Prognostic value of preoperative platelet-lymphocyte and neutrophil-lymphocyte ratio in patients undergoing surgery for esophageal squamous cell cancer.

Increasing evidence has suggested that the host inflammatory status is associated with prognosis of several solid tumors. Preoperative platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR), both acquired from routine blood tests, can reflect the status of systematic inflammation. However, whether they are correlated with clinical outcomes of esophageal carcinoma is still unknown. The purpose of this study was to determine the prognostic value of preoperative PLR and NLR in patients with resected esophageal squamous cell carcinoma (ESCC). Preoperative PLR and NLR were evaluated in 317 eligible ESCC patients from September 2008 to December 2010. Receiver operating characteristic curves were applied to establish optimal cutoff points. The prognostic values of PLR and NLR were determined by both univariate and multivariate analyses. The optimal cutoff value of preoperative PLR and NLR were 103.0 and 2.1, respectively. One hundred and ninety-seven (62.1%) patients showed high level of preoperative PLR, while 148 (46.7%) patients showed high level of preoperative NLR. Both elevated PLR (P < 0.001) and NLR (P = 0.009) were correlated with poor disease-specific survival in univariate analysis. However, only preoperative PLR (P = 0.003) had a significant correlation with prognosis in multivariate analysis. In subgroup analyses, the predictive value of PLR was significant for stage I (P = 0.008) and stage II (P = 0.044) patients, but not for stage III patients (P = 0.100). Preoperative PLR is easily obtained from a routine blood test and may provide additional prognostic information for ESCC patients, especially in the early stage.

Association between positive murine double minute 2 expression and clinicopathological characteristics of esophageal squamous cell carcinoma: a meta-analysis.

The correlations of murine double minute 2 (MDM2) T309G and esophageal cancer were elucidated because the association between MDM2 expression states and clinicopathological parameters of esophageal squamous cell carcinoma (ESCC) is controversial. We conducted a meta-analysis on studies screened from PubMed, Web of Science, Embase, the Cochrane Library, and the Chinese Biomedical Literature Databases that were published before October 2014. All studies describing the association between MDM2 and ESCC were traced. Meta-analysis was performed using the STATA software (Stata Corp., College Station, TX, USA). A total of 9 studies with 707 cases and 324 controls were included. MDM2 expression was higher in ESCC than in normal esophageal epithelium (odds ratio [OR] 10.38, 95% confidence interval [CI] 6.42-16.78, P < 0.001). High MDM2 expression was associated with early primary tumor stage (T1/T2 vs. T3/T4, OR 0.59, 95% CI 0.38-0.92, P = 0.018) and increased risk of regional lymph node metastasis (N0 vs. N1, OR 1.66, 95% CI 1.03-2.67, P = 0.039). However, no relationship was observed between MDM2 expression and the risk of distant metastasis (OR = 2.09, 95% CI 1.00-4.36, P = 0.050), and MDM2 was not significantly correlated with TP53 expression (OR 1.22, 95% CI 0.53-2.77, P = 0.643). Our analysis suggests that MDM2 acts as a potent marker of early primary tumor stage but higher risk of regional lymph node metastasis in ESCC. However, because of the limited number of studies included, the result should be further clarified by well-designed prospective studies.

Gene expression analysis of pretreatment biopsies predicts the pathological response of esophageal squamous cell carcinomas to neo-chemoradiotherapy.

BACKGROUND: Neoadjuvant chemoradiotherapy (neo-CRT) followed by surgery has been shown to improve esophageal squamous cell carcinoma (ESCC) patients' survival compared with surgery alone. However, the outcomes of CRT are heterogeneous, and no clinical or pathological method can currently predict CRT response. In this study, we aim to identify mRNA markers useful for ESCC CRT-response prediction. PATIENTS AND METHODS: Gene expression analyses were carried out on pretreated cancer biopsies from 28 ESCCs who received neo-CRT and surgery. Surgical specimens were assessed for pathological response to CRT. The differentially expressed genes identified by expression profiling were validated by real-time quantitative polymerase chain reaction (qPCR), and a classifying model was built from qPCR data using Fisher's linear discriminant analysis. The predictive power of this model was further assessed in a second set of 32 ESCCs. RESULTS: The profiling of the 28 ESCCs identified 10 differentially expressed genes with more than a twofold change between patients with pathological complete response (pCR) and less than pCR (

Prophylactic thoracic duct ligation has unfavorable impact on overall survival in patients with resectable oesophageal cancer.

PURPOSE: This study aimed to determine the impact of prophylactic thoracic duct ligation on overall survival in resectable oesophageal cancer patients. METHODS: We conducted a retrospective analysis of 1804 patients with oesophageal cancers who underwent complete resection between December 1996 and December 2008. Based on the management of the thoracic duct during surgery, patients were classified into the following two groups: no prophylactic thoracic duct ligation group (NPLG, n = 815) and prophylactic thoracic duct ligation group (PLG, n = 989). Log-rank test was used to assess the survival differences between groups. Subgroup analysis and the Cox proportional hazards model were used to further determine the impact of thoracic duct ligation on overall survival. RESULTS: The occurrence rate of postoperative chylothorax was comparable between NPLG and PLG (0.9% vs. 1.0%, p = 0.739). The median survival times for patients in the NPLG and PLG were 54.4 months (95% interval confidence, CI: 46.9-61.9) and 42.9 months (95% CI: 36.1-49.7), respectively (p = 0.002). The 2-year, 3-year, 5-year, and 10-year survival rates were 75.1%, 64.1%, 46.1%, and 35.1%, respectively, in the NPLG and 65.3%, 54.7%, 43.3%, and 30.9%, respectively, in the PLG, with a statistically significant difference between the groups (p = 0.002). Multivariate Cox regression analysis and subgroup analyses also demonstrated that thoracic duct ligation during oesophagectomy unfavorably impacted the overall survival of oesophageal cancer patients. CONCLUSIONS: Prophylactic thoracic ligation reduces the overall survival, but doesn't reduce the occurrence of chylothorax of resectable oesophageal cancer patients. We suggest more data from other institutions to validate our results.

Adjuvant chemotherapy versus surgery alone for esophageal squamous cell carcinoma: a meta-analysis of randomized controlled trials and nonrandomized studies.

The effect of adjuvant chemotherapy on survival of patients with thoracic esophageal squamous cell carcinomas is still controversial, and the subgroup of patients who will most likely benefit from the adjuvant chemotherapy on long-term survival has not yet been identified clearly. Studies published from 1995 to May 2012 were searched in Medline, Embase, PubMed, Cancerlit, the Cochrane Library, CNKI and major scientific meetings. Randomized controlled trials and nonrandomized studies comparing surgery plus adjuvant chemotherapy with surgery alone in patients with resectable thoracic esophageal squamous cell carcinomas were included. Eleven studies with a total of 2047 patients were identified, consisting of the adjuvant chemotherapy arm (n = 887) and surgery-alone arm (n = 1160). There was not statistically significant benefit on 3-year overall survival for adjuvant chemotherapy (risk ratio [RR] = 0.89, 95% confidence interval [CI], 0.72 to 1.09; P = 0.25). Adjuvant chemotherapy could significantly prolong the 1-year disease-free survival (DFS) (RR = 0.68, 95%CI, 0.51 to 0.89; P = 0.006), but not 3-year DFS (RR = 0.97, 95%CI, 0.73 to 1.29; P = 0.84). Further analysis showed that patients with stage III-IV diseases could benefit from adjuvant chemotherapy on 3-year overall survival (RR = 0.43, 95%CI, 0.31 to 0.61; P = 0.00001), but not in the case of patients with stageI-IIdiseases (RR = 1.12, 95%CI, 0.65 to 1.93; P = 0.68). Additionally, patients with positive lymph node could benefit on 5-year DFS from adjuvant chemotherapy (RR = 0.79, 95%CI, 0.64 to 0.99; P = 0.04). The modality treatment with adjuvant chemotherapy for patients with squamous cell carcinoma of thoracic esophagus might be determined according to pathological stage or the status of lymph node metastasis.

Protein kinase D1 mRNA level may predict cancer-specific survival in heavy smokers with esophageal squamous cell cancers.

Protein kinase D1 (PRKD1) is a kinase that regulates various pathways, which involve in cell proliferation, apoptosis, cell adhesion and invasion. Although PRKD1 expression has been observed in many cancers, its role in esophageal squamous cell cancer (ESCC) has not been well reported. As its dysregulation in cancers is organ specific, we sought to investigate the potential role of PRKD1 in the progression of ESCC. Samples were collected from 178 patients with completely resected ESCCs at Sun Yat-sen University Cancer Center, including 47 pairs of tumorous and non-tumorous tissues. PRKD1 mRNA expression was investigated by quantitative real-time polymerase chain reaction. Receiver operating characteristic (ROC) curve analysis was used to search for a feasible cut-off point of PRKD1 mRNA levels for predicting cancer-specific survival. Kaplan-Meier and multivariate Cox regression analysis were used to assess the prognostic value of PRKD1 mRNA level in ESCC patients. In result, upregulation of PRKD1 mRNA was detected in 55.3% (26/47) of ESCC tissues compared with paired non-tumorous ones (P = 0.011). ROC analysis indicated 3.28 as a cut-off point, and thus 72 and 106 tumors with low and high PRKD1 mRNA expression were categorized. High-PRKD1 mRNA expression in tumors appeared with more frequency in heavy smokers (P = 0.002) and patients with advanced pathological T category (P = 0.034). Kaplan-Meier analysis indicated that patients with low-PRKD1 mRNA had a longer cancer-specific survival than the ones with high-PRKD1 level (P = 0.044). Multivariate analysis showed that tumorous PRKD1 mRNA expression was an independent prognostic factor (hazard ratio: 1.538, 95% confidence interval: 1.018-2.323, P = 0.041) in resected ESCC. Subgroup analysis revealed that the discernibility of PRKD1 mRNA level on ESCC outcomes was only pronounced in heavy smokers (P = 0.002), but not in non-heavy smokers (P = 0.870). PRKD1 might play a potential oncogenic role in ESCC. It might be an independent biomarker to predict prognosis in heavy smokers with ESCC.

The impact of body mass index on complication and survival in resected oesophageal cancer: a clinical-based cohort and meta-analysis.

BACKGROUND: Body mass index (BMI) has been associated with the risk of oesophageal cancer. But the influence of BMI on postoperative complication and prognosis has always been controversial. METHODS: In total, 2031 consecutive patients who underwent oesophagectomy between 1998 and 2008 were classified according to Asian-specific BMI (kg m(-2)) cutoff values. The impact of BMI on overall survival (OS) was estimated using the Kaplan-Meier method and Cox proportional hazard models. We performed a meta-analysis to examine the association of BMI with OS and postoperative complication. RESULTS: Patients with higher BMI had more postoperative complication (P=0.002), such as anastomotic leakage (P=0.016) and cardiovascular diseases (P<0.001), but less incidence of chylous leakage (P=0.010). Logistic regression analysis showed that BMI (P=0.005) was a confounding factor associated with postoperative complication. Multivariate analysis showed that overweight and obese patients had a more favourable survival than normal weight patients (HR (hazard ratio) = 0.80, 95% CI (confidence interval): 0.70-0.92, P=0.001). Subgroup analysis showed that the association with higher BMI and increased OS was observed in patients with oesophageal squamous cell carcinoma (ESCC) (P<0.001), oesophageal adenocarcinoma (EA) (P=0.034), never-smoking (P=0.035), ever-smoking (P=0.035), never alcohol consumption (P=0.005), weight loss (P=0.003) and advanced pathological stage (P<0.001). The meta-analysis further corroborated that higher BMI was associated with increased complication of anastomotic leakage (RR (risk ratio)=1.04, 95% CI: 1.02-1.06, P=0.001), wound infection (RR=1.03, 95% CI: 1.00-1.05, P=0.031) and cardiovascular diseases (RR=1.02, 95% CI: 1.00-1.05, P=0.039), but decreased incidence of chylous leakage (RR=0.98, 95% CI: 0.96-0.99, P<0.001). In addition, high BMI could significantly improved OS (HR=0.78, 95% CI: 0.71-0.85, P<0.001). CONCLUSION: Preoperative BMI was an independent prognostic factor for survival, and strongly associated with postoperative complications in oesophageal cancer.

The value of multislice spiral CT features of cavitary walls in differentiating between peripheral lung cancer cavities and single pulmonary tuberculous thick-walled cavities.

OBJECTIVES: Form discordance of cavity walls (FDCW) and form concordance of cavity walls (FCCW) in multislice spiral CT (MSCT) were investigated to determine their value in differentiating between peripheral lung cancer cavities and single pulmonary tuberculous thick-walled cavities. An assessment of the role of multiplanar reconstruction (MPR) in detecting FDCW and FCCW was also performed. METHODS: MSCT cross-sectional images of 116 consecutive cases (including 60 cases with available MPR images) with peripheral lung cancer cavities and 118 consecutive cases (including 62 cases with available MPR images) with single pulmonary tuberculous thick-walled cavities (wall thickness >3 mm) were retrospectively analysed. According to the characteristics of cavitary internal and external walls on MSCT, these cavities were divided into two types (FDCW and FCCW). FDCW was further divided into three subtypes (FDCW-I, FDCW-II and FDCW-III); FCCW was further divided into two subtypes (FCCW-I and FCCW-II). RESULTS: On the cross-sectional and MPR images, the total detection rate of FDCW-I and FDCW-III in peripheral lung cancer cavities was 76.7% (89/116) and 93.3% (56/60), respectively, whereas the total detection rate of FCCW-I and FCCW-II in single pulmonary tuberculous thick-walled cavities was 75.4% (89/118) and 91.9% (57/62), respectively. CONCLUSIONS: FDCW-I, FDCW-III, FCCW-I and FCCW-II were valuable in differentiating between peripheral lung cancer cavities and single pulmonary tuberculous thick-walled cavities. MPR could improve the detection of FDCW-I and FDCW-III in peripheral lung cancer cavities and FCCW-I and FCCW-II in single pulmonary tuberculous thick-walled cavities.

Identification of EGFR and KRAS mutations in Chinese patients with esophageal squamous cell carcinoma.

The prognosis of esophageal squamous cell carcinoma (ESCC) is poor. It is urgent to improve this situation. Epidermal growth factor receptor (EGFR)-targeted therapy possesses a promising clinical efficacy. Mutations of EGFR and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) have been identified in esophageal carcinoma, but corresponding Chinese data are limited. So we investigated the mutation status of EGFR and KRAS in Chinese patients with ESCC, and explored their correlations with clinicopathological features. Formalin-fixed paraffin-embedded surgically resected tumor samples were obtained from 50 randomly selected Chinese patients with ESCC. EGFR mutations in exons 18-21 were detected by Scorpions amplification refractory mutation system technology. KRAS mutations in codons 12, 13 were detected by direct sequencing of polymerase chain reaction products. The correlations between clinicopathological features and the mutation status of EGFR and KRAS were analyzed using the Statistical Package for the Social Sciences. In the present study, EGFR mutations were found in 7 (14%) out of 50 patients, including G719X missense mutation (n= 1), in-frame deletion (n= 2), and L858R missense mutation (n= 5). Six (12%) out of 50 patients had KRAS mutations in codon 12. Concurrent EGFR and KRAS mutations were detected in one sample. The presences of EGFR and KRAS mutations were not associated with gender, age, smoking history, cell differentiation, or cancer stage. In conclusion, the incidence of EGFR mutations in Chinese patients with ESCC was higher than that of previous reports, and the incidence of KRAS mutations was not low. EGFR and KRAS mutations were mainly located in exons 19 and 21 and codon 12, respectively. Unlike in NSCLC, concurrent EGFR and KRAS mutations existed.

Overexpression of cyclooxygenase-2 is associated with chemoradiotherapy resistance and prognosis in esophageal squamous cell carcinoma patients.

Our objective was to investigate whether cyclooxygenase-2 (COX-2) expression can predict the patient's response to chemoradiotherapy (CRT) and ensuing prognosis in esophageal squamous cell carcinoma (ESCC). The clinicopathological and follow-up data of 112 patients with ESCC who underwent CRT from January 2001 to June 2006 were analyzed retrospectively. The immunohistochemical expression level of COX-2 was examined for all biopsy specimens of primary tumors, and the correlation of COX-2 expression with the patient's response to CRT and prognosis was examined. COX-2 positive immunostaining was detected in 111 (99.1%) of the patients, including overexpression in 54 (48.2%) patients and low expression in 58 (51.8%) of the patients. The response of tumors with a low level expression of COX-2 (70.7%, 41/58) was significantly higher than that of tumors with COX-2 overexpression (42.6%, 23/54; P = 0.003). Patients with a low level of COX-2 expression had a higher downstaged rate than those with a high level of COX-2 expression (9/13 vs 2/8), but the difference was not statistically significant (P = 0.08). In the definitive CRT group (91 cases), COX-2 overexpression was significantly associated with poor 3-year overall survival (P = 0.028). Multivariate analysis showed that only metastatic stage (nonregional node metastasis) was an independent prognosis factor. The assessment of COX-2 status may provide additional information to identify ESCC patients with poor chances of response to CRT and potential candidates for more individualized treatment.

Genetic characterization of H5N1 avian influenza viruses isolated in southern China during the 2003-04 avian influenza outbreaks.

The recent H5N1 avian influenza outbreaks in Asia spread over more than 8 countries. It has caused enormous economic loss and grand challenges for the public health. During these breakouts we isolated three strains of H5N1 Avian Influenza Virus (AIV) from chickens and one from duck in different farms of Southern China. We completely sequenced these four AIVs. Molecular characterization demonstrated that these strains retain the reported H5N1 AIV sequence properties relevant to virus virulence and host adaptation. Phylogeny results demonstrated that three of these isolates (except A/Chicken/Guangdong/174/04) were closely linked to other H5N1 AIVs isolated from the recent H5N1 outbreaks in Asia. Six of 8 segments (except PA and M) of A/Chicken/Guangdong/174/04 also shares a close linkage to other H5N1 AIVs isolated from the recent H5N1 outbreaks. However, the PA gene of A/Chicken/Guangdong/174/04 and another H5N1 strain forms a distinct subgroup along with an H6N1 AIV, and the M gene of A/Chicken/Guangdong/174/04 shows a close linkage to some H5N1 AIVs from aquatic species in China. Our findings suggest that a new genotype of AIV (in addition to previous reported ones) was present during the 2003-04 Asian bird flu outbreaks and that continuing virus surveillance of AIVs be conducted to monitor the evolutionary paths of the A/Chicken/Guangdong/174/04-like AIVs.

Interaction of antileukemia agents adriamycin and daunomycin with sphinganine on the differentiation of human leukemia cell line HL-60.

A slight induction of granulocytic differentiation of HL-60 cells occurred after treatment with antileukemia chemotherapeutic agents Adriamycin (ADM) and daunomycin (DM). Addition of an inhibitor (sphinganine, SP) of protein kinase C (PKC) enhanced 2-4-fold the ADM or DM-induced differentiation. This phenomenon was accompanied by a slightly augmented antiproliferative effect. The enhancement of differentiation induction in these treatments seemed to be absolute, since the combination treatment (ADM-SP or DM-SP) showed about 2.5-3.6 times as many differentiated cells as the treatment with the anticancer drugs ADM or DM alone. Further characterization of the interaction of ADM and DM with SP on differentiation of HL-60 cells was carried out. Whereas the addition of SP in the fresh medium after the removal of ADM or DM (0.5 h treatment) enhanced the induction of differentiation, a pretreatment (24 h) of the cells with SP followed by continuous exposure to ADM or DM did not show such enhancement effect. The addition of SP at as late as 48 h after the administration of ADM or DM potentiated the induction of differentiation to the same extent as in the simultaneous combination of ADM-SP or DM-SP. Similar results were obtained in the experiments with another PKC inhibitor, staurosporine. These results indicated that inhibition of PKC activities may play an important role in the later events during the induction of differentiation elicited by ADM or DM. The use of the antileukemia drugs ADM and DM in combination with an inhibition of PKC activity results in enhancement of induction of differentiation and suggests a new strategy and a promising approach to the treatment of leukemia.

Dipyridamole enhancement of doxorubicin-induced translocation of nucleophosmin and inhibition of cell growth in HL-60 cells.

Dipyridamole (DPM) enhanced sensitivity to doxorubicin (DOX) in a human leukemia cell line that was already relatively sensitive to this agent. Using an immunofluorescence technique, we determined the localization of nucleophosmin (protein B23) in HL-60 cells after incubation with DOX in the absence and presence of DPM. Bright nucleolar fluorescence was observed in control HL-60 cells. The addition of DOX (0.1-0.25 micrograms/ml) in the culture system resulted in time- and dose-dependent induction of nucleophosmin translocation from the nucleolus to nucleoplasm and inhibition of cell growth. DPM (5 microM) alone had no effect on nucleophosmin translocation and inhibition of cell growth. However, the addition of DPM to the cells enhanced DOX-stimulated translocation of nucleophosmin. There was a good correlation between the DPM enhancement of DOX-induced nucleophosmin translocation and the increased inhibition of cell growth. The cell number decreased to a greater extent within a shorter time period under treatment with DOX in the presence of DPM. Short exposure (0.5 hr) of HL-60 cells to DOX induced dose-response nucleophosmin translocation and cell growth inhibition. Such effects of a short exposure to DOX were also enhanced by DPM (5 microM) included in the fresh medium after removal of DOX. This was in agreement with the observation that DPM could increase the cellular DOX by inhibiting the drug efflux from the cells. These results demonstrate that DPM, being able to increase and retain the intracellular levels of DOX, can markedly enhance the cytotoxicity of DOX, and suggest possible clinical application. "Nucleophosmin translocation", as observed by immunofluorescence, could be useful in determining the efficacy of combinations of DOX and DPM in cancer chemotherapy.