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Aim: To examine the depth of tumor invasion and tumor length and assess the clinical impact of the primary tumor score (PTS), based on a combination of tumor invasion and tumor length, in patients with esophageal squamous cell carcinoma (ESCC)., Patients and Methods: A total of 237 patients with ESCC were classified into three PTS groups based on cut-off values for deeper tumor invasion (pT2-T4) and greater tumor length (≥44 mm). A PTS of 2 indicated the presence of both of these abnormalities, 1 indicated one of these abnormalities, and 0 indicated neither abnormality., Results: PTS was significantly positively correlated with depth of tumor invasion, lymph node metastasis, lymphovascular invasion, and stage (all p<0.001). The prognosis differed significantly among the three groups based on PTS (p<0.0001). Multivariate analysis demonstrated that PTS was an independent prognostic factor (p=0.0004)., Conclusion: PTS has a clinical utility as a prognostic predictor in patients with ESCC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Sex-determining region Y-box 9 (SOX9) is an important transcription factor for the development and differentiation of cells and their organization. In the present study, the clinical significance of SOX9 expression in oesophageal squamous cell carcinoma was examined., Materials and Methods: SOX9 expression in surgical specimens of primary tumours were immunohistochemically investigated in 175 patients with oesophageal squamous cell carcinomas., Results: SOX9 was expressed (moderately or strongly) in 62.9% of samples. Expression of SOX9 was significantly positively correlated with depth of invasion, advanced stage, lymphatic and venous invasion, and poor prognosis. Univariate analysis showed that depth of invasion, lymph node metastasis, distant metastasis, stage, lymphatic invasion, venous invasion, and SOX9 expression were prognostic factors. Multivariate analysis indicated that depth of invasion and stage were independent prognostic factors, but SOX9 expression was not., Conclusion: SOX9 expression is related to prognosis in patients with oesophageal squamous cell carcinoma, although it is not an independent prognostic factor., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: While chemoradiation therapy (CRT) is one of the most useful treatments for esophageal squamous cell carcinoma (ESCC), it is important to predict response prior to treatment by using markers because some patients respond well and others do not., Methods: Fifty-nine patients with ESCC were treated with neoadjuvant CRT at the Kagoshima University Hospital. The expression of seven types of biomarker candidate proteins in biopsy specimens of untreated primary tumors was evaluated to determine whether it correlated with response and prognosis., Results: The positive expression rates were 47% for p53, 83% for CDC25B, 68% for 14-3-3sigma, 76% for p53R2, 75% for ERCC1, 32% for Gli-1, and 54% for Nrf2. In terms of histological response, tumor grade of the 59 patients was 48.8% for grade 1 as the non-responder, 29.2% for grade 2, and 22.0% for grade 3 as the responder. CRT was significantly effective in p53(-), p53R2(-), ERCC1(-), and Nrf2(-) tumors, while p53(-), p53R2(-), and ERCC1(-) were factors independently correlated with effective histological response. Their combined expression of two or three negative expressions had 100% effective response and was a significant prognostic factor., Conclusion: Our results suggest that two or three negative expressions of p53, p53R2, and ERCC1 in biopsy specimens of primary tumors were associated with a favorable response to CRT for ESCC. Assessment of tumor suppressor and DNA repair protein expressions in biopsy specimens may be useful for the potential utility of CRT therapy for patients with ESCC prior to treatment.

Aim: The aim of this study was to assess the role of 18 F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG-PET/CT) in predicting pathological response and survival in patients with esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (nCRT)., Patients and Methods: Thirty patients with advanced ESCC received nCRT followed by surgery, and underwent FDG-PET/CT twice before and after nCRT. We compared the results of FDG-PET/CT with the pathological results and prognosis., Results: Pathological response was found to correlate with the maximum standardised uptake value (SUV max ) after nCRT and the rate of decrease of SUV max Using univariate analysis, pN, SUVmax after nCRT and the rate of decrease of SUV max were found to be prognostic factors. Multivariate analysis revealed that only pN was an independent prognostic factor., Conclusion: The prediction of pathological response and prognosis using FDG-PET/CT is not as reliable as pathological detection of lymph node metastasis, but could be a useful method contributing to treatment decisions., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Cysteine/histidine-rich 1 (CYHR1) was first discovered in a yeast two-hybrid screen with murine galectin-3, and no previous reports have described a relationship between the CYHR1 gene and human cancer. The current study evaluated the role and significance of CYHR1 in esophageal cancer., Methods: The human esophageal squamous cell carcinoma (ESCC) cell line TE-8 and the CYHR1 knock-down cell line TE-8/small interfering (si)-CYHR1 were used for in vitro and in vivo assays. For clinical study, ESCC tissues (n = 104) were used., Results: Compared with parental cells, TE-8/si-CYHR1 cells had suppressed proliferation and invasion activities. In the in vivo assay, the tumors from TE-8 cells treated with si-CYHR1 had abrogated tumorigenicity. In the clinical study, the expression of CYHR1 mRNA was associated with lymph node metastasis and stage and shown to be an independent prognostic factor., Conclusions: As the findings show, CYHR1 may represent not only a valuable prognostic marker but also a therapeutic target for ESCC patients.

Patients with advanced esophageal squamous cell carcinoma (ESCC) is received chemoradiotherapy or chemotherapy for clinical management. However, it is difficult to predict tumor response and prognosis using blood markers before starting treatments. The purpose of this study was to investigate the pre-treatment plasma fibrinogen and neutrophil-lymphocyte ratio (NLR) in patients with advanced ESCC treated with chemoradiotherapy or chemotherapy, and to assess the clinical utility of a combined score using these blood markers, named as the F-NLR (fibrinogen and NLR) score, as a predictor of tumor response and prognosis. A total of 98 advanced ESCC patients, treated with chemoradiotherapy or chemotherapy, were classified into three groups: F-NLR score of 2, having both hyperfibrinogenemia (>400 mg/dL) and high NLR (>3.0), score of 1, one of these hematological abnormalities, and score of 0, having neither hyperfibrinogenemia nor high NLR. Fibrinogen and NLR were significantly higher in the progressive disease (PD) group than the non-PD group (P = 0.0419, and P = 0.0001, respectively). A significantly higher F-NLR score was found in the PD group than the non-PD group (P = 0.0140). Overall survival was significantly lower in patients with an F-NLR score of 2 than in those with an F-NLR score of 0 or 1 (P < 0.0001). Multivariate analysis showed that the F-NLR score was one of the independent prognostic factors (P = 0.0081). Our study demonstrates that the F-NLR score is promising as a predictive marker for therapeutic effects and prognosis in patients with advanced ESCC., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Ferredoxin reductase (Fdxr) is the mitochondrial cytochrome P-450 NADPH reductase. Fdxr overexpression increases the sensitivity of tumor cells to apoptosis in response to chemotherapy through reactive oxygen species (ROS) production. The aim of the present study was to examine the Fdxr expression in esophageal squamous cell carcinoma (ESCC) and determine if the expression is useful for predicting response to chemoradiation therapy (CRT)., Materials and Methods: Fdxr expression in biopsy specimens from 50 patients before neoadjuvant CRT were immunohistochemically examined. Then, the correlation between Fdxr expression and response to CRT were analyzed., Results: Both clinically and histologically, significant correlations were found between positive Fdxr expression and favorable response to CRT. Furthermore, Fdxr was significantly correlated with postoperative outcomes and was found to be an independent prognostic factor., Conclusion: Fdxr expression was found to be closely related to the effect of CRT and could predict the CRT outcome in patients with ESCC., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Esophageal squamous cell carcinoma is an aggressive gastrointestinal tract cancer. To date, the presence of circulating tumor cells (CTC) has been reported as a prognostic factor in peripheral blood from patients with gastrointestinal cancers., Methods: The CellSearch system was used to isolate and enumerate CTCs. A total of 90 patients with esophageal squamous cell carcinoma who received chemotherapy or chemoradiotherapy were enrolled. Peripheral blood specimens were collected before and after treatments., Results: At baseline analysis, CTCs were detected in 25 patients (27.8 %). Overall survival was significantly shorter in patients with than without CTCs. Follow-up blood specimens were obtained from 71 patients. Partial response, stable disease, and progressive disease after treatment were seen in 32, 12, and 27 patients, respectively. CTC positivity after treatment in the progressive disease group (40.7 %) was significantly higher than that of the partial response group (6.3 %). Patients with a change in CTC status from positive to negative had a good prognosis as well as patients without baseline CTCs., Conclusions: Evaluation of CTCs may be a promising indicator for predicting tumor prognosis and the clinical efficacy of chemotherapy or chemoradiation therapy in patients with esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies in gastrointestinal tract cancers and even patients with early ESCC have a high metastatic potential. Difficulties are associated with clinically predicting tumor progression and prognosis based on conventional tumor markers determined from preoperative blood examinations. The aim of the present study was to measure plasma fibrinogen levels and the neutrophil-lymphocyte ratio (NLR) in blood and compare the clinical impacts of their combined values (fibrinogen and neutrophil-lymphocyte ratio score-F-NLR score) and the modified Glasgow Prognostic Score (mGPS) in patients with ESCC.We classified 238 patients with ESCC based on cut-off values for hyperfibrinogenemia (>400 mg/dL) and high NLR (>3.0) as F-NLR scores of 2 (both of these hematological abnormalities), 1 (one of these abnormalities), or 0 (neither abnormality). We also categorized patients based on cut-off values for high C-reactive protein (CRP) (>0.5 mg/dL) and hypoalbuminemia (<3.8 g/dL) as mGPS of 2 (elevated CRP and hypoalbuminemia), 1 (either elevated CRP or hypoalbuminemia), or 0 (neither elevated CRP nor hypoalbuminemia).The F-NLR score correlated with the depth of tumor invasion, lymph node metastasis, lymphovascular invasion, tumor size, and stage (all P < 0.05). Prognoses among the groups based on the F-NLR score and mGPS significantly differed (all P < 0.001). A multivariate analysis identified the depth of tumor invasion, lymph node metastasis, and F-NLR score as independent prognostic factors (P = 0.002, P = 0.007, and P = 0.037, respectively).The results of the present study showed that the F-NLR score is a promising blood predictor for tumor progression and outcomes in patients with ESCC.

Purpose: Mediastinoscope-assisted transhiatal esophagectomy (MATHE) is a useful surgical procedure in esophageal cancer patients who have limited indications for transthoracic operations due to preoperative complications., Methods: In the last 10 years, 63 patients underwent MATHE at our department. We examined the clinical data of these patients and assessed the indications, postoperative outcomes, and prognostic factors of MATHE., Results: The 5-year overall survival (OS) rate was 53.4 %, and disease-free survival (DFS) rate was 66.0 %. Postoperative complications were observed in 22 cases (34.9 %), and recurrent disease occurred in 17 cases (27.0 %). On univariate analyses of OS, location of the tumor, tumor depth, lymph node metastasis, clinical stage, simultaneous resection of other organs, postoperative pneumonia, and blood loss were significant prognostic factors. On multivariate analyses, location of the tumor and lymph node metastasis were independent prognostic factors of OS. On univariate analyses, location of the tumor, tumor depth, lymph node metastasis, clinical stage, and blood loss were significant prognostic factors of DFS, while on multivariate analyses of DFS, lymph node metastasis and blood loss were independent prognostic factors., Conclusion: MATHE is a useful procedure for the middle to lower thoracic esophageal cancer patients without clinical lymph node metastasis with serious complications who were unable to undergo thoracotomy.

Background/aim: Interleukin-32 (IL32) has been newly-identified as a proinflammatory cytokine. In the present study, we aimed to clarify the clinical role of IL32-positive cells in esophageal squamous cell cancer (ESCC) and regulatory T-cell (Treg) infiltration in the stroma. A total of 179 patients with ESCC who underwent surgical resection from 1990 to 2004 were eligible for this study. The expression of IL32 and the degree of stromal infiltration by Tregs were examined simultaneously. The association between each factor and the clinicopathological features was analyzed. Sixty and 74 out of 179 patients with ESCC were regarded as having IL32-positive tumors and many Tregs (high-Treg group), respectively. The IL32-positive and high-Treg groups had significantly deeper tumor invasion than did the IL32-negative and low-Treg groups (p<0.05, for both groups). The multivariate analysis indicated that a combination of IL32 expression and presence of Tregs was one of the poor independent factors (p<0.05). IL32 expression and Treg infiltration in ESCC play an important synergistic role in tumor growth and invasion. The combination of IL32 positivity and degree of infiltration of Treg is a useful prognostic marker in ESCC., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Chemoradiation therapy (CRT) is one of the most useful treatments for esophageal squamous cell carcinoma (ESCC). However, because some patients respond well to CRT and others do not, it is important to be able to predict response to CRT before beginning treatment by using markers. Aurora-A encodes a cell cycle regulated serine/threonine kinase that has essential functions in centrosome maturation and chromosome segregation. In this study, we investigated the relationship between the expression of Aurora-A and the response to CRT in patients with ESCC., Methods: We immunohistochemically investigated the expression of Aurora-A in biopsy specimens of untreated primary tumors of 78 patients with ESCC and determined the relationship between Aurora-A levels and patient responses to CRT, which consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation., Results: Tumors were judged as Aurora-A positive when more than 10% of the cancer cells displayed a distinct positive nuclear anti-Aurora-A immunoreaction by immunohistochemical evaluation. The tumors of 46 of 78 patients (58.9%) displayed positive expression of Aurora-A. In terms of clinical response the percentage of patients showing complete response (CR), incomplete response/stable disease of primary lesion (IR/SD), and progressive disease (PD) was 19.2, 69.2, and 11.5%, respectively. In terms of histological response the tumor grade of the 41 patients who underwent surgery was as follows: grade 1, 48.8%; grade 2, 29.2%; grade 3, 22.0%. CRT was effective for patients who had Aurora-A (+) tumors (clinically: P = 0.0003, histologically: P = 0.036)., Conclusions: Our results suggest that Aurora-A expression in biopsy specimens of primary tumors is associated with CRT efficacy in patients with ESCC. Assessment of Aurora-A expression in biopsy specimens maybe useful for regarding the potential utility of CRT therapy for patients with ESCC before treatment.

Background: The prognosis of patients with esophageal squamous-cell cancer (ESCC) and multiple lymph-node metastases is quite poor. We examined whether neoadjuvant chemoradiation therapy (CRT) has a beneficial effect in such patients., Methods: A total of 50 consecutive patients with T3-4 tumors and without organ metastases were prospectively enrolled. Of those patients, 20, who had four or more nodal metastases, underwent neoadjuvant CRT (CRT group), and the remaining 30 patients, who had three or fewer nodal metastases, underwent surgery alone (surgery group). CRT consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation. The groups' clinical outcomes were compared., Results: Surgery was performed in 48 patients: all enrolled patients except for 2 who had organ metastasis after CRT. In the CRT group, the number of patients with pathological complete response was observed in 8 patients (44 %), mean nodal metastases number was changed from 8.2 to 2.6 and 9 patients had pN0. The 3-year survival rate was 76 % in the CRT group (4 patients relapsed) and 68 % in the surgery group (8 patients relapsed), which is not a statistically significant difference (P = 0.61)., Conclusions: Neoadjuvant CRT is beneficial for locally advanced ESCC with four or more lymph-node metastases.

Background: The transcription factor NF-E2-related factor 2 (Nrf2) was originally identified to be a critical regulator of intracellular antioxidants and phase II detoxification enzymes. Recent studies have shown that high Nrf2 expression gives cancer cells an advantage for survival from anticancer chemotherapy and radiation therapy. The aims of this retrospective study were to examine the expression of Nrf2 in biopsy specimens of esophageal squamous cell carcinoma (ESCC) and to evaluate whether such expression is useful for predicting the response to chemoradiation therapy (CRT)., Methods: A total of 46 patients with ESCC who received curative surgery after CRT from 1997 to 2011 were enrolled in the current study. Nrf2 expression in the biopsy specimens before CRT was examined immunohistochemically using anti-Nrf2 antibody. The correlations between Nrf2 expression and clinical factors and histological and clinical response to CRT were analyzed., Results: The rate of Nrf2-positive expression was 39 %. Both clinically and histologically, significant correlations were found between positive Nrf2 expression and unfavorable response to CRT. Furthermore, Nrf2 was significantly correlated with clinical lymph node metastases and patients' postoperative outcomes. Multivariate analysis showed that Nrf2 expression status was an independent prognostic factor., Conclusions: Nrf2 expression was found to be closely related to the effect of CRT and could predict the CRT outcome in patients with ESCC.

Background: Angiogenic molecular markers such as vascular endothelial growth factor and tumor microvessel density reflect prognosis of human cancers. The present study clarified the usefulness of endothelial marker endoglin (CD 105) by assessing microvessel density in esophageal squamous cell carcinoma (ESCC)., Materials and Methods: We immunohistochemically investigated CD105, CD31, and vascular endothelial growth factor-A VEGF-A expression in primary esophageal squamous cell carcinoma specimens from 142 patients., Results: Microvessel density was 35.9±21.2 for CD105 and 46.3±25.4 for CD31. CD105 microvessel density was significantly associated with tumor length, tumor invasion depth, lymph node metastasis, stage, lymphatic invasion, venous invasion, and VEGF-A expression; its correlation with almost all clinicopathological parameters was stronger than CD31 microvessel density. And significantly better prognosis was achieved in patients with low, compared to high CD105, microvessel density., Conclusion: CD105 microvessel density reflected the degree of angiogenesis and prognosis in patients with esophageal squamous cell carcinoma., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Ghrelin, an orexigenic peptide, is primarily produced and secreted by the gastrointestinal tract. As far as we are aware of, there is no evidence of ghrelin expression in esophageal squamous cell carcinoma (ESCC)., Materials and Methods: Two hundred and ten patients with ESCC who underwent surgical resection were enrolled in this study. We immunohistochemically investigated ghrelin expression in primary ESCC specimens and analyzed the relationship with clinicopathological factors., Results: High ghrelin expression was observed in 61 patients (29.0%). Depth of tumor invasion and histological differentiation were statistically associated with ghrelin expression. As for depth of tumor invasion, the deeper it was, the higher was the expression of ghrelin. Well-differentiated tumors had a significantly higher proportion of ghrelin-expressing cells than other types., Conclusion: Ghrelin expression correlated with tumor depth and tumor differentiation, suggesting an important role of ghrelin in tumor growth in ESCC., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Cyclin-dependent kinase subunit 2 (CKS2) is a cyclin-dependent kinase subunit (CKS) family member that participates in cell cycle regulation. Few studies have investigated its involvement in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to assess the clinical significance of CKS2 in ESCC. We used immunohistochemistry to study the clinicopathologic significance of CKS2 protein expression in 121 patients with ESCC. Using real-time reverse transcriptase-polymerase chain reaction (RT-PCR), we examined the expression of CKS2 mRNA in tumors and the corresponding normal esophageal tissues that were obtained from 62 patients. Finally, siRNA-mediated attenuation of CKS2 expression was examined in vitro. CKS2 protein expression was significantly correlated with depth of tumor invasion, clinical stage, lymphatic invasion and distant metastasis (p=0.033, 0.028, 0.041 and 0.009, respectively). CKS2 mRNA expression was higher in cancer tissue than in corresponding normal tissue (p<0.001). Patients with positive-CKS2 protein expression had a poorer five year survival frequency than patients who did not express CKS2 protein (p=0.025). In vitro, siRNA-mediated suppression of CKS2 slowed the growth rate of ESCC cells compared to control cells (p<0.001). The evaluation of CKS2 expression is useful for predicting the cause of malignant tumors and the prognosis of patients with ESSC.

This review summarizes and evaluates the literature regarding the biomarkers for predicting the response and/or prognosis of esophageal squamous cell carcinoma (ESCC) patients treated with neoadjuvant chemoradiation therapy (CRT). There are seven categories of molecules known to correlate with the response and/or prognosis: tumor suppressors (p53, p21), cell cycle regulators (Cyclin D1, CDC25B, 14-3-3sigma), DNA repair molecules (p53R2, ERCC1), drug resistance proteins [metallothionein (MT)], angiogenic factors (VEGF), molecules involved in cell proliferation/invasion/metastasis (Ki-67, COX-2) and hedgehog signaling molecules (Gli-1). Of the above molecules, the tumor suppressor p53 is expected to be a representative biomarker for predicting the response and prognosis. The cell cycle markers CDC25B and 14-3-3sigma have potential as response biomarkers independent of the p53 status. The DNA repair markers, p53R2 or ERCC1, angiogenic molecule (VEGF), and hedgehog signaling pathway factor Gli-1 also have potential to predict the response and prognosis of ESCC. However, there are still many unanswered questions with regard to predicting the clinical effects of neoadjuvant CRT.

Autophagy is important in the development and remodeling of cells. It is required for cellular adaptation to nutrient deprivation and elimination of damaged organelles. Recently, autophagy has been implicated in carcinogenesis and metastasis. We hypothesized that autophagy-related proteins are initiated until nutrition is supplied by angiogenesis. We evaluated the clinicopathological significance of LC3, an autophagic marker, and its relationship to angiogenesis in patients with esophageal squamous cell carcinoma (ESCC). We immunohistochemically investigated the expression of LC3 as well as endoglin (CD105), a microvessel marker, and vascular endothelial growth factor A (VEGF-A) in 142 patients with ESCC. The high, moderate, and low expression rates of LC3 were 40, 31, and 29 %. LC3 expression inversely correlated with depth of invasion, lymph node metastasis, lymphatic invasion, MVD, VEGF-A expression, and poor prognosis. The overall survival rate was better in patients with high LC3 expression compared to patients with low LC3 expression. We demonstrate that low LC3 expression is related to tumor development as facilitated by angiogenesis and that alteration in LC3 expression is closely related to prognosis. Expression of LC3 proteins is a useful marker for determining tumor prognostic behavior in patients with ESCC.

Purpose: To assess the clinical usefulness and significance of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in superficial esophageal squamous cell carcinoma (ESCC)., Methods: We examined FDG-PET for 80 consecutive patients with superficial ESCC without neoadjuvant treatment. Fifty-seven patients underwent radical esophagectomy, and 23 patients received endoscopic resection. The FDG uptake index was evaluated with clinicopathological findings, and glucose transporter 1 (Glut-1) expression in primary tumors was examined immunohistochemically., Results: The FDG uptake in primary tumors correlated with histology, depth of tumor invasion, lymph node metastasis, lymphatic invasion, vascular invasion, and Glut-1 expression. All patients with more than 4.4 maximum standardized uptake value (SUVmax) had deeper invasion of submucosa. Among 16 patients with lymph node metastasis, only two were found to have lymph node metastasis. FDG uptake, depth of tumor invasion, lymph node metastasis, and histology were found to be prognostic factors, and histology was an independent prognostic factor. In FDG uptake-positive patients, depth of tumor invasion and histology were prognostic factors., Conclusions: FDG-PET is useful for diagnosing tumors with deeper invasion of submucosa and is helpful in making decisions regarding endoscopic treatment for superficial ESCC. Patients with FDG uptake-positive disease, deeper invasion of submucosa, poorly differentiated tumor, and poor prognosis should receive multimodal treatment.

Background: Definitive evaluation of surgical specimens obtained after neoadjuvant chemoradiation therapy (CRT) is important for assessing additional treatment or prognosis in patients with esophageal squamous cell carcinoma (ESCC). In this study, we examined the histological prognostic factors for ESCC patients treated with CRT and determined an appropriate strategy for their evaluation., Patients and Methods: The present study involved 38 consecutive ESCC patients who underwent CRT followed by curative operation. CRT consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation. We examined histological variables as follows: CRT effect on primary tumor (T-effect: T-effective/T-ineffective), tumor depth (pT), lymph node metastases (pN: pN0/N1), number of lymph node metastases (number-pN), lymphatic invasion, and venous invasion. Univariate and multivariate analyses were performed to examine the independent prognostic factors. Survivals and mode of recurrence were then evaluated according to the independent prognostic factors., Results: In the univariate analyses, T-effect, pN, number-pN, lymphatic invasion, and venous invasion were found to be prognostic factors with p < 0.01, and pT was a factor with p < 0.05. In the multivariate analysis, pN and T-effect were independent prognostic factors. The five-year survival rate of pN0 patients was more than 75%, even though the T-effect was poor. The 5-year survival rate of patients judged as pN1/T-effective was 50%, whereas all of the pN1/T-ineffective patients died within 2 years with relapse disease., Conclusion: The evaluation method using both pN status and T-effect is useful for assessing prognosis of ESCC patients treated with neoadjuvant CRT.

Background: Bone morphogenetic proteins (BMPs) are secreted signaling molecules belonging to the transforming growth factor-β (TGF-β) superfamily of growth factors. Recent studies have shown that the influence of the expression of BMP7 was altered in several tumors. The purpose of the current study was to examine the expression of BMP7 in esophageal squamous cell carcinoma and to clarify the clinical impact of BMP7 expression in esophageal squamous cell carcinoma (ESCC)., Methods: A total of 180 patients with ESCC who underwent surgical resection from 1991 to 2004 were eligible for this study. The expression of BMP7 in esophageal tumor tissues was examined immunohistochemically., Results: BMP7 expression was found in the cytoplasm of cancer cells. BMP7 positivity was observed in 61.7% of tumors. The BMP7-positive group had deeper progression, more advanced stages, and greater venous invasion than those without BMP7 expression (p < 0.001, p < 0.005, and p < 0.0005, respectively). In addition, expression of BMP7 correlated with poorer prognosis (p < 0.0005). Multivariate analysis showed that BMP7 expression status was an independent prognostic factor (p < 0.05)., Conclusions: Patients with expression of BMP7 in ESCC had high malignant potential. BMP7 could be a useful prognostic marker for patients with ESCC.

Background: Recently, neoadjuvant chemoradiation therapy (CRT) has been introduced for treatment of esophageal squamous cell carcinoma (ESCC). This study was performed to investigate the usefulness of endoscopic ultrasonography (EUS) in comparison with EUS findings before and after CRT, and histologic findings., Methods: There were 33 patients with potentially resectable ESCC who underwent neoadjuvant CRT. Preoperative EUS and histologic findings were compared. EUS criteria were established on the basis of low and high echoic regions. Resected specimens were examined by hematoxylin-eosin, azan, and cytokeratin immunohistochemical staining., Results: Azan and cytokeratin staining clearly delineated fibrous changes and residual tumor. Low echoic regions corresponded to residual tumor and high echoic spots corresponded to fibrosis. All 12 patients classified as grade 1 on EUS diagnosis had histologic grade 1 tumors. Nineteen of 21 cases that presented with high echo were grade 2 or 3. The prognosis according to EUS diagnosis was similar to the histologic effect., Conclusions: Preoperative EUS findings reflected the histologic effect after neoadjuvant CRT. EUS is a useful tool to assess the effect for CRT and to predict the prognosis in ESCC patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aim: To clarify human papillomavirus (HPV) involvement in carcinogenesis of the upper digestive tract of virological and pathological analyses., Methods: The present study examined the presence of HPV in squamous cell carcinomas of the oral cavity (n = 71), and esophagus (n = 166) collected from Japan, Pakistan and Colombia, with different HPV exposure risk and genetic backgrounds. The viral load and physical status of HPV16 and HPV16-E6 variants were examined. Comparison of p53 and p16(INK4a) expression in HPV-positive and HPV-negative cases was also made., Results: HPV16 was found in 39 (55%) oral carcinomas (OCs) and 24 (14%) esophageal carcinomas (ECs). This site-specific difference in HPV detection between OCs and ECs was statistically significant (P < 0.001). There was a significant difference in the geographical distribution of HPV16-E6 variants. Multiple infections of different HPV types were found in 13 ECs, but multiple infections were not found in OCs. This difference was statistically significant (P = 0.001). The geometric means (95% confidence interval) of HPV16 viral load in OCs and ECs were 0.06 (0.02-0.18) and 0.12 (0.05-0.27) copies per cell, respectively. The expression of p16(INK4a) proteins was increased by the presence of HPV in ECs (53% and 33% in HPV-positive and -negative ECs, respectively; P = 0.036), and the high-risk type of the HPV genome was not detected in surrounding normal esophageal mucosa of HPV-positive ECs., Conclusion: Based on our results, we cannot deny the possibility of HPV16 involvement in the carcinogenesis of the esophagus.

Background: If the sentinel node (SN) concept is established for esophageal cancer, it will be possible to reduce safely the extent of lymphadenectomy. Our objective was to perform SN mapping in esophageal cancer to assess distribution of lymph node metastases with the goal to reduce the need for extensive lymphadenectomy., Methods: A total of 134 patients who underwent esophagectomy with lymph node dissection were enrolled. The number of patients with clinical T1, T2, and T3 tumors was 60, 31, and 32, respectively. Eleven patients also received neoadjuvant chemoradiation therapy (CRT). (99m)Tc-Tin colloid was injected endoscopically into the esophageal wall around the tumor 1 day before surgery. SNs were identified by using radioisotope (RI) uptake. RI uptake of all dissected lymph nodes was measured during and after surgery. Lymph node metastases, including micrometastases, were confirmed by hematoxylin eosin and immunohistochemical staining., Results: Detection rates of SNs were 93.3% in cT1, 100% in cT2, 87.5% in cT3, and 45.5% in CRT patients. In the 120 cases where SNs were identified, lymph node metastases were found in 12 patients with cT1, 18 with cT2, 24 with cT3 tumors, and 3 with CRT. Accuracy rate of SN mapping was 98.2% in cT1, 80.6% in cT2, 60.7% in cT3, and 40% in CRT patients. Although one false-negative case had cT1 tumor, the lymph node metastasis was detected preoperatively., Conclusions: SN mapping can be applied to patients with cT1 and cN0 esophageal cancer. SN concept might enable to perform less invasive surgery with reduction of lymphadenectomy.

Background: The 14-3-3 sigma gene is transcriptionally activated by p53 after DNA damage and facilitates DNA repair during G2 arrest. The present study analyzed the clinical significance of 14-3-3 sigma expression in esophageal squamous cell carcinoma., Patients and Methods: The relationship between 14-3-3 sigma and p53 expressions was investigated immunohistochemically in surgical specimens of primary tumors from 248 patients with esophageal squamous cell carcinoma., Results: The positive expression rates of cytoplasmic and nuclear 14-3-3 sigma were 61.7% and 41.9%, respectively. There was no correlation between 14-3-3 sigma and p53 expression. Positive expression of nuclear 14-3-3 sigma was significantly correlated with depth of invasion, stage, lymphatic invasion, and poor prognosis. Multivariate analysis indicated that negative expression of nuclear 14-3-3 sigma was an independent prognostic factor., Conclusion: Evaluation of the expression of nuclear 14-3-3 sigma proteins may be useful in predicting the outcome in patients with esophageal squamous cell carcinoma.

Background: Twist is a basic helix-loop-helix (bHLH) transcriptional factor that has been identified to play an important role in epithelial-mesenchymal transition (EMT)-mediated metastasis through the regulation of E-cadherin expression. However, few authors have examined the expression of Twist and E-cadherin and their prognostic value in patients with esophageal squamous cell carcinoma (ESCC). The purpose of this study is to evaluate the clinical significance of Twist and E-cadherin expression in ESCC., Methods: We immunohistochemically investigated the relationship between their expression and clinicopathological factors including prognosis in surgical specimens of primary tumors in 166 patients with ESCC., Results: The expression rate of high Twist was 42.0% and that of preserved E-cadherin was 40.4%. The expression of high Twist and reduced E-cadherin was significantly associated with depth of tumor invasion, lymph node metastasis, distant nodal metastasis, stage and lymphatic invasion, and poor prognosis. High Twist expression significantly correlated with reduced E-cadherin expression. In the preserved E-cadherin group, the 5-year survival rate was better for patients who were low for Twist expression than for those who were high for Twist expression. Multivariate analysis indicated that the combination of low Twist and preserved E-cadherin expression was an independent prognostic factor along with tumor depth, distant nodal metastasis and E-cadherin expression., Conclusions: Evaluation of Twist and E-cadherin expressions should be useful for determining tumor properties, including prognosis, in patients with ESCC.

The receptor for advanced glycation end products (RAGE), known as a multiligand receptor for certain stress-associated factors, has been considered to affect the characteristic differences of various cancer cells. We analyzed the expression and clinicopathological significance of RAGE in esophageal squamous cell carcinoma. We investigated immunohistochemically the relationship between RAGE expression and clinicopathological factors, including prognosis, in surgical specimens of primary tumors in 216 patients with esophageal squamous cell carcinoma. Prognostic factors were examined by univariate and multivariate analyses (Cox proportional hazard regression model). The positive expression rate of RAGE was 50%. RAGE expression was negatively correlated with depth of invasion and venous invasion. Moreover, tumors with positive RAGE expression exhibited better prognosis than those with negative RAGE expression (5-year survival, 52% vs. 32%, respectively). Multivariate analysis indicated that the positive expression of RAGE was an independent prognostic factor, along with tumor depth and nodal metastasis. Our findings suggest that loss of RAGE expression may play an important role in the progression of esophageal squamous cell carcinoma. Evaluation of the expression of RAGE could be useful for determining the tumor properties, including those associated with prognosis, in patients with esophageal squamous cell carcinoma.

The chemokine CXCL12, also known as stromal cell-derived factor-1 and its receptor CXCR4 have been shown to play prominent roles in regulating the directional migration and proliferation of various types of cancer cells during the metastatic process. However, few researchers have examined the expression of CXCL12 and CXCR4 and their prognostic value in patients with esophageal squamous cell carcinoma (ESCC). We investigated immunohistochemically the relationship between CXCL12 and CXCR4 expression and clinicopathological factors including prognosis in surgical specimens of primary tumors in 214 patients with ESCC. The positive expression rate of CXCL12 was 53.7% and that of CXCR4 was 84.6%. Positive CXCL12 expression was significantly correlated with lymph node metastasis, tumor stage, gender and lymphatic invasion. The overall and disease-free survival rate was significantly lower in patients with positive CXCL12 expression than in those with negative CXCL12 expression. The expression of CXCR4 had no correlation with clinicopathological variables and prognosis. We showed that positive CXCL12 expression was related to a greater degree to tumor development, compared with CXCR4 expression. Evaluation of CXCL12 expression is useful for determining tumor properties, including nodal metastasis and prognosis in patients with ESCC.

Background and Objectives: The chemokine CXCL12 and its receptor CXCR4 are involved in cell migration, proliferation, and angiogenesis, and promote organ-specific localization of distant metastases in various carcinomas. We examined their expression and microvessel density (MVD) in submucosal esophageal squamous cell carcinoma (ESCC) and analyzed their connection to clinicopathological findings including lymph node micrometastasis (LMM)., Methods: Eighty-six patients with submucosal ESCC underwent curative resection from 1985 to 2002. Immunohistochemical staining of CXCL12, CXCR4, and CD34 was performed with primary tumors, and staining of cytokeratin was performed with dissected lymph nodes. MVD was calculated from CD34 expression, and LMM detected by cytokeratin staining., Results: Expression of CXCL12, but not CXCR4, correlated with lymph node metastasis. There was no significant correlation between the expression of CXCL12 and/or CXCR4 and MVD. LMM was detected in 8 cases and 14 lymph nodes. CXCL12 expression and high MVD were found in tumors with lymph node metastasis including LMM. Furthermore, in the CXCR4-positive tumors, positive CXCL12 expression was more significantly correlated with lymph node metastasis and/or LMM than negative CXCL12 expression., Conclusions: Evaluation of CXCL12 and CXCR4 expression should assist detection of lymph node metastasis including LMM in submucosal ESCC., ((Copyright) 2008 Wiley-Liss, Inc.)

Aim: Esophageal carcinoma is one of the most aggressive malignancies. Many studies have examined various biological factors associated with the malignant potential of esophageal carcinoma. Cyclooxygenase (COX)-2 is overexpressed in various types of human malignancies, including esophageal carcinomas. Although some groups have described COX-2 expression in esophageal adenocarcinoma, few studies have reported COX-2 expression in esophageal squamous cell carcinoma (ESCC)., Methods: We immunohistochemically investigated relationships between COX-2 overexpression in surgical specimens of primary tumors in 228 patients with ESCC. Relationships between COX-2 expression and clinicopathological factors, including prognosis, were analyzed. COX-2 expressions were classified into 4 criteria: Score 0, no staining; Score 1, <10% staining; Score 2, 10-90% staining; and Score 3, >90% staining., Results: Scores of COX-2 immunoreactivity in 228 patients were as follows: Score 0, 21 of 228; Score 1, 71of 228; Score 2, 117 of 228; and Score 3, 19 of 228, respectively. COX-2 expression was significantly correlated with depth of invasion and tumor stage (p=0.03 and p=0.04, respectively). The 5-year survival rate of patients decreased significantly with increased expression of COX-2 (p=0.005). Multivariate regression analysis indicated COX-2 expression as an independent prognostic factor for ESCC., Conclusions: COX-2 overexpression was significantly correlated with depth of invasion, tumor stage and survival in ESCC. Evaluation of COX-2 expression should be useful for determining tumor properties, including prognosis, in patients with ESCC.

Chemoradiation therapy (CRT), a combination of X-ray irradiation and anticancer agents as a radiosensitizer, has been found to be an effective treatment for esophageal cancer and has been linked to p53 genetics. The p53 gene family regulates cell-cycle arrest, apoptosis and DNA damage repair. A recently identified ribonucleotide reductase, p53R2, is directly regulated by p53 in the supply of nucleotides for repairing damaged DNA. In the present study, we investigated the improvement in radiosensitivity of human esophageal squamous cell carcinoma (ESCC) cell lines using p53R2 small interfering RNA (siRNA). p53R2 expression in ESCC cells (TE-8) with or without transfection of p53R2 siRNA was examined by Western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR). The radiosensitivity of TE-8 cells was also measured by cell survival assay. In addition, we investigated the relationship between the expression of p53R2 mRNA in the biopsy specimens of untreated primary tumors and the efficacy of CRT, using RT-PCR. The expression of p53R2 was amplified after X-ray irradiation (14 Gy) and diminished after X-ray irradiation following the transfection of p53R2 siRNA in TE-8 cells. The radiosensitivity of the TE-8 cells significantly improved following the transfection of p53R2 siRNA. In the clinical study, a significantly lower p53R2 mRNA expression was detected in the effective response cases. We demonstrated that p53R2 is associated with the radiosensitivity of ESCC cell lines, and that p53R2 expression is reduced after X-ray irradiation following the transfection of p53R2 siRNA. This protocol could potentially improve the efficacy of radiation therapy.

We report the case of a 56-year-old male who was diagnosed as advanced esophageal cancer with esophago-pulmonary fistula and lung abscess. He received radiation therapy in combination with chemotherapy using cisplatin and 5-FU after insertion of a self-expanding metallic stent. He had sufficient food intake during the chemoradiotherapy (CRT). CRT was very effective for not only primary tumor but also lymph node metastasis, with resulting partial response. We could not detect any relapses and metastases for 8 months after CRT. The CRT after insertion of self-expanding metallic stent is one of the useful and palliative treatments for advance esophageal cancer with esophago-pulmonary fistula.

Background: Patients with oesophageal squamous cell carcinoma have a high rate of recurrence, even after curative resection. The aim of this study was to examine the correlation between the presence of isolated tumour cells (ITCs) in the blood and recurrence, and between the presence of ITCs and E-cadherin expression in the primary tumour in these patients., Methods: Blood samples obtained immediately before and after resection in 125 patients with oesophageal squamous cell carcinoma were examined by real-time reverse transcription-polymerase chain reaction using carcinoembryonic antigen mRNA. Blood samples from 28 healthy volunteers and 42 patients with benign diseases were used as controls., Results: Seventy-seven patients (61.6 per cent) were ITC positive. ITC positivity correlated significantly with tumour depth, lymph node metastasis, stage, lymphatic invasion and venous invasion. Multivariable analysis revealed that tumour depth and ITC positivity were independent factors for a shortened haematogenous disease-free interval. A significant correlation was found between ITC positivity and reduced E-cadherin expression in the primary tumour (P < 0.001). ITC-positive patients with preserved E-cadherin expression had a longer disease-free interval (P = 0.016), haematogenous disease-free interval (P = 0.020) and overall survival (P = 0.004) than those with reduced E-cadherin expression., Conclusion: Examination of ITCs in the blood is useful for predicting haematogenous recurrence in patients with oesophageal squamous cell carcinoma., (Copyright (c) 2007 British Journal of Surgery Society Ltd.)

Snail is a zinc-finger transcription factor that triggers the epithelial-mesenchymal transition (EMT) by directly repressing E-cadherin expression. However, the relationship between E-cadherin and Snail expression remains unclear in esophageal squamous cell carcinoma (ESCC). The purpose of the present study was to evaluate the clinical significance of E-cadherin and Snail expression in ESCC. Immunohistochemistry was used to investigate the expression of E-cadherin and Snail proteins in 194 patients with ESCC. The relationship between expression of these proteins and clinicopathological factors was analyzed, and the usefulness of Snail in disease prognosis was evaluated in relation to E-cadherin expression. E-cadherin expression was preserved in 41.2% of tumors, and Snail expression was confirmed in 61.7%. Tumors with reduced E-cadherin expression invaded deeper (P<0.0001), had more lymph node metastasis (P<0.0001) and had more lymphatic invasion (P=0.0011) than tumors with preserved expression. Tumors that were positive for Snail expression invaded deeper (P=0.0385), had more distant lymph node metastasis (pM) (P=0.0051) and had a more advanced stage (P=0.0044) than those that were negative for Snail expression. Snail expression was not significantly correlated with reduced E-cadherin expression. Patients with reduced E-cadherin expression or positive Snail expression had poor clinical outcomes. In the preserved E-cadherin group, overall survival rate was better in patients with negative Snail expression than in those with positive Snail expression (P=0.035). Snail appears to play a key role in preserved E-cadherin expression. Further studies on other molecules in the pathways related to reduced E-cadherin expression in ESCC from the view-point of EMT are necessary.

Background and Objectives: The purpose of the present study was to analyze clinicopathologic variables in esophageal squamous cell carcinoma (ESCC) according to expression of E-cadherin and alpha-catenin which play an important role in cell adhesion., Methods: We immunohistochemically examined E-cadherin and alpha-catenin in 205 patients with ESCC. The expression results were classified into two groups: preserved expression (+) and reduced expression (-)., Results: The incidence of E-cadherin (-) and alpha-catenin (-) was 52% and 54%, respectively and significantly related each other. For both E-cadherin and alpha-catenin, reduced expression was significantly related to tumor depth, nodal metastasis, stage, recurrence, and prognosis. In the E-cadherin (+) group, the alpha-catenin (+) and alpha-catenin (-) patients differed significantly in tumor depth, nodal metastasis, stage, hematogenous and lymphatic recurrences (P < 0.001, <0.001, <0.001, <0.001 and =0.007, respectively). According to coexpression of E-cadherin and alpha-catenin, the prognosis was best in patients with E-cadherin (+) and alpha-catenin (+), and worst in patients with E-cadherin (-) and alpha-catenin (-). Multivariate analysis revealed that alpha-catenin expression was an independent prognostic factor., Conclusions: The examination of expression of E-cadherin and especially alpha-catenin is useful for predicting lymph node metastasis and clinical outcome of ESCC., ((c) 2007 Wiley-Liss, Inc.)

We applied oligomicroarray analysis of 17086 genes to identify the genes related to lymph node metastasis in esophageal squamous cell carcinoma (ESCC). The samples of cancer and non-cancerous paired tissue were taken from 16 patients with ESCC who underwent esophagectomy with lymph node dissection. Total ribonucleic acid was extracted from the cancer cells obtained by using laser microdissection and was amplified by T7 based-amplification for the application to the oligomicroarray. The oligomicroarray demonstrated 43 overexpressed genes, such as cell-cycle regulators, cell adhesion related genes, anti-apoptosis related genes, and 138 suppressed genes such as cell differentiation related and apoptosis related genes in ESCC cells with lymph node metastasis. Among them, 5 overexpressed genes (SPP-1, CKS2, CCT5, STMN1, NDUFB9) and one suppressed expression gene (GJB2) were selected in the gene profiles, and then the expressions of those genes were confirmed by real-time semi-quantitative reverse transcriptional polymerase chain reaction (RT-PCR) method for confirmation of the result not only in study cases but also in additional 21 cases. The gene expression by real-time semi-quantitative RT-PCR was in accordance with the microarray data. Although we were able to extract some genes related to nodal metastasis in ESCC, further examination is necessary in other genes as well as the interaction of stromal tissues.

Osteopontin is a multifunctional 34 kDa extracellular matrix protein with a cell-binding domain. It is involved cell adhesion and cell migration and is therefore considered to influence tumorigenesis and/or metastasis. The purpose of the present study was to evaluate the clinical significance of Osteopontin expression in oesophageal squamous cell carcinoma (ESCC). In the present study, we immunohistochemically investigated the relationship between Osteopontin expression and clinicopathological factors including prognosis in surgical specimens of primary tumours in 175 patients with ESCC. Osteopontin was expressed in 48% of 175 patients. Osteopontin expression was significantly correlated with lymph node metastasis, lymphatic invasion, and stage (P=0.0015, 0.037 and 0.033, respectively). Tumours with expressing Osteopontin exhibited more lymph node metastasis, lymphatic invasion and advanced stage than the tumour with negative Osteopontin expression. Five-year survival rate was better in patients with negative Osteopontin expression than in those with positive Osteopontin expression (P=0.035). However, multivariate analysis revealed that Osteopontin expression was not an independent prognostic factor. As our findings suggest that Osteopontin may play an important role in progress of ESCC, the evaluation of Osteopontin expression is useful for predicting the malignant properties of ESCC.

Lymph node metastasis, including lymph node micrometastasis (LMM), is one of the most important prognostic factors in esophageal squamous cell carcinoma (ESCC). Vascular endothelial growth factor C (VEGF-C) plays a key role in the process of lymphangiogenesis. We examined VEGF-C expression and tumor microvessel density of the primary tumors in ESCC and analyzed relationships between VEGF-C expression and clinicopathologic findings including LMM in submucosal ESCC. The subjects were 87 patients with submucosal ESCC. Immunohistochemical staining of VEGF-C and CD34 was performed with primary tumors, and staining of cytokeratin was performed with dissected lymph nodes. Microvessel density was calculated from CD34 expression, and LMM was detected by cytokeratin staining. VEGF-C overexpression significantly correlated with depth of tumor invasion, lymphatic invasion, and lymph node metastasis (P < 0.05, P < 0.0001, and P < 0.0001, respectively). High microvessel density also correlated with lymphatic invasion and lymph node metastasis (P < 0.005 and P < 0.05, respectively). LMM was detected in 8 cases and 14 lymph nodes by cytokeratin staining. VEGF-C overexpression and high microvessel density were found in tumors with lymph node metastasis and/or LMM, compared with tumors without nodal metastasis or LMM (P < 0.0001 and P < 0.01, respectively). The present findings indicate that in ESCC with submucosal invasion, VEGF-C overexpression of the primary tumor is a strong high risk factor for lymph node metastasis, including LMM.

Purpose: The p53 gene and its family are important factors for carcinogenesis, prognosis, and chemoresistance in esophageal squamous cell carcinoma. A recently identified ribonucleotide reductase, p53R2, is regulated by p53 for supplying nucleotides to repair damaged DNA. In the present study, we analyzed the expression and clinicopathologic significance of p53 and p53R2 in esophageal squamous cell carcinoma., Experimental Design: We immunohistochemically investigated the relationship between p53 and p53R2 expressions in surgical specimens of primary tumors in 222 patients with esophageal squamous cell carcinoma., Results: The positive expression rate of p53 was 47.1% and that of p53R2 was 61.7%. Positive p53R2 expression was significantly correlated with depth of invasion, lymph node metastasis, stage, and poor prognosis. In the p53-negative group, the 5-year survival rate was better in patients with negative p53R2 expression than in those with positive p53R2 expression. Multivariate analysis indicated that the negative expression of both p53 and p53R2 was an independent prognostic factor along with tumor depth nodal metastasis and stage., Conclusions: We showed that positive p53R2 expression was related to tumor development and that alteration of p53R2 expression in p53-negative tumors was closely related to prognosis. Evaluation of the expressions of p53 and p53R2 proteins should be useful for determining the tumor properties, including prognosis, in patients with esophageal squamous cell carcinoma.

Aim: A consensus treatment strategy for recurrent esophageal squamous cell cancer (ESCC) has not been established. The purpose of the present study was to analyse the mode of recurrence, and evaluate the role of surgical salvage treatment in recurrence of ESCC., Methods: Recurrence was detected in 131 of 367 consecutive patients with ESCC. We retrospectively analysed the mode of recurrence and treatment for recurrence. Recurrence was divided into four types; lymph node, hematogeneous, mixed and local. Treatments were classified into four groups; chemotherapy alone (C group), radiation therapy +/- chemotherapy (R group), surgery +/- other therapy (S group), and no therapy (N group)., Results: Of the 131 recurrences, the number of patients with lymph node, hematogeneous, mixed and local recurrence was 43, 44, 40 and 4, respectively. The number of patients in the C, R, S, N groups was 35, 35, 24 and 37, respectively. Of the 24 patients who received surgical treatment for recurrence, the number of patients with lymph node, hematogeneous, mixed and local recurrence was 11, 6, 6 and 1, respectively. The number of lesions in hematogeneous recurrence was 2 or less. The survival rate from recurrence to death in the C, R, S and N groups was 0, 3.9, 6.7 and 0%, respectively. A statistically significant difference was found in these groups (p < 0.0001)., Conclusions: Salvage surgery is one of the useful treatment tools for resectable metastatic lesions. In such cases, the number of lesions, recurrent sites and effectiveness of chemotherapy and/or radiotherapy should be carefully evaluated.

Background and Objectives: The p53 family regulates cell-cycle arrest, triggers apoptosis, repairs DNA damage caused by various genotoxic stresses, and protects cells from death upon irradiation. The purpose of the present study was to examine the expressions of p53 and one of the p53 family proteins, 14-3-3sigma, in biopsy specimens and to predict the clinical and histological responses to chemoradiation therapy (CRT) in patients with esophageal squamous cell carcinoma (ESCC)., Methods: We investigated with the relationship between p53 and 14-3-3sigma expressions in biopsy specimens obtained from 62 patients with ESCC and analyzed these patients' clinical and histological responses to CRT. Chemoradiation therapy consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation., Results: Following CRT, 71.0% of patients showed a positive clinical response and 52.8% showed a positive histological response. The rate of positive expression was 43.5% for p53 and 58.1% for 14-3-3sigma. Statistically significant correlations were found between p53 expression and clinical response to CRT (P = 0.001) and histological response to CRT (P = 0.041), and between 14-3-3sigma expression and histological response to CRT (P = 0.01). Furthermore, in p53-positive tumors, CRT was more effective in tumors with 14-3-3sigma-positive expressions than those with 14-3-3sigma-negative expressions (P = 0.037). The survival rate of the patients with 14-3-3sigma-positive tumors was better than those with 14-3-3sigma-negative tumors in patients with p53-positive tumors (P = 0.047)., Conclusions: We demonstrated that p53-negative or 14-3-3sigma-positive expressions were closely related to the response to CRT. It is clinically useful to examine the expression of these genes in biopsy specimens for predicting the CRT outcomes in patients with ESCC.

Background: Recurrent laryngeal nerve paralysis represents one of the major complications in esophageal cancer surgery, and patients with esophageal cancer sometimes develop recurrent laryngeal nerve paralysis before treatment. We evaluated recurrent laryngeal nerve reconstruction in patients with lymph node metastasis infiltrating the recurrent laryngeal nerve., Methods: Five patients with preoperative recurrent laryngeal nerve paralysis as a result of involvement of metastasis were enrolled in the present study. Ansa cervicalis-recurrent laryngeal nerve anastomosis in the neck was performed in 4 patients and direct anastomosis of recurrent laryngeal nerve in the mediastinum in 1 patient., Results: Six months after surgery, 3 patients who had undergone ansa cervicalis-recurrent laryngeal nerve anastomosis in the neck displayed good quality of life without hoarseness or aspiration. The patient who underwent direct anastomosis of the recurrent laryngeal nerve in the mediastinum experienced occasional aspiration and hoarseness. The remaining patient displayed poor condition because of recurrent lung tumor, and quality of life was decreased., Conclusions: If patients with recurrent laryngeal nerve paralysis before treatment can undergo potentially curative resection with lymph node dissection, including the metastatic lymph node infiltrating the recurrent laryngeal nerve, recurrent laryngeal nerve reconstruction should be performed to improve quality of life.

Cyclooxygenase-2 (COX-2) displays anti-apoptotic functions related to angiogenesis or blocking of bcl-2 functions. COX-2 overexpression has been found in various human malignancies, including esophageal squamous cell carcinoma (ESCC). The present study examined correlations between expression of COX-2 mRNA and ESCC responses to chemoradiotherapy (CRT). Expression of COX-2 mRNA obtained from 29 biopsy specimens before CRT was quantified using reverse transcriptase-polymerase chain reaction (RT-PCR) using Sybr Green I on the Roche LightCycler system. CRT comprised 5-fluorouracil plus cisplatin and 40 Gy of radiation. Mean COX-2 mRNA score was significantly higher in tumors (1222) than in normal epithelium (50; p=0.05). Expression of COX-2 mRNA was high in 14 patients, low in 8 and absent in 7. The effective response to CRT was achieved in 18 patients. Mean COX-2 mRNA score was significantly higher in ineffective cases (2910) than in effective cases (190; p<0.05). CRT was more effective in patients with low COX-2 mRNA expression than in those with high expression. COX-2 mRNA expression in biopsy specimens was closely related to CRT effectiveness. Examination of COX-2 mRNA expression is useful for predicting the effect of CRT in patients with ESCC.

Purpose: The expression of E-cadherin correlates with the development, progression, and metastasis of esophageal squamous cell carcinoma (ESCC). Slug, a member of the snail family of transcriptional factors, is a newly identified suppressive transcriptional factor of E-cadherin. The purpose of the present study was to evaluate the clinical significance of E-cadherin and Slug expression in ESCC., Experimental Design: Immunohistochemistry was used to investigate the expression of E-cadherin and Slug proteins in 203 patients with ESCC. The relationships between expression of these proteins and clinicopathologic factors, including prognosis, were analyzed., Results: Positive expression of E-cadherin and Slug was observed in 43% and 48% of cases, respectively. The tumors with reduced E-cadherin expression or positive Slug expression invaded deeper, had more lymph node metastasis, and had more lymphatic invasion than the tumors with preserved E-cadherin expression or negative Slug expression. Slug expression significantly correlated with reduced E-cadherin expression. Sixty-seven of the 98 (68.4%) tumors with positive Slug expression had reduced E-cadherin expression (P = 0.0011). Patients with reduced E-cadherin expression or positive Slug expression had poor clinical outcomes. In the preserved E-cadherin group, the 5-year survival rate was better for patients who were negative for Slug expression than for those who were positive for Slug expression (P = 0.035). Multivariate analysis indicated that E-cadherin expression and Slug expression were not independent prognostic factors., Conclusions: Evaluation of not only the expression of E-cadherin but also the co-expression of E-cadherin and Slug in preserved E-cadherin group is useful for predicting malignant properties of ESCC.

The p53 family regulates cell-cycle arrest, triggers apoptosis or is involved in repair of DNA damage. In the present study, we analysed the expression of some p53 family proteins and their responses to chemoradiation therapy (CRT) in cases of oesophageal squamous cell carcinoma (ESCC). We immunohistochemically investigated the relationship between p53, p53R2, and p21 expression in biopsy specimens of untreated primary tumours and their clinical and histological responses to CRT in 62 patients with ESCC. Chemoradiation therapy consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation. The rates of clinical and histological responses (complete or partial) to CRT were 71.0% (clinical) and 52.8% (histological). The rate of positive expression was 43.5% for p53, 37.1% for p53R2, and 54.8% for p21 expression. Statistically significant correlations were found between p53 or p53R2 expression and favourable response to CRT (P=0.0001 or 0.041 clinical, P=0.016 or 0.0018 histological, respectively). Furthermore, in p53-negative tumours, CRT was more effective in tumours with p53R2 negative expression than those with p53R2 positive expression (P=0.0014). We demonstrated that the negative expression of p53 and p53R2 expression was closely related to the effect of CRT and should predict the CRT outcome in patients with ESCC.

The incidence of multiple primary carcinomas (MPCs) associated with esophageal cancer has increased. The purpose of this study was to analyze clinicopathologic findings for MPC and for only esophageal cancer (OEC). Of 157 patients with MPCs, 60 had synchronous cancer and 97 metachronous cancer. Another 42 patients had antecedent esophageal cancer (AEC), and 55 patients had subsequent esophageal cancer (SEC). We retrospectively analyzed the clincopathologic findings for patients in these categories. The incidence of early-stage carcinoma was higher in patients with MPCs than in those with an OEC. Of patients with MPCs, those with metachronous cancer had a higher rate of early-stage carcinoma than those with synchronous cancer. The 5-year survival rates were not significantly different for MPC and OEC patients. Patients with metachronous cancer had a significantly better prognosis than those with synchronous cancer (p = 0.017); and in the metachronous cancer group the prognosis was significantly better for patients with AEC than for those with SEC (p = 0.0005). Meticulous follow-up after treatment of a first cancer should be required to detect other early-stage carcinomas.

Background and Objectives: It is important to identify the initial lymph node metastasis when performing less invasive surgery. The purpose of the present study was to analyze locations of solitary lymph node metastasis and micrometastasis in esophageal carcinoma., Methods: We retrospectively analyzed the initial sites of lymph node metastasis in esophageal cancer. Sixty-five consecutive patients with solitary lymph node metastasis, and 33 pN0 patients with only lymph node micrometastasis detected by immunohistochemistry, were classified according to tumor location and tumor depth., Results: The location of lymph node metastasis in the 22 patients with superficial cancer was limited to recurrent nerve nodes (RN) in the upper thoracic esophagus; RN, paraesophageal nodes (PE), or perigastric nodes (PG) in the middle or lower thoracic esophagus. Thirty-six patients with advanced cancer had lymph node metastasis at RN, PE, or PG locations, while in the remaining seven, lymph node metastasis was found in areas far from the primary tumor. Regarding the 33 patients with lymph node micrometastasis, the locations of micrometastasis were similar to those of solitary metastasis., Conclusions: Although less invasive surgery, such as reduction of lymphadenectomy, may be suitable for superficial cancer, it should be performed with special care in advanced cancer.

The detection rate of early-stage esophageal cancer has increased recently. Various types of treatment including endoscopic mucosal resection, blunt dissection, and esophagectomy with extended lymphadenectomy are employed in patients with submucosal esophageal cancer. The purpose of the present study was to analyze prognostic factors in patients with submucosal esophageal cancer. Univariate analysis showed that lymph node metastasis, subdivision of tumor depth, and lymphatic invasion were correlated with prognosis, whereas sex, age, tumor location, surgical procedure, adjuvant therapy, histologic findings, and venous invasion did not affect prognosis. Multivariate analysis demonstrated lymph node metastasis to be the only significant prognostic factor in submucosal esophageal cancer. Although subdivisions of tumor depth did not reach significance as prognostic factors, lymph node metastasis was strongly related to tumor depth. To select the individualized treatment in patients with submucosal esophageal cancer, accurate diagnosis of lymph node metastasis necessitates a combination of imaging methods such as endoscopic ultrasound-guided fine-needle aspiration, computed tomography, and positron emission tomography.

Objective: Esophageal cancer has been reported to be frequently associated with cancer of the head and neck. The iodine dye method is reportedly useful to detect early esophageal cancer. The aim of this study was to clarify clinicopathological and biological characteristics of esophageal squamous cell carcinoma associated with head and neck cancer (HN group)., Methods: Thirty-seven patients of the HN group who underwent esophagectomy were examined clinicopathologically compared to 42 patients with esophageal cancer alone (SE group). All resected specimens were histologically studied after iodine dye staining, and p53 and cyclin D1 (CD1) expression were immunohistochemically examined in esophageal cancer., Results: The HN group had more multiple iodine-unstained lesions and multiple primary cancers within the esophagus compared with the SE group (p = 0.0027, p = 0.067, respectively). There was no significant difference in smoking, drinking, family history and the other clinicopathological factors between the HN and SE groups. Coexpression of p53 and CD1 was found to be significant in the HN group (p = 0.03)., Conclusions: The coexistence of multiple iodine-unstained lesions, multiple cancers in the esophagus and overexpression of p53 and CD1 is suggested as a risk factor for the HN group., (2004 S. Karger AG, Basel.)