MIIP expression predicts outcomes of surgically resected esophageal squamous cell carcinomas.

The migration and invasion inhibitory protein (MIIP) was shown to function as a tumor suppressor gene in gliomas by inhibiting tumor cell growth, migration, and invasion. However, its role and clinical significance in esophageal squamous cell carcinoma (ESCC) have not been elucidated. We investigated the correlation of MIIP expression and clinical outcome in a group of surgically resected ESCCs. Tissue microarrays constructed of 253 surgically resected ESCC primary tumors and paired paracancerous normal esophageal epithelia were used for MIIP evaluation by immunohistochemistry. The clinical and prognostic significance of MIIP expression was analyzed statistically. The expression of MIIP expression in cancer tissues was increased significantly in comparison with the paired paracancerous normal epithelia (P < 0.001). And, MIIP expression was associated with ESCC cells' differentiation (P < 0.001). By Kaplan-Meier analysis, patients with low MIIP expression exhibited significantly improved overall survival (OS, P = 0.039) and a tendency of improved disease-free survival (DFS, P = 0.086) than those with high MIIP expression. In addition, MIIP expression could distinguish OS or DFS of patients with tumors in stage T3-4 (P = 0.020, 0.028), N0 (P = 0.008, 0.032), and stage II (P = 0.004, 0.019), as well as at lower thoracic esophagus (P = 0.024, 0.090). Multivariate analysis showed that MIIP expression was an independent prognostic factor in ESCC OS and DFS. In conclusion, MIIP expressed higher in ESCCs than in paracancerous normal esophageal epithelia and was a positive, independent prognostic factor in resected ESCCs.

Maximum standardized uptake value on PET/CT in preoperative assessment of lymph node metastasis from thoracic esophageal squamous cell carcinoma.

The presence of lymph node metastasis is an important prognostic factor for patients with esophageal cancer. Accurate assessment of lymph nodes in thoracic esophageal carcinoma is essential for selecting appropriate treatment and forecasting disease progression. Positron emission tomography combined with computed tomography (PET/CT) is becoming an important tool in the workup of esophageal carcinoma. Here, we evaluated the effectiveness of the maximum standardized uptake value (SUVmax) in assessing lymph node metastasis in esophageal squamous cell carcinoma (ESCC) prior to surgery. Fifty-nine surgical patients with pathologically confirmed thoracic ESCC were retrospectively studied. These patients underwent radical esophagectomy with pathologic evaluation of lymph nodes. They all had (18)F-FDG PET/CT scans in their preoperative staging procedures. None had a prior history of cancer. The pathologic status and PET/CT SUVmax of lymph nodes were collected to calculate the receiver operating characteristic (ROC) curve and to determine the best cutoff value of the PET/CT SUVmax to distinguish benign from malignant lymph nodes. Lymph node data from 27 others were used for the validation. A total of 323 lymph nodes including 39 metastatic lymph nodes were evaluated in the training cohort, and 117 lymph nodes including 32 metastatic lymph nodes were evaluated in the validation cohort. The cutoff point of the SUVmax for lymph nodes was 4.1, as calculated by ROC curve (sensitivity, 80%; specificity, 92%; accuracy, 90%). When this cutoff value was applied to the validation cohort, a sensitivity, a specificity, and an accuracy of 81%, 88%, and 86%, respectively, were obtained. These results suggest that the SUVmax of lymph nodes predicts malignancy. Indeed, when an SUVmax of 4.1 was used instead of 2.5, FDG-PET/CT was more accurate in assessing nodal metastasis.

Diagnostic yield using electromagnetic navigation bronchoscopy for peripheral pulmonary nodules <2 cm.

BACKGROUND: Although electromagnetic navigation bronchoscopy (ENB) is highly sensitive in the diagnosis of peripheral pulmonary nodules (PPNs), its diagnostic yield for subgroups of smaller PPNs is under evaluation. OBJECTIVES: Diagnostic yield evaluation of biopsy using ENB for PPNs <2 cm. DESIGN: The diagnostic yield, sensitivity, specificity, positive predictive value, and negative predictive value of the ENB-mediated biopsy for PPNs were evaluated. METHODS: Patients who had PPNs with diameters <2 cm and underwent ENB-mediated biopsy between May 2015 and February 2020 were consecutively enrolled. The final diagnosis was made via pathological examination after surgery. RESULTS: A total of 82 lesions from 65 patients were analyzed. The median tumor size was 11 mm. All lesions were subjected to ENB-mediated biopsy, of which 29 and 53 were classified as malignant and benign, respectively. Subsequent segmentectomy, lobectomy, or wedge resection, following pathological examinations were performed on 64 nodules from 57 patients. The overall sensitivity, specificity, positive predictive value, and negative predictive value for nodules <2 cm were 53.3%, 91.7%, 92.3%, and 51.2%, respectively. The receiver operating curve showed an area under the curve of 0.721 (p < 0.001). Additionally, the sensitivity, specificity, positive predictive value, and negative predictive value were 62.5%, 100%, 100%, and 42.9%, respectively, for nodules with diameters equal to or larger than 1 cm; and 30.8%, 86.7%, 66.7%, and 59.1%, respectively, for nodules less than 1 cm. In the subgroup analysis, neither the lobar location nor the distance of the PPNs to the pleura affected the accuracy of the ENB diagnosis. However, the spiculated sign had a negative impact on the accuracy of the ENB biopsy (p = 0.010). CONCLUSION: ENB has good specificity and positive predictive value for diagnosing PPNs <2 cm; however, the spiculated sign may negatively affect ENB diagnostic accuracy. In addition, the diagnostic reliability may only be limited to PPNs equal to or larger than 1 cm.

Metastatic lymph node CHIP expression is a potential prognostic marker for resected esophageal squamous cell carcinoma patients.

BACKGROUND: C-terminal Hsp-interacting protein (CHIP) is an HSP70 and HSP90 interacting co-chaperone and an E3 ubiquitin ligase. Previous studies have reported the role of CHIP in cancer progression by targeting protein degradation. However, its role and clinical significance in esophageal squamous cell carcinoma (ESCC) has not been elucidated. We investigated the correlation of CHIP expression and clinical outcome in a group of T3N1-3M0 surgically resected ESCCs. METHODS: Tissue microarrays constructed of 234 surgically resected T3N1-3M0 ESCC primary tumors (PTs) and 163 paired metastatic lymph nodes (MLNs), and sections of 56 cancer-adjacent normal epithelial blocks were used for CHIP evaluation by immunohistochemistry. The clinical and prognostic significance of CHIP expression was analyzed statistically. RESULTS: The expression level of CHIP in ESCC MLNs was significantly higher than that in PTs (P < 0.001). Patients with low MLNs' CHIP expression demonstrated better overall survival than those with high CHIP expression (median, 44 vs. 17.9 months; P = 0.010). Multivariate analysis showed that the MLNs' CHIP expression level was an independent prognostic factor in ESCC (relative risk, 2.157; P = 0.028). CONCLUSIONS: High expression of CHIP in MLNs suggests poor prognosis for patients with resected T3N1-3M0 ESCC. The result suggests that considering the protein expression of metastatic tumors is important for prognostic prediction.

Correlation of p53 status with the response to chemotherapy-based treatment in esophageal cancer: a meta-analysis.

BACKGROUND: The value of p53 status for predicting response to chemotherapy-based treatment in patients with esophageal cancer has been controversial. We conducted a meta-analysis to elucidate the correlation of p53 status with the response to chemotherapy-based treatment. METHODS: Studies were searched in PubMed, Embase, and Web of Science (up to September 2012). The p53 status and response to therapy were defined and standardized. Subgroup analyses based on the treatment and histopathology were performed to explore the usefulness of p53 status for predicting response to therapy in esophageal cancer. Sensitivity analyses were conducted by removing specific studies to assess the effects of study quality. RESULTS: We included 28 studies with 1497 cases in our meta-analysis. Wild-type form of p53 status (low expression of p53 protein and/or wild-type p53 gene) was associated with high response to chemotherapy-based treatment in esophageal cancer (total major response [MR]: risk ratio [RR] = 1.09, 95 % CI = 1.03-1.16, P = .003; pathological MR: RR = 1.15, 95 % CI = 1.06-1.25, P = .001; total complete response [CR]: RR = 1.08, 95 % CI = 1.00-1.17, P = .040). The similar correlation between the wild-type form p53 and response to therapy were also detected in subgroup analyses (total MR, pathological MR, and total CR in chemoradiotherapy subgroup; total MR in chemotherapy subgroup; total MR and pathological CR in esophageal squamous cell carcinoma [ESCC]). Additionally, patients with wild-type form p53 status had high pathological complete response rate to neoadjuvant chemoradiotherapy in ESCC. CONCLUSIONS: The current meta-analysis suggested that p53 status might be a predictive biomarker for response to chemotherapy-based treatment in esophageal cancer.

Prognostic value of HOXB7 mRNA expression in human oesophageal squamous cell cancer.

OBJECTIVE: This study was to determine the role of HOXB7 in predicting outcomes of patients with oesophageal squamous cell cancer (OSCC). METHODS: Samples were collected from 179 OSCC patients. HOXB7 mRNA expression was measured by quantitative real-time polymerase chain reaction. RESULTS: HOXB7 mRNA expression was up-regulated in 85.1% of OSCC tumorous tissues, and correlated with age, pathological T and N category, as well as cancer-specific survival (CSS). However, subgroup analysis revealed its discernibility on CSS was only pronounced in early stage. CONCLUSIONS: HOXB7 mRNA expression might serve as a novel prognostic biomarker for resected OSCC patients in early stage.

LncRNA TMPO-AS1 promotes esophageal squamous cell carcinoma progression by forming biomolecular condensates with FUS and p300 to regulate TMPO transcription.

Esophageal squamous cell carcinoma (ESCC) is one of the most life- and health-threatening malignant diseases worldwide, especially in China. Long noncoding RNAs (lncRNAs) have emerged as important regulators of tumorigenesis and tumor progression. However, the roles and mechanisms of lncRNAs in ESCC require further exploration. Here, in combination with a small interfering RNA (siRNA) library targeting specific lncRNAs, we performed MTS and Transwell assays to screen functional lncRNAs that were overexpressed in ESCC. TMPO-AS1 expression was significantly upregulated in ESCC tumor samples, with higher TMPO-AS1 expression positively correlated with shorter overall survival times. In vitro and in vivo functional experiments revealed that TMPO-AS1 promotes the proliferation and metastasis of ESCC cells. Mechanistically, TMPO-AS1 bound to fused in sarcoma (FUS) and recruited p300 to the TMPO promoter, forming biomolecular condensates in situ to activate TMPO transcription in cis by increasing the acetylation of histone H3 lysine 27 (H3K27ac). Targeting TMPO-AS1 led to impaired ESCC tumor growth in a patient-derived xenograft (PDX) model. We found that TMPO-AS1 is required for cell proliferation and metastasis in ESCC by promoting the expression of TMPO, and both TMPO-AS1 and TMPO might be potential biomarkers and therapeutic targets in ESCC.

CyclinD1, p53, E-cadherin, and VEGF discordant expression in paired regional metastatic lymph nodes of esophageal squamous cell carcinoma: a tissue array analysis.

BACKGROUND AND OBJECTIVES: The correlation of biomarker expression between primary tumors and corresponding metastases has not yet been well reported in esophageal squamous cell carcinoma (ESCC). This study was to confirm whether primary ESCC tumors differ from their regional metastatic lymph nodes (RMLN) in CyclinD1, p53, E-cadherin, and vascular endothelial growth factor (VEGF) expression and determine prognostic value of their alteration. METHODS: There were 134 patients with stage T3N1-3M0 ESCC recruited for the research. Expression of CyclinD1, p53, E-cadherin, and VEGF was evaluated in primary ESCC tumors and their paired RMLN assembled on tissue microarrays by immunohistochemistry (IHC). The comparison of expression in different lesion and their correlation with prognosis was analyzed. RESULTS: E-cadherin was discordant expression in 55.2% cases and appeared to be more frequently positive in metastatic lymph nodes (P < 0.001). The VEGF expression level was significantly higher in primary tumors (P < 0.001). Combined analysis of VEGF expressions in paired lesions (P = 0.003) and its decreased expression (P = 0.006) were both predictive. CONCLUSIONS: Biomarker expression was discordant between the primary tumor and its paired lymphatic metastasis in over 25% of patient with ESCC. VEGF discordant expression was a new prognostic factor and combined analysis of expression in paired lesions was useful to predict. Analysis of protein expression only in primary tumors would be inadequate to judge prognosis.

Prognostic analysis of the patients with stage-III esophageal squamous cell carcinoma after radical esophagectomy.

BACKGROUND AND OBJECTIVE: Most patients with esophageal carcinoma have disease in the locally late stage (stage III) when first diagnosed, with surgery as the first treatment of choice. This study analyzed the clinical data of patients with esophageal squamous carcinoma after radical esophagectomy and investigated prognostic factors. METHODS: The data of 361 patients with esophageal squamous carcinoma who underwent radical esophagectomy and were hospitalized at Sun Yat-sen University Cancer Center between January 1997 and March 2004 were analyzed. The Kaplan-Meier method was used to analyze prognosis, log-rank test was used to compare the groups, and the Cox proportional hazards model was used for multivariate analysis. RESULTS: The 1-, 2-, 3-, 4-, and 5-year survival rates were 67.7%, 40.6%, 27.5%, 23.4%, and 20.1%, respectively. Based on univariate analysis, the degree of invasion, rate of lymph node metastasis, number of metastatic regions, number of metastatic lymph nodes, postoperative complications, and duration of surgery were prognostic factors. Based on multivariate analysis, the degree of invasion, rate of lymph node metastasis, and postoperative complications were independent factors for the prognosis. CONCLUSIONS: Of all clinical and pathologic factors, the degree of invasion, rate of lymph node metastasis, and postoperative complications were independent prognostic factors for the patients with stage-III esophageal squamous carcinoma after radical esophagectomy.

[Significance of subcarinal lymph node selective dissection in thoracic esophageal carcinoma].

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.

Fibrin sealant for esophageal anastomosis: A phase II study.

BACKGROUND: Esophagectomy is a pivotal curative modality for localized esophageal or esophagogastric junction cancer (EC or EJC). Postoperative anastomotic leakage (AL) remains problematic. The use of fibrin sealant (FS) may improve the strength of esophageal anastomosis and reduce the incidence of AL. AIM: To assess the efficacy and safety of applying FS to prevent AL in patients with EC or EJC. METHODS: In this single-arm, phase II trial (Clinicaltrial.gov identifier: NCT03529266), we recruited patients aged 18-80 years with resectable EC or EJC clinically staged as T1-4aN0-3M0. An open or minimally invasive McKeown esophagectomy was performed with a circular stapled anastomosis. After performing the anastomosis, 2.5 mL of porcine FS was applied circumferentially. The primary endpoint was the proportion of patients with AL within 3 mo. RESULTS: From June 4, 2018, to December 29, 2018, 57 patients were enrolled. At the data cutoff date (June 30, 2019), three (5.3%) of the 57 patients had developed AL, including two (3.5%) with esophagogastric AL and one (1.8%) with gastric fistula. The incidence of anastomotic stricture and other major postoperative complications was 1.8% and 17.5%, respectively. The median time needed to resume oral feeding after operation was 8 d (Interquartile range: 7.0-9.0 d). No adverse events related to FS were recorded. No deaths occurred within 90 d after surgery. CONCLUSION: Perioperative sealing with porcine FS appears safe and may prevent AL after esophagectomy in patients with resectable EC or EJC. Further phase III studies are warranted.

Establishment and biological analysis of the EC109/CDDP multidrug-resistant esophageal squamous cell carcinoma cell line.

The aim of this study was to establish a stable, drug-resistant esophageal squamous cell carcinoma (ESCC) cell line. The human ESCC cell line EC109 was exposed to cisplatin (CDDP) by pulse treatment to select for the drug-resistant subline, EC109/CDDP cells. The MTT assay was used to test the drug resistance of EC109 and EC109/CDDP cells. In addition, cellular morphological changes were observed using microscopy and the growth curves of the two cell lines were drawn to calculate the doubling time. Furthermore, cell cycle distribution was analyzed by flow cytometry. Finally, RT-PCR was performed to determine the mRNA expression levels of drug-resistant-related genes, multidrug resistance 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), ATP-binding cassette, sub-family G, member 2 (ABCG2), lung resistance protein (LRP), and glutathione S-transferase (GST)-pi in both cell lines. EC109/CDDP cells exhibited increased resistance to CDDP, carboplatin, 5-fluorouracil, taxol, navelbine, irinotecan and etoposide, and changes in morphology, doubling time, and cell cycle distribution were detected as compared with EC109 cells. Although there was no significant difference in MRP1, ABCG2, LRP, and GST-pi expression, MDR1 expression in EC109/CDDP cells was lower than that of EC109 cells. EC109/CDDP cells are a stable, multidrug-resistant ESCC cell line and could serve as an important tool for further research concerning ESCC drug resistance.

Strong expression of Id-1 in metastatic lymph nodes from esophageal squamous cell carcinoma is associated with better clinical outcome.

BACKGROUND: Over-expression of inhibitor of differentiation or DNA binding 1 (Id-1) is associated with poor prognosis in esophageal squamous cell carcinoma (ESCC). However, some biomarkers discordant expression in metastasis has been reported previously. We aimed to confirm possible differential expression and prognostic value of Id-1 in paired metastatic lymph node (PMLN). METHODS: Expression of Id-1 in primary tumors (PT) and paired regional metastatic lymph nodes of ESCC were evaluated with immunohistochemical (IHC) analysis. Statistical analysis of Kaplan-Meier method was performed to test the prognostic significance of Id-1 expression. RESULTS: The expression of Id-1 was down-regulated in metastatic lymph nodes compared with primary esophageal tumors (P<0.001). Patients with 1 to 2 lymph nodes involved had significantly higher Id-1 expression in metastatic lymph nodes (P=0.028). The similar association was observed between a ratio of involved to examined lymph nodes ≤0.2 and high level Id-1 expression in lymphatic metastases (P=0.011). Better overall survival with statistical significance was observed in patients with higher level Id-1 expression in metastatic lymph nodes (P=0.015). The results of Id-1 expression in metastatic lymph node and paired PT was to predict prognosis effective in out cohort (P=0.035). CONCLUSIONS: The level of Id-1 protein expression was down-regulated from PT to metastatic lymph node. It was contrary to previous studies that strong expression of Id-1 in metastatic lymph nodes was associated with better clinical outcomes in patients with stage T3N1-3M0 ESCC.

Resectable left lower lobe non-small cell lung cancer with lymph node metastasis is related to unfavorable outcomes.

BACKGROUND: Despite numerous previous studies, the consideration of tumor location as a prognostic factor in resectable non-small cell lung cancer (NSCLC) remains controversial. The present study analyzed the association between tumor location and clinical outcome in patients with resectable NSCLC who had undergone lobectomy with systematic lymphadenectomy and who had presented with varying nodal statuses. METHODS: The data from a cohort of 627 eligible patients treated in Sun Yat-sen University Cancer Center between January 2000 and December 2008 were retrospectively collected, and the nodal statuses of patients with different tumor locations were compared. Cox proportional hazards regression model was used to determine the independent factors related to cancer-specific survival (CSS). RESULTS: Multivariate analysis demonstrated that left lower lobe (LLL) tumors [hazard ratio (HR): 1.465, 95% confidence interval (CI) 1.090-1.969, P = 0.011], lymph node metastasis (HR: 2.742, 95% CI 2.145-3.507, P < 0.001), and a tumor size of >4 cm (HR: 1.474, 95% CI 1.151-1.888, P = 0.002) were three independent prognosticators in patients with resectable NSCLC. However, LLL tumors were associated only with CSS in node-positive patients (HR: 1.528, 95% CI 1.015-2.301, P = 0.042), and a tumor size of >4 cm was the only independent risk predictor in the node-negative subgroup (HR: 1.889, 95% CI 1.324-2.696, P < 0.001). CONCLUSIONS: Tumor location is related to the long-term CSS of NSCLC patients with lymph node metastasis. LLL tumors may be upstaged in node-positive patients to facilitate an optimal treatment strategy.

The epithelial-mesenchymal transition phenotype of metastatic lymph nodes impacts the prognosis of esophageal squamous cell carcinoma patients.

Epithelial-mesenchymal transition (EMT) plays a key role in tumor metastasis, but the significance of EMT phenotype to the prognosis of esophageal squamous cell carcinoma (ESCC) patients remains unclear. We used immunohistochemistry to examine the expression of the EMT-related proteins E-cadherin, N-cadherin and vimentin in samples of T3N1-3M0 ESCC from 155 primary tumors (PTs) with paired metastatic lymph nodes (MLNs) and 58 PTs without paired MLNs. Based on the expression pattern of the EMT markers, PTs and MLNs were classified as EMT wild, hybrid, null or complete type. The hybrid (42.7%) and complete (39.4%) types predominated among PTs, whereas the wild (34.2%) and hybrid (52.9%) types predominated among MLNs, and EMT phenotypes differed between the paired PTs and MLNs (P < 0.001). Univariate analysis revealed that, for PTs, the EMT phenotype was associated with N-stage (P = 0.039) but not patient survival, and that patients with complete or hybrid type MLNs had better overall survival (OS, P = 0.001) and disease-free survival (DFS, P = 0.005) than patients with null and wild type MLNs, especially those with N1-stage disease (P = 0.017 for OS, and P = 0.017 for DFS, respectively). Multivariate analysis revealed that wild and null type MLNs as well as older age and N2-3 stage were independent predictors of OS and DFS (P < 0.05). Thus MLNs exhibit EMT phenotypes that are distinct from those of their PT and may serve as a novel independent prognostic indicator in ESCC.

MMP1 promotes tumor growth and metastasis in esophageal squamous cell carcinoma.

Matrix metalloproteinases play an essential role in the progression of esophageal squamous cell carcinoma (ESCC). Here, we show that MMP1 expression was markedly increased in a majority of ESCC compared with nontumorous tissue. High expressions of MMP1 were closely associated with lymph node metastasis, microvessel density and advanced TNM stage. Kaplan-Meier and multivariate analyses indicated MMP1 as an independent factor for overall survival in two independent cohorts of 613 patients with ESCC. In vitro studies demonstrated that MMP1 overexpression resulted in enhanced cell viability, abilities of colony formation and cell migration. The knockdown of MMP1 in ESCC cells resulted in the opposite phenomenon. Consistently, in vivo data showed that ectopic expression of MMP1 promoted tumor growth and metastasis. Further study revealed that MMP1 facilitated ESCC through the activation of the PI3K/AKT pathway. Inhibition of the PI3K/AKT pathway by LY294002 significantly attenuated MMP1-mediated cell proliferation and migration. Taken together, our data suggest that MMP1 functions as an oncogene and serves as a prognostic biomarker and a potential therapeutic target in ESCC.

TRPV6 plays a new role in predicting survival of patients with esophageal squamous cell carcinoma.

BACKGROUND: TRPV6 is over-expressed and promotes the proliferation and invasion in many cancers. The association between the expression of TRPV6 and clinical outcome in esophageal squamous cell carcinoma (ESCC) has not been studied yet. We aim to elucidate the role of TRPV6 in predicting prognosis of patients with ESCC. METHODS: In the retrospective study, mRNA level of TRPV6 was examined in patients (N = 174) from Sun Yat-sen University Cancer Center (mRNA cohort) and protein level of TRPV6 was examined in patients (N = 218) from Linzhou Cancer Hospital (protein cohort). Statistical analysis was performed to test the clinical and prognostic significance of TRPV6. RESULTS: TRPV6 was down-regulated in ESCC tissues and cell lines. Patients with downregulation of TRPV6 trended to have a higher rate of advanced pT stage in both mRNA cohort (P = 0.089) and protein cohort (P = 0.073), though not statistically significant. No significant association was observed between TRPV6 expression and disease-specific survival (DSS) in both two cohorts. However, stratified survival analysis based on the gender showed that in mRNA cohort, downregulation of TRPV6 was associated with an unfavorable 3-year DSS in patients with male (47.3 % vs 63.6 %, P = 0.027) and with favorable 3-year DSS in patients with female (66.7 % vs 43.0 %, P = 0.031). The result was confirmed in protein cohort. Male patients with downregulation of TRPV6 had a poor 3-year DSS (20.0 % vs 57.1 %,P < 0.001) while female counterparts showed an enhanced 3-year DSS (56.1 % vs 28.6 %, P = 0.005). CONCLUSION: TRPV6 is down-regulated in ESCC. As a predictive biomarker, TRPV6 plays a Janus-like role in predicting survival of male and female ESCC patients.

Preoperative serum fibrinogen is an independent prognostic factor in operable esophageal cancer.

In order to fully elucidate the association between serum fibrinogen and prognosis of esophageal cancer, we examined serum fibrinogen concentrations in 1512 patients who underwent esophagectomy by the Clauss method. The impact of fibrinogen on overall survival and disease-free survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models. Hyperfibrinogenemia was significantly associated with older age, male gender, smoking, alcohol consumption, weight loss, advanced pathological T stage and lymph node metastasis. Patients with hyperfibrinogenemia exhibited poor OS (HR=1.20, 95%CI: 1.04-1.38, P=0.012) and DFS (HR=1.18, 95%CI: 1.03-1.35, P=0.019). Subgroup analysis further exhibited an significant association between hyperfibrinogenemia and poor OS (P<0.001), DFS (P<0.001) in esophageal squamous cell carcinoma (P<0.001) and early pathological stage (I-II) (P=0.001). Collectively, this study indicates that preoperative serum fibrinogen is an independent prognostic factor for survival in esophageal cancer.

Decreased mRNA expression of transcription factor forkhead box F2 is an indicator of poor prognosis in patients with resected esophageal squamous cell carcinoma.

The transcription factor forkhead box F2 (FOXF2) is an evolutionarily conserved DNA-binding protein involved in embryogenesis and metabolism. Although recent studies prove that FOXF2 is a tumor suppressor in various human cancers, the role of FOXF2 in esophageal squamous cell carcinoma (ESCC) remains unknown. Therefore, samples were collected from 188 ESCC patients, including 33 pairs of tumor and non-tumor tissues, and FOXF2 mRNA expression was investigated by quantitative polymerase chain reaction. The results demonstrated that FOXF2 mRNA is downregulated in tumor tissues compared to paired non-tumor tissues (P=0.048). The receiver operating characteristic curve analysis indicated 1.2 as a cut-off point and, thus, 125 and 63 tumors were classified as low- and high-level FOXF2 mRNA expression, respectively. We observed that low-level FOXF2 mRNA expression in the tumors was associated with a higher frequency of lymph node metastasis (P=0.044), an effect further suggested by the multivariate logistic regression analysis (P=0.060). According to the univariate Cox analysis, patients harboring tumors with low-level FOXF2 mRNA expression had a significantly increased mortality risk compared to those with high-level expression (hazard ratio=1.700, 95% confidence interval, 1.077-2.681), with 5-year survival rates of 41.1 and 61.9%, respectively. This negative prognostic effect of low-level FOXF2 mRNA expression was further validated in the multivariate Cox analysis (P=0.021). The subgroup analysis demonstrated that the effect of FOX2 mRNA expression was limited to male patients and those with advanced-stage disease. Taken together, these findings suggest that FOXF2 may be an anti-oncogene for ESCC and decreased FOXF2 mRNA expression is associated with a poor prognosis in patients with ESCC.

Aggressive surgical resection does not improve survival in operable esophageal squamous cell carcinoma with N2-3 status.

AIM: To investigate the influence of nodal status on response and clarify the optimal treatment for operable esophageal squamous cell carcinoma (OSCC). METHODS: We retrospectively analyzed 1490 OSCC patients who underwent transthoracic esophagectomy and lymphadenectomy between December 1996 and December 2009 at the Sun Yat-sen University Cancer Center. The surgical approach and the number of resected lymph nodes (LNs) were considered in the assessment of surgery. Patients were classified according to their nodal statuses (N0 vs N1 vs N2-3). Overall survival was defined as the time from the date of death or final follow-up. Survival analysis was performed using the Kaplan-Meier method and differences between curves were assessed by the log-rank test. Univariate and multivariate Cox regression analyses were used to identify factors associated with prognosis. Statistical significance was assumed at a P < 0.05. RESULTS: With a median time from surgery to the last censoring date for the entire cohort of 72.2 mo, a total of 631 patients were still alive at the last follow-up and the median survival time was 35.5 mo. The surgical approach (left transthoracic vs Ivor-Lewis/tri-incisional) was verified as independent prognostic significance in patients with N0 or N1 status, but not in those with N2-3 status. Similar results were also observed with the number of resected LNs (≤ 14 vs ≥ 15). Compared with surgery alone, combined therapy achieved better outcomes in patients with N1 or N2-3 status, but not in those with N0 status. For those with N2-3 status, neither the surgical approach nor the number of resected LNs reached significance by univariate analysis, with unadjusted HRs of 0.826 (95%CI: 0.644-1.058) and 0.849 (95%CI: 0.668-1.078), respectively, and aggressiveness of surgery did not influence the outcome; the longest survival was observed in those patients who received the combined therapy. CONCLUSION: Combined therapy has a positive role in OSCC with LN metastasis, and aggressive surgical resection does not improve survival in patients with N2-3 status.