Esophageal squamous cell carcinoma (ESCC) remains a significant global health challenge, being the sixth leading cause of cancer mortality with pronounced geographic variability. The incidence rates range from 125 per 100,000 in northern China to 1-1.5 per 100,000 in the United States, driven by environmental and lifestyle factors such as tobacco and alcohol use, dietary habits, and pollution. Major modifiable risk factors include tobacco and alcohol consumption, with a synergistic risk increase when combined. Nonmodifiable risk factors include previous diagnoses of head and neck squamous cell carcinoma (H&N SCC), achalasia, and prior radiotherapy. Prevention strategies must be tailored to specific regional burdens to efficiently allocate medical and financial resources. Gastrointestinal endoscopy is crucial in reducing ESCC burden through early detection and characterization of neoplastic changes, such as high-grade dysplasia. Early diagnosis significantly improves survival rates, while endoscopic resection of noninvasive dysplasia can prevent ESCC onset, reducing treatment burden for advanced disease. Postresection surveillance can detect high-risk metachronous lesions. Despite these benefits, endoscopic prevention faces challenges, including the lack of high-level evidence supporting its efficacy, opportunity costs, the need for specialized training and techniques, and the requirement for advanced technology investments. This Position Statement from the World Endoscopy Organization (WEO) aims to address these challenges, supplying recommendations for the exploitation of endoscopic resources regarding the possible role of screening, quality, and training for the detection, characterization, resection, and surveillance of ESCC.

Detecting pathological complete response (pCR) preoperatively facilitated a non-surgical approach after neoadjuvant chemotherapy (NAC). We previously developed a deep neural network-based endoscopic evaluation to determine pCR preoperatively. Its quality warrants improvement with a larger data series for clinical application.

This study retrospectively reviewed patients with esophageal squamous cell carcinoma (ESCC) receiving NAC at 46 Japanese esophageal centers certified by the Japan Esophageal Society. Endoscopic images after NAC were collected with clinicopathological factors and long-term outcomes. We randomly selected the same number of patients with Grades 0-1a and Grades 1b-2 based on those with pCR (Grade 3). A deep neural network was used for endoscopic image analyses. A test data set, consisting of 100 photos, was utilized for validation. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the deep neural network-based model and experienced physicians were calculated.

The study enrolled 1041 patients, including 354 (33%) patients with pCR, the same number of histological non-responders (Grade 0-1a/1b-2, 352 [33%]/368 [34%]). The median values of sensitivity, specificity, PPV, NPV, and accuracy for pCR detection were 80%, 90%, 89%, 82%, and 85%, respectively. The patients with pCR preoperatively demonstrated significantly better overall survival and recurrence-free survival.

This large-scale study revealed that the deep neural network-based endoscopic evaluation after NAC identified pCR with feasible accuracy. The current artificial intelligence technology may guide an individualized treatment strategy, including a non-surgical approach, in patients with ESCC through prospective studies with careful external validation.

Neoadjuvant immunotherapy combined with chemotherapy or chemoradiotherapy has emerged as a promising approach in the treatment of esophageal cancer. However, there is a lack of comprehensive understanding regarding the clinical factors that can predict patient response to this therapy. The aim of this study was to develop a predictive model for assessing the efficacy of neoadjuvant immunotherapy in patients undergoing surgical treatment.

This study retrospectively enrolled 220 consecutive patients with preoperative immunotherapy combined chemotherapy or chemoradiotherapy. A logistic regression was used to evaluate the association between pathologic complete response (pCR) and endoscopic ultrasound parameters, constructing a predictive model for treatment response. Additional, overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and Cox regression analyses were introduced to explore the associations between EUS factors after neoadjuvant immunotherapy.

Logistic regression analysis identified that the significant predictors of pCR were treatment regimen, negative biopsy findings, RECIST assessment, endoscopic ultrasound responder, and downstaging in uN. A predictive model including above five variables was generated, and area under the curve was 0.840(95%CI 0.78-0.89), this nomogram was also adequately validated internally. In the cox regression analyses, EUS responder was found to be a significant predictor of overall survival with a hazard ratio (HR) of 0.38(95%CI 0.15-0.98), whereas only pCR status was a significant predictor of PFS (HR 0.80; 95%CI 0.01-0.60).

EUS responder can serve as a valuable predictor of the efficacy of adjuvant immunotherapy combined with chemotherapy or chemoradiotherapy, as well as of survival outcomes.

Herein, we aimed to examine the relationship between sarcopenia, neutrophil-lymphocyte ratio (NLR), Charlson comorbidity index (CCI), and prognostic nutritional index (PNI) in patients with superficial esophageal carcinoma who underwent definitive chemoradiotherapy (CRT).

We retrospectively analyzed 100 patients (87 males) diagnosed with cT1N0M0 esophageal squamous cell carcinoma. The included patients underwent CRT as an initial treatment. Muscle mass was assessed using the psoas muscle index (PMI). All patients received concurrent chemotherapy (5-fluorouracil plus cisplatin/nedaplatin) and radiotherapy (60 Gy). The duration of follow-up (median range) was 78 (2.5-197) months. During the follow-up period, 23 recurrences occurred, along with 37 deaths (11 deaths from esophageal cancer; only one treatment-related death).

The 5-year survival rate was 78.0%. The median (range) PMI was 6.55 (3.90-10.9) and 4.62 (2.28-6.60) cm2/m2 in males and females, respectively. The PNI was 46.6 (36.2-60.4), NLR was 2.45 (0.61-18.1), and CCI was 0 (0-10). Patients were divided into low PMI (sarcopenia) and high PMI (non-sarcopenia) groups. In the univariate survival time analysis, the low PMI group had a significant hazard ratio (HR) of 2.70 (p = 0.0049), the low Geriatric Nutritional Risk Index (GNRI) group had an HR of 2.30 (p = 0.0161), and the CCI ≥ 1 group had an HR of 2.19 (p = 0.0199). According to the multivariate analysis using these three factors and age (≥ 65 years), PMI was an independent prognostic factor (HR, 2.23; p = 0.0313).

PMI is a notable predictor of prognosis in patients undergoing CRT for T1N0M0 esophageal cancer.

Endoscopic radiofrequency ablation (ERFA) is a treatment option for superficial esophageal squamous cell neoplasia (ESCN), with a relatively low risk of stenosis; however, the long-term outcomes remain unclear. We aimed to compare the long-term outcomes of patients with widespread superficial ESCN who underwent endoscopic submucosal dissection (ESD) or ERFA.

We retrospectively analyzed the clinical data of patients with superficial ESCN who underwent ESD or ERFA between January 2015 and December 2021. The primary outcome measure was recurrence-free survival.

Ninety-two and 33 patients with superficial ESCN underwent ESD and ERFA, respectively. The en bloc, R0, and curative resection rates for ESD were 100.0%, 90.2%, and 76.1%, respectively. At 12 months, the complete response rate was comparable between the two groups (94.6% vs 90.9%, p=0.748). During a median follow-up of 66 months, recurrence-free survival was significantly longer in the ESD group than in the ERFA group (p=0.004), while no significant differences in overall survival (p=0.845) and disease-specific survival (p=0.494) were observed. Preoperative diagnosis of intramucosal cancer (adjusted hazard ratio, 5.55; vs high-grade intraepithelial neoplasia) was an independent predictor of recurrence. Significantly fewer patients in the ERFA group experienced stenosis compare to ESD group (15.2% vs 38.0%, p=0.016).

The risk of recurrence was higher for ERFA than ESD for ESCN but overall survival was not affected. The risk of esophageal stenosis was significantly lower for patients who underwent ERFA.

Platinum-based definitive chemoradiotherapy (dCRT) is the standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) that invades the aorta, vertebral body or trachea; however, complete response rates remain low (11-25%), leading to poor survival. To evaluate the additive efficacy of the anti-PD-L1 antibody drug atezolizumab, we conducted a phase 2, multicenter, single-arm trial of 1 year of atezolizumab treatment following dCRT in 40 patients with unresectable locally advanced ESCC recruited from seven Japanese centers (UMIN000034373). The confirmed complete response (cCR) rate (primary end point) of the first consecutive 38 patients was 42.1% (90% CI 28.5-56.7%). Regarding the secondary end points, the median progression-free survival and 12-month progression-free survival rates of all 40 patients were 3.2 months and 29.6%, respectively, and the preliminary median overall survival with short-term follow-up and 12-month overall survival rate were 31.0 months and 65.8%, respectively. Other secondary end points evaluated included the cCR rate determined by an investigator's assessment in the locoregionally recurrent ESCC cohort, cCR rate determined by central assessment, overall response rate and incidence of adverse events. No treatment-related death occurred during the study. Atezolizumab monotherapy after dCRT resulted in a promising cCR rate, although long-term survival data are required.

In esophageal cancer, the ypN0 status after induction therapy could be categorized into two primary groups: "natural N0" (cN0/ypN0) and "down-staged N0" (cN+/ypN0). The assessment of cN status is typically based on clinical imagination or pathological regression. However, there is no standardized method for evaluating cN/ypN status. This study aims to investigate the prognosis of patients with cN+/ypN0 using both assessment methods through a cohort study and meta-analysis.

A prospectively maintained database encompassing esophageal cancer patients undergoing induction therapy followed by radical esophagectomy was comprehensively reviewed. The prognostic significance of cN+/ypN0 across two evaluation methods was quantified. Additionally, a meta-analysis using data from previous studies was conducted.

578 patients were identified from the cohort analysis, with 342 classified as ypN0 and 236 as ypN+. When evaluated with clinical imagination, patients with cN+/ypN0 had survival outcomes comparable to those with natural N0 but significantly better than those with ypN+ (p < 0.001). Using pathological nodal regression, cN+/ypN0 patients showed superior overall survival compared to ypN+ patients (p = 0.0043), although their disease-free survival was notably inferior to that of natural N0 patients (p = 0.0088). A meta-analysis of 20 previous studies confirmed the prognostic value of cN+/ypN0 status in both clinical imagination and pathological regression.

For esophageal cancer patients receiving neoadjuvant, cN+/ypN0 status, assessed through both clinical imagination and pathological regression, serves as a significant prognostic factor. It holds precedence over ypN+ yet falls short of the natural N0. The pre-treatment categorizations warrant recognition as a novel and pertinent staging metric.

Resection is considered the standard of care for patients with localized esophageal cancer who are "physiologically fit". Patients who do not meet this standard are considered contraindicated to receive surgery. We hypothesized that among patients with non-metastatic esophageal cancer, the consideration of contraindication status would vary based on clinical and demographic factors and would vary between institutions.

We identified patients with non-metastatic gastric and esophageal cancer in the National Cancer Database (NCDB) from 2004 to 2018. Patients were categorized into three groups based on surgical treatment: surgical resection (including endoscopic mucosal resection), resection contraindicated, and refusal of resection based on the coding of the "reason for no surgery" data element. Demographic, clinical, and institutional characteristics were compared between the groups using bivariate and multivariate techniques to identify factors associated with contraindicated status. A subgroup analysis of cT1N0M0 patients was also used to assess every institution in the NCDB's observed-expected ratio for contraindication status.

In total, 144,591 patients with non-metastatic disease met inclusion criteria: 124,972 (86%) underwent resection, 13,793 (10%) were contraindicated for resection, and 5826 (4%) refused resection. Contraindication was associated with age, non-Hispanic Black race, socioeconomic status, Charlson-Deyo score, insurance type, institution characteristics, clinical T-stage, and clinical N-stage. There were 9459 patients who were cT1N0M0 and had no co-morbidities. In this cohort, there were more than 1000-fold differences between individual programs regarding observed-expected ratio of contraindication status when adjusting for clinical and demographic characteristics.

Variation in the assessment of contraindication status varies dramatically between institutions. Underserved minorities, including age, race, and insurance type, are risk factors for being considered contraindicated. These findings highlight the disparities that exist regarding surgical care of non-metastatic esophageal cancer in the United States.

Esophageal stricture ranks among the most significant complications following endoscopic submucosal dissection (ESD). Excessive fibrotic repair is a typical pathological feature leading to stenosis after ESD.

To examine the effectiveness and underlying mechanism of Kangfuxin solution (KFX) in mitigating excessive fibrotic repair of the esophagus post-ESD.

Pigs received KFX at 0.74 mL/kg/d for 21 days after esophageal full circumferential ESD. Endoscopic examinations occurred on days 7 and 21 post-ESD. In vitro, recombinant transforming growth factor (TGF)-β1 (5 ng/mL) induced a fibrotic microenvironment in primary esophageal fibroblasts (pEsF). After 24 hours of KFX treatment (at 1.5%, 1%, and 0.5%), expression of α-smooth muscle actin-2 (ACTA2), fibronectin (FN), and type collagen I was assessed. Profibrotic signaling was analyzed, including TGF-β1, Smad2/3, and phosphor-smad2/3 (p-Smad2/3).

Compared to the Control group, the groups treated with KFX and prednisolone exhibited reduced esophageal stenosis, lower weight loss rates, and improved food tolerance 21 d after ESD. After treatment, Masson staining revealed thinner and less dense collagen fibers in the submucosal layer. Additionally, the expression of fibrotic effector molecules was notably inhibited. Mechanistically, KFX downregulated the transduction levels of fibrotic functional molecules such as TGF-β1, Smad2/3, and p-Smad2/3. In vitro, pEsF exposed to TGF-β1-induced fibrotic microenvironment displayed increased fibrotic activity, which was reversed by KFX treatment, leading to reduced activation of ACTA2, FN, and collagen I. The 1.5% KFX treatment group showed decreased expression of p-Smad 2/3 in TGF-β1-activated pEsF.

KFX showed promise as a therapeutic option for post-full circumferential esophageal ESD strictures, potentially by suppressing fibroblast fibrotic activity through modulation of the TGF-β1/Smads signaling pathway.

Endoscopic resection (ER) of esophageal squamous cell carcinoma (ESCC) is an organ-preserving treatment; however, heterochronic carcinomas are often encountered. Most patients are treated using ER; however, for some, this is inadequate and requires additional treatment. We sought to identify the characteristics and frequency of lesions at high risk of metastasis during surveillance based on Lugol-voiding lesion (LVL) grading and esophagogastroduodenoscopy (EGD) intervals.

Of the 1301 patients who underwent ER, 956 underwent surveillance EGD at our hospital for at least 1 year (median, 59 months). We analyzed identified multiple ESCCs to reveal the characteristic of high-metastasis-risk lesions, which was defined ESCC with submucosal or lymphovascular invasion.

In the 956 patients, 444 multiple ESCCs were identified in 216 patients and the cumulative incidence of multiple ESCCs was 15.4% and 22.9% at 3 and 5 years, respectively, while for high-risk lesions, it was 1.0% and 1.8%. The risk factors for high-metastasis-risk lesions were being female (odds ratio (OR):5.58, 95% confidence interval (CI):1.96-15.9), lesions located in the cervical/upper thoracic esophagus (OR: 4.81, 95% CI:1.80-12.8), and the presence of submucosal tumor (SMT)-like marginal elevation (OR:65.4, 95% CI:11.0-390). No significant differences in the frequency of high-risk lesions were found based on LVL grade at any EGD intervals.

During endoscopic surveillance, attention should be given to the cervical/upper thoracic esophagus and lesions with SMT-like marginal elevation. The frequency of high-metastasis-risk lesions was not different by LVL grade or EGD intervals.

Lymphovascular invasion (LVI) or pT1b is noncurative after endoscopic resection (ER) for esophageal squamous cell carcinoma (ESCC), and therefore surgery or chemoradiotherapy (CRT) is recommended. However, there has been debate regarding which treatment has better outcomes and whether individual risks should be considered.

This was a multicenter, retrospective study conducted at 65 hospitals in Japan. The inclusion criteria were patients with ESCC who underwent ER between January 2006 and December 2015, with pT1a-muscularis mucosa (MM) with LVI or pT1b, with negative vertical margins, cN0M0, and who underwent surgery or CRT. A 1:1 propensity score-matched analysis was performed between two groups. The primary and secondary end points were overall survival (OS) and relapse-free survival (RFS). OS and RFS were also compared between two subgroups: low risk (pT1a-MM with LVI and pT1b without LVI) and high risk (pT1b with LVI) for metastatic recurrence.

Among 472 patients, 160 patients were selected from each group. The OS and RFS did not differ between surgery and CRT groups (hazard ratio, 0.887; P = .635 and hazard ratio, 1.036; P = .876, respectively). Subgroup analysis showed that CRT had a better prognosis in the low-risk group, and conversely, surgery had a better prognosis in the high-risk group. But these were not significant. The high-risk CRT group had a significant worse prognosis than the low-risk CRT group.

In patients with noncurative ER for ESCC, surgery and CRT showed no difference in long-term outcomes. Indications for CRT in the high-risk group need further investigation because of poor prognosis.

Prophylactic chemoradiation therapy (CRT) using 40-41.4 Gy post-endoscopic submucosal dissection (ESD) for clinical T1N0M0 esophageal cancer reportedly yields favorable outcomes. However, it cannot completely prevent locoregional lymph node (LN) metastases. We retrospectively analyzed outcomes and adverse events associated with our dose-escalated treatment regimen (definitive-dose radiotherapy [RT] of 50-61.2 Gy, with/without chemotherapy) for these patients, and predictors of progression-free survival (PFS) and overall survival (OS).

Between 2006 and 2018, 44 consecutive patients (42 men and 2 women; median age, 70 years) who underwent definitive-dose RT post-ESD and had a pathological depth of the muscularis mucosa with lymphovascular invasion (LVI) or the upper-middle submucosal third at our institution were included. We excluded patients who could not obtain a margin-free resection by ESD. If feasible, systemic chemotherapy with 5-fluorouracil plus high- or low-dose cisplatin or nedaplatin was administered concurrently.

Five-year PFS, OS, and disease-specific survival rates were 78.8%, 88.4%, and 97.7%, respectively. Six metachronous esophagus (14%), two locoregional LN within the irradiated area with a prophylactic dose of 41.4 Gy (5%), and two locoregional LN plus liver (5%) recurrences occurred. No LN recurrence occurred within the definitive dose of ≥ 50 Gy in the irradiated area. Metachronous esophageal recurrence involved areas receiving ≥ 50 Gy. Univariate and multivariate analyses revealed that age was an independent prognostic factor for both PFS and OS.

Definitive-dose RT/CRT post-ESD could provide favorable locoregional LN control and PFS/OS regardless of patient characteristics, including pathological findings and chemotherapy regimen/course, except for age. These results need to be interpreted carefully given several limitations, therefore, definitive-dose RT/CRT should be conducted with caution in clinical practice until high-quality prospective clinical trials evaluating the effectiveness and safety.

Esophageal cancer is a highly aggressive disease, and acquired resistance to chemotherapy remains a significant hurdle in its treatment. mtDNA, crucial for cellular energy production, is prone to mutations at a higher rate than nuclear DNA. These mutations can accumulate and disrupt cellular function; however, mtDNA mutations induced by chemotherapy in esophageal cancer remain unexplored. We aimed to identify such mutations in esophageal cancer, pre- and post-chemotherapy, and explore the relationship between them and clinicopathological factors associated with chemotherapy resistance. We investigated mtDNA mutations in Human esophageal squamous cell carcinoma (ESCC) cancer cell lines (TE8 and TE11) and patient samples (27 pre- and post-chemotherapy, and 96 post-chemotherapy) using next-generation sequencing. Our analysis revealed a rise in mtDNA mutations following chemotherapy, particularly within the D-loop region. Moreover, mutations in a specific D-loop segment (hypervariable segment 1; HVS1) were associated with lower mtDNA copy number, poorer response to chemotherapy, and decreased five-year survival rates. These findings suggest that HVS1 mutations in mtDNA acquired after chemotherapy may contribute to treatment resistance and poorer clinical outcomes in patients with esophageal cancer. This study sheds light on the mechanisms of chemotherapy resistance and provides valuable insights for future research to overcome this challenge.

As the population ages, the number of elderly patients with superficial esophageal squamous cell carcinoma (ESCC) is increasing. We aimed to clarify the indications for endoscopic resection (ER) in late-elderly patients with ESCC in terms of life expectancy.

Patients aged ≥75 years who underwent ER for ESCC at our institution from January 2005 to December 2018 were enrolled. Clinical data, including the Eastern Cooperative Oncology Group performance status, American Society of Anesthesiologists physical status (ASA-PS), Charlson comorbidity index, and prognostic nutritional index (PNI), were collected at the time of ER. The main outcome measure was overall survival (OS).

Two hundred eight consecutive patients were enrolled. The patients' median age was 78 years (range, 75-89 years). The 5-year follow-up rate was 88.5% (median follow-up period, 6.6 years). The 5-year OS rate was 79.2% (95% confidence interval [CI], 72.2-84.8), and 5-year net survival standardized for age, sex, and calendar year was 1.04 (95% CI, 0.98-1.09). In the multivariate analysis, an ASA-PS of 3 (hazard ratio, 2.45; 95% CI, 1.16-5.17) and PNI of <44.0 (hazard ratio, 2.73; 95% CI, 1.38-5.40) were independent prognostic factors. When neither of these factors was met, the 5-year OS rate was 87.8% (95% CI, 80.0-92.9), and 5-year net survival was 1.08 (95% CI, 1.02-1.14).

ER for ESCC in late-elderly patients may improve life expectancy. ER is recommended in patients with a good ASA-PS and PNI.

In submucosal invasive adenocarcinoma of the esophagogastric junction (pT1b-SM AEG), the extent of tumor submucosal (SM) invasion is measured using the vertical depth of SM invasion with the muscularis mucosa. This study aimed to investigate whether tumor thickness and depth of invasion without accounting for muscularis mucosa were superior to the vertical depth of SM invasion as metastasis predictors. We enrolled patients with pT1b-SM AEG who underwent endoscopic resection or surgical resection (SR) at our institution between January 2011 and September 2019 and were followed up for ≥2 years. The relationship between metastasis and clinicopathological factors was examined. Metastasis was defined as pathologically confirmed lymph node metastasis in the surgical specimen or recurrence during follow-up. This study included 57 patients (44 men; median age, 72 years). Endoscopic resection and SR were performed in 16 and 41 patients, respectively. Nine patients were diagnosed with metastasis: five who underwent SR showed pathologically confirmed lymph node metastasis in the surgical specimens, and four experienced recurrences during a median follow-up of 48 months. Univariate analyses showed that tumor thickness was significantly associated with metastasis (P = 0.021), and the vertical depth of SM invasion (P = 0.48) and depth of invasion (P = 0.38) were not. Furthermore, in multivariate analysis, tumor thickness ≥2800 μm (odds ratio, 38.70; P = 0.013) was a significant predictor for metastasis. Tumor thickness may be a more convenient and useful predictor of metastasis in patients with pT1b-SM AEG than the vertical depth of SM invasion.

Identifying prognostic and molecular markers as therapeutic targets for esophageal squamous cell carcinoma (ESCC) could enhance the efficacy of multidisciplinary treatments. While tissue expression of sirtuin 1 (SIRT1) has been linked to tumor progression in ESCC, prognostic significance of serum SIRT1 levels and their correlation with tissue SIRT1 remains unexplored. This study aimed to investigate the correlation between serum and tissue SIRT1 levels in patients with ESCC.

A total of 38 patients diagnosed with ESCC who were untreated preoperatively were recruited for this study. SIRT1 expression in the surgical specimens was assessed through immunostaining, while serum SIRT1 levels were measured using an enzyme-linked immunosorbent assay. We analyzed the association between tissue and serum SIRT1 levels, clinicopathological features, and patient prognosis.

Positive SIRT1 expression in tissue was significantly associated with deeper tumor depth (p=0.020). It was also significantly associated with poorer overall survival (OS) and relapse-free survival (RFS) (p=0.041 and p=0.012, respectively). Elevated serum SIRT1 levels were significantly correlated with increased tumor depth and weight loss (p=0.012 and p=0.030). While higher serum SIRT1 levels tended to be associated with poorer OS (p=0.069), no significant correlation was found between SIRT1 expression in tissue and its concentration in serum.

SIRT1 tissue expression may be a valuable prognostic marker in ESCC. However, the clinical significance of serum SIRT1 levels appears to differ from that of its tissue expression. Future research is required to clarify the role of serum SIRT1 in ESCC.

Although esophageal cancers invading the muscularis mucosa (pT1a-MM) or submucosa (pT1b-SM) after endoscopic resection (ER) are associated with a risk of lymph node metastasis, details of metastatic recurrence after additional treatment remain unknown. We aimed to identify the risk factors for metastatic recurrence and recurrence patterns in patients receiving additional treatment after ER for esophageal cancer. Between 2006 and 2017, patients with pT1a-MM/pT1b-SM esophageal cancer who underwent ER with additional treatment (esophagectomy, chemoradiotherapy [CRT], and radiation therapy) at 21 institutions in Japan were enrolled. We evaluated the risk factors for metastatic recurrence after ER with additional treatment. Subsequently, the rate and pattern (locoregional or distant) of metastatic recurrence were investigated for each additional treatment. Of the 220 patients who received additional treatment, 57, 125, and 38 underwent esophagectomy, CRT, and radiation therapy, respectively. In the multivariate analysis, lymphatic invasion was the sole risk factor for metastatic recurrence after additional treatment (hazard ratio, 3.50; P = 0.029). Although the risk of metastatic recurrence with additional esophagectomy was similar to that with CRT (hazard ratio, 1.01; P = 0.986), the rate of locoregional recurrence tended to be higher with additional esophagectomy (80.0% (4/5) vs. 36.4% (4/11)), leading to a better prognosis in patients with metastatic recurrence after additional esophagectomy than CRT (survival rate, 80.0% (4/5) vs. 9.1% (1/11)). Patients with lymphatic invasion have a high risk of metastatic recurrence after ER with additional treatment for pT1a-MM/pT1b-SM esophageal cancer. Additional esophagectomy may result in a better prognosis after metastatic recurrence.

Esophageal squamous cell carcinoma (ESCC) is the most common histological type of esophageal cancer with a poor prognosis. Early diagnosis and prognosis assessment are crucial for improving the survival rate of ESCC patients. With the advancement of artificial intelligence (AI) technology and the proliferation of medical digital information, AI has demonstrated promising sensitivity and accuracy in assisting precise detection, treatment decision-making, and prognosis assessment of ESCC. It has become a unique opportunity to enhance comprehensive clinical management of ESCC in the era of precision oncology. This review examines how AI is applied to the diagnosis, treatment, and prognosis assessment of ESCC in the era of precision oncology, and analyzes the challenges and potential opportunities that AI faces in clinical translation. Through insights into future prospects, it is hoped that this review will contribute to the real-world application of AI in future clinical settings, ultimately alleviating the disease burden caused by ESCC.

This study evaluated the association between the risk factors and prognosis for metachronous esophageal squamous cell carcinoma (ESCC) after endoscopic resection (ER) of esophageal cancer in older patients.

We conducted a retrospective observational study of 127 patients with ESCC who underwent ER from 2015 to 2020. Patients were classified as non-older (≤ 64 years), early older (65-74 years), and late older (≥ 75 years). We analyzed factors associated with poor overall survival and metachronous ESCC after ER using multivariate Cox regression analysis. A metachronous ESCC prediction scoring system was examined to validate the surveillance endoscopy program.

Body mass index (BMI) and Charlson Comorbidity Index (CCI) were significant risk factors for poor overall survival in the multivariate analysis (p = 0.050 and p = 0.037, respectively). Multivariate analysis revealed that age of < 64 years, Lugol-voiding lesions (grade B/C), and head and neck cancer were significantly related to metachronous ESCC (p = 0.035, p = 0.035, and p = 0.014, respectively). In the development cohort, BMI < 18.5 kg/m2, CCI > 2, age < 64 years, Lugol-voiding lesions (grade B/C), and head and neck cancer were significantly related to metachronous ESCC, and each case was assigned 1 point. Patients were classified into low (0, 1, and 2) and high (> 3) score groups based on total scores. According to Kaplan-Meier curves, the 3-year overall survival was significantly lower in the high-score group than in the low-score group (91.5% vs. 100%, p = 0.012).

We proposed an endoscopic surveillance scoring system for metachronous ESCC considering BMI and CCI in older patients.

Proton-based, definitive chemoradiotherapy (P-CRT) for esophageal squamous cell carcinoma (ESCC) previously showed comparable survival outcomes with the surgery-based therapy, i.e., neoadjuvant chemotherapy followed by esophagectomy (NAC-S), in a single-institutional study. This study aimed to validate this message in a Japanese multicenter study.

Eleven Japanese esophageal cancer specialty hospitals have participated. A total of 518 cases with clinical Stage I-IVA ESCC between 2010 and 2019, including 168 P-CRT and 350 NAC-S patients, were enrolled and long-term outcomes were evaluated. Propensity-score weighting analyses with overlap weighting for confounding adjustment were used.

The 3-year overall survival (OS) of the P-CRT group was equivalent to the NAC-S group (74.8% vs. 72.7%, hazard ratio [HR]: 0.87, 95% confidence interval [CI]: 0.61-1.25). Although, the 3-year P-CRT group progression-free survival (PFS) was inferior to the NAC-S group (51.4% vs. 59.6%, HR 1.39, 95% CI 1.04-1.85), the progression P-CRT group cases showed better survival than the NAC-S group (HR 0.58, 95% CI 0.38-0.88), largely because of salvage surgery or endoscopic submucosal dissection for local progression. The survival advantage of P-CRT over NAC-S was more pronounced in the cT1-2 (HR 0.61, 95% CI 0.29-1.26) and cStage I-II (HR 0.50, 95% CI 0.24-1.07) subgroups, although this trend was not evident in other populations, such as cT3-4 and cStage III-IVA.

Proton-based CRT for ESCC showed equivalent OS to surgery-based therapy. Especially for patients with cT1-2 and cStage I-II disease, proton-based CRT has the potential to serve as a first-line treatment.

Radical surgery for esophageal cancer requires macroscopic and microscopic clearance of all malignant tissue. A critical element of the procedure is achieving a negative circumferential margin (CRM) to minimize local recurrence. The utility of minimally invasive surgery poses challenges in replicating techniques developed in open surgery, particularly for hiatal dissection in esophago-gastrectomy. In this study, the technical approach and clinical and oncological outcomes for open and laparoscopic esophago-gastrectomy are described with particular reference to CRM involvement.

This cohort study included all patients undergoing either open or laparoscopic esophago-gastrectomy between January 2004 and June 2022 in a single tertiary center. A standard surgical technique for hiatal dissection of the esophago-gastric junction developed in open surgery was adapted for a laparoscopic approach. Clinical parameters, length of stay (LOS), postoperative complications, and mortality data were collected and analyzed by a Mann-Whitney U or Fisher's exact method.

Overall 447 patients underwent an esophago-gastrectomy in the study with 219 open and 228 laparoscopic procedures. The CRM involvement was 18.8% in open surgery and 13.6% in laparoscopic surgery. The 90-day-mortality for open surgery was 4.1 compared with 2.2% for laparoscopic procedures. Median Intensive care unit (ITU), inpatient LOS and 30-day readmission rates were shorter for laparoscopic compared with open esophago-gastrectomy (ITU: 5 versus 8 days, P= 0.0004; LOS: 14 versus 20 days, P= 0.022; 30-day re-admission 7.46 versus 10.50%). Postoperative complication rates were comparable across both cohorts. The rates of starting adjuvant chemotherapy were 51.8 after open and 74.4% in laparoscopic esophago-gastrectomy.

This study presents a standardized surgical approach to hiatal dissection for esophageal cancer. The authors present equivalence between open and laparoscopic esophago-gastrectomy in clinical, oncological, and survival outcomes with similar rates of CRM involvement. The authors also observe a significantly shorter hospital length of stay with the minimally invasive approach.

Esophageal squamous cell carcinoma (ESCC) presents significant clinical and therapeutic challenges due to its aggressive nature and generally poor prognosis. We initiated a Phase II clinical trial (ChiCTR1900027160) to assess the efficacy of a pioneering neoadjuvant chemo-immunotherapy regimen comprising programmed death-1 (PD-1) blockade (Toripalimab), nanoparticle albumin-bound paclitaxel (nab-paclitaxel), and the oral fluoropyrimidine derivative S-1, in patients with locally advanced ESCC. This study uniquely integrates clinical outcomes with advanced spatial proteomic profiling using Imaging Mass Cytometry (IMC) to elucidate the dynamics within the tumor microenvironment (TME), focusing on the mechanistic interplay of resistance and response. Sixty patients participated, receiving the combination therapy prior to surgical resection. Our findings demonstrated a major pathological response (MPR) in 62% of patients and a pathological complete response (pCR) in 29%. The IMC analysis provided a detailed regional assessment, revealing that the spatial arrangement of immune cells, particularly CD8+ T cells and B cells within tertiary lymphoid structures (TLS), and S100A9+ inflammatory macrophages in fibrotic regions are predictive of therapeutic outcomes. Employing machine learning approaches, such as support vector machine (SVM) and random forest (RF) analysis, we identified critical spatial features linked to drug resistance and developed predictive models for drug response, achieving an area under the curve (AUC) of 97%. These insights underscore the vital role of integrating spatial proteomics into clinical trials to dissect TME dynamics thoroughly, paving the way for personalized and precise cancer treatment strategies in ESCC. This holistic approach not only enhances our understanding of the mechanistic basis behind drug resistance but also sets a robust foundation for optimizing therapeutic interventions in ESCC.

This editorial comments on an article by Qu et al published in the World Journal of Gastrointestinal Oncology. It focuses on the importance of early detection of esophageal cancer, including recurrence or secondary malignancy after chemoradiotherapy (CRT). Endoscopic resection is the first choice for treatment for esophageal cancer remaining within the mucous membrane, while surgery or radical CRT are treatment options for advanced stages depending on the patient's general condition and desire. Although these treatments are potentially curative, they are more invasive than endoscopic resection. Early-stage esophageal cancer is often asymptomatic and difficult to detect. Uniform periodic endoscopy is unrealistic. Although less burdensome tests exist, including liquid biopsy and urinary biomarkers, these have not yet been widely used in clinical practice. Early detection is important after radical CRT because the local recurrence rate is higher than that after surgery. However, endoscopic resection or photodynamic therapy is indicated if detected in the early stages, and positive results have been reported. Early detection of esophageal cancer is crucial. Endoscopy is the main diagnostic method; however, new and less burdensome methods should be established to ensure early treatment for patients with esophageal cancer.

The higher pathologic complete response (pCR) after neoadjuvant chemoradiotherapy compared with neoadjuvant chemotherapy for locally advanced esophageal squamous cell carcinoma (ESCC) has not translated into significant gains in overall survival. Data on the long-term survival of patients who obtained a pCR after neoadjuvant chemotherapy are scarce. Therefore, this study aimed to evaluate the long-term prognosis and recurrence patterns in these patients.

The study enrolled patients with locally advanced ESCC after neoadjuvant chemotherapy followed by surgery in the authors' hospital between January 2007 and December 2020. The factors predictive of pCR were analyzed. Furthermore, propensity score-matching was performed for those who did and those who did not have a pCR using 1:5 ratio for a long-term survival analysis. Finally, the survival and recurrence patterns of patients obtaining pCR after neoadjuvant chemotherapy were analyzed.

A pCR was achieved for 61 (8.70%) of the 701 patients in the study. Univariate analysis showed that the patients without alcohol drinking had a higher possibility of obtaining a pCR, although multivariate analysis failed to confirm the difference as significant. After propensity score-matching, the 5-year overall survival was 84.50% for the patients who had a pCR and 52.90% for those who did not (p < 0.001). Among the 61 patients with a pCR, 9 patients (14.80%) experienced recurrence, including 6 patients with locoregional recurrence and 3 patients with distant metastasis.

Advanced ESCC patients with pCR after neoadjuvant chemotherapy had a favorable prognosis, yet some still experienced recurrence, particularly locoregional recurrence. Therefore, for this group of patients, regular follow-up evaluation also is needed.

Dysphagia after esophagectomy is a serious complication; however, no method has been established to accurately assess swallowing function. We evaluated the association of swallowing function tests with patients' post-esophagectomy complications and nutritional statuses. We retrospectively reviewed the data of 95 patients with esophageal cancer who underwent esophagectomy between 2016 and 2021. We performed perioperative swallowing function tests, including the repetitive saliva swallowing test (RSST), maximum phonation time (MPT), and laryngeal elevation (LE). Patients with recurrent laryngeal nerve palsy (RLNP) and respiratory complications (RC) had significantly lower postoperative RSST scores than patients without them; the scores in patients with or without anastomotic leakage (AL) were similar. Postoperative MPT in patients with RLNP was shorter than that in patients without RLNP; however, it was similar to that in patients with or without AL and RC. LE was not associated with any complications. Patients with an RSST score ≤2 at 2 weeks post-esophagectomy had significant weight loss at 1, 6, and 12 months postoperatively compared with patients with an RSST score ≥3. The proportion of patients with severe weight loss (≥20% weight loss) within 1 year of esophagectomy was significantly greater in patients with RSST scores ≤2 than in those with RSST scores ≥3. Multivariate analysis showed that an RSST score ≤2 was the only predictor of severe post-esophagectomy weight loss. RSST scoring is a simple tool for evaluating post-esophagectomy swallowing function. A lower RSST score is associated with postoperative RLNP, RC, and poor nutritional status.

Ambiguity exists over treatment and surveillance strategies after endoscopic submucosal dissection (ESD) for esophageal squamous cell neoplasia (ESCN) with unfavorable histologic features. This study investigated the long-term outcomes of ESD in high-risk ESCN patients. We retrospectively included early ESCN patients treated with ESD at two medical centers in Taiwan between August 2010 and December 2023. Demographic, endoscopic and pathological data were collected. Among 146 patients (mean age 59.17 years) with 183 lesions, 73 (50%) had a history of head and neck cancer (HNC). En bloc and R0 resections were achieved in 100% and 95.6% of the lesions, respectively. The 5-year overall survival (OS), disease-specific survival (DSS) and local recurrence rates were 42.7%, 94.7% and 11%. R0 resections were significantly associated with recurrence in a univariate analysis (HR: 0.19, 95% CI: 0.06-0.66, p = 0.008). Alcohol abstinence was independently associated with lower recurrence (HR: 0.34, 95% CI: 0.16-0.73, p = 0.006). Patients with pT1a-MM (muscularis mucosa invasion) had comparable OS (p = 0.82), DSS (p = 0.617) and recurrence (p = 0.63) rates to those with pT1a-EP/LPM (epithelium/lamina propria invasion). The long-term outcomes of ESCN patients after ESD for expanded indications were satisfactory. ESD could be considered in selected ESCN patients involving the muscularis mucosa, notably among high-risk HNC patients.

N-acetyltransferase 10 (NAT10) is acknowledged as a tumor promoter in various cancers due to its role as a regulator of acetylation modification. Tumor-associated macrophages (TAMs) play a pivotal role in the tumor microenvironment (TME). However, the intercellular communication between esophageal squamous cell carcinoma (ESCC) cells and TAMs involving NAT10 remains poorly understood. This study aimed to elucidate the regulatory mechanism of NAT10 in modulating macrophage lipid metabolism and polarization. Experimental evidence was derived from in vitro and in vivo analyses. We explored the association between upregulated NAT10 in ESCC tissues, macrophage polarization, and the therapeutic efficacy of PD-1. Furthermore, we investigated the impact of methyltransferase 3 (METTL3)-induced m6A modification on the increased expression of NAT10 in ESCC cells. Additionally, we examined the role of exosomal NAT10 in stabilizing the expression of fatty acid synthase (FASN) and promoting macrophage M2 polarization through mediating the ac4C modification of FASN. Results indicated that NAT10, packaged by exosomes derived from ESCC cells, promotes macrophage M2 polarization by facilitating lipid metabolism. In vivo animal studies demonstrated that targeting NAT10 could enhance the therapeutic effect of PD-1 on ESCC by mediating macrophage reprogramming. Our findings offer novel insights into improving ESCC treatment through NAT10 targeting.

With one of the highest mortality rates of all malignancies, the 5-year survival rate for esophageal cancer is under 20%. Depending on the stage and extent of the disease, the current standard of care treatment paradigm includes chemotherapy or chemoradiotherapy followed by surgical esophagogastrectomy, with consideration for adjuvant immunotherapy for residual disease. This regimen has high morbidity, due to anatomic changes inherent in surgery, the acuity of surgical complications, and off-target effects of systemic chemotherapy and immunotherapy. We begin with a review of current treatments, then discuss new and emerging targets for therapies and advanced drug delivery systems. Recent and ongoing preclinical and early clinical studies are evaluating traditional tumor targets (e.g., human epidermal growth factor receptor 2), as well as promising new targets such as Yes-associated protein 1 or mammalian target of rapamycin to develop new treatments for this disease. Due the function and location of the esophagus, opportunities also exist to pair these treatments with a drug delivery strategy to increase tumor targeting, bioavailability, and intratumor concentrations, with the two most common delivery platforms being stents and nanoparticles. Finally, early results with antibody drug conjugates and chimeric antigenic receptor T cells show promise as upcoming therapies. This review discusses these innovations in therapeutics and drug delivery in the context of their successes and failures, with the goal of identifying those solutions that demonstrate the most promise to shift the paradigm in treating this deadly disease.

Dysphagia is a leading cause of aspiration pneumonia and negatively affects tolerance of chemoradiotherapy in patients with esophageal cancer.

This study aimed to assess a protocol for preventing the occurrence of aspiration pneumonia for adult patients with esophageal cancer experiencing swallowing dysfunction.

This study tested a dysphagia intervention that included high-risk patients confirmed by the Eating Assessment Tool questionnaire and Water Swallowing Test. A protocol guide (Interventions for Esophageal Dysphagia [IED]) to prevent aspiration pneumonia during chemoradiotherapy was also implemented. Thirty participants were randomly assigned to an intervention or control group. The study period was 50 days; participants were visited every 7 days for a total of 7 times. Instruments for data collection included The Eating Assessment Tool, Water Swallowing Test, and personal information. The IED was administered only to the experimental group. All data were managed using IBM SPSS statistics version 21.0.

The IED significantly reduced the occurrence of aspiration pneumonia ( P = .012), delayed the onset of aspiration pneumonia ( P = .005), and extended the survival time ( P = .007) in the experimental group.

For patients with esophageal cancer undergoing chemoradiotherapy, this protocol improved swallowing dysfunction and reduced aspiration pneumonia.

The IED protocol should be included in continuous educational training for clinical nurses to help them become familiar with these interventions and to provide these strategies to patients.

Postoperative pneumonia in patients with esophageal cancer occurs due to swallowing dysfunction and aspiration. Recently, maximum phonation time (MPT) assessment and repetitive saliva swallowing test (RSST) have been focused on as swallowing function assessment methods that can identify patients as high risk for pneumonia. We aimed to evaluate the clinical utility of MPT assessment and RSST in patients undergoing oncological esophagectomy.

In total, 47 consecutive patients who underwent esophagectomy for esophageal cancer between August 2020 and July 2023 were eligible. The perioperative changes in MPTs and RSST scores were examined. In addition, univariate and multivariate analyses were performed to identify the predictive factors of postoperative pneumonia.

The median MPTs before surgery and on postoperative days (PODs) 3, 6, and 10 were 18.4, 7.2, 10.6, and 12.4 s, respectively; postoperative MPTs were significantly lower than preoperative MPT. In addition, the MPT of POD 6 was significantly longer than that of POD 3 (P < 0.05). Meanwhile, there were no significant changes in perioperative RSST scores. Overall, 8 of 47 patients (17.0%) developed pneumonia postoperatively. A short MPT on POD 6 was one of the independent predictive factors for the incidence of postoperative pneumonia (odds ratio: 12.6, 95% confidence interval: 1.29-123, P = 0.03) in the multivariate analysis.

The MPT significantly decreased after esophagectomy. However, the RSST score did not. The MPT on POD6 can be a predictor of postoperative pneumonia.