Feng Hua Wang

Elevated neutrophil to lymphocyte ratio predicts survival in advanced pancreatic cancer

Background: Elevated neutrophil to lymphocyte ratio (NLR) is linked with worse survival in many malignancies, whereas its association with pancreatic cancer (PC) remains unclear. Methods: We retrospectively reviewed 95 patients with locally advanced or metastatic PC receiving gemcitabine-based chemotherapy. The prognostic value of NLR was evaluated. Results: Elevated pretreatment NLR (>5) was observed in 16 out of 89 eligible patients, which was identified as an independent prognostic factor for overall survival (OS). The median OS for patients with elevated and normal NLR were 2.4 months and 7.7 months, respectively (p <0.001). Conclusions: Elevated NLR is a predictor of shorter survival in patients with advanced PC.

Plasma Epstein-Barr virus DNA level strongly predicts survival in metastatic/recurrent nasopharyngeal carcinoma treated with palliative chemotherapy

Plasma Epstein‐Barr virus (EBV) DNA is widely used in screening, monitoring, and prediction of relapse in nonmetastatic nasopharyngeal carcinoma (NPC). However, data regarding utility of plasma EBV DNA in metastatic NPC are rare. The current study was to test the prognostic implication of plasma EBV DNA level in metastatic/recurrent NPC patients treated with palliative chemotherapy.

Overexpression of paxillin induced by miR-137 suppression promotes tumor progression and metastasis in colorectal cancer

The deregulation of paxillin (PXN) has been involved in the progression and metastasis of different malignancies including colorectal cancer (CRC). miR-137 is frequently suppressed in CRC. PXN is predicted to be a direct target of miR-137 in CRC cells. On this basis, we hypothesized that overexpression of PXN induced by suppression of miR-137 may promote tumor progression and metastasis and predicts poor prognosis. We detected the expression of PXN and miR-137 in clinical tumor tissues by immunohistochemical analysis and real-time PCR, positive PXN staining was observed in 198 of the 247 (80.1%) cases, whereas no or weak PXN staining was observed in the adjacent non-cancerous area. Higher level of PXN messenger RNA (mRNA) and lower level of miR-137 was observed in cancer tissues than adjacent non-cancerous tissues. High expression of PXN and low expression of miR-137 was associated with aggressive tumor phenotype and adverse prognosis. Moreover, the expression of PXN was negatively correlated with miR-137 expression. A dual-luciferase reporter gene assay validated that PXN was a direct target of miR-137. The use of miR-137 mimics or inhibitor could decrease or increase PXN mRNA and protein levels in CRC cell lines. Knockdown of PXN or ectopic expression of miR-137 could markedly inhibit cell proliferation, migration and invasion in vitro and repress tumor growth and metastasis in vivo. Taken together, these results demonstrated that overexpression of PXN induced by suppression of miR-137 promotes tumor progression and metastasis and could serve as an independent prognostic indicator in CRC patients.

ABO blood group, hepatitis B viral infection and risk of pancreatic cancer

Little is known about the role of association between ABO blood type and risk of pancreatic cancer develops through effects on hepatitis B viral (HBV) infection. Our study aimed to determine whether joint ABO blood type and HBV infection could increase the risk for pancreatic cancer. A total of 645 patients with pancreatic adenocarcinoma and 711 age‐ and sex‐matched individuals who had nonmalignant diseases treated at the Sun Yat‐sen University Cancer Center in China were retrospectively analyzed. Blood samples were tested for ABO blood type and hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti‐HBs), hepatitis B e antigen (HBeAg), hepatitis B e antibody (anti‐HBe) and hepatitis B core antibody (anti‐HBc). Multivariable unconditional logistic regression analysis was used to estimate adjusted odds ratios [AORs] and 95% confidence interval [CI]. Multivariable analysis with adjustment for risk factors showed that A blood type, HBsAg‐positive/anti‐HBc‐positive, anti‐HBs‐positive/anti‐HBc‐positive were significantly associated with pancreatic cancer. The estimated AORs (95% CI) were as follows: A blood type, 1.425 (1.071–1.894), HBsAg‐positive/anti‐HBc‐positive, 1.610 (1.125–2.304), anti‐HBs‐positive/anti‐HBc‐positive, 1.526 (1.159–2.011). The effect of A blood type significantly modified the risk of pancreatic cancer among subjects with anti‐HBc‐positive (AORs = 1.882, 95% CI, 1.284–2.760). In our study, we reported an association between A blood type, infection with HBV and pancreatic cancer risk. Moreover, we found a synergism between A blood type and HBV infection in the development of pancreatic cancer.

Elevated neutrophil to lymphocyte ratio predicts poor prognosis in nasopharyngeal carcinoma

Elevated neutrophil to lymphocyte ratio (NLR) has been reported to be associated with worse survival in many malignancies, whereas its role in nasopharyngeal carcinoma (NPC) remains unclear. We retrospectively reviewed 363 consecutively, newly diagnosed, non-disseminated, and biopsy-proven NPC patients. Disease-specific survival (DSS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRFS) rates were compared according to NLR level. Multivariate analysis was performed to assess the prognostic value of NLR. The 5-year DSS, DMFS, and LRFS rates for patients with elevated or non-elevated NLR (> or ≤3.73) were 59.6% vs. 76.6% (p = 0.03), 69.7% vs. 86.6% (p = 0.002), and 78.5% vs. 87.3% (p = 0.105), respectively. For patients with locoregionally advanced disease, NLR was not only an independent prognostic factor, but also a predictor of response to chemoradiotherapy. The 5-year DSS, DMFS, and LRFS rates for patients with elevated or non-elevated NLR were 47.2% vs. 73.7% (p < 0.001), 59.2% vs. 85.1% (p < 0.001), and 72.3% vs. 84.6% (p = 0.041), respectively. Compared with radiation alone, chemoradiotherapy significantly improved DSS and LRFS for patients with non-elevated NLR, but not for those with elevated NLR. Pre-treatment NLR is a strong prognostic factor for NPC patients. For patients with locoregionally advanced disease, NLR might also be a useful indicator for selection of treatment strategies.

Identification of MicroRNA-214 as a negative regulator of colorectal cancer liver metastasis by way of regulation of fibroblast growth factor receptor 1 expression

The purpose of this study was to identify microRNAs (miRNAs) involved in the pathology of colorectal cancer (CRC) liver metastasis and investigate their underlying mechanisms. A total of 39 miRNAs were identified to be differentially expressed between 16 primary CRC tissues with liver metastases and 16 CRC tissues without liver metastases from 32 patients by Affymetric miRNA microarrays. A panel of eight miRNAs were confirmed to be significantly and differentially expressed between CRC tissues with and without liver metastases through quantitative reverse‐transcription polymerase chain reaction (RT‐PCR) analysis in the 32 patients. In a validated cohort of 99 CRC patients (44 with and 55 without liver metastases), only miR‐214 was validated to be significantly down‐regulated in CRC with liver metastases, which was associated with an unfavorable prognosis. Ectopic expression of miR‐214 suppressed proliferation, migration, and invasion in vitro, tumor growth and liver metastasis in an in vivo xenograft mouse model, whereas miR‐214 knockdown promoted proliferation, migration, and invasion in CRC cell lines. Further studies indicated that fibroblast growth factor receptor 1 (FGFR1) was a potential target of miR‐214. Restoring miR‐214 expression in CRC cells decreased endogenous FGFR1 messenger RNA (mRNA) and protein levels. FGFR1 knockdown mimicked the tumor suppressive effect of miR‐214 on CRC cells, while reintroduction of FGFR1 abolished the tumor suppressive effect of miR‐214 on CRC cells. Moreover, miR‐214 expression levels were inversely correlated with FGFR1 in CRC patients. Conclusion: Down‐regulation of miR‐214 expression was correlated with increased FGFR1 expression levels, which may contribute to increased CRC liver metastasis. miR‐214 may serve as a potential marker to predict survival, and the miR‐214‐FGFR1 axis may be a therapeutic target in CRC patients. (Hepatology 2014;60:598–609)

Impact of pretreatment hematologic profile on survival of colorectal cancer patients

Pretreatment hematologic abnormalities have been reported to have prognostic value in patients with solid tumors. The aim of our study was to determine the prevalence of abnormalities in the hematologic profile in patients with colorectal cancer before treatment and to evaluate if such a profile could be used for prognostic evaluations. We identified all patients in Cancer Center of Sun Yat-Sen University who were diagnosed as colorectal cancers between May 2005 and August 2009. All subjects were investigated regarding levels of white blood cells, platelets, and hemoglobin concentration. Survival was compared by using the log-rank test on the Kaplan–Meier life table. Multivariate Cox regression analysis was used to evaluate if the pretreatment hematologic profile was independent prognostic factor. We identified 363 patients with colorectal cancer and 315 patients with benign diseases for the final analysis. The percentages of leukocytosis, anemia, and thrombocytosis were significantly higher in colorectal cancer patients than in patients with benign diseases. Univariate analysis showed that advanced tumor stages, leukocytosis, anemia, thrombocytosis, and low histological grade were all significantly associated with shorter survival. The multivariate Cox analysis revealed that low histological grade, tumor stage, pretreatment anemia, and thrombocytosis remained independent prognostic variables for survival. The cumulative effect of anemia and thrombocytosis yielded shorter survival. Anemia and thrombocytosis can be considered as useful prognostic markers in patients with colorectal cancer.

Short term results of neoadjuvant chemoradiotherapy with fluoropyrimidine alone or in combination with oxaliplatin in locally advanced rectal cancer: A meta analysis

BACKGROUND Oxaliplatin (OX), in combination with fluoropyrimidine (5-fluorouracil or Capecitabine, FU)-based regimens and radiation, has been expected to both enhance primary tumour shrinkage and reduce micrometastases at distant sites in the neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). However, results in terms of pathologic complete response (pCR) and toxicities were inconsistent. The aim of this meta analysis was to evaluate the short term efficacy and toxicities of adding OX to FU in CRT for LARC. METHODS We searched PubMed, EMBASE, ISI databases, Chinese Biomedical Literature Database and the Cochrane library before December, 2011. Additionally, abstracts presented at American Society of Clinical Oncology conferences held between January, 2000, and July, 2011, were searched to identify relevant clinical trials. Only randomised studies with an analysis by an intention-to-treat principle were included, and searches were restricted to those databases citing articles in English. Summary incidence rates and 95% confidence intervals (CIs) were calculated using a fixed-effects or random-effects model, depending on the heterogeneity of the included studies. Four randomised clinical trials comparing OX/FU versus FU alone regimens in CRT for LARC met our search criteria and were assessed. A total of 3863 patients (FU, n=1937; OX/FU, n=1926) were included in the analysis. FINDINGS The addition of OX to FU significantly improved pathologic complete response (pCR), and reduced peri-operative metastases (including intra-abdominal metastases) with an odd ratios (OR) for OX/FU compared with FU of 1.20 (95% CI, 1.01-1.42; P=0.04) and 0.51 (95% CI, 0.34-0.77; P=0.001), respectively. The grade 3/4 toxicity rate was significantly higher for OX/FU versus FU alone with an OR of 2.29 (95% CI, 1.31-4.00; P=0.004). There was no difference in the rates of positive circumferential resection margin, permanent stoma, surgical complication and death within 60 d between the OX/FU and FU alone patients. The OR for the proportion of patients completing full-dose radiotherapy and completing full-dose chemotherapy were 0.32 (95% CI, 0.15-0.69; P=0.004), and 0.71 (95% CI, 0.35-1.42; P=0.33), respectively. INTERPRETATION Adding weekly OX to FU in neoadjuvant CRT of LARC appeared to modestly increase the pCR rate and reduced the rate of intra-abdominal or peri-operative metastases in this meta analysis. Although OX/FU significantly increased grade 3/4 toxicity, it did not result in more surgical complications or postoperative deaths within 60 d. The concept of combination of OX and FU in the pre-operative setting for LARC still seems promising, either with a modified schedule, or as induction therapy prior to CRT or after CRT, prior to surgery.

Expressions of hypoxia-inducible factor-1α and hexokinase-II in gastric adenocarcinoma: the impact on prognosis and correlation to clinicopathologic features

The impact of hypoxia-inducible factor (HIF)-1α and hexokinase-II (HK-II) expression on prognosis of gastric adenocarcinoma patients has not been clearly established. We identified all patients in Cancer Center of Sun Yat-Sen University who were diagnosed as gastric adenocarcinoma and underwent radical gastrectomy between January 1999 and December 2001. We used immunohistochemistry to determine the expressions of HIF-1α protein and HK-II in the surgical sections. We identified 188 patients with gastric adenocarcinoma for the final analysis. The positive rate of HIF-1α and HK-II were 110/188 (54.6%) and 40/188 (21.3%), respectively. Both HIF-1α and HK-II were all positively correlated with tumor size, lower differentiation, and tumor stage. Univariate analysis showed that advanced tumor stages (P < 0.001), tumor size (P = 0.003), HIF-1α expression (P < 0.001), and HK-II expression (P < 0.001) were all significantly associated with shorter survival. The multivariate Cox analysis revealed that tumor stage (P < 0.001), HIF-1α expression (P < 0.001), and HK-II expression (P = 0.002) remained independent prognostic variables for survival. In addition, there was a positive correlation of HIF-1α protein expression and HK-II (P = 0.022). Both HIF-1α and HK-II were overexpressed in gastric adenocarcinoma. The multivariate Cox analysis revealed that both of them were independent factors on survival of gastric adenocarcinoma patients.

MET amplification is not rare and predicts unfavorable clinical outcomes in patients with recurrent/metastatic gastric cancer after chemotherapy

Several large studies have reported an extremely low incidence of MET gene amplification (GA) in patients with radically resected gastric cancer. This study was conducted to evaluate the prevalence and prognostic role of MET in patients with recurrent/metastatic gastric cancer who received chemotherapy.