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Background/aim: Recurrent laryngeal nerve paralysis (RLNP) induces aspiration pneumonia and reduces the patient's quality of life. To decrease the incidence of RLNP, we performed intraoperative neural monitoring (IONM) during thoracoscopic surgery for esophageal cancer and evaluated its usefulness., Patients and Methods: A total of 737 consecutive patients who underwent thoracoscopic surgery for esophageal cancer were enrolled in this study. Between May 1995 and March 2016, thoracoscopic esophagectomies were performed using video-assisted thoracoscopic surgery (VATS) with a small incision, whereas from April to June 2023, we used positive pressure pneumothorax with port placement only [minimum invasive esophagectomy (MIE)]. A total of 110 consecutive patients who underwent thoracoscopic surgery with IONM (IONM group) were retrospectively compared with those who underwent VATS or MIE without IONM (No-IONM group)., Results: The incidence of RLNP [Clavien-Dindo (CD) classification of ≥1] on postoperative day (POD) 5 was 13.9% in the IONM group, which was significantly lower than that of the no-IONM group (31.2%, p<0.001). Even when comparing only patients who underwent MIE, the incidence of RLNP on POD5 was 13.9% in the IONM group, which was significantly lower than that in the no-IONM group (26.2%, p=0.035). The incidence of postoperative pneumonia (CD ≥2) was 10.9% in the IONM group, which was significantly lower than that in the no-IONM group (26.1%, p=0.005). Bilateral RLNP did not occur in any of the IONM groups., Conclusion: IONM is a useful tool for reducing RLNP incidence and postoperative pneumonia after thoracoscopic surgery for esophageal cancer., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Ferroptosis suppressor protein 1 and glutathione peroxidase 4 have been identified as key molecules in two independent pathways associated with ferroptosis inhibition. This study investigated the prognostic significance and clinical associations of FSP1 and GPX4 expression in esophageal squamous cell carcinoma (ESCC) and assessed the therapeutic potential of regulating these molecules in ESCC cells., Methods: Immunohistochemical analysis was performed on surgical specimens of 97 patients with ESCC for FSP1 and GPX4 expression. To identify the change in ESCC cell viability, FSP1 and GPX4 inhibitors were administered to three cell lines. In addition, ferroptosis as the cause of reduced cell viability by FSP1 and GPX4 inhibition was confirmed., Results: Prognosis was significantly worse for patients in the group positive for both FSP1 and GPX4 compared with the other groups (p < 0.001). In multivariate analysis, positivity for both FSP1 and GPX4 was an independent poor prognostic factor (p = 0.002). The combination of FSP1 and GPX4 inhibitors induced cell death more potently than each inhibitor did alone. Furthermore, the ferroptosis inhibitor markedly canceled this cell death., Conclusions: Overexpression of FSP1 and GPX4 is a poor prognostic factor for patients with ESCC. Simultaneous suppression of both FSP1 and GPX4 caused potent cell death, which was markedly abrogated by ferroptosis inhibitors. These findings indicate that simultaneous regulation of FSP1 and GPX4 may be a new therapeutic target in ESCC., (© 2022. The Author(s).)

Background: Preoperative inflammatory or nutritional biomarkers and clinicopathological features may be survival predictors in resectable esophageal squamous cell carcinoma., Methods: We included 118 patients with resectable squamous esophageal carcinoma (stages I-IV), assessing preoperative CRP- and albumin-based modified Glasgow prognostic score, the modified controlling nutritional status score, C-reactive protein, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, pathologic stage, and tumor location(s), looking for correlation with overall survival and relapse-free survival. Using univariate and Cox analysis, we selected the most reliable prognostic factors., Results: Five-year overall survival and recurrence-free survival were 54.9% and 48.5%, respectively. C-reactive protein values correlated negatively with hypoalbuminemia (P = 0.0036). On univariate analysis, tumor stage, invasion depth, location, nodal involvement, albumin, and modified Glasgow prognostic score were significant prognostic factors for overall and recurrence-free survival. Preoperative C-reactive protein was prognostic factor for overall survival, but not for relapse-free survival (P = 0.017, 0.063, respectively). The Cox proportional hazards model showed the modified Glasgow prognostic score to be an independent prognostic factor for relapse-free survival and overall survival after using the stepwise variable selection procedure. Cox analysis including clinicopathological factors and modified Glasgow prognostic scores showed that only tumor location(s) and pathologic stage were independent prognostic factors for overall survival and recurrence-free survival., Conclusion: Although the modified Glasgow prognostic score is not superior to pathologic stage and tumor location as a biomarker of preoperative nutrition/inflammation and clinicopathological factors, it remains an important prognostic marker in resectable esophageal cancers. Preoperative decreased inflammatory response and improved nutritional status may contribute to prognosis in patients with esophageal cancer., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

A 68-year-old man with dysphagia had advanced esophageal cancer with single liver metastasis(cT4bN2M1, cStage Ⅳb). After induction chemoradiotherapy, consisting of 2 courses of FP therapy and 40 Gy radiotherapy, thoracoscopic radical esophagectomy and laparoscopic partial resection of liver metastatic lesion were performed because the primary lesion was significantly reduced. Histopathological findings showed that the therapeutic effect of the primary lesion was Grade 3, and lymph node metastasis and liver metastasis disappeared, resulting in pathological CR. Postoperative chemotherapy was not performed. Esophageal cancer did not recur during 3 and a half years after the operation.

Background: Endoscopic submucosal dissection (ESD) is becoming widely popular as a less invasive treatment option for superficial esophageal squamous cell carcinoma. However, data on long-term survival after esophageal ESD in patients with severe comorbidities are limited. This study aimed to evaluate long-term survival after ESD in such patients., Methods: Altogether, 584 consecutive patients underwent esophageal ESD at our institution from May 2004 to September 2016. Based on the American Society of Anesthesiologists Physical Status (ASA-PS) classification system, patients were grouped according to severe (ASA-PS ≥ 3) or non-severe comorbidities (ASA-PS 1/2). The overall survival (OS), disease-specific survival (DSS), and risk factors for mortality were compared between the groups using a propensity score matching analysis., Results: In a matched cohort of 69 pairs, the 5-year OS rate was poorer in ASA-PS 3 patients than in ASA-PS 1/2 patients (63.9% vs. 92.5%, P < 0.01), while the 5-year DSS rate was similar between the groups (100% vs. 100%). The mortality rate was significantly higher in ASA-PS 3 patients than in ASA-PS 1/2 patients (hazard ratio 3.47; 95% confidence interval 1.79-6.74; P < 0.01). Death due to exacerbation of comorbidities was significantly more frequent in ASA-PS 3 patients than in ASA-PS 1/2 patients (42.4% vs. 8.3%, P < 0.04)., Conclusion: Because of the exacerbation of comorbidities, patients with severe comorbidities had poorer long-term outcomes after esophageal ESD than those with non-severe comorbidities. Further studies will be necessary to evaluate esophageal ESD in patients with severe comorbidities., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: To date, no in-depth studies have focused on the impact of various clinical characteristics of esophageal squamous cell carcinoma (ESCC), including its association with subjective symptoms, on patient prognosis. We aimed to investigate the clinical factors that affect the prognosis of patients with ESCC and to clarify how subjective symptoms are related to prognosis., Methods: We retrospectively evaluated the clinical records of 503 consecutive patients with ESCC from April 2011 to December 2019. Six established prognostic factors for ESCC (body mass index, alcohol drinking, cigarette smoking, sex, clinical stage, and age) and subjective symptoms were used to subgroup patients and analyze survival differences. Next, the patients were divided into two groups: a symptomatic group and an asymptomatic group. In the symptomatic group, differences in the incidence of subjective symptoms according to tumor size, tumor location, macroscopic tumor type, and clinical stage were examined. Finally, subjective symptoms were divided into swallowing-related symptoms and other symptoms, and their prognosis was compared., Results: Multivariate Cox regression analysis identified sex [hazard ratio (HR) 1.778; 95% CI 1.004-3.149; p = 0.049], TNM classification (HR 6.591; 95% CI 3.438-12.63; p < 0.001), and subjective symptoms (HR 1.986; 95% CI 1.037-3.803; p = 0.0386) as independent risk factors for overall survival. In the symptomatic group, the mean time from symptom onset to diagnosis was 2.4 ± 4.3 months. The incidence of subjective symptoms differed by clinical stage, and the prognosis of patients with swallowing-related symptoms was significantly worse than that of patients with other symptoms., Conclusion: The results of this study suggest that screening by upper gastrointestinal endoscopy, independent of subjective symptoms (especially swallowing-related symptoms), may play an important role in the early detection and improvement of prognosis of ESCC, although further validation in a large prospective study is needed., (© 2022. The Author(s).)

Background: Thoracoscopic esophagectomy has been extensively used worldwide as a curative surgery for patients with esophageal cancer; however, complications such as anastomotic leakage and stenosis remain a major concern. Therefore, the objective of this study was to evaluate the efficacy of circular stapling anastomosis with indocyanine green (ICG) fluorescence imaging, which was standardized for cervical esophagogastric anastomosis after thoracoscopic esophagectomy., Methods: Altogether, 121 patients with esophageal cancer who underwent thoracoscopic esophagectomy with radical lymph node dissection and cervical esophagogastric anastomosis from November 2009 to December 2020 at Tottori University Hospital were enrolled in this study. Patients who underwent surgery before the anastomotic method was standardized were included in the classical group (n = 82) and patients who underwent surgery after the anastomotic method was standardized were included in the ICG circular group (n = 39). The short-term postoperative outcomes, including anastomotic complications, were compared between the two groups using propensity-matched analysis and the risk factors for anastomotic leakage were evaluated using logistic regression analyses., Results: Of the 121 patients, 33 were included in each group after propensity score matching. The clinicopathological characteristics of patients did not differ between the two groups after propensity score matching. In terms of perioperative outcomes, a significantly higher proportion of patients who underwent surgery using the laparoscopic approach (P < 0.001) and narrow gastric tube (P = 0.003), as well as those who had a lower volume of blood loss (P = 0.009) in the ICG circular group were observed after matching. Moreover, the ICG circular group had a significantly lower incidence of anastomotic leakage (39% vs. 9%, P = 0.004) and anastomotic stenosis (46% vs. 21%, P = 0.037) and a shorter postoperative hospital stay (30 vs. 20 days, P < 0.001) than the classical group. According to the multivariate analysis, the anastomotic method was an independent risk factor for anastomotic leakage after thoracoscopic esophagectomy (P = 0.013)., Conclusions: Circular stapling anastomosis with ICG fluorescence imaging is effective in reducing complications such as anastomotic leakage and stenosis., (© 2022. The Author(s).)

A 56-years old man was diagnosed with cervical esophageal cancer with lymph node metastasis. After definitive chemoradiotherapy as the first-line therapy, complete response(CR)was obtained. One year and 3 months after the therapy, lymph node dissection and postoperative chemotherapy was performed for the lymph node metastases of the left neck and axillary lymph node. After 3 years and 10 months from the first-line therapy, follow-up CT revealed left axillary lymph node swelling and diagnosed with lymph node recurrence. Chemoradiotherapy was performed for the recurrence of the lymph node and CR was achieved for the lymph node. However, left axillary lymph node swelling were detected again 6 years after the first-line therapy. After 6 months of chemotherapy with S-1, CR was achieved for the lymph node again. He is now alive without recurrence for 10 years after the first-line therapy.

Background: Lugol chromoendoscopy has been conventionally used for the detection and delineation of esophageal squamous cell carcinoma (SCC). However, the boundaries of some lesions are unclear even with Lugol chromoendoscopy, and there is a risk of residual lesions or over-excision. This study aimed to evaluate the utility of narrow-band imaging (NBI) for the delineation of esophageal SCC in endoscopic resection., Methods: Among 367 esophageal SCCs endoscopically resected between January and December 2019 at our institute, this retrospective study included consecutive lesions, which were first marked with NBI, followed by Lugol chromoendoscopy. The proportion of residual cancer, which was defined as histologically proven cancer confirmed adjacent to the scar within 1 year after endoscopic resection, was evaluated. To evaluate whether the marks added by Lugol chromoendoscopy after NBI marking were more reliable, we evaluated the presence of cancer in the iodine-unstained area outside the NBI-determined marks, i.e., the cancerous area missed by NBI. The presence of cancer in the iodine-stained areas inside the NBI-determined marks, i.e., the cancerous area missed by Lugol, was also evaluated. These were compared to assess the risk of residual cancer in endoscopic resection with NBI and Lugol chromoendoscopy., Results: Among 304 lesions, 2 (0.7%) residual cancers were detected. The cancerous area missed by NBI and the cancerous area missed by Lugol were identified in 18 (6%) and 43 (14%) lesions, respectively (P = 0.001)., Conclusions: NBI might be acceptable for delineating the extent of esophageal SCCs that are difficult to delineate with Lugol chromoendoscopy., (© 2021. The Japan Esophageal Society.)

Background: Due to its tumor-specific metabolic pathway characteristics, 5-aminolevulinic acid (5-ALA) is a natural amino acid widely used in cancer treatment. The current study, demonstrated that 5-ALA induced ferroptosis via glutathione peroxidase 4 (GPX4) and heme oxygenase 1 (HMOX1) and had an antitumor effect in esophageal squamous cell carcinoma (ESCC)., Methods: Expression of GPX4 and HMOX1 in pathologic specimens of 97 ESCC patients was examined, and prognostic analyses were performed. Real-time polymerase chain reaction (RT-PCR), RNA microarray, and Western blotting analyses were used to evaluate the role of 5-ALA in ferroptosis in vitro. In addition, this study used ferrostatin-1, a ferroptosis inhibitor, and a lipid peroxidation reagent against cell lines treated with 5-ALA. Finally, the role of 5-ALA was confirmed by its effect on an ESCC subcutaneous xenograft mouse model., Results: The study showed that upregulation of GPX4 and downregulation of HMOX1 were poor prognostic factors in ESCC. In an RNA microarray analysis of KYSE30, ferroptosis was one of the most frequently induced pathways, with GPX4 suppressed and HMOX1 overexpressed by 5-ALA treatment. These findings were verified by RT-PCR and Western blotting. Furthermore, 5-ALA led to an increase in lipid peroxidation and exerted an antitumor effect in various cancer cell lines, which was inhibited by ferrostatin-1. In vivo, 5-ALA suppressed GPX4 and overexpressed HMOX1 in tumor tissues and led to a reduction in tumor size., Conclusions: Modulation of GPX4 and HMOX1 by 5-ALA induced ferroptosis in ESCC. Thus, 5-ALA could be a promising new therapeutic agent for ESCC.

Background: Endoscopic submucosal dissection (ESD) is accepted as the standard treatment for early-stage esophageal neoplasia. However, esophageal perforation may occur, leading to mediastinitis and pneumothorax, which occasionally require emergency surgery. Moreover, failure of en bloc resection causes local recurrence. However, studies on the predictors of such difficulties during ESD are limited. Hence, we evaluated the predictors associated with the difficulty of ESD for esophageal neoplasia including failure of en bloc resection or perforation., Methods: Data of 549 consecutive patients who were treated with ESD between May 2004 and March 2016 at a single institution were retrospectively studied. Exclusion criteria were the presence of metachronous esophageal neoplasia or missing data. The primary outcome was determining the predictors associated with the difficulty of ESD for esophageal neoplasia including failure of en bloc resection or perforation., Results: Altogether, 543 patients with 736 lesions were evaluated. Failure of en bloc resection occurred in 6 patients (1.1%) with 6 lesions, and perforation occurred in 11 patients (2.0%) with 11 lesions (1.5%). Multivariate logistic regression analysis showed that large lesion diameter (odds ratio [OR] 1.49; 95% confidence interval [CI] 1.21-1.84; p < 0.001) and previous chemoradiotherapy (OR 5.24; 95% CI 1.52-18.06; p = 0.009) were independent predictive factors., Conclusions: Larger lesions and previous chemoradiotherapy for esophageal cancer increased the risk for failure of en bloc resection or perforation in patients who underwent esophageal ESD.

Introduction: Endoscopic submucosal dissection (ESD) could become a standard treatment for early stage esophageal neoplasia. Recurrence sometimes develops close to a previous ESD scar. These lesions are predictably difficult to treat with ESD because of severe fibrosis. We evaluated the clinical outcomes of ESD for esophageal neoplasia located close to a previous ESD scar., Methods: This was a retrospective observational study in a single institution. A total of 549 consecutive patients with 927 esophageal lesions were treated with ESD. The primary outcomes were resectability and adverse events of esophageal neoplasia located close to previous ESD scars (ESD scar group) than in primary esophageal ESD (primary group). Furthermore, predictive factors of perforation were examined., Results: A total of 545 primary and 29 ESD scars in consecutive patients were evaluated. En bloc and complete (R0) resection rates in the ESD scar group were lower than those in the primary group (79.3% vs 98.3%, P < 0.01 and 75.9% vs 93.4%, P < 0.01). Perforations occurred more frequently in the ESD scar group (10.3% vs 2.0%, P = 0.03). The ESD scar group was a predictive factor for perforation (odds ratio = 10.37, 95% confidence interval: 2.15-49.94, P = 0.004). There were similar results for inverse probability of treatment weighting methods (odds ratio = 6.78, 95% confidence interval: 1.40-32.98, P = 0.018)., Discussion: ESD for esophageal neoplasia located close to a previous ESD scar was difficult to completely resect and increased the likelihood of perforation but could be a treatment option.

A 68-year-old man presented to our hospital. An upper gastrointestinal tract endoscopy performed elsewhere revealed an elevated lesion with a circumferential esophageal cancer(identified as small cell carcinoma). Perthe treatment forsmall cell cancer and the standard treatment for esophageal neuroendocrine carcinoma, 7 courses of CBDCA(5mg/m2)plus ETP (100mg/m2)were administered. The lesion shrank and the lymph node swelling disappeared and the patient was deemed to be in partial remission. Nine months later, however, the primary tumor increased in size. A transthoracic subtotal esophagectomy( laparoscope-assisted), 2 area dissection, and gastric tube reconstruction(post-sternal)were performed at 2 years and 10 months afterdiagnosis.

Purpose: The platelet distribution width (PDW) is reportedly useful as a prognostic indicator for some cancers. However, its prognostic significance in esophageal squamous cell carcinoma (ESCC) is unclear., Methods: We enrolled 104 patients with thoracic ESCC, who underwent curative esophagectomy., Results: Receiver operating curve analyses indicated that the optimal cut-off values of pre- and postoperative PDW were 16.9 and 17.0, respectively. The 5-year overall survival (OS) rate was significantly lower in patients with a high-preoperative PDW (≥ 16.9; 52.6%) than in those with a low-preoperative PDW (< 16.9; 61.0% P = 0.045). The 5-year disease-specific survival (DSS) rates were 64.3% in patients with a high-preoperative PDW and 69.3% in those with a low-preoperative PDW (P = 0.13). Regarding the postoperative PDW, the 5-year OS rate was significantly lower in patients with a high-postoperative PDW (≥ 17.0; 35.7%) than in those with a low-postoperative PDW (< 17.0; 66.8% P = 0.0017). The 5-year DSS rates were 52.2% in patients with a high-postoperative PDW and 73.2% in those with a low-postoperative PDW (P = 0.037). Finally, a multivariate analysis revealed that the postoperative PDW but not the preoperative PDW was an independent prognostic factor., Conclusions: The postoperative PDW was useful for predicting the prognosis of patients with ESCC.

Purpose: The prognostic significance of the peripheral platelet count × serum C-reactive protein level multiplier (P-CRP) has not been widely studied in patients with esophageal squamous cell carcinoma (ESCC)., Methods: We retrospectively analyzed data from 116 thoracic ESCC patients who underwent curative esophagectomy., Results: The patients were divided into the P-CRP High ( > 1.674) and P-CRP Low ( ≤ 1.674) groups, according to a cut-off value determined by a receiver operator curve. The 5-year overall survival (OS) rates significantly differed between the groups (P-CRP High : 46.4% and P-CRP Low : 77.3%; P = 0.0056). In the multivariate analysis, the P-CRP was an independent prognostic factor. We also evaluated the survival in the subgroup of patients who received neoadjuvant chemotherapy (NAC; n = 49). Among 28 patients who were P-CRP High before NAC, 20 remained. P-CRP High after NAC, while eight became post-P-CRP Low . Among 21 patients who were P-CRP Low before NAC, 16 remained post-P-CRP Low after NAC, while five became post-P-CRP High . The 5-year OS rate for patients who were P-CRP Low both before and after NAC was 92.9%, compared with 30.2% in other patients (P = 0.0034). In the multivariate analysis, the combination of P-CRP + post-P-CRP was an independent prognostic factor in ESCC patients who underwent NAC., Conclusions: The P-CRP is useful for predicting the prognosis in ESCC patients.

A 71-year-oldman with voice hoarseness was referredto our hospital for further examination. He was diagnosedwith unresectable Stage Ⅳb esophageal cancer, with direct invasion to the aorta andtrachea andmultiple metastases to the lymph nodes, lungs, and adrenal gland. Because his performance status(PS)was deemedto be favorable, he receivedchemotherapy with docetaxel(DOC), cisplatin, and5 -FU(DCF therapy). After 2 cycles of DCF therapy, the primary lesion was scarred. No malignant lesions were detected in the biopsy performed. No distant metastases were identified on PET-CT. As a subsequent treatment, S-1 plus DOC therapy was administered. Finally, single S-1 administration was continued. The treatment periodwas 14 months. Treatment was concludedbecause a complete response(CR)was maintained. Three years after the conclusion of treatment, CR remains maintained. The overall survival in cases of unresectable advanced esophageal cancer is saidto be 3-10 months, but there are remarkable cases such as this one. If a goodPS is maintained, treatment shouldbe actively considered because CR is possible.

Background: We have sometimes experienced technical difficulty performing thoracoscopic esophagectomy because of the position of the descending aorta or width of the mediastinal space. In this study, we retrospectively investigated predictive preoperative factors that influence the procedure of thoracoscopic esophagectomy with a focus on the position of the descending aorta and width of the mediastinal space., Methods: Ninety-five patients who underwent thoracoscopic esophagectomy for esophageal cancer by two specialists were included in this study. Thirty patients in whom both the operation time and blood loss in the thoracic region exceeded the median were categorized to the difficult group. The remaining 65 patients were categorized into the common group. During the evaluation of the position of the descending aorta, we measured the aorta-vertebra angle at the level of the left inferior pulmonary vein. During the evaluation of the width of the mediastinal space, we measured the sternum-vertebra distance at the level of the tracheal bifurcation., Results: A forward stepwise logistic regression analysis revealed the following independent predictive factors of the technical difficulty of thoracoscopic esophagectomy: aorta-vertebra angle (≥ 30°), sternum-vertebra distance (< 100 mm), and clinical T stage (T3)., Conclusions: The position of the descending aorta, width of the mediastinal space, and clinical T stage are predictive factors of the technical difficulty of thoracoscopic esophagectomy. These factors might become supporting indices for the indication for thoracoscopic esophagectomy among trainees or the surgeons who introduce this procedure.

The large Maf transcription factors are expressed in immune cells including macrophages and lymphocytes. To investigate the distribution of Maf expression in human organs, immunostaining for Maf was performed using sections of several human organs. High Maf expression was seen in the nucleus of macrophages in the gastrointestinal tract and lymph node sinus macrophages (LySMs). Then, we assessed whether Maf expression in LySMs was correlated with CD169 expression and the clinical prognosis in patients with esophageal cancer. Maf expression was associated with CD169 expression, but Maf expression in LySMs was not associated with the clinical course in patients with esophageal cancer. We determined which cytokines stimulate Maf expression using cultured macrophages. Immunocytochemistry showed that Maf expression was significantly elevated by interferon-γ. These results are the first report of Maf expression in human samples. Maf expression may be a marker for the macrophage population in humans.

Background and Objective: Esophagectomy, which is one of the most invasive operations among gastrointestinal surgeries, deteriorates the physical condition of patients. Such deterioration may be severe in elderly patients and advanced age may negatively affect long-term survival. However, elderly patients are more likely to die from cancer-unrelated causes than younger patients. Therefore, when comparing the survival of elderly patients after cancer surgery with that of younger patients, it is necessary to control the influence of cancer-unrelated death. To address this problem, we calculated the relative survival and applied the excess hazard model to control the influence of competing risk of death from cancer., Methods: We retrospectively analyzed 505 patients with thoracic esophageal cancer who underwent transthoracic esophagectomy. Prognostic information was followed up to 10 years after surgery or until death in all patients. Prognostic information of patients lost to follow-up was retrieved from the Osaka Cancer Registry's database. First, we identified prognostic variables as confounders of age by univariate and multivariate analysis. Then, we estimated age effects using the excess hazard model including the prognostic variables as confounders., Results: Univariate and multivariate analysis showed that clinical stage, residual tumor, and postoperative complications (p < 0.1) were confounders of age. Multivariate excess hazard model revealed that age was not a significant prognostic factor at any cutoff point. However, the excess hazard ratio of death tended to increase continuously in patients aged 70 years or older., Conclusions: When clinicians offer esophagectomy for esophageal cancer, age per se should not be a limiting factor. Strict evaluation of patients should be performed before surgery, especially in the elderly., (© 2019 S. Karger AG, Basel.)

Background: Neoadjuvant chemotherapy (NAC) involving two cycles of cisplatin plus fluorouracil is recommended in Japan as a standard treatment for resectable, locally advanced esophageal squamous cell carcinoma (ESCC). We have encountered patients who were administered incomplete chemotherapy because of adverse events or the patient's refusal of treatment. Here, we retrospectively investigated the influence on perioperative outcomes and long-term prognosis of patients with ESCC who underwent complete (two cycles) or incomplete (one cycle) NAC., Methods: We retrospectively investigated 133 patients with locally advanced ESCC of the thoracic esophagus who underwent NAC. We compared the perioperative results and prognoses of patients who underwent complete or incomplete NAC because of adverse events or the patient's refusal of treatment., Results: Of 133 patients, 37 patients did not receive the second cycle of NAC; the remaining 96 patients received the second cycle of NAC as scheduled. There were no significant differences in the clinical backgrounds, surgical results, or operative morbidity rates between the groups. Patients in both groups were similarly administered postoperative chemotherapy regimens. There was no significant difference in disease-free survival or overall survival., Conclusions: We suggest that perioperative outcomes and long-term prognosis of patients with locally advanced ESCC were not significantly influenced, even if the patients did not receive a complete cycle of NAC. When certain adverse events occur after the first cycle of NAC, we believe that it is nevertheless possible to discontinue chemotherapy.

Background: Interruption of sedation due to a poor response to modified neuroleptanalgesia (m-NLA) with midazolam often occurs during endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) because most patients have a history of heavy alcohol intake. Recently, propofol has been used feasibly and safely during endoscopic procedures. The aim of this study was to clarify the efficacy and safety of propofol compared with that of midazolam during ESD for ESCC., Methods: This was a single-blind, randomized controlled trial in a single center. Patients with ESCC scheduled for ESD were included in the study. Patients were randomly assigned to one of two groups: the propofol group and the midazolam group. The main outcome was the incidence of discontinuation of the procedure due to a poor response to sedation. Secondary outcomes included risk factors for a poor response to sedation., Results: Between April 2014 and October 2015, 132 patients (n = 66 per group) who underwent ESD for ESCC were enrolled in this study. The incidence of discontinuation due to a poor response to sedation in the propofol and midazolam groups was 0% (0/66) and 37.9% (25/66), respectively (p < 0.01). Multivariate analyses revealed that use of midazolam [Odds ratio (OR), 7.61; 95% confidence interval (CI), 2.64-21.92; p < 0.01] and age (OR, 0.93; 95% CI, 0.86-0.98; p < 0.01) were risk factors for a poor response to sedation., Conclusions: Our study indicates that, compared with midazolam, propofol is a more efficient sedative for m-NLA during ESD for ESCC.

Background: This report focuses on the surgical manipulation and spread of cancer cells. Our previous study suggested an association between a poor prognosis and positive pleural lavage cytology after resection of esophageal cancer without preoperative treatment. However, little is known regarding the clinical significance of the lavage procedure in esophageal cancer patients who undergo preoperative treatment., Methods: A cohort of 94 patients with squamous cell carcinoma of the esophagus who underwent esophagectomy with radical lymph node dissection was prospectively analyzed for free cancer cells in the pleural cavity after mediastinal lymphadenectomy. Reverse transcription-polymerase chain reaction was performed to detect free cancer cells in the pleural lavage fluid by measuring squamous cell carcinoma-related antigen (SCC) and carcinoembryonic antigen (CEA)., Results: Forty-two patients (44.7%) were positive for SCC after thoracic lymphadenectomy, and 15 patients (15.9%) were positive for CEA. SCC positivity was significantly associated with venous invasion (p = 0.037) and with the clinical response to preoperative treatment (p = 0.001). Furthermore, SCC positivity was associated with poor prognosis compared with negative SCC (p = 0.026). Multivariate analysis revealed that SCC positivity was an independent prognostic factor. Regarding recurrence patterns, SCC positivity tended to be associated with hematogenous recurrence (p = 0.063). Conversely, positive CEA was not associated with any clinicopathological finding, treatment response, prognosis, or recurrence pattern., Conclusions: Tumor spillage during the evaluated surgical manipulation was assessed in esophageal cancer patients who underwent preoperative treatment. Tumor spillage as evaluated by SCC mRNA was associated with a poor prognosis.

Background and Aim: Esophageal endoscopic submucosal dissection (ESD) to resect widespread lesions has increased the incidence of strictures, and some patients develop strictures despite receiving prophylactic locoregional triamcinolone injections. The present study evaluated the predictive factors for esophageal stricture formation in patients given prophylactic triamcinolone injections after ESD., Methods: This was a retrospective observational study. Of 552 consecutive patients who underwent ESD, those who received prophylactic triamcinolone injections immediately after ESD were enrolled. Primary outcome was predictive factors for esophageal stricture formation in patients given prophylactic triamcinolone injections., Results: We evaluated 101 en bloc resections involving 144 lesions in 96 patients. Strictures occurred following 17 (16.8%) resections. Wider circumferential mucosal defect (odds ratio [OR] 2.42, 95% confidence interval [CI]: 1.01-5.80; P = 0.048) was an independent predictive factor for stricture development. Cut-off value associated with stricture formation was five-sixths of the circumferential mucosal defect. Propensity analysis determined that frequency of esophageal strictures increased in patients with circumferential mucosal defects of more than five-sixths compared with those less than five-sixths (OR = 5.70, 95% CI: 1.61-20.18; P = 0.007)., Conclusion: Resections involving circumferential mucosal defects of more than five-sixths increased the likelihood of stricture formation in patients given prophylactic locoregional triamcinolone injections after esophageal ESD., (© 2017 Japan Gastroenterological Endoscopy Society.)

Background: Adenocarcinoma of the esophagogastric junction (EGJ) is uncommon in Eastern countries, including Japan, but it is believed that the incidence of EGJ adenocarcinoma will increase in Asia in the future due to the decreasing incidence of Helicobacter pylori infection. Endoscopic submucosal dissection (ESD) is a minimally invasive and curative treatment that allows precise pathological assessment., Summary: Magnifying endoscopy with narrow-band imaging may be useful for differential diagnoses and for delineating the cancer margin of EGJ adenocarcinoma, but subsquamous carcinoma extension, which is the invasion of EGJ adenocarcinoma beneath the normal esophageal squamous epithelium, makes it difficult to detect cancer margins of the oral side in ESD for EGJ adenocarcinoma. Since subsquamous carcinoma extension was reported to be less than 1 cm in most cases, the oral safety margin that is placed 1 cm from the squamocolumnar junction is useful for negative cancerous horizontal margin. A multicenter retrospective study of esophageal adenocarcinoma including EGJ adenocarcinoma showed that mucosal and submucosal cancer within 500 μm from the muscularis mucosa without lymphovascular involvement, a poorly differentiated component, and lesion size over 3 cm were not associated with metastasis. Several retrospective studies about ESD for EGJ adenocarcinoma have suggested feasible short-term and long-term outcomes using curative criteria based on gastric cancer guidelines. Key Messages: ESD would be a good first-line treatment for superficial EGJ adenocarcinoma, including Barrett's adenocarcinoma. Additional information about the incidence of metastasis would help confirm the indication of ESD for EGJ adenocarcinoma., (© 2018 S. Karger AG, Basel.)

Purpose: We evaluated the effectiveness of neoadjuvant chemoradiotherapy (CRT) followed by esophagectomy for cT4 esophageal cancer or lymph node metastases (LNM) invading adjacent structures., Materials and Methods: We retrospectively evaluated 42 consecutive patients with thoracic esophageal cancer who underwent CRT followed by esophagectomy between 2008 and 2013. All were initially considered to be unresectable because of cT4 (n = 32) disease or LN invasion (n = 10). Radiotherapy was administered at 41.4 Gy/23 fr with concurrent chemotherapy. At completion of CRT, restaging was performed using computed tomography (CT)., Results: All cT4 tumors were downstaged, LNM invading to adjacent structures were considered to be released, and subtotal esophagectomy was performed. The median follow-up period was 42 months. The curative resection (R0) rate was 94% in cT4 group and 70% in LN invasion group. The 3-year overall survival (OS) and 3-year locoregional control (LRC) rates were 65-80% in the cT4 group and 50-67% in LN invasion group, respectively., Conclusions: The cT4 group showed good rates of R0, OS, and LRC. Surgical resection should be an effective option when downstaging is achieved by CRT for patients with initially inoperable thoracic esophageal cancer.

Background: Antibody-drug conjugates have emerged as a powerful strategy in cancer therapy and combine the ability of monoclonal antibodies to specifically target tumour cells with the highly potent killing activity of drugs with payloads too toxic for systemic administration. Trastuzumab deruxtecan (also known as DS-8201) is an antibody-drug conjugate comprised of a humanised antibody against HER2, a novel enzyme-cleavable linker, and a topoisomerase I inhibitor payload. We assessed its safety and tolerability in patients with advanced breast and gastric or gastro-oesophageal tumours., Methods: This was an open-label, dose-escalation phase 1 trial done at two study sites in Japan. Eligible patients were at least 20 years old with breast or gastric or gastro-oesophageal carcinomas refractory to standard therapy regardless of HER2 status. Participants received initial intravenous doses of trastuzumab deruxtecan from 0·8 to 8·0 mg/kg and dose-limiting toxicities were assessed over a 21-day cycle; thereafter, dose reductions were implemented as needed and patients were treated once every 3 weeks until they had unacceptable toxic effects or their disease progressed. Primary endpoints included identification of safety and the maximum tolerated dose or recommended phase 2 dosing and were analysed in all participants who received at least one dose of study drug. The dose-escalation study is the first part of a two-part study with the second dose-expansion part ongoing and enrolling patients as of July 8, 2017, in Japan and the USA. This trial is registered at ClinicalTrials.gov, number NCT02564900., Findings: Between Aug 28, 2015, and Aug 26, 2016, 24 patients were enrolled and received trastuzumab deruxtecan (n=3 for each of 0·8, 1·6, 3·2, and 8·0 mg/kg doses; n=6 for each of 5·4 and 6·4 mg/kg). Up to the study cutoff date of Feb 1, 2017, no dose-limiting toxic effects, substantial cardiovascular toxic effects, or deaths occurred. One patient was removed from the activity analysis because they had insufficient target lesions for analysis. The most common grade 3 adverse events were decreased lymphocyte (n=3) and decreased neutrophil count (n=2); and grade 4 anaemia was reported by one patient. Three serious adverse events-febrile neutropenia, intestinal perforation, and cholangitis-were reported by one patient each. Overall, in 23 evaluable patients, including six patients with low HER2-expressing tumours, ten patients achieved an objective response (43%, 95% CI 23·2-65·5). Disease control was achieved in 21 (91%; 95% CI 72·0-98·9) of 23 patients. Median follow-up time was 6·7 months (IQR 4·4-10·2), with nine (90%) of ten responses seen at doses of 5·4 mg/kg or greater., Interpretation: The maximum tolerated dose of trastuzumab deruxtecan was not reached. In this small, heavily pretreated study population, trastuzumab deruxtecan showed antitumour activity, even in low HER2-expressing tumours. Based on safety and activity, the most likely recommended phase 2 dosing is 5·4 or 6·4 mg/kg., Funding: Daiichi Sankyo Co, Ltd., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: Neoadjuvant chemotherapy (NAC) with cisplatin and fluorouracil is the recommended standard treatment for resectable locally advanced esophageal cancer (EC) in Japan. We investigated the effects of NAC on the safety and feasibility of thoracoscopic esophagectomy with total mediastinal lymphadenectomy for EC., Methods: This retrospective study analyzed data from 225 consecutive patients who underwent thoracoscopic esophagectomy with lymph node dissection between April 2007 and December 2015. Patients with clinical stage IB, IIA, IIB, IIIA, or IIIB EC, and no active concomitant malignancy were included. We compared intraoperative outcomes, and postoperative morbidity and mortality between patients who received NAC (n = 139; NAC group) and patients who did not (n = 86; non-NAC group)., Results: Preoperative laboratory data revealed that anemia, thrombopenia, and renal dysfunction were more common in the NAC group than in the non-NAC group. There were no differences between the groups in operating times, blood loss, number of dissected lymph nodes, overall complication rates, or length of postoperative hospital stay., Conclusion: Based on our findings, thoracoscopic esophagectomy is safe and effective for locally advanced EC, even after NAC.

Background: Total pharyngolaryngoesophagectomy (PLE) is used as a curative treatment for synchronous laryngopharyngeal and thoracic esophageal cancer or for multiple cancers in the cervical and thoracic esophagus. Gastric pull-up is commonly used after PLE, but postoperative complications are common. The present study evaluated these procedures in patients with esophageal cancer., Methods: Fourteen patients (7 with synchronous pharyngeal and thoracic esophageal cancer, 4 with synchronous cervical and thoracic esophageal cancer, and 3 with cervicothoracic esophageal cancer) underwent reconstructive surgery after PLE involving gastric pull-up combined with free jejunal graft between 2004 and 2015., Results: Esophagectomy via right thoracotomy was performed in 9 patients, and transhiatal esophagectomy was used in 5. The posterior mediastinal route was used in 13 patients, excluding one patient with early gastric cancer. Interposition of a free jejunal graft included microvascular anastomosis using two arteries and two veins in all patients. Anastomotic leakage and graft necrosis did not occur in any of the 14 patients who underwent the above surgical procedures. Tracheal ischemia close to the tracheostomy orifice occurred in 4 patients (28.6%), but none of these patients developed pneumonia. No hospital deaths were recorded., Conclusions: The results indicate that gastric pull-up combined with free jejunal graft is a feasible reconstructive surgery after PLE. This procedure is a promising treatment strategy for synchronous pharyngeal and thoracic esophageal cancer or multiple cancers in the cervical and thoracic esophagus. Larger series are needed to show the distinct advantages of this procedure in comparison with conventional methods of reconstruction after PLE.

Metastasis to the posterior thoracic paraaortic lymph nodes rarely occurs in esophageal cancer, and a treatment strategy has not been established. We treated two cases of esophageal cancer with this type of metastasis; in both cases, we successfully performed surgical resection after neoadjuvant chemotherapy. In case 1, the patient received neoadjuvant chemotherapy, which consisted of docetaxel, cisplatin and 5-fluorouracil, and then underwent dissection of the posterior thoracic paraaortic lymph nodes. The left thoracic approach was used together with subtotal esophagectomy via a right thoracotomy. In case 2, the patient also received neoadjuvant chemotherapy and underwent dissection of the posterior thoracic paraaortic lymph nodes. The left thoracoscopic approach was used together with a subtotal esophagectomy and a right upper and middle pulmonary lobectomy (due to lung cancer) with a right thoracotomy. After 42 and 12 months' post-surgery, respectively, the patients were doing well without any evidence of recurrence.

Aim: The aim of this study was to assess changes in body composition during neoadjuvant chemotherapy (NAC) and investigate whether chemotherapy-related toxicities affect body composition in patients with esophageal cancer., Patients and Methods: In ninety-four patients who underwent NAC for esophageal cancer, body composition was assessed before and after NAC. Associations between the incidence of toxicities and change in body composition during NAC were investigated., Results: Forty-four (46.8%) and 50 (53.2%) out of 94 patients were defined as having sarcopenia before and after NAC, respectively. There was no significant difference in the incidence of any toxicity pre-treatment between patients with sarcopenia and those without sarcopenia. No significant reduction in skeletal muscle mass or fat mass was observed in the patients during NAC (p=0.501 and p=0.072). However, patients who experienced grade 4 neutropenia or febrile neutropenia during NAC showed a significantly larger decrease in change of skeletal muscle mass compared to patients who did not experience those toxicities (p=0.013 and 0.036, respectively)., Conclusion: The incidence of serious adverse events such as febrile neutropenia and grade 4 neutropenia is associated with a significant reduction of skeletal muscle mass during NAC. We should make an effort to reduce the incidence of adverse events in order to maintain an appropriate body composition during NAC., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Endoscopic submucosal dissection (ESD) is a widely accepted procedure for superficial esophageal squamous cell neoplasia (ESCN) because of a high complete resection rate. However, there were a few reports about the long-term outcomes of these patients due to short follow-up periods., Aims: We aimed to evaluate the 5-year survival after ESD for superficial ESCN., Methods: This was a retrospective cohort study performed at a single institution. Between 2006 and 2009, 94 patients with superficial ESCN underwent ESD. Eighty-three patients (93.3%) who had completed an extended period of observation of at least 5 years were enrolled. The main outcomes were the 5-year survival rates. The secondary outcomes were the cumulative incidence rate of metachronous ESCN, and the clinical outcomes., Results: The 5-year relative overall survival rate was 99.0%, whereas the cause specific survival rate was 100% during 72.9 months of median follow up period. Subgroup analysis showed that the 5year survival of patients with EP/LPM and MM/SM1 (submucosal invasion ≤200μm) were 100% and 89.0%, respectively. The cumulative incidence rate of metachronous ESCN at 5 years was 16.8%., Conclusion: ESD for superficial ESCN is a curative treatment with a favorable 5-year survival rate., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: The clinical value of synbiotics in patients receiving neoadjuvant chemotherapy currently remains unclear. The aim of this study was to investigate the effects of synbiotics in esophageal cancer patients receiving neoadjuvant chemotherapy on the intestinal microbiota and the adverse events of chemotherapy., Methods: Sixty-one patients with advanced esophageal cancer who were scheduled to receive neoadjuvant chemotherapy were randomly allocated to 2 groups. One group received synbiotics during chemotherapy (n = 30), while the other group did not (n = 31). The fecal microbiota and organic acid concentrations were analyzed. The primary endpoint was the incidence of chemotherapy-related adverse events., Results: The numbers of beneficial and harmful bacteria were significantly larger and smaller, respectively, in the synbiotics group than in the control group on day 10 of chemotherapy. The concentrations of acetic acid and propionic acid were significantly higher in the synbiotics group on day 10 of chemotherapy. The frequencies of severe lymphopenia and diarrhea were significantly less in the synbiotics group than in the control group (P = 0.033, 0.035, respectively). Furthermore, febrile neutropenia occurred less in the synbiotics group (10/30 in the synbiotics group vs 19/31 in the control group, P = 0.029)., Conclusions: Synbiotics during neoadjuvant chemotherapy in esophageal cancer patients reduced the occurrence of adverse events of chemotherapy through adjustments to the intestinal microbiota. (University Hospital Medical Information Network (http://www.umin.ac.jp), registration number UMIN000006875)., (Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Recent studies suggest that chronic inflammation-associated cancer is relevant to microbiome. Esophageal adenocarcinoma arises from an inflammatory condition called Barrett's esophagus, which is caused by gastroesophageal reflux. We hypothesized that esophageal microbiome plays a role in carcinogenesis of esophageal adenocarcinoma., Aim: We investigated whether alteration of microbiome using antibiotics affects the development of esophageal adenocarcinoma in a rat model., Methods: Seven-week-old male Wistar rats which had undergone esophagojejunostomy were divided into control (n = 21) and antibiotic groups (n = 22) at 21 weeks after surgery. Control animals were given drinking water, while the other group was given penicillin G and streptomycin in drinking water until rats were killed at 40 weeks after operation. Incidence rates of Barrett's esophagus and adenocarcinoma in each group were evaluated by histological analysis. DNA was extracted from a portion of the distal esophagus, and the microbiome was investigated using terminal restriction fragment length polymorphism (T-RFLP) analysis., Results: All rats in both groups developed Barrett's esophagus. Incidence of esophageal adenocarcinoma was similar between both groups with a trend to reduced incidence in the antibiotics group (89 % in the control group, 71 % in the antibiotics group, P = 0.365). T-RFLP analysis showed that esophageal microbiome was different between two groups such as the proportion of Lactobacillales was lower in the antibiotics group and Clostridium cluster XIVa and XVIII was higher in the antibiotics group., Conclusions: Alteration of microbiome does not affect the incidence of esophageal adenocarcinoma. Microbiome may not contribute to the development of esophageal adenocarcinoma.

Background: Although endoscopic submucosal dissection (ESD) has become accepted for the treatment of superficial esophageal cancer, the incidence of stricture formation caused by ESD for widespread lesions is high and leads to a low quality of life. A few studies reported that locoregional steroid injections are useful for the prevention of such stricture formation compared with historical controls. We evaluated the efficacy of prophylactic locoregional steroid injections for stricture formation caused by ESD using quasi-randomized analysis., Methods: This matched case-control study included 461 superficial esophageal cancers from 305 patients who underwent ESD between 2006 and 2013. We used two methods of locoregional steroid injection to prevent stricture formation after ESD. A propensity score matching analysis was performed to reduce the effects of a selection bias for steroid injections and other potential confounding factors. In addition, generalized estimating equations were used to analyze repeated measures data. We compared the incidence of stricture formation with or without steroid injections., Results: Forty-two lesions were treated with locoregional steroid injection (dexamethasone/triamcinolone, 23/19) after ESD and esophageal stricture formation occurred in 36 lesions. Fifty-six lesions treated with or without steroid injections were matched after propensity score matching. Locoregional steroid injection reduced the incidence of stricture formation to 10.7% (3/28) of patients compared with 35.7% (10/28) in the control group (odds ratio 4.63, 95% confidence interval 1.11-19.25, p = 0.035)., Conclusions: Locoregional steroid injections could be efficient for the prevention of stricture formation after ESD for superficial esophageal cancer.

Background/aims: Modified neuroleptanalgesia (m-NLA) with midazolam is often used for sedation and analgesia during endoscopic submucosal dissection (ESD) for gastrointestinal neoplasia. However, interruption due to poor response to midazolam is often experienced during ESD for esophageal squamous cell carcinoma (ESCC) because most patients with ESCC have a history of heavy alcohol intake. We examined the incidence and risk factors for poor response to m-NLA with midazolam and pethidine hydrochloride., Methods: This retrospective cross-sectional study was conducted at a single institution. Between April 2007 and July 2013, 151 patients with superficial ESCC who underwent ESD under sedation using m-NLA with midazolam and pethidine hydrochloride were enrolled. Poor response to sedation was defined as the use of a second drug when Ramsay Sedation Score 1-2., Results: Poor response to sedation occurred in 66.2% patients. Most cases of poor response were controlled by using additional flunitrazepam. Multivariate logistic regression analysis showed that cumulative alcohol intake and major specimen size were independent risk factors for poor response to sedation (OR 3.63, 95% CI 1.20-10.99, and OR 3.23, 95% CI 1.26-8.25)., Conclusion: Our study indicated that cumulative alcohol intake and major specimen size were associated with poor response to m-NLA with midazolam and pethidine hydrochloride., (© 2016 S. Karger AG, Basel.)

Purpose: Patients with resectable thoracic esophageal squamous cell cancer (TESCC) and positron emission tomography (PET)-positive lymph nodes (PET-N positive) are likely to have ≥3 pathological lymph node metastases (pLNMs) and show a higher rate of postoperative recurrence despite curative resection than PET-N-negative TESCC patients. We examined the prognostic significance of (18)F-fluorodeoxyglucose uptake into lymph node metastases after neoadjuvant chemotherapy (NAC) for PET-N positive TESCC and aimed to propose the optimal NAC response criteria for these patients., Methods: Fifty-one patients with PET-N positive TESCC underwent two courses of NAC followed by surgery. Metabolic responses of primary tumors and LNs were prospectively evaluated and associations with clinicopathological data and patient survival assessed by univariate and multivariate analyses., Results: After NAC, 21 patients were post-treatment (post-) PET-N positive and 30 post-PET-N negative. A significantly (p < 0.001) high proportion of the post-PET-N-negative group had ≤2 pLNMs than the post-PET-N positive group (86.7 vs. 28.6 %). The PET-N negative group also had a significantly lower distant metastasis rate (23.3 vs. 75.0 %) and higher 5-year relapse-free survival (RFS) rate (69.0 vs. 20.0 %). Univariate and multivariate Cox's proportional hazard regression analyses identified post-PET-N negative status as the only significant favorable predictive factor for low postoperative recurrence (p = 0.015) independent of the primary tumor response., Conclusions: PET-N negative status predicts ≤2 pLNMs and longer RFS in resectable TESCC patients even after NAC. Therefore, post-PET-N status, not the effects on the primary tumor, is a critical NAC treatment response criterion for evaluating prognosis and guiding subsequent treatment.

Purpose: (18)F-fluorodeoxyglucose positron emission tomography-positive lymph nodes (PET-N positive) in patients with resectable thoracic esophageal squamous cell carcinoma (TESCC) are associated with a high rate of postoperative distant recurrence. The purpose of this study was to evaluate the systemic control and survival benefit of neoadjuvant chemotherapy (NAC, cisplatin + doxorubicin + 5-fluorouracil) in these patients., Methods: Of 77 patients with resectable TESCC who were PET-N positive, we evaluated 51 treated with NAC + surgery in this study and 26 who had undergone surgery alone (SA) in a previous study. Historical comparisons of the groups were made, and the response to treatment was evaluated in the NAC group., Results: The NAC group had a higher rate of pN0-1 and a lower rate of postoperative recurrence (p < 0.0001 and p < 0.024, respectively) than the SA group; however, their relapse-free survival (RFS) rates were not significantly different. The NAC group had a significantly higher RFS in cT1/T2 cases, but showed similar survival in cT3 cases. On the other hand, post-treatment PET-N-negative patients had a higher RFS (p = 0.008) and a lower rate of distant recurrence (p = 0.021), even with cT3 disease. A multivariate analysis identified the post-treatment PET-N evaluation to be the only significant predictor of the RFS in cT3 cases., Conclusions: NAC significantly suppressed postoperative recurrence in TESCC PET-N-positive patients, but the survival benefit was unclear. However, post-treatment PET-N-negative patients were likely responders to NAC.

Objective: To identify predictive factors for the development of pericardial effusion (PCE) in patients with oesophageal cancer treated with chemotherapy and radiotherapy (RT)., Methods: From March 2006 to November 2012, patients with oesophageal cancer treated with chemoradiotherapy (CRT) using the following criteria were evaluated: radiation dose >50 Gy; heart included in the radiation field; dose-volume histogram (DVH) data available for analysis; no previous thoracic surgery; and no PCE before treatment. The diagnosis of PCE was independently determined by two radiologists. Clinical factors, the percentage of heart volume receiving >5-60 Gy in increments of 5 Gy (V5-60, respectively), maximum heart dose and mean heart dose were analysed., Results: A total of 143 patients with oesophageal cancer were reviewed retrospectively. The median follow-up by CT was 15 months (range, 2.1-72.6 months) after RT. PCE developed in 55 patients (38.5%) after RT, and the median time to develop PCE was 3.5 months (range, 0.2-9.9 months). On univariate analysis, DVH parameters except for V60 were significantly associated with the development of PCE (p < 0.001). No clinical factor was significantly related to the development of PCE. Recursive partitioning analysis including all DVH parameters as variables showed a V10 cut-off value of 72.8% to be the most influential factor., Conclusion: The present results showed that DVH parameters are strong independent predictive factors for the development of PCE in patients with oesophageal cancer treated with CRT., Advances in Knowledge: A heart dosage was associated with the development of PCE with radiation and without prophylactic nodal irradiation.

Background: Neoadjuvant chemotherapy (NACT) improves the prognosis of patients with esophageal cancer who respond, but it is not effective in nonresponders. Therefore, it is crucial to establish a reliable method of predicting response before initiation of chemotherapy. Hypercoagulability, which is thought to be because of upregulation of tissue factor (TF) in cancer cells, was reported to be associated with chemoresistance. The aim of this study was to investigate the association between TF expression and response to NACT in esophageal cancer., Methods: In 67 patients with advanced esophageal cancer, TF expression in pretreatment biopsy samples was evaluated immunohistochemically and correlated with clinicopathologic factors and response to chemotherapy., Results: TF was expressed by 43.3% of the tumors, but there were no correlations observed with any clinicopathologic parameters examined. Clinical and histologic responses to chemotherapy were significantly worse in TF-positive patients compared with TF-negative patients. Multivariate analysis revealed that TF expression was significantly associated with a poor clinical response (P = 0.0431). TF expression was also independently associated with poor progression-free survival (P = 0.0353)., Conclusions: TF expression levels in pretreatment biopsy samples are useful for predicting response to NACT in advanced esophageal cancer. Further studies of mechanisms underlying the relationship between TF expression and chemosensitivity are needed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: The usefulness of non-magnifying endoscopy with narrow-band imaging (NBI; NM-NBI) in the screening of early esophageal squamous cell carcinoma (SCC) and high-grade intraepithelial neoplasia (HGIN) remains unclear. Here, we aimed to compare NM-NBI and chromoendoscopy with iodine staining (CE-Iodine) in terms of the diagnostic performance, and to evaluate the usefulness of NM-NBI in detecting early esophageal SCC., Methods: We prospectively enrolled 202 consecutive patients (male/female=180/22; median age, 67 years) with high-risk factors for esophageal SCC. All patients received endoscopic examination with NM-NBI and CE-Iodine to screen for early esophageal SCC or HGIN. We conducted the examinations sequentially, and calculated the accuracy, sensitivity, and specificity through a per-lesion-based analysis. A propensity score matching analysis was performed to reduce the effects of selection bias, and we compared the respective outcomes according to NM-NBI and CE-Iodine after matching., Results: The accuracy, sensitivity, and specificity of NM-NBI were 77.0, 88.3, and 75.2%, respectively, and those for unstained areas by CE-Iodine were 68.0, 94.2, and 64.0, respectively. The accuracy and specificity of NM-NBI were superior to those of CE-Iodine (P=0.03 and P=0.01, respectively). However, the sensitivity did not significantly differ between NM-NBI and CE-Iodine (P=0.67). The accuracy and specificity of NM-NBI before matching were superior to those of CE-Iodine after matching (P=0.04 and P=0.03)., Conclusions: NM-NBI was useful and reliable for the diagnosis of esophageal SCC and can be a promising screening strategy for early esophageal SCC.

Background: Anastomosis performed during esophagectomy for esophageal cancer is usually involves hand-sewn or circular stapled methods. However, these techniques have been reported to be associated with a high frequency of anastomotic complications, including leakage and benign stenosis. Here a novel triangulating stapling technique for esophagogastrostomy after esophagectomy for esophageal cancer and its retrospective investigation are described., Methods: Forty-eight patients were underwent esophagectomy for esophageal cancer from January 2006 to December 2009 by the same surgeon using the triangulating stapling technique. The short-term outcomes were evaluated retrospectively. This end-to-end anastomosis used three linear staplers in an everted fashion., Results: Patients comprised 36 men and 12 women with a mean age of 59.4 years. Anastomotic leakage occurred in 4 patients (8.3 %), while anastomotic stenosis was observed in 6 (12.5 %). The average number of endoscopic pneumatic dilatations in patients with anastomotic stenosis was 2.4. The median (range) duration of hospital stay was 40.8 (19-154) days., Conclusions: Our modified triangulating stapling technique for esophagogastrostomy may be a feasible alternative, resulting in a lower frequency of postoperative anastomotic complications.

A 59-year-old woman and a 69-year-old man had esophageal strictures that were refractory to over 10 therapeutic attempts with endoscopic balloon dilation (EBD) after endoscopic submucosal dissections (ESD) for superficial esophageal carcinoma (SEC). The strictured lesions in both patients improved remarkably with a new endoscopic modality (endoscopic radial incision and cutting [ERIC]), which was carried out one to three times, and stricture recurrence was not noted throughout the follow-up period. ERIC is a safe and efficient method for treating refractory strictures after EBD caused by ESD for SEC., (© 2012 The Authors. Digestive Endoscopy © 2012 Japan Gastroenterological Endoscopy Society.)

Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive cancers with poor prognosis regardless of a several reports that indicate a better therapeutic efficacy using some new chemotherapeutic agents. Recent drug development has contributed to an improved specificity to suppress mTOR activity by which many types of malignancies can be explosively progressed. Temsirolimus (CCI-779, TricelTM) is one of recently synthesized analogs of rapamycin and has provided better outcomes for patients with renal cell carcinoma. In this study, we experimentally evaluated an efficacy of targeting mTOR by temsirolimus for ESCC treatment, with an assessment of its survival advantage using an advanced ESCC animal model. First, we confirmed that the expression of phosphorylated mTOR was increased in 46 of 58 clinical ESCC tumor tissues (79.3%) and appeared to get strengthened with tumor progression. All of ESCC cell lines used in this study revealed an increase of mTOR phosphorylation, accompanied with the upregulation of hypoxia inducible factor-I α (HIF-1α), one of the critical effectors regulated by mTOR. Temsirolimus treatment apparently suppressed the activation of mTOR and its downstream effectors, resulting in the reduced ability of ESCC cell proliferation. Finally, the weekly administration of temsirolimus significantly diminished the size of subcutaneous tumors (vehicle, 3261.6 ± 722.0; temsirolimus, 599.2 ± 122.9; p = 0.007) in nude mice and effectively prolonged orthotopic esophageal cancer-bearing mice (median survival periods: control, 31 d; temsirolimus, 43 d; p = 0.0024). These data suggests that targeting mTOR by temsirolimus may become a therapeutic alternative for esophageal cancer, with a contribution to a better outcome.

Background: Recently, reports from the West have indicated three-field lymphadenectomy (3FL) for esophageal cancer increases the accuracy of tumor staging and survival. However, this cervical procedure is likely to lead to swallowing dysfunction and aspiration, which are barriers to introducing this procedure in clinical practice., Methods: Our goal is to elucidate the etiology of swallowing dysfunction after 3FL and devise a remedy. First, based on evaluation of swallowing function in ten patients with two-field lymphadenectomy (2FL) and ten with 3FL, we hypothesized that the scarred sternohyoid and sternothyroid muscles might be impairing laryngeal elevation after 3FL; thus, complete division of the bilateral infrahyoid muscles attached to the sternum (CDBIMS) could be an effective remedy. Next, the utility of this additive procedure was examined in 20 patients with 3FL. Swallowing function was evaluated by the distance of total laryngeal elevation (TLE) and the frequency of incomplete airway protection (IAP) (laryngeal penetration or aspiration) on videofluoroscopic study., Results: The average TLE and frequency of IAP were, respectively, 0.37 cm and 70 % in the 3FL group, showing significant deterioration (p < 0.001 and 0.025), in contrast to 1.79 cm and 20 % in the 2FL group. The 3FL + CDBIMS group showed significant improvements in the average TLE and the frequency of IAP (1.70 cm and 25 %), compared with the 3FL group (p < 0.001 and 0.018). Multivariate logistic regression identified additive CDBIMS as a significant suppressor of IAP after 3FL., Conclusions: Laryngeal elevation was significantly impaired after 3FL. Adding CDBIMS might improve swallowing function in these patients.

Aim: The aim of this study was to evaluate the clinical outcomes and prognostic factors of thoracoscopic esophagectomy with two-field lymph node dissection for lower thoracic esophageal cancer., Patients and Methods: From January 2003 to December 2011, 84 patients with lower thoracic esophageal cancer underwent thoracoscopic esophagectomy with two-field lymph node dissection. Clinicopathological information, postoperative complications, mortality, type of recurrent diseases and factors predictive of survival were analyzed., Results: Postoperative complications were diagnosed in 37 patients and the mortality was 1.2%. Lymph node metastases were found in 43 patients (51.2%). The 5-year survival rate of all patients was 60.5%. Pathological T factor, lymph node metastasis, pathological staging, and venous invasion were independent prognostic factors. Among the patients with lymph node metastasis, the survival rate of those with upper mediastinal and/or celiac area involvement was significantly worse than that of those without involvement of these areas., Conclusion: Thoracoscopic esophagectomy with two-field lymph node dissection is a safe and appropriate surgical intervention for patients with lower thoracic esophageal cancer without complication of lymph node metastases to the upper mediastinum and/or celiac area.