ARRB2 promotes colorectal cancer growth through triggering WTAP.

Colorectal cancer (CRC) is one of the most lethal cancers worldwide. The expression of ß-arrestin2 (ß-Arr2, ARRB2) in CRC has been well investigated; however, its exact mechanism causing the cancer progression remains unclear. In this study, we discovered that the expression level of ARRB2 was significantly upregulated in CRC as compared to the normal tissues by employing the Cancer Genome Atlas (TCGA) data, western blot analysis, and immunohistochemistry. Furthermore, the level of ARRB2 was correlated with the patients' overall survival by Kaplan-Meier analysis. The higher expression of ARRB2 promoted CRC cell growth, enhanced the cell motility, and blocked cell apoptosis, which is crucial for tumor growth. Lastly, the suppression of ARRB2 expression was enough to attenuate the progression of CRC induced by azoxymethane/dextran sodium sulfate. Interestingly, we also found that the knockdown of ARRB2 decreased several cancer pathways mediated by the expression of Wilms tumor 1 associated protein (WTAP), which led to the inhibition of cell proliferation and migration. Altogether, our results demonstrated that ARRB2 promoted the growth and migration of CRC cells by regulating the WTAP expression.

Propofol-induced miR-219-5p inhibits growth and invasion of hepatocellular carcinoma through suppression of GPC3-mediated Wnt/ß-catenin signalling activation.

Propofol is one of the most extensively used intravenous anaesthetic agents, which has been found to improve the surgical intervention outcome of several types of cancer, including hepatocellular carcinoma (HCC). Additionally, in vitro and in vivo experiments have also indicated that propofol affects the biological behaviour of HCC. However, the underlying mechanisms of the surgical resection of HCC with propofol have not been fully understood. In the present study, we aimed to investigate the underlying mechanism of propofol inhibition of the growth and invasion of HCC cells. Our results showed that treatment with propofol suppressed the proliferation, invasion and migration of HCC in vitro. The subcutaneous xenograft tumour and orthotopic xenograft tumour experiments in nude mice showed that propofol significantly decreased tumour volumes, growth rates and the liver orthotopic xenograft tumour in vivo. Furthermore, the underlying mechanism investigations of the suppressive effects of propofol on HCC cells revealed that propofol treatment upregulated the expression levels of the candidate tumour suppressor miR-219-5p. Silencing of propofol-induced miR-219-5p using anti-miR-219-5p abrogated the inhibitory effects on the proliferation, migration and invasion of HCC cells exerted by propofol treatment. Additionally, we demonstrated that propofol reversed the epithelial-mesenchymal transition of Huh7 and SMMC7721 cells via miR-219-5p induction. The molecular mechanism behind these findings is that propofol-induced miR-219-5p inhibits HCC cell progression by targeting glypican-3 and subsequently results in the inhibition of Wnt/ß-catenin signalling. Taken together, our study provides new insights into the advantages of the surgical intervention of HCC with propofol anaesthetization.

miR-26a promotes hepatocellular carcinoma invasion and metastasis by inhibiting PTEN and inhibits cell growth by repressing EZH2.

A previous study revealed that therapeutic miR-26a delivery suppresses tumorigenesis in a murine liver cancer model, whereas we found that forced miR-26a expression increased hepatocellular carcinoma (HCC) cell migration and invasion, which prompted us to characterize the causes and mechanisms underlying enhanced invasion due to ectopic miR-26a expression. Gain-of-function and loss-of-function experiments demonstrated that miR-26a promoted migration and invasion of BEL-7402 and HepG2 cells in vitro and positively modulated matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, and MMP-10 expression. In addition, exogenous miR-26a expression significantly enhanced the metastatic ability of HepG2 cells in vivo. miR-26a negatively regulated in vitro proliferation of HCC cells, and miR-26a overexpression suppressed HepG2 cell tumor growth in nude mice. Further studies revealed that miR-26a inhibited cell growth by repressing the methyltransferase EZH2 and promoted cell migration and invasion by inhibiting the phosphatase PTEN. Furthermore, PTEN expression negatively correlated with miR-26a expression in HCC specimens from patients with and without metastasis. Thus, our findings suggest for the first time that miR-26a promotes invasion/metastasis by inhibiting PTEN and inhibits cell proliferation by repressing EZH2 in HCC. More importantly, our data also suggest caution if miR-26a is used as a target for cancer therapy in the future.

Knockout of NCOA5 impairs proliferation and migration of hepatocellular carcinoma cells by suppressing epithelial-to-mesenchymal transition.

Nuclear receptor coactivator 5 (NCOA5) plays important roles in the development of a variety of malignancies. However, the underlying mechanisms remain obscure. In this study, we successfully generated the NCOA5 knockout hepatocellular carcinoma (HCC) cells by CRISPR/Cas9 - mediated genome editing and found that knockout of NCOA5 inhibited the proliferation and tumor microsphere formation of HCC cells significantly. Moreover, the migration ability of NCOA5 knockout HCC cells declined. Mechanistic analyses indicated that knockout of NCOA5 can suppress the epithelial - mesenchymal transition (EMT) in HCC cells. In conclusion, our findings provide a mechanistic insight into the role of NCOA5 in HCC progression.

LncRNA FUNDC2P4 down-regulation promotes epithelial-mesenchymal transition by reducing E-cadherin expression in residual hepatocellular carcinoma after insufficient radiofrequency ablation.

PURPOSE: Hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA) could induce epithelial-mesenchymal transition (EMT) in residual tumours, resulting in rapid and aggressive recurrence. However, the role of EMT-related Long noncoding RNAs (lncRNAs) in residual tumour progression remains unclear. METHODS: Insufficient RFA was simulated in vitro by heating Huh7 cells in water bath at 47 °C, named as Huh7-H. Cell invasion, migration assays and wound healing assay were conducted for functional analysis. Cell proliferation was determined by CCK8 assay. Differential expression profile of EMT-related lncRNAs between Huh7-H and Huh7 was analysed by LncPath human EMT array, and validated by qRT-PCR. Gain/loss-of-function assays of selected lncRNA were conducted by over-expressing or silencing its expression. RESULTS: Huh7-H presented characteristic EMT morphological changes. WB analysis showed significantly decreased E-cadherin in Huh7-H cells. Transwell assays indicated the abilities of Huh7-H cells in migration and invasion were evidently strengthened. A new lncRNA, FUNDC2P4, was identified by LncPath human EMT array to be significantly down-regulated in Huh7-H cells. In vitro studies showed overexpression of FUNDC2P4 inhibited proliferation, invasion and migration potential and up-regulated E-cadherin expression in SMMC-7721 cells, whereas silencing FUNDC2P4 promoted these potentials and down-regulated E-cadherin expression in Huh7 cells. CONCLUSIONS: We explored that lncRNA FUNDC2P4 down-regulation promoted EMT leading to tumour proliferation, invasion and migration by reducing E-cadherin expression in residual HCC after insufficient RFA in vitro. These results suggest that FUNDC2P4 may have potentially therapeutic value for prevention and treatment of HCC recurrence after RFA in the future.

TIMELESS contributes to the progression of breast cancer through activation of MYC.

BACKGROUND: Breast cancer is the most common malignancy and the leading cause of cancer death among women. TIMELESS (TIM), a circadian rhythm regulator, has been recently implicated in the progression of human cancer. However, the role of TIM in the progression of breast cancer has not been well-characterized. METHODS: Immunohistochemistry (IHC) staining was used to examine TIM levels in breast cancer specimens. Mammosphere formation analysis and side population analysis were used to examine the effect of TIM on the self-renewal of breast cancer stem cells. A wound healing assay and a Transwell assay were used to determine the role of TIM in breast cancer cell migration and invasion. A soft agar growth assay in vitro and tumorigenicity in vivo were used to determine the role of TIM in tumorigenicity. RESULTS: TIM levels in both breast cancer cell lines and tissues were significantly upregulated. Patients with high TIM had poorer prognosis than patients with low TIM. Overexpression of TIM dramatically enhanced, while knockdown of TIM suppressed the self-renewal of cancer stem cells (CSCs), cell invasion and migration abilities of breast cancer cells in vitro. Moreover, overexpression of TIM significantly augmented, while knockdown of TIM reduced the tumorigenicity of breast cancer cells in vivo. Mechanism studies revealed that TIM upregulated the expression and the trans-activity of the well-known oncogene MYC. Inhibition of MYC significantly blocked the effects of TIM on CSC population, cell invasion and anchor-independent cell growth. CONCLUSION: TIM plays an important role in promoting breast cancer progression and may represent a novel therapeutic target for breast cancer.

MiR-661 promotes tumor invasion and metastasis by directly inhibiting RB1 in non small cell lung cancer.

BACKGROUND: Aberrant microRNA expression has been implicated in metastasis of cancers. MiR-661 accelerates proliferation and invasion of breast cancer and ovarian cancer, while impedes that of glioma. Its role in non small cell lung cancer (NSCLC) and underlying mechanism are worthy elucidation. METHODS: Expression of miR-661 was measured with real-time PCR in both NSCLC tissues and cell lines. The effects of miR-661 on migration, invasion and metastasis capacity of NSCLC were evaluated using wound healing, transwell assay and animal models. Dual reporter luciferase assay and complementary experiments were performed to validate RB1 as a direct target of miR-661 for participation in the progression of NSCLC. RESULTS: MiR-661 was upregulated in NSCLC tissues as compared to paired adjacent tissues and associated with shorter overall survival. Furthermore, miR-661 promoted proliferation, migration and metastasis of NSCLC. Then, we identified RB1 as a direct target of miR-661 through which miR-661 affected EMT process and metastasis of NSCLC. RB1 interacted with E2F1 and both could mediate EMT process in NSCLC. CONCLUSION: MiR-661 promotes metastasis of NSCLC through RB/E2F1 signaling and EMT events, thus may serves as a negative prognostic factor and possible target for treatment of NSCLC patient.

NCOA5 is correlated with progression and prognosis in luminal breast cancer.

Nuclear receptor coactivator 5 (NCOA5) is known to modulate ERα-mediated transcription and has been found to be involved in the progression of several malignancies. However, the potential correlation between NCOA5 and clinical outcome in patients with luminal breast cancer remains unknown. In the present study, we demonstrated that NCOA5 was significantly up-regulated in luminal breast cancer tissues compared with adjacent non-cancerous tissues both in validated cohort and TCGA cohort. Moreover, Kaplan-Meier analysis indicated that patients with high NOCA5 expression had significantly lower overall survival (P = 0.021). Cox regression analysis indicated that the high NOCA5 expression was independent high risk factor as well as old age (>60) and HER-2 expression (P = 0.039; P = 0.003; P = 0.005; respectively). This study provides new insights and evidences that NOCA5 over-expression was significantly correlated with progression and prognosis in luminal breast cancer. However, the precise cellular mechanisms for NOCA5 in luminal breast cancer need to be further explored.

Over-expression of cathepsin B in hepatocellular carcinomas predicts poor prognosis of HCC patients.

BACKGROUND: Several studies have found that Cathepsin B (CTSB) is up-regulated in many tumor types and facilitates tumor progression. However, the role of CTSB in hepatocellular carcinoma (HCC) progression remains unclear. This study was aimed at investigating the expression and role of CTSB in HCC in a large set of samples and cell lines (MHCC-97H and MHCC-97 L), and evaluating the clinical and prognostic significance of CTSB protein in patients with HCC. METHODS: The expression of CTSB was examined in HCC tissue and cell lines by Western-blotting, Real-time PCR, and immunohistochemical staining. Wound healing assay and invasion assay were used to verify the effect of CTSB on the migration and invasion ability of HCC cell lines. Tumor formation assay in nude mice was used to analyze the effect of CTSB on the tumorigenicity of HCC cell lines. RESULTS: The status of CTSB protein in carcinoma tissues is much higher than that in paracarcinoma tissues. The overall survival of the patients with high CTSB expression was significantly shorter than the low CTSB expression group. High CTSB expression was significantly correlated with advanced clinical staging, histological grade, and tumor recurrence. In vitro and in vivo experiments demonstrated that over-expression of CTSB in MHCC-97 L cells promoted cell invasion and tumor progression ability. Down-regulation of CTSB in MHCC-97H showed the opposite effects. These phenotypic changes caused by CTSB knockdown or over-expression correlated with expression of the matrix metallopeptidase MMP-9. Moreover, multivariate analysis suggested that CTSB expression might be an independent prognostic indicator for the survival of HCC patients after curative surgery. CONCLUSIONS: CTSB might be involved in the development and progression of HCC as an oncogene, and thereby may be a valuable prognostic marker for HCC patients.

MLF1IP is correlated with progression and prognosis in luminal breast cancer.

Myeloid leukemia factor 1-interacting protein (MLF1IP) has been found to be involved in the progression of several malignancies. The potential correlation between MLF1IP and clinical outcome in patients with luminal breast cancer, however, remains unknown. In the present study, we demonstrated that MLF1IP was significantly upregulated in luminal breast cancer tissue compared with adjacent normal tissue both in validated cohort and TCGA cohort. Upregulated expression of MLF1IP was correlated with more often lymph node metastasis and negative progesterone receptor expression in TCGA cohorts. Kaplan-Meier analysis indicated that patients with high MLF1IP expression had significantly lower overall survival. Moreover, multivariate analysis revealed that high MLF1IP expression was independent high risk factor as well as old age (>60) and distant metastasis. This study provides new insights and evidences that MLF1IP over-expression plays important roles in progression of luminal breast cancer. However, the precise cellular mechanisms for MLF1IP in luminal breast cancer need to be further explored.

Direct interaction between miR-203 and ZEB2 suppresses epithelial-mesenchymal transition signaling and reduces lung adenocarcinoma chemoresistance.

miR-203 is a tumor suppressor which participates in the pathogenesis of many tumors including lung adenocarcinoma. However, the role of miR-203 in suppressing chemotherapy resistance to cisplatin (cis-diamminedichloroplatinum; DDP) as well as its molecular mechanism is still to be determined in lung adenocarcinoma. In this study, we found that miR-203 decreased lung cancer cell migration and invasion, and that increased miR-203 expression sensitized lung adenocarcinoma cells to DDP in vitro Furthermore, ZEB2 was found to be a direct target of miR-203, which induces epithelial-mesenchymal transition (EMT) signal. Knock-down of ZEB2 significantly increased DDP chemosensitivity in lung adenocarcinoma. More interestingly, we also demonstrated that ZEB2 could directly bind to E-box of the miR-203 promoter and suppress its expression in lung adenocarcinoma. Our data reveal that miR-203 serves as a negative feedback by directly suppressing the upstream ZEB2 gene, which inhibits EMT signaling and reduces chemoresistance of DDP. Together, these results highlight a feedback loop between miR-203 and ZEB2, which participates in the pathogenesis of lung adenocarcinoma.

The pretreatment albumin to globulin ratio, a validated biomarker, predicts prognosis in hepatocellular carcinoma.

PURPOSE: Although the albumin to globulin ratio (AGR) has been proven to be a prognostic factor in several cancers, no studies have assessed its prognostic significance in hepatocellular carcinoma (HCC). Therefore, this study aimed to investigate the prognostic value of the pretreatment AGR in the survival in HCC patients. METHODS: 150 patients were enrolled, who were confirmed of HCC from October 2008 to December 2012 in Nanfang Hospital of Southern Medical University. Demographic, clinical and laboratory data were obtained. Univariate and multivariate Cox regression analysis were used to investigate the association of clinicopathological parameters with HCC patients' survival. RESULTS: Patients were divided into 2 groups: AGR?1.18 and AGR ?1.18. Patients in the high AGR (?1.18) group had longer overall survival (OS) than those in the low AGR (<1.18) group (60.16 vs 20.48 months, p<0.001). Univariate analysis showed that portal vein tumor thrombosis, grade of differentiation, extrahepatic metastasis, BCLC stage, AFP level and AGR at diagnosis were significantly associated with OS. Multivariate analysis revealed that AGR (p<0.001) and grade of differentiation (p=0.007) were independent prognostic factors for survival of HCC patients. In subgroup analysis based on age and Child-Pugh class, AGR remained a significant prognostic parameter. CONCLUSION: Low pretreatment AGR was significantly associated with shorter OS in HCC patients. The pretreatment AGR could be a useful and effective prognostic index for identifying patients with poor prognosis, even when patients have well-preserved liver reserve function.

Clinical and pathological response to neoadjuvant chemotherapy based on primary tumor reduction is correlated to survival in hormone receptor-positive but not hormone receptor-negative locally advanced breast cancer.

PURPOSE: This study was designed to examine the relationship between different methodologies for response evaluation and long-term survival estimation in patients underwent neoadjuvant chemotherapy (NCT) for breast cancer. METHODS: We retrospectively analyzed 569 patients who were diagnosed with LABC and received NCT followed by breast and axilla surgery. The RECIST 1.1 criteria and Miller-Payne (MP) grading scale were used to evaluate patient responses to NCT. Univariate and multivariate survival analyses were performed to investigate the correlation between treatment response and long-term patient survival. RESULTS: Clinical response (RFS [P < 0.001]; OS [P = 0.003]), pathological response evaluated by pCR (RFS [P < 0.001]; OS [P < 0.001]), and MP grade (RFS [P < 0.001]; OS [P < 0.001]) were significant predictors of risks of relapse and survival. However, in hormone receptor-positive (ER and/or PR+) subtypes, the clinical response (P = 0.004 for Luminal-A and P = 0.038 for Luminal-B) and MP grade (P = 0.002 for Luminal-A and P < 0.001 for Luminal-B) significantly predicted RFS independently according to multivariate Cox regression model. MP grade (P = 0.015 for Luminal-A and P = 0.009 for Luminal-B) also was an independent predictor of patients' OS. However, these two methods failed to predict patient survival in hormone receptor-negative (ER and PR-) subtypes. CONCLUSIONS: Our findings indicate that the value of response evaluation methods varies for different breast cancer subtypes. Conceiving of further prospective approaches for new individualized response-evaluation models are needed in the neoadjuvant setting.

Predictive value of microtubule-associated protein Tau in patients with recurrent and metastatic breast cancer treated with taxane-containing palliative chemotherapy.

Tau is a member of microtubule-associated proteins (MAPs) and expressed in normal breast epithelium and breast cancer cells. Tau expression levels in early breast cancer were correlated with the responsiveness of taxane-containing chemotherapy. However, it is unknown whether Tau contributes to breast cancer progression. Herein, Tau expression in recurrent and metastatic breast cancer (RMBC) and its predictive significance in taxane-containing palliative chemotherapy were investigated. Immunohistochemical (IHC) staining was conducted to detect Tau protein expression levels in biopsies from 285 patients with RMBC, and the correlation between Tau expression and sensitivity to taxane was evaluated. One hundred twenty-one (42.46 %, 121/285) patients were Tau positive in their tumor. One hundred ninety-four (68.07 %, 194/285) patients were effective clinical remission, which evaluated with response evaluation criteria in solid tumors (RECIST) criteria. In this group, 141 (85.98 %, 141/194) patients were Tau negative. We further analyzed the correlation between Tau expression and clinicopathological characteristics. Tau expression was positively correlated to estrogen receptor (ER) status. Multivariate logistic regression analysis showed that Tau expression significantly differentiated patients with effective response to treatment (95 % confidence interval (CI): 4.230-13.88, P < 0.01). Tau expression was identified as an independent factor to predict the sensitivity of tumors to taxane-containing palliative chemotherapy in RMBC, suggesting that Tau expression in RMBC may serve as a clinical predictor for taxane-containing palliative chemotherapy.

Small interfering RNA (siRNA)-mediated knockdown of Notch1 suppresses tumor growth and enhances the effect of IL-2 immunotherapy in malignant melanoma.

PURPOSE: Malignant melanoma (MM) is a highly aggressive neoplasm that is resistant to conventional therapies. In this study, we aimed to investigate the effects of antitumor and immune enhancement of Notch1 knockdown on MM. METHODS: Mouse melanoma cells B16F1 were transfected with a small interfering RNA (siRNA) targeting Notch1 (siNotch1). RESULTS: The expression of Notch1 and its downstream hey1 was significantly decreased, resulting in reduced cell proliferation in vitro. Furthermore, intratumoral injection of siNotch1 successfully inhibited the expression of Notch1 and hey1, which suppressed tumor growth, and increased the number of tumor-infiltrating CD8+ T lymphocytes and IFN-γ secretion in vivo, especially when combined with IL-2 immunotherapy. CONCLUSION: These results suggested that siRNA-mediated Notch1 knockdown might be an effective method for the inhibition of tumor growth both in vivo and in vitro, and might potentially enhance the effect of IL-2 immunotherapy in MM. Notch1 knockdown concurrently administered with IL-2 might be a novel therapeutic approach for the treatment of MM.

TRPM8 promotes aggressiveness of breast cancer cells by regulating EMT via activating AKT/GSK-3ß pathway.

Breast cancer already taken the first place of incidence in Chinese female cancer patients. TRPM8 is found to be over-expressed in breast cancer, but whether it promotes breast cancer aggressiveness remains unknown. In our study, TRPM8 was identified highly expressing in all the tested breast cancer cell lines including MCF-7, T47D, MDA-MB-231, BT549, SKBR3 and ZR-75-30, while it just could be detected in MCF-10A, the normal breast epithelial cell. Then four pairs of clinical samples were analyzed using Western blotting and the result showed that TRPM8 expression is higher in tumor tissues than in adjacent nontumor tissues. Subsequently, we established TRPM8 high-expressing MCF-7 cell line and TRPM8 knockout MDA-MB-231 cell line to explore expression status of cancer-related proteins. The Western blotting and immunofluorescence analysis outcomes demonstrated that TRPM8 might influence cancer cell metastasis by regulating the EMT phenotype via activating AKT/GSK-3ß pathway, and the hypothesis had been supported by cell function tests. All the results demonstrated that TRPM8 significantly up-expressed in breast cancer cells and promoted their metastasis by regulating EMT via activating AKT/GSK-3ß pathway, indicating TRPM8 gets the prospects of to be developed as medication or diagnostic indicator to be applied in clinical work.

Aberrant PTPRO methylation in tumor tissues as a potential biomarker that predicts clinical outcomes in breast cancer patients.

BACKGROUND: Aberrant hypermethylation of gene promoter regions is a primary mechanism by which tumor suppressor genes become inactivated in breast cancer. Epigenetic inactivation of the protein tyrosine phosphatase receptor-type O gene (PTPRO) has been described in several types of cancer. RESULTS: We screened primary breast cancer tissues for PTPRO promoter hypermethylation and assessed potential associations with pathological features and patient outcome. We also evaluated its potential as a breast cancer biomarker. PTPRO methylation was observed in 53 of 98 (54%) breast cancer tissues but not in adjacent normal tissue. Among matched peripheral blood samples from breast cancer patients, 33 of 98 (34%) exhibited methylated PTPRO in plasma. In contrast, no methylated PTPRO was observed in normal peripheral blood from 30 healthy individuals. PTPRO methylation was positively associated with lymph node involvement (P = 0.014), poorly differentiated histology (P = 0.037), depth of invasion (P = 0.004), and HER2 amplification (P = 0.001). Multivariate analysis indicated that aberrant PTPRO methylation could serve as an independent predictor for overall survival hazard ratio (HR): 2.7; 95% CI: 1.1-6.2; P = 0.023), especially for patients with HER2-positive (hazard ratio (HR): 7.5; 95% CI: 1.8-31.3; P = 0.006), but not in ER + and PR + subpopulation. In addition, demethylation induced by 5-azacytidine led to gene reactivation in PTPRO-methylated and -silenced breast cancer cell lines. CONCLUSIONS: Here, we report that tumor PTPRO methylation is a strong prognostic factor in breast cancer. Methylation of PTPRO silences its expression and plays an important role in breast carcinogenesis. The data we present here may provide insight into the development of novel therapies for breast cancer treatment. Additionally, detection of PTPRO methylation in peripheral blood of breast cancer patients may provide a noninvasive means to diagnose and monitor the disease.

Implanting totally implantable venous access port via the internal jugular vein guided by ultrasonography is feasible and safe in patients with breast cancer.

BACKGROUND: Because of long-term use for chemotherapy and fluid administration in cancer patients, a totally implantable venous access port (TIVAP) has been advised as a feasible catheter. The purpose of this study was to evaluate the effectiveness and safety of ultrasound (US)-guided internal jugular vein (IJV) puncture for TIVAP implantation in patients with breast cancer. METHODS: We reviewed the medical records of 492 patients who underwent US-guided IJV puncture for TIVAP implantation at our oncology department between 2010 and 2013. Indications, surgical complications, and early and long-term complications were analyzed. RESULTS: All TIVAPs were implanted successfully. Indications for TIVAP were chemotherapy alone (88 patients), chemoradiotherapy (387 patients), surgery (12 patients), and parenteral nutrition (5 patients). Complications were observed in 65 (13.21%) patients. The median duration of the TIVAP was 359 days (range, 28 to 712 days) without damage to the port or catheter, or leakage of drugs outside of the port system. CONCLUSIONS: A TIVAP can be employed for chemotherapy and parenteral nutrition on the implantation day. Using a US-guided IJV puncture to completely implant a TIVAP is feasible and safe in patients with breast cancer.

The true role of mRECIST guideline: does it really estimate viable tumor or merely improve accuracy in hepatocellular carcinoma response evaluation?

PURPOSE: Modified Response Evaluation Criteria In Solid Tumors (mRECIST), developed by the American Association for the Study of Liver Diseases (AASLD) criteria measure changes in arterialized hepatocellular carcinoma (HCC) and aim at providing a common framework for the design of clinical trials. It still isn't determined whether mRECIST can be applied in routine clinical practice and whether mRECIST could estimate viable tumor correctly. METHODS: We retrospectively analyzed data from patients subjected to transcatheter arterial chemoembolization (TACE) as initial treatment for advanced HCC in our institution. Not suitable for using mRECIST standard cases and the agreement in response between RECIST and mRECIST were assessed. Then we selected HCC patients who achieved complete response (CR) according to mRECIST, following PET-CT examinations. We also compared arterial enhanced computed tomography (CT) or magnetic resonance imaging (MRI) with positron emission tomography (PET)-CT examination and analyzed their correlation. RESULTS: Out of 143 HCC patients, mRECIST evaluation appeared to be applicable for 128 (89.51%) assessable patients. In these 128 assessable patients, the objective response (OR) rates (complete/CR+partial response/PR) according to RECIST and mRECIST were 64.06% (82 of 128 patients) and 78.13% (100 of 128; p<0.001), respectively. Discordance in the response evaluations between the two methods was observed in 46 patients (35.94%) and was statistically significant (Kappa=0.491; p<0.001). The overall survival (OS) of patients who achieved an OR as assessed by mRECIST or by RECIST was significantly better than the survival of non-responding patients (stable disease/SD, or progressive disease/PD). CONCLUSIONS: Although mRECIST criteria show a good correlation with prognosis, they demand strict requirements for patient selection and couldn't be useful as a tool for routine clinical practice. Furthermore, merely by means of contrast-enhanced CT or MRI, mRECIST couldn't estimate viable tumor sufficiently.

Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial.

BACKGROUND: Icotinib, an oral EGFR tyrosine kinase inhibitor, had shown antitumour activity and favourable toxicity in early-phase clinical trials. We aimed to investigate whether icotinib is non-inferior to gefitinib in patients with non-small-cell lung cancer. METHODS: In this randomised, double-blind, phase 3 non-inferiority trial we enrolled patients with advanced non-small-cell lung cancer from 27 sites in China. Eligible patients were those aged 18-75 years who had not responded to one or more platinum-based chemotherapy regimen. Patients were randomly assigned (1:1), using minimisation methods, to receive icotinib (125 mg, three times per day) or gefitinib (250 mg, once per day) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, analysed in the full analysis set. We analysed EGFR status if tissue samples were available. All investigators, clinicians, and participants were masked to patient distribution. The non-inferiority margin was 1·14; non-inferiority would be established if the upper limit of the 95% CI for the hazard ratio (HR) of gefitinib versus icotinib was less than this margin. This study is registered with ClinicalTrials.gov, number NCT01040780, and the Chinese Clinical Trial Registry, number ChiCTR-TRC-09000506. FINDINGS: 400 eligible patients were enrolled between Feb 26, 2009, and Nov 13, 2009; one patient was enrolled by mistake and removed from the study, 200 were assigned to icotinib and 199 to gefitinib. 395 patients were included in the full analysis set (icotinib, n=199; gefitinib, n=196). Icotinib was non-inferior to gefitinib in terms of progression-free survival (HR 0·84, 95% CI 0·67-1·05; median progression-free survival 4·6 months [95% CI 3·5-6·3] vs 3·4 months [2·3-3·8]; p=0·13). The most common adverse events were rash (81 [41%] of 200 patients in the icotinib group vs 98 [49%] of 199 patients in the gefitinib group) and diarrhoea (43 [22%] vs 58 [29%]). Patients given icotinib had less drug-related adverse events than did those given gefitinib (121 [61%] vs 140 [70%]; p=0·046), especially drug-related diarrhoea (37 [19%] vs 55 [28%]; p=0·033). INTERPRETATION: Icotinib could be a new treatment option for pretreated patients with advanced non-small-cell lung cancer.