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Purpose: Few studies have reported the impact of chemoradiotherapy (CRT) on the objective response of patients with locally advanced unresectable esophageal squamous cell carcinoma (ESCC). We evaluated the factors predicting therapeutic effectiveness and the short- and long-term outcomes in patients with T4b ESCC treated with CRT., Methods: We included 155 patients with T4b ESCC who underwent CRT at the Department of Surgery, Gastroenterological Center, Yokohama City University, between January 2000 and December 2018. Responders were defined as patients who demonstrated a complete response (CR) or partial response (PR). Multivariate analysis for objective response was performed using a logistic regression model, and prognostic factors were evaluated by univariate and multivariate analyses., Results: Among the 155 patients included, 20 and 84 patients demonstrated a CR and PR, respectively, resulting in a response rate of 67.1%. The median overall survival (OS) was 15.2 months, and the 3-year survival rate was 32.1%. High Glasgow prognostic score (GPS) and advanced N-category independently predicted the objective response to CRT. GPS and objective response were independent prognostic factors for OS. There was no significant difference in the long-term survival of responders who received subsequent chemotherapy or salvage surgery., Conclusions: High GPS and advanced N-category predicted a poor objective response to CRT in patients with T4b ESCC. Therefore, chemotherapeutic regimens with a higher efficacy are required. The indications for salvage surgery for responders should be carefully considered, with care taken to avoid complications. To confirm this, prospective randomized controlled studies are necessary., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Surgery in elderly patients with esophageal cancer is challenging due to high mortality and limited survival. This study aimed to evaluate the safety and effectiveness of curative esophagectomy in elderly patients with esophageal cancer., Methods: This study included 77 and 112 patients with esophageal cancer aged ≥ 70 and 40-64 years, respectively, who underwent R0 esophagectomy between January 1998 and December 2016. Patient characteristics, intraoperative outcomes, postoperative complications, and long-term survival were compared., Results: The proportions of comorbid diseases (85.7% vs. 57.1%; P < 0.001), the American Society of Anesthesiologists score (1/2/3; 2.6%/94.8%/2.6% vs. 42.9%/57.1%/0%; P < 0.001), the preoperative systemic inflammation score (SIS) (0/1/2; 20.8%/48.1%/31.2% vs. 38.4%/38.4%/23.2%; P = 0.036), and postoperative complications (Clavien-Dindo grade ≥ III) (33.8% vs. 20.5%; P = 0.041) were significantly higher in the elderly group than those in the non-elderly group. However, long-term overall survival (OS) and relapse-free survival were not significantly different between the groups. On multivariate analysis, SIS (hazard ratio, 3.06; P = 0.037) and severe postoperative complications (hazard ratio, 2.01; P = 0.039) were significantly correlated with OS in the elderly group., Conclusions: As SIS and severe postoperative complications lead to poor prognosis after R0 esophagectomy in elderly patients, selecting appropriate patients for esophagectomy and preventing severe postoperative complications is essential., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/aim: The purpose of this study was to evaluate the usefulness of minimally invasive esophagectomy (MIE) for stage II/III esophageal cancer (EC)., Patients and Methods: We compared surgical outcomes between MIE and open esohagectomy in EC patients with pStage II/III using the propensity scoring system., Results: Fifty-seven patients were classified into the MIE group and 57 patients into the open esophagectomy (OE) group. The incidence of major complications was similar between the two groups. The 5-year OS was significantly better in the MIE group (69.0% vs. 35.5%; p=0.004) and no significant difference was observed in the 5-year recurrence-free survival (RFS, 52.2% vs. 29.2%; p=0.064). Multivariate analysis showed MIE was a prognostic factor of OS (p<0.001) and RFS (p=0.032)., Conclusion: MIE was as safe and feasible as OE, and an independent prognostic factor for OS and RFS in patients with stage II/III EC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The tumor, node, metastasis classification system for staging esophageal cancer does not include tumor volume although it may be an important prognostic factor. We evaluated the prognostic value of tumor volume in esophageal cancer., Methods: We performed a retrospective study in patients with histologically confirmed primary esophageal cancer who underwent curative esophagectomy at our facility between April 1992 and December 2013. The Tumor Depth Parameter (TDP) was defined as mucosa = 1, submucosa = 2, muscularis propria = 3, adventitia = 4, and invasion into adjacent organs = 5. The pathological Tumor Volume Index (TVI) was defined as the major axis × the minor axis × TDP. The appropriate tumor diameter and TVI cutoff values were determined by the Youden index obtained from the receiver operating characteristic curve. Prognostic factors for overall survival were evaluated by univariate analysis and Cox proportional hazards regression models., Results: We enrolled 302 patients. In the univariate analysis, patient age and sex, thoracoscopic surgery, tumor depth of invasion and diameter, lymph node metastasis, and the TVI were significantly associated with overall survival. In our multivariate analysis, patient age and sex, thoracoscopic surgery, lymph node metastasis, and the TVI were independently associated with overall survival., Conclusions: The pathological TVI was an independent prognostic factor in patients with esophageal carcinoma and could be included in the staging system of esophageal cancer.

Background: Esophageal cancer often involves direct invasion of adjacent organs and patient survival rates are low. Sarcopenia has been reported to be associated with a poor prognosis in several types of malignancies. However, the impact of sarcopenia on the long-term survival of patients with unresectable locally advanced esophageal cancer remains unclear., Patients and Methods: A total of 48 patients undergoing definitive chemoradiotherapy at our Institution from October 2012 to December 2015 were enrolled; their data were compared according to patient skeletal muscle index (SMI): low SMI (sarcopenia group), n=34; normal SMI (non-sarcopenia group), n=14., Results: There were no significant differences in the incidence of severe adverse events and dose reduction rate between the two groups. The incidence of nutritional support was significantly higher in the groups with sarcopenia than in the non-sarcopenia group (44.1% vs. 7.1%, p=0.077). Response rates were significantly lower in the sarcopenia group than in the non-sarcopenia group (43.8% vs. 78.6%, p=0.025). The overall survival rate in the group with sarcopenia was significantly lower than that in the non-sarcopenia group (3-year: 36.95% vs. 63.9%, p=0.018)., Conclusion: Sarcopenia prior to treatment may worsen the long-term survival of patients with unresectable locally advanced esophageal cancer. Further well-designed prospective trials are needed to estimate whether adequate nutritional support has a favorable impact on therapeutic outcomes in this population., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

High Glasgow Prognostic scores (GPSs) have been associated with poor outcomes in various tumors, but the values of GPS and modified GPS (mGPS) in patients with advanced esophageal cancer receiving chemoradiotherapy (CRT) has not yet been reported. We have evaluated these with respect to predicting responsiveness to CRT and long-term survival. Between January 2002 and December 2011, tumor responses in 142 esophageal cancer patients (131 men and 11 women) with stage III (A, B and C) and IV receiving CRT were assessed. We assessed the value of the GPS as a predictor of a response to definitive CRT and also as a prognostic indicator in patients with esophageal cancer receiving CRT. We found that independent predictors of CRT responsiveness were Eastern Cooperative Oncology Group (ECOG) performance status, GPS and cTNM stage. Independent prognostic factors were ECOG performance status and GPS for progression-free survival and ECOG performance status, GPS and cTNM stage IV for disease-specific survival. GPS may be a novel predictor of CRT responsiveness and a prognostic indicator for progression-free and disease-specific survival in patients with advanced esophageal cancer. However, a multicenter study as same regime with large number of patients will be needed to confirm these outcomes., (© 2015 International Society for Diseases of the Esophagus.)

Tumor-associated macrophages (TAMs) have important roles in the angiogenesis and tumor immunosuppression of various cancers, including esophageal squamous cell carcinomas (ESCCs). To elucidate the roles of TAMs in ESCCs, we compared the gene expression profiles between human peripheral blood monocyte-derived macrophage-like cells (Macrophage&#95;Ls) and Macrophage&#95;Ls stimulated with conditioned medium of the TE series human ESCC cell line (TECM) (TAM&#95;Ls) using cDNA microarray analysis. Among the highly expressed genes in TAM&#95;Ls, we focused on neural cell adhesion molecule (NCAM). NCAM knockdown in TAM&#95;Ls revealed a significant decrease of migration and survival via a suppression of PI3K-Akt and fibroblast growth factor receptor 1 (FGFR1) signaling. Stimulation by TECM up-regulated the level of FGFR1 in Macrophage&#95;Ls. Recombinant human fibroblast growth factor-2 (rhFGF-2) promoted the migration and survival of TAM&#95;Ls and TE-cells through FGFR1 signaling. Our immunohistochemical analysis of 70 surgically resected ESCC samples revealed that the up-regulated FGF-2 in stromal cells, including macrophages, was associated with more aggressive phenotypes and a high number of infiltrating M2 macrophages. These findings may indicate a novel role of NCAM- and FGF-2-mediated FGFR1 signaling in the tumor microenvironment of ESCCs., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: We investigated the efficacy of nutritional support in patients treated with chemoradiotherapy (CRT) for locally advanced esophageal cancer (LAEC)., Methods: Eleven patients treated with CRT for locally advanced esophageal squamous cell carcinoma were included. Oral intake energy expenditure (OIE) and total energy expenditure (TEE) of all patients were calculated. Oral nutrition supplementations (ONSs) were utilized as nutritional therapy for the patients with malnutrition (OIE/TEE<0.6). Enteral nutrition (EN) was used in the patients with tumor obstruction., Result: Two patients (18.9%) received ONS and 2 other patients received EN. Seven patients were able to take enough energy in the meal. The mean energy charge was increased from 67.9%to 84.9%. Nine patients (81.8%) completed the treatment regimen. During the CRT period, the prognostic nutritional index (PNI) and C-reactive protein level (mg/dL) were not significantly different. The body mass index decreased to 0.39 kg/m2 (p=0.039) and the mean weight loss was 1.57%. The overall response rate was 81.8%., Conclusion: The nutritional support in the patients treated with CRT for LAEC is effective for maintaining nutritional status. Moreover, the response rate is satisfactory.

Tumor-associated macrophages (TAMs) are known to be involved in the progression of various human malignancies. We previously demonstrated that CD204 was a useful marker for TAMs contributing to the angiogenesis, progression, and prognosis of human esophageal squamous cell carcinoma (ESCC). We also showed that conditioned media of ESCC cell lines induced CD204 expression in THP-1 human monocytic leukemia cells. Here, we performed a cDNA microarray analysis between THP-1 cells stimulated with TPA (macrophage [MΦ]-like THP-1 cells) treated with and without conditioned medium of ESCC cell line to clarify the molecular characteristics of TAMs in ESCC. From the microarray data, we discovered that Cyr61 was induced in CD204-positive-differentiated THP-1 cells (TAM-like THP-1 cells). In the ESCC microenvironment, not only cancer cells but also TAMs expressed Cyr61. Interestingly, the expression levels of Cyr61 showed a significant positive correlation with the number of CD204-positive macrophages in ESCCs by immunohistochemistry. Recombinant human Cyr61 (rhCyr61) promoted cell migration and induced the expression of CD204 along with the activation of the MEK/ERK pathway in MΦ-like THP-1 cells. Pretreatment with a MEK1/2 inhibitor significantly inhibited not only the Cyr61-mediated migration but also the CD204 expression in the MΦ-like THP-1 cells. These results suggest that Cyr61 may contribute to the expression of CD204 and the promotion of cell migration via the MEK/ERK pathway in TAMs in the ESCC microenvironment., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background/aims: Here we investigated postoperative prognostic factors and surveillance in patients with esophageal cancer. METHODOLOGY Prognostic factors were evaluated at several different postoperative stages in 257 patients with curative (R0) esophagectomy. Cause of death and pattern of tumor recurrence were also analyzed., Results: There was a significant difference in the distribution of cause of death according to the time after surgery (p<0.001). The pattern of recurrence also differed according to the time after surgery, although this was not statistically significant. A Cox proportional regression hazard model for disease-specific survival revealed that Tumor-Node-Metastasis (TNM) stage was an independent prognostic factor only from the time of initial surgery until the third postoperative year, and no postoperative prognostic factors were detected after the fourth and fifth years. There were significant differences in disease-specific survival among pathological TNM stages between the time of initial surgery and postoperative year five, but not between stages I and II at postoperative years two, three, or four. There were no significant differences between the stages at postoperative year five. Relapse-free survival differed between stages II and III at postoperative year five, although the other results were similar to those for disease-specific survival., Conclusions: Prognostic factors for esophageal cancer alter during the postoperative period. Although the pathological stage at the time of initial surgery has less prognostic power after 3 years, it remains important to monitor treatments for esophageal cancer continuously, as well as concomitant diseases and other malignancies.

To identify potential molecular targets for diagnosis, treatment and/or prevention of lung and esophageal carcinomas, we screened for genes that were overexpressed in tumors through gene expression analyses of 120 lung cancers and 19 esophageal squamous-cell carcinomas using a cDNA microarray consisting of 27,648 cDNA or expressed sequence tags. In this process, we identified a gene, Opa interacting protein 5 (OIP5), to be highly transactivated in the majority of lung and esophageal cancers. Immunohistochemical staining using 336 archived non-small cell lung cancers and 305 esophageal squamous-cell carcinomas specimens demonstrated that OIP5 expression was significantly associated with poor prognosis of lung and esophageal cancer patients (P = 0.0053 and 0.0168, respectively), and multivariate analysis confirmed its independent prognostic value for non-small cell lung cancers (P = 0.0112). Suppression of OIP5 expression with siRNA effectively suppressed the growth of cancer cells, whereas the exogenous expression of OIP5 enhanced the growth of cancer cells. In addition, OIP5 protein is likely to be stabilized through its interaction with Raf1. OIP5 is a promising target for developing new prognostic biomarkers and anti-cancer drugs., (© 2011 Japanese Cancer Association.)

Background: This retrospective study evaluated the surgical learning curve and outcomes of thoracolaparoscopic esophagectomy., Patients and Methods: The study group comprised a series of 92 patients with preoperatively diagnosed resectable thoracic esophageal cancer. Additionally, the surgical outcomes in 79 esophageal cancer patients receiving open esophagectomies were compared. All patients underwent thoracolaparoscopic esophagectomy in the lateral decubitus position. The short- and long-term outcomes were evaluated, and the surgical learning curve was assessed., Results: The total operation time was 477.8 ± 102.2 min, the thoracoscopic time was 157.9 ± 61.3 min, the total blood loss was 554.4 ± 280.5 ml, and the number of retrieved lymph nodes was 34.3 ± 14.3. Postoperative morbidity was observed in 23 patients. After the surgeon's first 40 cases, the surgical technique and short-term outcomes were stable. The 5-year disease-specific survival was 66.6% and the 5-year overall survival was 64.6% in patients receiving R0 thoracolaparoscopic esophagectomy. Comparison of 5-year disease-specific survival rate according to tumor-node-metastasis stage between patients receiving R0 thoracolaparoscopic esophagectomy and conventional open esophagectomy showed that there were no significant differences in survival in any stage between the two groups. Loco-regional recurrence was observed in 6 patients, distant recurrence in seven, and combined recurrence in nine after R0 thoracolaparoscopic esophagectomy. There was no significant difference in the pattern of recurrence between the two groups., Conclusions: Thoracolaparoscopic esophagectomy for esophageal cancer was technically feasible and oncologically satisfactory, according to the surgical learning curve.

Background/aims: It is essential to perform appropriate lymph node dissection in esophageal cancer. However, it may be beneficial if lymph node dissection could be minimized to reduce the surgical stress., Methodology: Between April 1992 and March 2005, 121 esophageal cancer patients (42 patients with solitary lymph node metastasis and 79 N0 patients) were enrolled. The survival time, distribution of solitary lymph node metastasis and the pattern of recurrence were evaluated., Results: The distribution of solitary lymph node metastasis was extensively observed in cervical, thoracic and abdominal cavities and the site of lymph node recurrence could even be detected in non-regional lymph nodes in N0 patients. It was difficult to predict the site of initial lymph node metastasis in patients with esophageal cancer., Conclusions: Systemic lymph node dissection for regional lymph nodes is recommended for resectable esophageal cancer as the concept of sentinel lymph nodes has not yet been proven.

Background: This study was undertaken to assess the value of administering perioperative sivelestat sodium hydrate (SSH), a selective neutrophil elastase inhibitor, after video-assisted thoracoscopic oesophagectomy for cancer., Method: Thirty-one consecutive patients with thoracic oesophageal cancer selected to undergo video-assisted thoracoscopic oesophagectomy with lymph node dissection between March 2007 and March 2009 were assigned randomly to a treatment group that received SSH intravenously for 7 days from the beginning of surgery (16 patients) and a control group that received saline (15). The primary endpoint was pulmonary function based on the arterial partial pressure of oxygen/fraction of inspired oxygen ratio (P/F ratio) during the first 9 days after surgery. Secondary endpoints included platelet count, serum C-reactive protein (CRP) concentration, plasma neutrophil elastase-α(1)-antitrypsin complex level, duration of mechanical ventilation and systemic inflammatory response syndrome (SIRS), and length of intensive care unit (ICU) and hospital stay., Results: The mean P/F ratio of patients who received SSH was significantly higher than that of the control group on postoperative days 1-5 and 7. Duration of mechanical ventilation and SIRS, and length of ICU stay were significantly shorter in the treatment group. Serum CRP concentration on postoperative day 9 was significantly lower (P = 0·048), platelet counts on days 2, 3 and 5 were higher (P = 0·012, P = 0·049 and P = 0·006 respectively), and the incidence of postoperative acute lung injury was significantly lower following SSH treatment (P = 0·023)., Conclusion: Perioperative sivelestat may maintain postoperative pulmonary function following video-assisted oesophagectomy., (Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Background: The prognosis for patients with N0 oesophageal cancer is favourable, but relevant prognostic factors and appropriate surveillance protocols have not been identified for these patients., Patients and Methods: A total of 210 oesophageal cancer patients were included in this study. Of these, 92 (43.8%) had no lymph node metastasis. Predictive factors for lymph node metastasis were evaluated in N0 oesophageal cancer. Survival, prognostic factors, causes of death and pattern of recurrence were assessed between patients with and without lymph node metastasis., Results: Logistic regression analysis revealed that depth of tumour invasion (T1) was an independent predictive factor for N0. The Cox proportional hazard regression model showed that venous invasion was an independent prognostic factor for disease-specific survival in N0 oesophageal cancer patients (hazard ratio=3.977, p=0.042). Locoregional recurrence was less frequent in patients with N0 oesophageal cancer (p=0.0319)., Conclusion: Meticulous and long-term follow-up is necessary even for patients with N0 oesophageal cancer, particularly for those with adverse prognostic factors.

Background and Objectives: We retrospectively compared surgical outcomes between patients with intra-thoracic and extra-thoracic (cervical and abdominal) lymph-node metastasis., Methods: The study population comprised 96 patients with lymph-node metastasis who had undergone curative esophagectomy for thoracic esophageal cancer. The patients were grouped according to whether the site of lymph-node metastasis was intra-thoracic, extra-thoracic, or both intra-thoracic and extra-thoracic. The patient characteristics, survival time, and prognostic factors were compared., Results: The most significant difference in disease-specific survival was detected at a threshold value of four metastatic lymph nodes. Lymph-node metastasis was observed at intra-thoracic sites in 41 patients, at extra-thoracic sites in 20 patients, and at both intra-thoracic and extra-thoracic sites in 35 patients. Intra-thoracic lymph-node metastasis was frequently observed in patients with middle and upper thoracic esophageal cancer. There was no difference in the number of metastatic lymph nodes between patients with intra-thoracic and extra-thoracic lymph-node metastasis. Multivariate analysis revealed that the number of metastatic lymph nodes was an independent prognostic factor, whereas the site of metastatic lymph nodes was not., Conclusions: These findings suggest that the surgical outcomes in patients with thoracic esophageal cancer depend on the number, but not the site, of metastatic lymph nodes after curative esophagectomy.

We retrospectively investigated the efficacy of a chemoradiotherapy regimen using daily low-dose cisplatin and continuous 5-fluorouracil infusion in 71 registered patients with unresectable esophageal cancer. The overall response rate (complete response plus partial response) was 59%. The major toxicities observed were leukopenia and anorexia. The 1- and 3-year overall survival rates were 54.6% and 18.4%, respectively. A low preoperative C-reactive protein level was found to be associated with a good response. The pretreatment performance status and response results were both shown to be prognostic factors for overall survival. These findings confirmed that the chemoradiotherapy regimen had curative potential for unresectable esophageal cancer.

Background: Pulmonary metastasectomy is a standard method for treatment of selected pulmonary metastases cases. Nevertheless, because prognosis for patients with lung metastases from esophageal cancer who have undergone pulmonary metastasectomy is poor, candidates for this method of treatment are rare. Therefore, the efficacy of surgical treatment for pulmonary metastatic lesions from esophageal cancer has not been thoroughly examined., Methods: Between March 1984 and May 2006, 57 patients underwent resection of pulmonary metastases from primary esophageal cancer. These cases were registered in the database developed by the Metastatic Lung Tumor Study Group of Japan and were retrospectively reviewed from the registry. After excluding eight cases because of missing information, we reviewed the remaining 49 cases and examined the prognostic factors for pulmonary metastasectomy for metastases from esophageal cancer., Results: There were no perioperative deaths. After pulmonary metastasectomy, disease recurred in 16 (33%) of the 49 patients. The overall 5-year survival was 29.6%. Median survival time was 18 months. The survival of patients with a disease-free interval (DFI) less than 12 months was significantly lower than patients with a DFI greater than 12 months. Through multivariate analysis, we identified DFI as a clinical factor significantly related to overall survival (p = 0.04)., Conclusions: We identified that patients with a DFI less than 12 months who underwent pulmonary metastasectomy for metastases from esophageal cancer had a worse prognosis. Pulmonary metastasectomy for esophageal cancer should be considered for selected patients with a DFI >/=12 months.

This study aimed to identify predictive factors and to evaluate appropriate treatments for recurrence of esophageal cancer after curative esophagectomy. About 166 consecutive patients, who underwent curative esophagectomy, were enrolled between April 1994 and March 2003. Recurrence was classified as loco-regional or distant. Logistic regression analysis was used to identify predictive factors for recurrence. Prognostic factors were evaluated by Log-rank test and Cox proportional hazard regression analysis. The disease-specific 5-year survival was 56.8%. Recurrence was observed in 72 patients (43.4%), with 64 of these occurring within 3 years. The number of metastatic lymph nodes and lymphatic invasion independently predicted recurrence. There were significant differences in time to recurrence and survival time between loco-regional, distant recurrence, and combined recurrence. The 5-year survival time in patients with recurrence was 11.9%, and median survival time was 24 months. There was also a significant difference in survival after recurrence between treatment methods (no treatment vs chemo-radiotherapy, p=0.0063; chemotherapy, p=0.0247; and radiotherapy, p<0.0001). Meticulous, long-term follow-up is particularly necessary in patients with four or more metastatic lymph nodes to achieve early detection of recurrence. Randomized controlled trials should be used to develop effective modalities for each recurrence pattern to improve therapeutic outcomes.

Background/aims: Anastomotic leakage after transthoracic esophagectomy for esophageal cancer can induce life-threatening morbidity. This study investigated the predictive factors for anastomotic leakage in the neck after retrosternal reconstruction., Methodology: A total of 129 esophageal carcinoma patients undergoing transthoracic esophagectomy and esophagogastric anastomosis in the neck via a retrosternal approach were enrolled between April 1985 and March 2002. Predictive factors for anastomotic leakage were statistically evaluated. In a preliminary study using 18 cases, thoracic inlet space (TIS) was recommended to be extended more than 700 mm2., Results: Partial resection of the bony structures was performed in 32 patients. The method of anastomosis and partial resection of bony structures according to the TIS independently influenced the likelihood of anastomotic leakage, with hand-sewn anastomosis and an absence of partial resection increasing its occurrence., Conclusions: Stapled anastomosis following the partial resection of the sternum and the left clavicle is recommended to avoid anastomotic leakage. These findings should be clarified by a randomized controlled study in a high-volume hospital.

Objectives: Gene expression profiling using pretreatment biopsies has been limited due to their small sample sizes. This study evaluated the usefulness of an ultrasensitive new DNA microarray chip, which has a unique array structure, for the clinical diagnosis of esophageal cancer using preoperative biopsies., Methods: Paired cancer and normal esophageal epithelial tissues from 56 patients who underwent esophagectomy and from 48 patients who underwent preoperative endoscopy were studied. Among 2 feature gene sets selected by a reference DNA chip discriminating malignant status of samples, 20 feature genes were selected for the development of the new DNA chip. The new DNA chip was hybridized with 0.1 mug of total RNA per slide without RNA amplification., Results: Twenty feature genes, including RRM-2 and XRCC-3, for the new DNA chip could discriminate cancer from noncancer at a 95.2% rate of accuracy in 42 biopsies (sensitivity 95.7%, specificity 94.7%). A receiver operating characteristic (ROC) curve analysis showed that the area under ROC curve for the prediction was 0.966., Conclusions: The gene expression profiles from the preoperative biopsies could diagnose esophageal cancer accurately, using the ultrasensitive DNA chip without RNA amplification. This new DNA chip technology might contribute further to the development of customized therapeutic strategies for various cancer patients., (2008 S. Karger AG, Basel.)

Background/aims: It is important to clarify the predictive and prognostic factors for chemoradiotherapy (CRT) in patients with inoperable esophageal cancer., Methodology: Forty-one patients with inoperable advanced esophageal cancer were evaluated. The predictive factors for the response to CRT (low-dose 5-FU and Cisplatin (FP) therapy plus 60 Gy of radiation) and the prognostic factors after CRT were analyzed., Results: Of the 41 patients, seven achieved complete remission, 21 achieved partial remission, nine showed no change and four showed progressive disease. The median survival time was 19 months in patients with a tumor response, compared to 7 months in patients with non-responsive tumors. Only the serum cytokeratin (CYFRA) level independently predicted the responsiveness to treatment. In the multivariate analysis, the serum CYFRA level and the p53 gene mutation independently influenced prognosis., Conclusions: The presence of a p53 mutation in the biopsy specimen or a high serum CYFRA level may be predictive of an adverse therapeutic outcome.

Background: Development of an optimal staging system for esophageal cancer is essential to estimate prognostic factors accurately and treat them appropriately. In this study, we evaluated the surgical outcomes of esophageal cancer according to five existing staging systems and assessed their prognostic significance., Study Design: For 113 patients with esophageal cancer who had undergone curative resection, lymph-node metastasis was classified using the 8th and 9th editions of the Japanese classification, the 6th edition of the Union Internationale Contre le Cancer (UICC) TNM classification, and systems based on the number (0, 1 to 3, or > or = 4) or ratio (0, < 0.15, or > or = 0.15) of metastatic lymph nodes. Survival and prognostic factors of the respective stages were evaluated., Results: Univariate analysis of disease-specific survival revealed that depth of invasion and lymph-node classification notably affected prognosis. Multivariate analysis confirmed that each classification independently influenced prognosis. According to the criteria of the two Japanese classifications, there was no clear correlation between lymph-node stage and survival. The Union Internationale Contre le Cancer/TNM classification, and those based on the number or ratio of metastatic lymph nodes showed a clear correlation between lymph-node metastasis and survival. These systems had better stratification than the Japanese classifications., Conclusions: Staging systems for esophageal cancer based on the number or ratio of metastatic lymph nodes showed better prognostic significance than those based on the anatomic distribution of metastatic lymph nodes, because of their good stratification and clinical utility. Such classifications are suitable for use throughout the world.

The authors attempted to clarify the feasibility and safety of thoracoscopic esophagectomy with a voice-controlled robot, the AESOP system (3000 HR), and further determine whether innovative surgical equipment could allow the performance of complex thoracoscopic esophagectomy. Thoracoscopic surgery with a voice-controlled robot system has already been used in single-surgeon lung resection. Intra-operative and postoperative outcomes were compared between patients receiving hand-assisted laparoscopic surgery (HALS) and video-assisted thoracoscopic surgery (VATS) with the AESOP system (n = 15) and patients receiving open surgery (n = 30). In the AESOP group, the volume of blood loss was significantly less, but the total operation time was longer than in the open group. There were no significant differences in postoperative outcomes or the incidences of morbidity and mortality between the two groups. The surgeon using the AESOP system could obtain a stable, close-up, and long-lasting operative view. Laparoscopic and thoracoscopic surgery with the AESOP system has the potential to enable a single surgeon to perform a complex surgical procedure like esophagectomy.

Background/aims: Despite the advances in surgical treatment and the improvements in perioperative care for esophageal cancer, the long-term prognosis of this disease is poor. To improve long-term survival, it is essential to identify prognostic factors. This paper deals with the prognostic factors in esophageal cancer after potentially curative resection. Furthermore, correlation of the genetic alteration obtained from biopsy specimens with the prognostic factor was determined., Methodology: A total of 102 patients, who underwent transthoracic esophagectomy, were retrospectively analyzed. In 18 recent patients, the genetic alteration of E-cadherin, cyclin D1, and p16INK4 were evaluated in the biopsy specimens., Results: Univariate analysis revealed that the number of metastatic lymph nodes and the tumor diameter significantly influenced prognosis. A Cox proportional regression hazard model showed that only the number of metastatic lymph nodes significantly affected prognosis. Overexpression of E-cadherin and amplification of cyclin D1 was correlated with the number of metastatic lymph nodes but not with p16INK4., Conclusions: Preoperative genetic assessment of biopsy specimens obtained endoscopically provides useful information concerning selection of treatment modalities.

Background: There are many reports suggesting predictive factors for respiratory complications after esophagectomy, but few studies have focused on this problem from the aspect of immunonutrition., Methods: A series of 45 esophageal cancer patients who underwent potentially curative resection between April 1996 and March 2001 was enrolled in this study. Preoperative and intraoperative variables were analyzed for a correlation between risk factors and respiratory complications. In this study, immunonutrition variables as assessed by ultrasonography and indirect calorimetry were used. Uni- and multivariate analyses were performed to determine the predictive factors., Results: Of 45 patients, nine patients (20%) developed respiratory complications. In univariate analysis, forced expiratory volume in 1 s per body surface area (m(2)) in preoperative respiratory parameters, respiratory quotient, and caloric contributions of fat (percentage) and carbohydrate according to indirect calorimetry, and serum CH50 level significantly influenced the occurrence of postoperative respiratory complications. In multivariate analysis, the caloric contribution of fat (percentage) by indirect calorimetry and serum alpha(1)-antitrypsin (serine protease inhibitor) independently affected the occurrence of respiratory complications., Conclusions: Preoperative excessive fat oxidation (potential starvation) and alpha(1)-antitrypsin were independent predictive factors for postoperative complications. Nutrition support such as enteral feeding to improve this malnourished state would reduce the incidence of postoperative respiratory complications.

A 51-year-old man was admitted to our hospital with a tumor in the right anterior region of his neck. Aspiration biopsy revealed squamous cell carcinoma (SCC). Further investigations, including upper gastro-intestinal series and endoscopy, showed two flush lesions in the middle and lower thoracic esophagus. An endoscopic biopsy was done and the pathological findings indicated poorly differentiated SCC. He underwent esophagectomy with three-field lymph node dissection, including the neck tumor. Histological findings revealed that the tumor in the middle thoracic esophagus was moderately differentiated SCC, and that the other tumor below it was basaloid cell carcinoma (BCC). The depths of invasion were to the lamina propria mucosae for the former and to the submucosal layer for the latter. There was no lymphatic invasion, venous invasion, or lymph node metastasis. A diagnosis of poorly differentiated SCC of unknown origin was made for the neck tumor. Postoperative recombinant chemotherapy with cisplatin and 5-fluorouracil was given for the unknown primary site, which we still have not identified. No recurrence of the esophageal cancer has been detected.

Patients with thoracic esophageal carcinoma who underwent extended lymph node (LN) dissection were studied to assess the state of LN metastasis and evaluate its outcome in terms of a prognostic benefit. Pertaining to LN metastasis, it was found that depending on the location of a primary tumor, the area of choice, in which metastasis tends to develop predominantly, showed some variation. However, irrespective of the location of the tumor, the predominant growth of positive nodes was found to locate among three fields, namely the neck, mediastinum and abdomen even in patients with a single metastatic node. This suggests that extended LN dissection including the neck, mediastinum and abdomen should be considered mandatory, if a complete removal of the tumors for carcinoma of the thoracic esophagus is to be desired. Multivariate analysis revealed importance of LN dissection as a prognostic factor. A cumulative survival rate in the patients with lymphadenectomy through right thoracotomy was statistically better than that in the patients who underwent blunt extraction of the esophagus without lymphadenectomy. Furthermore, extensiveness of LN dissection could effectively serve as a prognostic factor. Consequently, three-field LN dissection yields a prognostic benefit to improve a long term survival in patients with carcinoma of the thoracic esophagus.

Esophageal cancer can metastasize to the lymph nodes at a very early stage of the disease, and spread occurs both upwards and downwards. We have developed the 'three-field lymphadenectomy' (3-FD) technique, in which more than 100 lymph nodes are completely dissected from the lower neck, mediastinum, and upper abdomen. More than 700 patients have undergone 3-FD since 1984. Three-field lymphadenectomy is associated with considerable morbidity, although efforts have been made to reduce this by preserving tracheobronchial circulation and innervation. The mortality associated with 3-FD is acceptable (5-year survival rate of 53.8% for patients treated with curative surgery). We believe that 3-FD is a suitable standard operation for the treatment of thoracic esophageal cancer. Further trials are now under way with the aim of improving the results of the technique and also extending the applications of limited surgery and non-surgical therapy.

Background: A retrospective investigation was conducted to determine whether autologous blood collection could reduce allogenic transfusion after resection of esophageal cancer and whether allogenic transfusion influenced postoperative infection., Methods: Patients (n = 100) who met the criteria for hemoglobin, age, body weight, and serum protein donated 800 mL of autologous blood from May 1994 to December 1997. The control group (n = 248) was selected from patients who met the same criteria and did not donate autologous blood over the 10 years before the start of autologous blood collection., Results: Only three patients (3%) from the autologous group required allogenic transfusion versus 84 patients (33.7%) from the control group. Sixteen of the 26 patients who received more than 4 units of allogenic blood contracted postoperative infections compared with 25 of 165 patients who did not (P < .0001). Autologous blood transfusion significantly increased the probability of avoiding allogenic transfusion (odds ratio, 27.58), and allogenic transfusion was significantly related to postoperative infection (odds ratio, 1.19), according to logistic regression analysis., Conclusions: Autologous blood collection reduces the need for allogenic transfusion in patients undergoing resection of esophageal cancer, and avoidance of allogenic transfusion may reduce the risk of postoperative infection.

We attempt to clarify the problems of pulmonary thromboembolism (PTE), which occurs less frequently in Japan than in the West, regarding its special perioperative management and prophylaxis for PTE after esophagectomy. We studied 26 patients with PTE following esophagectomy among 1023 patients with esophageal cancer between 1984 and 1997. The presence of embolism was confirmed by pulmonary perfusion scintigraphy. The incidence, diagnosis, and other issues of PTE were all reviewed. The incidence of PTE was 2.5%, with patients showing a biphasic early and late onset. The main symptoms were dyspnea in 19 patients and tachycardia in 17. Scintigraphy demonstrated 154 lesions, 35.7% of which were located in the left lower lobe and 25.3% in the right lower lobe. Treatment mainly consisted of the administration of heparin and urokinase. Four of the 26 patients died. Intermittent pneumatic compression (IPC) with the administration of heparin has been used in our department since 1994 to prevent PTE and this has also helped to decrease the incidence from 3.2% to 0.7%. Because the incidence of PTE following esophagectomy is higher than expected, PTE should be considered whenever hypoxemia of some unknown cause is found. Both early diagnosis and treatment are essential. It is also important to prevent PTE by the use of IPC.

We report on the problems of diagnosis and surgical technique from the standpoint of mediastinal anatomy in patients with esophageal cancer and right aortic arch associated with a vascular ring. We propose that left thoracotomy plus sternotomy is the best approach to allow visualization of the bilateral recurrent laryngeal nerves.

For thoracic esophageal cancer, we perform extended three field lymph node dissection, and have achieved nearly 50% of overall 5-year survival. However, patients sometimes develop lymph node recurrences in spite of having no lymph node metastases found by conventional histopathologic examination. In a patient with esophageal squamous cell carcinoma, we sequenced all the p53 cDNA translated regions (exon 2-10) of primary carcinoma, and confirmed one p53 nonsense mutation in exon 10. Then we extracted genomic DNA from 150 surgically dissected lymph nodes from that patient, and performed polymerase chain reaction analysis (PCR-RFLP) to detect the same p53 mutation in the lymph nodes. PCR-RFLP analysis showed the same p53 mutation in six lymph nodes. One node was located along the right recurrent laryngeal nerve, where no positive nodes was identified by conventional histopathologic examination. The p53 mutational diagnosis of metastatic cancer may be useful in detecting minimal residual disease.

The most conspicuous difference between Japan and Western countries in the treatment strategy for esophageal cancer is the attitude to lymph node dissection. Japanese surgeons have aimed at complete eradication of lymphatic spread of cancer cells and have reached the level of three-field lymph node dissection. In Western countries, however, surgeons rely more on chemotherapy or radiotherapy because they consider that most patients who present with esophageal cancer already have disseminated disease. Phase II studies of neoadjuvant chemotherapy and chemoradiotherapy have yielded encouraging results, and recently, positive reports on phase III studies of neoadjuvant therapy vs. surgery alone began to be announced. No such studies have included surgery with radical lymph node dissection. With the rapid advance in information technology, radical esophagectomy has gradually gained acceptance in the West, while many trials of neoadjuvant therapy have been carried out in Japan. Theoretically, the next step should be a phase III study of neoadjuvant therapy vs. surgery in which highly radical procedures such as three-field lymph node dissection are carried out.

Carcinosarcoma of the esophagus includes both carcinomatous and sarcomatous elements. The classification and histogenesis of carcinosarcoma is controversial. In a polypoid carcinosarcoma diagnosed in a resected esophagus the sarcomatous component was composed of dense interlacing bundles of spindle-shaped cells in the submucosa. Areas with transitional features between the two components were observed. Immuno-histochemical examination showed vimentin-positive cells in the sarcomatous areas. Subsequently, obtained autopsy specimens from the lung, kidney and iliac bone showed metastatic osteosarcoma composed of an interlacing pattern of bone or osteoid components. We suspected that the sarcomatous elements in the esophagus resulted from sarcomatous transformation of carcinoma cells, and that the metastatic lesions showed differentiation of neoplastic cells to the osteosarcoma.

We discussed the rational extent of the lymph node dissection for carcinoma of the lower third of the esophagus of T2 or T3 stage with abdominal lymph node metastasis. Lymph node metastasis developed in 89.5% of patients. Cervical lymph node metastasis was seen in 35.8%. In the cases with positive abdominal lymph node, 40.9% of the patients had cervical node metastasis. The most frequent site of the positive node in the neck is the area along the right recurrent laryngeal nerve. On the stand point of removal of metastatic lymph node, neck dissection should be required. Three-field dissection yielded better survival rate than two-field dissection but statistical significance was not obtained. When the patients have cervical lymph node metastasis, they have greater possibility of developing blood borne metastasis. However, this observation does not deny the validity of the three-field dissection. Because this dissection may help reducing nodal spread and nodal recurrence. We have to wait for accumulation of the patients to analyze the definite extent of node dissection for T2 or T3 stage of carcinoma of the lower third of the esophagus with positive abdominal lymph node.

Objective: The authors documented the localization and frequency of lymphatic spread in squamous cell carcinoma of the thoracic esophagus and evaluated the influence of radical systematic lymph node dissection on patient survival., Summary Background Data: From accumulated surgical experience, it was suggested that some of the patients with lymph nodal involvement from cancer could be cured by its clearance. However, it is only recently that cancer of the esophagus has been evaluated in terms of analyzing lymphatic spread and results of lymphadenectomy., Methods: Among 1298 patients admitted to the Toranomon Hospital between 1973 and 1993, 913 (70.3%) had resections, including curative and palliative procedures. For this study, 717 patients with TNM RO (resection with no residual tumor at operation in TNM classification) were analyzed. Survival was compared between groups of patients with less extensive thoracoabdominal (two-field) dissections and extensive collothoracoabdominal (three-field) dissections., Results: Comparative study revealed that 5-year survival rate for TNM RO patients after free-field dissection (55.0%) was significantly better (log rank test, p = 0.0013) than the rate after two-field dissection (38.3%). The results were particularly significant in subgroups with stage III and IV (because of nodal factor). Overall 5-year survival rate after all resections was 42.4%., Conclusions: The role of radical lymph node dissection in cancer of the thoracic esophagus evaluated. Long-term survival was compared between two groups with two- and three-field dissection. It was concluded that survival rate was significantly better in patients with extensive three-field dissection.

During the period from October 1972 to January 1983, 462 patients with squamous cell carcinoma of the esophagus were admitted to Toranomon Hospital. Those patients with carcinoma of the hypopharynx, cervical esophagus, or cardia extending to the esophagus were excluded from the study. Resection and reconstruction were carried out in 295 patients with a resectability rate of 63.9 percent and an operative mortality rate of 1.7 percent. The 5 year survival rate for 101 patients who had resection with minimum 5 year follow-up was 34.7 percent. Although the ultimate outcome is largely influenced by the tumor type representing malignancy, it is worthwhile to make all efforts to resect the tumor with a negative surgical margin and to resect concomitant lesions if there are any. Surgeons should not be discouraged by the length or size of a tumor. The extent of positive lymph node is closely related to long-term results. However, systemic lymph node dissection should be carried out because 5 year survival can then be expected, even when positive nodes are dissected from various areas.

Five hundred and forty three cases of intrathoracic esophageal carcinoma were reviewed. Of these, one hundred and sixty one cases had collo-thoraco-abdominal (CTA) dissection and three hundred and eighty two cases had thoraco-abdominal (TA) dissection. Postoperative pulmonary complications occurred in 35.5% of the patients who had CTA dissection and in 18.0% of those who had TA dissection. Incidences of postoperative hoarseness of voice and anastomotic leakage were almost similar in the two groups. However, the mortality rates within 30 postoperative days was 4.3% for the CTA groups compared to 1.8% for the TA group. The average number of lymph nodes resected per case was much higher in the CTA group than than the TA group. This implied that the dissection was more extensively performed in the CTA group involving not only bilateral cervical regions but also the upper mediastinum continuing into the neck. Better 1, 2 and 3 years survival rates were observed in the CTA group than the TA group, but for the 4, 5 years survival rates there was no statistical difference noted. For stage-0 and stage-4 carcinoma of the upper third esophagus, marked improvement in the survival rates were obtained in the CTA dissection cases. In conclusion, collo-thoraco-abdominal dissection can be justified for the surgical treatment of intrathoracic esophageal carcinoma despite its postoperative mortality rate of 4.3%.

The technique and results of oesophageal resection through a right thoracotomy and laparotomy with reconstruction utilizing the stomach via a retrosternal route are reported. Forty patients underwent this procedure, with no mortality. The average blood loss during operation was 424 ml, and 72% of this series underwent the operation without blood transfusion. It is believed that this type of one-stage operation for carcinoma of the oesophagus is reasonable from the viewpoint of adequate resection of malignancies, and it can be performed with minimal surgical risk. With experience, perhaps it will become a standard method such as the Billroth I method in gastric surgery.

Extensive lymph node dissections in the posterior mediastinum and abdomen were performed during resections of esophageal carcinomas. Analysis of lymph nodes demonstrated a widespread distribution of positive lymph nodes regardless of the location of the tumor. The distribution of positive lymph nodes was noticed in the area between the superior mediastinum and the celiac region. The studies were also made on the distribution of positive lymph nodes in the superior gastric region, particularly in the region of the lesser curvature of the stomach. The following principles should be followed when carcinoma of the esophagus is surgically treated. 1) Lymph node dissection of the whole length of the posterior mediastinum, superior gastric region, and celiac region must be performed. 2) Total thoracic and abdominal esophagectomy with resection of the proximal lesser curvature and cardia, including the first to fourth branches, and preferably the fifth branch of the left gastric artery, is mandatory in order to remove possible lymphatic and intramural spread of tumors. 3) Satisfactory esophageal replacement in one stage must follow. Of the Toranomon Hospital, 210 underwent resections and reconstructions, for a resectability rate of 59.3%. The operative mortality rate was 1.4% and the overall five-year survival rate was 34.6%.