normal tissues (). The results showed that the ZNF674-AS1 expression level was significantly correlated with metastasis (), clinical stage (), and histopathologic grading (). In addition, the Kaplan–Meier survival curves revealed that low ZNF674-AS1 expression was associated with poor prognosis in patients with HCC. Our data suggest that ZNF674-AS1 may play some role during cancer occurrence and progression and may be a new biomarker for HCC. Lufei Zhang, Tianyu He, Yingcai Yan, Yuan Zhang, Xiaohu Zhou, Pengfei Huang, Yang Kong, Minjie Xie, Linshi Zhang, Qiang Sun, Dongkai Zhou, Haiyang Xie, Lin Zhou, Shusen Zheng, and Weilin Wang Copyright © 2016 Lufei Zhang et al. All rights reserved. Lack of Associations between XPC Gene Polymorphisms and Neuroblastoma Susceptibility in a Chinese Population Wed, 26 Oct 2016 14:03:35 +0000 Neuroblastoma is one of the most malignant solid tumors in infants and young children. No more than 40% of neuroblastoma patients can survive for longer than five years after it has been diagnosed. XPC protein is a pivotal factor that recognizes DNA damage and starts up the nucleotide excision repair (NER) in mammalian cells. This makes up the first group to defend against the cancer. Previous studies have identified that XPC gene polymorphisms were associated with various types of cancer. However, the associations between XPC gene polymorphisms and neuroblastoma risk have not yet been studied. We investigated the associations between three XPC gene polymorphisms (rs2228001 A>C, rs2228000 C>T, and rs2229090 G>C) and neuroblastoma risk with 256 neuroblastoma patients and 531 healthy controls in a Chinese Han population. Odds ratios and 95% confidence intervals were used to access the association between these three polymorphisms and neuroblastoma risk. No significant association was detected between these three polymorphisms and neuroblastoma risk in the overall analysis as well as in the stratification analysis. These results suggest that none of these three polymorphisms may be associated with the risk of neuroblastoma in the Chinese Han population. Jintao Zheng, Ruizhong Zhang, Jinhong Zhu, Fenghua Wang, Tianyou Yang, Jing He, and Huimin Xia Copyright © 2016 Jintao Zheng et al. All rights reserved. Mast Cells: Key Players in the Shadow in Oral Inflammation and in Squamous Cell Carcinoma of the Oral Cavity Wed, 26 Oct 2016 07:12:04 +0000 Although mast cells (MCs) have been discovered over 130 years ago, their function was almost exclusively linked to allergic affections. At the time being, it is well known that MCs possess a great variety of roles, in both physiologic and pathologic conditions. In the oral tissues, MCs release different proinflammatory cytokines, tumor necrosis factor alpha (TNF-α), that promote leukocyte infiltration in various inflammatory states of the oral cavity. These cells play a key role in the inflammatory process and, as a consequence, their number changes in different pathologic conditions of the oral cavity, like gingivitis, periodontitis, and so on. MCs also represent a rich source of proteases, especially of mast cell tryptase and chymase, which directly degrade the extracellular matrix through their proteolytic activity and thus indirectly stimulate angiogenesis and facilitate invasion and metastasis. It may be stated that mast cells could have an impact on primary tumor development, progression, and metastases in oral squamous cell carcinoma. By understanding the role of mast cells in the pathogenesis of different inflammatory and tumor diseases of the oral cavity, these cells may become therapeutic targets that could possibly improve the prognosis and survival of these patients. Pusa Nela Gaje, Raluca Amalia Ceausu, Adriana Jitariu, Stefan Ioan Stratul, Laura-Cristina Rusu, Ramona Amina Popovici, and Marius Raica Copyright © 2016 Pusa Nela Gaje et al. All rights reserved. Prognostic Role of the Circulating Tumor Cells Detected by Cytological Methods in Gastric Cancer: A Meta-Analysis Mon, 24 Oct 2016 13:37:48 +0000 Objective. We performed a meta-analysis of available studies to assess the prognostic value of circulating tumor cells detected by cytological methods for patients with gastric cancer. Methods. Two authors systematically searched the studies independently with key words in PubMed, MEDLINE, EMBASE, Science Citation Index Expanded, and Cochrane Library (from inception to April 2016). The estimated hazard ratio, risk ratio, odds ratio, and their 95% confidence intervals were set as effect measures. All analyses were performed by STATA 12.0. Results. Sixteen studies were included in this meta-analysis. CTCs-high status was significantly associated with poor overall survival (, 95% CI: 1.86–2.66) and progression-free survival (, 95% CI: 1.36–2.99). CTCs-high status was also associated with depth of infiltration (OR = 2.07, 95% CI: 1.16–3.70), regional lymph nodes metastasis (OR = 1.85, 95% CI: 1.26–2.71), and distant metastasis (OR = 2.83, 95% CI: 1.77–4.52). For unresectable gastric cancer patients, CTCs-high status was significantly associated with poor overall survival, progression-free survival, and disease control rate before and during chemotherapy group. Conclusions. Our meta-analysis has evidenced the significant prognostic value of CTCs detected for both PFS and OS in gastric cancer patients. For patients treated with chemotherapy alone, we proved that CTCs detected by cytological method showed a significant prognostic value and poor response to chemotherapy. Kun Zou, Shuailong Yang, Liang Zheng, Shuyi Wang, and Bin Xiong Copyright © 2016 Kun Zou et al. All rights reserved. β-Catenin Expression Negatively Correlates with WIF1 and Predicts Poor Clinical Outcomes in Patients with Cervical Cancer Mon, 24 Oct 2016 07:35:31 +0000 Aberrant activation of the canonical Wnt pathway plays a significant role in cervical cancer (CC). However, limited data show the correlation between the cancer clinicopathological characteristics and the key molecules such as β-catenin and Wnt inhibitory factor 1 (WIF1). In this study, β-catenin and WIF1 expression were analyzed by immunohistochemistry for 196 patients with CC, 39 with cervical intraepithelial neoplasia (CIN), and 41 with normal cervical epithelium (NCE). Significant overexpression of β-catenin was detected in CC (67.9%) when compared to CIN (43.6%) or NCE (34.1%), , while low WIF1 expression was detected in CC (24.0%) when compared to CIN (59.0%) or NCE (58.5%), . Negative correlation was shown between β-catenin and WIF1 expression (, ). In addition, multivariate analysis revealed that both lymph node metastasis and β-catenin expression were the independent prognostic factors not only for disease-free survival (HR = 5.029, ; HR = 2.588, , resp.), but also for overall survival (HR = 5.058, ; HR = 2.873, , resp.). Our findings indicate that, besides lymph node metastasis, β-catenin expression may also be a poor prognostic factor for CC while WIF1 could be a potential drug target for treatment of advanced CC. Jinxiao Liang, Hui Zhou, Yongpai Peng, Xiaofei Xie, Ruixin Li, Yunyun Liu, Qingsheng Xie, and Zhongqiu Lin Copyright © 2016 Jinxiao Liang et al. All rights reserved. PTEN Inhibits Cell Proliferation, Promotes Cell Apoptosis, and Induces Cell Cycle Arrest via Downregulating the PI3K/AKT/hTERT Pathway in Lung Adenocarcinoma A549 Cells Sun, 16 Oct 2016 09:01:55 +0000 PTEN plays an essential role in tumorigenesis and both its mutation and inactivation can influence proliferation, apoptosis, and cell cycle progression in tumor cells. However, the precise role of PTEN in lung cancer cells has not been well studied. To address this, we have generated lung adenocarcinoma A549 cells overexpressing wild-type or mutant PTEN as well as A549 cells expressing a siRNA directed toward endogenous PTEN. Overexpression of wild-type PTEN profoundly inhibited cell proliferation, promoted cell apoptosis, caused cell cycle arrest at G1, downregulated p-AKT, and decreased expression of the telomerase protein hTERT. In contrast, in cells expressing a PTEN directed siRNA, the opposite effects on cell proliferation, apoptosis, cell cycle arrest, p-AKT levels, and hTERT protein expression were observed. A549 cells transfected with a PTEN mutant lacking phosphatase activity (PTEN-C124A) or an empty vector (null) did not show any effect. Furthermore, using the PI3K/AKT pathway blocker LY294002, we confirmed that the PI3K/AKT pathway was involved in mediating these effects of PTEN. Taken together, we have demonstrated that PTEN downregulates the PI3K/AKT/hTERT pathway, thereby suppressing the growth of lung adenocarcinoma cells. Our study may provide evidence for a promising therapeutic target for the treatment of lung adenocarcinoma. Xiao-Xiao Lu, Lan-Yu Cao, Xi Chen, Jian Xiao, Yong Zou, and Qiong Chen Copyright © 2016 Xiao-Xiao Lu et al. All rights reserved. Association between Tumor Vasculogenic Mimicry and the Poor Prognosis of Gastric Cancer in China: An Updated Systematic Review and Meta-Analysis Wed, 12 Oct 2016 09:32:16 +0000 Background. Vasculogenic mimicry can promote tumor growth and metastasis. This article is aimed at conducting a systematic meta-analysis to explore the clinicopathological and prognostic significance of vasculogenic mimicry and gastric cancer. Methods. We searched Pubmed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, and the VIP and Wanfang Database for eligible studies. We manually searched for printed journals and relevant textbooks. Subgroups analyses were performed based on the region, manuscript quality, methods of vasculogenic mimicry identification, pathology, and number of patients. Results. Nine studies with 997 patients were included in this meta-analysis. A significant association was observed between vasculogenic mimicry-positive patients and those with gastric cancer with poor overall survival (hazard ratio = 2.24, 95% confidence interval: 1.45–3.47), poor pathological grading, high tumor node metastasis clinical stage, lymph node metastasis, deep tumor invasion, and distant metastasis. Conclusions. Vasculogenic mimicry is associated with a poor prognosis in patients with gastric cancer in China. Clinical studies with large samples are needed worldwide and standardized protocols should be adopted in the future to achieve a better understanding of the relationship between gastric cancer and vasculogenic mimicry. Qiujun Guo, Yuan Yuan, Zhichao Jin, Tao Xu, Yebo Gao, Huamin Wei, Conghuang Li, Wei Hou, and Baojin Hua Copyright © 2016 Qiujun Guo et al. All rights reserved. Specific Aspects of Breast Cancer Therapy of Elderly Women Tue, 11 Oct 2016 14:14:13 +0000 Breast cancer is the leading cause of death among women, and its incidence increases with age. The average age at diagnosis is 61 years, and the majority of deaths occurs after the age of 65 years. Optimal approach to elderly women with breast cancer is still a major challenge. Elderly patients with cancer should have at least a brief geriatric assessment to detect potentially treatable problems not always adequately evaluated by the oncologists. Therapeutic nihilism should be avoided and effective treatment provided, unless there are compelling reasons against it. Sharing the care for the patient with geriatricians or primary care physicians trained in geriatrics should be considered for all vulnerable and frail elderly patients. Petra Tesarova Copyright © 2016 Petra Tesarova. All rights reserved. Bioguided Fraction and Isolation of the Antitumor Components from Phyllanthus niruri L. Thu, 29 Sep 2016 12:24:03 +0000 Phyllanthus niruri L., a well-known medicinal plant, has been used as a folk antitumor remedy in the worldwide scale. However, the antitumor components in P. niruri have not been reported. In order to verify the antitumor components of P. niruri and the plants which have the high content of these components, we isolated the antitumor components with bioguided fraction and isolation, by different chromatographic methods from the ethyl acetate fraction of P. niruri., and identified them as ethyl brevifolincarboxylate and corilagin by 1H-NMR, 13C-NMR, 2D-NMR, and mass spectrometric analyses. Cell cytotoxicity assays showed that corilagin has broad-spectrum antitumor activity, a better antitumor potential, and lower toxicity in normal cells. Besides, the coefficient of drug interaction (CDI) of 10 μM corilagin and 20 μM cDDP reached up to 0.77, which means corilagin can promote the antitumor activity of cDDP. Furthermore, by the extensive screening among 10 species of plants reported to contain corilagin, we found that Dimocarpus longan Lour. has the maximum content of corilagin. In conclusion, corilagin is the major active antitumor composition in P. niruri. L. on HCC cells and has high content in D. longan. Zhi-Zhong Zheng, Liang-Hua Chen, Shao-Song Liu, Yuan Deng, Guo-Hua Zheng, Yue Gu, and Yan-Lin Ming Copyright © 2016 Zhi-Zhong Zheng et al. All rights reserved. Predictors of Survival in Esophageal Squamous Cell Carcinoma with Pathologic Major Response after Neoadjuvant Chemoradiation Therapy and Surgery: The Impact of Chemotherapy Protocols Thu, 29 Sep 2016 12:06:55 +0000 Tumor recurrence is an important problem threatening esophageal cancer patients after surgery, even when they achieve a pathologic major response (pMR) after neoadjuvant concurrent chemoradiation therapy (CCRT). The predictors related to overall survival and disease progression for these patients remain elusive. We aimed to identify factors that predict disease progression and overall survival in esophageal squamous cell carcinoma (SCC) patients who achieve a pMR after neoadjuvant CCRT followed by surgery. We conducted a retrospective study to analyze the factors influencing survival and disease progression after esophagectomy for esophageal cancer patients who had a major response to CCRT, which is defined by complete pathological response or microscopic residual disease without lymph node metastasis. From our study cohort, 285 patients underwent CCRT and subsequent esophagectomy; 171 (60%) of these patients achieved pMR. After excluding patients with lymph node metastases, incomplete clinical data, and adenocarcinomas, we enrolled 117 patients in this study. We found that the CCRT regimen was the only factor that influenced overall survival. The overall survival of the patients receiving taxane-incorporated CCRT was superior to that of patients receiving traditional cisplatin and 5-fluorouracil (PF) (). The CCRT regimen can significantly influence the clinical outcome of esophageal SCC patients who achieve pMR after neoadjuvant CCRT and esophagectomy. Incorporation of taxanes into cisplatin-based CCRT may be associated with prolonged survival. Chia-Ying Li, Pei-Ming Huang, Pei-Yi Chu, Po-Ming Chen, Mong-Wei Lin, Shuenn-Wen Kuo, and Jang-Ming Lee Copyright © 2016 Chia-Ying Li et al. All rights reserved. The Significance of Long Noncoding RNA H19 in Predicting Progression and Metastasis of Cancers: A Meta-Analysis Thu, 08 Sep 2016 10:11:20 +0000 Recently, numerous studies indicate that H19 plays a key role in tumorigenesis, but the results have been disputed, especially in the aspects of tumor progression and metastasis. Therefore, we performed this meta-analysis to systematically summarize the relationship between H19 and cancers. We searched PubMed, the Cochrane Library, CNKI, and Chinese Wan Fang to identify eligible studies. Odds ratios and 95% confidence intervals were calculated to assess the effect size. A total of 13 studies were enrolled in this meta-analysis, which was performed by Revman5.3 and Stata11.0 software. Our meta-analysis showed that the expression of H19 was associated with distant metastasis in nongastrointestinal tumors (OR = 3.85, 95% CI = 1.31–11.36, ) and, in gastrointestinal tumors (OR = 0.34, 95% CI = 0.15–0.78, ), lymph node metastasis (OR = 2.04, 95% CI = 1.19–3.48, ). Moreover, in gastric cancer, H19 expression was significantly related to histological grade (OR = 0.50, 95% CI = 0.29–0.86, ), TNM stage (OR = 0.19, 95% CI = 0.11–0.33, ), and tumor invasion depth (OR = 0.11, 95% CI = 0.04–0.27, ). Therefore, H19 could serve as a potential marker for progression and metastasis evaluation of cancers. Wei Jing, Man Zhu, Xian-wei Zhang, Zhong-ya Pan, Shan-shan Gao, Hu Zhou, Shi-li Qiu, Chun-zi Liang, and Jian-cheng Tu Copyright © 2016 Wei Jing et al. All rights reserved. Can Molecular Biomarkers Change the Paradigm of Pancreatic Cancer Prognosis? Thu, 01 Sep 2016 16:05:31 +0000 Pancreatic ductal adenocarcinoma is one of the most lethal types of tumour, and its incidence is rising worldwide. Although survival can be improved when these tumours are detected at an early stage, this cancer is usually asymptomatic, and the disease only becomes apparent after metastasis. The only prognostic biomarker approved by the FDA to date is carbohydrate antigen 19-9 (CA19-9); however, the specificity of this biomarker has been called into question, and diagnosis is usually based on clinical parameters. Tumour size, degree of differentiation, lymph node status, presence of distant metastasis at diagnosis, protein levels of KI-67 or C-reactive protein, and mutational status of P53, KRAS, or BRCA2 are the most useful biomarkers in clinical practice. In addition to these, recent translational research has provided evidence of new biomarkers based on different molecules involved in endoplasmic reticulum stress, epithelial-to-mesenchymal transition, and noncoding RNA panels, especially microRNAs and long noncoding RNAs. These new prospects open new paths to tumour detection using minimally or noninvasive techniques such as liquid biopsies. To find sensitive and specific biomarkers to manage these patients constitutes a challenge for the research community and for public health policies. Javier Martinez-Useros and Jesus Garcia-Foncillas Copyright © 2016 Javier Martinez-Useros and Jesus Garcia-Foncillas. All rights reserved. Role of Long Noncoding RNA HOTAIR in the Growth and Apoptosis of Osteosarcoma Cell MG-63 Wed, 31 Aug 2016 06:59:47 +0000 This study investigated the function of HOTAIR in the growth and apoptosis of OS MG-63 cell line in vitro and further clarified its mechanism. The expression levels of HOTAIR in OS MG-63 cell line and normal osteoblast hFOB1.19 cell line were determined by RT-PCR, respectively. The growth and apoptosis of MG-63 cells in vitro were investigated by MTT assay and flow cytometry assay after HOTAIR was knocked down with retroviral vector construction. And the expression levels of cell growth and apoptosis related factors TGF-β, p53, Bcl-2, and TNF-α were determined to clarify the mechanism. We found that HOTAIR was highly expressed in osteosarcoma MG-63 cell line compared with normal osteoblast hFOB1.19 cell line. The proliferation rate was lower and the apoptosis rate was higher significantly in shHOTAIR MG-63 cells than those in EV MG-63 cells. TGF-β and Bcl-2 were downregulated significantly when HOTAIR was knocked down. p53 and TNF-α were upregulated significantly when HOTAIR was knocked down. These results indicated that HOTAIR functioned as a carcinogenic lncRNA, which could promote the proliferation and inhibit the apoptosis of MG-63 cells in vitro. HOTAIR could be a potential target for the treatment of osteosarcoma. Hua Zheng and Jing Min Copyright © 2016 Hua Zheng and Jing Min. All rights reserved. Predictors and Modulators of Synthetic Lethality: An Update on PARP Inhibitors and Personalized Medicine Wed, 24 Aug 2016 17:53:25 +0000 Poly(ADP-ribose) polymerase (PARP) inhibitors have proven to be successful agents in inducing synthetic lethality in several malignancies. Several PARP inhibitors have reached clinical trial testing for treatment in different cancers, and, recently, Olaparib (AZD2281) has gained both United States Food and Drug Administration (USFDA) and the European Commission (EC) approval for use in BRCA-mutated advanced ovarian cancer treatment. The need to identify biomarkers, their interactions in DNA damage repair pathways, and their potential utility in identifying patients who are candidates for PARP inhibitor treatment is well recognized. In this review, we detail many of the biomarkers that have been investigated for their ability to predict both PARP inhibitor sensitivity and resistance in preclinical studies as well as the results of several clinical trials that have tested the safety and efficacy of different PARP inhibitor agents in BRCA and non-BRCA-mutated cancers. Stephen Murata, Catherine Zhang, Nathan Finch, Kevin Zhang, Loredana Campo, and Eun-Kyoung Breuer Copyright © 2016 Stephen Murata et al. All rights reserved. Circulating Resistin Levels and Risk of Colorectal Cancer: A Meta-Analysis Wed, 24 Aug 2016 10:12:56 +0000 Objectives. Published data on resistin levels in patients with colorectal cancer (CRC) were conflicting and heterogeneous. We conducted a meta-analysis of observational studies to examine the association of circulating resistin levels with carcinogenesis of the CRC. Methods. Potentially eligible studies published up to November 2015 were searched through MEDLINE, EMBASE, Science Citation Index Expanded database, CNKI, and WanFang database. The pooled weighted mean differences (WMDs) with 95% confidence intervals (CIs) calculated by fixed- or random-effect model were used to estimate the effects. Results. A total of 11 studies involving 965 patients were admitted in our meta-analysis. The pooled effects indicated that resistin levels were higher in CRC patients compared to healthy controls (WMD: 1.47 ng/mL; 95% CI: 0.78 to 2.16), with significant heterogeneity across the studies (%, ). Subgroup analyses and sensitivity analyses revealed that study quality, design, sample type, and resistin assays may account for this heterogeneity. No publication bias was observed. Conclusions. Our meta-analysis suggests that increased circulating resistin levels are associated with greater risk of colorectal cancer. Given the limited number of available studies and significant heterogeneity, larger well-designed randomized studies are warranted. Gui Yang, Wei Fan, Baohong Luo, Zhigao Xu, Ping Wang, Shihui Tang, Peipei Xu, and Mingxia Yu Copyright © 2016 Gui Yang et al. All rights reserved. Circular RNA-ITCH Suppresses Lung Cancer Proliferation via Inhibiting the Wnt/β-Catenin Pathway Wed, 24 Aug 2016 06:38:23 +0000 As a special form of noncoding RNAs, circular RNAs (circRNAs) played important roles in regulating cancer progression mainly by functioning as miRNA sponge. While the function of circular RNA-ITCH (cir-ITCH) in lung cancer is still less reported, in this study, we firstly detected the expression of cir-ITCH in tumor tissues and paired adjacent noncancer tissues of 78 patients with lung cancer using a TaqMan-based quantitative real-time PCR (qRT-PCR). The results showed that the expression of cir-ITCH was significantly decreased in lung cancer tissues. In cellular studies, cir-ITCH was also enhanced in different lung cancer cell lines, A549 and NIC-H460. Ectopic expression of cir-ITCH markedly elevated its parental cancer-suppressive gene, ITCH, expression and inhibited proliferation of lung cancer cells. Molecular analysis further revealed that cir-ITCH acted as sponge of oncogenic miR-7 and miR-214 to enhance ITCH expression and thus suppressed the activation of Wnt/β-catenin signaling. Altogether, our results suggested that cir-ITCH may play an inhibitory role in lung cancer progression by enhancing its parental gene, ITCH, expression. Li Wan, Lin Zhang, Kai Fan, Zai-Xing Cheng, Quan-Chao Sun, and Jian-Jun Wang Copyright © 2016 Li Wan et al. All rights reserved. Corrigendum to “Calcium Channel Expression and Applicability as Targeted Therapies in Melanoma” Wed, 17 Aug 2016 09:46:23 +0000 A. Macià, J. Herreros, R. M. Martí, and C. Cantí Copyright © 2016 A. Macià et al. All rights reserved. In Vitro Growth Inhibitory Activities of Natural Products from Irciniid Sponges against Cancer Cells: A Comparative Study Thu, 11 Aug 2016 14:04:05 +0000 Marine sponges of the Irciniidae family contain both bioactive furanosesterterpene tetronic acids (FTAs) and prenylated hydroquinones (PHQs). Both classes of compounds are known for their anti-inflammatory, antioxidant, and antimicrobial properties and known to display growth inhibitory effects against various human tumor cell lines. However, the different experimental conditions of the reported in vitro bioassays, carried out on different cancer cell lines within separate studies, prevent realistic actual discrimination between the two classes of compounds from being carried out in terms of growth inhibitory effects. In the present work, a chemical investigation of irciniid sponges from Tunisian coasts led to the purification of three known FTAs and three known PHQs. The in vitro growth inhibitory properties of the six purified compounds have been evaluated in the same experiment in a panel of five human and one murine cancer cell lines displaying various levels of sensitivity to proapoptotic stimuli. Surprisingly, FTAs and PHQs elicited distinct profiles of growth inhibitory-responses, differing by one to two orders of magnitude in favor of the PHQs in all cell lines. The obtained comparative results are discussed in the light of a better selection of drug candidates from natural sources. Yosr BenRedjem Romdhane, Monia Elbour, Marianna Carbone, Maria Letizia Ciavatta, Margherita Gavagnin, Véronique Mathieu, Florence Lefranc, Leila Ktari, Karim Ben Mustapha, Abdellatif Boudabous, Robert Kiss, and Ernesto Mollo Copyright © 2016 Yosr BenRedjem Romdhane et al. All rights reserved. Predictive Significance of Serum Level of Vascular Endothelial Growth Factor in Gastric Cancer Patients Thu, 11 Aug 2016 13:36:21 +0000 The study aims to evaluate serum VEGF expression in gastric cancer patients and investigate its relationship with clinicopathological parameters. We also examined the serum VEGF levels in GC patients having received surgery or chemotherapy treatment to assess its predictive and prognostic value as a biomarker. We enrolled 154 GC patients having not received neoadjuvant treatment and 100 healthy controls. In the treatment groups, 13 surgery patients and 15 chemotherapy patients were investigated. 42 chemotherapy patients with different chemotherapy efficacy were recruited as well. The serum VEGF was examined by ELISA. Serum VEGF level was remarkably upregulated in GC group compared with healthy group (). The serum VEGF level of GC group was significantly correlated with tumor cells differentiation degree, clinical stages, tumor infiltration depth, lymph node metastasis, and tumor size. The serum VEGF level of the 1 to 3 days after operation group was much lower than that of the preoperative group () and the 7 days after operation group (). By contrast, serum VEGF level was decreased significantly after chemotherapy (). Importantly, serum VEGF level in PD+SD group was significantly higher compared to the PR+CR group (). Therefore, serum VEGF was a valuable biomarker in clinically monitoring the condition of GC patients. Lu Wang, Yanli Chang, Jianjun Xu, and Qingyun Zhang Copyright © 2016 Lu Wang et al. All rights reserved. Cancer: An Oxidative Crosstalk between Solid Tumor Cells and Cancer Associated Fibroblasts Tue, 09 Aug 2016 13:29:30 +0000 Redox balance is associated with the regulation of several cell signalling pathways and functions. In fact, under physiological conditions, cells maintain a balance between oxidant and antioxidant systems, and reactive oxygen species (ROS) can act as second messengers to regulate cell proliferation, cell death, and other physiological processes. Cancer tissues usually contain higher levels of ROS than normal tissues, and this ROS overproduction is associated with tumor development. Neoplastic tissues are very heterogeneous systems, composed of tumor cells and microenvironment that has a critical role in tumor progression. Cancer associated fibroblasts (CAFs) represent the main cell type of tumor microenvironment, and they contribute to tumor growth by undergoing an irreversible activation process. It is known that ROS can be transferred from cancer cells to fibroblasts. In particular, ROS affect the behaviour of CAFs by promoting the conversion of fibroblasts to myofibroblasts that support tumor progression and dissemination. Furthermore, the wrecking of redox homeostasis in cancer cells and tumor microenvironment induces a metabolic reprogramming in tumor cells and cancer associated fibroblasts, giving advantage to cancer growth. This review describes the role of ROS in tumor growth, by focusing on CAFs activation and metabolic interactions between cancer cells and stromal fibroblasts. Alessandro Arcucci, Maria Rosaria Ruocco, Giuseppina Granato, Anna Maria Sacco, and Stefania Montagnani Copyright © 2016 Alessandro Arcucci et al. All rights reserved. Targeting Lung Cancer Stem Cells with Antipsychological Drug Thioridazine Sun, 31 Jul 2016 11:59:32 +0000 Lung cancer stem cells are a subpopulation of cells critical for lung cancer progression, metastasis, and drug resistance. Thioridazine, a classical neurological drug, has been reported with anticancer ability. However, whether thioridazine could inhibit lung cancer stem cells has never been studied. In our current work, we used different dosage of thioridazine to test its effect on lung cancer stem cells sphere formation. The response of lung cancer stem cells to chemotherapy drug with thioridazine treatment was measured. The cell cycle distribution of lung cancer stem cells after thioridazine treatment was detected. The in vivo inhibitory effect of thioridazine was also measured. We found that thioridazine could dramatically inhibit sphere formation of lung cancer stem cells. It sensitized the LCSCs to chemotherapeutic drugs 5-FU and cisplatin. Thioridazine altered the cell cycle distribution of LCSCs and decreased the proportion of G0 phase cells in lung cancer stem cells. Thioridazine inhibited lung cancer stem cells initiated tumors growth in vivo. This study showed that thioridazine could inhibit lung cancer stem cells in vitro and in vivo. It provides a potential drug for lung cancer therapy through targeting lung cancer stem cells. Haiying Yue, Dongning Huang, Li Qin, Zhiyong Zheng, Li Hua, Guodong Wang, Jian Huang, and Haixin Huang Copyright © 2016 Haiying Yue et al. All rights reserved. Overexpression of β-Catenin Induces Cisplatin Resistance in Oral Squamous Cell Carcinoma Wed, 27 Jul 2016 06:18:41 +0000 Abnormal expression of -catenin contributes to tumor development, progression, and metastasis in various cancers. However, little is known about the relationship between abnormal expression of -catenin and cisplatin chemotherapy in oral squamous cell carcinoma (OSCC). The present study aimed to investigate the effect of -catenin on OSCC cisplatin resistance and evaluated the drug susceptibility of stable cell lines with -catenin knockin and knockdown. In this study, we found that higher expression level of -catenin can be observed in CDDP-treated cell lines as compared with the control group. Furthermore, the expression levels of -catenin increased in both a concentration- and time-dependent manner with the cisplatin treatment. More importantly, the nuclear translocation of -catenin could also be observed by confocal microscope analysis. Stable cell lines with CTNNB1 knockin and knockdown were established to further investigate the potential role and mechanism of -catenin in the chemoresistance of OSCC in vitro and in vivo. Our findings indicated that overexpression of -catenin promoted cisplatin resistance in OSCC in vitro and in vivo. We confirmed that GSK-3β, C-myc, Bcl-2, P-gp, and MRP-1 were involved in -catenin-mediated drug resistance. Our findings indicate that the Wnt/-catenin signaling pathway may play important roles in cisplatin resistance in OSCC. Long Li, Hai-Chao Liu, Cheng Wang, Xiqiang Liu, Feng-Chun Hu, Nan Xie, Lanhai Lü, Xiaohua Chen, and Hong-Zhang Huang Copyright © 2016 Long Li et al. All rights reserved. Clinical Outcomes of Patients with Rare and Heavily Pretreated Solid Tumors Treated according to the Results of Tumor Molecular Profiling Thu, 21 Jul 2016 09:54:07 +0000 Patients with heavily pretreated advanced cancer or with rare tumors are difficult to treat. Molecular profiling (MP) of tumors to identify biomarkers that predict potential outcomes with individual therapies is an emerging strategy to guide treatment decisions. Patients with rare tumors for which standard-of-care therapy was unavailable or more common tumors for which standard-of-care options had been exhausted underwent MP at a single Australian center. Data regarding treating physicians’ choice of therapy, MP results and recommendations, and patient outcomes were collected. Seven patients had received prior standard first-line therapy (PST), 16 had rare tumors, and 31 had been heavily pretreated (HPT; ≥2 prior lines). Most treatments suggested by MP (541/594; 91.1%) were common chemotherapy drugs available in generic formulations. MP-guided therapy recommendations differed from physician’s recommendations in 48 patients (88.9%). MP-guided therapy produced clinical benefit (improved QOL and/or performance status, symptoms, bodyweight, or RECIST) in 19/31 (61.3%), 11/16 (68.8%), and 3/7 (42.9%) patients with HPTs, rare tumors, and PSTs, respectively, and had a PFS ratio ≥1.3 in 22/37 evaluable patients (59.5%; 95% confidence interval 44–76%). The null hypothesis that ≤15% of these patients would have a PFS ratio ≥1.3 was rejected (one-sided ). In conclusion, using MP to guide therapy selection is feasible in clinical practice and may improve patient outcomes. Andrew Dean, Aisling Byrne, Mira Marinova, and Ingrid Hayden Copyright © 2016 Andrew Dean et al. All rights reserved. Interplay between Tumor Microenvironment and Cancer Cells Tue, 12 Jul 2016 13:43:05 +0000 Kallesh D. Jayappa, Ramesh C. Kovi, and Sumanta Chatterjee Copyright © 2016 Kallesh D. Jayappa et al. All rights reserved. Mitochondria Biogenesis and Bioenergetics Gene Profiles in Isogenic Prostate Cells with Different Malignant Phenotypes Sun, 10 Jul 2016 09:56:07 +0000 Background. The most significant hallmarks of cancer are directly or indirectly linked to deregulated mitochondria. In this study, we sought to profile mitochondria associated genes in isogenic prostate cell lines with different tumorigenic phenotypes from the same patient. Results. Two isogenic human prostate cell lines RC77N/E (nonmalignant cells) and RC77T/E (malignant cells) were profiled for expression of mitochondrial biogenesis and energy metabolism genes by qRT-PCR using the Human Mitochondria and the Mitochondrial Energy Metabolism RT2 PCR arrays. Forty-seven genes were differentially regulated between the two cell lines. The interaction and regulatory networks of these genes were generated by Ingenuity Pathway Analysis. UCP2 was the most significantly upregulated gene in primary adenocarcinoma cells in the current study. The overexpression of UCP2 upon malignant transformation was further validated using human prostatectomy clinical specimens. Conclusions. This study demonstrates the overexpression of multiple genes that are involved in mitochondria biogenesis, bioenergetics, and modulation of apoptosis. These genes may play a role in malignant transformation and disease progression. The upregulation of some of these genes in clinical samples indicates that some of the differentially transcribed genes could be the potential targets for therapeutic interventions. Tanya C. Burch, Johng S. Rhim, and Julius O. Nyalwidhe Copyright © 2016 Tanya C. Burch et al. All rights reserved. Corrigendum to “A Versatile Orthotopic Nude Mouse Model for Study of Esophageal Squamous Cell Carcinoma” Mon, 04 Jul 2016 11:42:04 +0000 Joseph Chok Yan Ip, Josephine Mun Yee Ko, Valen Zhuoyou Yu, Kwok Wah Chan, Alfred K. Lam, Simon Law, Daniel King Hung Tong, and Maria Li Lung Copyright © 2016 Joseph Chok Yan Ip et al. All rights reserved. High Expression of PTGR1 Promotes NSCLC Cell Growth via Positive Regulation of Cyclin-Dependent Protein Kinase Complex Sun, 26 Jun 2016 07:54:13 +0000 Lung cancer has been the most common cancer and the main cause of cancer-related deaths worldwide for several decades. PTGR1 (prostaglandin reductase 1), as a bifunctional enzyme, has been involved in the occurrence and progression of cancer. However, its impact on human lung cancer is rarely reported. In this study, we found that PTGR1 was overexpressed in lung cancer based on the analyses of Oncomine. Moreover, lentivirus-mediated shRNA knockdown of PTGR1 reduced cell viability in human lung carcinoma cells 95D and A549 by MTT and colony formation assay. PTGR1 depletion led to G2/M phase cell cycle arrest and increased the proportion of apoptotic cells in 95D cells by flow cytometry. Furthermore, silencing PTGR1 in 95D cells resulted in decreased levels of cyclin-dependent protein kinase complex (CDK1, CDK2, cyclin A2, and cyclin B1) by western blotting and then PTGR1 is positively correlated with cyclin-dependent protein by using the data mining of the Oncomine database. Therefore, our findings suggest that PTGR1 may play a role in lung carcinogenesis through regulating cell proliferation and is a potential new therapeutic strategy for lung cancer. Xianping Huang, Weihe Zhou, Yuefeng Zhang, and Yong Liu Copyright © 2016 Xianping Huang et al. All rights reserved. Clinical Significance of miR-149 in the Survival of Patients with Laryngeal Squamous Cell Carcinoma Wed, 15 Jun 2016 15:34:29 +0000 MicroRNAs (miRNAs) play critical roles in the progression of laryngeal cancer (LC). In this study, we aimed to investigate whether miR-149 is associated with the prognosis of patients with LC. A total of 97 laryngeal squamous cell carcinoma patients who underwent tumor resection were included in our follow-up study. In vitro studies was performed in cancer cell line Hep-2 to explore the antitumor role of miR-149 in LC. We found that the expression of miR-149 was significantly lower in tumor tissues, compared with vocal cord polyp tissues (). Kaplan-Meier analysis revealed that miR-149 expression status is significantly associated with survival duration (log rank test, ), and multivariate Cox regression analysis revealed that patients with low miR-149 expression had shorter survival times compared with patients with high miR-149 expression. In vitro studies revealed that the exogenous expression of miRNA-149 inhibits the proliferation of human Hep-2 cells and induces cell apoptosis. Our study suggests that miR-149 expression in laryngeal squamous cell carcinoma tissues is critically associated with the prognosis of patients, and the ectopic expression of miR-149 in Hep-2 cells inhibits proliferation and cell cycle progression. Yi Xu, Yun-Peng Lin, Dong Yang, Geng Zhang, and Hui-Fang Zhou Copyright © 2016 Yi Xu et al. All rights reserved. Potential Roles of Amiloride-Sensitive Sodium Channels in Cancer Development Wed, 15 Jun 2016 08:54:05 +0000 The ENaC/degenerin ion channel superfamily includes the amiloride-sensitive epithelial sodium channel (ENaC) and acid sensitive ionic channel (ASIC). ENaC is a multimeric ion channel formed by heteromultimeric membrane glycoproteins, which participate in a multitude of biological processes by mediating the transport of sodium (Na+) across epithelial tissues such as the kidney, lungs, bladder, and gut. Aberrant ENaC functions contribute to several human disease states including pseudohypoaldosteronism, Liddle syndrome, cystic fibrosis, and salt-sensitive hypertension. Increasing evidence suggests that ion channels not only regulate ion homeostasis and electric signaling in excitable cells but also play important roles in cancer cell behaviors such as proliferation, apoptosis, invasion, and migration. Indeed, ENaCs/ASICs had been reported to be associated with cancer characteristics. Given their cell surface localization and pharmacology, pharmacological strategies to target ENaC/ASIC family members may be promising cancer therapeutics. Siguang Xu, Cui Liu, Yana Ma, Hong-Long Ji, and Xiumin Li Copyright © 2016 Siguang Xu et al. All rights reserved. Salivary Secretory Immunoglobulin (SIgA) and Lysozyme in Malignant Tumor Patients Tue, 17 May 2016 11:25:08 +0000 Background. The purpose of this study is to understand the oral mucosal immune status of cancer patients and to make clear whether antibacterial proteins such as salivary secretory immunoglobulin (SIgA) and lysozyme in saliva were influenced by patients’ health status and certain medical treatment therapy. Materials and Methods. This study included 221 patients with malignant tumor receiving antineoplastic treatment and 171 age- and gender-matched healthy controls. Results. The results showed that patients suffering malignant tumor had lower level of SIgA and higher level of lysozyme than healthy subjects (). The SIgA level was significantly different among different cancer tumors, while the lysozyme level showed significant difference only between patients with digestive tract malignant tumor and hematopoietic system tumor. Pretreatment before transplantation for hematopoietic system tumor patients significantly affected the lysozyme level other than SIgA. SIgA level was affected by many factors such as age, therapy factors, and oral hygiene. Conclusion. Malignant tumor and the antineoplaston may weaken the patients’ oral mucosal immunity, influence levels of some salivary proteins, and decrease the level of SIgA, resulting in aggregation of oral bacteria and failure of clearing them from the oral cavity. Haiyan Sun, Yong Chen, Xuan Zou, Qihong Li, Huan Li, Yao Shu, Xia Li, Weihong Li, Li Han, and Cheng Ge Copyright © 2016 Haiyan Sun et al. All rights reserved. Differentially Expressed miRNAs in Tumor, Adjacent, and Normal Tissues of Lung Adenocarcinoma Tue, 10 May 2016 07:08:43 +0000 Lung cancer is the leading cause of cancer deaths. Non-small-cell lung cancer (NSCLC) is the major type of lung cancer. The aim of this study was to characterize the expression profiles of miRNAs in adenocarcinoma (AC), one major subtype of NSCLC. In this study, the miRNAs were detected in normal, adjacent, and tumor tissues by next-generation sequencing. Then the expression levels of differential miRNAs were quantified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). In the results, 259, 401, and 389 miRNAs were detected in tumor, adjacent, and normal tissues of pooled AC samples, respectively. In addition, for the first time we have found that miR-21-5p and miR-196a-5p were gradually upregulated from normal to adjacent to tumor tissues; miR-218-5p was gradually downregulated with 2-fold or greater change in AC tissues. These 3 miRNAs were validated by qRT-PCR. Lastly, we predicted target genes of these 3 miRNAs and enriched the potential functions and regulatory pathways. The aberrant miR-21-5p, miR-196a-5p, and miR-218-5p may become biomarkers for diagnosis and prognosis of lung adenocarcinoma. This research may be useful for lung adenocarcinoma diagnosis and the study of pathology in lung cancer. Fei Tian, Rui Li, Zhenzhu Chen, Yanting Shen, Jiafeng Lu, Xueying Xie, and Qinyu Ge Copyright © 2016 Fei Tian et al. All rights reserved. Combinatorial Antitumor Effect of Rapamycin and β-Elemene in Follicular Thyroid Cancer Cells Wed, 04 May 2016 16:31:40 +0000 Background. mTOR signaling would be a promising target for thyroid cancer therapy. However, in clinical trials, objective response rate with mTOR inhibitor monotherapy in most cancer types was modest. A new focus on development of combinatorial strategies with rapalogs is increasing. Objective. Investigating the combinatorial antitumor effect of rapamycin and β-elemene in follicular thyroid cancer cells. Methods. MTT assay was used to determine the FTC-133 cell proliferation after culturing with rapamycin and/or β-elemene. To analyze their combinatorial effect, immunoblotting was performed to analyze the activation status of AKT. Moreover, β-elemene attenuated rapamycin-induced immunosuppression was tested in mice. Results. Combination of rapamycin and β-elemene exerted significant synergistic antiproliferative effects in FTC-133 cell lines in vitro, based on inhibiting the AKT feedback activation induced by rapamycin. In vivo, the β-elemene could attenuate rapamycin-induced immunosuppression via reversing imbalance of Treg/Th17, with the underlying mechanism needed to be declared. Conclusions. We demonstrate that the novel combination of mTOR inhibitor with β-elemene synergistically attenuates tumor cell growth in follicular thyroid cancer, which requires additional preclinical validation. Jun Zhou, Li-Li He, Xiao-Fei Ding, Qiu-Qi Yuan, Jian-Xin Zhang, Shuang-Chun Liu, and Guang Chen Copyright © 2016 Jun Zhou et al. All rights reserved. Clinical Outcome and Prognostic Factors of Intensity-Modulated Radiotherapy for T4 Stage Nasopharyngeal Carcinoma Tue, 19 Apr 2016 11:51:10 +0000 Objective. To analyze the clinical outcomes and prognostic factors of intensity-modulated radiotherapy (IMRT) for T4 stage nasopharyngeal carcinoma (NPC). Methods. Between March 2005 and March 2010, 110 patients with T4 stage NPC without distant metastases were treated. All patients received IMRT. Induction and/or concurrent chemotherapy were given. 47 (42.7%) patients received IMRT replanning. Results. The 5-year local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) rates were 90.1%, 97.0%, 67.5%, 63.9%, and 64.5%, respectively. Eleven patients experienced local-regional failure and total distant metastasis occurred in 34 patients. 45 patients died and 26 patients died of distant metastasis alone. The 5-year LRFS rates were 97.7% and 83.8% for the patients that received and did not receive IMRT replanning, respectively (). Metastasis to the retropharyngeal lymph nodes (RLN) was associated with inferior 5-year OS rate (61.0% versus 91.7%, ). The gross tumor volume of the right/left lymph nodes (GTVln) was an independent prognostic factor for DMFS () and PFS (). GTVln was with marginal significance as the prognostic factor for OS (). Conclusion. IMRT provides excellent local-regional control for T4 stage NPC. Benefit of IMRT replanning may be associated with improvement in local control. Incorporating GTVln into the N staging system may provide better prognostic information. Yangkun Luo, Yang Gao, Guangquan Yang, and Jinyi Lang Copyright © 2016 Yangkun Luo et al. All rights reserved. Steroid Tumor Environment in Male and Female Mice Model of Canine and Human Inflammatory Breast Cancer Mon, 18 Apr 2016 07:25:23 +0000 Canine inflammatory mammary cancer (IMC) shares clinical and histopathological characteristics with human inflammatory breast cancer (IBC) and has been proposed as a good model for studying the human disease. The aim of this study was to evaluate the capacity of female and male mice to reproduce IMC and IBC tumors and identify the hormonal tumor environment. To perform the study sixty 6–8-week-old male and female mice were inoculated subcutaneously with a suspension of 106 IPC-366 and SUM149 cells. Tumors and serum were collected and used for hormonal analysis. Results revealed that IPC-366 reproduced tumors in 90% of males inoculated after 2 weeks compared with 100% of females that reproduced tumor at the same time. SUM149 reproduced tumors in 40% of males instead of 80% of females that reproduced tumors after 4 weeks. Both cell lines produce distant metastasis in lungs being higher than the metastatic rates in females. EIA analysis revealed that male tumors had higher T and SO4E1 concentrations compared to female tumors. Serum steroid levels were lower than those found in tumors. In conclusion, IBC and IMC male mouse model is useful as a tool for IBC research and those circulating estrogens and intratumoral hormonal levels are crucial in the development and progression of tumors. Sara Caceres, Laura Peña, Gema Silvan, Maria J. Illera, Wendy A. Woodward, James M. Reuben, and Juan C. Illera Copyright © 2016 Sara Caceres et al. All rights reserved. The Antitumor Effect of Gekko Sulfated Glycopeptide by Inhibiting bFGF-Induced Lymphangiogenesis Tue, 12 Apr 2016 13:10:30 +0000 Objective. To study the antilymphangiogenesis effect of Gekko Sulfated Glycopeptide (GSPP) on human lymphatic endothelial cells (hLECs). Methods. MTS was conducted to confirm the antiproliferation effect of GSPP on hLECs; flow cytometry was employed to detect hLECs cycle distribution; the antimigration effect of GSPP on hLECs was investigated by wound healing experiment and transwell experiment; tube formation assay was used to examine its inhibitory effect on the lymphangiogenesis; western blotting was conducted to detect the expression of extracellular signal-regulated kinase1/2 (Erk1/2) and p-Erk1/2 after GSPP and basic fibroblast growth factor (bFGF) treatment. Nude mice models were established to investigate the antitumor effect of GSPP in vivo. Decreased lymphangiogenesis caused by GSPP in vivo was verified by immunohistochemical staining. Results. In vitro, GSPP (10 μg/mL, 100 μg/mL) significantly inhibited bFGF-induced hLECs proliferation, migration, and tube-like structure formation () and antagonized the phosphorylation activation of Erk1/2 induced by bFGF. In vivo, GSPP treatment (200 mg/kg/d) not only inhibited the growth of colon carcinoma, but also inhibited the tumor lymphangiogenesis. Conclusion. GSPP possesses the antitumor ability by inhibiting bFGF-inducing lymphangiogenesis in vitro and in vivo, which may further inhibit tumor lymphatic metastasis. Xiu-Li Ding, Ya-Nan Man, Jian Hao, Cui-Hong Zhu, Chang Liu, Xue Yang, and Xiong-Zhi Wu Copyright © 2016 Xiu-Li Ding et al. All rights reserved. Cancerous Inhibitor of PP2A Silencing Inhibits Proliferation and Promotes Apoptosis in Human Multiple Myeloma Cells Wed, 06 Apr 2016 12:31:15 +0000 Multiple myeloma is the second most prevalent type of blood cancer, representing approximately 1% of all cancers and 2% of all cancer deaths. There is therefore a strong need to identify critical targets in multiple myeloma neoplasia and progression. Cancerous inhibitor of PP2A (CIP2A) is a human oncoprotein that regulates cancer cell viability and anchorage-independent growth and induces apoptosis. The present study investigated CIP2A function in the human multiple myeloma cell lines RPMI-8226 and NCI-H929 to determine whether it can serve as a potential therapeutic target. CIP2A was silenced in the cells by transfection of short interfering RNA and cell proliferation and apoptosis were evaluated by a tetrazolium salt-based assay and flow cytometry, respectively. CIP2A knockdown inhibited proliferation and induced apoptosis in RPMI-8226 and NCI-H929 cells and decreased the phosphorylation of phosphoinositide 3-kinase (PI3K) p85, AKT1, and mammalian target of rapamycin (mTOR) without affecting total protein levels. Treatment of CIP2A-depletion cells with insulin-like growth factor 1 decreased the effects of CIP2A inhibition on cell viability and apoptosis. These results indicate that CIP2A modulates myeloma cell proliferation and apoptosis via PI3K/AKT/mTOR signaling and suggest that it can potentially serve as a drug target for the treatment of multiple myeloma. Xi Yang, Yaping Zhang, Hong Liu, and Zenghua Lin Copyright © 2016 Xi Yang et al. All rights reserved. Cell Cycle Arrest and Apoptosis Induction via Modulation of Mitochondrial Integrity by Bcl-2 Family Members and Caspase Dependence in Dracaena cinnabari-Treated H400 Human Oral Squamous Cell Carcinoma Wed, 30 Mar 2016 08:36:19 +0000 Dracaena cinnabari Balf.f. is a red resin endemic to Socotra Island, Yemen. Although there have been several reports on its therapeutic properties, information on its cytotoxicity and anticancer effects is very limited. This study utilized a bioassay-guided fractionation approach to determine the cytotoxic and apoptosis-inducing effects of D. cinnabari on human oral squamous cell carcinoma (OSCC). The cytotoxic effects of D. cinnabari crude extract were observed in a panel of OSCC cell lines and were most pronounced in H400. Only fractions DCc and DCd were active on H400 cells; subfractions DCc15 and DCd16 exhibited the greatest cytotoxicity against H400 cells and D. cinnabari inhibited cells proliferation in a time-dependent manner. This was achieved primarily via apoptosis where externalization of phospholipid phosphatidylserine was observed using DAPI/Annexin V fluorescence double staining mechanism studied through mitochondrial membrane potential assay cytochrome enzyme-linked immunosorbent and caspases activities revealed depolarization of mitochondrial membrane potential (MMP) and significant activation of caspases 9 and 3/7, concomitant with S phase arrest. Apoptotic proteins array suggested that MMP was regulated by Bcl-2 proteins family as results demonstrated an upregulation of Bax, Bad, and Bid as well as downregulation of Bcl-2. Hence, D. cinnabari has the potential to be developed as an anticancer agent. Aied M. Alabsi, Kai Li Lim, Ian C. Paterson, Rola Ali-Saeed, and Bushra A. Muharram Copyright © 2016 Aied M. Alabsi et al. All rights reserved. Proapoptotic Role of Potassium Ions in Liver Cells Wed, 16 Mar 2016 07:59:42 +0000 Potassium channels are transmembrane proteins that selectively promote the infiltration of potassium ions. The significance of these channels for tumor biology has become obvious. However, the effects of potassium ions on the tumor or normal cells have seldom been studied. To address this problem, we studied the biological effects of L02 and HepG2 cells with ectogenous potassium ions. Cell proliferation, cell cycle, and apoptosis rate were analyzed. Our results indicated that potassium ions inhibited proliferation of L02 and HepG2 cells and promoted their apoptosis. Potassium ions induced apoptosis through regulating Bcl-2 family members and depolarized the mitochondrial membrane, especially for HepG2 cell. These biological effects were associated with channel protein HERG. By facilitating expression of channel protein HERG, potassium ions may prevent it from being shunted to procancerous pathways by inducing apoptosis. These results demonstrated that potassium ions may be a key regulator of liver cell function. Thus, our findings suggest that potassium ions could inhibit tumorigenesis through inducing apoptosis of hepatoma cells by upregulating potassium ions transport channel proteins HERG and VDAC1. Zhenglin Xia, Xusen Huang, Kaiyun Chen, Hanning Wang, Jinfeng Xiao, Ke He, Rui Huang, Xiaopeng Duan, Hao Liu, Jinqian Zhang, and Guoan Xiang Copyright © 2016 Zhenglin Xia et al. All rights reserved. Synergistic Effect and Molecular Mechanisms of Traditional Chinese Medicine on Regulating Tumor Microenvironment and Cancer Cells Wed, 02 Mar 2016 12:57:40 +0000 The interaction of tumor cells with the microenvironment is like a relationship between the “seeds” and “soil,” which is a hotspot in recent cancer research. Targeting at tumor microenvironment as well as tumor cells has become a new strategy for cancer treatment. Conventional cancer treatments mostly focused on single targets or single mechanism (the seeds or part of the soil); few researches intervened in the whole tumor microenvironment and achieved ideal therapeutic effect as expected. Traditional Chinese medicine displays a broad range of biological effects, and increasing evidence has shown that it may relate with synergistic effect on regulating tumor microenvironment and cancer cells. Based on literature review and our previous studies, we summarize the synergistic effect and the molecular mechanisms of traditional Chinese medicine on regulating tumor microenvironment and cancer cells. Jingnan Xu, Zhuo Song, Qiujun Guo, and Jie Li Copyright © 2016 Jingnan Xu et al. All rights reserved. Novel Technologies for Improved Treatment Outcome and Patient Safety in Cancer Radiotherapy Tue, 01 Mar 2016 11:03:27 +0000 Jun Deng, Yuanming Feng, Charlie Ma, and Fang-Fang Yin Copyright © 2016 Jun Deng et al. All rights reserved. 3D-2D Deformable Image Registration Using Feature-Based Nonuniform Meshes Thu, 25 Feb 2016 09:44:52 +0000 By using prior information of planning CT images and feature-based nonuniform meshes, this paper demonstrates that volumetric images can be efficiently registered with a very small portion of 2D projection images of a Cone-Beam Computed Tomography (CBCT) scan. After a density field is computed based on the extracted feature edges from planning CT images, nonuniform tetrahedral meshes will be automatically generated to better characterize the image features according to the density field; that is, finer meshes are generated for features. The displacement vector fields (DVFs) are specified at the mesh vertices to drive the deformation of original CT images. Digitally reconstructed radiographs (DRRs) of the deformed anatomy are generated and compared with corresponding 2D projections. DVFs are optimized to minimize the objective function including differences between DRRs and projections and the regularity. To further accelerate the above 3D-2D registration, a procedure to obtain good initial deformations by deforming the volume surface to match 2D body boundary on projections has been developed. This complete method is evaluated quantitatively by using several digital phantoms and data from head and neck cancer patients. The feature-based nonuniform meshing method leads to better results than either uniform orthogonal grid or uniform tetrahedral meshes. Zichun Zhong, Xiaohu Guo, Yiqi Cai, Yin Yang, Jing Wang, Xun Jia, and Weihua Mao Copyright © 2016 Zichun Zhong et al. All rights reserved. Combining Whole-Brain Radiotherapy with Gefitinib/Erlotinib for Brain Metastases from Non-Small-Cell Lung Cancer: A Meta-Analysis Wed, 24 Feb 2016 08:59:21 +0000 Background. To comprehensively assess the efficacy and safety of whole-brain radiotherapy (WBRT) combined with gefitinib/erlotinib for treatment of brain metastases (BM) from non-small-cell lung cancer (NSCLC). Methods. Databases including PubMed,, Web of Science, and Cochrane Library were searched from inception to April 12, 2015. Studies on randomized controlled trials (RCTs) and case-control trials comparing WBRT combined with gefitinib/erlotinib versus WBRT alone for BM from NSCLC were included. Literature selection, data extraction, and quality assessment were performed independently by two trained reviewers. RevMan 5.3 software was used to analyze data. Results. A total of 7 trials involving 622 patients were included. Compared with WBRT alone or WBRT plus chemotherapy, WBRT plus gefitinib/erlotinib could significantly improve response rate (OR = 2.16, 95% CI: 1.35–3.47; ), remission rate of central nervous system (OR = 6.06, 95% CI: 2.57–14.29; ), disease control rate (OR = 3.34, 95% CI: 1.84–6.07; ), overall survival (HR = 0.72, 95% CI: 0.58–0.89; ), and 1-year survival rate (OR = 2.43, 95% CI: 1.51–3.91; ). In adverse events (III-IV), statistically significant differences were not found, except for rash (OR = 7.96, 95% CI: 2.02–31.34; ) and myelosuppression (OR = 0.19, 95% CI: 0.07–0.51; ). Conclusions. WBRT plus gefitinib/erlotinib was superior to WBRT alone and well tolerated in patients with BM from NSCLC. Mao-hua Zheng, Hong-tao Sun, Ji-guang Xu, Gang Yang, Lei-ming Huo, Pan Zhang, Jin-hui Tian, and Ke-hu Yang Copyright © 2016 Mao-hua Zheng et al. All rights reserved. Short-Term Side Effects after Radioiodine Treatment in Patients with Differentiated Thyroid Cancer Wed, 17 Feb 2016 12:29:51 +0000 Objectives. I-131 therapy for differentiated thyroid cancer (DTC) could induce adverse effects. The purpose of this study was to report and analyze symptoms after I-131 treatment within the hospitalization and present relevant medical intervention. Methods. I-131 doses ranging from 3.7 to 9.25 GBq (100–250 mCi) were administrated for thyroid remnant ablation or treating DTC metastases. 117 patients with DTC for I-131 therapy were monitored through the video and intercommunicating with standardized questionnaire at different time points after I-131 oral administration. Adverse effects were recorded and relevant clinical factors were analyzed. Results. Among all the 117 patients, 55 cases complained of neck’s pain or swelling and 79 cases presented with gastrointestinal symptoms. Pain or swelling of salivary gland occurred in 15 patients, headache and vertigo in 10, insomnia in 9, vocal cord paralysis in 6, fatigue or general malaise in 6, and foreign body sensation in 5. Body numbness and urinary symptoms were observed in only 1 case, respectively. Those side effects were related with sex, pre-I-131 treatment TSH levels, frequency of I-131 therapy, and lymph node metastases. Conclusions. Short-term side effects after I-131 therapy for DTC patients varied individually; severe symptoms were not uncommon but generally did not need emergent medical intervention. Liyan Lu, Fengling Shan, Wenbin Li, and Hankui Lu Copyright © 2016 Liyan Lu et al. All rights reserved. New Prognostic and Predictive Markers in Head and Neck Tumors Tue, 16 Feb 2016 16:15:48 +0000 Monica Cantile, Francesco Longo, Gerardo Botti, and Franco Fulciniti Copyright © 2016 Monica Cantile et al. All rights reserved. Cancer Related Fatigue and Quality of Life in Patients with Advanced Prostate Cancer Undergoing Chemotherapy Sun, 14 Feb 2016 11:07:30 +0000 Cancer related fatigue (CRF) is a common and debilitating symptom that can influence quality of life (QoL) in cancer patients. The increase in survival times stresses for a better understanding of how CRF affects patients’ QoL. This was a cross-sectional descriptive study with 148 randomly recruited prostate cancer patients aiming to explore CRF and its impact on QoL. Assessments included the Cancer Fatigue Scale, EORTC QLQ-C30, and EORTC QLQ-PR25. Additionally, 15 in-depth structured interviews were performed. Quantitative data were analyzed with simple and multiple regression analysis and independent samples -test. Qualitative data were analyzed with the use of thematic content analysis. The 66.9% of the patients experienced CRF with higher levels being recorded for the affective subscale. Statistically significant differences were found between the patients reporting CRF and lower levels of QoL (mean = 49.1) and those that did not report fatigue and had higher levels of QoL (mean = 72.1). The interviews emphasized CRF’s profound impact on the patients’ lives that was reflected on the following themes: “dependency on others,” “loss of power over decision making,” and “daily living disruption.” Cancer related fatigue is a significant problem for patients with advanced prostate cancer and one that affects their QoL in various ways. Andreas Charalambous and Christiana Kouta Copyright © 2016 Andreas Charalambous and Christiana Kouta. All rights reserved. Energy Modulated Photon Radiotherapy: A Monte Carlo Feasibility Study Tue, 09 Feb 2016 05:52:29 +0000 A novel treatment modality termed energy modulated photon radiotherapy (EMXRT) was investigated. The first step of EMXRT was to determine beam energy for each gantry angle/anatomy configuration from a pool of photon energy beams (2 to 10 MV) with a newly developed energy selector. An inverse planning system using gradient search algorithm was then employed to optimize photon beam intensity of various beam energies based on presimulated Monte Carlo pencil beam dose distributions in patient anatomy. Finally, 3D dose distributions in six patients of different tumor sites were simulated with Monte Carlo method and compared between EMXRT plans and clinical IMRT plans. Compared to current IMRT technique, the proposed EMXRT method could offer a better paradigm for the radiotherapy of lung cancers and pediatric brain tumors in terms of normal tissue sparing and integral dose. For prostate, head and neck, spine, and thyroid lesions, the EMXRT plans were generally comparable to the IMRT plans. Our feasibility study indicated that lower energy (<6 MV) photon beams could be considered in modern radiotherapy treatment planning to achieve a more personalized care for individual patient with dosimetric gains. Ying Zhang, Yuanming Feng, Xin Ming, and Jun Deng Copyright © 2016 Ying Zhang et al. All rights reserved. Efficacy and Safety of Novel Agent-Based Therapies for Multiple Myeloma: A Meta-Analysis Mon, 01 Feb 2016 09:58:50 +0000 This study aimed at comparing bortezomib, thalidomide, and lenalidomide in patients with multiple myeloma (MM) for safety and efficacy using meta-analysis. This meta-analysis identified 17 randomized controlled trials (RCTs) including 6742 patients. These RCTs were separated according to the different agent-based regimens and to autologous stem-cell transplantation (ASCT). Complete response (CR), progression-free survival (PFS), overall survival (OS), and adverse events (AE) were combined. The total weighted risk ratio (RR) of CR was 3.29 [95% confidence interval (95% CI): 2.22–4.88] () for the novel agent-based regimens. These novel agent-based regimens showed greater benefit in terms of PFS of all subgroups irrespective of whether the patient received ASCT or not. The hazard ratio (HR) for PFS was 0.64 [95% CI: 0.60–0.69] (). Improvements of OS could be found only in the bortezomib- and thalidomide-based regimens without ASCT. The pooled HRs were 0.74 [95% CI: 0.65–0.86] () and 0.80 [95% CI: 0.70–0.90] (), respectively. Several AEs were shown more frequently in the novel agent-based regimens compared with controls such as hematologic events (neutropenia, anemia, and thrombocytopenia), gastrointestinal infection, peripheral neuropathy, thrombosis, and embolism events. In conclusion, in spite of the AEs, novel agent-based regimens are safe and effective for the treatment of MM. Xiaoxue Wang, Yan Li, and Xiaojing Yan Copyright © 2016 Xiaoxue Wang et al. All rights reserved. The Association between Abnormal Long Noncoding RNA MALAT-1 Expression and Cancer Lymph Node Metastasis: A Meta-Analysis Wed, 27 Jan 2016 06:58:23 +0000 Previous studies have investigated that the expression levels of MALAT-1 were higher in cancerous tissues than matched histologically normal tissues. And, to some extent, overexpression of MALAT-1 was inclined to lymph node metastasis. This meta-analysis collected all relevant articles and explored the association between MALAT-1 expression levels and lymph node metastasis. We searched PubMed, EmBase, Web of Science, Cochrane Library, and OVID to address the level of MALAT-1 expression in cancer cases and noncancerous controls (accessed February 2015). And 8 studies comprising 696 multiple cancer patients were included to assess this association. The odds ratio (OR) and its corresponding 95% confidence interval (CI) were calculated to assess the strength of the association using Stata 12.0 version software. The results revealed there was a significant difference in the incidence of lymph node metastasis between high MALAT-1 expression group and low MALAT-1 expression group (OR = 1.94, 95% CI 1.15–3.28, random-effects model). Subgroup analysis indicated that MALAT-1 high expression had an unfavorable impact on lymph node metastasis in Chinese patients (OR = 1.87, 95% CI 1.01–2.46). This study demonstrated that the incidence of lymph node metastasis in patients detected with high MALAT-1 expression was higher than that in patients with low MALAT-1 expression in China. Jun Wang, Yongsheng Pan, Jie Wu, Cheng Zhang, Yuan Huang, Ruizhe Zhao, Gong Cheng, Jinliang Liu, Chao Qin, Pengfei Shao, Lixin Hua, and Zengjun Wang Copyright © 2016 Jun Wang et al. All rights reserved. Metformin Synergistically Enhances Cisplatin-Induced Cytotoxicity in Esophageal Squamous Cancer Cells under Glucose-Deprivation Conditions Sun, 24 Jan 2016 11:30:17 +0000 Previous studies suggest that metformin may exert a protective effect on cisplatin-induced cytotoxicity in cancer cells, and this finding has led to a caution for considering metformin use in the treatment of cancer patients. However, in this paper we provide the first demonstration that metformin synergistically augments cisplatin cytotoxicity in the esophageal squamous cancer cell line, ECA109, under glucose-deprivation conditions, which may be more representative of the microenvironment within solid tumors; this effect is very different from the previously reported cytoprotective effect of metformin against cisplatin in commonly used high glucose incubation medium. The potential mechanisms underlying the synergistic effect of metformin on cisplatin-induced cytotoxicity under glucose-deprivation conditions may include enhancement of metformin-associated cytotoxicity, marked reduction in the cellular ATP levels, deregulation of the AKT and AMPK signaling pathways, and impaired DNA repair function. Hongliang Yu, Xiuhua Bian, Dayong Gu, and Xia He Copyright © 2016 Hongliang Yu et al. All rights reserved. Expressing Status and Correlation of ARID1A and Histone H2B on Breast Cancer Thu, 21 Jan 2016 08:49:30 +0000 ARID1A is one of the important cancer-related genes and regulates transcription of certain genes by altering chromatin structure. Inactivated mutations and decreased expression of ARID1A gene have been reported in several kinds of cancer. Histone H2B is a major component of chromatin and encoded by HIST1H2BE. The goal of the study is to evaluate expressing status of ARID1A and H2B as well as their correlation on breast cancer. Gene expression profiles of ARID1A and H2B on Oncomine database are analyzed. Tissue microarray of breast cancer was used for examination of ARID1A and H2B expression by immunohistochemistry. As a result, the disagreement of ARID1A expression was found, while HIST1H2BE expression is elevated in 4 out of 5 datasets on Oncomine database. There were 15 cases (20%) of breast cancers that were positive for ARID1A. Fifty-eight out of 75 cases of breast cancer (77.3%) were highly expressed for H2B protein and 17 cases (22.7%) were low expressed for H2B protein. All cases with ARID1A expression are overlapped with H2B high expression. Among 15 cases with ARID1A and H2B coexpression, 13 are invasive ductal carcinoma and 2 are mucinous carcinoma. Our results indicate that ARID1A gene may be involved in carcinogenesis of some subtypes of breast cancer. Yan Wu, Yan Gu, Shanyu Guo, Qiancheng Dai, and Wei Zhang Copyright © 2016 Yan Wu et al. All rights reserved. Volumetric Modulated Arc Therapy for Spine Radiosurgery: Superior Treatment Planning and Delivery Compared to Static Beam Intensity Modulated Radiotherapy Wed, 13 Jan 2016 13:36:03 +0000 Purpose. Spine stereotactic radiosurgery (SRS) delivers an accurate and efficient high radiation dose to vertebral metastases in 1–5 fractions. We aimed to compare volumetric modulated arc therapy (VMAT) to static beam intensity modulated radiotherapy (IMRT) for spine SRS. Methods and Materials. Ten spine lesions of previously treated SRS patients were planned retrospectively using both IMRT and VMAT with a prescribed dose of 16 Gy to 100% of the planning target volume (PTV). The plans were compared for conformity, homogeneity, treatment delivery time, and safety (spinal cord dose). Results. All evaluated parameters favored the VMAT plan over the IMRT plans. in the IMRT was significantly lower than in the VMAT plan (7.65 Gy/10.88 Gy, ), the Dice Similarity Coefficient (DSC) was found to be significantly better for the VMAT plans compared to the IMRT plans (0.77/0.58, resp., ), and an almost 50% reduction in the net treatment time was calculated for the VMAT compared to the IMRT plans (6.73 min/12.96 min, ). Conclusions. In our report, VMAT provides better conformity, homogeneity, and safety profile. The shorter treatment time is a major advantage and not only provides convenience to the painful patient but also contributes to the precision of this high dose radiation therapy. Leor Zach, Lev Tsvang, Dror Alezra, Maoz Ben Ayun, and Ran Harel Copyright © 2016 Leor Zach et al. All rights reserved. Downregulation of Heparanase Expression Results in Suppression of Invasion, Migration, and Adhesion Abilities of Hepatocellular Carcinoma Cells Tue, 29 Dec 2015 07:25:34 +0000 Objective. Heparanase (HPSE) is high-expressed in most malignant tumors including hepatocellular carcinoma (HCC) and promotes cancer cell invasion and migration. The aim of the study is to explore whether HPSE enhances adhesion in metastasis of HCC cells. Methods. HPSE expressions in human HCC cells were measured with real-time RT-PCR and Western blot analysis. Four recombinant miRNA vectors pcDNATM6.2-GW/EmGFP-miR-HPSE (pmiR-HPSE) were transfected into HCCLM3 cell. HPSE expression in transfected cell was measured. The cell invasion, migration, and adhesion abilities were detected, respectively. Results. Both HPSE mRNA and protein relative expression levels were higher in HepG2, BEL-7402, and HCCLM3 cells than those in normal hepatocyte (). HPSE showed highest expression level in HCCLM3 cell (). Transfection efficiencies of four miRNA vectors were 75%–85%. The recombinant vectors significantly decreased HPSE expression in transfected HCCLM3 cells (), and pmiR-HPSE-1 showed best interference effect (). pmiR-HPSE-1 significantly decreased the penetrated and migrating cells numbers and adherence rate of HCCLM3 cells (). Conclusion. HPSE is a potentiator of cell adhesion in metastasis of HCC. Xiao-Peng Chen, Jun-Sheng Luo, Ye Tian, Chen-Lin Nie, Wei Cui, and Wei-Dong Zhang Copyright © 2015 Xiao-Peng Chen et al. All rights reserved. Serial Patterns of Ovarian Cancer Biomarkers in a Prediagnosis Longitudinal Dataset Thu, 24 Dec 2015 13:29:15 +0000 Early detection of ovarian cancer through screening may have impact on mortality from the disease. Approaches based on CA125 cut-off have not been effective. Longitudinal algorithms such as the Risk of Ovarian Cancer Algorithm (ROCA) to interpret CA125 have been shown to have higher sensitivity and specificity than a single cut-off. The aim of this study was to investigate whether other ovarian cancer-related biomarkers, Human Epididymis 4 (HE4), glycodelin, mesothelin, matrix metalloproteinase 7 (MMP7), and cytokeratin 19 fragment (CYFRA 21-1), could improve the performance of CA125 in detecting ovarian cancer earlier. Serum samples (single and serial) predating diagnosis from 47 women taking part in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) who went on to develop primary invasive ovarian, fallopian tube, or peritoneal cancer (index cancer) (170 samples) and 179 matched controls (893 samples) were included in the study. A multiplex immunobased assay platform (Becton Dickinson) allowing simultaneous measurement of the six serum markers was used. The area under the ROC curve for the panel of three biomarkers (CA125, HE4, and glycodelin) was higher than for CA125 alone for all analysed time groups, indicating that these markers can improve on sensitivity of CA125 alone for ovarian cancer detection. Oleg Blyuss, Alex Gentry-Maharaj, Evangelia-Orania Fourkala, Andy Ryan, Alexey Zaikin, Usha Menon, Ian Jacobs, and John F. Timms Copyright © 2015 Oleg Blyuss et al. All rights reserved. Replanning Criteria and Timing Definition for Parotid Protection-Based Adaptive Radiation Therapy in Nasopharyngeal Carcinoma Thu, 17 Dec 2015 06:18:55 +0000 The goal of this study was to evaluate real-time volumetric and dosimetric changes of the parotid gland so as to determine replanning criteria and timing for parotid protection-based adaptive radiation therapy in nasopharyngeal carcinoma. Fifty NPC patients were treated with helical tomotherapy; volumetric and dosimetric (, , and ) changes of the parotid gland at the 1st, 6th, 11th, 16th, 21st, 26th, 31st, and 33rd fractions were evaluated. The clinical parameters affecting these changes were studied by analyses of variance methods for repeated measures. Factors influencing the actual parotid dose were analyzed by a multivariate logistic regression model. The cut-off values predicting parotid overdose were developed from receiver operating characteristic curves and judged by combining them with a diagnostic test consistency check. The median absolute value and percentage of parotid volume reduction were 19.51 cm3 and 35%, respectively. The interweekly parotid volume varied significantly (). The parotid , , and increased by 22.13%, 39.42%, and 48.45%, respectively. The actual parotid dose increased by an average of 11.38% at the end of radiation therapy. Initial parotid volume, initial parotid , and weight loss rate are valuable indicators for parotid protection-based replanning. Wei-Rong Yao, Shou-Ping Xu, Bo Liu, Xiu-Tang Cao, Gang Ren, Lei Du, Fu-Gen Zhou, Lin-Chun Feng, Bao-Lin Qu, Chuan-Bin Xie, and Lin Ma Copyright © 2015 Wei-Rong Yao et al. All rights reserved. Downregulation of miR-221 Inhibits Cell Migration and Invasion through Targeting Methyl-CpG Binding Domain Protein 2 in Human Oral Squamous Cell Carcinoma Cells Wed, 16 Dec 2015 11:17:25 +0000 Oral squamous cell carcinoma (OSCC), the most frequent of all oral cancers, is a type of highly malignant tumors with a high capacity to invade locally and form distant metastases. An increasing number of studies have shown that microRNAs (miRNAs) play an important role in regulating cancer metastasis and invasion. In the present study, we detected the expression of miR-221 in two highly metastatic OSCC cell lines and two OSCC cell lines that are less metastatic using quantitative real-time PCR analysis (qRT-PCR). The qRT-PCR results indicate that miR-221 is upregulated in highly metastatic OSCC cell lines. Then, miR-221 expression was knocked down by transfection with miR-221 inhibitor, and UM1 cell migration and invasion were assessed using transwell migration and invasion assays. The results indicate that inhibition of miR-221 suppressed migration and invasion of UM1 cells. Furthermore, methyl-CpG binding domain protein 2 (MBD2) was identified as a direct target gene of miR-221. Additionally, MBD2 silencing could partly reverse the effect of miR-221 on cell migration and invasion. In conclusion, downregulation of miR-221 inhibits cell migration and invasion at least partially through targeting MBD2 in the human OSCC cell line UM1. Shuqi He, Renfa Lai, Dan Chen, Wangxiang Yan, Zhaoqiang Zhang, Zhiguo Liu, Xueqiang Ding, and Yu Chen Copyright © 2015 Shuqi He et al. All rights reserved. The Role of FGFR1 Gene Amplification as a Poor Prognostic Factor in Squamous Cell Lung Cancer: A Meta-Analysis of Published Data Wed, 16 Dec 2015 09:35:47 +0000 Objectives. The prognostic factors of the fibroblast growth factor receptor 1 (FGFR1) in non-small cell lung cancer (NSCLC) remain controversial. Methods. We conducted a meta-analysis of published studies from 1974 to February 2015. In absence of quality difference between studies of reporting significant and nonsignificant results, the relationship between FGFR1 amplification and clinicopathological parameters in NSCLC was analyzed. And also the combined hazard ratio (HR) and their corresponding 95% confidence interval (CI) were calculated in terms of overall survival. Results. 3178 patients (12 studies) were included in the analysis. It was shown that FGFR1 amplification was significantly more prevalent among male patients (RR 2.03, 95% CI 1.57–2.63) with squamous cell lung cancer (SQCC) (RR 3.49, 95% CI 2.62–4.64) and current smokers (RR 2.63, 95% CI 1.92–3.60). The pooled data also showed that the FGFR1 amplification was a poor prognostic factor in SQCC (HR 1.38, 95% CI 1.07–1.78), Asian patients (HR 1.78, 95% CI 1.22–2.60), and fluorescence in situ hybridization (FISH) method (HR 1.30, 95% CI 1.06–1.58). Conclusions. This meta-analysis strongly suggests that FGFR1 amplification occurs more frequently in male, SQCC and smokers, and it is a risk factor for poor prognosis among Asian patients with SQCC. Yang Wang, Wen Gao, Jiali Xu, Xiaojun Chen, Yang Yang, Yizhi Zhu, Yongmei Yin, Renhua Guo, Ping Liu, Yongqian Shu, and Lingxiang Liu Copyright © 2015 Yang Wang et al. All rights reserved. Genetic Variations in Inflammatory Response Genes and Their Association with the Risk of Prostate Cancer Mon, 14 Dec 2015 09:39:40 +0000 Prostate cancer is a common cancer in men. Genetic variations in inflammatory response genes can potentially influence the risk of prostate cancer. We aimed to examine the association between PPARG Pro12Ala, NFKB1 -94 ins/del, NFKBIA -826C/T, COX-1 (50C>T), and COX-2 (-1195G>A) polymorphisms on prostate cancer risk. The genotypes of the polymorphisms were ascertained in 543 prostate cancer patients and 753 controls through PCR-RFLP and the risk association was evaluated statistically using logistic regression analysis. The NFKB1 -94 polymorphism was shown to decrease prostate cancer risk in both heterozygous and homozygous comparison models (odds ratios of 0.74 (95% CI = 0.58–0.96) () and 0.57 (95% CI = 0.42–0.78) (), resp.). An opposite finding was observed for COX-2 (-1195) polymorphism (odds ratios of 1.58 (95% CI = 1.15–2.18) () for heterozygous comparison model and 2.08 (95% CI = 1.48–2.92) () for homozygous comparison model). No association was observed for other polymorphisms. In conclusion, NFKB1 -94 ins/del and COX-2 (-1195G>A) polymorphisms may be, respectively, associated with decreased and increased prostate cancer risk in the Chinese population. Xin Cui, Hao Yan, Tong-Wen Ou, Chun-Song Jia, Qi Wang, and Jian-Jun Xu Copyright © 2015 Xin Cui et al. All rights reserved. Silencing of Eag1 Gene Inhibits Osteosarcoma Proliferation and Migration by Targeting STAT3-VEGF Pathway Wed, 09 Dec 2015 07:22:12 +0000 So far, the role of Ether à go-go 1 (Eag1) potassium channels in migration and invasion progression of cancers remains elusive. In the present study, the effects of Eag1 knockdown on osteosarcoma cell proliferation, growth, and apoptosis were examined. Then, we evaluated the effects of Eag1 silencing on osteosarcoma cell migration and invasion. In addition, we detected the expression of vascular endothelial growth factor (VEGF) and signal transducer and activator of transcription 3 (STAT3) in osteosarcoma cell treated with Eag1 small interfering RNAs (siRNAs). Finally, STAT3 siRNA was employed to determine the influence of downregulation of STAT3 on cell proliferation and migration. The results showed that knockdown of Eag1 significantly suppressed osteosarcoma cell proliferation and osteosarcoma xenografts growth. However, Eag1 silencing had little effect on cell apoptosis. Additionally, osteosarcoma cell adhesion, migration, and invasion were also potently attenuated. Notably, the expression levels of VEGF decreased evidently upon Eag1 siRNAs treatment, paralleled with reductions in the expression levels of STAT3. Moreover, a similar pattern was observed in osteosarcoma cell proliferation and migration suppression between STAT3 siRNA and Eag1 siRNAs groups. Our data indicated that Eag1 promotes osteosarcoma proliferation and migration, at least in part, by targeting STAT3-VEGF pathway. Xinyu Wu, Zhida Chen, Wengrong Zeng, Yuanfu Zhong, Qingjun Liu, and Jin Wu Copyright © 2015 Xinyu Wu et al. All rights reserved. Prognostic Indications of Elevated MCT4 and CD147 across Cancer Types: A Meta-Analysis Tue, 08 Dec 2015 08:22:07 +0000 Background. Metabolism in the tumor microenvironment can play a critical role in tumorigenesis and tumor aggression. Metabolic coupling may occur between tumor compartments; this phenomenon can be prognostically significant and may be conserved across tumor types. Monocarboxylate transporters (MCTs) play an integral role in cellular metabolism via lactate transport and have been implicated in metabolic synergy in tumors. The transporters MCT1 and MCT4 are regulated via expression of their chaperone, CD147. Methods. We conducted a meta-analysis of existing publications on the relationship between MCT1, MCT4, and CD147 expression and overall survival and disease-free survival in cancer, using hazard ratios derived via multivariate Cox regression analyses. Results. Increased MCT4 expressions in the tumor microenvironment, cancer cells, or stromal cells were all associated with decreased overall survival and decreased disease-free survival ( for all analyses). Increased CD147 expression in cancer cells was associated with decreased overall survival and disease-free survival ( for both analyses). Few studies were available on MCT1 expression; MCT1 expression was not clearly associated with overall or disease-free survival. Conclusion. MCT4 and CD147 expression correlate with worse prognosis across many cancer types. These results warrant further investigation of these associations. Cory D. Bovenzi, James Hamilton, Patrick Tassone, Jennifer Johnson, David M. Cognetti, Adam Luginbuhl, William M. Keane, Tingting Zhan, Madalina Tuluc, Voichita Bar-Ad, Ubaldo Martinez-Outschoorn, and Joseph M. Curry Copyright © 2015 Cory D. Bovenzi et al. All rights reserved. Decorin: A Growth Factor Antagonist for Tumor Growth Inhibition Mon, 30 Nov 2015 13:51:10 +0000 Decorin (DCN) is the best characterized member of the extracellular small leucine-rich proteoglycan family present in connective tissues, typically in association with or “decorating” collagen fibrils. It has substantial interest to clinical medicine owing to its antifibrotic, anti-inflammatory, and anticancer effects. Studies on DCN knockout mice have established that a lack of DCN is permissive for tumor development and it is regarded as a tumor suppressor gene. A reduced expression or a total disappearance of DCN has been reported to take place in various forms of human cancers during tumor progression. Furthermore, when used as a therapeutic molecule, DCN has been shown to inhibit tumor progression and metastases in experimental cancer models. DCN affects the biology of various types of cancer by targeting a number of crucial signaling molecules involved in cell growth, survival, metastasis, and angiogenesis. The active sites for the neutralization of different growth factors all reside in different parts of the DCN molecule. An emerging concept that multiple proteases, especially those produced by inflammatory cells, are capable of cleaving DCN suggests that native DCN could be inactivated in a number of pathological inflammatory conditions. In this paper, we review the role of DCN in cancer. Tero A. H. Järvinen and Stuart Prince Copyright © 2015 Tero A. H. Järvinen and Stuart Prince. All rights reserved. Docosahexaenoic Acid Modulates a HER2-Associated Lipogenic Phenotype, Induces Apoptosis, and Increases Trastuzumab Action in HER2-Overexpressing Breast Carcinoma Cells Thu, 12 Nov 2015 07:27:21 +0000 In breast cancer, lipid metabolic alterations have been recognized as potential oncogenic stimuli that may promote malignancy. To investigate whether the oncogenic nature of lipogenesis closely depends on the overexpression of HER2 protooncogene, the normal breast cell line, HB4a, was transfected with HER2 cDNA to obtain HER2-overexpressing HB4aC5.2 cells. Both cell lines were treated with trastuzumab and docosahexaenoic acid. HER2 overexpression was accompanied by an increase in the expression of lipogenic genes involved in uptake (CD36), transport (FABP4), and storage (DGAT) of exogenous fatty acids (FA), as well as increased activation of “de novo” FA synthesis (FASN). We further investigate whether this lipogenesis reprogramming might be regulated by mTOR/PPARγ pathway. Inhibition of the mTORC1 pathway markers, p70S6 K1, SREBP1, and LIPIN1, as well as an increase in DEPTOR expression (the main inhibitor of the mTOR) was detected in HB4aC5.2. Based on these results, a PPARγ selective antagonist, GW9662, was used to treat both cells lines, and the lipogenic genes remained overexpressed in the HB4aC5.2 but not HB4a cells. DHA treatment inhibited all lipogenic genes (except for FABP4) in both cell lines yet only induced death in the HB4aC5.2 cells, mainly when associated with trastuzumab. Neither trastuzumab nor GW9662 alone was able to induce cell death. In conclusion, oncogenic transformation of breast cells by HER2 overexpression may require a reprogramming of lipogenic genetic that is independent of mTORC1 pathway and PPARγ activity. This reprogramming was inhibited by DHA. Graziela Rosa Ravacci, Maria Mitzi Brentani, Tharcisio Citrângulo Tortelli, Raquel Suzana M. M. Torrinhas, Jéssica Reis Santos, Angela Flávia Logullo, and Dan Linetzky Waitzberg Copyright © 2015 Graziela Rosa Ravacci et al. All rights reserved. Expression and Prognostic Significance of Macrophage Inflammatory Protein-3 Alpha and Cystatin A in Nasopharyngeal Carcinoma Sun, 08 Nov 2015 13:07:03 +0000 This study aims to investigate the expression of macrophage inflammatory protein-3 alpha (MIP-3α) and cystatin A in nasopharyngeal carcinoma (NPC) and their association with clinical characteristics and prognosis. Primary tumor specimens from 114 NPC patients and associated clinical follow-up data were collected, and the expression of MIP-3α and cystatin A proteins was investigated by immunohistochemistry. Expression of MIP-3α was significantly associated with TNM stage in patients with NPC (). NPC patients with positive expression of MIP-3α exhibited shorter median overall survival (OS) and distant metastasis-free survival (DMFS), compared with patients with negative expression (OS: 50.5 months versus 59.0 months, ; DMFS: 50.1 months versus 60.2 months, ). NPC patients with positive expression of cystatin A exhibited shorter median OS, local recurrence-free survival (LRFS), and DMFS, compared with patients with negative expression (OS: 51.1 months versus 60.0 months, ; LRFS: 54.5 months versus 59.5 months, ; DMFS: 52.3 months versus 58.8 months, ). Both MIP-3α and cystatin A overexpressions in NPC tumor tissues were strong independent factors of poor prognosis in NPC patients. MIP-3α and cystatin A expressions may be valuable prognostic markers in NPC patients. Minzhong Tang, Ningjiang Ou, Cheng Li, Aiying Lu, Jun Li, Liping Ma, Weiming Zhong, Jianquan Gao, Yuming Zheng, and Yonglin Cai Copyright © 2015 Minzhong Tang et al. All rights reserved. HPV Infection, but Not EBV or HHV-8 Infection, Is Associated with Salivary Gland Tumours Thu, 05 Nov 2015 08:49:51 +0000 Benign and malignant salivary gland tumours are clinically heterogeneous and show different histology. Little is known about the role of human herpes virus 8 (HHV-8), Epstein-Barr virus (EBV), and human papillomavirus (HPV) infection in salivary gland neoplasms. We investigated the presence of the three viruses in formalin-fixed, paraffin-embedded tissue samples in a cohort of 200 different salivary gland tumours. We performed EBV-LMP-1 and HHV-8 and p16 immunohistochemistry, a specific chip based hybridization assay for detection and typing of HPV and a chromogenic in situ hybridization for EBV analysis. Only one case, a polymorphic low-grade carcinoma, showed HHV-8 expression and one lymphoepithelial carcinoma was infected by EBV. In 17 cases (9%) moderate or strong nuclear and cytoplasmic p16 expression was detected. The HPV type was investigated in all of these cases and additionally in 8 Warthin’s tumours. In 19 cases HPV type 16 was detected, mostly in Warthin’s tumour, adenoid cystic carcinoma, and adenocarcinoma NOS. We concluded that HHV-8 infection and EBV infection are not associated with salivary gland cancer, but HPV infection may play a role in these tumour entities. Maja Hühns, Georg Simm, Andreas Erbersdobler, and Annette Zimpfer Copyright © 2015 Maja Hühns et al. All rights reserved. Diagnostic, Prognostic, and Predictive Molecular Biomarkers and the Utility of Molecular Imaging in Common Gastrointestinal Tumors Wed, 04 Nov 2015 13:46:59 +0000 Michael O. Idowu, Jennifer Laudadio, and Kathryn Rizzo Copyright © 2015 Michael O. Idowu et al. All rights reserved. Prognostic Significance of Serum Alkaline Phosphatase Level in Osteosarcoma: A Meta-Analysis of Published Data Wed, 04 Nov 2015 09:28:46 +0000 Background. Serum alkaline phosphatase (SALP) is commonly elevated in osteosarcoma patients. A number of studies have investigated the prognostic role of SALP level in patients with osteosarcoma but yielded inconsistent results. Method. Systematic computerized searches were performed in PubMed, Embase, and Web of Science databases for relevant original articles. The pooled hazard ratios (HRs) and relative risks (RRs) with corresponding confidence intervals (CIs) were calculated to assess the prognostic value of SALP level. Results. Finally, 21 studies comprising 3228 patients were included. Overall, the pooled HRs of SALP suggested that elevated level had an unfavorable impact on osteosarcoma patients’ overall survival (OS) (HR = 1.82; 95% CI: 1.61–2.06; ) and event-free survival (EFS) (HR = 1.97; 95% CI: 1.61–2.42; ). Combined RRs of SALP indicated that elevated level was associated with presence of metastasis at diagnosis (RR = 5.55; 95% CI: 1.61–9.49; ). No significantly different results were obtained after stratified by variables of age range, cancer stage, sample size, and geographic region. Conclusion. This meta-analysis demonstrated that high SALP level is significantly associated with poor OS or EFS rate and presence of metastasis at diagnosis. SALP level is a convenient and effective biomarker of prognosis for osteosarcoma. Hai-Yong Ren, Ling-Ling Sun, Heng-Yuan Li, and Zhao-Ming Ye Copyright © 2015 Hai-Yong Ren et al. All rights reserved. A Tetrameric Peptide Derived from Bovine Lactoferricin Exhibits Specific Cytotoxic Effects against Oral Squamous-Cell Carcinoma Cell Lines Mon, 02 Nov 2015 12:07:19 +0000 Several short linear peptides derived from cyclic bovine lactoferricin were synthesized and tested for their cytotoxic effect against the oral cavity squamous-cell carcinoma (OSCC) cell lines CAL27 and SCC15. As a control, an immortalized and nontumorigenic cell line, Het-1A, was used. Linear peptides based on the RRWQWR core sequence showed a moderate cytotoxic effect and specificity towards tumorigenic cells. A tetrameric peptide, LfcinB(20–25)4, containing the RRWQWR motif, exhibited greater cytotoxic activity (>90%) in both OSCC cell lines compared to the linear lactoferricin peptide or the lactoferrin protein. Additionally, this tetrameric peptide showed the highest specificity towards tumorigenic cells among the tested peptides. Interestingly, this effect was very fast, with cell shrinkage, severe damage to cell membrane permeability, and lysis within one hour of treatment. Our results are consistent with a necrotic effect rather than an apoptotic one and suggest that this tetrameric peptide could be considered as a new candidate for the therapeutic treatment of OSCC. Víctor A. Solarte, Jaiver E. Rosas, Zuly J. Rivera, Martha L. Arango-Rodríguez, Javier E. García, and Jean-Paul Vernot Copyright © 2015 Víctor A. Solarte et al. All rights reserved. The Impact of Sequence of Chemotherapy and EGFR-TKI Treatment on Different EGFR Mutation Lung Adenocarcinoma Mon, 02 Nov 2015 11:11:41 +0000 Objectives. Chemotherapy as first-/second-line treatment in different epidermal growth factor receptor (EGFR) mutation lung adenocarcinoma remains controversial. Methods. Consecutive patients were collected between 2009 and 2012. Patients were divided into two groups (1st-line chemotherapy: n = 56 and 2nd-line chemotherapy: n = 55). Their outcomes profiles were analyzed. Results. The overall survival (OS) of all patients (390 versus 662 days, p < 0.0001), as well as both progression-free survival (PFS, 151 versus 252 days, p = 0.0001) and OS (308 versus 704 days, p = 0.0001) of patients with L858R mutation (n = 63), who received 2nd-line chemotherapy, was significantly poor. By univariate and multivariate analysis, 2nd-line chemotherapy, and L858R mutation were significantly related to poor PFS and OS. Conclusion. In advanced lung adenocarcinoma, L858R mutation and 2nd-line chemotherapy caused a poor outcome. It is a consideration to choice of 1st-line chemotherapy in these subjects. A prospective design is warranted to confirm this finding. Fu-Tsai Chung, Ming-Yun Ho, Yueh-Fu Fang, Meng-Heng Hshieh, Tsai-Yu Wang, Chih-Hsi Kuo, Hao-Cheng Chen, Chun-Hwa Wang, Shu-Min Lin, Chih-Teng Yu, Horng-Chyuan Lin, and Han-Pin Kuo Copyright © 2015 Fu-Tsai Chung et al. All rights reserved. Prognostic Significance of the Tumor-Stroma Ratio in Epithelial Ovarian Cancer Sun, 01 Nov 2015 13:44:20 +0000 Tumor-stroma ratio (TSR) has recently been identified as a promising prognostic parameter for several solid tumors. This study aimed to evaluate the prognostic role of TSR in epithelial ovarian cancer (EOC) and 838 EOC patients were enrolled in this study. TSR was estimated on hematoxylin-and-eosin-stained tissue sections from the most invasive part of the primary tumor. Patients were classified as stroma-rich or stroma-poor according to the proportion of stroma ≥50% or <50%. Chi-square test analysis revealed that TSR were significantly associated with FIGO stage, LN status, and recurrence or not (all of them ). The higher stroma-rich proportions were found in EOC patients with advanced stage (36.13% versus 19.75%), LN metastasis (51.93% versus 27.25%), and recurrence (34.27% versus 6.82%). Stroma-rich EOC patients had obvious shorter median time of progression-free survival (29 versus 39 months) and overall survival (50 versus 58 months), respectively. TSR was an independent prognostic factor for the evaluation of PFS in EOC. Stroma-rich tumors had worse prognosis and higher risk of relapse compared with those in stroma-poor tumors in EOC patients. Considered easy to determine for routine pathological examination, TSR may serve as a new prognostic histological parameter in EOC. Ying Chen, Lei Zhang, Wenxin Liu, and Xiangyu Liu Copyright © 2015 Ying Chen et al. All rights reserved. Breast Cancer Metabolism and Mitochondrial Activity: The Possibility of Chemoprevention with Metformin Wed, 28 Oct 2015 13:03:51 +0000 Metabolic reprogramming refers to the ability of cancer cells to alter their metabolism in order to support the increased energy request due to continuous growth, rapid proliferation, and other characteristics typical of neoplastic cells. It has long been believed that the increase of metabolic request was independent of the mitochondrial action but recently we know that mitochondrial activity together with metabolism plays a pivotal role in the regulation of the energy needed for tumor cell growth and proliferation. For these reasons the mitochondria pathways could be a new target for therapeutic and chemopreventive intervention. Metformin in particular is actually considered a promising agent against mitochondrial activity thanks to its ability to inhibit the mitochondrial complex I. Massimiliano Cazzaniga and Bernardo Bonanni Copyright © 2015 Massimiliano Cazzaniga and Bernardo Bonanni. All rights reserved. Phosphorylation, Signaling, and Cancer: Targets and Targeting Wed, 21 Oct 2015 11:34:07 +0000 Sandra Marmiroli, Doriano Fabbro, Yoshihiko Miyata, Mariaelena Pierobon, and Maria Ruzzene Copyright © 2015 Sandra Marmiroli et al. All rights reserved. 18F-FDG Uptake Characteristics in Differentiating Benign from Malignant Nasopharyngeal Lesions in Children Tue, 20 Oct 2015 09:22:37 +0000 The characteristics of FDG uptake in the physiologic and malignant nasopharynx were investigated in the paper which was correlated with either pathologic findings or clinical follow-up. Three patients had pathologically established nasopharyngeal malignancy. In the 3 nasopharyngeal malignancies, 2 had diffusely and expansively increased FDG uptake, and one had asymmetric uptake. Our results indicated that the difference between adenoid hypertrophy and malignancy is asymmetric or diffusely expansive 18F-FDG uptake with or without correlating morphologic lesion on diagnostic CT in children under 10 years of age. The typical characteristics of physiologic and inflammatory 18F-FDG uptake in nasopharynx are symmetrically trapezoid. Diffusely increased nasopharyngeal FDG uptake can be considered physiologic if SUVmax is less than 7.6 but should be carefully assessed by pharyngorhinoscopy if SUVmax is greater than 11 and there is no correlating morphologic lesion on diagnostic CT. The diffusely, expansively increased uptake, and asymmetric uptake in particular, should be considered as malignancy. Further biopsy is especially indicated in patients with retropharyngeal space and bilateral cervical lymph node abnormality but no history of malignancy. Chao Ma, Renjian Zou, Yanlei Huo, Suyun Chen, Shaoyan Wang, Shuqi Wu, Zhiyi Ye, Zhenyu Wu, Feng Fang, and Hui Wang Copyright © 2015 Chao Ma et al. All rights reserved. Targeting Cellular Metabolism Chemosensitizes the Doxorubicin-Resistant Human Breast Adenocarcinoma Cells Mon, 19 Oct 2015 13:54:20 +0000 Metabolic energy preferentially produced by glycolysis was an advantageous metabolic phenotype of cancer cells. It is also an essential contributor to the progression of multidrug resistance in cancer cells. By developing human breast cancer MCF-7 cells resistant to doxorubicin (DOX) (MCF-7/MDR cells), the effects and mechanisms of 2-deoxy-D-glucose (2DG), a glucose analogue, on reversing multidrug resistance were investigated. 2DG significantly inhibited the viability of MCF-7/MDR cells and enhanced DOX-induced apoptosis by upregulating protein expression of AMPKα, P53, and caspase-3. The study demonstrated that energy restriction induced by 2DG was relevant to the synergistic effect of 2DG and DOX. The proteins of multidrug gene (the MDR-related protein, MRP1) and P-glycoprotein (P-gp) in MCF-7/MDR cells were downregulated after exposure to 2DG, accompanied with the suppression of the activity of ATP-dependent drug-efflux pump and transmembrane transporter, increasing the intracellular accumulation of DOX to reverse the chemoresistance in multidrug cancer cells. Shulan Ma, Rongfei Jia, Dongju Li, and Bo Shen Copyright © 2015 Shulan Ma et al. All rights reserved. The Selectivity of CK2 Inhibitor Quinalizarin: A Reevaluation Mon, 19 Oct 2015 07:47:49 +0000 Many polyphenolic compounds have been reported to inhibit protein kinases, with special reference to CK2, a pleiotropic serine/threonine kinase, implicated in neoplasia, neurodegenerative disease, and viral infections. In general however these compounds are not endowed with stringent selectivity. Among them quinalizarin (1,2,5,8-tetrahydroxyanthraquinone) turned out to be particularly potent (Ki = 0.058 μM) and quite selective as judged by profiling it on a small panel of 70 protein kinases. Here, by profiling quinalizarin on a larger panel of 140 kinases we reach the conclusion that quinalizarin is one of the most selective inhibitors of CK2, superior to the first-in-class CK2 inhibitor, CX-4945, now in clinical trials for the treatment of cancer. Moreover here we show that quinalizarin is able to discriminate between the isolated CK2 catalytic subunit (CK2α) and CK2 holoenzyme (CK2α2β2), consistent with in silico and in vitro analyses. Giorgio Cozza, Andrea Venerando, Stefania Sarno, and Lorenzo A. Pinna Copyright © 2015 Giorgio Cozza et al. All rights reserved. Different Persistence of the Cellular Effects Promoted by Protein Kinase CK2 Inhibitors CX-4945 and TDB Mon, 19 Oct 2015 06:14:33 +0000 We compare the cellular efficacy of two selective and cell permeable inhibitors of the antiapoptotic kinase CK2. One inhibitor, CX-4945, is already in clinical trials as antitumor drug, while the other, TDB, has been recently successfully employed to demonstrate the implication of CK2 in cellular (dis)regulation. We found that, upon treatment of cancer cells with these compounds, the extent of inhibition of endocellular CK2 is initially comparable but becomes significantly different after the inhibitors are removed from the cellular medium: while in CX-4945 treated cells CK2 activity is restored to control level after 24 h, in the case of TDB it is still strongly reduced after 4 days from removal. The biological effects of the two inhibitors have been analyzed by performing clonogenic, spheroid formation, and wound-healing assays: we observed a permanent inhibition of cell survival and migration in TDB-treated cells even after the inhibitor removal, while in the case of CX-4945 only its maintenance for the whole duration of the assay insured a persisting effect. We suggest that the superiority of TDB in maintaining kinase activity inhibited and perpetuating the consequent effects is an added value to be considered when planning new therapies based on CK2 targeting. Cristina Girardi, Daniele Ottaviani, Lorenzo A. Pinna, and Maria Ruzzene Copyright © 2015 Cristina Girardi et al. All rights reserved. Helicobacter pylori CagA Suppresses Apoptosis through Activation of AKT in a Nontransformed Epithelial Cell Model of Glandular Acini Formation Sun, 18 Oct 2015 13:36:26 +0000 H. pylori infection is the most important environmental risk to develop gastric cancer, mainly through its virulence factor CagA. In vitro models of CagA function have demonstrated a phosphoprotein activity targeting multiple cellular signaling pathways, while cagA transgenic mice develop carcinomas of the gastrointestinal tract, supporting oncogenic functions. However, it is still not completely clear how CagA alters cellular processes associated with carcinogenic events. In this study, we evaluated the capacity of H. pylori CagA positive and negative strains to alter nontransformed MCF-10A glandular acini formation. We found that CagA positive strains inhibited lumen formation arguing for an evasion of apoptosis activity of central acini cells. In agreement, CagA positive strains induced a cell survival activity that correlated with phosphorylation of AKT and of proapoptotic proteins BIM and BAD. Anoikis is a specific type of apoptosis characterized by AKT and BIM activation and it is the mechanism responsible for lumen formation of MCF-10A acini in vitro and mammary glands in vivo. Anoikis resistance is also a common mechanism of invading tumor cells. Our data support that CagA positive strains signaling function targets the AKT and BIM signaling pathway and this could contribute to its oncogenic activity through anoikis evasion. Gabriela Vallejo-Flores, Javier Torres, Claudia Sandoval-Montes, Haruki Arévalo-Romero, Isaura Meza, Margarita Camorlinga-Ponce, Julián Torres-Morales, Adriana Karina Chávez-Rueda, María Victoria Legorreta-Haquet, and Ezequiel M. Fuentes-Pananá Copyright © 2015 Gabriela Vallejo-Flores et al. All rights reserved. Trigonella foenum (Fenugreek) Induced Apoptosis in Hepatocellular Carcinoma Cell Line, HepG2, Mediated by Upregulation of p53 and Proliferating Cell Nuclear Antigen Sun, 18 Oct 2015 12:26:08 +0000 Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and most current therapies are of limited efficacy. Trigonella foenum (Fenugreek) is a traditional herbal plant with antitumor activity, although the mechanisms of its activity remain unclear. Herein, a crude methanol extract was prepared from Fenugreek seeds (FCE) and its anticancer mechanism was evaluated, using HepG2 cell line. Growth-inhibitory effect and apoptosis induction of HepG2 cells were evidenced by MTT assay, cell morphology alteration, apoptosis enzyme-linked immunosorbent assay, flow cytometric analysis, caspase-3 activity, and expression of p53, proapoptotic protein, Bax, and proliferating cell nuclear antigen (PCNA) after (100∼500 μg/mL) FCE treatment for 48 h. Furthermore, FCE was analyzed by Chromatography-Mass Spectrometry (GC/MS). Our results revealed that FCE treatment for 48 h showed a cytotoxic effect and apoptosis induction in a dose-dependent manner that was mediated by upregulation of p53, Bax, PCNA, and caspase-3 activation in HepG2 cells. GC-MS analysis of FCE showed the presence of fourteen bioactive compounds such as Terpenoids and Flavonoids, including two main constituents with anticancer activity, Squalene and Naringenin (27.71% and 24.05%), respectively. Our data introduced FCE as a promising nontoxic herbal with therapeutic potential to induce apoptosis in HepG2 cells through p53, Bax, and PCNA upregulation in caspase-3 dependent manner. Mahmoud I. M. Khalil, Mohamed M. Ibrahim, Gehan A. El-Gaaly, and Ahmed S. Sultan Copyright © 2015 Mahmoud I. M. Khalil et al. All rights reserved. Inhibition of PI3K Signalling Selectively Affects Medulloblastoma Cancer Stem Cells Sun, 18 Oct 2015 12:09:16 +0000 Medulloblastoma is the most common malignant brain tumor of childhood. Although survival has slowly increased in the past years, the prognosis of these patients remains unfavourable. In this context, it has been recently shown that the intracellular signaling pathways activated during embryonic cerebellar development are deregulated in MDB. One of the most important is PI3K/AKT/mTOR, implicated in cell proliferation, survival, growth, and protein synthesis. Moreover, a fraction of MDB cells has been shown to posses stemlike features, to express typical neuronal precursor markers (Nestin and CD133), and to be maintained by the hypoxic cerebellar microenvironment. This subpopulation of MDB cells is considered to be responsible for treatment resistance and recurrence. In this study, we evaluated the effects of PI3K/AKT pathway inhibition on primary cultures of MDB and particularly on the cancer stem cell (CSC) population (CD133+). PI3K inhibition was able to counteract MDB cell growth and to promote differentiation of stemlike MDB cells. Moreover, PI3K/AKT pathway suppression induced dramatic cell death through activation of the mitochondrial proapoptotic cascade. Finally, analysis on the stem cells fraction revealed that the MDB CSC population is more sensitive to PI3K targeting compared to the whole cancerous population and its nonstem cell counterpart. Chiara Frasson, Elena Rampazzo, Benedetta Accordi, Giacomo Beggio, Francesca Pistollato, Giuseppe Basso, and Luca Persano Copyright © 2015 Chiara Frasson et al. All rights reserved. All-Trans Retinoic Acid Induces Proliferation, Survival, and Migration in A549 Lung Cancer Cells by Activating the ERK Signaling Pathway through a Transcription-Independent Mechanism Sun, 18 Oct 2015 11:53:44 +0000 All-trans retinoic acid (ATRA) has been used as an antineoplastic because of its ability to promote proliferation, inhibition, and differentiation, primarily in leukemia; however, in other types of cancer, such as lung cancer, treatment with ATRA is restricted because not all the patients experience the same results. The ERK signaling pathway is dysregulated in cancer cells, including lung cancer, and this dysregulation promotes proliferation and cell invasion. In this study, we demonstrate that treatment with ATRA can activate the ERK signaling pathway by a transcription-independent mechanism through a signaling cascade that involves RARα and PI3K, promoting growth, survival, and migration in lung cancer cells. Until now, this mechanism was unknown in lung cancer cells. The inhibition of the ERK signaling pathway restores the beneficial effects of ATRA, reduces proliferation, increases apoptosis, and blocks the cell migration process in lung cancer cells. In conclusion, our results suggest that the combination of ATRA with ERK inhibitor in clinical trials for lung cancer is warranted. Reyna Sara Quintero Barceinas, Alejandro García-Regalado, Elena Aréchaga-Ocampo, Nicolás Villegas-Sepúlveda, and Claudia Haydée González-De la Rosa Copyright © 2015 Reyna Sara Quintero Barceinas et al. All rights reserved. Activity of BKM120 and BEZ235 against Lymphoma Cells Sun, 18 Oct 2015 11:34:18 +0000 Non-Hodgkin lymphomas encompass a heterogeneous group of cancers, with 85–90% arising from B lymphocytes and the remainder deriving from T lymphocytes or NK lymphocytes. These tumors are molecularly and clinically heterogeneous, showing dramatically different responses and outcomes with standard therapies. Deregulated PI3K signaling is linked to oncogenesis and disease progression in hematologic malignancies and in a variety of solid tumors and apparently enhances resistance to antineoplastic therapy, resulting in a poor prognosis. Here, we have evaluated and compared the effects of the pan-PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitor BEZ235 on mantle, follicular, and T-cell lymphomas. Our results suggest that BKM120 and BEZ235 can effectively inhibit lymphoma cell proliferation by causing cell cycle arrest and can lead to cell death by inducing apoptosis and autophagy mediated by ROS accumulation. Despite great advances in lymphoma therapy after the introduction of monoclonal antibodies, many patients still die from disease progression. Therefore, novel treatment approaches are needed. BKM120 and BEZ235 alone and in combination are very effective against lymphoma cells in vitro. If further studies confirm their effectiveness in animal models, they may be promising candidates for development as new drugs. Monica Civallero, Maria Cosenza, Samantha Pozzi, Alessia Bari, Paola Ferri, and Stefano Sacchi Copyright © 2015 Monica Civallero et al. All rights reserved. Ras Oncogene-Mediated Progressive Silencing of Extracellular Superoxide Dismutase in Tumorigenesis Thu, 15 Oct 2015 09:25:43 +0000 Extracellular superoxide dismutase (SOD3) is a secreted enzyme that uses superoxide anion as a substrate in a dismutase reaction that results in the formation of hydrogen peroxide. Both of these reactive oxygen species affect growth signaling in cells. Although SOD3 has growth-supporting characteristics, the expression of SOD3 is downregulated in epithelial cancer cells. In the current work, we studied the mechanisms regulating SOD3 expression in vitro using thyroid cell models representing different stages of thyroid cancer. We demonstrate that a low level of RAS activation increases SOD3 mRNA synthesis that then gradually decreases with increasing levels of RAS activation and the decreasing degree of differentiation of the cancer cells. Our data indicate that SOD3 regulation can be divided into two classes. The first class involves RAS–driven reversible regulation of SOD3 expression that can be mediated by the following mechanisms: RAS GTPase regulatory genes that are responsible for SOD3 self-regulation; RAS-stimulated p38 MAPK activation; and RAS-activated increased expression of the mir21 microRNA, which inversely correlates with sod3 mRNA expression. The second class involves permanent silencing of SOD3 mediated by epigenetic DNA methylation in cells that represent more advanced cancers. Therefore, the work suggests that SOD3 belongs to the group of ras oncogene-silenced genes. Francesca Cammarota, Gabriella de Vita, Marco Salvatore, and Mikko O. Laukkanen Copyright © 2015 Francesca Cammarota et al. All rights reserved. The Diagnosis Value of Promoter Methylation of UCHL1 in the Serum for Progression of Gastric Cancer Thu, 15 Oct 2015 08:46:05 +0000 Background. Aberrant promoter methylation has been considered as a potential molecular marker for gastric cancer (GC). However, the role of methylation of FLNC, THBS1, and UCHL1 in the development and progression of GC has not been explored. Methods. The promoter methylation status of UCHL1, FLNC, THBS1, and DLEC1 was assessed by quantitative methylation-specific PCR (QMSP) in the serum of 82 GC patients, 46 chronic atrophic gastritis (CAG) subjects, and 40 healthy controls. Results. All four genes had significantly higher methylation levels in GC patients than in CAG and control subjects. However, only UCHL1 methylation was significantly correlated with the tumor stage and lymph node metastasis. While THBS1 methylation was altered in an age-dependent manner, FLNC methylation was correlated with differentiation and Helicobacter pylori infection. DLEC1 methylation was only associated with tumor size. Moreover, methylated UCHL1 with or without THBS1 in the serum was found to be significantly associated with a poor prognosis. Conclusion. The promoter methylation degree of FLNC, THBS1, UCHL1, and DLEC1 in serum could tell the existence of GC and only UCHL1 in the serum was also associated with poor prognosis of GC. Gongping Wang, Wei Zhang, Bo Zhou, Canhui Jin, Zengfang Wang, Yantong Yang, Zhenzhen Wang, Ye Chen, and Xiaoshan Feng Copyright © 2015 Gongping Wang et al. All rights reserved. Cancer Diagnostic and Predictive Biomarkers 2015 Mon, 12 Oct 2015 14:04:29 +0000 Franco M. Buonaguro, C. David Pauza, Maria Lina Tornesello, Pierre Hainaut, and Renato Franco Copyright © 2015 Franco M. Buonaguro et al. All rights reserved. Effect of Laryngeal Squamous Cell Carcinoma Tissue Implantation on the Chick Embryo Chorioallantoic Membrane: Morphometric Measurements and Vascularity Sun, 11 Oct 2015 13:57:59 +0000 Background. The aim of this study was to develop chick embryo chorioallantoic membrane (CAM) model of laryngeal squamous cell carcinoma (LSCC) and to evaluate the morphological and morphometric characteristics and angiogenic features of it. Methods. Fresh LSCC tissue samples obtained from 6 patients were implanted onto 15 chick embryo CAMs. Morphological, morphometric, and angiogenic changes in the CAM and chorionic epithelium were evaluated up to 4 days after the tumor implantation. Immunohistochemical analysis (34βE12, CD31, and Ki67 staining) was performed to detect cytokeratins and tumor endothelial cells and to evaluate the proliferative capacity of the tumor before and after implantation on the CAM. Results. The implanted LSCC tissue samples survived on the CAM in all the experiments and retained the essential morphologic characteristics and proliferative capacity of the original tumor. Implants induced thickening of both the CAM (103–417%, ) and the chorionic epithelium (70–140%, ) and increase in number of blood vessels (75–148%, ) in the CAM. Conclusions. This study clarifies that chick embryo CAM is a relevant assay for implanting LSCC tissue and provides the first morphological and morphometric characterization of the LSCC CAM model that opens new perspectives to study this disease. Virgilijus Uloza, Alina Kuzminienė, Sonata Šalomskaitė-Davalgienė, Jolita Palubinskienė, Ingrida Balnytė, Ingrida Ulozienė, Viktoras Šaferis, and Angelija Valančiūtė Copyright © 2015 Virgilijus Uloza et al. All rights reserved. Volumetric Modulated Arc Therapy of the Pelvic Lymph Nodes to the Aortic Bifurcation in Higher Risk Prostate Cancer: Early Toxicity Outcomes Sun, 11 Oct 2015 13:55:37 +0000 Background. Treatment of pelvic lymph nodes (PLNs) in higher risk prostate carcinoma is controversial. The primary focus of the study was to evaluate the early toxicity profile for this cohort of patients treated with Volumetric Modulated Arc Therapy (VMAT). Methods. Patient, tumour, and treatment characteristics of those who received VMAT from May 2010 to December 2012 were analysed. A simplified contouring process of the PLNs to the aortic bifurcation was developed based on consensus guidelines. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities were documented according to the Radiation Therapy Oncology Group (RTOG) Version 2 Guidelines. Successive Prostate Specific Antigen (PSA) values after treatment were measured on average 3 months apart. Results. 113 patients were treated between May 2010 to December 2012 with a median follow-up of 14 months. No patients experienced acute grade 3 or 4 GU and GI toxicity. Only 1 patient experienced a late grade 3 GU complication. No late grade 4 GU or GI events have yet occurred. Conclusions. This study reviews the first Australian experience of VMAT in the treatment of pelvic lymph nodes in prostate cancer, specifically to the level of the aortic bifurcation. It demonstrates a favorable acute toxicity profile whilst treating large PLN volumes with optimal dose coverage. Gina Hesselberg, Gerald Fogarty, Lauren Haydu, Nicole Dougheney, and Phillip Stricker Copyright © 2015 Gina Hesselberg et al. All rights reserved. Second Surgery in Insular Low-Grade Gliomas Sun, 11 Oct 2015 13:51:43 +0000 Background. Given the technical difficulties, a limited number of works have been published on insular gliomas surgery and risk factors for tumor recurrence (TR) are poorly documented. Objective. The aim of the study was to determine TR in adult patients with initial diagnosis of insular Low-Grade Gliomas (LGGs) that subsequently underwent second surgery. Methods. A consecutive series of 53 patients with insular LGGs was retrospectively reviewed; 23 patients had two operations for TR. Results. At the time of second surgery, almost half of the patients had experienced progression into high-grade gliomas (HGGs). Univariate analysis showed that TR is influenced by the following: extent of resection (EOR) (), ΔVT2T1 value (), histological diagnosis of oligodendroglioma (), and mutation of IDH1 (). The multivariate analysis showed that EOR at first surgery was the independent predictor for TR (). Conclusions. In patients with insular LGG the EOR at first surgery represents the major predictive factor for TR. At time of TR, more than 50% of cases had progressed in HGG, raising the question of the oncological management after the first surgery. Tamara Ius, Giada Pauletto, Daniela Cesselli, Miriam Isola, Luca Turella, Riccardo Budai, Giovanna DeMaglio, Roberto Eleopra, Luciano Fadiga, Christian Lettieri, Stefano Pizzolitto, Carlo Alberto Beltrami, and Miran Skrap Copyright © 2015 Tamara Ius et al. All rights reserved. An IMRT/VMAT Technique for Nonsmall Cell Lung Cancer Sun, 11 Oct 2015 13:33:45 +0000 The study is to investigate a Hybrid IMRT/VMAT technique which combines intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) for the treatment of nonsmall cell lung cancer (NSCLC). Two partial arcs VMAT, 5-field IMRT, and hybrid plans were created for 15 patients with NSCLC. The hybrid plans were combination of 2 partial arcs VMAT and 5-field IMRT. The dose distribution of planning target volume (PTV) and organs at risk (OARs) for hybrid technique was compared with IMRT and VMAT. The monitor units (MUs) and treatment delivery time were also evaluated. Hybrid technique significantly improved the target conformity and homogeneity compared with IMRT and VMAT. The mean delivery time of IMRT, VMAT, and hybrid plans was 280 s, 114 s, and 327 s, respectively. The mean MUs needed for IMRT, VMAT, and hybrid plans were 933, 512, and 737, respectively. Hybrid technique reduced , , , and MLD of normal lung compared with VMAT and spared the OARs better with fewer MUs with the cost of a little higher , , and mean lung dose (MLD) of normal lung compared with IMRT. Hybrid IMRT/VMAT can be a viable radiotherapy technique with better plan quality. Nan Zhao, Ruijie Yang, Junjie Wang, Xile Zhang, and Jinna Li Copyright © 2015 Nan Zhao et al. All rights reserved. Clinical Significance of Cannabinoid Receptors CB1 and CB2 Expression in Human Malignant and Benign Thyroid Lesions Sun, 11 Oct 2015 13:29:54 +0000 The endocannabinoid system is comprised of cannabinoid receptors (CB1 and CB2), their endogenous ligands (endocannabinoids), and proteins responsible for their metabolism participate in many different functions indispensable to homeostatic regulation in several tissues, exerting also antitumorigenic effects. The present study aimed to evaluate the clinical significance of CB1 and CB2 expression in human benign and malignant thyroid lesions. CB1 and CB2 proteins’ expression was assessed immunohistochemically on paraffin-embedded thyroid tissues obtained from 87 patients with benign and malignant lesions and was statistically analyzed with clinicopathological parameters, follicular cells’ proliferative capacity, and risk of recurrence rate estimated according to the American Thyroid Association (ATA) staging system. Enhanced CB1 and CB2 expression was significantly more frequently observed in malignant compared to benign thyroid lesions ( and , resp.). Enhanced CB1 and CB2 expression was also significantly more frequently observed in papillary carcinomas compared to hyperplastic nodules ( and , resp.). In malignant thyroid lesions, elevated CB2 expression was significantly associated with the presence of lymph node metastases . Enhanced CB2 expression was also more frequently observed in malignant thyroid cases with presence of capsular , lymphatic , and vascular invasion , as well as in those with increased risk of recurrence rate , at a nonsignificant level though, whereas CB1 expression was not associated with any of the clinicopathological parameters examined. Our data suggest that CB receptors may be involved in malignant thyroid transformation and especially CB2 receptor could serve as useful biomarker and potential therapeutic target in thyroid neoplasia. Eleftheria Lakiotaki, Constantinos Giaginis, Maria Tolia, Paraskevi Alexandrou, Ioanna Delladetsima, Ioanna Giannopoulou, George Kyrgias, Efstratios Patsouris, and Stamatios Theocharis Copyright © 2015 Eleftheria Lakiotaki et al. All rights reserved. miR-193b Modulates Resistance to Doxorubicin in Human Breast Cancer Cells by Downregulating MCL-1 Wed, 07 Oct 2015 09:05:17 +0000 MicroRNAs (miRNAs) family, which is involved in cancer development, proliferation, apoptosis, and drug resistance, is a group of noncoding RNAs that modulate the expression of oncogenes and antioncogenes. Doxorubicin is an active cytotoxic agent for breast cancer treatment, but the acquisition of doxorubicin resistance is a common and critical limitation to cancer therapy. The aim of this study was to investigate whether miR-193b mediated the resistance of breast cancer cells to doxorubicin by targeting myeloid cell leukemia-1 (MCL-1). In this study, we found that miR-193b levels were significantly lower in doxorubicin-resistant MCF-7 (MCF-7/DOXR) cells than in the parental MCF-7 cells. We observed that exogenous miR-193b significantly suppressed the ability of MCF-7/DOXR cells to resist doxorubicin. It demonstrated that miR-193b directly targeted MCL-1 3′-UTR (3′-Untranslated Regions). Further studies indicated that miR-193b sensitized MCF-7/DOXR cells to doxorubicin through a mechanism involving the downregulation of MCL-1. Together, our findings provide evidence that the modulation of miR-193b may represent a novel therapeutic target for the treatment of breast cancer. Jingpei Long, Zhiwei Ji, Kai Jiang, Zhaoyang Wang, and Guanmin Meng Copyright © 2015 Jingpei Long et al. All rights reserved. The Quantified Level of Circulating Prostate Stem Cell Antigen mRNA relative to GAPDH Level Is a Clinically Significant Indictor for Predicting Biochemical Recurrence in Prostate Cancer Patients after Radical Prostatectomy Wed, 07 Oct 2015 07:15:54 +0000 The study quantified the relative absolute PSCA level in relation to the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) level in the peripheral blood of 478 hormone-naive prostate cancer (PC) patients who underwent radical prostatectomy from 2005 to 2012 and evaluated its prognostic significance as a risk factor for predicting biochemical recurrence (BCR), compared to known parameters. Nested real-time polymerase chain reaction (RT-PCR) and gel electrophoresis detected PSCA levels and measured the PSCA/GAPDH ratio. Clinicopathological data from the institutional database were examined to determine the adequate cut-off level to predict postoperative BCR. A total of 110 patients had a positive PSCA result (23.0%) via RT-PCR (mean blood ratio 1.1 ± 0.4). The BCR was significantly higher in the PSCA-positive detection group (). A multivariate model was created to show that a PSCA/GAPDH ratio between 1.0 and 1.5 (HR 12.722), clinical T2c stage (HR 0.104), preoperative PSA (HR 1.225), extraprostatic capsule extension (HR 0.006), lymph node dissection (HR 16.437), and positive resection margin (HR 27.453) were significant predictive factors for BCR (). The study showed successful quantification of PSCA with its significance for BCR-related risk factor; however, further studies are needed to confirm its clinical predictive value. Sung Han Kim, Weon Seo Park, Sang Jin Lee, Moon Kyung Choi, Seung Min Yeon, Jeong Nam Joo, Ara Ko, Eun Sik Lee, Jae Young Joung, Ho Kyung Seo, Jinsoo Chung, and Kang Hyun Lee Copyright © 2015 Sung Han Kim et al. All rights reserved. The Expression and Correlation of iNOS and p53 in Oral Squamous Cell Carcinoma Wed, 07 Oct 2015 06:59:40 +0000 Oral squamous cell carcinoma (OSCC) is the most prevalent form of oral cancer. Inducible nitric oxide synthase (iNOS) and p53 are associated with a variety of human cancers, but their expression and interaction in OSCC have not been fully explored. In this study, we investigated the expression of iNOS and p53 in OSCC and their correlation with tumor development and prognosis. In addition, we explored the interaction of iNOS and p53 in OSCC. The expression of iNOS and p53 in OSCC was investigated using immunohistochemical method and their interaction was studied using RNAi technique. Our results showed that the expression of both iNOS and p53 was significantly correlated with tumor stages and pathological grade of OSCC (). In contrast, there was no correlation between iNOS and p53 expression and lymph node metastasis (). The OSCC survival rate was negatively associated with iNOS expression, but not with p53. A significant increase in the expression of the p53 was observed when iNOS expression was knocked down. The immunoexpression of iNOS is correlated with tumorigenesis and prognosis of OSCC and may serve as a prognostic marker. Lan Yang, Youyuan Wang, Lvhua Guo, Liping Wang, Weiliang Chen, and Bin Shi Copyright © 2015 Lan Yang et al. All rights reserved. High 15-F2t-Isoprostane Levels in Patients with a Previous History of Nonmelanoma Skin Cancer: The Effects of Supplementary Antioxidant Therapy Mon, 05 Oct 2015 09:38:17 +0000 Background. Phase I of this study was aimed at comparing the profiles of oxidative stress biomarkers in patients with history of nonmelanoma skin cancer (NMSC), previously treated with surgery, to the healthy subjects. Phase II aimed to evaluate the effects of supplementary antioxidant therapy on the levels of biomarkers in the case group. Materials and Methods. In Phase I, oxidative stress biomarkers were measured in blood samples obtained from 24 healthy subjects and 60 patients with history of NMSC previously treated with surgery. In Phase II, the 60 patients with history of NMSC were randomized into two subgroups, one receiving placebo () and the other () receiving vitamin C, vitamin E, and zinc supplementation for 8 weeks, followed by reevaluation of biomarkers. Results. In Phase I, patients with history of NMSC showed increased plasma concentrations of all biomarkers, but only 15--isoprostane was significantly higher than in the healthy subjects. Risk of NMSC increased by 4% for each additional 1 pg/mL increase in 15--isoprostane. In Phase II, supplementation did not significantly reduce levels of oxidative stress biomarkers. Conclusion. Patients with history of NMSC had significantly high 15--isoprostane plasma levels; supplementation did not result in significant reduction of oxidative stress biomarkers. This trial was registered with (ID NCT02248584). Betânia de Jesus e Silva de Almendra Freitas, Gustavo Rafaini Lloret, Marília Berlofa Visacri, Bruna Taliani Tuan, Lais Sampaio Amaral, Daniele Baldini, Vanessa Marcílio de Sousa, Laís Lima de Castro, Jordana Rayane Sousa Aguiar, Eder de Carvalho Pincinato, Priscila Gava Mazzola, and Patricia Moriel Copyright © 2015 Betânia de Jesus e Silva de Almendra Freitas et al. All rights reserved. Identification of Human Herpesvirus 8 Sequences in Conjunctiva Intraepithelial Neoplasia and Squamous Cell Carcinoma of Ugandan Patients Mon, 05 Oct 2015 08:18:16 +0000 The incidence of squamous cell carcinoma of the conjunctiva is particularly high in sub-Saharan Africa with temporal trends similar to those of Kaposi sarcoma (KS). Human herpesvirus type 8 (HHV8), has not yet been investigated in conjunctiva tumors. In this study biopsies and PBMCs of conjunctiva neoplasia patients along with nonneoplastic conjunctiva tissues have been analyzed for HHV8 sequences by PCR targeting ORF26. All amplimers were subjected to nucleotide sequencing followed by phylogenetic analysis. HHV8 DNA has been identified in 12 out of 48 (25%) HIV-positive, and in 2 out of 24 (8.3%) HIV-negative conjunctiva neoplastic tissues and in 4 out of 33 (12.1%) PBMC samples from conjunctiva neoplasia diseased patients as well as in 4 out of 60 (6.7%) nontumor conjunctiva tissues. The viral load ranged from 1 to 400 copies/105 cells. Phylogenetic analysis showed that the majority of HHV8 ORF26 amplimers clustered with subtypes R () and B2 (). This variant distribution is in agreement with that of HHV8 variants previously identified in Ugandan KS cases. The presence of HHV8 in conjunctiva tumors from HIV-positive patients warrants further studies to test whether HHV8 products released by infected cells may have paracrine effects on the growth of conjunctiva lesions. Noemy Starita, Clorinda Annunziata, Keith M. Waddell, Luigi Buonaguro, Franco M. Buonaguro, and Maria Lina Tornesello Copyright © 2015 Noemy Starita et al. All rights reserved. CT Perfusion Characteristics Identify Metastatic Sites in Liver Mon, 05 Oct 2015 07:23:23 +0000 Tissue perfusion plays a critical role in oncology because growth and migration of cancerous cells require proliferation of new blood vessels through the process of tumor angiogenesis. Computed tomography (CT) perfusion is an emerging functional imaging modality that measures tissue perfusion through dynamic CT scanning following intravenous administration of contrast medium. This noninvasive technique provides a quantitative basis for assessing tumor angiogenesis. CT perfusion has been utilized on a variety of organs including lung, prostate, liver, and brain, with promising results in cancer diagnosis, disease prognostication, prediction, and treatment monitoring. In this paper, we focus on assessing the extent to which CT perfusion characteristics can be used to discriminate liver metastases from neuroendocrine tumors from normal liver tissues. The neuroendocrine liver metastases were analyzed by distributed parameter modeling to yield tissue blood flow (BF), blood volume (BV), mean transit time (MTT), permeability (PS), and hepatic arterial fraction (HAF), for tumor and normal liver. The result reveals the potential of CT perfusion as a tool for constructing biomarkers from features of the hepatic vasculature for guiding cancer detection, prognostication, and treatment selection. Yuan Wang, Brian P. Hobbs, and Chaan S. Ng Copyright © 2015 Yuan Wang et al. All rights reserved. Glycosylation-Based Serum Biomarkers for Cancer Diagnostics and Prognostics Mon, 05 Oct 2015 07:18:43 +0000 Cancer is the second most common cause of death in developed countries with approximately 14 million newly diagnosed individuals and over 6 million cancer-related deaths in 2012. Many cancers are discovered at a more advanced stage but better survival rates are correlated with earlier detection. Current clinically approved cancer biomarkers are most effective when applied to patients with widespread cancer. Single biomarkers with satisfactory sensitivity and specificity have not been identified for the most common cancers and some biomarkers are ineffective for the detection of early stage cancers. Thus, novel biomarkers with better diagnostic and prognostic performance are required. Aberrant protein glycosylation is well known hallmark of cancer and represents a promising source of potential biomarkers. Glycoproteins enter circulation from tissues or blood cells through active secretion or leakage and patient serum is an attractive option as a source for biomarkers from a clinical and diagnostic perspective. A plethora of technical approaches have been developed to address the challenges of glycosylation structure detection and determination. This review summarises currently utilised glycoprotein biomarkers and novel glycosylation-based biomarkers from the serum glycoproteome under investigation as cancer diagnostics and for monitoring and prognostics and includes details of recent high throughput and other emerging glycoanalytical techniques. Alan Kirwan, Marta Utratna, Michael E. O’Dwyer, Lokesh Joshi, and Michelle Kilcoyne Copyright © 2015 Alan Kirwan et al. All rights reserved. Expression of Stem Cell Markers in Preinvasive Tubal Lesions of Ovarian Carcinoma Sun, 04 Oct 2015 13:42:31 +0000 In order to better understand the ovarian serous carcinogenic process with tubal origin, we investigated the expression of stem cell markers in premalignant tubal lesions (serous tubal intraepithelial carcinoma or STIC). We found an increased stem cell marker density in the normal fallopian tube followed by a high CD117 and a low ALDH and CD44 expression in STICs raising the question of the role of the stem cell markers in the serous carcinogenic process. G. Chene, V. Ouellet, K. Rahimi, V. Barres, L. Meunier, M. De Ladurantaye, D. Provencher, and A. M. Mes-Masson Copyright © 2015 G. Chene et al. All rights reserved. Predictive Biomarkers to Chemoradiation in Locally Advanced Rectal Cancer Sun, 04 Oct 2015 12:49:29 +0000 There has been a high local recurrence rate in rectal cancer. Besides improvements in surgical techniques, both neoadjuvant short-course radiotherapy and long-course chemoradiation improve oncological results. Approximately 40–60% of rectal cancer patients treated with neoadjuvant chemoradiation achieve some degree of pathologic response. However, there is no effective method of predicting which patients will respond to neoadjuvant treatment. Recent studies have evaluated the potential of genetic biomarkers to predict outcome in locally advanced rectal adenocarcinoma treated with neoadjuvant chemoradiation. The articles produced by the PubMed search were reviewed for those specifically addressing a genetic profile’s ability to predict response to neoadjuvant treatment in rectal cancer. Although tissue gene microarray profiling has led to promising data in cancer, to date, none of the identified signatures or molecular markers in locally advanced rectal cancer has been successfully validated as a diagnostic or prognostic tool applicable to routine clinical practice. Raquel Conde-Muíño, Marta Cuadros, Natalia Zambudio, Inmaculada Segura-Jiménez, Carlos Cano, and Pablo Palma Copyright © 2015 Raquel Conde-Muíño et al. All rights reserved. miR-125b Suppresses Proliferation and Invasion by Targeting MCL1 in Gastric Cancer Sun, 04 Oct 2015 11:10:42 +0000 Understanding the molecular mechanisms underlying gastric cancer progression contributes to the development of novel targeted therapies. In this study, we found that the expression levels of miR-125b were strongly downregulated in gastric cancer and associated with clinical stage and the presence of lymph node metastases. Additionally, miR-125b could independently predict OS and DFS in gastric cancer. We further found that upregulation of miR-125b inhibited the proliferation and metastasis of gastric cancer cells in vitro and in vivo. miR-125b elicits these responses by directly targeting MCL1 (myeloid cell leukemia 1), which results in a marked reduction in MCL1 expression. Transfection of miR-125b sensitizes gastric cancer cells to 5-FU-induced apoptosis. By understanding the function and molecular mechanisms of miR-125b in gastric cancer, we may learn that miR-125b has the therapeutic potential to suppress gastric cancer progression and increase drug sensitivity to gastric cancer. Shihua Wu, Feng Liu, Liming Xie, Yaling Peng, Xiaoyuan Lv, Yaping Zhu, Zhiwei Zhang, and Xiusheng He Copyright © 2015 Shihua Wu et al. All rights reserved. Prognostic Value of Homotypic Cell Internalization by Nonprofessional Phagocytic Cancer Cells Sun, 04 Oct 2015 10:29:16 +0000 Background. In this study, we investigated the prognostic role of homotypic tumor cell cannibalism in different cancer types. Methods. The phenomenon of one cell being internalized into another, which we refer to as “cell-in-cell event,” was assessed in 416 cases from five head and neck cancer cohorts, as well as one anal and one rectal cancer cohort. The samples were processed into tissue microarrays and immunohistochemically stained for E-cadherin and cleaved caspase-3 to visualize cell membranes and apoptotic cell death. Results. Cell-in-cell events were found in all of the cohorts. The frequency ranged from 0.7 to 17.3 cell-in-cell events per mm2. Hardly any apoptotic cells were found within the cell-in-cell structures, although apoptotic cell rates were about 1.6 to two times as high as cell-in-cell rates of the same tissue sample. High numbers of cell-in-cell events showed adverse effects on patients’ survival in the head and neck and in the rectal cancer cohorts. In multivariate analysis, high frequency was an adverse prognostic factor for overall survival in patients with head and neck cancer (). Conclusion. Cell-in-cell events were found to predict patient outcomes in various types of cancer better than apoptosis and proliferation and might therefore be used to guide treatment strategies. Manuela Schwegler, Anna M. Wirsing, Hannah M. Schenker, Laura Ott, Johannes M. Ries, Maike Büttner-Herold, Rainer Fietkau, Florian Putz, and Luitpold V. Distel Copyright © 2015 Manuela Schwegler et al. All rights reserved. Prognostic Value of Cancer Stem Cells Markers in Triple-Negative Breast Cancer Sun, 04 Oct 2015 10:08:15 +0000 Triple-negative breast cancer (TNBC) has a significant clinical relevance of being associated with a shorter median time to relapse and death and does not respond to endocrine therapy or other available targeted agents. Increased aggressiveness of this tumor, as well as resistance to standard drug therapies, may be associated with the presence of stem cell populations within the tumor. Several stemness markers have been described for the various histological subtypes of breast cancer, such as CD44, CD24, CD133, ALDH1, and ABCG2. The role of these markers in breast cancer is not clear yet and above all there are conflicting opinions about their real prognostic value. To investigate the role of CSCs markers in TNBC cancerogenesis and tumor progression, we selected 160 TNBCs samples on which we detected protein expression of CD44, CD24, CD133, ALDH1, and ABCG2 by immunohistochemistry. Our results highlighted a real prognostic role only for CD44 in TNBCs. All other CSCs markers do not appear to be related to the survival of TNBC patients. In conclusion, despite the fact that the presence of the cancer stem cells in the tumor provides important information on its potential aggressiveness, today their detection by immunohistochemistry is not sufficient to confirm their role in carcinogenesis, because specific markers probably are not yet identified. Francesca Collina, Maurizio Di Bonito, Valeria Li Bergolis, Michelino De Laurentiis, Carlo Vitagliano, Margherita Cerrone, Francesco Nuzzo, Monica Cantile, and Gerardo Botti Copyright © 2015 Francesca Collina et al. All rights reserved. Genomic and Histopathological Tissue Biomarkers That Predict Radiotherapy Response in Localised Prostate Cancer Sun, 04 Oct 2015 09:18:55 +0000 Localised prostate cancer, in particular, intermediate risk disease, has varied survival outcomes that cannot be predicted accurately using current clinical risk factors. External beam radiotherapy (EBRT) is one of the standard curative treatment options for localised disease and its efficacy is related to wide ranging aspects of tumour biology. Histopathological techniques including immunohistochemistry and a variety of genomic assays have been used to identify biomarkers of tumour proliferation, cell cycle checkpoints, hypoxia, DNA repair, apoptosis, and androgen synthesis, which predict response to radiotherapy. Global measures of genomic instability also show exciting capacity to predict survival outcomes following EBRT. There is also an urgent clinical need for biomarkers to predict the radiotherapy fraction sensitivity of different prostate tumours and preclinical studies point to possible candidates. Finally, the increased resolution of next generation sequencing (NGS) is likely to enable yet more precise molecular predictions of radiotherapy response and fraction sensitivity. Anna Wilkins, David Dearnaley, and Navita Somaiah Copyright © 2015 Anna Wilkins et al. All rights reserved. MicroRNAs as Important Players and Biomarkers in Oral Carcinogenesis Sun, 04 Oct 2015 09:10:46 +0000 Oral cancer, represented mainly by oral squamous cell carcinoma (OSCC), is the eighth most common type of human cancer worldwide. The number of new OSCC cases is increasing worldwide, especially in the low-income countries, and the prognosis remains poor in spite of recent advances in the diagnostic and therapeutic modalities. MicroRNAs (miRNAs), 18–25 nucleotides long noncoding RNA molecules, have recently gained significant attention as potential regulators and biomarkers for carcinogenesis. Recent data show that several miRNAs are deregulated in OSCC, and they have either a tumor suppressive or an oncogenic role in oral carcinogenesis. This review summarizes current knowledge on the role of miRNAs as tumor promotors or tumor suppressors in OSCC development and discusses their potential value as diagnostic and prognostic markers in OSCC. Anjie Min, Chao Zhu, Shuping Peng, Saroj Rajthala, Daniela Elena Costea, and Dipak Sapkota Copyright © 2015 Anjie Min et al. All rights reserved. A Pyrosequencing Assay for the Quantitative Methylation Analysis of GALR1 in Endometrial Samples: Preliminary Results Sun, 04 Oct 2015 09:10:13 +0000 Endometrial cancer is the most common malignancy of the female genital tract while aberrant DNA methylation seems to play a critical role in endometrial carcinogenesis. Galanin’s expression has been involved in many cancers. We developed a new pyrosequencing assay that quantifies DNA methylation of galanin’s receptor-1 (GALR1). In this study, the preliminary results indicate that pyrosequencing methylation analysis of GALR1 promoter can be a useful ancillary marker to cytology as the histological status can successfully predict. This marker has the potential to lead towards better management of women with endometrial lesions and eventually reduce unnecessary interventions. In addition it can provide early warning for women with negative cytological result. Christine Kottaridi, Nikolaos Koureas, Niki Margari, Emmanouil Terzakis, Evripidis Bilirakis, Asimakis Pappas, Charalampos Chrelias, Aris Spathis, Evangelia Aga, Abraham Pouliakis, Ioannis Panayiotides, and Petros Karakitsos Copyright © 2015 Christine Kottaridi et al. All rights reserved. Osteopontin Involves Cisplatin Resistance and Poor Prognosis in Oral Squamous Cell Carcinoma Wed, 30 Sep 2015 16:27:07 +0000 Background. Osteopontin (OPN) is a multifunctional cytokine involved in cell survival, migration, and adhesion. However, its role in chemosensitivity in locally advanced oral squamous cell carcinoma (OSCC) in humans has not yet been investigated. Methods. We enrolled 121 patients with locally advanced stage IVA/B OSCC receiving cisplatin-based IC followed by CCRT from January 1, 2006, through January 1, 2012. Immunohistochemistry was used to assess OPN expression in OSCC patients’ biopsy specimens from paraffin blocks before treatment. In addition, MTT/colony formation assay was used to estimate the influence of OPN in an oral cancer cell line treated with cisplatin. Results. Of the 121 patients, 94 had positive OPN findings and 52 responded to IC followed by CCRT. Positive osteopontin immunostaining also correlated significantly with positive N status/TNM stage/male gender and smoking. Univariate analyses showed that patients whose tumors had a low expression of OPN were more likely to respond to chemotherapy and have a significantly better OS than those whose tumors had a high expression of OPN. Multivariate analysis revealed that prolonged survival was independently predicted for patients with stage IVA disease, negative lymph nodes, and negative expressions of OPN and for those who received chemotherapy with Docetaxel/cisplatin/fluorouracil (TPF). An oral cancer line stimulated with OPN exhibited a dose-dependent resistance to cisplatin treatment. Conversely, endogenous OPN depletion by OPN-mediated shRNA increased sensitivity to cisplatin. Conclusions. A positive expression of OPN predicts a poor response and survival in patients with locally advanced stage IVA/B OSCC treated with cisplatin-based IC followed by CCRT. Sheng-Dean Luo, Yi-Ju Chen, Chien-Ting Liu, Kun-Ming Rau, Yi-Ching Chen, Hsin-Ting Tsai, Chang-Han Chen, and Tai-Jan Chiu Copyright © 2015 Sheng-Dean Luo et al. All rights reserved. Molecular Markers in the Diagnosis and Treatment of Cancer Mon, 14 Sep 2015 11:19:16 +0000 Murat Gokden, Aurelio Ariza, and Konstantinos Arnaoutakis Copyright © 2015 Murat Gokden et al. All rights reserved. Clinical Impact of the KL-6 Concentration of Pancreatic Juice for Diagnosing Pancreatic Masses Mon, 14 Sep 2015 06:30:13 +0000 Background and Aim. Pancreatic juice cytology (PJC) is considered optimal for differentially diagnosing pancreatic masses, but the accuracy of PJC ranges from 46.7% to 93.0%. The aim of this study was to evaluate the clinical impact of measuring the KL-6 concentration of pancreatic juice for diagnosing pancreatic masses. Methods. PJC and the KL-6 concentration measurements of pancreatic juice were performed for 70 consecutive patients with pancreatic masses (39 malignancies and 31 benign). Results. The average KL-6 concentration of pancreatic juice was significantly higher for pancreatic ductal adenocarcinomas (PDACs) ( U/mL) and intraductal papillary mucinous carcinomas (IPMCs) ( U/mL) than for pancreatic inflammatory lesions ( U/mL, ) and intraductal papillary mucinous neoplasms ( U/mL, ), respectively. When the cut-off level of the KL-6 concentration of pancreatic juice was 16 U/mL, the sensitivity, specificity, and accuracy of the KL-6 concentration of pancreatic juice alone were 79.5%, 64.5%, and 72.9%, respectively. Adding the KL-6 concentration of pancreatic juice to PJC when making a diagnosis caused the values of sensitivity and accuracy of PJC to increase by 15.3% () and 8.5% (), respectively. Conclusions. The KL-6 concentration of pancreatic juice may be as useful as PJC for diagnosing PDACs. Kazuya Matsumoto, Yohei Takeda, Kenichi Harada, Takumi Onoyama, Soichiro Kawata, Yasushi Horie, Teruhisa Sakamoto, Masaru Ueki, Norimasa Miura, and Yoshikazu Murawaki Copyright © 2015 Kazuya Matsumoto et al. All rights reserved. Ki-67 Expression in CRC Lymph Node Metastasis Does Not Predict Survival Sun, 13 Sep 2015 13:56:58 +0000 Colorectal cancer is one of the most common malignancies and a leading cause of cancer death worldwide. Molecular markers may improve clinicopathologic staging and provide a basis to guide novel therapeutic strategies which target specific tumour-associated molecules according to individual tumour biology; however, so far, no ideal molecular marker has been found to predict disease progression. We tested Ki-67 proliferation marker in primary and lymph node metastasis of CRC. We observed a statistical significant difference between the positive rates of neoplastic cells positively stained by Ki-67 in both sites, with remarkable increased number of Ki-67 positive cells in primary tumor cells compared to cancer cells that invaded lymph nodes. We can speculate that the metastatic CRC in lymph node can be more resistant to the drugs that target cellular division. Sandra F. Martins, Ricardo Amorim, Sílvia Coelho Mota, Luís Costa, Fernando Pardal, Mesquita Rodrigues, and Adhemar Longatto-Filho Copyright © 2015 Sandra F. Martins et al. All rights reserved. Metastatic Salivary Gland Tumors: A Single-Center Study Demonstrating the Feasibility and Potential Clinical Benefit of Molecular-Profiling-Guided Therapy Sun, 13 Sep 2015 11:18:23 +0000 We evaluated the use of molecular profiling (MP) for metastatic salivary gland adenoid cystic carcinoma (SACC), for which there is no standard treatment. MP (Caris Molecular Intelligence) was performed on biopsy samples from all metastatic SACC patients attending a tertiary medical center between 2010 and 2013 . Treatment was selected according to the biomarkers identified. Findings were compared with all similarly diagnosed patients treated in the same center between 1996 and 2009 . For each patient, MP identified 1–13 biomarkers associated with clinical benefit for specific therapies (most commonly low/negative TS, low ERCC1). Eleven patients (79%) received MP-guided treatment (2 died prior to treatment initiation, 1 opted not to be treated), with complete response in 1, partial response (PR) in 3, and stable disease in 4. In the historical controls, 2 patients (22%) were treated (1 had PR). Median (range) progression-free survival in the first line after MP was 8.2 months (1.4–49.5+). Median (range) overall survival from diagnosis of metastatic disease was 31.3 (1.4–71.1+) versus 14.0 (1.5–116) months in the historical controls. In conclusion, MP expands treatment options and may improve clinical outcomes for metastatic SACC. In orphan diseases where randomized trials cannot be performed, MP could become a standard clinical tool. Aron Popovtzer, Michal Sarfaty, Dror Limon, Gideon Marshack, Eli Perlow, Addie Dvir, Lior Soussan-Gutman, and Salomon M. Stemmer Copyright © 2015 Aron Popovtzer et al. All rights reserved. MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors Sun, 13 Sep 2015 10:29:50 +0000 Aims. Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available. Methods and Results. MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (). MET expression weakly correlated between primary and matched metastatic sites () and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (). Conclusions. We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents. Brian Shuch, Ryan Falbo, Fabio Parisi, Adebowale Adeniran, Yuval Kluger, Harriet M. Kluger, and Lucia B. Jilaveanu Copyright © 2015 Brian Shuch et al. All rights reserved. Molecular Biology in Pediatric High-Grade Glioma: Impact on Prognosis and Treatment Sun, 13 Sep 2015 10:26:06 +0000 High-grade gliomas are the main cause of death in children with brain tumours. Despite recent advances in cancer therapy, their prognosis remains poor and the treatment is still challenging. To date, surgery followed by radiotherapy and temozolomide is the standard therapy. However, increasing knowledge of glioma biology is starting to impact drug development towards targeted therapies. The identification of agents directed against molecular targets aims at going beyond the traditional therapeutic approach in order to develop a personalized therapy and improve the outcome of pediatric high-grade gliomas. In this paper, we critically review the literature regarding the genetic abnormalities implicated in the pathogenesis of pediatric malignant gliomas and the current development of molecularly targeted therapies. In particular, we analyse the impact of molecular biology on the prognosis and treatment of pediatric high-grade glioma, comparing it to that of adult gliomas. Daniela Rizzo, Antonio Ruggiero, Maurizio Martini, Valentina Rizzo, Palma Maurizi, and Riccardo Riccardi Copyright © 2015 Daniela Rizzo et al. All rights reserved. Overexpression of GPC6 and TMEM132D in Early Stage Ovarian Cancer Correlates with CD8+ T-Lymphocyte Infiltration and Increased Patient Survival Sun, 13 Sep 2015 10:02:31 +0000 Infiltration of cytotoxic T-lymphocytes in ovarian cancer is a favorable prognostic factor. Employing a differential expression approach, we have recently identified a number of genes associated with CD8+ T-cell infiltration in early stage ovarian tumors. In the present study, we validated by qPCR the expression of two genes encoding the transmembrane proteins GPC6 and TMEM132D in a cohort of early stage ovarian cancer patients. The expression of both genes correlated positively with the mRNA levels of CD8A, a marker of T-lymphocyte infiltration [Pearson coefficient: 0.427 () and 0.861 (), resp.]. GPC6 and TMEM132D expression was also documented in a variety of ovarian cancer cell lines. Importantly, Kaplan-Meier survival analysis revealed that high mRNA levels of GPC6 and/or TMEM132D correlated significantly with increased overall survival of early stage ovarian cancer patients . Thus, GPC6 and TMEM132D may serve as predictors of CD8+ T-lymphocyte infiltration and as favorable prognostic markers in early stage ovarian cancer with important consequences for diagnosis, prognosis, and tumor immunobattling. Athanasios Karapetsas, Antonis Giannakakis, Denarda Dangaj, Evripidis Lanitis, Spyridon Kynigopoulos, Maria Lambropoulou, Janos L. Tanyi, Alex Galanis, Stylianos Kakolyris, Gregorios Trypsianis, George Coukos, and Raphael Sandaltzopoulos Copyright © 2015 Athanasios Karapetsas et al. All rights reserved. Long Noncoding RNAs as New Architects in Cancer Epigenetics, Prognostic Biomarkers, and Potential Therapeutic Targets Sun, 13 Sep 2015 10:01:40 +0000 Recent advances in genome-wide analysis have revealed that 66% of the genome is actively transcribed into noncoding RNAs (ncRNAs) while less than 2% of the sequences encode proteins. Among ncRNAs, high-resolution microarray and massively parallel sequencing technologies have identified long ncRNAs (>200 nucleotides) that lack coding protein function. LncRNAs abundance, nuclear location, and diversity allow them to create in association with protein interactome, a complex regulatory network orchestrating cellular phenotypic plasticity via modulation of all levels of protein-coding gene expression. Whereas lncRNAs biological functions and mechanisms of action are still not fully understood, accumulating data suggest that lncRNAs deregulation is pivotal in cancer initiation and progression and metastatic spread through various mechanisms, including epigenetic effectors, alternative splicing, and microRNA-like molecules. Mounting data suggest that several lncRNAs expression profiles in malignant tumors are associated with prognosis and they can be detected in biological fluids. In this review, we will briefly discuss characteristics and functions of lncRNAs, their role in carcinogenesis, and their potential usefulness as diagnosis and prognosis biomarkers and novel therapeutic targets. Didier Meseure, Kinan Drak Alsibai, Andre Nicolas, Ivan Bieche, and Antonin Morillon Copyright © 2015 Didier Meseure et al. All rights reserved. Inverse Association between Prediagnostic IgE Levels and the Risk of Brain Tumors: A Systematic Review and Meta-Analysis Sun, 13 Sep 2015 09:59:08 +0000 An inverse association between allergic conditions and glioma risk has been suggested in many epidemiological studies. However, the evidence is inadequate to draw robust conclusions for the association between prediagnostic IgE levels and brain tumors risk. The aim of this study was to provide more precise estimates for this association by meta-analysis of all published studies. Overall, 8 individual studies with 2,461 cases and 3,934 controls were included in our study. A decreased risk of brain tumors (RR = 0.73, 95% CI 0.61–0.86, ) was observed in relation to elevated level of total IgE. The negative association was significant between elevated total IgE level and the risk of glioma (RR = 0.74, 95% CI 0.62–0.88, ). However, no significant relationship was demonstrated between testing positive for respiratory allergen-specific IgE and brain tumors risk. In addition, the role of prediagnostic IgE levels in brain tumors risk did not alter in men and women. The present study suggests that increased level of total prediagnostic IgE but not respiratory allergen-specific IgE plays a protective role in brain tumors risk, glioma in particular. More studies are warranted for further elucidation of the meningioma risk related to prediagnostic IgE levels. Chong Ma, Lei Cao, Jianping Zhao, Xing Ming, Ming Shang, Hailiang Zong, Hai Du, Kai Li, Xiaoguang He, and Hongsheng Xu Copyright © 2015 Chong Ma et al. All rights reserved. Plasma Protein Biomarker Candidates for Myelodysplastic Syndrome Subgroups Sun, 13 Sep 2015 09:54:40 +0000 In recent years the plasma proteomes of several different myelodysplastic syndrome (MDS) subgroups have been investigated and compared with those of healthy donors. However, the resulting data do not facilitate a direct and statistical comparison of the changes among the different MDS subgroups that would be useful for the selection and proposal of diagnostic biomarker candidates. The aim of this work was to identify plasma protein biomarker candidates for different MDS subgroups by reanalyzing the proteomic data of four MDS subgroups: refractory cytopenia with multilineage dysplasia (RCMD), refractory anemia or refractory anemia with ringed sideroblasts (RA-RARS), refractory anemia with excess blasts subtype 1 (RAEB-1), and refractory anemia with excess blasts subtype 2 (RAEB-2). Reanalysis of a total of 47 MDS patients revealed biomarker candidates, with alpha-2-HS-glycoprotein and leucine-rich alpha-2-glycoprotein as the most promising candidates. Pavel Majek, Klara Pecankova, Jaroslav Cermak, and Jan E. Dyr Copyright © 2015 Pavel Majek et al. All rights reserved. Potential Role of MicroRNA-210 as Biomarker in Human Cancers Detection: A Meta-Analysis Sun, 13 Sep 2015 09:50:37 +0000 We conducted this meta-analysis aimed to evaluate diagnostic accuracy of miR-210 in human cancers. A total of 673 cancer patients and 606 cancer-free individuals from 13 studies were contained in this meta-analysis. The overall diagnostic results in our study showed that the pooled sensitivity was 0.70, specificity was 0.76, and the AUC was 0.80. In addition, the PLR and NLR were 2.9 and 0.39, with DOR of 8. After the outliner exclusion detected by sensitivity analysis, these parameters had minimal change, which confirmed the stability of our work. The results in our studies showed that the miR-210 assay yielded relatively moderate accuracy in cancer patients and cancer-free individual differentiation. More basic researches are needed to highlight its role as supplement in clinical treatment. Jiongjiong Lu, Feng Xie, Li Geng, Weifeng Shen, Chengjun Sui, and Jiamei Yang Copyright © 2015 Jiongjiong Lu et al. All rights reserved. Statistical Methods for Establishing Personalized Treatment Rules in Oncology Sun, 13 Sep 2015 09:28:59 +0000 The process for using statistical inference to establish personalized treatment strategies requires specific techniques for data-analysis that optimize the combination of competing therapies with candidate genetic features and characteristics of the patient and disease. A wide variety of methods have been developed. However, heretofore the usefulness of these recent advances has not been fully recognized by the oncology community, and the scope of their applications has not been summarized. In this paper, we provide an overview of statistical methods for establishing optimal treatment rules for personalized medicine and discuss specific examples in various medical contexts with oncology as an emphasis. We also point the reader to statistical software for implementation of the methods when available. Junsheng Ma, Brian P. Hobbs, and Francesco C. Stingo Copyright © 2015 Junsheng Ma et al. All rights reserved. The Diagnostic Ability of Follow-Up Imaging Biomarkers after Treatment of Glioblastoma in the Temozolomide Era: Implications from Proton MR Spectroscopy and Apparent Diffusion Coefficient Mapping Sun, 13 Sep 2015 09:26:11 +0000 Objective. To prospectively determine institutional cut-off values of apparent diffusion coefficients (ADCs) and concentration of tissue metabolites measured by MR spectroscopy (MRS) for early differentiation between glioblastoma (GBM) relapse and treatment-related changes after standard treatment. Materials and Methods. Twenty-four GBM patients who received gross total resection and standard adjuvant therapy underwent MRI examination focusing on the enhancing region suspected of tumor recurrence. ADC maps, concentrations of N-acetylaspartate, choline, creatine, lipids, and lactate, and metabolite ratios were determined. Final diagnosis as determined by biopsy or follow-up imaging was correlated to the results of advanced MRI findings. Results. Eighteen (75%) and 6 (25%) patients developed tumor recurrence and pseudoprogression, respectively. Mean time to radiographic progression from the end of chemoradiotherapy was 5.8 ± 5.6 months. Significant differences in ADC and MRS data were observed between those with progression and pseudoprogression. Recurrence was characterized by N-acetylaspartate ≤ 1.5 mM, choline/N-acetylaspartate ≥ 1.4 (sensitivity 100%, specificity 91.7%), N-acetylaspartate/creatine ≤ 0.7, and ADC ≤ 1300 × 10−6 mm2/s (sensitivity 100%, specificity 100%). Conclusion. Institutional validation of cut-off values obtained from advanced MRI methods is warranted not only for diagnosis of GBM recurrence, but also as enrollment criteria in salvage clinical trials and for reporting of outcomes of initial treatment. Martin Bulik, Tomas Kazda, Pavel Slampa, and Radim Jancalek Copyright © 2015 Martin Bulik et al. All rights reserved. Long Noncoding RNA KIAA0125 Potentiates Cell Migration and Invasion in Gallbladder Cancer Sun, 13 Sep 2015 09:21:04 +0000 Gallbladder cancer (GBC) is one of the mostly aggressive diseases with poor prognosis due to the lack of severe symptoms. To date, little is known about the potential roles and underlying mechanisms of long noncoding RNAs (lncRNAs) in GBC initiation and progression. Thus, it provides us with a novel insight into the contribution of lncRNAs to GBC development. Remarkably, we found the differential expression of a lncRNA, namely, KIAA0125, in a pair of GBC cell sublines which possess different metastatic potentials. Then the effects of KIAA0125 on GBC cell migration, invasion, and epithelial-mesenchymal transitions (EMT) were investigated by using a lentivirus-mediated RNA interference (RNAi) system. Notably, cell migration and invasion were strongly inhibited by KIAA0125 suppression. Moreover, the expression of β-Catenin was increased and the expression of Vimentin was decreased in GBC-SD/M cells after KIAA0125 knockdown. Thus, our findings suggested that KIAA0125 promoted the migration and invasion of GBC cells and could serve as a potential therapeutic target in advanced GBC. Wenjie Lv, Lei Wang, Jianhua Lu, Jiasheng Mu, Yingbin Liu, and Ping Dong Copyright © 2015 Wenjie Lv et al. All rights reserved. Long Noncoding RNA Expression Signatures of Metastatic Nasopharyngeal Carcinoma and Their Prognostic Value Sun, 13 Sep 2015 09:18:59 +0000 Long noncoding RNAs (lncRNAs) have recently been found to play important roles in various cancer types. The elucidation of genome-wide lncRNA expression patterns in metastatic nasopharyngeal carcinoma (NPC) could reveal novel mechanisms underlying NPC carcinogenesis and progression. In this study, lncRNA expression profiling was performed on metastatic and primary NPC tumors, and the differentially expressed lncRNAs between these samples were identified. A total of 33,045 lncRNA probes were generated for our microarray based on authoritative data sources, including RefSeq, UCSC Knowngenes, Ensembl, and related literature. Using these probes, 8,088 lncRNAs were found to be significantly differentially expressed (2-fold). To identify the prognostic value of these differentially expressed lncRNAs, four lncRNAs (LOC84740, ENST00000498296, AL359062, and ENST00000438550) were selected; their expression levels were measured in an independent panel of 106 primary NPC samples via QPCR. Among these lncRNAs, ENST00000438550 expression was demonstrated to be significantly correlated with NPC disease progression. A survival analysis showed that a high expression level of ENST00000438550 was an independent indicator of disease progression in NPC patients (). In summary, this study may provide novel diagnostic and prognostic biomarkers for NPC, as well as a novel understanding of the mechanism underlying NPC metastasis and potential targets for future treatment. Wei Zhang, Lin Wang, Fang Zheng, Ruhai Zou, Changqing Xie, Qiannan Guo, Qian Hu, Jianing Chen, Xing Yang, Herui Yao, Erwei Song, and Yanqun Xiang Copyright © 2015 Wei Zhang et al. All rights reserved. The Fine LINE: Methylation Drawing the Cancer Landscape Sun, 13 Sep 2015 09:15:48 +0000 LINE-1 (L1) is the most abundant mammalian transposable element that comprises nearly 20% of the genome, and nearly half of the mammalian genome has stemmed from L1-mediated mobilization. Expression and retrotransposition of L1 are suppressed by complex mechanisms, where the key role belongs to DNA methylation. Alterations in L1 methylation may lead to aberrant expression of L1 and have been described in numerous diseases. Accumulating evidence clearly indicates that loss of global DNA methylation observed in cancer development and progression is tightly associated with hypomethylation of L1 elements. Significant progress achieved in the last several years suggests that such parameters as L1 methylation status can be potentially utilized as clinical biomarkers for determination of the disease stage and in predicting the disease-free survival in cancer patients. In this paper, we summarize the current knowledge on L1 methylation, with specific emphasis given to success and challenges on the way of introduction of L1 into clinical practice. Isabelle R. Miousse and Igor Koturbash Copyright © 2015 Isabelle R. Miousse and Igor Koturbash. All rights reserved. Collagen Type XI Alpha 1 Expression in Intraductal Papillomas Predicts Malignant Recurrence Sun, 13 Sep 2015 09:08:29 +0000 Despite the progress achieved in the treatment of breast cancer, there are still many unsolved clinical issues, being the diagnosis, prognosis, and treatment of papillary diseases, one of the highest challenges. Because of its unpredictable clinical behavior, treatment of intraductal papilloma has generated a great controversy. Even though considered as a benign lesion, it presents high rate of malignant recurrence. This is the reason why there are clinicians supporting a complete excision of the lesion, while others support an only expectant follow-up. Previous results of our group suggested that procollagen 11 alpha 1 (pro-COL11A1) expression correlates with infiltrating phenotype in breast lesions. We analyzed the correlation between expression of pro-COL11A1 in intraductal papilloma and their risk of malignant recurrence. Immunohistochemistry of pro-COL11A1 was performed in 62 samples of intraductal papilloma. Ten out 11 cases relapsed as carcinoma presents positive staining for COL11A1, while just 17 out of 51 cases with benign behaviour present immunostaining. There were significant differences () when comparing patients with malignant recurrence versus nonmalignant relapse patients. These data suggest that pro-COL11A1 expression is a highly sensitive biomarker to predict malignant relapse of intraductal papilloma and it can be used as indicative factor for prevention programs. Javier Freire, Lucia García-Berbel, Pilar García-Berbel, Saray Pereda, Ainara Azueta, Pilar García-Arranz, Ana De Juan, Alfonso Vega, Ángela Hens, Ana Enguita, Pedro Muñoz-Cacho, and Javier Gómez-Román Copyright © 2015 Javier Freire et al. All rights reserved. Circulating Galectin-1 and 90K/Mac-2BP Correlated with the Tumor Stages of Patients with Colorectal Cancer Sun, 13 Sep 2015 09:02:41 +0000 Background. The simultaneous correlation of serum galectin-1, galectin-3, and 90K/Mac-2BP levels with clinical stages of patients with colorectal cancer has not yet been clarified. We plan to measure the serum levels of galectin-1, galectin-3, and 90K/Mac-2BP of patients at different stages of colorectal cancer and analyze the correlation of these galectins with stages of colorectal cancers. Methods. 198 colorectal cancer patients (62 ± 13 (range 31–85) years old, 43.6% female) were recruited for this study. Subjects’ blood samples were checked for serum galectin-1, galectin-3, 90K/Mac-2BP, and carcinoembryonic antigen by sandwich enzyme-linked immunosorbent assay. We determined the correlation between plasma concentrations with clinical tumor stages. Results. Colorectal cancer patients with larger cancer sizes (stages T3, T4 rather than T1, T2) have higher serum 90K/Mac-2BP (P = 0.014) and patients with lymph node metastasis have higher serum galectin-1 (P = 0.002) but there was not a significant correlation between galectin-3 and tumor staging of colon cancer. In colorectal cancer patients even with normal carcinoembryonic antigen, serum galectin-1 could predict more lymph node metastasis. Conclusions. We found 90K/Mac-2BP correlated with the size of colorectal cancer. Galectin-1 but not galectin-3 was associated with lymph node metastasis. Galectin-1 could predict more lymph node metastasis in colorectal cancer patients with normal serum carcinoembryonic antigen. Keng-Liang Wu, Hong-Hwa Chen, Chen-Tzi Pen, Wen-Ling Yeh, Eng-Yen Huang, Chang-Chun Hsiao, and Kuender D. Yang Copyright © 2015 Keng-Liang Wu et al. All rights reserved. BRAF Testing in Multifocal Papillary Thyroid Carcinoma Sun, 13 Sep 2015 07:41:09 +0000 Background. BRAF V600E mutation is associated with poor prognosis in patients with papillary thyroid carcinoma (PTC). PTC is often multifocal, and there are no guidelines on how many tumors to test for BRAF mutation in multifocal PTC. Methods. Fifty-seven separate formalin-fixed and paraffin-embedded PTCs from twenty-seven patients were manually macrodissected and tested for BRAF mutation using a commercial allele-specific real-time polymerase chain reaction-based assay (Entrogen, Woodland Hills, CA). Data related to histologic characteristics, patient demographics, and clinical outcomes were collected. Results. All mutations detected were BRAF V600E. Seventeen patients (63%) had concordant mutation status in the largest and second-largest tumors (i.e., both were positive or both were negative). The remaining ten patients (37%) had discordant mutation status. Six of the patients with discordant tumors (22% overall) had a BRAF-negative largest tumor and a BRAF-positive second-largest tumor. No histologic feature was found to help predict which cases would be discordant. Conclusions. Patients with multifocal PTC whose largest tumor is BRAF-negative can have smaller tumors that are BRAF-positive. Therefore, molecular testing of more than just the dominant tumor should be considered. Future studies are warranted to establish whether finding a BRAF mutation in a smaller tumor has clinical significance. Hillary Z. Kimbrell, Andrew B. Sholl, Swarnamala Ratnayaka, Shanker Japa, Michelle Lacey, Gandahari Carpio, Parisha Bhatia, and Emad Kandil Copyright © 2015 Hillary Z. Kimbrell et al. All rights reserved. LINE-1 Methylation Patterns as a Predictor of Postmolar Gestational Trophoblastic Neoplasia Sun, 13 Sep 2015 07:41:05 +0000 Objective. To study the potential of long interspersed element-1 (LINE-1) methylation change in the prediction of postmolar gestational trophoblastic neoplasia (GTN). Methods. The LINE-1 methylation pattern from first trimester placenta, hydatidiform mole, and malignant trophoblast specimens were compared. Then, hydatidiform mole patients from 11999 to 2010 were classified into the following 2 groups: a remission group and a group that developed postmolar GTN. Specimens were prepared for a methylation study. The methylation levels and percentages of LINE-1 loci were evaluated for their sensitivity, specificity, and accuracy for the prediction of postmolar GTN. Results. First, 12 placentas, 38 moles, and 19 malignant trophoblast specimens were compared. The hydatidiform mole group had the highest LINE-1 methylation level ( = 0.003) and the uCuC of LINE-1 increased in the malignant trophoblast group ( ≤ 0.001). One hundred forty-five hydatidiform mole patients were classified as 103 remission and 42 postmolar GTN patients. The %mCuC and %uCmC of LINE-1 showed the lowest value for distinguishing between the two groups ( < 0.001). The combination of the pretreatment β-hCG level (≥100,000 mIU/mL) with the %mCuC and %uCmC, sensitivity, specificity, PPV, NPV, and accuracy modified the levels to 60.0%, 92.2%, 77.4%, 83.8%, and 82.3%, respectively. Conclusions. A reduction in the partial methylation of LINE-1 occurs early before the clinical appearance of malignant transformation. The %mCuC and %uCmC of LINE-1s may be promising markers for monitoring hydatidiform moles before progression to GTN. Ruangsak Lertkhachonsuk, Krissada Paiwattananupant, Patou Tantbirojn, Prakasit Rattanatanyong, and Apiwat Mutirangura Copyright © 2015 Ruangsak Lertkhachonsuk et al. All rights reserved. The Emergent Landscape of Detecting EGFR Mutations Using Circulating Tumor DNA in Lung Cancer Sun, 13 Sep 2015 07:41:00 +0000 The advances in targeted therapies for lung cancer are based on the evaluation of specific gene mutations especially the epidermal growth factor receptor (EGFR). The assays largely depend on the acquisition of tumor tissue via biopsy before the initiation of therapy or after the onset of acquired resistance. However, the limitations of tissue biopsy including tumor heterogeneity and insufficient tissues for molecular testing are impotent clinical obstacles for mutation analysis and lung cancer treatment. Due to the invasive procedure of tissue biopsy and the progressive development of drug-resistant EGFR mutations, the effective initial detection and continuous monitoring of EGFR mutations are still unmet requirements. Circulating tumor DNA (ctDNA) detection is a promising biomarker for noninvasive assessment of cancer burden. Recent advancement of sensitive techniques in detecting EGFR mutations using ctDNA enables a broad range of clinical applications, including early detection of disease, prediction of treatment responses, and disease progression. This review not only introduces the biology and clinical implementations of ctDNA but also includes the updating information of recent advancement of techniques for detecting EGFR mutation using ctDNA in lung cancer. Wei-Lun Huang, Fang Wei, David T. Wong, Chien-Chung Lin, and Wu-Chou Su Copyright © 2015 Wei-Lun Huang et al. All rights reserved. Genetic and Chromosomal Aberrations and Their Clinical Significance in Renal Neoplasms Sun, 13 Sep 2015 07:28:00 +0000 The most common form of malignant renal neoplasms is renal cell carcinoma (RCC), which is classified into several different subtypes based on the histomorphological features. However, overlaps in these characteristics may present difficulties in the accurate diagnosis of these subtypes, which have different clinical outcomes. Genomic and molecular studies have revealed unique genetic aberrations in each subtype. Knowledge of these genetic changes in hereditary and sporadic renal neoplasms has given an insight into the various proteins and signalling pathways involved in tumour formation and progression. In this review, the genetic aberrations characteristic to each renal neoplasm subtype are evaluated along with the associated protein products and affected pathways. The potential applications of these genetic aberrations and proteins as diagnostic tools, prognostic markers, or therapeutic targets are also assessed. Ning Yi Yap, Retnagowri Rajandram, Keng Lim Ng, Jayalakshmi Pailoor, Ahmad Fadzli, and Glenda Carolyn Gobe Copyright © 2015 Ning Yi Yap et al. All rights reserved. Reviving Lonidamine and 6-Diazo-5-oxo-L-norleucine to Be Used in Combination for Metabolic Cancer Therapy Sun, 06 Sep 2015 11:31:22 +0000 Abnormal metabolism is another cancer hallmark. The two most characterized altered metabolic pathways are high rates of glycolysis and glutaminolysis, which are natural targets for cancer therapy. Currently, a number of newer compounds to block glycolysis and glutaminolysis are being developed; nevertheless, lonidamine and 6-diazo-5-oxo-L-norleucine (DON) are two old drugs well characterized as inhibitors of glycolysis and glutaminolysis, respectively, whose clinical development was abandoned years ago when the importance of cancer metabolism was not fully appreciated and clinical trial methodology was less developed. In this review, a PubMed search using the words lonidamine and 6-diazo-5-oxo-L-norleucine (DON) was undertaken to analyse existing information on the preclinical and clinical studies of these drugs for cancer treatment. Data show that they exhibit antitumor effects; besides there is also the suggestion that they are synergistic. We conclude that lonidamine and DON are safe and potentially effective drugs that need to be reevaluated in combination as metabolic therapy of cancer. Diana Cervantes-Madrid, Yair Romero, and Alfonso Dueñas-González Copyright © 2015 Diana Cervantes-Madrid et al. All rights reserved. Effects of a Particular Heptapeptide on the IFN-α-Sensitive CML Cells Tue, 01 Sep 2015 14:13:02 +0000 Using the phage display biopanning technique, we have previously identified a heptapeptide KLWVIPQ which specifically binds to the surface of the IFN-α-sensitive but not the IFN-α-resistant CML cells. The effects of this heptapeptide on the IFN-α-sensitive CML cells were investigated in the present study. IFN-α-sensitive KT-1/A3 and IFN-α-resistant KT-1/A3R CML cells were transfected by pEGFP-KLWVIPQ expression vector and/or induced by IFN-α. WST-1 cell proliferation assay, flow cytometry, and western blotting were performed to determine the effects of this heptapeptide and/or IFN-α on CML cells. The viability of the KT-1/A3 cells was inhibited and apoptosis was induced by either expression of the heptapeptide KLWVIPQ or IFN-α treatment with concurrent upregulation of P53 and downregulation of P210bcr/abl. However, these effects were not observed in the IFN-α-resistant KT-1/A3R cells. These results suggest that the heptapeptide KLWVIPQ shares a similar mechanism with IFN-α in the regulation of CML cell growth and apoptosis, implying that the heptapeptide KLWVIPQ could be a novel target to go further into mechanisms of IFN-α sensitivity and/or resistance in CML. Fu-lan Yang, Fang-zhi Chen, Xin-xing Wan, Xi Zhou, Mei-juan Zhou, Han-chun Chen, Jun-jiang Fu, and Dian-zheng Zhang Copyright © 2015 Fu-lan Yang et al. All rights reserved. Prognostic Significance of mTOR and PTEN in Patients with Esophageal Squamous Cell Carcinoma Tue, 18 Aug 2015 10:12:54 +0000 The prognostic value of mTOR in ESCC is much controversial; this study aimed to determine the prognostic importance of mTOR and PTEN in patients with ESCC. A total of 148 consecutive patients who underwent esophagectomy from 2010 to 2012 were included in this study, tested by western bolt and immunohistochemistry for mTOR and PTEN expression. Correlation coefficient was calculated using Pearson’s correlation test. The 3-year overall survival (OS) and disease-free survival (DFS) were calculated in relation to the two markers. 94 (63.5%) of 148 were mTOR high expression, and PTEN high expression was detected in 46 (31.1%) of the 148 patients with ESCC. The Pearson correlation coefficient revealed a significant negative correlation in two proteins (correlation coefficient = −0.189, ). The 3-year OS and DFS time in the mTOR-high group was 23.9 and 18.4 months, respectively, and the time in the mTOR-low group was 33.9 months and 31.4 months, respectively. The difference of survival rate between the two groups remained statistically significant. mTOR-low or PTEN-high patients had better 3-year rates of OS and DFS than mTOR-high or PTEN-low group ( by the log-rank test). This study also found that mTOR was an independence prognostic factor by multivariate analysis. Jianjun Lu, You Pan, Xin Xia, Yong Gu, and Yiyan Lei Copyright © 2015 Jianjun Lu et al. All rights reserved. A Method to Improve Electron Density Measurement of Cone-Beam CT Using Dual Energy Technique Wed, 05 Aug 2015 11:55:37 +0000 Purpose. To develop a dual energy imaging method to improve the accuracy of electron density measurement with a cone-beam CT (CBCT) device. Materials and Methods. The imaging system is the XVI CBCT system on Elekta Synergy linac. Projection data were acquired with the high and low energy X-ray, respectively, to set up a basis material decomposition model. Virtual phantom simulation and phantoms experiments were carried out for quantitative evaluation of the method. Phantoms were also scanned twice with the high and low energy X-ray, respectively. The data were decomposed into projections of the two basis material coefficients according to the model set up earlier. The two sets of decomposed projections were used to reconstruct CBCT images of the basis material coefficients. Then, the images of electron densities were calculated with these CBCT images. Results. The difference between the calculated and theoretical values was within 2% and the correlation coefficient of them was about 1.0. The dual energy imaging method obtained more accurate electron density values and reduced the beam hardening artifacts obviously. Conclusion. A novel dual energy CBCT imaging method to calculate the electron densities was developed. It can acquire more accurate values and provide a platform potentially for dose calculation. Kuo Men, Jian-Rong Dai, Ming-Hui Li, Xin-Yuan Chen, Ke Zhang, Yuan Tian, Peng Huang, and Ying-Jie Xu Copyright © 2015 Kuo Men et al. All rights reserved. Optimal Use of Biomarkers in Oncology Tue, 04 Aug 2015 11:17:56 +0000 Marie Karlikova, Ondrej Topolcan, Olive T. J. Wolfe, Vivian Barak, and Tomas Zima Copyright © 2015 Marie Karlikova et al. All rights reserved. Concordance of Hypermethylated DNA and the Tumor Markers CA 15-3, CEA, and TPA in Serum during Monitoring of Patients with Advanced Breast Cancer Mon, 03 Aug 2015 12:18:55 +0000 The serological protein tumor markers CA 15-3, CEA, and TPA are frequently used to monitor tumor burden among metastatic breast cancer patients. Breast cancer is associated with global DNA hypomethylation and hypermethylation of some promoter regions. No monitoring study has yet investigated the interrelationship between protein tumor markers, the global DNA hypomethylation, and hypermethylated genes in serum from patients with advanced disease. Twenty-nine patients with histologically proven advanced breast cancer received first-line chemotherapy with epirubicin. Samples were collected prior to each treatment and prospectively analyzed for CA 15-3, CEA, and TPA. The same samples were retrospectively analyzed for the concentration of hypermethylated RASSF1A and for global DNA hypomethylation using LINE-1. Among patients with elevated concentrations of the protein markers, concordance could be observed between serial changes of the hypermethylated RASSF1A gene and the protein markers. Among patients with lower concentrations, RASSF1A could only be detected periodically. There was discordance between changes of the hypomethylated LINE-1 as compared to the protein markers. Circulating hypermethylated RASSF1A and protein markers may have similar kinetics during monitoring of tumor burden. Further investigations are needed to determine whether any of the hypermethylated DNA genes may provide predictive information during monitoring. Søren Kristiansen, Lars Mønster Jørgensen, Morten Høgh Hansen, Dorte Nielsen, and György Sölétormos Copyright © 2015 Søren Kristiansen et al. All rights reserved. Gamma-Glutamylcyclotransferase: A Novel Target Molecule for Cancer Diagnosis and Treatment Mon, 03 Aug 2015 11:33:40 +0000 Gamma-glutamylcyclotransferase (GGCT) is one of the major enzymes involved in glutathione metabolism. However, its gene locus was unknown for many years. Recently, the gene for GGCT was found to be identical to C7orf24, which is registered as a hypothetical protein. Orthologs have been found in bacteria, plants, and nematodes as well as higher organisms, and the GGCT gene is highly preserved among a wide range of species. GGCT (C7orf24) was also reported as an upregulated protein in various cancers. Although the function of GGCT in cancer cells has not been determined, the following important activities have been reported: (1) high expression in various cancer tissues and cancer cell lines, (2) low expression in normal tissues, (3) inhibition of cancer cell proliferation via anti-GGCT RNAi, (4) inhibition of cancer cell invasion and migration via anti-GGCT RNAi, (5) an epigenetic transcriptional regulation in cancer cells, and (6) an antitumor effect in cancer-bearing xenograft mice. Therefore, GGCT is promising as a diagnostic marker and a therapeutic target for various cancers. This review summarizes these interesting findings. Susumu Kageyama, Eiki Hanada, Hiromi Ii, Keiji Tomita, Tatsuhiro Yoshiki, and Akihiro Kawauchi Copyright © 2015 Susumu Kageyama et al. All rights reserved. Reproductive Factors but Not Hormonal Factors Associated with Thyroid Cancer Risk: A Systematic Review and Meta-Analysis Mon, 03 Aug 2015 11:33:38 +0000 Many studies have investigated the association between hormonal and reproductive factors and thyroid cancer risk but provided contradictory and inconclusive findings. This review was aimed at precisely estimating this association by pooling all available epidemiological studies. 25 independent studies were retrieved after a comprehensive literature search in databases of PubMed and Embase. Overall, common hormonal factors including oral contraceptive and hormone replacement therapy did not alter the risk of thyroid cancer. Older age at menopause was associated with weakly increased risk of thyroid cancer in overall analysis (RR = 1.24, 95% CI 1.00–1.53, ); however, longer duration of breast feeding was related to moderately reduced risk of thyroid cancer, suggested by pooled analysis in all cohort studies (RR = 0.7, 95% CI 0.51–0.95, ). The pooled RR in hospital-based case-control studies implicated that parous women were more susceptible to thyroid cancer than nulliparous women (RR = 2.30, 95% CI 1.31–4.04, ). The present meta-analysis suggests that older age at menopause and parity are risk factors for thyroid cancer, while longer duration of breast feeding plays a protective role against this cancer. Nevertheless, more relevant epidemiological studies are warranted to investigate roles of hormonal and reproductive factors in thyroid carcinogenesis. Yijuan Cao, Zengyan Wang, Juan Gu, Fangfang Hu, Yujuan Qi, Qianqian Yin, Qingqing Sun, Guotao Li, and Bin Quan Copyright © 2015 Yijuan Cao et al. All rights reserved. B-Cell Activating Factor as a Cancer Biomarker and Its Implications in Cancer-Related Cachexia Mon, 03 Aug 2015 11:05:51 +0000 B-cell activating factor (BAFF) is a cytokine and adipokine of the TNF ligand superfamily. The main biological function of BAFF in maintaining the maturation of B-cells to plasma cells has recently made it a target of the first FDA-approved selective BAFF antibody, belimumab, for the therapy of systemic lupus erythematosus. Concomitantly, the role of BAFF in cancer has been a subject of research since its discovery. Here we review BAFF as a biomarker of malignant disease activity and prognostic factor in B-cell derived malignancies such as multiple myeloma. Moreover, anti-BAFF therapy seems to be a promising approach in treatment of B-cell derived leukemias/lymphomas. In nonhematologic solid tumors, BAFF may contribute to cancer progression by mechanisms both dependent on and independent of BAFF’s proinflammatory role. We also describe ongoing research into the pathophysiological link between BAFF and cancer-related cachexia. BAFF has been shown to contribute to inflammation and insulin resistance which are known to worsen cancer cachexia syndrome. Taking all the above together, BAFF is emerging as a biomarker of several malignancies and a possible hallmark of cancer cachexia. Michal Rihacek, Julie Bienertova-Vasku, Dalibor Valik, Jaroslav Sterba, Katerina Pilatova, and Lenka Zdrazilova-Dubska Copyright © 2015 Michal Rihacek et al. All rights reserved. Integration of DCE-MRI and DW-MRI Quantitative Parameters for Breast Lesion Classification Mon, 03 Aug 2015 09:38:27 +0000 Objective. The purpose of our study was to evaluate the diagnostic value of an imaging protocol combining dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI) in patients with suspicious breast lesions. Materials and Methods. A total of 31 breast lesions (15 malignant and 16 benign proved by histological examination) in 26 female patients were included in this study. For both DCE-MRI and DW-MRI model free and model based parameters were computed pixel by pixel on manually segmented ROIs. Statistical procedures included conventional linear analysis and more advanced techniques for classification of lesions in benign and malignant. Results. Our findings indicated no strong correlation between DCE-MRI and DW-MRI parameters. Results of classification analysis show that combining of DCE parameters or DW-MRI parameter, in comparison of single feature, does not yield a dramatic improvement of sensitivity and specificity of the two techniques alone. The best performance was obtained considering a full combination of all features. Moreover, the classification results combining all features are dominated by DCE-MRI features alone. Conclusion. The combination of DWI and DCE-MRI does not show a potential to dramatically increase the sensitivity and specificity of breast MRI. DCE-MRI alone gave the same performance as in combination with DW-MRI. Roberta Fusco, Mario Sansone, Salvatore Filice, Vincenza Granata, Orlando Catalano, Daniela Maria Amato, Maurizio Di Bonito, Massimiliano D’Aiuto, Immacolata Capasso, Massimo Rinaldo, and Antonella Petrillo Copyright © 2015 Roberta Fusco et al. All rights reserved. Risk Factors of the Invasive Breast Cancer Locoregional Recurrence Mon, 03 Aug 2015 09:35:42 +0000 Background. The aim of the research was to estimate the frequency of the locoregional breast cancer recurrence appearance, the recurrence-free period continuance, and the 3- and 5-year survival depending on the scope of the surgical intervention, menstrual profile, and histological and molecular-biologic characteristics of the primary tumor. Patients and Methods. Among 218 patients with a breast cancer, 99 patients had breast-conserving surgery (BCS) and 119 underwent radical mastectomy (RME); all patients had regional lymphatic nodes dissection. The size and the primary tumor differentiation degree, metastasis presence in the regional lymph nodes, ER expression, PR, and Her/2neu were assessed as the prognostics factors. Results. It was defined that the locoregional recurrence appearance frequency in patients with BCS turned out to be 13%, and in patients after RME it turned out to be 9%; the recurrence-free period continuance was months and months, respectively. Conclusions. The locoregional cancer recurrence frequency is higher in women with the menstrual function being preserved at the moment of the primary tumor detection than in postmenopausal patients and also in patients having the hyperexpression of the Her/2neu. The ipsilateral cancer recurrence decreases the 3-year survival by 7,1% and the 5-year one by 20,3%, respectively. R. V. Liubota, A. S. Zotov, R. I. Vereshchako, I. I. Liubota, and V. V. Zaychuk Copyright © 2015 R. V. Liubota et al. All rights reserved. Prognostic Value of MRS Metabolites in Postoperative Irradiated High Grade Gliomas Mon, 03 Aug 2015 08:13:32 +0000 Purpose. We studied the prognostic significance of Magnetic Resonance Spectroscopy (MRS) in operated high grade gliomas. Materials and Methods. Twelve patients were treated with radiotherapy and Temozolomide. The MRS data were taken four weeks after operation (before radiotherapy) and every six months after the completion of RT. The N-acetyl aspartate, choline, creatine, and myo-inositol parameters were quantified, analyzed, and correlated to recurrence-free survival (RFS). Results. The median RFS was 26.06 months. RFS was significantly worse in elderly patients along with the higher choline/creatine ratios at either baseline or six months post Radiotherapy . Median RFS was 23 months in high choline/creatine levels ≥2 at 6 months after radiotherapy and 11 months for those with <2 choline/creatine levels. There was a significant correlation of maximum difference of choline/creatine ratio with RFS (rho = 0.64, ). Conclusion. Age and choline/creatine ratio are strong independent prognostic factors in high grade gliomas. Maria Tolia, Dimitrios Verganelakis, Nikolaos Tsoukalas, George Kyrgias, Matilda Papathanasiou, Eftichia Mosa, Ioannis Kokakis, John R. Kouvaris, George Pissakas, Kyriaki Pistevou-Gombaki, Nikolaos Kelekis, and Vasileios Kouloulias Copyright © 2015 Maria Tolia et al. All rights reserved. The Application of Classification and Regression Trees for the Triage of Women for Referral to Colposcopy and the Estimation of Risk for Cervical Intraepithelial Neoplasia: A Study Based on 1625 Cases with Incomplete Data from Molecular Tests Mon, 03 Aug 2015 08:12:52 +0000 Objective. Nowadays numerous ancillary techniques detecting HPV DNA and mRNA compete with cytology; however no perfect test exists; in this study we evaluated classification and regression trees (CARTs) for the production of triage rules and estimate the risk for cervical intraepithelial neoplasia (CIN) in cases with ASCUS+ in cytology. Study Design. We used 1625 cases. In contrast to other approaches we used missing data to increase the data volume, obtain more accurate results, and simulate real conditions in the everyday practice of gynecologic clinics and laboratories. The proposed CART was based on the cytological result, HPV DNA typing, HPV mRNA detection based on NASBA and flow cytometry, p16 immunocytochemical expression, and finally age and parous status. Results. Algorithms useful for the triage of women were produced; gynecologists could apply these in conjunction with available examination results and conclude to an estimation of the risk for a woman to harbor CIN expressed as a probability. Conclusions. The most important test was the cytological examination; however the CART handled cases with inadequate cytological outcome and increased the diagnostic accuracy by exploiting the results of ancillary techniques even if there were inadequate missing data. The CART performance was better than any other single test involved in this study. Abraham Pouliakis, Efrossyni Karakitsou, Charalampos Chrelias, Asimakis Pappas, Ioannis Panayiotides, George Valasoulis, Maria Kyrgiou, Evangelos Paraskevaidis, and Petros Karakitsos Copyright © 2015 Abraham Pouliakis et al. All rights reserved. Cytoglobin as a Biomarker in Cancer: Potential Perspective for Diagnosis and Management Mon, 03 Aug 2015 08:06:57 +0000 The search for biomarkers to detect the earliest glimpse of cancer has been one of the primary objectives of cancer research initiatives. These endeavours, in spite of constant clinical challenges, are now more focused as early cancer detection provides increased opportunities for different interventions and therapies, with higher potential for improving patient survival and quality of life. With the progress of the omics technologies, proteomics and metabolomics are currently being used for identification of biomarkers. In this line, cytoglobin (Cygb), a ubiquitously found protein, has been actively reviewed for its functional role. Cytoglobin is dynamically responsive to a number of insults, namely, fibrosis, oxidative stress, and hypoxia. Recently, it has been reported that Cygb is downregulated in a number of malignancies and that an induced overexpression reduces the proliferative characteristics of cancer cells. Thus, the upregulation of cytoglobin can be indicative of a tumour suppressor ability. Nevertheless, without a comprehensive outlook of the molecular and functional role of the globin, it will be most unlikely to consider cytoglobin as a biomarker for early detection of cancer or as a therapeutic option. This review provides an overview of the proposed role of cytoglobin and explores its potential functional role as a biomarker for cancer and other diseases. Tatsha C. Bholah, Vidushi S. Neergheen-Bhujun, Nikolas J. Hodges, Sabrina D. Dyall, and Theeshan Bahorun Copyright © 2015 Tatsha C. Bholah et al. All rights reserved. Prognostic Significance of Serum Inflammatory Response Markers in Newly Diagnosed Non-Small Cell Lung Cancer before Chemoirradiation Mon, 03 Aug 2015 07:21:48 +0000 Purpose. To identify whether the serum’s baseline C-reactive protein (CRP) and albumin (Alb) levels related to clinicopathological parameters and overall survival (OS) in non-small cell lung cancer (NSCLC). Methods. In total, 100 consecutive patients (mean age = 68.38 ± 10.85 years) that underwent chemoradiotherapy were studied. Measurements of CRP and Alb were performed before any treatment. Results. Serum CRP levels were significantly associated with histological grade , TNM stage , PS , and Alb . Additionally CRP and Alb levels were found significantly associated with overall survival in univariate analysis (log-rank test, and , resp.) and CRP remained significant after controlling for age, alcohol, performance status, and TNM stage, whereas albumin showed a borderline effect on the hazard rate . Conclusions. CRP and Alb are both promising biomarkers in identification of NSCLC patients with poor prognosis and form a possible target for intensifying their therapies. Maria Tolia, Nikolaos Tsoukalas, George Kyrgias, Eftychia Mosa, Apostolos Maras, Ioannis Kokakis, Zoi Liakouli, John R. Kouvaris, Konstantinos Liaskonis, Nikolaos Charalampakis, Kyriaki Pistevou-Gombaki, Nikolaos Kelekis, and Vassilis Kouloulias Copyright © 2015 Maria Tolia et al. All rights reserved. Potential Utility of Novel Biomarkers in Active Surveillance of Low-Risk Prostate Cancer Mon, 03 Aug 2015 06:31:54 +0000 Active surveillance (AS) is now an accepted management strategy for men with low-risk localized prostate cancer (PCa). However, detecting disease progression in a patient selected for AS remains a challenge. It is crucial to know what will serve as the best parameter to correctly identify tumors that progress to a more aggressive phenotype so as not to miss the window of curability. Several biomarkers are now being actively investigated as novel tools to improve PCa risk assessments. To date, several serum, urinary, and tissue biomarkers have shown promising prognostic value. %[−2]proPSA and PHI showed improved predictive value for an unfavorable biopsy conversion at annual surveillance biopsy in the AS program. PCA3 and TMPRSS2:ERG had additional independent predictive value for the prediction of PCa detection and progression, although PCA3 was limited in predicting aggressive cancer. Other tissue biomarkers also showed promising ability to predict disease progression. Although several of these novel biomarkers have an improved predictive accuracy that is better than classical parameters, there is still a need for further well-designed, large, multicenter, prospective trials to avoid common bias and clinical validation. Jeong Hyun Kim and Sung Kyu Hong Copyright © 2015 Jeong Hyun Kim and Sung Kyu Hong. All rights reserved. hERG1 Potassium Channels: Novel Biomarkers in Human Solid Cancers Mon, 03 Aug 2015 06:14:35 +0000 Because of their high incidence and mortality solid cancers are a major health problem worldwide. Although several new biomarkers and potential targets for therapy have been identified through biomolecular research in the last years, the effects on patients’ outcome are still unsatisfactory. Increasing evidence indicates that hERG1 potassium channels are overexpressed in human primary cancers of different origin and several associations between hERG1 expression and clinicopathological features and/or outcome are emerging. Aberrant hERG1 expression may be exploited either for early diagnosis (especially in those cancers where it is expressed in the initial steps of tumor progression) or for therapy purposes. Indeed, hERG1 blockage impairs tumor cell growth both in vitro and in vivo in preclinical mouse model. hERG1-based tumor therapy in humans, however, encounters the major hindrance of the potential cardiotoxicity that many hERG1 blockers exert. In this review we focus on recent advances in translational research in some of the most frequent human solid cancers (breast, endometrium, ovary, pancreas, esophagus, stomach, and colorectum) that have been shown to express hERG1 and that are a major health problem. Elena Lastraioli, Tiziano Lottini, Lapo Bencini, Marco Bernini, and Annarosa Arcangeli Copyright © 2015 Elena Lastraioli et al. All rights reserved. Radiologic Evaluation of Compressive Osseointegration for the Fixation of Reconstruction Prostheses after Tumor Resection Wed, 22 Jul 2015 06:39:37 +0000 Objective. In pursuance of thoroughly understanding and facilitating the evaluation of the radiological changes in the preloaded bone by Compliant Pre-Stress osseointegration (Compress Biomet, Warsaw, Indiana) a new staging method was created depicting four stages. Methods. Two cohorts (10 and 17 patients resp., not-receiving and receiving chemotherapy) were compared in terms of progression of osseointegration. Based on the changes at the bone-metal interface seen on röntgenorgrams four stages were defined: stage 0: immediate postoperative status, no ingrowth, or noncalcified callus; stage 1: early mineralization, calcified callus; stage 2: mature mineralization; and stage 3: hypertrophy at the level of the pins. Results. There were no significant differences between the two cohorts. Group 2, which was significantly younger than group 1 (), presented a delayed initial rate of bone formation and reached stage 1 at 6 months instead of 3 months like group 1. The children from the group 2 demonstrated a visible rebound ingrowth. Conclusion. Despite the fact that the staging fails to demonstrate a statistical difference, it is rather simple and can be used for future studies. Manol Lazarov, Thomas De Bo, Bart Poffyn, and Gwen Sys Copyright © 2015 Manol Lazarov et al. All rights reserved. RLN2 Is a Positive Regulator of AKT-2-Induced Gene Expression Required for Osteosarcoma Cells Invasion and Chemoresistance Thu, 02 Jul 2015 05:48:19 +0000 The aim of the study was to determine the effect of H2 relaxin (RLN2) on invasion, migration, and chemosensitivity to cisplatin in human osteosarcoma U2-OS and MG-63 cells and then to investigate the effect of RLN2 on the AKT/NF-κB signaling pathway. The expression of RLN2, p-AKT (Ser473), and p-ERK1/2 (Phospho-Thr202/Tyr204) proteins was detected by western blot in OS tissues from 21 patients with pulmonary metastatic disease, and the correlation between RLN2 and p-AKT or RLN2 and p-ERK1/2 expression was investigated. RLN2 expression was inhibited by RLN2 siRNA transfection in the MG-63 cells. RLN2 was overexpressed in the U2-OS cells by treatment with recombinant relaxin. The results showed that positive relation was found between RLN2 and p-AKT expression in tissues of OS. Silencing RLN2 inhibited cell migratory and invasive ability and angiogenesis formation and increased the chemosensitivity to cisplatin in MG-63 cells. RLN2 overexpression promoted migratory and invasive ability and angiogenesis and increased the chemoresistance to cisplatin in U2-OS cells. Silencing RLN2 inhibited the activity of AKT/NF-κB signaling pathway in MG-63 cells, and vice versa. Blockage of both pathways by specific inhibitors abrogated RLN2-induced survival and invasion of OS cells, and vice versa. Our results indicated RLN2 confers to migratory and invasive ability, angiogenesis, and chemoresistance to cisplatin via modulating the AKT/NF-κB signaling pathway in vitro. Jinfeng Ma, Hai Huang, Zenggang Han, Changzheng Zhu, and Bin Yue Copyright © 2015 Jinfeng Ma et al. All rights reserved. β-Elemene Inhibits Cell Proliferation by Regulating the Expression and Activity of Topoisomerases I and IIα in Human Hepatocarcinoma HepG-2 Cells Mon, 29 Jun 2015 11:17:46 +0000 Objective. To investigate the effects of β-Elemene (β-ELE) on the proliferation, apoptosis, and topoisomerase I (TOPO I) and topoisomerase IIα (TOPO IIα) expression and activity of human hepatocarcinoma HepG-2 cells. Methods. After treatment with β-ELE, morphological alterations of HepG-2 cells were observed under an inverted microscope. Cell proliferation was assessed using an MTT assay, cell cycles were analyzed using flow cytometry, and apoptosis was detected by Annexin V/PI staining. The expression of TOPO I and TOPO IIα was analyzed by Western blot techniques, and their activity was measured using the TOPO I-mediated, supercoiled pBR322 DNA relaxation and TOPO IIα-mediated Kinetoplast DNA (kDNA) decatenation assays, respectively. Supercoiled pBR322 and kDNA were also used to determine the direct effect of β-ELE on DNA breaks. Results. β-ELE significantly inhibited HepG-2 cell proliferation in a dose- and time-dependent manner. β-ELE also induced tumor cell arrest at S phase, induced cell apoptosis, and downregulated the protein expression of TOPO I and TOPO IIα in a dose-dependent manner. β-ELE also inhibited TOPO I- and TOPO IIα-mediated DNA relaxation but did not directly induce DNA breakage at any concentration. Conclusion. β-ELE could inhibit the proliferation of HepG-2 cells and interfere with the expression and activity of TOPO I and TOPO IIα. Min Gong, Ying Liu, Jian Zhang, Ya-jie Gao, Ping-ping Zhai, Xi Su, Xiang Li, Yan Li, Li Hou, and Xiao-nan Cui Copyright © 2015 Min Gong et al. All rights reserved. Revealing Glycoproteins in the Secretome of MCF-7 Human Breast Cancer Cells Wed, 17 Jun 2015 08:19:34 +0000 Breast cancer is one of the major issues in the field of oncology, reported with a higher prevalence rate in women worldwide. In attempt to reveal the potential biomarkers for breast cancer, the findings of differentially glycosylated haptoglobin and osteonectin in previous study have drawn our attention towards glycoproteins of secretome from the MCF-7 cancer cell line. In the present study, further analyses were performed on the medium of MCF-7 cells by subjecting it to two-dimensional analyses followed by image analysis in contrast to the medium of human mammary epithelial cells (HMEpC) as a negative control. Carboxypeptidase A4 (CPA4), alpha-1-antitrypsin (AAT), haptoglobin (HP), and HSC70 were detected in the medium of MCF-7, while only CPA4 and osteonectin (ON) were detected in HMEpC medium. In addition, CPA4 was detected as upregulated in the MCF-7 medium. Further analysis by lectin showed that CPA4, AAT, HP, and HSC70 were secreted as N-glycan in the medium of MCF-7, with HP also showing differentially N-glycosylated isoforms. For the HMEpC, only CPA4 was detected as N-glycan. No O-glycan was detected in the medium of HMEpC but MCF-7 expressed O-glycosylated CPA4 and HSC70. All these revealed that glycoproteins could be used as glycan-based biomarkers for the prognosis of breast cancer. Aik-Aun Tan, Wai-Mei Phang, Subash C. B. Gopinath, Onn H. Hashim, Lik Voon Kiew, and Yeng Chen Copyright © 2015 Aik-Aun Tan et al. All rights reserved. Liver-Specific Inactivation of the Proprotein Convertase FURIN Leads to Increased Hepatocellular Carcinoma Growth Mon, 08 Jun 2015 09:12:47 +0000 Proprotein convertases are subtilisin-like serine endoproteases that cleave and hence activate a variety of proproteins, including growth factors, receptors, metalloproteases, and extracellular matrix proteins. Therefore, it has been suggested that inhibition of the ubiquitously expressed proprotein convertase FURIN might be a good therapeutic strategy for several tumor types. Whether this is also the case for hepatocellular carcinoma (HCC) is currently not clear. In a mouse model for HCC expression of Furin was not altered in the tumors, while those of PC7, PC5/6, and PACE4 significantly decreased, at least at some time points. To investigate the impact of Furin inhibition on the development and progression of HCC in this model, Furin was genetically ablated in the liver. Furin inactivation resulted in an increased tumor mass after 5 weeks. This was not caused by decreased apoptosis, since no differences in the apoptosis index could be observed. However, it could at least partially be explained by increased hepatocyte proliferation at 5 weeks. The tumors of the Furin knockout mice were histologically similar to those in wild type mice. In conclusion, liver-specific Furin inhibition in HCC enhances the tumor formation and will not be a good therapeutic strategy for this tumor type. Jeroen Declercq, Bas Brouwers, Vincent P. E. G. Pruniau, Pieter Stijnen, Krizia Tuand, Sandra Meulemans, Annik Prat, Nabil G. Seidah, Abdel-Majid Khatib, and John W. M. Creemers Copyright © 2015 Jeroen Declercq et al. All rights reserved. Single Nucleotide Polymorphism (rs4932178) in the P1 Promoter of FURIN Is Not Prognostic to Colon Cancer Sun, 07 Jun 2015 14:17:53 +0000 High expression of the proprotein processing enzyme FURIN has been associated with tumor progression and metastasis. A SNP (rs4932178) in the promoter of FURIN has been reported to affect expression in liver, with the T allele resulting in higher expression than the C allele. In this study we have investigated the association of this SNP with prognostic and biological subgroups of colorectal cancer (CRC). In a panel of 1382 patients with CRC, this SNP had no impact on overall survival or on postoperative risk of relapse. This SNP also could not be linked with FURIN expression levels in CRC samples from the patients. Furthermore, we demonstrate in luciferase reporter experiments in the colon cancer cell lines Caco-2 and SW480 and in the hepatocellular carcinoma cell line Huh 7 that expression is not affected by the SNP. Since, FURIN inhibition in human colon cancer cell lines has previously been shown to repress tumor metastases, association between FURIN gene expression levels and postoperative relapse-free survival was also investigated. However, no association could be found. Altogether, we could not confirm an effect of the SNP on FURIN expression in vitro and no correlations could be found in vivo with FURIN expression or outcome. Jeroen Declercq, Bart Jacobs, Bart Biesmans, Arnaud Roth, Dirk Klingbiel, Sabine Tejpar, and John W. Creemers Copyright © 2015 Jeroen Declercq et al. All rights reserved. Anatomical, Physiological, and Molecular Imaging for Pancreatic Cancer: Current Clinical Use and Future Implications Thu, 04 Jun 2015 08:21:52 +0000 Pancreatic adenocarcinoma is one of the deadliest human malignancies. Early detection is difficult and effective treatment is limited. Verifying the presence of micrometastatic dissemination and vessel invasion remains elusive, limiting radiological staging once this diagnosis is made. Diagnostic imaging provides independent tools to evaluate and characterize the biologic behavior of pancreatic cancer. Conventional anatomic imaging alone with either CT or MRI yields useful information on organ involvement but is limited in providing molecular and physiological information. Molecular imaging techniques such as PET or MRS provide information on metabolic and signaling pathways. Advanced MR sequences that target physiological parameters expand imaging options to characterize these tumors. By considering the parametric data from these three imaging approaches (anatomic, molecular, and physiological) we can better define specific tumor signatures. Such parametric characterization can provide insight into tumor metabolism, cellular density, protein expression, focal perfusion, and vascular permeability of these tumors. Radiogenomics research has already demonstrated ability to obtain information about cancer’s genotype and phenotype; this is without invasive procedures or surgery. Further advances in these areas of experimental imaging hold promise to enable future clinical advances in detection and therapy of pancreatic cancer. John Chang, Donald Schomer, and Tomislav Dragovich Copyright © 2015 John Chang et al. All rights reserved. Minimally Invasive Spine Metastatic Tumor Resection and Stabilization: New Technology Yield Improved Outcome Wed, 03 Jun 2015 07:27:39 +0000 Spinal metastases compressing the spinal cord are a medical emergency and should be operated on if possible; however, patients’ medical condition is often poor and surgical complications are common. Minimizing surgical extant, operative time, and blood loss can potentially reduce postoperative complications. This is a retrospective study describing the patients operated on in our department utilizing a minimally invasive surgery (MIS) approach to decompress and instrument the spine from November 2013 to November 2014. Five patients were operated on for thoracic or lumbar metastases. In all cases a unilateral decompression with expandable tubular retractor was followed by instrumentation of one level above and below the index level and additional screw at the index level contralateral to the decompression side. Cannulated fenestrated screws were used (Longitude FNS) and cement was injected to increase pullout resistance. Mean operative time was 134 minutes and estimated blood loss was minimal in all cases. Improvement was noticeable in neurological status, function, and pain scores. No complications were observed. Technological improvements in spinal instruments facilitate shorter and safer surgeries in oncologic patient population and thus reduce the complication rate. These technologies improve patients’ quality of life and enable the treatment of patients with comorbidities. Ran Harel, Omer Doron, and Nachshon Knoller Copyright © 2015 Ran Harel et al. All rights reserved. Multi-Leu PACE4 Inhibitor Retention within Cells Is PACE4 Dependent and a Prerequisite for Antiproliferative Activity Sun, 31 May 2015 12:05:30 +0000 The overexpression as well as the critical implication of the proprotein convertase PACE4 in prostate cancer progression has been previously reported and supported the development of peptide inhibitors. The multi-Leu peptide, a PACE4-specific inhibitor, was further generated and its capability to be uptaken by tumor xenograft was demonstrated with regard to its PACE4 expression status. To investigate whether the uptake of this inhibitor was directly dependent of PACE4 levels, uptake and efflux from cancer cells were evaluated and correlations were established with PACE4 contents on both wild type and PACE4-knockdown cell lines. PACE4-knockdown associated growth deficiencies were established on the knockdown HepG2, Huh7, and HT1080 cells as well as the antiproliferative effects of the multi-Leu peptide supporting the growth capabilities of PACE4 in cancer cells. Frédéric Couture, Kévin Ly, Christine Levesque, Anna Kwiatkowska, Samia Ait-Mohand, Roxane Desjardins, Brigitte Guérin, and Robert Day Copyright © 2015 Frédéric Couture et al. All rights reserved. Molecular Profiling-Selected Therapy for Treatment of Advanced Pancreaticobiliary Cancer: A Retrospective Multicenter Study Thu, 28 May 2015 06:29:10 +0000 This multicenter cohort study assessed the impact of molecular profiling (MP) on advanced pancreaticobiliary cancer (PBC). The study included 30 patients treated with MP-guided therapy after failing ≥1 therapy for advanced PBC. Treatment was considered as having benefit for the patient if the ratio between the longest progression-free survival (PFS) on MP-guided therapy and the PFS on the last therapy before MP was ≥1.3. The null hypothesis was that ≤15% of patients gain such benefit. Overall, ≥1 actionable (i.e., predictive of response to specific therapies) biomarker was identified/patient. Immunohistochemistry (the most commonly used method for guiding treatment decisions) identified 1–6 (median: 4) actionable biomarkers per patient. After MP, patients received 1–4 (median: 1) regimens/patient (most commonly, FOLFIRI/XELIRI). In a decision-impact analysis, of the 27 patients for whom treatment decisions before MP were available, 74.1% experienced a treatment decision change in the first line after MP. Twenty-four patients were evaluable for clinical outcome analysis; in 37.5%, the PFS ratio was ≥1.3. In one-sided exact binomial test versus the null hypothesis, P = 0.0015; therefore, the null hypothesis was rejected. In conclusion, our analysis demonstrated the feasibility, clinical decision impact, and potential clinical benefits of MP-guided therapy in advanced PBC. Ron Epelbaum, Einat Shacham-Shmueli, Baruch Klein, Abed Agbarya, Baruch Brenner, Ronen Brenner, Eliahu Gez, Talia Golan, Ayala Hubert, Ofer Purim, Mark Temper, Ella Tepper, Andreas Voss, Kenneth Russell, Addie Dvir, Lior Soussan-Gutman, Salomon M. Stemmer, and Ravit Geva Copyright © 2015 Ron Epelbaum et al. All rights reserved. Endoscopic Raman Spectroscopy for Molecular Fingerprinting of Gastric Cancer: Principle to Implementation Wed, 27 May 2015 14:06:38 +0000 Currently, positive endoscopic biopsy is the standard criterion for gastric cancer diagnosis but is invasive, often inconsistent, and delayed although early detection and early treatment is the most important policy. Raman spectroscopy is a spectroscopic technique based on inelastic scattering of monochromatic light. Raman spectrum represents molecular composition of the interrogated volume providing a direct molecular fingerprint. Several investigations revealed that Raman spectroscopy can differentiate normal, dysplastic, and adenocarcinoma gastric tissue with high sensitivity and specificity. Moreover, this technique can indentify malignant ulcer and showed the capability to analyze the carcinogenesis process. Automated on-line Raman spectral diagnostic system raised possibility to use Raman spectroscopy in clinical field. Raman spectroscopy can be applied in many fields such as guiding a target biopsy, optical biopsy in bleeding prone situation, and delineating the margin of the lesion. With wide field technology, Raman spectroscopy is expected to have specific role in our future clinical field. Hyung Hun Kim Copyright © 2015 Hyung Hun Kim. All rights reserved. Transcriptomic and Immunohistochemical Profiling of SLC6A14 in Pancreatic Ductal Adenocarcinoma Wed, 27 May 2015 13:57:54 +0000 We used a target-centric strategy to identify transporter proteins upregulated in pancreatic ductal adenocarcinoma (PDAC) as potential targets for a functional imaging probe to complement existing anatomical imaging approaches. We performed transcriptomic profiling (microarray and RNASeq) on histologically confirmed primary PDAC tumors and normal pancreas tissue from 33 patients, including five patients whose tumors were not visible on computed tomography. Target expression was confirmed with immunohistochemistry on tissue microarrays from 94 PDAC patients. The best imaging target identified was SLC6A14 (a neutral and basic amino acid transporter). SLC6A14 was overexpressed at the transcriptional level in all patients and expressed at the protein level in 95% of PDAC tumors. Very little is known about the role of SLC6A14 in PDAC and our results demonstrate that this target merits further investigation as a candidate transporter for functional imaging of PDAC. Alan R. Penheiter, Sibel Erdogan, Stephen J. Murphy, Steven N. Hart, Joema Felipe Lima, Fariborz Rakhshan Rohakhtar, Daniel R. O’Brien, William R. Bamlet, Ryan E. Wuertz, Thomas C. Smyrk, Fergus J. Couch, George Vasmatzis, Claire E. Bender, and Stephanie K. Carlson Copyright © 2015 Alan R. Penheiter et al. All rights reserved. Lack of Association between Membrane-Type 1 Matrix Metalloproteinase Expression and Clinically Relevant Molecular or Morphologic Tumor Characteristics at the Leading Edge of Invasive Colorectal Carcinoma Wed, 27 May 2015 13:50:28 +0000 Colorectal cancer (CRC) is one of the leading causes of death from cancer in the western world, but tumor biology and clinical course show great interindividual variation. Molecular and morphologic tumor characteristics, such as KRAS/BRAF mutation status, mismatch repair (MMR) protein expression, tumor growth pattern, and tumor cell budding, have been shown to be of key therapeutic and/or prognostic relevance in CRC. Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a membrane-anchored zinc-binding endopeptidase that is expressed at the leading edge of various invasive carcinomas and promotes tumor cell invasion through degradation of the extracellular matrix. The aim of this study was to investigate possible associations between MT1-MMP expression and molecular tumor characteristics as well as morphologic features of tumor aggressiveness in a consecutive series of 79 CRC tissue samples. However, although MT1-MMP was expressed in 41/79 samples (52%), there was no significant association between MT1-MMP expression and KRAS/BRAF mutation status, MMR protein expression, presence of lymphovascular invasion, tumor growth pattern, tumor-infiltrating lymphocytes, or tumor cell budding in our sample cohort (). Thus, we conclude that although MT1-MMP may play a role in CRC invasion, it is not of key relevance to the current models of CRC invasion and aggressiveness. Annette Arndt, Klaus Kraft, Eva Wardelmann, and Konrad Steinestel Copyright © 2015 Annette Arndt et al. All rights reserved. Colorectal Cancer Biomarkers: Where Are We Now? Wed, 27 May 2015 13:48:18 +0000 Colorectal cancer is one of the major causes of cancer-related death in the Western world. Patient survival is highly dependent on the tumor stage at the time of diagnosis. Reduced sensitivity to chemotherapy is still a major obstacle in effective treatment of advanced disease. Due to the fact that colorectal cancer is mostly asymptomatic until it progresses to advanced stages, the implementation of screening programs aimed at early detection is essential to reduce incidence and mortality rates. Current screening and diagnostic methods range from semi-invasive procedures such as colonoscopy to noninvasive stool-based tests. The combination of the absence of symptoms, the semi-invasive nature of currently used methods, and the suboptimal accuracy of fecal blood tests results in colorectal cancer diagnosis at advanced stages in a significant number of individuals. Alterations in gene expression leading to colorectal carcinogenesis are reflected in dysregulated levels of nucleic acids and proteins, which can be used for the development of novel, minimally invasive molecular biomarkers. The purpose of this review is to discuss the commercially available colorectal cancer molecular diagnostic methods as well as to highlight some of the new candidate predictive and prognostic molecular markers for tumor, stool, and blood samples. Maria Gonzalez-Pons and Marcia Cruz-Correa Copyright © 2015 Maria Gonzalez-Pons and Marcia Cruz-Correa. All rights reserved. HMGB1-Induced Cross Talk between PTEN and miRs 221/222 in Thyroid Cancer Wed, 27 May 2015 06:50:04 +0000 High mobility group box 1 (HMGB1) is an ubiquitous protein that plays different roles in the nucleus, cytoplasm, and extracellular space. It is an important DAMP molecule that allows communication between damaged or tumor cells and the immune system. Tumor cells exploit HMGB1’s ability to activate intracellular pathways that lead to cell growth and migration. Papillary thyroid cancer is a well-differentiated tumor and is often used to study relationships between cells and the inflammatory microenvironment as the latter is characterized by high levels of inflammatory cells and cytokines. Anaplastic thyroid cancer is one of the most lethal human cancers in which many microRNAs and tumor suppressor genes are deregulated. Upregulation of microRNAs 221 and 222 has been shown to induce the malignant phenotype in many human cancers via inhibition of PTEN expression. In this study we suggest that extracellular HMGB1 interaction with RAGE enhances expression of oncogenic cluster miR221/222 that in turn inhibits tumor suppressor gene PTEN in two cell lines derived from human thyroid anaplastic and papillary cancers. The newly identified pathway HMGB1/RAGE/miR221/222 may represent an effective way of tumor escape from immune surveillance that could be used to develop new therapeutic strategies against anaplastic tumors. S. Mardente, E. Mari, I. Massimi, F. Fico, A. Faggioni, F. Pulcinelli, A. Antonaci, and A. Zicari Copyright © 2015 S. Mardente et al. All rights reserved. CF750-A33scFv-Fc-Based Optical Imaging of Subcutaneous and Orthotopic Xenografts of GPA33-Positive Colorectal Cancer in Mice Thu, 21 May 2015 13:46:17 +0000 Antibody-based imaging agents are attractive as adjuvant diagnostic tools for solid tumors. GPA33 is highly expressed in most human colorectal cancers and has been verified as a diagnostic and therapeutic target. Here, we built an A33scFv-Fc antibody against GPA33 by fusing A33scFv to the Fc fragment of human IgG1 antibodies. The A33scFv-Fc specifically binds GPA33-positive colorectal cancer cells and tumor tissues. After the intravenous injection of mice bearing subcutaneous GPA33-positive LS174T tumor grafts with near-infrared fluorescence probe CF750-labeled A33scFv-Fc (CF750-A33scFv-Fc), high contrast images of the tumor grafts could be kinetically documented within 24 h using an optical imaging system. However, GPA33-negative SMMC7721 tumor grafts could not be visualized by injecting the same amount of CF750-A33scFv-Fc. Moreover, in subcutaneous LS174T tumor-bearing mice, tissue scanning revealed that the CF750-A33scFv-Fc accumulated in the tumor grafts, other than the kidney and liver. In mice with orthotopic tumor transplantations, excrescent LS174T tumor tissues in the colon were successfully removed under guidance by CF750-A33scFv-Fc-based optical imaging. These results indicate that CF750-A33scFv-Fc can target GPA33, suggesting the potential of CF750-A33scFv-Fc as an imaging agent for the diagnosis of colorectal cancer. Danfeng Wei, Qing Fan, Huawei Cai, Hao Yang, Lin Wan, Lin Li, and Xiaofeng Lu Copyright © 2015 Danfeng Wei et al. All rights reserved. The MicroRNA3686 Inhibits the Proliferation of Pancreas Carcinoma Cell Line by Targeting the Polo-Like Kinase 1 Thu, 21 May 2015 11:39:14 +0000 The Polo-like kinase 1 (PLK1) is one member of the so-called Polo-like kinase family which plays an important role in tumorigenesis. By analyzing the potential complementary microRNA (miRNA) targeting sequence of PLK1, we identified that miRNA-3686 (hereby and thereafter mir3696) could be the potential regulator for PLK1. Real-time PCR demonstrated that the mir3686 has a relatively higher expression in the immortalized pancreas cell HPDE6C7 than pancreas carcinoma derived cell line PANC1. The upregulation of mir3686 in HPDE6C7 cell corresponded with the low expression of PLK1 as well. Both luciferase based reporter assay and evaluation of endogenous PLK1 expression demonstrated that mir3686 regulated PLK1, which confirms our speculation. Moreover, we found that transfection of mir3686 in PANC1 cell could lead to proliferation inhibition and promote apoptosis. Further analysis demonstrated that mir3686 transfection in PANC1 cell also inhibited cell invasion, and clone formation in cell invasion assay and clonogenic cell survival assay, respectively. In contrast, inhibition of mir3686 expression in HPDE6C7 cell enhanced the capability of proliferation, cell invasion and clone formation. Taken together, our results indicated that mir3686 could target PLK1 to inhibit the cell proliferation in pancreas cancer derived cell line and mir3686 could be a new therapeutic target for pancreas cancer treatment. Hong-Yi Jin, Xin-Guang Qiu, and Bo Yang Copyright © 2015 Hong-Yi Jin et al. All rights reserved. In Vitro Antiproliferative Effect of the Acetone Extract of Rubus fairholmianus Gard. Root on Human Colorectal Cancer Cells Thu, 21 May 2015 11:30:27 +0000 Plants and plant derived products exert chemopreventive effects on various cancer cell lines by the induction of cell death mechanisms. The effects of root acetone extract of Rubus fairholmianus (RFRA) on the proliferation of human colorectal cancer (Caco-2) cells have been investigated in this study. The extract led to a dose dependent decrease in both viability and proliferation and increased cytotoxicity using trypan blue exclusion, adenosine 5′-triphosphate (ATP), and lactate dehydrogenase (LDH) assay. The morphological features of the treated cells were supportive for the antiproliferative activity. The Annexin V/propidium iodide staining indicated that R. fairholmianus induced toxic effects in Caco-2 cells and the percentages of the early and late apoptotic population significantly increased when compared with control cells. Also we studied the apoptosis inducing ability of the extract by analysing caspase 3/7 activity and the induction of cell death via the effector caspases was confirmed; the activity increased in treated cells compared with control. Thus the present findings highlight that the R. fairholmianus root acetone extract exhibits antiproliferative activity on Caco-2 cells by the induction of apoptosis via caspase dependent pathway. Blassan Plackal Adimuriyil George, Ivan Mfouo Tynga, and Heidi Abrahamse Copyright © 2015 Blassan Plackal Adimuriyil George et al. All rights reserved.