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Abstract Background Increase of Serum amyloid A (SAA) level has been observed in patients with a variety of cancers. The objective of this study was to determined whether SAA level could be used as a prognostic parameter in patients with esophageal squamous cell carcinoma (ESCC). Methods SAA levels were measured by rate nephelometry immunoassay in 167 healthy controls and 167 ESCC patients prior to surgical resection. Statistical associations between clinicopathological observations and SAA levels were determined using the Mann–Whitney U test. The clinical value of SAA level as a prognostic parameter was evaluated using the Cox’s proportional hazards model. Results SAA levels were significantly higher in patients with ESCC compared to levels in healthy controls (13.88 ± 15.19 mg/L vs. 2.26 ± 1.66 mg/L, P P P = 0.015), T classification (P P P P P Conclusions An elevated level of preoperative SAA was found to associate with tumor progression and poor survival in patients with ESCC.

Abstract Background Overexpression of Bmi-1 has been observed in a variety of cancers, and it has been suggested to be an independent prognostic marker for the patients. The objective of this study was to determine the level of Bmi-1 expression or its autoantibodies in human esophageal squamous cell carcinoma (ESCC) and to correlate it with clinicopathologic data. Methods We first examined Bmi-1 expression in ESCC cell lines and tumor samples by RT-PCR and Western blot analysis. We then analyzed Bmi-1 protein expression in 171 clinicopathologically characterized ESCC cases by immunohistochemistry. In addition, we detected its autoantibodies in sera of patients with ESCC by ELISA. Results We found that Bmi-1 expression was higher in the immortalized cells, cancer cell lines and most cancer tissue than in non-tumorous control tissue at both mRNA and protein level. In addition, Bmi-1 expression was observed in 64.3% (110 of 171) archive ESCC specimen by immunohistochemistry analysis, and the location of Bmi-1 in ESCC was in the nuclei instead of cytoplasm of tumor cells. There was a significant difference of Bmi-1 expression in patients categorized according to stage (P = 0.003) and pN classification (P = 0.047). Multivariate analysis suggested that Bmi-1 expression was an independent prognostic marker for ESCC patients. A prognostic significance of Bmi-1 was also found in the subgroup of T3~T4 and N1 tumor classification. Bmi-1 autoantibodies were detected in sera of 39.0% (62 of 159) ESCC patients. The correlations between anti-Bmi-1 antibodies and tumor stage (P = 0.040), or lymph node status (P < 0.001) were significant. Conclusions Our results suggest that Bmi-1 protein is a valuable marker of ESCC progression. The presence of Bmi-1 autoantibodies in sera from patients with ESCC may have clinical utility in esophageal cancer diagnosis.

Abstract Background The oncogene CDC25B phosphatase plays an important role in cancer cell growth. We have recently reported that patients with esophageal squamous cell carcinoma (ESCC) have significantly higher serum levels of CDC25B autoantibodies (CDC25B-Abs) than both healthy individuals and patients with other types of cancer; however, the potential diagnostic or prognostic significance of CDC25B-Abs is not clear. The aim of this study is to evaluate the clinical significance of serum CDC25B-Abs in patients with ESCC. Methods CDC25B autoantibodies were measured in sera from both 134 patients with primary ESCC and 134 healthy controls using a reverse capture enzyme-linked immunosorbent assay (ELISA) in which anti-CDC25B antibodies bound CDC25B antigen purified from Eca-109 ESCC tumor cells. The clinicopathologic significance of CDC25B serum autoantibodies was compared to that of the tumor markers carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC-Ag) and cytokeratin 19 fragment antigen 21-1(CYFRA21-1). Results Higher levels of CDC25B autoantibodies were present in sera from patients with ESCC (A450 = 0.917, SD = 0.473) than in sera from healthy control subjects (A450 = 0.378, SD = 0.262, P < 0.001). The area under the receiver operating characteristic (ROC) curve for CDC25B-Abs was 0.870 (95% CI: 0.835-0.920). The sensitivity and specificity of CDC25B-Abs for detection of ESCC were 56.7% and 91.0%, respectively, when CDC25-Abs-positive samples were defined as those with an A450 greater than the cut-off value of 0.725. Relatively few patients tested positive for the tumor markers CEA, SCC-Ag and CYFRA21-1 (13.4%, 17.2%, and 32.1%, respectively). A significantly higher number of patients with ESCC tested positive for a combination of CEA, SCC, CYFRA21-1 and CDC25B-Abs (64.2%) than for a combination of CEA, SCC-Ag and CYFRA21-1 (41.0%, P < 0.001). The concentration of CDC25B autoantibodies in serum was significantly correlated with tumor stage (P < 0.001). Although examination of the total patient pool showed no obvious relationship between CDC25B autoantibodies and overall survival, in the subgroup of patients with stage III-IV tumors, the cumulative five-year survival rate of CDC25B-seropositive patients was 6.7%, while that of CDC25B-seronegative patients was 43.4% (P = 0.001, log-rank). In the N1 subgroup, the cumulative five-year survival rate of CDC25B-seropositive patients was 13.6%, while that of CDC25B-seronegative patients was 54.5% (P = 0.040, log-rank). Conclusions Detection of serum CDC25B-Abs is superior to detection of the tumor markers CEA, SCC-Ag and CYFRA21-1 for diagnosis of ESCC, and CDC25B-Abs are a potential prognostic serological marker for advanced ESCC.

Abstract Background Many kinetochore proteins have been shown to be associated with human cancers. The aim of the present study was to clarify the expression of Centromere protein H (CENP-H), one of the fundamental components of the human active kinetochore, in esophageal carcinoma and its correlation with clinicopathological features. Methods We examined the expression of CENP-H in immortalized esophageal epithelial cells as well as in esophageal carcinoma cells, and in 12 cases of esophageal carcinoma tissues and the paired normal esophageal tissues by RT-PCR and Western blot analysis. In addition, we analyzed CENP-H protein expression in 177 clinicopathologically characterized esophageal carcinoma cases by immunohistochemistry. Statistical analyses were applied to test for prognostic and diagnostic associations. Results The level of CENP-H mRNA and protein were higher in the immortalized cells, cancer cell lines and most cancer tissues than in normal control tissues. Immunohistochemistry showed that CENP-H was expressed in 127 of 171 ESCC cases (74.3%) and in 3 of 6 esophageal adenocarcinoma cases (50%). Statistical analysis of ESCC cases showed that there was a significant difference of CENP-H expression in patients categorized according to gender (P = 0.013), stage (P = 0.023) and T classification (P = 0.019). Patients with lower CENP-H expression had longer overall survival time than those with higher CENP-H expression. Multivariate analysis suggested that CENP-H expression was an independent prognostic marker for esophageal carcinoma patients. A prognostic value of CENP-H was also found in the subgroup of T3~T4 and N0 tumor classification. Conclusion Our results suggest that CENP-H protein is a valuable marker of esophageal carcinoma progression. CENP-H might be used as a valuable prognostic marker for esophageal carcinoma patients.

Cisplatin resistance frequently occurs in esophageal squamous cell carcinoma (ESCC). The underlying mechanism for cisplatin resistance in ESCC remains largely obscure. Here we report that entinostat reversed cisplatin resistance in ESCC both in vitro and in vivo by induction of apoptosis and inhibition of cell proliferation, accompanied by a decrease of multidrug resistance gene 1 (MDR1), P-Src, Mcl-1, Cyclin D1 and an increase of cleaved PARP. MDR1 expression was associated with worsen survival of ESCC patients with cisplatin-based chemotherapy. Dasatinib potentiated entinostat to overcome cisplatin resistance. By inhibiting Src, dasatinib reduced the expression of MDR1 and Mcl-1. Furthermore, Obatoclax, an inhibitor of Mcl-1, obviously decreased the expression of MDR1, suggesting that entinostat might surmount cisplatin resistance in ESCC via a Src-Mcl-1-MDR1 pathway. Interestingly, cisplatin also enhanced the effect of entinostat both in vitro and in vivo. Our data disclose a molecular basis that entinostat reverses cisplatin resistance, and provide a promising strategy with combinatorial drugs to treat cisplatin resistant ESCC patients. [ABSTRACT FROM AUTHOR]

Objective: The emerging reverse sequence on syphilis screening program generates special discordant results, characterized with the appearance of both positive treponemal test and negative nontreponemal test at the same time. The aim of this study was to analyze the characteristics of the discordant results among low syphilis prevalence population in China, to provide evidence for improving the process of reverse sequence syphilis screening program., Methods: Laboratory data was retrospectively analyzed, under reverse sequence screening algorithm selecting ELISA as the initial screening test for syphilis. All the screening reactive samples were tested by TPPA for confirmation and by quantitative TRUST for the reactivity of syphilis., Results: 666 out of a total of 21 049 serum samples were reactive under the screening program. Among the 666 reactive samples, 169 were reactive to TRUST. One in the 169 samples was confirmed negative on TPPA, and the faulse positive rate on ELISA was 0.6% (1/169). In those 666 reactive samples, 497 were nonreactive to TRUST. 74 in the 497 samples were confirmed negative to TPPA, with faulse positive rate of ELISA as 14.9% (74/497). In the group of 591 TPPA confirmed positive samples, the TRUST negative rate was found 71.6% (423/591), significantly higher than the TRUST positive rate(chi-square test, χ(2) = 110.025, P = 0.000)., Conclusion: Among the results from reverse sequence syphilis screening program, majority of the samples which showed positive treponemal antibody, would have negative nontreponemal antibody. We therefore recommended a more reasonable reverse sequence syphilis algorithm to be used. Faulse positivity could be eliminated if TPPA was performed on all screening reactive samples by ELISA a first and then followed by quantitative TRUST on samples that were TPPA confirmed as positive.

The management of postoperative leaks into the mediastinum after esophagectomy remains a challenge. We describe our clinical management of this complication through endoscopic transluminal drainage. Between 2008 and 2011, 4 patients with esophageal squamous cell carcinoma (ESCC) who underwent McKeown-type esophagectomy with two-field lymphadenectomy experienced complicated anastomotic fistulae in the presence of superior mediastinal sepsis. All 4 patients underwent endoscopic transluminal drainage, and all survived. The mean healing period was 50 days (range, 31 to 58 days), the mean stay in the intensive care unit was 7.3 days (range, 1 to 18 days), and the mean hospital stay was 64.5 days (range, 49 to 70 days). Endoscopically guided transluminal drainage should be considered for ESCC patients with superior mediastinal fistulae after esophagectomy.

Aim: To evaluate whether preoperative mean corpuscular volume (MCV) is a prognostic indicator in patients with resectable esophageal squamous cell carcinoma (ESCC)., Methods: A total of 298 consecutive, prospectively enrolled patients with histologically diagnosed ESCC who underwent surgery with curative intent from 2001 to 2011 were retrospectively evaluated. Patients were excluded if they had previous malignant disease, distant metastasis at the time of primary treatment, a history of neoadjuvant treatment, had undergone non-radical resection, or had died of a non-tumor-associated cause. Survival status was verified in September 2011. Pathological staging was performed based on the 2010 American Joint Committee on Cancer criteria. Preoperative MCV was obtained from blood counts performed routinely within 7 d prior to surgery. Receiver operating characteristic (ROC) curve analysis was used to determine a cutoff for preoperative MCV., Results: The 298 patients consisted of 230 males and 68 females, with a median follow-up of 30.1 mo. ROC analysis showed an optimal cutoff for preoperative MCV of 95.6 fl. Fifty-nine patients (19.8%) had high (> 95.6 fl) and 239 (80.2%) had low (≤ 95.6 fl) preoperative MCV. Preoperative MCV was significantly associated with gender (P = 0.003), body mass index (P = 0.017), and preoperative red blood cell count (P < 0.001). The predicted 1-, 3- and 5-year overall survival (OS) rates were 72%, 60% and 52%, respectively. Median OS was significantly longer in patients with low than with high preoperative MCV (27.5 mo vs 19.4 mo, P < 0.001). Multivariate analysis showed that advanced pT (P = 0.018) and pN (P < 0.001) stages, upper thoracic location (P = 0.010), lower preoperative albumin concentration (P = 0.002), and high preoperative MCV (P = 0.001) were negative prognostic factors in patients with ESCC. Preoperative MCV also stratified OS in patients with T3, N1-N3, G2-G3 and stage III tumors., Conclusion: Preoperative MCV is a prognostic factor in patients with ESCC.

Aim: To compare postoperative complications and prognosis of esophageal squamous cell carcinoma patients treated with different routes of reconstruction., Methods: After obtaining approval from the Medical Ethics Committee of the Sun Yat-Sen University Cancer Center, we retrospectively reviewed data from 306 consecutive patients with histologically diagnosed esophageal squamous cell carcinoma who were treated between 2001 and 2011. All patients underwent radical McKeown-type esophagectomy with at least two-field lymphadenectomy. Regular follow-up was performed in our outpatient department. Postoperative complications and long-term survival were analyzed by treatment modality, baseline patient characteristics, and operative procedure. Data from patients treated via the retrosternal and posterior mediastinal routes were compared., Results: The posterior mediastinal and retrosternal reconstruction routes were employed in 120 and 186 patients, respectively. Pulmonary complications were the most common complications experienced during the postoperative period (46.1% of all patients; 141/306). Compared to the retrosternal route, the posterior mediastinal reconstruction route was associated with a lower incidence of anastomotic stricture (15.8% vs 27.4%, P = 0.018) and less surgical bleeding (242.8 ± 114.2 mL vs 308.2 ± 168.4 mL, P < 0.001). The median survival time was 26.8 mo (range: 1.6-116.1 mo). Upon uni/multivariate analysis, a lower preoperative albumin level (P = 0.009) and a more advanced pathological stage (pT; P = 0.006; pN; P < 0.001) were identified as independent factors predicting poor prognosis. The reconstruction route did not influence prognosis (P = 0.477)., Conclusion: The posterior mediastinal route of reconstruction reduces incidence of postoperative complications but does not affect survival. This route is recommended for resectable esophageal squamous cell carcinoma.

Objective: To evaluate the learning process of video-assisted minimally invasive esophagectomy (MIE)., Methods: One hundred consecutive patients with thoracic esophageal carcinoma were treated by a same team of surgeons, and were divided into 3 groups in chronological order. The former two groups both consisted of 25 patients with thoracoscopy plus laparotomy. The remaining 50 patients were enrolled in the third group with thoracoscopy plus laparoscopy. Clinicopathological data including operative time, blood loss, protection of normal structures, complications, length of ICU stay, postoperative stay, and lymph nodes harvest, were collected and compared between groups., Results: Procedures were accomplished successfully in 96 patients. Only 4 cases were converted to open thoracotomy and none to laparotomy. The median operative time was 310 min and blood loss was 200 ml. The median number of lymph node harvest was 22. The overall complication rate was 50%. Comparison of first two groups revealed that significant differences existed in the preservation rate of arch of azygos vein (P=0.010), bronchial vessels (P=0.038), and exposure rate of thoracic part of left recurrent laryngeal nerve( P=0.048). Comparison of the former and latter 50 patients revealed that significant differences existed in thoracic operative time (P<0.001), blood loss (P=0.025), preservation rate of arch of azygos vein (P=0.001) and bronchial vessels (P<0.001), the number of lymph node harvest in thoracoscopy (P=0.022) and in left recurrent laryngeal nerve chain (P<0.001), and exposure rate of initiate part of left recurrent laryngeal nerve (P=0.002)., Conclusion: The learning curve of MIE is long and beginners should proceed step by step.

The indoleamine 2,3-dioxygenase-(IDO-) mediated microenvironment plays an important role in tumor immune escape. However, the inhibitory effects of IDO on the CD8(+) tumour-infiltrating lymphocytes (CD8(+) TILs) in esophageal squamous cell carcinoma (ESCC) have not been clarified yet. Here, we found that the level of IDO expression in ESCC tumor specimens correlated with a reduction in the number of CD8(+) TILs. Patients with high IDO expression and a low number of CD8(+) TILs had significantly impaired overall survival time. IDO expression and functional enzyme activity in ESCC cell lines could be induced by IFNγ. When exposed to the milieu generated by IDO-expressing Eca109 cells, the CD8(+) TILs were suppressed in proliferation, and their cytolytic functions against target tumor cells were lost. These results suggested that impairing CD8(+) TIL functions by IDO expressed in ESCC possibly contributed to the finding that patients with higher IDO expression have more aggressive disease progression and shorter overall survival time.

Objective: Surgical resection remains the cornerstone of treatment for esophageal carcinoma. Mediastinal lymphadenectomy including subcarinal nodes has always been considered to be a reasonable extent, because of close anatomical relationship between subcarinal nodes and tracheobronchial tree. Metastatic involvement of subcarinal nodes alone is rare in esophageal carcinoma. In view of special anatomical features of subcarinal lymph nodes, it is worth exploring and discussing whether or not subcarinal lymph nodes dissection shall be routinely performed for thoracic esophageal carcinoma., Methods: The data from a cohort of 676 patients with thoracic esophagus carcinoma who underwent esophagectomy with lymphadenectomy were analyzed retrospectively with respect to the impact of subcarinal lymph nodes dissection or non-dissection on the incidence of postoperative complications and patient survival., Results: The rate of subcarinal lymph nodes metastasis was 10.4%. The metastasis rates in upper, middle and lower esophageal carcinoma were 0%, 13.2% and 6.8% respectively (P = 0.001); for Tis, T1, T2, T3 and T4, they were 0%, 0%, 6.5%, 13.3% and 28.6% respectively (P = 0.008). The overall incidence of postoperative complications with and without subcarinal lymph nodes dissection was 36.8% versus 26.6% (P = 0.013). And the incidence of pulmonary complications were 22.2% versus 14.1% (P = 0.020). Survival analysis showed that: the 5-year survival rates were 50.9% versus 62.8% in the groups A and B of N0 patients (P = 0.083); 14.7% versus 29.3% in N1 patients (P = 0.112). In the group with metastasis of subcarinal lymph nodes, the 5-year survival rate was 22.6% versus 31.7% in those without metastasis (P = 0.142)., Conclusion: It may be unnecessary to dissect the subcarinal lymph nodes routinely for upper thoracic esophageal carcinoma. Elective subcarinal lymph nodes dissection can be planned for middle, lower, T3 or T4 thoracic esophageal carcinoma, or highly suspected subcarinal metastasis based on radiological imaging.

Objectives: To analyze associated factors and the prognosis of patients with residual cancer after esophagectomy for squamous cell carcinoma of the esophagus, and to assess outcomes after salvage treatment., Methods: Clinical and pathological data of 1074 patients with squamous cell carcinoma of the esophagus who underwent esophagectomy in the Cancer Center of Sun Yat-sen University from 1997 to 2003 were analyzed retrospectively. The relationship between the associated factors (differentiation, location, length of the lesion, surgical route, anastomosis site, T stage, N stage) and the incidence of residual cancer was analyzed, using the chi-squared test and Logistic regression analysis methods. The value and the modality of the salvage treatment were investigated., Results: Forty-four patients had residual cancer (4.3%). Cancers in the upper esophagus were associated with the highest incidence of residual cancer on esophageal stump (6.5%), while the lower esophagus had the highest incidence of residual cancer on gastric stump (0.78%). The Incidence correlated with T and N stage. Logistic regression analysis showed that T and N stage were the risk factors of residual cancer. Three-year survival rate was 22.7% in patients with residual cancer. The mean survival time was 25.2+/-3.3 months. Three-year survival rates of patients with and without salvage treatment were 53.2% and 7.8%, respectively (P=0.027). Three-year survival rate of patients with salvage radiotherapy was 56.0%., Conclusions: Advanced T and N stage are the risk factors of residual cancer after esophagectomy in the patients with squamous cell carcinoma of the esophagus. Salvage treatment can improve the survival of the patients.