Published papers

Over the past 30 years, the prevalence of upper third gastric cancer (GC) and gastroesophageal junction (GEJ) cancer has increased. Total gastrectomy with D2 lymph node dissection is the standard surgical treatment for non-early (T2 or higher) upper third and GEJ cancers, but total gastrectomy often results in post-gastrectomy syndrome (5–50%), consisting of weight loss, dumping syndrome, and anemia. Proximal gastrectomy (PG) has the potential to avoid these postoperative problems by preserving stomach function. However, PG has historically been discouraged by surgeons owing to the high incidence of postoperative reflux esophagitis (20–65%), anastomotic stenosis, and decreased quality of life. In recent years, anti-reflux reconstruction techniques, such as the double flap technique and double-tract reconstruction, have been developed to be performed after PG, and evidence has emerged that these techniques not only reduce the incidence of postoperative reflux esophagitis but also decrease postoperative weight loss and prevent anemia. Prospective studies are underway to determine whether PG with anti-reflux techniques improves patient-reported quality of life. In the present work, we reviewed available evidence for the use of PG for GC and GEJ cancer, including oncologically appropriate patient selection for PG, potential functional benefits of PG over TG, and various types of reconstructions that can be performed after PG, as well as future research on the use of PG.

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.

Background: Thoracoscopic oesophagectomy, a minimally invasive treatment for oesophageal cancer, is used worldwide. However, no large-scale, multicentre, randomised controlled trial has compared long-term survival as the primary endpoint between thoracoscopic and open oesophagectomy. We aimed to confirm the non-inferiority in overall survival of thoracoscopic oesophagectomy over open oesophagectomy in patients with resectable thoracic oesophageal cancer. Methods: This multicentre, open-label, randomised, controlled, phase 3, non-inferiority trial was conducted at 31 hospitals across Japan. Patients aged 20–80 years were eligible if they had histologically confirmed oesophageal squamous cell carcinoma, oesophageal adenosquamous carcinoma, or oesophageal basaloid squamous cell carcinoma, which was located in the thoracic oesophagus; an Eastern Cooperative Oncology Group performance status of 0 or 1; clinical stage I, II, or III (but not T4) disease; and had not received previous treatment for oesophageal cancer, except for endoscopic resection of superficial lesions and preoperative chemotherapy (doublet or triplet) per Japanese guidelines. Patients were randomly assigned (1:1) using a web-based system with adjustment factors by clinical stage (IA vs IB, II, or III), age (<76 years vs ≥76 years), and institution, to right open transthoracic oesophagectomy or right thoracoscopic oesophagectomy, both with at least D2 lymphadenectomy. The primary endpoint was investigator-assessed overall survival, analysed in the intention-to-treat population. The non-inferiority margin was 9% for 3-year overall survival (hazard ratio [HR] 1·44). Two formal interim analyses of overall survival were planned: the first after half of the expected number of patients were enrolled and the second after patients had been accrued and protocol treatment completed. The trial would be terminated for efficacy if non-inferiority and superiority in overall survival was shown for thoracoscopic oesophagectomy in the first interim analysis and if non-inferiority in overall survival was shown in the second interim analysis. This trial was registered with UMIN Clinical Trials Registry, UMIN000017628 (follow-up ongoing). Findings: From May 20, 2015, to June 17, 2022, 300 patients were randomly assigned (150 to open oesophagectomy and 150 to thoracoscopic oesophagectomy). 247 (82%) of 300 patients were male and 53 (18%) were female. The median age was 68 years (IQR 64–72). 148 (99%) of 150 patients underwent open oesophagectomy, and all 150 patients underwent thoracoscopic oesophagectomy. In the first interim analysis at a median follow-up of 1·6 years (IQR 0·8–2·5), non-inferiority was not confirmed (HR 0·56 [99·99990046% CI 0·05–5·73]; one-sided pnon-inferiority=0·002326, greater than the prespecified non-inferiority threshold). At a median follow-up of 2·6 years (IQR 1·4–4·9) for the second interim analysis, 3-year overall survival was 82·0% (95% CI 73·8–87·8) with thoracoscopic oesophagectomy and 70·9% (61·6–78·4) with open oesophagectomy (HR 0·64 [98·8% CI 0·34–1·21]), confirming non-inferiority (one-sided pnon-inferiority=0·000726, less than the prespecified non-inferiority threshold of 0·00616). The Data and Safety Monitoring Committee then recommended terminating the trial and publishing the results, and the trial was terminated in June 19, 2023. Intraoperative complications (grade ≥3) were similar between study groups (one [1%] of 150 in the thoracoscopic group vs two [1%] of 148 in the open group; all three events were intraoperative bleeding), as were postoperative complications before first discharge (grade ≥3; 63 [42%] vs 65 [44%]). Grade 3 or higher pneumonia occurred in 12 (8%) patients in the thoracoscopic group and in 18 (12%) in the open group; grade 3 anastomotic leakage occurred in 17 (11%) patients in the thoracoscopic group and seven (5%) in the open group. Four treatment-related deaths occurred in the thoracoscopic group and two in the open group. Interpretation: Thoracoscopic oesophagectomy, a standard treatment in Japan, was non-inferior to open oesophagectomy for patients with resectable thoracic oesophageal cancer. Funding: Japan Agency for Medical Research and Development and the National Cancer Center Research and Development Fund.

Background: The current standard operation for proximal gastric and gastroesophageal junction (P/GEJ) cancers with limited esophageal extension is total gastrectomy (TG). TG is associated with impaired appetite and weight loss due to the loss of gastric functions such as production of ghrelin and with anemia due to intrinsic factor loss and vitamin B12 malabsorption. Theoretically, proximal gastrectomy (PG) can mitigate these problems by preserving gastric function. However, PG with direct esophagogastric reconstruction is associated with severe postoperative reflux, delayed gastric emptying, and poor quality of life (QoL). Minimally invasive PG (MIPG) with antireflux techniques has been increasingly performed by experts but is technically demanding owing to its complexity. Moreover, the actual advantages of MIPG over minimally invasive TG (MITG) with regards to postoperative QoL are unknown. Our overall objective of this study is to determine the short-term QoL benefits of MIPG. Our central hypotheses are that MIPG is safe and that patients have improved appetite after MIPG with effective antireflux techniques, which leads to an overall QoL improvement when compared with MITG. Methods: Enrollment of a total of 60 patients in this prospective survey-collection study is expected. Procedures (MITG versus MIPG, antireflux techniques for MIPG [double-tract reconstruction versus the double-flap technique]) will be chosen based on surgeon and/or patient preference. Randomization is not considered feasible because patients often have strong preferences regarding MITG and MIPG. The primary outcome is appetite level (reported on a 0-10 scale) at 3 months after surgery. With an expected 30 patients per cohort (MITG versus MIPG), this study will have 80% power to detect a one-point difference in appetite level. Patient-reported outcomes will be longitudinally collected (including questions about appetite and reflux), and specific QoL items, body weight, body mass index and ghrelin, albumin, and hemoglobin levels will be compared. Discussion: Surgeons from the US, Japan, and South Korea formed this collaboration with the agreement that the surgical approach to P/GEJ cancers is an internationally important but controversial topic that requires immediate action. At the completion of the proposed research, our expected outcome is the establishment of the benefit and safety of MIPG. Trial registration: This trial was registered with Clinical Trials Reporting Program Registration under the registration number NCI-2022–00267 on January 11, 2022, as well as with ClinicalTrials.gov under the registration number NCT05205343 on January 11, 2022.

Background: Total gastrectomy (TG) remains the standard surgical approach for proximal gastric and gastroesophageal junction (P/GEJ) cancers. However, experts increasingly perform proximal gastrectomy (PG) with anti-reflux reconstruction. The benefits of minimally invasive PG (MIPG) over minimally invasive TG (MITG), particularly regarding postoperative quality of life (QoL), remain unclear. Methods: We conducted a transpacific, multicenter, nonrandomized, prospective cohort study to compare symptom burden outcomes (symptom occurrence, symptom severity, and daily functioning) between MIPG and MITG in patients with P/GEJ cancers. Symptom burden data was collected using the MD Anderson Symptom Inventory (MDASI-GI +). Results: Among 71 patients with P/GEJ cancers enrolled from 2022 through 2024, 64 underwent either MITG (n = 26, 41%) or MIPG (n = 38, 59%). Thirty-nine (61%) patients were treated at Asian centers, and 25 (39%) patients were treated at U.S. centers. Compared to the MIPG patients, the MITG patients had a larger mean tumor size (5.7 vs. 2.3 cm) and a higher prevalence of signet ring cell histology (50 vs. 18%). Operation times were comparable between the MITG and MIPG groups (median: 288.5 vs. 277.0 min), as were the rates of postoperative complications (19 vs. 24%), anastomotic leaks (0 vs. 3%), 90-day mortality (0 vs. 3%), and positive proximal margins (8 vs. 0%, all p > 0.05). QoL data (MDASI-GI +) were collected from at least 95% of patients at all time points. Key metrics related to QoL—appetite, reflux, total symptom burden, and functional interference—did not differ significantly between groups at 1 and 3 months postoperatively. A linear mixed-effects model showed that body-weight trajectories over time did not differ significantly between the MITG and MIPG groups, and there was no significant difference between their highest weight loss percentages within the first 3 months postoperatively. At postoperative month 3, hemoglobin, albumin, vitamin B12, and ghrelin levels were comparable between the groups. Conclusion: MIPG and MITG demonstrated equivalent short-term safety, and MIPG did not confer measurable QoL advantages, including in appetite, within 3 months after surgery. Longer-term follow-up is ongoing to evaluate potential delayed advantages. Trial registration number: On January 11, 2022, this trial was registered with the Clinical Trials Reporting Program under the registration number NCI-2022-00267 and with ClinicalTrials.gov under the registration number NCT05205343.

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.

Esophageal cancer has one of the poorest prognoses among all cancer types, due to the propensity for an early spread through the lymphatics and the difficulty to perform surgical treatment. To improve the prognosis, the management of esophageal cancer has been developed through the conduct of several clinical trials worldwide. In western societies, neoadjuvant chemoradiotherapy has been established as the standard treatment approach, as indicated by the results of the CROSS trial. Recently, the Japanese JCOG1109 trial demonstrated the significant improvement of survival by neoadjuvant triplet chemotherapy. As an adjuvant treatment, an immune checkpoint inhibitor has shown promising results in the CheckMate-577 trial. Including adjuvant S-1 mono therapy as another option, a randomised control phase III study will determine the ideal treatment for surgically resectable esophageal cancer. Furthermore, the efficacy and safety of neoadjuvant cisplatin +5-fluorouracil or DCF plus nivolumab are examined in the JCOG1804E (FRONTiER) study. In addition to definitive chemoradiation therapy, the SANO trial is examining the safety and efficacy of active surveillance after neoadjuvant chemoradiotherapy, which might give us the choice to adopt organ preservation approach. The development of treatment has progressed dramatically with the advent of immunotherapy. Considering the biomarkers to predict the treatment response and prognosis, individualised multidisciplinary treatment strategies should be established for esophageal cancer patients.

Background: Recurrent laryngeal nerve (RLN) palsy is a common complication in esophagectomy and its main risk factor is reportedly intraoperative procedure associated with surgeons’ experience. We aimed to improve surgeons’ recognition of the RLN during robot-assisted minimally invasive esophagectomy (RAMIE) by developing an artificial intelligence (AI) model. Methods: We used 120 RAMIE videos from four institutions to develop an AI model and eight other surgical videos from another institution for AI model evaluation. AI performance was measured using the Intersection over Union (IoU). Furthermore, to verify the AI’s clinical validity, we conducted the two experiments on the early identification of RLN and recognition of its location by eight trainee surgeons with or without AI. Results: The IoUs for AI recognition of the right and left RLNs were 0.40 ± 0.26 and 0.34 ± 0.27, respectively. The recognition of the right RLN presence in the beginning of right RLN lymph node dissection (LND) by surgeons with AI (81.3%) was significantly more accurate (p = 0.004) than that by surgeons without AI (46.9%). The IoU of right RLN during right RLN LND recognized by surgeons with AI (0.59 ± 0.18) was significantly higher (p = 0.010) than that by surgeons without AI (0.40 ± 0.29). Conclusions: Surgeons’ recognition of anatomical structures in RAMIE was improved by our AI system with high accuracy. Especially in right RLN LND, surgeons could recognize the RLN more quickly and accurately by using the AI model.

Background: Although radical esophagectomy with multifield lymph node dissection is a promising treatment to achieve long-term survival for resectable esophageal cancer, survival after postoperative recurrence remains poor. To select the optimal treatment for patients with recurrent esophageal cancer, simple, objective indicators for predicting of long-term outcomes are needed. Patients and Methods: We conducted a single-institution, retrospective cohort study between 2004 and 2019, wherein 586 patients underwent transthoracic esophagectomy for primary esophageal squamous cell carcinoma. Of these, 133 patients with postoperative recurrence were included in this analysis. Several predictors of survival after recurrence were investigated. Results: Among all patients, the 1- and 3-year survival rates after recurrence were 48.0% and 23.1%, respectively. On multivariate analysis, the neutrophil to lymphocyte ratio (NLR) at recurrence was identified as a significant predictor of death after recurrence (hazard ratio 1.061; 95% confidence interval 1.002–1.125; p = 0.043). Time-dependent receiver operating characteristics curves showed that the area under the curve value of the NLR at recurrence was superior to the modified Glasgow Prognostic Score at recurrence in all terms. To simulate the clinical decision process, we set the cut-off NLR at recurrence for survival using survival classification and regression tree (CART) and defined the optimal cut-off value as 3.374. Conclusions: NLR at recurrence was a significant indicator of survival after recurrence in patients with recurrent esophageal cancer. CART analysis was used to determine the optimal cut-off value for the prediction of survival, allowing the NLR to be used clinically to facilitate decision making.

Purpose: To arrange multidisciplinary treatment for esophageal cancer, a simple and accurate predictive marker for prognosis is required. The current multicenter prospective study aims to validate the prognostic significance of fibrinogen and albumin score (FA score) for esophageal cancer patients. Patients and Methods: Patients who were planned to undergo surgical resection for esophageal cancer at four participating institutions were enrolled in this study. Patient background, clinicopathological factors, and blood concentration of plasma fibrinogen and albumin were collected. Patients with elevated fibrinogen and decreased albumin levels were allocated a score of 2; those with only one of these abnormalities were allocated a score of 1; and those with neither of these abnormalities were allocated a score of 0. Recurrence-free survival (RFS) and overall survival (OS) were evaluated as a primary endpoint. Results: From four participating institutions, 133 patients were registered for the current analysis. The distribution of FA score of 0/1/2 was 84 (63%)/34 (26%)/15 (11%), respectively. In the analysis of primary endpoint, the preoperative FA score significantly classified RFS (FA score 1/2: HR 2.546, p = 0.013/6.989, p < 0.001) and OS (FA score 1/2: HR 2.756, p = 0.010/6.970, p < 0.001). We further evaluated the prognostic significance of FA score under stratification by pStage. As a result, with increasing FA score, RFS and OS were significantly worse in both pStage 0–I and II–IV groups. Conclusions: The prognostic impact of preoperative FA score was confirmed for esophageal cancer patients in the current multicenter prospective trial. FA score can be considered to predict postoperative survival and rearrange the treatment strategy before esophagectomy.

BACKGROUND: Neoadjuvant therapy (NAT) has become common worldwide for resectable advanced esophageal cancer and frequently involves weight loss. Although failure to rescue (death after major complications) is known as an emerging surgical quality measure, little is known about the impact of weight loss during NAT on failure to rescue. This retrospective study aimed to investigate the association of weight loss during NAT and short-term outcomes, including failure to rescue after esophagectomy. MATERIALS AND METHODS: Patients who underwent esophagectomy after NAT between July 2010 and March 2019 were identified from a Japanese nationwide inpatient database. Based on quartiles of percent weight change during NAT, patients were grouped into four categories of gain, stable, small loss, and loss (>4.5%). The primary outcomes were failure to rescue and in-hospital mortality. The secondary outcomes were major complications, respiratory complications, anastomotic leakage, and total hospitalization costs. Multivariable regression analyses were used to compare outcomes between the groups, adjusting for potential confounders, including baseline BMI. RESULTS: Among 15 159 eligible patients, in-hospital mortality and failure to rescue occurred in 302 (2.0%) and 302/5698 (5.3%) patients, respectively. Weight loss (>4.5%) compared to gain was associated with increased failure to rescue and in-hospital mortality [odds ratios 1.55 (95% CI: 1.10-2.20) and 1.53 (1.10-2.12), respectively]. Weight loss was also associated with increased total hospitalizations costs, but not with major complications, respiratory complications, and anastomotic leakage. In subgroup analyses, regardless of baseline BMI, weight loss (>4.8% in nonunderweight or >3.1% in underweight) was a risk factor for failure to rescue and in-hospital mortality. CONCLUSION: Weight loss during NAT was associated with failure to rescue and in-hospital mortality after esophagectomy, independent of baseline BMI. This emphasizes the importance of weight loss measurement during NAT to assess the risk for a subsequent esophagectomy.

Background Overall survival (OS) is the standard endpoint for oncological treatment efficacy, but requires long follow-up. The aim of this study was to evaluate pCR as a surrogate for OS in oesophageal cancer. Methods An integrated analysis of individual patient data (IPD) from phase III trials comparing perioperative therapies for resectable oesophageal and gastro-oesophageal junction cancer was conducted. Individual-level surrogacy between pCR and OS was assessed using Kendall's rank correlation coefficient (τ). A τ of 0.8 was considered a threshold for a good surrogate. As no method estimating τ between an ordinal endpoint and OS has been reported, a new method was proposed using the inverse-probability-of-censoring weighted estimator adjusted for tied data. Results Of 22 eligible trials, 10 provided IPD for 1641 patients, including 624 who received neoadjuvant chemotherapy (NAC; 45 (7.2%) achieved pCR) and 1017 who received neoadjuvant chemoradiotherapy (NACRT; 299 (29.4%) achieved pCR). In the NAC subgroup, patients with pCR had an HR for OS of 0.12 (95% c.i. 0.05 to 0.33), the C-index was 0.54 (95% c.i. 0.52 to 0.56), and τ was 0.256. In the NACRT subgroup, the HR was 0.57 (95% c.i. 0.47 to 0.70), the C-index was 0.56 (95% c.i. 0.54 to 0.58), and τ was 0.174. Hypothetical data suggested that achieving strong surrogacy (τ of 0.8) required an HR of 0.09 (95% c.i. 0.07 to 0.11). Conclusion Although pCR was correlated with OS, no evidence of individual-level surrogacy with OS was demonstrated, making it inappropriate to consider pCR as a surrogate endpoint for OS in resectable oesophageal cancer.

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.

Sarcopenia, which involves two important aspects, namely skeletal muscle loss and decreased physical function, was suggested as a poor prognostic factor in esophageal cancer surgery. The purpose of this study was to clarify the perioperative change in daily physical activity and propose effective preventive strategies. We prospectively enrolled patients with esophageal cancer who were scheduled to undergo radical esophagectomy. Their daily physical activities were recorded using an accelerometer before surgery, immediately after discharge, and 6 months after surgery. The relationships of physical activity level and the perioperative factors, especially skeletal muscle change, with the risk factors of low daily activity level were investigated. The data of 20/28 enrolled patients were analyzed. The mean activity level of the 20 patients decreased after discharge and subsequently recovered on postoperative month 6. The percentage of activity levels >1.5 metabolic equivalents/day after discharge significantly correlated to the change rate in total muscle cross-sectional area from baseline to POM 6 (r = 0.452, P = 0.045). In a stepwise multiple regression analysis, age, neoadjuvant chemotherapy, and anastomotic leakage were identified as negative associated factors of activity time at >1.5 metabolic equivalents at postoperative month 6. Activity level immediately after discharge was significantly associated with skeletal muscle loss at postoperative month 6 in patients with esophageal cancer who underwent esophagectomy. Elderly patients and patients who received neoadjuvant chemotherapy and had an anastomotic leakage might require intensive prevention. Prospective interventions aimed at increasing daily activity can prevent sarcopenia.

Purpose: The contribution of postoperative coagulation–fibrinolysis status to prognosis is yet to be fully investigated. Thus, in this study, we aimed to elucidate the relationship between postoperative hypercoagulable state (PHS) after transthoracic esophagectomy and long-term outcome in patients with esophageal cancer. Methods: Patients with esophageal cancer who underwent transthoracic esophagectomy were selected from a prospectively maintained database. Based on the trend of postoperative plasma fibrin–fibrinogen degradation product (FDP) levels, patients with PHS were identified. The prognostic significance of PHS was evaluated via multivariate analysis using the Cox regression model. Results: Based on the plasma FDP levels of 172 patients that reached a plateau between POD5 and POD7, we calculated the mean FDP value of POD5, 6, and 7, setting a median value as a cutoff. Consequently, 87 patients were classified as PHS. The overall survival (OS) in the PHS group was determined to be significantly lower than in the non-PHS group (5-year OS; 68% and 80%, p = 0.012). Recurrence-free survival (RFS) in the PHS group was significantly lower than in the non-PHS group (5-year RFS; 60% and 79%, p = 0.017). Using the pathological stage as a covariate in the multivariate analysis, PHS was an independent prognostic factor of OS [hazard ratio (HR) 2.517, p = 0.009] and RFS (HR 1.905, p = 0.041). Conclusions: PHS was found to be an independent negative prognostic factor in patients with esophageal cancer. Possible improvement of the oncological outcome by early postoperative intervention with anticoagulants should be explored in clinical trials.

Background: Innovations in artificial intelligence (AI) are revolutionizing surgical practices, enhancing the analysis and outcomes of complex procedures. Recent advances in AI-based computer vision have enabled our team to develop a novel artificial intelligence model that can recognize defined steps of robotic distal gastrectomy (RDG). Methods: This study assessed 130 robotic surgical videos from two institutions, 69 and 61 videos, respectively. The AI model used TeCNO, a multi-stage temporal convolutional network, and was trained using annotated videos with surgical steps defined by qualified surgeons. RDG step recognition predicted by the model was assessed using accuracy, precision, recall, and F-value metrics, and statistical analysis was assessed. Results: Three data sets were established to train and test the model. AI trained on single institution training sets performs moderately well at predicting RDG surgical steps with accuracies ranging from 56% to 63%, whereas AI trained on the multi-institutional data yielded a step recognition accuracy of 86%. These results were confirmed with F-scores and precision tests. Conclusions: We demonstrated that an AI step recognition model for RDG can predict surgical steps in an external video dataset with moderate accuracy. Furthermore, we conclude that training an AI model on a multi-institutional dataset significantly increases its step recognition capabilities. These results confirm that our model can be utilized by external institutions, and that a diverse training set of RDG procedures from multiple institutions is valuable to developing an AI model with precise step recognition capabilities in new institutions.

Background: The standard neoadjuvant treatment in Japan for resectable locally advanced esophageal squamous cell carcinoma (ESCC) is DTX + CDDP + 5-FU (DCF). In addition, immune checkpoint inhibitors (ICIs) have shown a survival benefit for ESCC and are promising as neoadjuvant treatment for several cancers. We previously reported that neoadjuvant CDDP + 5-FU + nivolumab (Nivo) or DCF + Nivo therapy was tolerable and showed promising efficacy for ESCC. However, the efficacy of neoadjuvant treatment and safety of subsequent surgery remain unclear for 5-FU + l-LV + L-OHP + DTX (FLOT), the global standard of care for perioperative esophagogastric adenocarcinoma, plus ICI for ESCC. Methods: JCOG1804E (FRONTiER) is a multi-cohort phase I study designed to evaluate the safety and efficacy of Nivo combined with neoadjuvant chemotherapy in ESCC. The eligibility criteria were histologically proven ESCC staged as cT1N1-3M0 or cT2-3N0-3M0 (8th UICC TNM classification), age 20-75 years, performance status (PS) ≤1, and no prior cancer therapy. The primary endpoint was the incidence of dose-limiting toxicity (DLT) from the initial dose to postoperative day 30. The secondary endpoints included adverse events during the perioperative period and at 30 days and the objective response rate, R0 resection rate, histopathological complete response rate, and completion rate of the protocol treatment including planned chemotherapy as below followed by R0 resection. Among five study cohorts, patients in cohort E were planned to receive four courses of FLOT+Nivo–5-FU (2600 mg/m2), l-LV (200 mg/m2), L-OHP (85 mg/m2), DTX (50 mg/m2), and Nivo (240 mg)–on day 1 every 2 weeks. Results: Of the 12 patients enrolled in cohort E (median age [range]: 64.5 [53-71] years, PS 0/1: 12/0, clinical stage I/II/III/IVA: 4/5/3/0), 4 developed DLT (grade 3 mucositis, erythema multiforme, and pneumonitis, n=1 each; grade 5 pneumonitis, n=1), which was within the prespecified range of safety (n ≤ 4). Other grades≥3 adverse events were neutropenia (n=7), leukopenia (n=6), fever, fatigue, febrile neutropenia, rash, elevated amylase, elevated hepatic enzyme, hypotension, and thrombocytopenia (n=1 each) during FLOT + Nivo, and anastomotic leakage (n=1) during the postoperative period. One patient discontinued FLOT + Nivo due to DLT of erythema multiforme, eleven patients (91.7%) completed the protocol treatment and R0 resection rate achieved 91.7% (11/12). In cohort E, the objective response rate in patients with measurable lesion was 0% (0/4). However, 5 patients (41.7%) achieved a pathological complete response, and 6 (50.0%) achieved a pathological complete response in primary tumors among 12 patients. Conclusions: Neoadjuvant FLOT + Nivo followed by surgery for locally advanced ESCC was tolerated and showed promising efficacy.

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, I2 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, I2 = 82%). That for the lowest versus highest vegetable consumption was 0.61 (95% CI 0.50–0.74, I2 = 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 (I2 = 48% for fruit, I2 = 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.

Objective: To establish a risk-stratification system for predicting the postoperative recurrence of esophageal squamous cell carcinoma, this study aimed to evaluate the prognostic value of clusters based on blood inflammation and coagulation markers and investigate their correlation with serum cytokines and genetic alteration. Method: This single-center, retrospective cohort study enrolled 491 patients with esophageal cancer who underwent subtotal esophagectomy between 2004 and 2012. For cluster exploration, nonhierarchical cluster analysis and k-means were applied using serum C-reactive protein, albumin, fibrinogen, and platelet–lymphocyte ratio as variables. Then, multivariate survival analysis was conducted to investigate the association of clusters with recurrence-free survival. To characterize the clusters, serum interleukin-6, interleukin-8, and genetic alteration in primary tumors, the PleSSision-Rapid panel, which can evaluate 160 representative driver genes, was used. Results: Patients were classified into clusters 1, 2, and 3, which included 24 (5%), 161 (33%), and 306 (62%) patients, respectively. Compared with cluster 3, cluster 1 or 2 had significantly worse recurrence-free survival. Based on the multivariable analysis using cluster, pStage, and age as covariates, cluster was an independent prognostic factor for recurrence-free survival (hazard ratio, 1.55; 95% confidence interval, 1.08–2.21; P = 0.02). The percentage of serum interleukin-6 and interleukin-8 levels was the highest in cluster 1, followed by clusters 2 and 3. In 23 patients with available genomic profiles, no significant difference in representative genomic alterations was observed. Conclusions: Non-biased clustering using inflammation and coagulation markers identified the intense inflammatory subtype, which had an independent prognostic effect on recurrence-free survival.

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.