Digital subtraction angiography-guided pancreatic arterial infusion of GEMOX chemotherapy in advanced pancreatic adenocarcinoma: a phase II, open-label, randomized controlled trial comparing with intravenous chemotherapy.

BACKGROUND: Advanced pancreatic adenocarcinoma lacks effective treatment options, and systemic gemcitabine-based chemotherapy offers only marginal survival benefits at the cost of significant toxicities and adverse events. New therapeutic options with better drug availability are warranted. This study aims to evaluate the safety and efficacy of digital subtraction angiography (DSA)-guided pancreatic arterial infusion (PAI) versus intravenous chemotherapy (IVC) using the gemcitabine and oxaliplatin (GEMOX) regimen in unresectable locally advanced or metastatic pancreatic cancer (PC) patients. MATERIALS AND METHODS: This study prospectively enrolled 51 eligible treatment-naive patients with unresectable PC to receive GEMOX treatment via PAI or IVC (1:1 ratio randomization) from December 2015 to December 2019. Cycles were repeated monthly, and each process consisted of two treatments administered bi-weekly. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), 1-year survival, 6-month survival, tumor-site subgroup survival, and incidences of adverse events were compared. RESULTS: The median OS of the PAI and IVC groups were 9.93 months and 10.07 months, respectively (p = 0.3049). The median PFS of the PAI and IVC groups were 5.07 months and 4.23 months (p = 0.1088). No significant differences were found in the ORR (11.54% vs. 4%, p = 0.6312), DCR (53.85% vs. 44%, p = 0.482), and 1-year OS rate (44% vs. 20.92%, p = 0.27) in PAI and IVC groups. The 6-month OS rate was significantly higher in the PAI group (100%) than in the IVC group (83.67%) (p = 0.0173). The median OS of patients in PAI group with pancreatic head and neck tumors were significantly higher than those of body and tail tumors (12.867 months vs. 9 months, p = 0.0214). The incidences of hematologic disorders, liver function disorders, and digestive disorders in the IVC group were higher than in the PAI group (p < 0.05). CONCLUSION: GEMOX PAI therapy presented a higher 6-month OS rate and fewer adverse events than IVC in advanced pancreatic adenocarcinoma patients. Those with pancreatic head and neck tumors may yield a superior treatment outcome from PAI treatment. TRIAL REGISTRATION NUMBER: NCT02635971. DATE OF REGISTRATION: 21/12/2015.

Sublethal irradiation promotes the metastatic potential of hepatocellular carcinoma cells.

Radiotherapy (RT) represents one of the major treatment methods for cancers. However, many studies have observed that in descendant surviving tumor cells, sublethal irradiation can promote metastatic ability, which is closely related to the tumor microenvironment. We therefore investigated the functions and mechanisms of sublethal irradiated liver nonparenchymal cells (NPCs) in hepatocellular carcinoma (HCC). In this study, primary rat NPCs and McA-RH7777 hepatoma cells were irradiated with 6 Gy X-ray. Conditioned media (CM) from nonirradiated (SnonR), irradiated (SR), or irradiated plus radiosensitizer celecoxib-treated (S[R + D]) NPCs were collected and added to sublethal irradiated McA-RH7777 cells. We showed that CM from sublethal irradiated NPCs significantly promoted the migration and invasion ability of sublethal irradiated McA-RH7777 cells, which was reversed by celecoxib. The differentially expressed genes in differently treated McA-RH7777 cells were enriched mostly in the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway. SR increased the migration and invasion ability of HCC cells by inhibiting AMPK/mTOR signaling, which was enhanced by the AMPK inhibitor compound C and blocked by the AMPK activator GSK-621. Analyses of HCC tissues after neoadjuvant radiotherapy confirmed the effects of radiation on the AMPK/mTOR pathway. Cytokine antibody arrays and further functional investigations showed that matrix metalloproteinase-8 (MMP-8) partly mediates the promotion effects of SR on the migration and invasion ability of HCC cells by regulating AMPK/mTOR signaling. In summary, our data indicate that MMP-8 secreted by irradiated NPCs enhanced the migration and invasion of HCC by regulating AMPK/mTOR signaling, revealing a novel mechanism mediating sublethal irradiation-induced HCC metastasis at the level of the tumor microenvironment.

ARHGAP4 regulates the cell migration and invasion of pancreatic cancer by the HDAC2/ß-catenin signaling pathway.

ß-catenin is a subunit of the cadherin protein complex and acts as an intracellular signal transducer in the Wnt signaling pathway that mediates multiple cellular processes, such as cell migration and invasion. HDAC2 (histone deacetylase 2), a deacetylase that maintains histone H3 in a deacetylated state in the promoter region of Wnt-targeted genes where ß-catenin is bound, negatively regulating ß-catenin activation. However, the regulation of HDAC2/ß-catenin pathway remains unclear. Here, we report ARHGAP4 as a new regulator of the ß-catenin pathway that regulates cell invasion and migration of pancreatic cancer as well as the downstream effector MMP2 and MMP9 expression in vitro. Mechanistically, ARHGAP4 interacts with and ubiquitinates HDAC2, which in turn inhibits ß-catenin activation. Furthermore, treatment of CAY10683, an HDAC2 inhibitor, and XAV939, a Wnt/ß-catenin pathway inhibitor, attenuated the effects of ARHGAP4 silencing on pancreatic cancer cells. Overall, our findings establish ARHGAP4 as a novel regulator of HDAC2/ß-catenin pathway with a critical role in tumorigenesis.

Radiofrequency ablation for hepatic oligometastatic pancreatic cancer: An analysis of safety and efficacy.

OBJECTIVES: This study was to evaluate the value of radiofrequency ablation (RFA) in the treatment of pancreatic cancer with synchronous liver oligometastasis. METHODS: 102 patients diagnosed with pancreatic cancer with synchronous liver oligometastasis undergoing RFA were recruited in this retrospective study between January 2012 and December 2015. Clinical efficacy was evaluated by computed tomography or magnetic resonance imaging 1 month later. All patients were treated with RFA and systemic chemotherapy based on NCCN guideline. RESULTS: The median follow-up was 21 months (range, 4.0-43.8 months). Of all patients, the 1-year survival rate was 47.1% and the median overall survival time was 11.40 months. Complete tumor ablation was achieved in 137 of 145 RFA sessions (94.5%), and in 244 of 254 tumors (96.1%). The incidence of common complications was 9.8%, and no severe complications were reported in any patient. Multivariate Cox regression analysis revealed that primary tumor in the head of the pancreas (HR = 1.868, 95% CI: 1.023-3.409; P = 0.042), maximum diameter of liver metastasis 3-5 cm (HR = 1.801, 95% CI: 1.081-3.001, P = 0.024) and neutrophil/lymphocyte ratio (NLR) ≥2.5 (HR = 1.716, 95% CI: 1.047-2.811; P = 0.032) were independent predictors of poorer survival. CONCLUSION: RFA provides a minimally invasive and safe treatment for patients with pancreatic cancer with liver oligometastases. The clinical efficiency of RFA for hepatic oligometastatic pancreatic cancer was easily affected by the following factors: primary tumor location, maximum diameter of liver metastasis and NLR. These factors could be helpful for treatment decision and clinical trial design.

High intensity focused ultrasound ablation for patients with inoperable liver cancer.

BACKGROUND/AIMS: To analyses the feasibility and efficacy of high intensity focused ultrasound (HIFU) treatment in patients with inoperable liver cancer. METHODOLOGY: 187 patients were treated with HIFU, of all these patients 116 cases were Primary Liver Cancer (PLC) and 71 cases were Metastatic Liver Cancer (MLC). According to some parameters, such as clinical symptoms, the basis of main organs functional tests, imaging examinations, and progression-free survival (PFS) time to assess the safety and efficacy of HIFU in the treatment of liver cancer. RESULTS: 55 patients (29.4%) achieved CR and 73 patients (39.0%) achieved PR, 32 patients (17.1%) had responses of SD, and 27 patients (14.4%) were PD, respectively. Response rates were 90.5% (32 CR + 6 PR/42) in left lobe cancer and 64.1% (22 CR + 62 PR/131) in right lobe cancer. The median PFS for those CR case was 7 months, of PLC was 8 months, of MLC was 5 months. CONCLUSIONS: HIFU is effective and feasible in the treatment of liver cancer. It offer a significant noninvasive therapy for local treatment of liver cancer. For those right lobe liver cancers or with poor ultrasonic window, increasing treatment time or repeated treatment may improve the efficiency of HIFU ablation.

RNA interference against MDM2 suppresses tumor growth and metastasis in pancreatic carcinoma SW1990HM cells.

In our previous study, the mouse double minute 2 (MDM2) was identified as one of the leading genes that promote the metastasis of pancreatic cancer (PC). However, the mechanism by which MDM2 promotes metastasis of PC is not understood. In this study, we show that down-regulation of MDM2 through lentivirus-mediated RNA interference could also suppress in vitro proliferation and in vivo tumor growth, and led to an obvious inhibition of both in vitro invasion and in vivo live metastases of SW1990HM cells which had an over-expression of MDM2 and a higher metastatic potential. Moreover, we also show that the down-regulation of MDM2 induced a significant decrease in MMP9, Ki-67 and increase in P53, E-Cadherin expression, and results in an altered expression of genes involved in metastasis, apoptosis, and cell proliferation. Our results suggest that MDM2 plays an important role in metastasis as well as tumor growth of PC. MDM2 could be a hopeful target for the control of PC.

Safety evaluation of high-intensity focused ultrasound in patients with pancreatic cancer.

INTRODUCTION: This study was performed to analyze the safety of high-intensity focused ultrasound (HIFU) for treating pancreatic cancer. METHODS: 224 cases with advanced pancreatic cancer were enrolled into this study. Real-time sonographic images were taken, and vital signs, liver and kidney function, skin burns, local reactions, and systemic effects were monitored and recorded before, during, and after HIFU. Computed tomography or magnetic resonance imaging (MRI) was also performed before and after HIFU. RESULTS: Serum amylase level increased in 16 cases (7.1%) 1 day after HIFU treatment, and 9 of these cases also had abnormal urinary amylase levels. Gastrointestinal (GI) dysfunction such as abdominal distension and anorexia with slight nausea was observed in 10 cases (4.5%) after HIFU treatment. 1 case with pancreatic head cancer developed obstructive jaundice 2 weeks after HIFU treatment. Vertebral injury, identified by MRI, occurred in 2 cases, although no symptoms were seen. No severe complications such as skin burns, lesion bleeding, GI tract bleeding or GI perforation were observed in any of the cases. CONCLUSION: For specific patients, HIFU treatment is a safe, non-invasive treatment for pancreatic cancer but requires careful preoperative preparation and exact operative performance.

High intensity focused ultrasound treatment for patients with local advanced pancreatic cancer.

BACKGROUND/AIMS: To evaluate the safety and efficacy of high intensity focused ultrasound (HIFU) therapy in patients with local advanced pancreatic cancer. METHODOLOGY: 39 patients with local advanced pancreatic cancer were treated with HIFU, including 26 male and 13 female patients. The locations of the tumours were as follows: head of pancreas in 7 patients, body and/or tail of pancreas in 32 patients. Pain relief, time to progression (TTP), median survival and complications were analysed after HIFU treatment. RESULTS: There were no severe complications or adverse events related to HIFU therapy in any of the patients treated. Pain relief was achieved in 79.5% of patients. Median TTP was 5.0 months. The median overall survival time was 11 months. 6-month and 1-year survival rate for patients were 82.1% and 30.8% respectively. CONCLUSIONS: Although this study may have limitations, preliminary results demonstrate the safetyof clinical application of HIFU for pancreatic cancer and reveal it to be a promising mode of treatment for local advanced pancreatic cancers.

Transarterial chemoembolization plus lenvatinib with or without a PD-1 inhibitor for advanced and metastatic intrahepatic cholangiocarcinoma: a retrospective real-world study.

OBJECTIVES: Most patients with intrahepatic cholangiocarcinoma (ICC) present with locally advanced or metastatic disease. We report the combined potency of transarterial chemoembolization (TACE), lenvatinib and programmed cell death-1 (PD-1) inhibitors in patients with advanced and metastatic ICC. METHODS: This retrospective study enrolled 32 patients with advanced or metastatic ICC between January 2017 and August 2021. Eligible patients had received gemcitabine-based TACE combined with lenvatinib with or without PD-1 inhibitor in any line of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Risk factors associated with OS were assessed using univariate and multivariate Cox regression analyses. RESULTS: Eighteen patients received a combination of TACE and lenvatinib (TL group) and 14 patients received TACE and lenvatinib plus aPD-1 inhibitor (TLP group). The median follow-up time was 19.8 months (range 1.8-37.8). The median OS was 25.3 months (95% CI 18.5-32.1) and the median PFS was 7.3 months (95% CI 4.9-9.7). Partial response was achieved in 10 patients (31.3%), and stable disease in 13 (40.6 %) with disease control rate of 71.9%. The median OS was comparable in the TL and TLP groups (22.4 vs 27.3 months, respectively; hazard ratio: 1.245, 95% CI 0.4245-3.653; p = 0.687). The regression analysis revealed that, regardless of treatment group, a favorable independent prognostic factor for OS was HBV/HCV infection (HR: 0.063, 95% CI 0.009-0.463; p = 0.007). There were no treatment-related deaths and 81.3% of study participants experienced adverse events (AEs), the majority of which were of moderate severity (71.8% Grade 1-2). CONCLUSIONS: Gemcitabine-based TACE plus lenvatinib with or without aPD-1 inhibitor was well tolerated and provided promising therapeutic outcomes for patients with advanced and metastatic ICC. ADVANCES IN KNOWLEDGE: Monotherapy with TACE, or Lenvatinib, or PD-1 inhibitors has shown limited efficacy over standard first-line chemotherapy in advanced and metastatic ICC. This work suggested the combined potency of these treatments and well-tolerance.

High intensity focused ultrasound treatment for patients with advanced pancreatic cancer: a preliminary dosimetric analysis.

OBJECTIVE: To analyse the clinical dosimetry of high intensity focused ultrasound (HIFU) for the treatment of inoperable pancreatic cancer in humans. METHODS: 136 patients with advanced pancreatic cancer were treated with HIFU, including 89 male and 47 female patients. The median targeted volume (V(t)) was 31.1 cm(3) (range: 9.8-102.1). The median of the average ultrasound power (P(avg)) was 225 W (range: 117-399), and the median energy of the ultrasound (E(total)) was 278.3 kJ (range: 70.5-1195.2). Spearman rank correlation analysis for HIFU dosimetric analysis was conducted. RESULTS: There was a significant correlation between greyscale changes after HIFU ablation and HIFU dose intensity (DI), P(avg), and unit time (T(u)). However, no correlation was found between greyscale changes after HIFU ablation and gender, age, pancreatic cancer position, or depth of tumour. CONCLUSIONS: We preliminarily deem that dose intensity and sound power can act as good reference points for HIFU dosimetry in the treatment of pancreatic tumours using the Chongqing system. If there was no obvious change in the ultrasound-monitored image following HIFU treatment for pancreatic cancer, the P(avg) and DI should be no less than 260 W and 11 kJ/cm(3), respectively.

Elevated serum chemerin levels are associated with the presence of coronary artery disease in patients with type 2 diabetes.

BACKGROUND: Coronary artery disease (CAD) is a major vascular complication of type 2 diabetes mellitus (T2DM) and reveals high mortality. Serum levels of chemerin have been suggested to be involved in glucose and lipid metabolism and associated with several cardiovascular factors. The aim of this study is to investigate the association of serum chemerin levels with the presence of CAD in patients with T2DM. METHODS: Serum levels of chemerin were determined in 286 patients with T2DM who underwent coronary angiography for the evaluation of CAD and 128 healthy subjects. The T2DM patients group included 150 patients with CAD and 136 patients without CAD. RESULTS: Serum chemerin levels were significantly higher in T2DM patients with CAD compared with those without CAD and healthy controls. However, there was no significant difference in the levels of serum chemerin between T2DM patients without CAD and healthy controls. Multivariable logistic regression analysis revealed that serum chemerin levels were an independent determinant of the presence of CAD in patients with T2DM (OR 1.057, 95% CI 1.040 to 1.075; p < 0.001). In addition, linear regression analysis showed that serum chemerin levels were positively correlated with body mass index, systolic blood pressure, homeostasis model assessment of insulin resistance, and serum triglycerides. CONCLUSIONS: There is an independent association between serum levels of chemerin and the presence of CAD in patients with T2DM.

RUNX1 and CCL3 in Diabetes Mellitus-Related Coronary Artery Disease: A Bioinformatics Analysis.

BACKGROUND: Cardiovascular complications are a major cause of death and disability in patients with diabetes mellitus, but how such complications arise is unclear. METHODS: Weighted gene correlation network analysis (WGCNA) was performed on gene expression profiles from healthy controls, individuals with diabetes mellitus, and individuals with diabetes mellitus-associated coronary artery disease (DMCAD). Phenotypically related module genes were analyzed for enrichment in Gene Ontology (GO) terms and Kyoto Gene and Genome Encyclopedia (KEGG) pathways. Predicted biological functions were validated using gene set enrichment analysis (GSEA) and ClueGo analysis. Based on the TRRUST v2 database and hypergeometric tests, a global network was built to identify transcription factors (TFs) and downstream target genes potentially involved in DMCAD. RESULTS: WGCNA identified three modules associated with progression from diabetes mellitus to DMCAD. The module genes were significantly involved in biological processes related to interferon and viral infection, while GSEA of DMCAD samples suggested involvement in viral myocarditis, chemokine signaling and phagosomes. RUNX1 was identified as a potential TF regulating these module genes. Analysis of the global regulatory network of TFs and their targets suggested that CCL3 may be a key regulator in DMCAD. CONCLUSION: We found bioinformatic evidence that CCL3 may be a key regulator and RUNX1 a key TF in DMCAD.

Effect and Mechanism of the Lenvatinib@H-MnO2-FA Drug Delivery System in Targeting Intrahepatic Cholangiocarcinoma.

BACKGROUND: To investigate the effects of the Lenvatinib@H-MnO2-FA administration system on the proliferation and apoptosis of Intrahepatic cholangiocarcinoma (ICC) and the underlying molecular mechanism. MATERIALS AND METHODS: In this research, hollow MnO2 (H-MnO2) was synthesized via the modified Stöber method, and H-MnO2 was modified with polyethylene glycol-bis (Amine) (NH2-PEG-NH2) and folic acid (FA) to obtain H-MnO2-PEG-FA (H-MnO2-FA). Lenvatinib was coated in the hollow cavity of H-MnO2-PEG-FA to further form a nanometre drug-carrying system (Lenvatinib@H-MnO2-PEG-FA). Lenvatinib@H-MnO2-FA was characterized through transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Fourier transform infrared spectroscopy (FT-IR) was used to verify that Lenvatinib was loaded on nanoparticles. Functionally, confocal laser scanning microscopy (CLSM), 2-(4-Amidinophenyl)-6-indolecarbamidine dihydrochloride (DAPI) staining, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were performed to determine the effect of Lenvatinib@H-MnO2-FA on the proliferation and apoptosis of ICC cells (9810 cells). Finally, the protein levels of Raf-1MEK1/2-ERK1/2 signalling pathway components were detected through Western blotting analysis. RESULTS: We successfully synthesised a Lenvatinib@H-MnO2-PEG-FA administration system. The resulting nanomaterials had excellent biological stability and improved targeting effects. Functionally, Lenvatinib@ H-MnO2-FA inhibited the proliferation of 9810 cells. The Bcl-2 protein level was significantly downregulated, and the caspase-3 protein level was significantly upregulated, indicating that Lenvatinib@H-MnO2- PEG- FA promoted the apoptosis of 9810 cells. Mechanistically, Lenvatinib@H-MnO2-FA increased the phosphorylation levels of Raf, MEK1/2, and ERK1/2. CONCLUSION: H-MnO2-FA can more effectively deliver Lenvatinib to inhibit proliferation and promote apoptosis in ICC, which could be the promising drug delivery nano-vehicles for delivery drugs.

Analgesic effect of high intensity focused ultrasound therapy for unresectable pancreatic cancer.

OBJECTIVE: To evaluate the pain-alleviating action, feasibility and efficacy of high intensity focused ultrasound (HIFU) for palliation of inoperable pancreatic cancer in humans. METHODS: Forty patients with advanced pancreatic cancer were treated with HIFU. There were 13 patients with stage III, and 27 patients with stage IV disease. The locations of the tumours were as follows: head of pancreas in 9 patients, body and/or tail of pancreas in 31 patients. Pain relief, local tumour control rate, median survival and complications were monitored after HIFU treatment. The primary endpoint was to assess pain relief rate and pain relief time (PRT). Secondary endpoints included local progression-free survival time, overall survival (OS), and side effects. RESULTS: There were no severe complications or adverse events related to HIFU therapy in any of the patients treated. Pain relief was achieved in 87.5% of patients, median PRT was 10 weeks. The median local progression-free survival time for all patients was 5 months. The median overall survival time was 10 months for patients with stage III disease, and 6 months for patients with stage IV disease. The median OS time, 6-month and 1-year survival rate for patients as a whole were 8 months, 58.8% and 30.1%, respectively. CONCLUSIONS: Although this study may have limitations, preliminary results demonstrate the safety of clinical application of HIFU for pancreatic cancer and reveal it to be a promising mode of treatment for palliation of pain associated with pancreatic cancers.

Anisakis pegreffii: a quantitative fluorescence PCR assay for detection in situ.

To facilitate improved diagnosis and detection of the third stage larva (L3) of Anisakis pegreffii from the Minnan-Taiwan bank fishing ground in Taiwan Strait, a real-time PCR method for the detection in situ and differentiation was developed to amplify a region of the second internal transcribed spacer (ITS-2) of this parasite. The real-time PCR assay was capable of detecting 1/3 of a single L3 in 30 mg of marine fish tissue, and also exhibited a high level of specificity for A. pegreffii, no fluorescence signals were observed in other five major larval anisakid species found in commercial marine fishes caught in this fishing ground.

Classifiers for Predicting Coronary Artery Disease Based on Gene Expression Profiles in Peripheral Blood Mononuclear Cells.

OBJECTIVE: Coronary artery disease (CAD) is a serious global health concern. Current diagnostic methods for CAD involve risk to the patient and are costly, so better diagnostic tools are needed. We defined four classifiers based on gene expression profiles in peripheral blood mononuclear cells and determined their potential for CAD detection. METHODS: We downloaded a CAD-related data set (GSE113079) from the Gene Expression Omnibus (GEO) database. We identified differentially expressed genes (DEGs) in peripheral blood mononuclear cells between CAD samples and healthy controls. DEGs were analyzed for functional enrichment. To create a robust CAD classifier, DEGs were identified by feature selection using the principal component analysis. Then, least absolute shrinkage and selection operator (LASSO) logistic regression, random forest, and support vector machine (SVM) models were created. Gene set variation analysis (GSVA) score and gene set enrichment analysis (GSEA) were also conducted. The performance of the models was evaluated in terms of the area under receiver operating characteristic curves (AUC). RESULTS: In the training set, we found 135 up-regulated genes and 104 down-regulated genes in CAD patients compared with controls. The DEGs were involved in some pathways associated with CAD, such as pathways involving calcium and interleukin-17 signaling. Twenty genes were identified as optimal features and used to generate the logistic classifier based on LASSO. The AUC for the classifier was 1.00 in the training set and 0.997 in the test set. Using the 20 DEGs, SVM and random forest classifiers were also generated and showed high diagnostic efficacy, with respective AUCs of 0.997 and 1.00 against the training set. A GSVA score was also established using the top 20 significant DEGs, which showed an AUC of 0.971 in the training set and 0.989 in the test set. Furthermore, GSEA showed autophagy and the proteasome to be major pathways involving the DEGs. CONCLUSION: We identified a set of genes specific for CAD whose expression can be measured non-invasively. Using these genes, we defined four diagnostic classifiers using multiple methods.

[Clinical observation of transarterial chemoembolization combined with sorafenib for advanced hepatocellular carcinoma].

OBJECTIVE: To observe the efficacy and side effects of transarterial chemoembolization (TACE) combined with sorafenib for advanced hepatocellular carcinoma (HCC). METHODS: Forty patients with HCC were treated with sorafenib (400 mg bid) after TACE. The efficacy was evaluated according to RECIST 1.1 criteria, and side effects were assessed by NCI CTC 3.0 criteria. RESULTS: Among the forty cases, one case achieved complete remission (CR), seven cases achieved partial remission (PR), nineteen cases achieved stable disease (SD) and thirteen cases had progressive disease (PD). The disease control rate (DCR) was 67.5%. The overall survival time was 1 - 18 months, and 1-year survival rate was 54.0%. The major adverse events were hand-foot skin reaction, diarrhea and thrombocytopenia. CONCLUSION: The combined therapy of TACE and sorafenib is effective and well tolerated for advanced HCC.

Overexpression of a Long Non-Coding RNA BC037916 is Associated with Pancreatic Tumorigenesis and Poor Prognosis.

BACKGROUND: Pancreatic cancer is one of the most lethal malignancies. Accumulating evidence supports for the critical contribution of long noncoding RNAs (lncRNAs) to the cancer development and progression. We tried to identify novel lncRNAs involved in the pancreatic carcinogenesis. MATERIALS AND METHODS: Two independent datasets (Gene Expression Omnibus datasets: GSE16515 and GSE32688) were obtained from the Gene Expression Omnibus (GEO). The level of BC037916 was detected in pancreatic cancer tissues and adjacent no-tumorous tissues (n=86) by qRT-PCR. Effects of BC037916 on proliferation, apoptosis, and invasion of pancreatic cancer cells were examined. RESULTS: We identified a novel lncRNA BC037916 involved in the pancreatic carcinogenesis by analyzing GEO datasets. Quantitative RT-PCR analysis showed that 86.0% (74/86) pancreatic cancer tissues had increased BC037916 expression as compared with normal counterparts. Further, positive correlation was observed between BC037916 expression and clinical stage, primary tumor, and regional lymph node invasion. Importantly, BC037916 was an independent prognostic factor of pancreatic cancer. Functionally, knockdown of BC037916 repressed cell proliferation, inhibited cell invasion, halted cell cycle progression, and promoted apoptosis in both PANC-1 and SW1990 cells. In contrast, overexpression of BC037916 in CAPAN-1 had opposite effects. Moreover, silencing of BC037916 significantly inhibited the tumor growth of xenografted SW1990 cells in vivo. Results of Western blot assays suggested that BC037916 knockdown also suppressed the activation of JAK2/STAT3 and TGF-ß signaling. Further experiments suggested that BC037916 positively regulated the expression of Twist through miR-3145-3p. CONCLUSION: BC037916 exhibited oncogenic potential in pancreatic cancer development.

Dual role of Ski in pancreatic cancer cells: tumor-promoting versus metastasis-suppressive function.

Ski used to be defined as an oncogene that contributes to the resistance of tumor cells to transforming growth factor-beta (TGF-beta)-induced growth arrest. As TGF-beta has a dual effect on tumor growth with both tumor-suppressing and -promoting activity depending on the stage of carcinogenesis and the cell type, the precise role of Ski in carcinogenesis remains unclear. In this study, we show that downregulation of Ski through lentivirus-mediated RNA interference decreases tumor growth both in vitro and in vivo, yet promotes cell invasiveness in vitro, and lung metastasis in vivo in the pancreatic cancer cell line SW1990, which contain wild-type Smad4 expression, and the BxPC3 cell line, which is Smad4 deficient. We also show that the downregulation of Ski increases TGF-beta-induced transcriptional activity, which is associated with increased TGF-beta-dependent Smad2/3 phosphorylation, and results in an altered expression profile of TGF-beta-inducible genes involved in metastasis, angiogenesis and cell proliferation and epithelial-mesenchymal transition. Immunohistochemical analysis of specimens from 71 patients with pancreatic adenocarcinoma showed a significant association between overexpression of Ski and decreased patient survival time (P = 0.0024). Our results suggest that Ski may act as a tumor proliferation-promoting factor or as a metastatic suppressor in human pancreatic cancer.

Low-level expression of Smad7 correlates with lymph node metastasis and poor prognosis in patients with pancreatic cancer.

BACKGROUND: Whether Smad7 acts as a tumor proliferation promoting factor or as a metastatic suppressor in human pancreatic cancer remains unclear. This study aims to determine the prognostic value of Smad7 in patients with pancreatic adenocarcinoma. METHODS: Surgical specimens obtained from 71 patients with pancreatic adenocarcinoma were immunohistochemically assessed for Smad7, Ki-67, MMP2, CD34, and Smad4 expression. The relationship between Smad7 expression and the clinicopathological characteristics of patients with pancreatic adenocarcinoma were also evaluated. RESULTS: Fifty-one of 71 specimens (71.8%) were Smad7 positive and 20 specimens were Smad7 negative. Negative expression of Smad7 correlated with lymph node metastasis, liver metastasis after surgery, and a poor survival rate (P = 0.0004, 0.0044, and 0.0003, respectively). We also found an inverse correlation between the expression of Smad7 and MMP2 (P = 0.0189). Multivariate analysis revealed that Smad7 expression was an independent prognostic factor [hazard ratio (HR) 0.3902; 95% confidence interval (CI) 0.1839-0.8277; P = 0.0142]. Furthermore, in both Smad4-negative and Smad4-positive groups, survival of patients with Smad7-positive tumors was significantly better than those with Smad7-negative tumors (both P < 0.0001). CONCLUSIONS: We conclude that low-level expression of Smad7 in pancreatic cancer is significantly associated with lymph node metastasis, high MMP2 expression, and poor prognosis.