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Background: Patients with esophageal squamous cell carcinoma (ESCC) with distant metastasis were treated with systemic chemotherapy. Recent advances in multimodal treatments have made conversion therapy a viable option for patients with incurable ESCC., Objective: We aimed to assess the safety and efficacy of conversion therapy for ESCC with distant metastases., Methods: Conversion therapy was defined as surgery or chemoradiotherapy (CRT) used to cure tumors that were previously considered incurable because of distant metastasis. We conducted a retrospective review of patients who underwent ESCC conversion therapy and assessed the treatment outcomes, including adverse events and survival rates., Results: A total of 147 patients from 22 institutions were included. Systemic chemotherapy was initially administered to all patients. The most common M1 factor was the para-aortic lymph node, accounting for 55% of cases. Following the initial treatment, 116 patients underwent surgery, with 31 receiving CRT as conversion therapy. Postoperative complications in surgery patients included pneumonia (16%), anastomotic leakage (7%), and recurrent laryngeal nerve palsy (6%). During CRT, 18% of patients developed grade 3 or higher non-hematological toxicities. The 5-year overall survival (OS) rate was 31.7%. Pathological responders had significantly longer OS than non-responders (hazard ratio 0.493, p = 0.012). The distribution of distant metastasis, regimen type, clinical response, and conversion therapy modality did not have a significant impact on OS., Conclusions: Conversion therapy can be safely performed for ESCC with distant metastasis and has a favorable prognosis., (© 2024. Society of Surgical Oncology.)

Background: Cricothyrotomy is a widely performed potentially life-saving treatment to secure an airway in emergencies. It is also a pneumonia-preventing treatment to secure an expectorant route in patients with difficulty self-expelling sputum; however, its safety and usefulness remain unclear. Thus, we conducted a nationwide survey of cricothyrotomy., Methods: We retrospectively collected and analyzed cricothyrotomy data from the institutions certified by the Japan Broncho-Esophagological Society or the Japanese Esophageal Society. Ultimately, 116 facilities responded to the survey and the present study included 1001 patients from 26 facilities who underwent cricothyrotomies from January 1, 2010 to December 31, 2021., Results: Cricothyrotomy was performed for sputum suctioning after esophagectomy or other surgical procedures in 945 (94.4%) cases and for emergency airway clearance in 48 (4.8%) cases. Complications during puncture were observed in 12 (1.2%) cases. We found significantly fewer complications during puncture for sputum suction (1.0%) compared with emergency airway clearance (4.2%) (p = 0.002), and also at the condition after esophagectomy (0.5%) compared with other surgical procedures (7.8%) (p < 0.001). Complications after puncture were observed in 45 (4.5%) cases, and we found significantly fewer complications after puncture at the condition after esophagectomy (4.2%) compared with other surgical procedures (11.8%) (p = 0.032). There were no significant differences in the type of kit used for complications during and after the puncture., Conclusions: Cricothyrotomy for prophylactic sputum suctioning after esophagectomy was safer compared to emergency airway clearance. However, future studies should verify the efficacy of cricothyrotomy., (© 2024. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: The irrigation efficacy of a povidone-iodine solution to prevent surgical site infection is still controversial. We assessed the irrigation effect with a povidone-iodine solution on the incidence of surgical site infection after gastroenterological surgery., Methods: This study is a single-center, prospective, randomized, blinded-end point superiority trial for surgical wound irrigation. Patients undergoing gastroenterological surgery were randomly assigned in a 1:1 replacement ratio using computer-generated randomization. Patients were grouped according to their surgical wound treatment into the control group using the normal sterile saline and the povidone-iodine group using 10% povidone-iodine solution after the NS solution. The main finding was 30-day surgical site infections assessed in the full analysis set., Results: From November 2020 to December 2022, 697 of 894 patients were eligible for the study, among which 347 were in the povidone-iodine group and 350 in the control group. Thirty-day surgical site infections occurred in 100 (14%) patients-54 (16%) in the povidone-iodine group and 46 (13%) in the control group (odds ratio, 1.229; 95% CI, 0.800-1.889; P = .406). Superficial incisional surgical site infections occurred in 30 (9%) and 15 (4%) patients, respectively (odds ratio, 2.154; 95% CI, 1.134-4.090; P = .026). Only 3 patients (1%) in the control group developed adverse skin reactions., Conclusion: This study examined the irrigation efficacy of povidone-iodine for surgical site infection prevention compared to control in gastroenterological surgery. Povidone-iodine wound irrigation has shown no additional beneficial effect on the occurrence of surgical site infections., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To identify the problems trainees face during surgical training in Japan., Methods: A nationwide online questionnaire survey was conducted targeting newly certified surgical trainees., Results: The response rate was 53.8% (758/1410). Among those respondents, 25.6% were women, 71.4% were either married or had a partner, 41.3% had children, 72.7% had performed over 200 surgeries under general anesthesia, and 54.1% had chosen, before graduating from medical school, to become a surgeon. While 88.8% were interested in learning surgical techniques, 63.8% were hesitant to become a surgeon for fear of a compromised quality of private life (QOL). Conversely, only 1.4% chose their surgical training programs based on QOL. Overall, 84.6% of the trainees were satisfied with their training and this correlated with the number of surgeries performed. Only 29.9% received non-technical skill training. The average number of night shifts per month was 5.6, and 10.6% worked over 80 h per week. Harassment was reported by 41.5% of the respondents. Moreover, 33.0% had considered dropping out at some time, primarily because of their QOL (51.1%) or the harassment they had encountered (50.4%)., Conclusion: This survey revealed that while trainees were satisfied with the overall training system, issues such as long working hours and harassment are prevalent. Working to improve these issues could make surgery more attractive for young trainees., (© 2024. The Author(s).)

Purpose: To compare changes in liver enzyme levels on postoperative day 1 between patients with and without silicone disc (SD) use during liver retraction in laparoscopic gastrectomy for gastric cancer and laparoscopic gastric mobilization for esophageal cancer., Methods: This prospective randomized controlled phase II trial was conducted between June 30, 2020, and November 30, 2022, to investigate the benefits of using an SD with a Nathanson liver retractor (NLR) compared with those using an NLR in laparoscopic gastrectomy and gastric mobilization. The primary endpoint was the change in transaminase level on postoperative day 1., Results: A total of 86 patients received randomized assignments and were included in the analysis, with 44 assigned to the SD (-) group and 42 to the SD (+) group. On postoperative day 1, the SD (+) group showed a significantly lower increase in the aspartate aminotransferase levels than the SD (-) group (SD [+], 94.4% vs. SD [-], 179.8%; p = 0.012). Similarly, the SD (+) group showed a significantly lower increase in alanine aminotransferase levels than the SD (-) group (SD [+], 71.6% vs. SD [-], 201.5%; p = 0.014)., Conclusion: In laparoscopic gastrectomy, the use of an SD combined with an NLR appears to mitigate postoperative liver dysfunction., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

The assessment of programmed death-ligand 1 (PD-L1) expression in esophageal squamous cell carcinoma (ESCC) has become increasingly important with the rise of immune checkpoint inhibitors (ICIs). However, challenges persist, including subjective interpretation and the unclear significance of staining intensity, as well as contrasting roles in tumoral and stromal regions. Our study enhances the understanding of PD-L1 in ESCCs by analyzing its expression in tumors and stroma with H-scores, highlighting its distinct clinicopathological impacts. In a retrospective cohort of 194 ESCC specimens from surgical resection, we quantified PD-L1 expression in tumoral and stromal compartments using H-scores, analyzing whole slide images with digital pathology analysis software. Kaplan-Meier analysis demonstrated that higher PD-L1 expression is significantly associated with improved postoperative overall survival (OS) and recurrence-free survival (RFS) in both tumoral and stromal areas. Multivariable analysis identified high tumoral PD-L1 expression as an independent prognostic factor for prolonged OS and RFS (HR = 0.47, p = 0.007; HR = 0.54, p = 0.022, respectively). In a separate analysis, high stromal PD-L1 expression was found to correlate with less advanced pathological stages and a prolonged response to cytotoxic chemotherapy, with no similar correlation found for ICI treatment response. This study reveals PD-L1's contrasting role in the ESCC tumor immune microenvironment, impacting prognosis, tumor stage, and treatment response.

Treatment strategies for oesophagogastric junction adenocarcinoma have not been standardized despite its poor prognosis due to differences in the incidence rates between Western countries and Asia. This randomized Phase II/III trial was initiated in June 2023 to determine which neoadjuvant chemotherapy regimen, docetaxel, oxaliplatin and S-1 or fluorouracil, oxaliplatin and docetaxel, is a more promising treatment in Phase II and confirm the superiority of neoadjuvant chemotherapy with docetaxel, oxaliplatin and S-1 or fluorouracil, oxaliplatin and docetaxel followed by surgery and postoperative chemotherapy over upfront surgery and postoperative chemotherapy in terms of overall survival in patients with Clinical Stage III or IVA oesophagogastric junction adenocarcinoma in Phase III. A total of 460 patients, including 150 patients in Phase II and 310 patients in Phase III, are planned to be enrolled from 85 hospitals in Japan over 5 years. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031230182 (https://jrct.niph.go.jp/latest-detail/jRCTs031230182)., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Enteral feeding (EF) is recommended to enhance nutritional status after esophagectomy; however, diarrhea is a common complication of EF. We investigated the clinical and prognostic impact of diarrhea during EF after esophagectomy., Methods: One hundred and fifty-two patients who underwent transthoracic esophagectomy were enrolled. The King's stool chart was used for stool characterization. The short- and long-term outcomes were compared between a non-diarrhea (Group N) and diarrhea group (Group D)., Results: A higher dysphagia score (≥ 1) was observed more frequently in Group D than in Group N (45.7% vs. 19.8%, p = 0.002). Deterioration of serum total protein, serum albumin, serum cholinesterase, and the prognostic nutritional index after esophagectomy was greater in Group D than in Group N (p = 0.003, 0.004, 0.014, and 0.001, respectively). Patients in Group D had significantly worse overall survival (OS) and recurrence-free survival (RFS) than those in Group N (median survival time (MST): OS, 21.9 vs. 30.6 months, p = 0.001; RFS, 12.4 vs. 27.7 months, p < 0.001). In stratified analysis due to age, although there was no difference in OS with or without diarrhea in young patients (MST: 24.1 months in a diarrhea group vs. 33.6 months in a non-diarrhea group, p = 0.218), patients in a diarrhea group had significantly worse OS than those in a non-diarrhea group in elderly patients (MST: 17.8 months vs. 27.9 months, p < 0.001)., Conclusions: Diarrhea during EF can put elderly patients at risk of postoperative malnutrition and a poor prognosis after esophagectomy., (© 2023. The Author(s).)

Background: Detecting pathological complete response (pCR) before surgery would facilitate nonsurgical approach after neoadjuvant chemotherapy (NAC). We developed an artificial intelligence (AI)-guided pCR evaluation using a deep neural network to identify pCR before surgery., Methods: This study examined resectable esophageal squamous cell carcinoma (ESCC) patients who underwent esophagectomy after NAC. The same number of histological responders without pCR and non-responders were randomly selected based on the number of pCR patients. Endoscopic images were analyzed using a deep neural network. A test dataset consisting of 20 photos was used for validation. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of AI and four experienced endoscopists' pCR evaluations were calculated. For pathological response evaluation, Japanese Classification of Esophageal Cancer was used., Results: The study enrolled 123 patients, including 41 patients with pCR, the same number of histological responders without pCR, and non-responders [grade 0, 5 (4%); grade 1a, 36 (30%); grade 1b, 21 (17%); grade 2, 20 (16%); grade 3, 41 (33%)]. In 20 models, the median values of sensitivity, specificity, PPV, NPV, and accuracy for endoscopic response (ER) detection were 60%, 81%, 77%, 67%, and 70%, respectively. Similarly, the endoscopists' median of these was 43%, 90%, 85%, 65%, and 66%, respectively., Conclusions: This proof-of-concept study demonstrated that the AI-guided endoscopic response evaluation after NAC could identify pCR with moderate accuracy. The current AI algorithm might guide an individualized treatment strategy including nonsurgical approach in ESCC patients through prospective studies with careful external validation to demonstrate the clinical value of this diagnostic approach including primary tumor and lymph node., (© 2023. Society of Surgical Oncology.)

This systematic review was performed to investigate the superiority of proton beam therapy (PBT) to photon-based radiotherapy (RT) in treating esophageal cancer patients, especially those with poor cardiopulmonary function. The MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases were searched from January 2000 to August 2020 for studies evaluating one end point at least as follows; overall survival, progression-free survival, grade ≥ 3 cardiopulmonary toxicities, dose-volume histograms, or lymphopenia or absolute lymphocyte counts (ALCs) in esophageal cancer patients treated with PBT or photon-based RT. Of 286 selected studies, 23 including 1 randomized control study, 2 propensity matched analyses, and 20 cohort studies were eligible for qualitative review. Overall survival and progression-free survival were better after PBT than after photon-based RT, but the difference was significant in only one of seven studies. The rate of grade 3 cardiopulmonary toxicities was lower after PBT (0-13%) than after photon-based RT (7.1-30.3%). Dose-volume histograms revealed better results for PBT than photon-based RT. Three of four reports evaluating the ALC demonstrated a significantly higher ALC after PBT than after photon-based RT. Our review found that PBT resulted in a favorable trend in the survival rate and had an excellent dose distribution, contributing to reduced cardiopulmonary toxicities and a maintained number of lymphocytes. These results warrant novel prospective trials to validate the clinical evidence., (© 2023. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Thoracic esophagectomy is a particularly invasive and complicated surgical procedure, with a reconstruction of the gastrointestinal tract, such as the stomach, jejunum, or colon. The posterior mediastinal, retrosternal, and subcutaneous routes are the three possible esophageal reconstruction routes. Each route has advantages and disadvantages, and the optimal reconstruction route after esophagectomy remains controversial. Additionally, the best anastomotic techniques after esophagectomy in terms of location (Ivor Lewis or McKeown) and suturing (manual or mechanical) are debatable. Our meta-analysis investigating postoperative complications after esophagectomy between the posterior mediastinal and retrosternal routes revealed that the posterior mediastinal route was associated with a significantly lower anastomotic leakage rate than the retrosternal route (odds ratio = 0.78, 95% confidence interval: 0.70-0.87, p  < 0.0001). Conversely, pulmonary complications (odds ratio = 0.80, 95% confidence interval: 0.58-1.11, p  = 0.19) and mortality between the posterior mediastinal and retrosternal routes (odds ratio = 0.79, 95% confidence interval: 0.56-1.12, p  = 0.19) were not significantly different. However, the incidence of pneumonia may be lower when using the retrosternal route rather than the posterior mediastinal route for performing minimally invasive esophagectomy. The McKeown procedure is oncologically necessary for tumors located above the carina to dissect upper mediastinal and cervical lymph nodes; however, the Ivor Lewis procedure offers perioperative and oncological safety for tumors located under the carina. An individualized treatment strategy for selecting the optimal reconstruction procedure can be proposed in future studies based on oncological and patient risk factors considering mid- to long-term quality of life., Competing Interests: Authors declare no conflict of interests for this article. Hiroya Takeuchi is an editorial board member of Annals of Gastroenterological Surgery., (© 2023 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

Maintaining the postoperative quality of life (QOL) while ensuring curability without overtreatment is important in the treatment of early gastric cancer. Postoperative QOL is anticipated to be maintained through minimally invasive function-preserving gastrectomy in early gastric cancer. The concept of the sentinel lymph node (SN) basin is essential to maintain the curability of early gastric cancer using minimally invasive function-preserving gastrectomy. However, additional resection after surgery is difficult to perform in gastric cancer. Thus, the SN basin theory is important. Recently, a multicenter randomized phase III trial in South Korea (SENORITA trial) proved that laparoscopic sentinel node navigation surgery (LSNNS) for stomach preservation results in better postoperative QOL compared with standard gastrectomy in patients with early gastric cancer. LSNNS contributes to patients' QOL based on the concept that curability is not impaired. A multicenter nonrandomized phase III trial is ongoing in Japan, and oncologic safety is expected to be demonstrated. LSNNS has been established as a treatment option for selected patients with early gastric cancer, and its application will become widespread in the future., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2023. Korean Gastric Cancer Association.)

Background: The aim of this study was to evaluate clinical validity of the S-1 dosage formula based on body surface area (BSA) and creatinine clearance (CLcr) to achieve the target area under the concentration-time curve of 5-FU, which we had developed and refined in each prospective pharmacokinetic study., Methods: The recommended dose determined by the refined formula was assessed using data of the SPIRITS (S-1 vs. S-1 plus cisplatin [SP]) and the G-SOX (SP vs. S-1 plus oxaliplatin [SOX]) trials. Nine hundred and thirty-eight patients in these trials were classified into three groups according to their actual S-1 starting doses compared with the recommended doses (under-dosed, recommended dose)., Results: The patients in the under-dosed group in both trials showed similar tendencies: male, younger, higher BSA, and higher CLcr. The incidence of any grade neutropenia was significantly greater in the over-dosed group compared with the equal-dosed group in the S-1 and the SOX arms. The hazard ratios (HR) of overall survival (OS) (under-dosed vs. equal-dosed) were 1.361 (S-1 arm), 1.259 (SP arm) in the SPIRITS trial, and 1.381 (SOX arm), 0.999 (SP arm) in the G-SOX trial. Multivariate analysis in all the patients demonstrated that OS of the over-dosed group was equivalent (HR 1.002, 95% confidence interval [CI] 0.850-1.182, p = 0.980) and that of the under-dosed group was inferior (HR 1.267, 95% CI 1.005-1.597, p = 0.045) to the equal-dosed group., Conclusions: It is suggested that the refined S-1 dosage formula can recommend optimal dose in terms of safety and efficacy., (© 2022. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Endoscopic diagnosis of the invasion depth of superficial esophageal squamous cell carcinoma (ESCC) is an important determinant of the treatment strategy. The three endoscopic imaging modalities commonly used to predict the invasion depth of superficial ESCC in Japan are non-magnifying endoscopy (non-ME), magnifying endoscopy (ME), and endoscopic ultrasonography (EUS). However, which of these three modalities is most effective remains unclear. We performed a systematic review of the literature to compare the diagnostic accuracy of the three modalities for prediction of the invasion depth of superficial ESCC. We used Medical Subject Heading terms and free keywords to search the PubMed, Cochrane Central, and Ichushi databases to identify direct comparison studies published from January 2000 to August 2020. The results of direct comparison studies were used to compare the diagnostic accuracy of each modality. The primary outcome was defined as the proportion of overdiagnosis of pT1b-SM2/3 cancers, and the main secondary outcome was the proportion of underdiagnosis of pT1b-SM2/3 cancers. Other secondary outcomes were the sensitivity and specificity values of the modalities. Four articles were finally selected for qualitative evaluation. Although ME showed no significant advantages over non-ME in terms of sensitivity and specificity, it had a slightly lower proportion of overdiagnosis. EUS had sensitivity and specificity similar to those of non-ME and ME, but EUS had a higher proportion of overdiagnosis. Non-ME and ME are useful for the diagnosis of cancer invasion depth. EUS may increase overdiagnosis, and caution is required in determining its indications., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

The aim of this study was to investigate the relationship between serum procalcitonin (PCT) levels after esophagectomy and infectious complications and long-term prognosis. A total of 105 patients who underwent esophagectomy between 2012 and 2019 were stratified into two groups: PCT-High group of ≥1 ng/mL and PCT-Low group of <1 ng/mL. The clinical outcomes and prognostic factors were compared between the two groups 2 postoperative days (POD), 4 POD, and 7 POD after esophagectomy. As the postoperative days passed, the association between PCT and infectious complications became stronger, and the positive predictive value was 100% at 7 POD. At 2 POD, there was no significant association between PCT elevation and infectious complications. Patients in the PCT-Low group had significantly worse overall survival (OS) and recurrence-free survival (RFS) than those in the PCT-High group at 2 POD (p = 0.026 and p = 0.011, respectively). In multivariate analysis, advanced pathological stage (hazard ratio (HR), 5.348; 95% confidence interval (CI), 2.299−12.500; p < 0.001) and PCT-Low group at 2 POD (HR, 3.673; 95% CI, 1.116−12.092; p = 0.032) were also independent predictors of worse OS. PCT in the early postoperative period after esophagectomy could be a good predictor of prognosis.

Background/aim: Although the effectiveness of immune checkpoint inhibitors (ICIs) in upper gastrointestinal (UGI) cancer including esophageal squamous cell carcinoma (ESCC) and gastric/gastroesophageal adenocarcinoma (GEA) has been proven, prediction of their efficacy remains unknown. This study aimed to develop optimal serum nutritional indicators or a combination of blood cell components to predict the efficacy of ICI before beginning UGI cancer treatment., Patients and Methods: We retrospectively reviewed the data of 61 UGI cancers (31 ESCC and 30 GEA) patients treated with nivolumab or pembrolizumab. We investigated the impact of serum albumin level, total lymphocyte count (TLC), prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) on the efficacy of ICIs and long-term survival. The median cutoff value was adopted separately in ESCC and GEA., Results: NLR-Low was significantly correlated with better overall survival (p=0.014), and PLR-Low was significantly correlated with improved disease control rate and better progression-free survival in UGI cancer patients. Both results indicate that a better prognosis is correlated to a greater number of lymphocytes. Multivariate analysis revealed that NLR-High [hazard ratio (HR)=2.865; 95% confidence interval (CI)=1.030-7.937; p=0.044] was the only independent poor prognostic factor., Conclusion: NLR-Low has the potential to predict the good efficacy of ICIs and survival outcomes in patients with UGI cancer. NLR could be useful in determining the optimal treatment strategies for these patients., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Esophageal cancer surgery requires maintenance and enhancement of perioperative nutritional status and physical function to prevent postoperative complications. Therefore, awareness of the importance of preoperative patient support is increasing. This study examined the usefulness of using a diary in combination with a wearable fitness tracking device (WFT) in patients undergoing surgery for esophageal cancer., Methods: Ninety-four patients who underwent esophagectomy between February 2019 and April 2021 were included. Physicians, nurses, dietitians, and physical therapists provided diary-based education for the patients. In addition, a WFT was used by some patients. The perioperative outcomes of patients who used both the diary and WFT (WFT group) and those who used the diary alone (non-WFT group) were compared. In addition, propensity score matching was performed to improve comparability between the two groups., Results: After the propensity score matching, the rate of postoperative pneumonia was significantly lower in the WFT group (0% vs. 22.6%, P = 0.005). The postoperative hospital stay was shorter in the WFT group (P = 0.012). Nutritional status indices, such as the prognostic nutritional index, also improved significantly in the WFT group at 1 month after surgery (P = 0.034). The rate of diary entries was significantly higher in the WFT group (72.3% vs. 28.3%, P < 0.001)., Conclusion: The use of a WFT reduced the incidence of postoperative pneumonia and improved postoperative nutritional status and rates of diary entries after esophagectomy, suggesting that its use may be useful for promoting recovery after esophagectomy., (© 2021. The Author(s).)

Background: The clinical significance of circumferential resection margin (CRM) in esophageal squamous cell carcinoma (ESCC) remains unclear. Optimal CRM for predicting the recurrence of pathological T3 ESCC was investigated., Methods: Seventy-three patients were retrospectively investigated in the development cohort. Patients were divided into CRM-negative and CRM-positive groups, and clinicopathological factors and survival outcomes were compared between the groups. The cutoff value was validated in another validation cohort (n = 99)., Results: Receiver operating characteristic analysis in the development cohort showed the cutoff value of CRM was 600 μm. In the validation cohort, patients in the CRM-positive group showed a significantly higher rate of locoregional recurrence (p = 0.006) and worse recurrence-free survival (RFS) (p < 0.001) than those in the CRM-negative group. Multivariate analysis identified positive CRM as an independent predictive factor for poor RFS (hazard ratio, 2.695; 95% confidence interval, 1.492-4.867; p = 0.001). The predictive value of our criteria of positive CRM for RFS was higher than that of the Royal College of Pathologists (RCP) and the College of American Pathologists (CAP) criteria. Stratified analysis in the neoadjuvant chemotherapy groups also revealed that the rate of locoregional recurrence was higher in the CRM-positive group than in the CRM-negative group both in the pathological N0 and N1-3 subgroups., Conclusions: CRM of 600 μm can be the optimal cutoff value rather than the RCP and CAP criteria for predicting locoregional recurrence after esophagectomy. These results may support the impact of perioperative locoregional control of locally advanced ESCC., (© 2022. Society of Surgical Oncology.)

Alcohol consumption is a major risk factor for esophageal cancer. In Asia, heavy drinkers are considered to have a higher risk of esophageal cancer than nondrinkers and light drinkers. However, no study has shown an association between alcohol reduction and the morbidity of esophageal cancer in Asian heavy drinkers. Therefore, this study investigated the significance of reducing alcohol consumption to prevent esophageal cancer in Asian heavy drinkers by conducting a systematic review and meta-analysis. The MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases were searched from January 1995 to December 2020. The hazard ratio (HR) and 95% confidence interval (CI) were calculated using a random-effects model. I 2 statistics were used to detect heterogeneity. This study included 21 articles in the qualitative synthesis. Light drinkers and heavy drinkers were categorized based on alcohol consumption amount as ≤ 25 ethanol g/day and ≥ 66 ethanol g/day, respectively, as described in many previous studies, and five cohort studies were eligible for this meta-analysis. The HR of esophageal cancer among heavy drinkers versus nondrinkers was 4.18 (95% CI 2.34-7.47, I 2  = 74%). On the other hand, the HR of esophageal cancer among light drinkers was 1.82 compared with nondrinkers (95% CI 1.57-2.10, I 2  = 0%). Heavy drinkers have a higher esophageal cancer incidence than light drinkers and nondrinker. It is possible that alcohol reduction may decrease the risk of esophageal cancer in Asian heavy drinkers., (© 2021. The Japan Esophageal Society.)

Background: No post-treatment follow-up methods have been established yet for patients with esophageal carcinoma who undergo radical esophagectomy (Surg) or who show complete response to definitive chemoradiotherapy (dCRT-CR). The purpose of this study was to investigate the current status of follow-up of the Surg and dCRT-CR patients in Japan, and understand the current reality and problems to establish an optimal follow-up method., Methods: A questionnaire on the follow-up method adopted was sent by e-mail to 124 institutions approved by the Japan Esophageal Society as training institutions for board-certified esophageal surgeons; responses were received from 89 institutions. The data were compared with those obtained by a similar survey conducted in 2014., Results: Follow-up methods markedly varied among institutions. Almost all institutions scheduled computed tomography and upper gastrointestinal endoscopy at least once a year up to postoperative year 5 for both the Surg and dCRT-CR groups. At least 70% of the institutions continued follow-up up to postoperative year 10, and this proportion had increased as compared to that reported from the 2014 survey. Only 25-30% of the institutions scheduled follow-up screening for metachronous head and neck cancer for both groups, and the health-related quality of life (HR-QOL) after the treatment were seldom assessed. These trends remained unchanged as compared to those reported from the 2014 survey., Conclusions: The results suggest that the consensus of follow-up protocol could not be established. More attention is required for detection of metachronous cancers and assessment of the HR-QOL. Establishment of a consensus-based follow-up system and verification of its effectiveness are required., (© 2021. The Japan Esophageal Society.)

The consumption of fruit and vegetables was reported to be associated with a reduced risk of esophageal cancer (EC) in many studies of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) from different regions worldwide. Therefore, to provide precise information to reduce the risk of EC in Asia, we performed a systematic review and meta-analysis of studies conducted in the Asian region about fruit and vegetable consumption and the risk of EC. We searched the MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases from January 2010 to December 2020. The summary relative risk (SRR) and 95% CI were calculated using a random-effects model. In addition, I 2 statistics were used to detect heterogeneity. Twenty-two studies were eligible for meta-analysis (16 case-control studies and 6 cohort studies). The SRR for the lowest versus highest fruit consumption was 0.64 (95% CI 0.53-0.77, I 2  = 82%). That for the lowest versus highest vegetable consumption was 0.61 (95% CI 0.50-0.74, I 2  = 81%). Based on subgroup analysis, a validated Food Frequency Questionnaire (FFQ) was significantly associated (SRR for fruit: 0.54; 95% CI 0.40-0.74, SRR for vegetable: 0.60; 95% CI 0.48-0.76) with low heterogeneity (I 2  = 48% for fruit, I 2  = 0% for vegetables). Egger's funnel plot asymmetry test demonstrated publication bias (P < 0.001 for fruit, P = 0.009 for vegetables). Fruit and vegetable consumption might be associated with a lower risk of EC in the Asian region. However, further substantial prospective studies with a validated FFQ and well-controlled important confounding factors are required to confirm the association., (© 2021. The Japan Esophageal Society.)

Despite advances in the perioperative management of esophagectomy, it is still a highly invasive procedure for esophageal cancer and is associated with severe postoperative complications. The two major postoperative infectious complications after esophagectomy are pulmonary complications and anastomotic leakage. We previously reported that postoperative infectious complications after esophagectomy adversely affect long-term survival significantly in a single institution and meta-analysis. Additionally, we reviewed the mechanisms of proinflammatory cytokines, such as C-X-C motif ligand 8 (CXCL8) and its cognate receptor, C-X-C chemokine receptor 2 (CXCR2), in contributing to tumorigenesis and tumor progression. Moreover, we previously reported that introducing minimally invasive esophagectomy, including robot assistance, laparoscopic gastric mobilization, and multidisciplinary team management, significantly reduced postoperative infectious complications after esophagectomy. Further, this review also suggests future treatment strategies for esophageal cancer, considering the adverse effect of postoperative infectious complications after esophagectomy.

Background: Recent comprehensive mutation analyses have revealed a relatively small number of driver mutations in esophageal cancer, implicating a limited number of molecular targets, most of which are also implicated in squamous cell carcinoma., Methods: In this study, we investigated genetic alterations in 44 esophageal squamous cell carcinomas (ESCC) and 8 adenocarcinomas (EAC) from Japanese patients as potential molecular targets, based on data from the Japanese version of The Genome Atlas (JCGA)., Results: Esophageal cancer was characterized by TP53 somatic mutations in ESCC (39/44, 88.6%) and EAC (5/8, 62.5%). In addition to TP53 mutations, somatic mutations in NFE2L2 (16/44, 36.4%), CDKN2A (7/44, 15.9%), and KMT2D (7/44, 15.9%) were more frequently detected in ESCC than in EAC. WRN-truncated type mutations that lead to genomic instability correlate with EAC, but not ESCC. ESCC samples were enriched in ALDH2-associated mutational signature 16 as well as the APOBEC signature. Patients with FAT2 mutations had significantly poorer overall survival compared with those with wild-type status at FAT2 (p < 0.05). Patients with EP300 or PTPRD mutations also had poor progression-free survival compared with respective wild-types (p < 0.05 or p < 0.001)., Conclusions: These findings may facilitate future precision medicine approaches based on genomic profiling in ESCC and EAC., (© 2021. The Author(s).)

Background/aim: There is no study comparing open esophagectomy (OE), video-assisted thoracic surgery (VATS), and robot-assisted minimally invasive esophagectomy (RAMIE) in a single institution., Patients and Methods: This study included 272 patients who underwent subtotal esophagectomy divided into three groups: OE (n=110), VATS (n=127), and RAMIE (n=35) groups. Moreover, short-term outcomes were compared., Results: Overall complications (CD≥II) were significantly less in the RAMIE than the OE and VATS groups. Recurrent laryngeal nerve paralysis (CD≥II) was significantly lower in the RAMIE than the OE group (p=0.026) and tended to be lower than that in the VATS group (p=0.059). The RAMIE group had significantly less atelectasis (CD≥I and II), pleural effusion (CD≥I and II), arrhythmia (CD≥II), and dysphagia (CD≥II), than both the OE and VATS groups., Conclusion: RAMIE reduced overall postoperative complications after esophagectomy compared with both OE and VATS., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The development of immune-related adverse events (irAEs) has been found to be associated with survival benefits in some cancers. However, data on the relation between irAEs and gastroesophageal adenocarcinoma (GEA) or esophageal squamous cell carcinoma (ESCC) are scarce., Patients and Methods: We retrospectively reviewed the data of 29 GEA and 21 ESCC patients treated with nivolumab. We investigated the impact of the development of irAEs in GEA and ESCC patients on best overall response and survival., Results: Patients with irAEs had significantly better best overall response, overall survival and progression-free survival than those without irAEs (p=0.007, p<0.001 and p=0.005, respectively). Multivariate analyses identified an Eastern Cooperative Oncology Group performance status ≥2 and the absence of an irAE as independent poor prognostic factors (p<0.001 and 0.016, respectively)., Conclusion: The development of irAEs has the potential to predict survival outcomes in patients with GEA and ESCC treated with nivolumab., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The standard treatment for patients with clinical T1bN0M0 esophageal squamous cell carcinoma is radical esophagectomy. Definitive chemoradiotherapy is regarded as a treatment option, and recently, good clinical outcomes of this treatment have been reported. This study compared prognosis after definitive chemoradiotherapy with radical esophagectomy., Methods: From January 2011 to December 2019, 68 consecutive patients who were diagnosed clinical T1bN0M0 squamous cell carcinoma were enrolled and investigated retrospectively. Patients were classified into two groups whether treated by surgery or definitive chemoradiotherapy. Survival outcomes were compared, and subsequent therapies after recurrence were also investigated., Results: Among 68 patients, 39 patients underwent surgery and 29 patients received definitive chemoradiotherapy. No significant difference was noted in overall survival between the two groups. However, the rate of 5-year recurrence-free survival was significantly lower in definitive chemoradiotherapy group than that of surgery group (91.1 vs. 62.7%, hazard ratio 3.976, 95% confidence interval 1.076-14.696, p = 0.039). Patients who had local recurrence after definitive chemoradiotherapy received endoscopic submucosal dissection or photodynamic therapy as salvage therapies, which resulted in no disease progression and a good prognosis., Conclusions: Definitive chemoradiotherapy may become a promising alternative therapy comparable with radical esophagectomy in patients with clinical T1bN0M0 esophageal squamous cell carcinoma. Early detection of recurrence by frequent follow-up after definitive chemoradiotherapy is important to control disease within local recurrence, and salvage therapy for local lesions could contribute to long-term survival.

Background: The standard treatment for patients 75 years of age or younger with cStage 2 or 3 esophageal cancer is preoperative chemotherapy followed by esophagectomy. The optimal treatment for elderly patients, especially those considered vulnerable, remains unclear., Methods: This study retrospectively reviewed the data for 42 patients ages 75-80 years with cStage 2 or 3 esophageal cancer who underwent esophagectomy between October 2002 and February 2019. The patients who received preoperative chemotherapy were compared with those who did not. The study also examined short- and long-term outcomes and the impact of preoperative chemotherapy on overall survival (OS) stratified by performance status (PS)., Results: Of the 42 patients, 18 underwent esophagectomy without preoperative chemotherapy and 24 underwent esophagectomy after preoperative chemotherapy. A significantly greater proportion of the patients with PS 0 received preoperative chemotherapy than the patients with PS 1 (P =0.007). The multivariate analysis showed preoperative chemotherapy to be an independent negative prognostic factor for OS (hazard ratio [HR], 5.025; 95% confidence interval [CI] 1.136-22.222; P = 0.033). Subgroup analysis showed that preoperative chemotherapy had a significant negative impact on the OS of the patients with PS 1 (P < 0.001)., Conclusion: Preoperative chemotherapy was ineffective for the patients with PS 0 and had a significantly negative impact on the OS of the patients with PS 1. Preoperative chemotherapy should not be administered to patients 75 years of age or older with cStage 2 or 3 esophageal cancer.

In patients with impaired renal function, S-1-related toxicities increase due to higher exposure of 5-fluorouracil (5-FU). Our previous pharmacokinetic study in 16 cancer patients with various renal functions developed an S-1 dosage formula based on individual creatinine clearance (CLcr) and body surface area (BSA). To evaluate and refine the formula, this prospective study was conducted. Thirty-three patients with various renal functions received S-1 for 4 weeks at doses determined by the nomogram derived from the previously developed formula. A series of blood samples were collected after the first dose to calculate the area under the concentration-time curve (AUC) of 5-FU. Thirty patients with BSA of 1.14-1.84 m 2 and CLcr of 23.8-96.4 mL/min were assessable for pharmacokinetics. The observed daily AUC ranged from 712.6 to 2868.7 ng·h/mL, and 18 patients achieved the target AUC (1447.8 ± 545.4 ng·h/mL). Three patients experienced S-1-related grade 3 adverse events during the first course. In the population pharmacokinetic analysis from the combined data of 46 patients in this study and the previous study, sex was identified as a statistically significant covariate for 5-FU clearance. Hence, the refined formula includes sex as an additional factor: Recommended daily dose = target AUC × (14.5 + 8.23 × SEX [0 for female and 1 for male] + 0.301 × CLcr) × BSA. Revised nomograms for recommended daily doses derived from the refined formula can be used in clinical practice to achieve the target AUC ensuring efficacy and safety of S-1., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Pedicled jejunal flap can be utilized with various tips for esophageal reconstruction in patients with a history of gastrectomy or those who have undergone synchronous esophagogastrectomy. However, the rate of anastomosis leakage is high; therefore, we considered the evaluation of blood flow of the remnant esophagus with indocyanine green in setting the anastomosis site., Methods: Fifty patients who underwent radical esophagectomy with pedicled jejunal flap between January 2011 and June 2020 were identified. From June 2019, blood flow in the pedicled jejunum and remnant esophagus were evaluated to set the anastomosis site of the latter. Usually, the second and third jejunal vessels are transected, and if the jejunal flap cannot reach to the anastomosis point, we actively transect the marginal vessels to stretch the jejunal flap. Microvascular anastomosis between the jejunal branches and the internal thoracic vessels is usually made, and the anastomosis site is set at the well-stained part of the esophagus., Results: Overall, 39 patients underwent the procedure before June 2019 (Group A), and 11 patients underwent the procedure since June 2019 (Group B). No significant difference was found in the patients' background, type of preoperative therapy, presence or absence of ligation of marginal vessels and two-stage operation between the groups. Group A had 16 cases of anastomosis leakage; B had only 1 case ( p  < 0.05). There were no cases of pedicled jejunum graft necrosis., Conclusion: Assessing remnant esophageal perfusion by indocyanine green imaging in pedicled jejunum reconstruction resulted in a lower anastomotic leak rate., Competing Interests: The authors declare that they have no conflicts of interest., (© 2021 The Authors.)

Postoperative chylothorax is a potentially lethal complication after esophagectomy. A 53-year-old woman underwent subtotal esophagectomy. The thoracic duct was resected due to swollen lymph nodes. Postoperative chylothorax was diagnosed but conservative treatment was ineffective. Lipiodol lymphangiography revealed leakage from a duplicated left-sided thoracic duct. Left-sided video-assisted thoracoscopic ligation of the left-sided thoracic duct was performed. Because anatomical variations in the thoracic duct contribute to refractory chylothorax, lymphangiography is useful in detecting the position of thoracic duct injury as well as any duct anomalies. Based on lymphangiography, left-sided video-assisted thoracoscopic surgery could be considered in case of left-sided thoracic duct injury.

Background: Standard treatment for unresectable locally advanced esophageal cancer is definitive chemoradiotherapy (dCRT). Although salvage esophagectomy is the only curative treatment available following dCRT failure, the appropriate candidates for salvage esophagectomy remain unclear., Patients and Methods: Three hundred seventeen patients who underwent dCRT from April 2004 to December 2016 were stratified into three study groups-a complete response (CR) group, chemotherapy or best supportive care (BSC) group, and salvage esophagectomy group-and compared. We also investigated the clinical outcomes and prognostic factors of salvage esophagectomy., Results: Seventy-one patients (22.4%) achieved CR after dCRT, 18 patients (5.7%) underwent salvage esophagectomy, and 228 patients (71.9%) underwent palliative chemotherapy or BSC. The 5-year overall survival (OS) rates of the CR group, salvage esophagectomy group, and chemotherapy or BSC group were 83.0%, 51.6%, and 1.3%, respectively. Salvage esophagectomy recipients had a worse OS rate than CR patients (p < 0.001) but a better OS rate than those in the chemotherapy or BSC group (p < 0.001). Incomplete resection was the only significant variable associated with poor OS on univariate Cox proportional-hazards analysis (hazard ratio: 7.633, 95% confidence interval: 1.692-34.482; p = 0.008). Patients with tumors in the upper thoracic esophagus were more likely to undergo incomplete resection (p = 0.011)., Conclusions: Patients who achieve R0 resection are good candidates for salvage esophagectomy regardless of their response to dCRT. Those with upper thoracic esophageal tumors are at risk of incomplete resection; careful attention is required when considering these patients for salvage esophagectomy.

Background: Although the effectiveness of epidural anesthesia on pain control after esophagectomy has been reported, the appropriate insertion level of the epidural catheter remains unclear for adequate postoperative pain control. We investigated the relationship between the epidural catheter insertion level and postoperative pain control after esophagectomy for esophageal cancer., Methods: We analyzed retrospectively 63 patients who underwent McKeown esophagectomy for esophageal cancer between October 2014 and November 2018. The epidural catheter was inserted at the T4-T10 level before general anesthesia induction, and epidural anesthesia was started during the operation. In the analysis, the epidural catheter insertion level was divided into three groups (over T6/T7, T7/T8, and under T8/T9) and determined. Postoperative pain was evaluated a numeric rating scale (NRS) for at least 7 postoperative days, and the first NRS after extubation was used to evaluate the impact of the epidural catheter insertion level on pain control., Results: Ten patients (15.9%) failed pain control. The χ 2 test and a forward stepwise logistic regression analysis revealed that only the epidural catheter insertion level affected pain control (P < 0.05). The T7/T8 insertion level significantly decreased postoperative pain after esophagectomy. In the subgroup analysis, epidural catheter insertion under T8/T9 significantly increased postoperative pain after esophagectomy when thoracoscopy/laparoscopy was assisted. No significant differences were observed in the incidence of postoperative complications among the epidural catheter insertion levels., Conclusions: The T7/T8 epidural catheter insertion level contributed to postoperative pain relief and could lead to enhanced recovery after esophagectomy for esophageal cancer.

Background: Esophagectomy has a high risk of postoperative morbidity, and pulmonary complications are the most common causes of serious morbidity. Thoracoscopic esophagectomy has been reported to reduce postoperative pulmonary complications; however, it remains unclear whether laparoscopic gastric mobilization can reduce the occurrence of postoperative pulmonary complications after open thoracotomy or thoracoscopic esophagectomy. The present meta-analysis assessed the ability of laparoscopic gastric mobilization to prevent postoperative complications after open thoracotomy or thoracoscopic esophagectomy., Method: Studies reported between January 2000 and April 2019 in the PubMed and the Cochrane Library databases that analyzed the impact of laparoscopy on postoperative complications were systematically reviewed. In the meta-analysis, data were pooled and the primary outcome was postoperative pulmonary complications. The secondary outcomes were other postoperative complications, operative details, length of hospital stay and postoperative mortality., Results: A total of 13 studies (1915 patients; 1 randomized trial, 1 prospective study and 11 observational studies) were included. Laparoscopic gastric mobilization after open thoracotomy resulted in significantly reduced postoperative pulmonary complications (OR = 0.47, 95% confidence interval (CI): 0.27-0.82, p = 0.008) and postoperative mortality (OR = 0.49, 95%CI: 0.25-0.94, p = 0.03). Similarly, laparoscopic gastric mobilization after thoracoscopic esophagectomy resulted in significantly reduced postoperative pulmonary complications (OR = 0.56, 95%CI: 0.37-0.84, p = 0.005) and anastomotic leakage (OR = 0.59, 95%CI: 0.39-0.91, p = 0.02)., Conclusions: Laparoscopic gastric mobilization could be recommended for reducing postoperative pulmonary complications after esophagectomy irrespective of the thoracic approach.

Background: Despite the poor prognosis of recurrent esophageal squamous cell cancer (ESCC), long-term survival could be achieved in a subset of patients who successfully underwent surgical resection for recurrence. In this study, we investigated the outcomes of surgical resection for lymph node (LN) or pulmonary (PUL) recurrence in ESCC patients., Methods: We retrospectively analyzed the outcomes of ESCC patients who underwent surgical resection between January 2008 and March 2015 for either LN or PUL recurrence after complete response (CR) by chemoradiotherapy or R0 esophagectomy. Every patient fulfilled the original institutional criteria: no recurrence at primary site; recurrence involving in only one organ; expectation of complete resection; and for PUL recurrence, no rapid growth with at least 2 months of observation., Results: Among the 13 patients analyzed, surgical resection was performed in nine and four patients with LN and PUL recurrence, respectively. R0 resection was achieved in all patients with no fatal surgical complications. Mean duration from the day of the first CR/R0 to the recurrence was 809 (110-2575) days. Median recurrence-free survival following surgical resection for recurrence and overall survival following the first diagnosis of recurrence was 387 and 1297 days, respectively., Conclusion: Surgical resection for LN or PUL recurrence of ESCC according to our institutional criteria can be performed safely for selected patients.

The patient was a 62-year-old man with no specific medical history. Lateral segmentectomy was performed for hepatocellular carcinoma with a tumor size of approximately 14×13 cm. The histopathological diagnosis was moderately differentiated hepatocellular carcinoma: Fc(-), Fc-Inf(-), Sf(-), S0, N0, Vp2, Vv1, Va0, B0, P0, SM(-), CH. Five years after the first surgery, computed tomography(CT)revealed a left lung tumor in segment 9/10 and left lymph nodes; thus, left pneumonectomy was performed, and these tumors were identified to have metastasized from the primary tumor. Six years after the first surgery, his serum alpha-fetoprotein level was remarkably elevated from 254.9 ng/mL to 3,143.0 ng/mL for three months, and at the same time, he developed left meralgia and swelling of the left femur. Magnetic resonance imaging showed a high-density mass(30×14 cm)in the left quadriceps, and positron emission tomography-CT revealed high uptake in the left quadriceps with a maximum standardized uptake value of 12.3. A needle biopsy of the left femur tumor confirmed metastasis from the primary tumor. Radiotherapy was administered because general anesthesia can prove to be hazardous due to the patient having undergone left pneumonectomy.