Identifying the Trends of Urinary microRNAs within Extracellular Vesicles for Esophageal Cancer.

Background: The advancement of multidisciplinary treatment has increased the need to develop tests to monitor tumor burden during treatment. We herein analyzed urinary microRNAs within extracellular vesicles from patients with esophageal squamous cell carcinoma (ESCC) and normal individuals using a microarray. Methods: Patients with advanced ESCC who underwent esophagectomy (A), endoscopic submucosal resection (ESD) (B), and healthy donors (C) were included. Based on microRNA expression among the groups (Analysis 1), microRNAs with significant differences between groups A and C were selected (Analysis 2). Of these candidates, microRNAs in which the change between A and C was consistent with the change between B and C were selected for downstream analysis (Analysis 3). Finally, microRNA expression was validated in patients with recurrence from A (exploratory analysis). Results: For analysis 1, 205 microRNAs were selected. For Analyses 2 and 3, the changes in 18 microRNAs were consistent with changes in tumor burden as determined by clinical imaging and pathological findings. The AUC for the detection of ESCC using 18 microRNAs was 0.72. In exploratory analysis, three of eighteen microRNAs exhibited a concordant trend with recurrence. Conclusions: The current study identified the urinary microRNAs which were significantly expressed in ESCC patients. Validation study is warranted to evaluate whether these microRNAs could reflect tumor burden during multidisciplinary treatment for ESCC.

Automated artificial intelligence-based phase-recognition system for esophageal endoscopic submucosal dissection (with video).

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) for superficial esophageal cancer is a multistep treatment involving several endoscopic processes. Although analyzing each phase separately is worthwhile, it is not realistic in practice owing to the need for considerable manpower. To solve this problem, we aimed to establish a state-of-the-art artificial intelligence (AI)-based system, specifically, an automated phase-recognition system that can automatically identify each endoscopic phase based on video images. METHODS: Ninety-four videos of ESD procedures for superficial esophageal cancer were evaluated in this single-center study. A deep neural network-based phase-recognition system was developed in an automated manner to recognize each of the endoscopic phases. The system was trained with the use of videos that were annotated and verified by 2 GI endoscopists. RESULTS: The overall accuracy of the AI model for automated phase recognition was 90%, and the average precision, recall, and F value rates were 91%, 90%, and 90%, respectively. Two representative ESD videos predicted by the model indicated the usability of AI in clinical practice. CONCLUSIONS: We demonstrated that an AI-based automated phase-recognition system for esophageal ESD can be established with high accuracy. To the best of our knowledge, this is the first report on automated recognition of ESD treatment phases. Because this system enabled a detailed analysis of phases, collecting large volumes of data in the future may help to identify quality indicators for treatment techniques and uncover unmet medical needs that necessitate the creation of new treatment methods and devices.

The impact of thoracic duct resection on the long-term body composition of patients who underwent esophagectomy for esophageal cancer and survived without recurrence.

BACKGROUND: We have reported the possible benefits of radical esophagectomy with thoracic duct (TD) resection in elective esophageal cancer surgery. However, the effect of TD resection on the long-term nutrition status remains unclear. METHODS: Patients who underwent esophagectomy at Keio University between January 2006 and December 2018 were included, and those who had no recurrence for more than three years were evaluated. Changes in each body composition (muscle mass and body fat) were comparatively assessed between those who underwent TD resection or not, before and at, one, three and five years after surgery. Computed tomography images were analyzed on postoperative year 1, 3 and 5. RESULTS: This study included 217 patients categorized in the TD-resected (TD-R) (156 patients) and TD-preserved (TD-P) (61 patients) groups. The loss of muscle mass was comparable between the groups. On the other hand, the loss of adipose tissues was significantly greater in the TD-R group than in the TD-P group at one and three years after surgery, while there was no statistical difference five years after surgery. Additionally, among patients with cT1N0M0 disease in whom survival advantage of TD resection has been reported previously, the loss of muscle mass did not differ between each group. CONCLUSIONS: The change of muscle mass between the two groups was comparable. Although body fat mass was reduced by TD resection, it eventually recovered in the long term. In patients with esophageal cancer, TD resection may be acceptable without significant impact on body composition in the long term.

Clinical predictors of early postoperative recurrence after radical esophagectomy for thoracic esophageal cancer.

PURPOSE: Esophagectomy for esophageal cancer has a high incidence rate of early postoperative recurrence and death. This study aimed to identify the clinical and pathological features in early recurrence cases and to confirm the usefulness of prediction using these factors for effective adjuvant therapy and postoperative surveillance. METHODS: One hundred and twenty five patients who developed postoperative recurrence after undergoing radical esophagectomy for thoracic esophageal cancer were classified into two groups as follows: those with early recurrence at ≤ 6 months and those with nonearly recurrence at > 6 months after surgery. After identifying related factors of early recurrence, usefulness of these factors for prediction were examined in all patients with and without recurrence. RESULTS: The analysis cohort consisted of 43 and 82 patients in the early and nonearly recurrence groups, respectively. In multivariate analysis, factors associated with early recurrence were higher initial levels of tumor markers (squamous cell carcinoma [SCC] ≥ 1.5 ng/ml in tumors, except for adenocarcinoma, and carcinoembryonic antigen [CEA] ≥ 5.0 ng/ml in adenocarcinoma) and higher venous invasion (v), i.e., ≥ 2 (p = 0.040 and p = 0.004, respectively). The usefulness of these two factors for recurrence prediction was confirmed in 378 patients, including 253 patients without recurrence. Patients with at least one of the two factors had significantly higher early recurrence rates than those without any factors in pStages II and III (odds ratio [OR], 6.333; p = 0016 and OR, 4.346; p = 0.008, respectively). CONCLUSIONS: Early recurrence of thoracic esophageal cancer (i.e., during ≤ 6 months after esophagectomy) was associated with higher initial tumor marker levels and pathological findings of v ≥ 2. The combination of these two factors is useful as a simple and critical predictor of early postoperative recurrence.

Evaluation of Endoscopic Response Using Deep Neural Network in Esophageal Cancer Patients Who Received Neoadjuvant Chemotherapy.

BACKGROUND: We previously reported that endoscopic response evaluation can preoperatively predict the prognosis and distribution of residual tumors after neoadjuvant chemotherapy (NAC). In this study, we developed artificial intelligence (AI)-guided endoscopic response evaluation using a deep neural network to discriminate endoscopic responders (ERs) in patients with esophageal squamous cell carcinoma (ESCC) after NAC. METHOD: Surgically resectable ESCC patients who underwent esophagectomy following NAC were retrospectively analyzed in this study. Endoscopic images of the tumors were analyzed using a deep neural network. The model was validated with a test data set using 10 newly collected ERs and 10 newly collected non-ER images. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the endoscopic response evaluation by AI and endoscopists were calculated and compared. RESULTS: Of 193 patients, 40 (21%) were diagnosed as ERs. The median sensitivity, specificity, PPV, and NPV values for ER detection in 10 models were 60%, 100%, 100%, and 71%, respectively. Similarly, the median values by the endoscopist were 80%, 80%, 81%, and 81%, respectively. CONCLUSION: This proof-of-concept study using a deep learning algorithm demonstrated that the constructed AI-guided endoscopic response evaluation after NAC could identify ER with high specificity and PPV. It would appropriately guide an individualized treatment strategy that includes an organ preservation approach in ESCC patients.

Tumor Burden Monitoring with Circulating Tumor DNA During Treatment in Patients with Esophageal Squamous Cell Carcinoma.

BACKGROUND: To guide appropriate treatment strategy, an accurate tumor monitoring modality that reflects tumor burden during neoadjuvant treatment is required for esophageal squamous cell carcinoma (ESCC). We aimed to investigate the clinical utility of circulating tumor DNA (ctDNA) in plasma in patients who received neoadjuvant chemotherapy (NAC) followed by esophagectomy. PATIENTS AND METHODS: Longitudinally collected plasma samples for ctDNA combined with genomic DNA from primary lesions were obtained from patients with histologically confirmed ESCC who underwent NAC followed by subtotal esophagectomy. Next-generation sequencing was performed to identify mutations from the plasma and the primary tumor. The relationships between changes in ctDNA and the pathological response and recurrence were assessed in patients with locally advanced ESCC. RESULTS: In pretreatment samples from 13 patients, multiple concordant mutations in ctDNA and primary tumors were observed in 11 patients (85%), who were classified as ctDNA positive before treatment. The ctDNA positive rate after NAC correlated with the pathological response (responders, 25%; nonresponders, 100%; p = 0.007). The risk of recurrence increased significantly in patients with positive ctDNA after surgery in analysis of 16 patients; the 1-year recurrence-free survival rates were 90 and 0% in ctDNA-negative and ctDNA-positive groups, respectively (p = 0.0008). In two patients with postoperative recurrence, ctDNA was detected approximately 5.5 months earlier than the diagnosis using radiographical imaging. CONCLUSIONS: ctDNA is a promising biomarker for predicting pathological response and postoperative recurrence in ESCC. To demonstrate the external validity, we are currently preparing a multicenter prospective study.

Evaluation of surgical complexity by automated surgical process recognition in robotic distal gastrectomy using artificial intelligence.

BACKGROUND: Although radical gastrectomy with lymph node dissection is the standard treatment for gastric cancer, the complication rate remains high. Thus, estimation of surgical complexity is required for safety. We aim to investigate the association between the surgical process and complexity, such as a risk of complications in robotic distal gastrectomy (RDG), to establish an artificial intelligence (AI)-based automated surgical phase recognition by analyzing robotic surgical videos, and to investigate the predictability of surgical complexity by AI. METHOD: This study assessed clinical data and robotic surgical videos for 56 patients who underwent RDG for gastric cancer. We investigated (1) the relationship between surgical complexity and perioperative factors (patient characteristics, surgical process); (2) AI training for automated phase recognition and model performance was assessed by comparing predictions to the surgeon-annotated reference; (3) AI model predictability for surgical complexity was calculated by the area under the curve. RESULT: Surgical complexity score comprised extended total surgical duration, bleeding, and complications and was strongly associated with the intraoperative surgical process, especially in the beginning phases (area under the curve 0.913). We established an AI model that can recognize surgical phases from video with 87% accuracy; AI can determine intraoperative surgical complexity by calculating the duration of beginning phases from phases 1-3 (area under the curve 0.859). CONCLUSION: Surgical complexity, as a surrogate of short-term outcomes, can be predicted by the surgical process, especially in the extended duration of beginning phases. Surgical complexity can also be evaluated with automation using our artificial intelligence-based model.

Inhibitory effect of aspirin on inflammation-induced lung metastasis of cancer cells associated with neutrophil infiltration.

PURPOSE: Systematic inflammation has been reported to contribute to cancer progression through various mechanisms; however, the exact mechanism is still the subject of research. In this study, we evaluated the influence of systematic inflammation on lung metastasis, using a murine abdominal sepsis model, and assessed its relationship with pneumonia after curative esophagectomy in patients with esophageal cancer. METHODS: We used a murine abdominal sepsis model given highly metastatic osteosarcoma, to reveal the mechanism of systematic inflammation and its potential for lung metastasis. The therapeutic effect of aspirin (ASA) in preventing distant metastasis was also investigated. Subsequently, we analyzed, retrospectively, the relationship between pneumonia and lung metastasis after esophagectomy in patients who underwent esophagectomy at Keio University between January, 2007 and October, 2020. RESULTS: Abdominal sepsis provoked lung injury in the acute phase. ASA inhibited the recruitment of neutrophils triggered by the lung injury, and it also suppressed lung metastasis. Our retrospective study revealed that lung metastasis was more frequent in patients with postoperative pneumonia. CONCLUSIONS: Postoperative acute lung injury is associated with a higher risk of lung metastasis. ASA may be a potential preoperative treatment for inhibiting lung metastasis by preventing the recruitment of neutrophils.

Comparison of changes in body-fat mass and reflux esophagitis among reconstruction methods for proximal gastrectomy.

BACKGROUND: Although proximal gastrectomy (PG) is a function-preserving surgical option, it remains unclear as to which reconstruction method can prevent reflux and maintain body composition. METHODS: Patients who underwent PG at Keio University between April 2011 and November 2018 were analyzed. Changes in the subcutaneous and visceral adipose tissues were comparatively assessed before and after a year of surgery for three common reconstruction methods. We also compared the endoscopic findings of reflux esophagitis and the number of patients prescribed with proton-pump inhibitor after a year of surgery. RESULTS: This study included 76 patients, of which 33 patients underwent esophagogastrostomy with a circular stapler (CS), 35 under double flap (DF) reconstruction, and 8 underwent double tract (DT) reconstruction. Comparing esophagogastrostomy (CS and DF) and DT showed that esophagogastrostomy could significantly preserve both subcutaneous and visceral adipose tissues (P < 0.001 and P = 0.04, respectively). However, the change in the subcutaneous and visceral adipose tissues was comparable between CS and DF. As for reflux esophagitis, DF showed the lowest incidence rate for esophagitis and the least number of patients who were prescribed a proton-pump inhibitor. CONCLUSION: DF is a relatively better reconstruction method for preserving fat mass and preventing reflux among the three common reconstruction methods.

The Usability of Intensive Imaging Surveillance After Esophagectomy in Patients with Esophageal Cancer.

BACKGROUND: Although imaging surveillance after esophagectomy is required to achieve long-term survival for patients with esophageal cancer, the optimal surveillance timing and interval remain unclear. This study was designed to investigate the differences in oncological outcomes based on the detection method for recurrence and surveillance interval in patients with recurrence detected by routine imaging examination after esophagectomy. METHODS: A total of 527 patients who underwent thoracic esophagectomy for esophageal cancer with R0 resection between 2003 and 2021 in our department were enrolled in this study. Postoperative, routine surveillance was conducted at an outpatient clinic every 3 months, thoracoabdominal computed tomography (CT) every 4-6 months, and esophagogastroduodenoscopy every 6 months. The detection method and optimal interval of imaging surveillance also were investigated. RESULTS: Of all patients, 161 patients developed recurrence during surveillance; 110 (68.3 %) by routine surveillance and 37 (23.0%) not detected by routine surveillance. Among patients who were diagnosed with recurrence following routine surveillance, patients with pStage IV disease on imaging surveillance by thoracoabdominal CT at an interval of ≤ 5 months had a better survival rate than those with an interval of 6 months (P = 0.004), whereas no significant difference among different intervals was observed in patients with pStage I-III disease. CONCLUSIONS: Recurrence may have been detectable by our routine surveillance in approximately 70% of patients who developed recurrence. These findings demonstrate the necessity of different imaging surveillance intervals for different pStages of esophageal cancer.

The relationship between the esophageal endoscopic submucosal dissection technical difficulty and its intraoperative process.

BACKGROUND: Estimating the esophageal endoscopic submucosal dissection (ESD) technical difficulty is important to reduce complications. Endoscopic duration is one of the related factors to a technical difficulty. The relationship between the esophageal ESD technical difficulty and its intraoperative process was analyzed as a first step toward automatic technical difficulty recognition using artificial intelligence. METHODS: This study enrolled 75 patients with superficial esophageal cancer who underwent esophageal ESD. The technical difficulty score was established, which consisted of three factors, including total procedure duration, en bloc resection, and complications. Additionally, technical difficulty-related factors, which were perioperative factors that included the intraoperative process, were investigated. RESULTS: Eight (11%) patients were allocated to high difficulty, whereas 67 patients (89%) were allocated to low difficulty. The intraoperative process, which was shown as the extension of each endoscopic phase, was significantly related to a technical difficulty. The area under the curve (AUC) values were higher at all the phase duration than at the clinical characteristics. Submucosal dissection phase (AUC 0.902; 95% confidence intervals (CI) 0.752-1.000), marking phase (AUC 0.827; 95% CI 0.703-0.951), and early phase which was defined as the duration from the start of marking to the end of submucosal injection (AUC 0.847; 95% CI 0.701-0.992) were significantly related to technical difficulty. CONCLUSIONS: The intraoperative process, particularly early phase, was strongly associated with esophageal ESD technical difficulty. This study demonstrated the potential for automatic evaluation of esophageal ESD technical difficulty when combined with an AI-based automatic phase evaluation system.

Comparison of hand-sewn and circular stapled esophagogastric anastomoses in the neck after esophagectomy for thoracic esophageal cancer: a propensity score-matched analysis.

Esophagectomy is a highly invasive surgical procedure; however, anastomotic leakage is one of the major surgical complications that should be prevented. Institutions have their own inherited or specialized anastomosis methods. The superior anastomosis procedure remains unknown despite the many studies to determine the optimal method. The present study enrolled 341 patients who underwent esophagectomy at Keio University Hospital, Tokyo, Japan, between January 2009 and January 2019. The anastomosis method was changed from circular stapled anastomosis to hand-sewn anastomosis in February 2014 to reduce the risk of anastomotic leakage. We retrospectively compared short-term results (anastomotic leakage and stricture) between hand-sewn and circular stapled anastomoses. Analysis of heterogeneity after propensity score matching between the 107 patients in the hand-sewn anastomosis group and 107 patients in the circular stapled anastomosis group revealed almost equal distributions. The incidence rate of anastomotic leakage was significantly lower in the hand-sewn anastomosis group than in the circular stapled anastomosis group (9 vs. 20%, hazard ratio: 2.521; 95% confidence interval: 1.112-5.716; P = 0.027). No significant difference was found in the incidence of anastomotic stricture (16 vs. 18%, P = 0.844). Furthermore, no significant difference was found in the incidence of anastomotic leakage in any of the tumor locations between the two anastomosis procedures. For esophagogastric anastomosis in the neck after esophagectomy, hand-sewn anastomosis is superior to circular stapled anastomosis with regard to reducing the risk of anastomotic leakage.

Long-term variation in psoas muscle mass index is affected by short-term loss after esophagectomy in survivors of esophageal cancer.

Changes in muscle mass may be an objective approach toward measuring the quality of life after surgery, but long-term changes due to surgery without the effect of cachexia remain unclear. Patients with esophageal cancer who underwent esophagectomy and did not experience cancer recurrence for 3 years were analyzed. The psoas muscle mass index (PMI) was assessed before surgery and 7 days, 1 year, and 3 years after surgery. Patients with no change or increased PMI within 7 days after surgery were categorized into the Nondecreasing-PMI group, whereas those with decreased PMI were categorized into the Decreasing-PMI group. Eighty-four and 51 patients were categorized into the Nondecreasing- and Decreasing-PMI groups, respectively. The Decreasing-PMI group had a higher incidence rate of anastomotic leakage than the Nondecreasing-PMI group (25% vs. 12%, respectively; P = 0.042). Moreover, the Decreasing-PMI group showed a significantly greater decrease in the PMI 1 year after surgery than the Nondecreasing-PMI group (-9.2% vs. -4.0%, respectively; P = 0.048). However, although the Decreasing-PMI group had a greater decrease in the PMI than the Nondecreasing-PMI group, no significant difference was observed 3 years after surgery (-9.8% vs. -5.3%, respectively; P = 0.115). A decrease in PMI in the acute phase after esophagectomy may contribute to a long-term decrease in the PMI. Intensive interventions may be beneficial for these patients to improve their long-term quality of life.

Effects of let-7a microRNA and C-C chemokine receptor type 7 expression on cellular function and prognosis in esophageal squamous cell carcinoma.

BACKGROUND: C-C chemokine receptor type 7 (CCR7) participates in chemotactic and metastatic responses in various cancers, including in esophageal squamous cell carcinoma (ESCC). The microRNA (miRNA) let-7a suppresses migration and invasion of various types of cancer cells by downregulating CCR7 expression. METHODS: The expression levels of CCR7 and let-7a were measured in the cell lines, tumor, and peritumoral tissues of ESCC patients. KYSE cell lines were transfected with synthetic let-7a miRNA and a let-7a miRNA inhibitor, and their CCR7 expression levels as well as invasive ability were evaluated. A highly invasive cell line was established via an invasion assay, and CCR7 expression level along with let-7a level was subsequently evaluated. Cancer cells overexpressing CCR7 were injected subcutaneously into mice, and the animals were monitored for tumor growth along with lymph node metastasis. RESULTS: A negative correlation between CCR7 and let-7a expression was observed in the ESCC cell lines as well as in tissue samples from patients. Synthetic let-7a decreased CCR7 expression level, while the let-7a inhibitor increased it. In vitro, the established highly invasive cancer cells with high and low levels of CCR7 and let-7a expression, respectively, exhibited a greater invasive ability than the wild-type cell line. The cells were associated with tumor growth and lymph node metastasis in mice. Patients in the high-CCR7/low-let-7a group had the worst prognosis, with a five-year recurrence free survival (5-RFS) rate of 37.5%, followed by the high-CCR7/high-let-7a (5-RFS: 60.0%) and low-CCR7 (5-RFS: 85.7%; p = 0.038) groups. CONCLUSIONS: The expression of CCR7 was downregulated by let-7a miRNA in esophageal cancer cells. The decrease in let-7a expression level led to the increased expression level of CCR7 in ESCC cells, consequently increasing their invasive ability and malignancy and resulting in a worse prognosis for ESCC patients. TRIAL REGISTRATION: Retrospectively registered.