BackgroundsIn Western countries, the standard perioperative treatment for resectable locally advanced esophagogastric junction adenocarcinoma (EGJ-AC) is 5-fluorouracil, oxaliplatin, and docetaxel (FLOT) therapy based on the results of the FLOT4 and ESOPEC trials. On the other hand, there was little evidence based on optimal perioperative treatment for resectable locally advanced EGJ-AC in Japan. Our previous report showed that neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy demonstrated modest efficacy for resectable locally advanced EGJ-AC. Therefore, we compared neoadjuvant DCF to FLOT therapy in terms of efficacy and safety in this study.MethodsWe retrospectively analyzed the data of patients who received DCF or FLOT therapy for resectable EGJ-AC between 2015 and 2024 in our hospital. We assessed the R0 resection rate, histopathological response, disease-free survival (DFS), overall survival, and adverse events.ResultsThirty-two patients in the DCF therapy group and 20 patients in the FLOT therapy group were analyzed. The patients’ characteristics in the DCF group and FLOT group were as follows: median age, 63/59 years; ECOG PS 0, 66%/85%, respectively. The pCR rate was numerically higher in the FLOT group (20%) compared with the DCF group (3%) (p = 0.07). Similarly, the 1-year DFS rate was higher in the FLOT group (93%) than in the DCF group (68%) (p = 0.02), although this difference did not remain statistically significant after adjustment for baseline factors. Febrile neutropenia was significantly lower in the FLOT group (0%) than in the DCF group (12.5%).ConclusionsNeoadjuvant FLOT therapy is well-tolerated and has comparable short-term efficacy to DCF therapy.

BackgroundWe aimed to identify an acceptable waiting period between the diagnosis of superficial esophageal squamous cell carcinoma (SESCC) and endoscopic submucosal dissection (ESD).MethodsThis retrospective, single-center study included 423 patients with 514 SESCC lesions. All patients underwent image-enhanced magnifying endoscopy at initial evaluation and on the day of ESD. Following three outcomes were assessed: the diagnostic accuracy of tumor invasion depth on the day of ESD using the Japanese Esophageal Society classification; changes in diagnosis between initial and final evaluations across different waiting intervals; and 5-year survival rates based on intrapapillary capillary loop patterns (B1 vs. B2) and waiting duration.ResultsThe diagnostic accuracy was 96.6% for B1 vessels (EP/LPM), 59.6% for B2 vessels (MM/SM1), and 84.6% for B3 vessels (SM2 or deeper). Among B1 lesions, 100% remained B1 on the day of ESD across all time groups. For B2 lesions, stability was observed in 100% of cases within one month, 98.2% in one to two months, 92.9% in two to three months, and 100% after three months. Five-year survival rates showed no significant differences among waiting period groups in both B1 and B2 categories.ConclusionsA waiting period of 3 months is acceptable for patients with SESCC classified as B1 vessels, provided the diagnostic accuracy is maintained. Thorough endoscopic evaluation supports safe scheduling flexibility without adversely affecting long-term outcomes.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10388-025-01156-1.

Delayed gastric conduit emptying (DGCE) is a significant and prevalent complication following esophagectomy, adversely affecting recovery and quality of life. The true burden of DGCE remains uncertain due to considerable variability in reported incidence rates. This study aimed to determine the incidence of DGCE following esophagectomy and how this is impacted with varying diagnostic criteria. A systematic review was conducted across major databases, including PubMed, MEDLINE, Embase, Web of Science, and Cochrane, to identify studies reporting the incidence of DGCE following esophagectomy. The incidence rates were pooled and analyzed using a random-effects model, with subgroup analyses for potential sources of heterogeneity such as pyloric interventions, conduit dimensions, and anastomotic height. Among 5176 screened records, 125 studies met the eligibility criteria. The pooled incidence of early DGCE was 15.9% (95% CI 11–21%), and late DGCE was 9.4% (95% CI 7.1–11.9%). Significant heterogeneity was observed across studies, driven by variations in diagnostic methods. Subgroup analysis indicated that prophylactic pyloric drainage was not associated with a statistically significant effect on early DGCE (OR 0.76; p = 0.38) or late DGCE (OR 0.71; p = 0.44). DGCE represents a significant burden for esophageal cancer survivors, with considerable variability in its reported incidence, underscoring the urgent need for a standardized diagnostic criterion. The adoption of the recently published international consensus definition is crucial for reducing the heterogeneity, as well as improving the identification and management of DGCE.

BackgroundPreoperative treatment has become widely recognized for improving survival in patients with esophageal cancer. The present study aimed to compare the prognosis between patients with pathological node-negative status treated with surgery alone (SA-pN0) and those who were clinically node-positive but converted to ypN0 following neoadjuvant chemotherapy (NAC-ypN0) in cases of advanced thoracic esophageal squamous cell carcinoma (ESCC).MethodsThis retrospective analysis used a multicenter database of 4849 consecutive patients who underwent treatment for esophageal cancer. Patients with clinical T2 or more advanced ESCC who underwent standard subtotal esophagectomy between 1990 and 2017 were included. The NAC-ypN0 group was compared with the SA-pN0 group in terms of patient characteristics, recurrence patterns, and survival outcomes using propensity score-matched analysis.ResultsIn total, 109 patients were classified as NAC-ypN0 and 137 as SA-pN0. Propensity score matching resulted in the selection of 87 patients per group. Compared with the SA-pN0 group, the NAC-ypN0 group had a significantly more advanced clinical TNM stage and underwent significantly more three-field lymphadenectomies. Pathological findings showed downstaging of the pT stage in the NAC-ypN0 group, resulting in an equivalent distribution between the two groups. Additionally, the NAC-ypN0 group had significantly lower rates of lymphatic invasion (33% vs. 56%) and venous invasion (21% vs. 52%). Recurrence rates (21% vs. 22%) and survival outcomes (5-year overall survival: 83.9% vs. 76.1%, P = 0.110) were comparable between the two groups.ConclusionsThe NAC-ypN0 group demonstrated reduced lymphovascular invasion and showed a prognosis comparable to that of the SA-pN0 group.

BackgroundProgrammed cell death protein-1 (PD-1) blockade has improved survival for patients with esophageal squamous cell carcinoma (ESCC), but response rates are low. Biomarkers to predict who will benefit from PD-1 blockade are urgently needed.MethodsThis multicenter study involved 250 patients with recurrent/unresectable advanced ESCC receiving nivolumab as second- or later-line therapy. We assessed tumor-infiltrating T lymphocytes (TILs) and tertiary lymphoid structure (TLS) density using immunohistochemistry and hematoxylin/eosin staining in surgical specimens and pre-nivolumab endoscopic biopsies.ResultsIn surgical specimens, clinical response (vs. non-response) to nivolumab correlated significantly with CD8+ lymphocyte count (160 vs. 95.2 cells/field, P = 0.0494), CD8/Foxp3 ratio (6.52 vs. 2.72, P = 0.0053), and TLS density (0.21/mm2 vs. 0.10/mm2, P = 0.0005). In terms of overall survival, multivariate analysis identified CD8/Foxp3 ratio (hazard ratio [HR] = 1.83, P = 0.0050) and TLS density (HR = 1.67, P = 0.0171 as independent prognostic parameters in surgical specimens. Similarly, in endoscopic biopsies, clinical response (vs. non-response) to nivolumab correlated significantly with CD8+ counts (254 cells/mm2 vs. 124 cells/mm2, P = 0.0344), CCR8+ lymphocyte count (62.6 cells/mm2 vs. 140 cells/mm2, P = 0.0355), CD8/Foxp3 ratio (2.09 vs. 0.89, P = 0.040), and CD8/CCR8 ratio (2.34 vs. 0.89, P = 0.0020). Multivariate analysis also identified CD8/CCR8 ratio in endoscopic biopsies (HR = 1.66, P = 0.0313) as an independent prognostic parameter.ConclusionsCD8+ and CCR8+ cell counts, CD8/Foxp3 and CD8/CCR8 ratios, and TLS density may be predictive biomarkers of therapeutic efficacy and survival with PD-1 blockade for ESCC.

BackgroundEsophageal cancer is highly prevalent in China, predominantly represented by squamous cell carcinoma. This retrospective study sought to evaluate the diagnostic efficacy of four staining protocols in identifying early stage esophageal squamous cell carcinoma (ESCC).MethodsA consecutive series of ninety biopsy samples of esophageal mucosa, collected retrospectively from March 2016 to December 2019, were obtained at Beijing Chao-Yang Hospital, a tertiary care facility in Beijing, China. These samples were categorized into four groups: non-neoplastic squamous lesions (Non-NSL), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and early stage ESCC. Baseline, molecular analyses (p53 by immunohistochemistry and Ki-67 by immunohistochemistry), and staining analyses (hematoxylin & eosin (HE) and periodic acid-Schiff (PAS) were conducted across the categories. The staining protocols included HE, HE + p53 + Ki-67, HE + p53 + Ki-67 + PAS, and HE + p53/PAS + Ki-67/PAS.ResultsPatients with HGD and ESCC were significantly older and had larger lesions. Elevated p53 and Ki-67 mutation rates were observed in HGD and ESCC, while increased PAS positivity was noted in RE and LGD. The p53, Ki-67, and PAS staining results showed mostly no correlation among the four groups. Abnormal Ki-67 basal layer distribution pattern correlated with histological grades, with higher proportions in HGD and ESCC. HE + p53 + Ki-67 + PAS and HE + p53/PAS + Ki-67/PAS demonstrated complete consistency with the reference standard, with weighted κ values of 1. HE + p53 + Ki-67 + PAS and HE + p53/PAS + Ki-67/PAS protocols exhibited 100% accuracy, sensitivity, and specificity for diagnosing ESCC or ESCC combined with HGD, outperforming the other protocols.ConclusionsIncorporating specific staining protocols, particularly HE + p53 + Ki-67 + PAS and HE + p53/PAS + Ki-67/PAS, enhances the diagnostic accuracy for early stage ESCC, showing promise in advancing the pathology diagnostic pathway.

BackgroundReal-world clinical outcomes of and prognostic factors for nivolumab treatment for esophageal squamous-cell carcinoma (ESCC) remain unclear. This study aimed to evaluate real-world outcomes of nivolumab monotherapy in association with relevant clinical parameters in recurrent/unresectable advanced ESCC patients.MethodsThis population-based multicenter cohort study included a total of 282 patients from 15 institutions with recurrent/unresectable advanced ESCC who received nivolumab as a second-line or later therapy between 2014 and 2022. Data, including the best overall response, progression-free survival (PFS), and overall survival (OS), were retrospectively collected from these patients.ResultsObjective response and disease control rates were 17.0% and 47.9%, respectively. The clinical response to nivolumab treatment significantly correlated with development of overall immune-related adverse events (P < .0001), including rash (P < .0001), hypothyroidism (P = .03), and interstitial pneumonia (P = .004). Organ-specific best response rates were 20.6% in lymph nodes, 17.4% in lungs, 15.4% in pleural dissemination, and 13.6% in primary lesions. In terms of patient survival, the median OS and PFS was 10.9 and 2.4 months, respectively. Univariate analysis of OS revealed that performance status (PS; P < .0001), number of metastatic organs (P = .019), C-reactive protein-to-albumin ratio (CAR; P < .0001), neutrophil–lymphocyte ratio (P = .001), and PMI (P = .024) were significant. Multivariate analysis further identified CAR [hazard ratio (HR) = 1.61, 95% confidence interval (CI) 1.15–2.25, P = .0053)] in addition to PS (HR = 1.65, 95% CI 1.23–2.22, P = .0008) as independent prognostic parameters.ConclusionsCAR and PS before nivolumab treatment are useful in predicting long-term survival in recurrent/unresectable advanced ESCC patients with second-line or later nivolumab treatment.Trial RegistrationUMIN000040462

Progression of the physical weakness during neoadjuvant therapy (NAT) in patients with esophageal or gastroesophageal junction cancer is a serious problem; however, prehabilitation during NAT has the potential to overcome the unmet need. Nevertheless, systematic reviews on this topic have not been summarized. Therefore, this systematic review aimed to determine prehabilitation’s effectiveness, acceptability, and safety during NAT for patients with esophageal or gastroesophageal junction cancer. An electronic search was performed in the MEDLINE, Web of Science, CENTRAL, CINAHL, and PEDro databases. A meta-analysis was conducted to assess the effectiveness of prehabilitation during NAT, along with a descriptive analysis of acceptance and safety. This study analyzed data from three randomized controlled trials (RCTs) and nine non-RCTs involving 664 patients. The meta-analysis of two RCTs demonstrated that prehabilitation during NAT may be more effective than usual care in enhancing tolerance to NAT and grip strength; moreover, one RCT and three non-RCTs revealed that prehabilitation may reduce the risk of postoperative complications. The adherence rates for exercise programs in two RCTs and seven non-RCTs were 55–76%. Additionally, two studies reported a 76% adherence rate for multimodal prehabilitation programs, including exercise, dietary, and psychological care. Six studies reported no serious prehabilitation-related adverse events during NAT. Prehabilitation during NAT may be a safe and beneficial intervention strategy for patients with esophageal or gastroesophageal junction cancer. However, the investigation of strategies to enhance adherence is essential. Furthermore, additional high-quality RCTs are needed to examine the effect of prehabilitation during NAT.

Classification of extramural invasion of esophagogastric junction carcinoma (EGJC) is not yet established. The anatomy surrounding the EGJ alters between the mediastinum and the abdominal cavity. This review proposed a T3 classification of EGJC based on anatomical continuity. Analysis of endoscopic ultrasound images, review of intraoperative images, and detailed observation of surgical specimens were followed by a review of the literature. In the EGJ, the muscularis propria of the esophagus is enclosed in mediastinal adipose tissue called the adventitia, which is surrounded by the diaphragmatic crus and contains the paraesophageal lymph nodes (LNs). After passing through the esophageal hiatus along with the vagus nerves and blood vessels, the adventitia joins the adipose tissue containing the paracardial LNs, which is covered by the peritoneum, and then further divides into the lesser and greater omentum. The connective tissue outside the muscularis propria of the stomach, including the adipose tissue of the omentum, is called the subserosa. According to the TNM classification, T3 esophageal and gastric cancer is defined as invasion of the adventitia and subserosa, respectively. Given that the adventitia is anatomically continuous with the subserosa, T3 tumors of the EGJ can be described as those that extend through the muscularis propria but do not invade the peritoneum or diaphragmatic crus. We propose classifying T3 EGJC as "tumor extends through muscularis propria" rather than using the separate terms "adventitia" and "submucosa". T4 could be "tumor perforates serosa or invades adjacent structures", as per the current gastric cancer classification.

Neoadjuvant chemotherapy followed by surgery is Japan's most effective treatment modality for advanced thoracic esophageal squamous cell carcinoma. However, the prognosis is not as expected. This study aimed to examine prognostic factors in patients with pathologically ineffective neoadjuvant chemotherapy followed by surgery for esophageal squamous cell carcinoma. We retrospectively analyzed patients who underwent neoadjuvant chemotherapy followed by curative esophagectomy for esophageal squamous cell carcinoma between December 2008 and July 2021. The patients were divided into the neoadjuvant chemotherapy effective group and the neoadjuvant chemotherapy ineffective group according to the pathological diagnosis. Clinicopathological data, prognosis, and recurrence were analyzed. A total of 143 patients (121 males, 22 females; median age, 67years) were included in this study. Of these, 34 patients were classified into the effective group and the remaining 109 patients were assigned to the ineffective group. The ineffective group had significantly worse overall survival and recurrence-free survival than the effective group (p = 0.0192 and p = 0.0070, respectively). In the ineffective group, multivariate analysis demonstrated that microscopic venous invasion was an independent prognostic factor for overall survival (hazard ratio 2.44; 95% confidence interval 1.13-5.30) and recurrence-free survival (hazard ratio 2.43; 95% confidence interval 1.24-4.73). Microscopic venous invasion was associated with poor survival and cancer recurrence in the neoadjuvant chemotherapy ineffective group of patients who underwent esophagectomy for esophageal squamous cell carcinoma.