Tetsuhiro Owaki

Significance of Twist expression and its association with E-cadherin in esophageal squamous cell carcinoma.

BackgroundTwist 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.MethodsWe immunohistochemically investigated the relationship between their expression and clinicopathological factors including prognosis in surgical specimens of primary tumors in 166 patients with ESCC.ResultsThe 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.ConclusionsEvaluation of Twist and E-cadherin expressions should be useful for determining tumor properties, including prognosis, in patients with ESCC.

Biomarkers for predicting the response of esophageal squamous cell carcinoma to neoadjuvant chemoradiation therapy.

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.

Expression of p53R2 Is Related to Prognosis in Patients with Esophageal Squamous Cell Carcinoma

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.

Expression of CXCL12 and its receptor CXCR4 correlates with lymph node metastasis in submucosal esophageal cancer.

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).

Multiple Primary Carcinomas with Esophageal Squamous Cell Cancer: Clinicopathologic Outcome

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.

Prognostic factors in patients with submucosal esophageal 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.

Carcinoembryonic Antigen Messenger RNA Expression in Blood Predicts Recurrence in Esophageal Cancer

Purpose: The clinical significance of isolated tumor cells (ITC) in blood has not been clearly established, particularly during follow-up in cancer patients. We conducted a longitudinal analysis of the relationship between ITC in blood during follow-up and clinicopathologic findings in patients with esophageal squamous cell carcinoma. Experimental Design: Blood samples obtained from 106 patients were examined by real-time RT-PCR assay targeting carcinoembryonic antigen (CEA) mRNA. Follow-up examination every 3 months after surgery included testing for CEA mRNA and tumor markers, as well as imaging. Results: Thirty-nine (36.8%) patients were positive for CEA mRNA expression. CEA mRNA positivity significantly correlated with tumor depth, lymph node metastasis, stage, and venous invasion. Recurrent disease was found in 34 of 106 (32.1%) cases. CEA mRNA was found in 28 (76.5%) patients experiencing relapse. Of these 28 patients, the number positive of CEA mRNA before detection by imaging, at the same time of detection by imaging, and after detection by imaging was 18 (52.9%), 8 (23.5%), and 2 (5.9%), respectively. The sensitivity, specificity, positive predictive value, and negative predictive value for CEA mRNA were higher than those for serum CEA or squamous cell carcinoma. Patients positive for CEA mRNA experienced significantly shorter disease-free interval than those with negative CEA mRNA (P < 0.001). According to multivariate analysis, CEA mRNA positivity was an independent factor for disease-free interval. Conclusions: Examination of CEA mRNA in peripheral blood during follow-up is useful for early detection of occult recurrence. We believe that CEA mRNA in blood will be a new marker for recurrence in esophageal squamous cell carcinoma.

Analysis of the Fibrinogen and Neutrophil-Lymphocyte Ratio in Esophageal Squamous Cell Carcinoma: A Promising Blood Marker of Tumor Progression and Prognosis.

Abstract 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.

Expression of vascular endothelial growth factor‑C and vascular endothelial growth factor receptor‑3 in esophageal squamous cell carcinoma

Lymph node metastasis is one of the most important prognostic factors in esophageal squamous cell carcinoma (ESCC). Vascular endothelial growth factor (VEGF)-C and its receptor, VEGF receptor-3 (VEGFR-3), are key in the process of lymphangiogenesis. The present study immunohistochemically examined the expression of VEGF-C, VEGFR-3 and D2-40 in 119 patients with ESCC, and microlymphatic vessel density (MLVD) was calculated based on D2-40 expression counts. Positive expression of VEGF-C was found to correlate significantly with depth of tumor invasion, lymphatic invasion and lymph node metastasis (P<0.001, P<0.0001 and P<0.0001, respectively). Patients with deeper tumor invasion showed higher positivity of VEGFR-3 expression (P<0.05), while patients with lymph node metastasis showed higher MLVD (P<0.05). When patients were divided into three groups according to the expression of VEGF-C and VEGFR-3, patients with coexpression of VEGF-C and VEGFR-3 exhibited poorer prognosis and higher MLVD. The VEGF-C/VEGFR-3 axis is important in tumor lymphangiogenesis.

Massive Bleeding from Dieulafoy’s Lesion of the Small Intestine in a Child – Therapy for the Bleeding from Gastrointestinal Tract Out of Endoscopic Observation

Dieulafoy’s lesion is recognized as a submucosal artery associated with a minute mucosal defect and a rare cause of severe gastrointestinal hemorrhage. Especially, that of distal jejunum or ileum is extraordinarily rare. It is very difficult to detect the lesion in these parts. We experienced massive bleeding from Dieulafoy’s lesion of the distal jejunum in a 12-year-old girl. Preoperative angiography and intraoperative palpation detected the point of bleeding. She was rescued by partial jejunectomy. Compiled reports suggested that careful palpation was useful for detection of the location of the bleeding point, which was enhanced as vascular dilatation by the angiogram, during the operation comparatively.