The standard of care for locally advanced esophageal cancer includes perioperative chemotherapy or neo-adjuvant chemo-radiotherapy (CRT), followed by surgery. At our institution, a modified neo-adjuvant regimen combining elements from CROSS and CALGB 9781 trials was adopted. This study aimed to assess the impact of our modified regimen on oncological outcomes, toxicity profile and pathological complete response rates compared to the CROSS trial.

This observational study included patients with esophageal cancer who underwent neo-adjuvant CRT followed by tumor resection at a tertiary care university hospital between 2014 and 2018. The modified radiation therapy consisted of 28 fractions of 1.8 Gy (50.4 Gy in total) with weekly carboplatin/paclitaxel. We assessed mortality over time using the median survival time. The impact of pathological complete response and radiation intensity on mortality was assessed in multivariable Cox regression analysis, adjusting for clinically relevant variables, including sex, age, American Society of Anesthesiologists (ASA) physical status classification system score, tumor and nodal stage, and the histological tumor type.

A total of 46 patients were included. Median age was 67 years (IQR 9), 36 patients (78.3%) were male. An ASA score ≥ 3 was reported in 90.7% of the patients. Among the patients, 38 (82.6%) had a clinical tumor stage (cT) of ≥ 3, and 42 (91.3%) showed a positive endo-sonographic nodal stage (uN+). Pathological complete response was found in 7/42 patients (16.7%). Median survival time was 2.7 years (95% CI 1.340-4.084). In multivariable Cox regression analysis, pathological complete response was associated with significantly lower mortality over time (OR 0.152, 95%CI 0.049-0.989, p = 0.048). For larger radiation volumes, a trend towards increased mortality was shown, although not statistically significant (radiation volume/100: OR 1.172, 95%CI 0.987-1.392).

In patients with esophageal cancer undergoing trimodal therapy, the radiation dose escalation to 50.4 Gy was not associated with higher rates of pathological complete response or a survival benefit compared to the results of the CROSS trial. However, multivariable analysis revealed a trend toward increased mortality with larger radiation volumes. Based on these results, using modern radiotherapy techniques such as online adaptive radiotherapy might be more beneficial instead of escalating the radiation dose.

This study aims to examine the recurrence patterns in patients with locally advanced esophageal squamous cell carcinoma who underwent surgery following neoadjuvant chemotherapy combined with immunotherapy. Retrospective analysis of patients with esophageal squamous cell carcinoma who received neoadjuvant Chemo-IO before surgery at Zhejiang Cancer Hospital between 2019 and 2023. The clinicopathological features, recurrence patterns, overall survival (OS), and disease-free survival (DFS) were analyzed, and the impact of postoperative adjuvant radiotherapy on prognosis was evaluated. In total, 422 patients were included in the study. After a median follow-up of 22 months, disease recurrence was observed in 89 (21.1%) patients, comprising 37 cases (8.8%) of locoregional recurrence, 30 cases (7.1%) of distant metastasis, and 22 cases (5.2%) of combined recurrence. Patients who achieved a pathologic complete response demonstrated significantly higher 3-year OS rates (90.0% vs. 72.5%; P = 0.01) and DFS rates (73.2% vs. 61.8%; P = 0.046). Univariable and multivariable analyses identified pathological lymph node staging (ypN0 vs. ypN+; HR: 1.73; 95% CI: 1.01-2.99; P = 0.047) as an independent prognostic factor for locoregional recurrence. Kaplan-Meier curves for OS and DFS demonstrated that postoperative radiotherapy (PORT) significantly improved OS and DFS in ypN+ patients after propensity score matching. Additionally, PORT significantly enhanced locoregional recurrence-free survival and distant recurrence-free survival in ypN+ patients. In patients receiving neoadjuvant Chemo-IO, locoregional recurrence is the predominant recurrence pattern. For ypN+ patients, PORT significantly improved survival outcomes. However, long-term outcomes require further investigation through randomized controlled trials.

This study proposes a modified lymph node (LN) staging category (BALN) on the basis of the number of positive LNs before (prepN) and after (ypN) neoadjuvant chemoradiotherapy (nCRT) to improve prognostic stratification in esophageal squamous cell carcinoma (ESCC).

A total of 381 patients with ESCC who underwent nCRT at three medical centers were retrospectively enrolled. The ypN categories were scored according to the eighth edition of the American Joint Committee of Cancer (AJCC) staging manual. LNs with regression changes or vital tumor cells were used for interpretation of the prepN stage, reflecting the estimated number of originally involved LNs. BALN category was organized on the basis of the sum of the number of positive LNs in prepN and ypN categories.

BALN category revealed clearer survival classification and prognostic value of disease-free survival (DFS) in patients with ESCC (p < 0.0001). Multivariate cox proportional risk model identified BALN stage as a significant risk factor of DFS of patients with ESCC (p < 0.001). The results of 5-year time-area under the curve (AUC) demonstrated better predictive ability of the BALN category than the ypN category (AUC 0.755 versus 0.707, p = 0.004). The rypTNM system based on BALN category exhibited comparable survival discrimination and better predictive performance than ypTNM system (AUC 0.799 versus 0.756, p = 0.020).

The BALN stage and the revised ypTNM system showed preferable prognosis outcomes to the ypN stage and the ypTNM system, respectively. Evaluating LN status before and after nCRT could allow for more accurate esophageal cancer staging.

Soft tissue metastasis in esophageal cancer is a very rare entity. A 76-year-old man was referred for a week's history of dysphagia. Upper gastrointestinal endoscopy was performed, and biopsies were consistent with an adenocarcinoma of the lower esophagus. The patient was free of metastasis on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT). The patient was treated with pre-operative chemoradiation, followed by surgery. Intravenous carboplatin [area under the curve of 2 mg/mL/min (AUC2)] and intravenous paclitaxel 50 mg/m2 with concurrent radiotherapy (RT) (45 Gy delivered in 25 fractions of 1.8 Gy per fraction) were introduced from May 31st, 2021, to July 2nd, 2021. Lewis-Santy subtotal esophagectomy was performed, and pathology revealed a ypT3 ypN0 (0/26) L0 V1 Pn1 G3 R0. Adjuvant nivolumab was introduced for a total of 12 months. After five months of nivolumab, the patient complained of a painful left shoulder subcutaneous tumefaction in routine evaluation. Biopsy of the deltoid muscle demonstrated a poorly differentiated adenocarcinoma consistent with esophageal metastasis. Additional skeletal muscle (one) and bone metastases (two) were revealed on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT). After multidisciplinary team approach, palliative radiation therapy to all metastases, denosumab and FOLFOX were introduced. Despite initial excellent clinical outcomes, patient presented avascular necrosis of left femoral head managed by surgery but died after post-operative complications. To the best of our knowledge, it is the first reported case with rare soft-tissue metastasis occurring during adjuvant nivolumab in esophageal cancer.

Esophageal cancer is the seventh most common cause of cancer-related death worldwide [...].

Neoadjuvant chemoradiotherapy (NCRT) combined with surgery is the standard treatment option for patients with locally advanced esophageal squamous cell carcinoma (ESCC). However, whether adjuvant chemotherapy (AC) administered postoperatively has a survival benefit remains inconclusive.

To investigate whether AC is necessary after NCRT and esophagectomy and determine which patients might benefit from it.

A retrospective study.

This retrospective study examined patients with ESCC treated with NCRT followed by radical esophagectomy at three hospitals between March 2016 and December 2022. Patients were assigned into the adjuvant and non-adjuvant therapy groups based on whether they received postoperative AC, allowing the comparison of disease-free survival (DFS) and overall survival (OS) between the two groups. In addition, based on whether postoperative pathology indicated pathological complete response (pCR), patients were classified into the pCR and non-pCR populations, with DFS and OS separately analyzed for each subgroup.

Overall, 218 eligible patients were enrolled. No significant advantage was found in DFS (p = 0.540) and OS (p = 0.058) between the adjuvant and non-adjuvant therapy groups. In the non-pCR population, the adjuvant therapy groups had a significant advantage in DFS (p = 0.046) and OS (p = 0.011) compared to the non-adjuvant therapy group. However, in the pCR population, no significant advantage was found in DFS (p = 0.490) and OS (p = 0.110) analyses between the adjuvant and non-adjuvant therapy groups.

In the real world, patients with ESCC who underwent NCRT combined with radical esophagectomy and whose postoperative pathology was pCR did not benefit from AC. However, AC significantly improved DFS and OS in patients whose postoperative pathology did not reach pCR.

SOX2 overlapping transcript (SOX2-OT) is a long non-coding RNA located at chromosome 3q26.33 in humans. Convincing data confirm that SOX2-OT is evolutionarily conserved and plays a significant role in various malignant and non-malignant diseases. In most cancers, the upregulation of SOX2-OT acts as an oncogenic factor, strongly correlating with tumor risk, adverse clinicopathological features, and poor prognosis. Mechanistically, SOX2-OT is regulated by seven transcription factors and influences cellular behavior by modulating SOX2 expression, competitively binding 20 types of miRNAs, stabilizing protein expression, or promoting protein ubiquitination. It also participates in epigenetic modifications and activates multiple signaling pathways to regulate cancer cell proliferation, apoptosis, migration, invasion, autophagy, immune evasion, and resistance to chemotherapy/targeted therapies. Additionally, SOX2-OT triggers apoptosis, oxidative stress, and inflammatory responses, contributing to neurodevelopmental disorders, cardiovascular diseases, and diabetes-related conditions. Genetic polymorphisms of SOX2-OT have also been linked to breast cancer, gastric cancer, recurrent miscarriage, sepsis, and eating disorders in patients with bipolar disorder. This review provides an overview of recent research progress on SOX2-OT in human diseases, highlights its substantial potential as a prognostic and diagnostic biomarker, and explores its future clinical applications.

Currently, optimal treatment strategy for resectable primary small cell carcinoma of the esophagus (PSmCCE) remains controversial. To address this, we conducted a multicenter study to evaluate treatment patterns and long-term survival of PSmCCE patients who underwent radical resection.

This retrospective multicenter study included resected PSmCCE patients who received radical resection at seven high-volume cancer centers. Overall survival (OS) and median survival time (MST) were calculated by using a Kaplan-Meier method and the log-rank test was utilized to assess differences. Multivariable Cox analysis was performed to identify independent prognostic factors.

A total of 352 patients with resected PSmCCE were included. For PSmCCE with stage cT1-2N0M0, patients who received surgery plus adjuvant therapy showed better survival than those who received surgery alone (5-year OS rate: 32.8% vs. 19.2%, MST: 44.0 vs. 33.0 months, P = 0.035). Multivariable Cox survival analysis revealed an independent correlation between receiving surgery plus adjuvant therapy and improved OS (hazard ratio [HR] 0.529; 95% confidence interval [CI] 0.280-0.997; P = 0.049). For stage cT3N0M0/T1-3N1M0 PSmCCE, patients who received neoadjuvant therapy followed by surgery had superior long-term survival compared with those who received surgery combined with adjuvant therapy and those who received surgery alone (5-year OS rate: 27.2% vs. 9.5% vs. 0%, MST: 36.0 vs. 24.0 vs. 20.0 months, P = 0.014). Multivariable Cox survival analysis showed that neoadjuvant therapy was independently associated with improved OS (HR 0.384, 95% CI 0.203-0.728; HR 0.550, 95% CI 0.312-0.968; P = 0.013).

Adjuvant therapy was associated with improved survival in stage cT1-2N0M0 PSmCCE, but this should be confirmed in prospective studies. For stage cT3N0M0/T1-3N1M0 cases, neoadjuvant therapy followed by surgery should be considered.

The purpose of this study was to conduct a systematic review and meta-analysis to investigate the association between the utilization of metformin and the occurrence and survival rate of esophageal cancer (EC) in individuals with diabetes.

A systematic review and a meta-analysis were performed. Related literature was searched from databases, including PubMed, Embase, Web of Science, and Cochrane Library, covering the period from the inception of these databases until July 2023.

A total of 16 studies were eligible, including twelve reporting incidences of EC and four reporting OS of EC patients. The combined findings revealed a significant association between the use of metformin and a lower risk of EC (OR, 0.87, P = 0.04). Furthermore, metformin could significantly prolong the OS time (HR, 0.87, P = 0.002). In analyses stratified by treatment modalities, metformin combined with surgery and neoadjuvant chemoradiotherapy presented the strongest protective effect on EC patients with diabetes (HR, 0.38, P = 0.003).

Our meta-analysis indicated that the use of metformin might reduce the EC incidence and improve the OS in EC patients with diabetes.

Esophageal adenocarcinoma (EAC) is an aggressive cancer characterized by a high risk of relapse post-surgery. Current follow-up methods (serum carcinoembryonic antigen detection and PET-CT) lack sensitivity and reliability, necessitating a novel approach. Analyzing cell-free DNA (cfDNA) from blood plasma emerges as a promising avenue. This study aims to evaluate the cost-effective and genome-wide cell-free reduced representation bisulfite sequencing (cfRRBS) method combined with computational deconvolution for effective disease monitoring in EAC patients. cfDNA methylation profiling with cfRRBS was performed on 162 blood plasma samples from 33 EAC cancer patients and 28 blood plasma samples from 20 healthy donors. The estimated tumor fraction for EAC patients at the time of diagnosis was significantly different from the healthy donor plasma samples (one-sided Wilcoxon rank-sum test: p-value = 0.032). Tumor fractions above 15% and focal gains/amplifications in MYC (chr8), KRAS (chr12), EGFR (chr7) and NOTCH2 (chr1) were observed in four samples of distinct patients at the time metastatic disease was detected. This study showed feasibility to estimate tumor fractions in blood plasma of EAC patients based on cfDNA methylation using cfRRBS and computational deconvolution. Nevertheless, in this study only cancer patients with evidence of metastatic disease show high tumor fractions and copy number alterations.

Early detection of recurrent gastric and esophageal cancers remains a critical challenge. Innovative and non-invasive cancer screening technologies, such as N-NOSE, can improve early detection. N-NOSE is a urine-based scent test that leverages the olfactory abilities of the nematode C. elegans. For the first time, this prospective study evaluates the efficacy of the N-NOSE chemotaxis index as a novel biomarker for postoperative surveillance and recurrence in patients with upper gastrointestinal cancers.

A two-year prospective cohort study was conducted at The University of Tokyo Hospital, involving 40 patients with gastric and esophageal cancers. Urine samples were collected pre- and postoperatively and analysed using the N-NOSE technique.

In cases of recurrence with vascular invasion, the chemotaxis index at 100-fold urine dilution was significantly elevated compared to the non-recurrence group.

This study suggests the potential of N-NOSE as an effective follow-up tool for patients with upper gastrointestinal cancer, particularly those with vascular invasion. While N-NOSE has been validated to distinguish between cancer and non-cancer, and its performance compared to traditional markers has been proven, it has not been studied for recurrence. Our data highlights, for the first time, the capability of N-NOSE in the surveillance of cancer recurrence.

To evaluate the safety and efficacy of neoadjuvant immunotherapy in patients with esophageal squamous cell carcinoma (ESCC) and construct a prognostic model.

Clinical data were retrospectively collected from patients with locally advanced ESCC who received neoadjuvant immunotherapy and chemotherapy. The primary endpoints were major pathologic remission rate and disease-free survival, and secondary endpoints were treatment-related adverse events and perioperative complications. Correlates affecting pathological response were analyzed using univariate and multivariate logistic regression, survival-related variables were screened by Boruta and least absolute shrinkage and selection operator Cox regression analysis. A nomogram was constructed and utilized to test the predictive efficacy of the treatment with receiver operating characteristic curve and decision curve analysis.

A total of 181 patients were enrolled, of whom 119 (66 %) patients received 3-4 cycles of treatment. Treatment-related adverse events occurred in 65.2 % of the patients, with 13.3 % experiencing severe complications. Major pathological remission rate was achieved in 68 (37.6 %) patients, with no significant difference between the treatment cycle groups (P=0.925). The nomogram included pathologic TNM stage, lymphovascular invasion, post-treatment and post-surgery albumin levels, and post-treatment systemic immune-inflammation index. One-year disease-free survival area under the curve was 0.86 (95 %CI, 0.75-0.97) in the derivation cohort and 0.75 (95 %CI, 0.50-0.99) in the validation cohort, with good calibration performance.

Pathological staging combined with albumin level and systemic immune-inflammation index could be a superior predictor of survival prognosis in ESCC patients receiving neoadjuvant immunotherapy. The findings of this study yield new evidence regarding the efficacy and safety of neoadjuvant immunotherapy in ESCC and provide a tool for identifying patients at risk of recurrence.

Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is a standard treatment for locally advanced esophageal squamous cell carcinomas (ESCCs). However, the evolution of genome and immunogenome in ESCCs driven by NCRT remains incompletely elucidated. We performed whole-exome sequencing of 51 ESCC tumors collected before and after NCRT, 36 of which were subjected to transcriptome sequencing. Clonal analysis identified clonal extinction in 13 ESCC patients wherein all pre-NCRT clones disappeared after NCRT, and clonal persistence in 9 patients wherein clones endured following NCRT. The clone-persistent patients showed higher pre-NCRT genomic intratumoral heterogeneity and worse prognosis than the clone-extinct ones. In contrast to the clone-extinct patients, the clone-persistent patients demonstrated a high proportion of subclonal neoantigens within pre-treatment specimens. Transcriptome analysis revealed increased immune infiltrations and up-regulated immune-related pathways after NCRT, especially in the clone-extinct patients. The number of T cell receptor-neoantigen interactions was higher in the clone-extinct patients than in the clone-persistent ones. The decrease in T cell repertoire evenness positively correlated to the decreased number of clonal neoantigens after NCRT, especially in the clone-extinct patients. In conclusion, we identified two prognosis-related clonal dynamic modes driven by NCRT in ESCCs. This study extended our knowledge of the ESCC genome and immunogenome evolutions driven by NCRT.

After neoadjuvant therapy (NAT) and surgery, up to one third and one half of patients with esophagogastric adenocarcinoma with a pathologic complete response (pCR; tumor regression grade 0 [TRG-0]) and near-pCR (TRG-1) will recur, respectively. Our study aims to evaluate postoperative circulating tumor DNA (ctDNA) as a predictor of recurrence in patients with pCR or near-pCR after curative-intent neoadjuvant chemotherapy or neoadjuvant chemoradiation and surgery.

We retrospectively identified patients from 11 institutions with stages I-IV esophagogastric cancers (EGCs) who completed NAT and had TRG-0/1 scores at the time of curative-intent surgery. Postoperative plasma samples were collected for ctDNA analysis within a 16-week molecular residual disease (MRD) window after definitive surgery, and during surveillance from January 7, 2020, to November 9, 2023, at the provider's discretion. ctDNA was assessed using a clinically validated, personalized, tumor-informed ctDNA assay (Signatera, Natera, Inc). The primary outcome was recurrence-free survival (RFS).

We obtained 309 blood samples from 42 patients with esophagogastric adenocarcinoma with a pCR after neoadjuvant treatment over a median follow-up time of 28.5 months (range, 0.2-81.7). Detectable ctDNA in the 16-week MRD window (N = 23) correlated with higher rates of recurrence (67%; 2/3) compared with undetectable ctDNA (15%; 3/20). Detectable ctDNA within the MRD window was associated with a significantly shorter RFS (hazard ratio [HR], 6.2; P = .049). Among 32 patients who had ctDNA analyzed in the surveillance setting, the recurrence rate was 100% (5/5) in the ctDNA-positive cohort compared with 7.4% (2/27) in ctDNA-negative patients and was associated with shorter RFS (HR, 37.6; P < .001).

Within the subgroup of patients with EGC and favorable pathologic responses (TRG 0-1) after NAT, the presence of postoperative ctDNA identified patients with elevated recurrence risk.

Oesophageal cancer (EC), ranking 11th in incidence and 7th in mortality globally, presents a significant health challenge, with a notable prevalence in India, especially in the northeastern region. This article examines the efficacy of neoadjuvant chemoradiotherapy (NACRT) versus neoadjuvant chemotherapy (NACT) in treating locally advanced EC, analyzing data from randomized controlled trials (RCTs) between 2000 and 2024. NACRT, involving preoperative chemoradiotherapy followed by surgery, has shown improved survival rates, notably in the CROSS trial, which reported a 10-year overall survival benefit of 13%. Conversely, NACT is supported by key trials like the OE02 and MAGIC trials, demonstrating comparable survival outcomes. Key points of debate include compliance, complications, response and resection status, survival rates, and health-related quality of life (HRQOL). Compliance rates are similar for both modalities, though disease progression is more common after NACT. Postoperative complications and mortality rates are comparable, with NACTRT showing higher pathologic complete response (pCR) and R0 resection rates, potentially avoiding additional adjuvant radiation. While NACRT shows marginally better 3-year survival rates, particularly for squamous cell carcinoma, 5-year survival rates and HRQOL outcomes are similar for both treatments. NACTRT is associated with more respiratory symptoms, whereas NACT patients experience more gastrointestinal issues. Both NACT and NACTRT are viable options, with the choice depending on patient-specific factors and a thorough assessment of potential benefits and risks. Further research is needed to optimize treatment protocols for EC.

Neoadjuvant chemoimmunotherapy (nCIT) for locally advanced esophageal squamous cell cancer (ESCC) has shown short-term benefits, but long-term survival outcomes are unclear. This study compares nCIT and neoadjuvant chemotherapy (nCT) in resectable ESCC.

A retrospective analysis was conducted on ESCC patients who underwent nCT or nCIT followed by esophagectomy. Propensity score matching (PSM) with a caliper of 0.02 was employed to minimize bias. The primary endpoints included disease-free survival (DFS) and overall survival (OS).

A total of 131 comparable pairs of ESCC patients receiving nCT and nCIT were selected for the final analysis. The nCIT had higher rates of pathological complete response (pCR) and major pathological response (mPR) compared to nCT. Additionally, nCIT led to significant tumor down-staging, higher rates of R0 resection, and increased lymph node clearance during surgery. Patients who received nCIT exhibited improved disease-free survival (DFS) and overall survival (OS) at the 3-year follow-up. The incidence of distant and mixed relapses was lower in the nCIT group compared to the nCT group. However, the risk of locoregional relapse was comparable between the two groups. Subgroup analyses showed that the benefits of nCIT were generally observed across most patient subgroups. Interestingly, in patients without pCR or mPR, nCIT still demonstrated better survival benefits than nCT.

nCIT demonstrated superior pathological response rates and improved 3-year DFS and OS compared to nCT alone in locally advanced ESCC, but long-term survival validation is needed.

Esophageal carcinoma (ESCA) is a frequently detected gastrointestinal cancer. Copy number variants (CNVs) have a dramatic impact on the screening, diagnosis and prognostic prediction of cancers. However, the mechanism of action of CNVs on ESCA occurrence and progression remains unclear.

ESCA samples from The Cancer Genome Atlas (TCGA) were typed by consensus clustering using CNV-associated genes. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to section gene modules closely related to the two clusters, and sub-networks were constructed as hub genes. In addition, seven prognosis-correlated genes were further screened and retained by multivariate Cox regression analysis to develop a prognostic assessment model. The ssGSEA algorithm assessed energy metabolism levels in patients from different clusters and risk groups. Finally, quantitative real-time PCR (qRT-PCR) and live-dead cell staining verified the expression of genes associated with CNV risk scores.

ESCA was classified into two subtypes based on CNV values. Compared with cluster 1, cluster 2 had significantly higher level of immune score and tumor-associated immune cell infiltration as well as a noticeably better overall survival. The three modules most associated with the two clusters were identified by WGCNA, and a prognostic model with a strong prediction performance was constructed with their genes. Glycolysis, lactate metabolism, fatty acid synthesis, glutathione, methionine, and tryptophan metabolic pathway enrichment scores were remarkably higher in patients in cluster 1 and the high-risk group than in cluster 2 and the low-risk group. Knockdown PIK3C2A promoted ESCA cells apoptosis and inhibited cell vibiality.

The current research maybe provides new understanding for the pathogenesis of ESCA based on CNV, providing an effective guidance for its clinical diagnosis and prognostic evaluation.

This study aims to delineate the long-term outcomes and recurrence patterns of locally advanced thoracic esophageal squamous cell carcinoma (TESCC) patients managed with or without postoperative radiotherapy (PORT).

A retrospective cohort from two academic centers, encompassing patients who initially underwent esophagectomy and were pathologically staged T3-4, was analyzed. Survival outcomes were constructed using Kaplan-Meier method, with survival significance was evaluated using the log-rank test. Propensity score matching (PSM) was utilized to balance potential selection bias.

Among the 506 patients, 251 underwent surgery alone and 255 received radiotherapy following radical surgery. With a median follow-up of 49.1 months, PORT significantly improved 5-year overall survival (53.8% vs. 25.3%; p < 0.001) and 5-year disease-free survival rates (45.3% vs. 8.5%; p < 0.001) compared to surgery alone. These differences in survival outcomes persisted even after PSM (p < 0.001 for both). Treatment failure was significantly less frequent in the PORT group (46.7%) compared to the surgery-only group (90.0%; p < 0.001), with corresponding reductions in locoregional recurrence (9.4% vs. 54.1%; p < 0.001). This underscores the significant association between PORT and disease control.

The absence of neoadjuvant chemoradiotherapy highlights the importance of PORT in improving survival and reducing recurrence in advanced T3-4 TESCC patients. This study underscores the importance of PORT as a salvage treatment for locally advanced TESCC patients without neoadjuvant chemoradiotherapy.

The differences in tumor behavior between adenocarcinoma (AC) and squamous cell carcinoma (SCC) of the esophagogastric junction (EGJ) have yet to be well investigated. The purpose of this study was to gain insights that can contribute to tailored treatments and follow-up strategies by analyzing the correlation between histological subtypes and oncological outcomes.

A retrospective analysis was used to determine the characteristics of the histological subtypes of EGJ cancer by comparing the appearance of postoperative recurrence. A total of 102 consecutive patients with pathological stage IIA to IVA EGJ cancer, who underwent R0 surgery in our department from 2004 to 2020, were enrolled. The recurrence pattern, timing, survival, and potential prognostic factors were compared.

After a median follow-up time of 70.1 months, the AC group demonstrated comparable lymph node failure-free survival (P = 0.291) and significantly worse non-lymphogenous recurrence-free survival (P = 0.035) than did the SCC group. A significantly longer period from surgery to recurrence was also observed in the AC group (P = 0.029). Multivariate analysis indicated that histological subtype (P = 0.015, 95% CI 1.24-7.28) was significantly correlated with the incidence of non-lymphogenous recurrence.

The pattern and timing of postoperative recurrence were significantly different between the histological subtypes of EGJ cancer. Compared with EGJ SCC, EGJ AC may have a greater tendency toward non-lymphogenous progression and a greater propensity for longer surgery-to-recurrence periods.

This study aimed to establish a consensus on the delineation of target volumes for neoadjuvant radiation therapy (nRT) in esophageal squamous cell carcinoma (ESCC) within China.

From February 2020 to June 2021, nine ESCC patients who received nRT were retrospectively selected from Sun Yat-sen University Cancer Center and Shandong Cancer Hospital. A panel from eight cancer radiotherapy centers performed two rounds of nRT target volume delineation for these patients: the first round for cases 1-6 and the second for cases 7-9. Online meetings were held after each delineation round to discuss findings. The consistency of delineations across centers was compared using mean undirected Hausdorff distances (Hmean), dice similarity coefficients (DSC), and total volumes, analyzed with the Mann-Whitney U test.

The second round of delineations showed improved consistency across centers (total clinical target volume (CTVtotal): mean DSC = 0.76-0.81; mean Hmean = 2.11-3.14 cm) compared to the first round (CTVtotal: mean DSC = 0.63-0.64; mean Hmean = 5.66-7.34 cm; DSC and Hmean: P < 0.050 between rounds), leading to the formation of a consensus and an atlas for ESCC nRT target volume delineation. A proposal was reached through evaluating target volume delineations, analyzing questionnaire survey outcomes, and reviewing pertinent literature.

We have developed guidelines and an atlas for target volume delineation in nRT therapy for ESCC in China. These resources are designed to facilitate more consistent delineation of target volumes in both clinical practice and clinical trials.

Recent single-arm studies involving neoadjuvant camrelizumab, a PD-1 inhibitor, plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) have shown promising results. This multicenter, randomized, open-label phase 3 trial aimed to further assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy followed by adjuvant camrelizumab, compared to neoadjuvant chemotherapy alone. A total of 391 patients with resectable thoracic LA-ESCC (T1b-3N1-3M0 or T3N0M0) were stratified by clinical stage (I/II, III or IVA) and randomized in a 1:1:1 ratio to undergo two cycles of neoadjuvant therapy. Treatments included camrelizumab, albumin-bound paclitaxel and cisplatin (Cam+nab-TP group; n = 132); camrelizumab, paclitaxel and cisplatin (Cam+TP group; n = 130); and paclitaxel with cisplatin (TP group; n = 129), followed by surgical resection. Both the Cam+nab-TP and Cam+TP groups also received adjuvant camrelizumab. The dual primary endpoints were the rate of pathological complete response (pCR), as evaluated by a blind independent review committee, and event-free survival (EFS), as assessed by investigators. This study reports the final analysis of pCR rates. In the intention-to-treat population, the Cam+nab-TP and Cam+TP groups exhibited significantly higher pCR rates of 28.0% and 15.4%, respectively, compared to 4.7% in the TP group (Cam+nab-TP versus TP: difference 23.5%, 95% confidence interval (CI) 15.1-32.0, P < 0.0001; Cam+TP versus TP: difference 10.9%, 95% CI 3.7-18.1, P = 0.0034). The study met its primary endpoint of pCR; however, EFS is not yet mature. The incidence of grade ≥3 treatment-related adverse events during neoadjuvant treatment was 34.1% for the Cam+nab-TP group, 29.2% for the Cam+TP group and 28.8% for the TP group; the postoperative complication rates were 34.2%, 38.8% and 32.0%, respectively. Neoadjuvant camrelizumab plus chemotherapy demonstrated superior pCR rates compared to chemotherapy alone for LA-ESCC, with a tolerable safety profile. Chinese Clinical Trial Registry identifier: ChiCTR2000040034 .

Esophageal cancer is a therapeutic challenge in most healthcare systems. Most patients present with locally advanced disease at diagnosis. Concurrent chemoradiotherapy (CRT) is the standard treatment for locally advanced esophageal carcinoma. Since achieving a complete pathological response in postoperative specimens following neoadjuvant therapy is associated with improved patient survival, this study was designed to evaluate the pathologic response of localized or locally advanced esophageal carcinoma to induction chemotherapy followed by preoperative concurrent chemotherapy and hypofractionated radiotherapy (HFR).

This single-arm clinical trial (IRCT20210623051676N1) evaluated patients with squamous cell carcinoma or adenocarcinoma of the esophagus, stage cT2-T4a N0 M0 or cT1-T4a N+ M0. Patients received 3-5 cycles of weekly induction chemotherapy with the paclitaxel (50 mg/m2) and carboplatin (AUC=2) regimen, followed by weekly concurrent CRT with the same chemotherapy regimen. The radiation dose was 40 Gy, delivered over 16 fractions, 5 days per week (2.5 Gray/fraction). Patients underwent surgery 4-6 weeks after completion of CRT. The surgical specimens were evaluated for pathological response. A p-value of < 0.05 was considered significant in all analyses.

Out of 54 patients enrolled in this study, 45 completed the neoadjuvant protocol. Of these 45 patients, 32 underwent surgery and were finally analyzed. The mean age of the patients was 59.9 ± 8.6 years (range, 37-75 years). The location of the tumor was in the mid-thoracic esophagus in most patients (21, 65.6%) and the most common histological type was SCC (29, 90.6%). The median number of induction and concurrent chemotherapy cycles was 5 (4.8 ± 1.3 course, range, 1-10) and 3 (2.6 ± 0.8 course, range, 0-4), respectively. Among 45 patients who completed the neoadjuvant protocol, the most common toxicities were grade 3 neutropenia (15.6%), acute renal failure (4.4%), and odynophagia (37.8%). Nearly two-thirds of the patients experienced complete or near-complete responses (71.9%, 23 patients). Partial response was reported in 6 patients (18.8%) and poor response in 3 patients (9.4%).

Preoperative induction chemotherapy followed by HFR with concurrent chemotherapy has low toxicity and side effects, good tolerance, and significant efficacy in the treatment of patients with esophageal cancer.

https://irct.behdasht.gov.ir/trial/59930, identifier NCT05745545.

Emerging evidence has shown remarkable advances in the multimodal treatment of esophageal squamous-cell carcinoma. Despite these advances, the oncological outcomes for advanced esophageal cancer remain controversial due to the frequent observation of local recurrence in the regional or other lymph nodes and distant metastasis after curative treatment. For cases of locoregional recurrence in the cervical lymph nodes alone, salvage surgery with lymph node dissection generally provides a good prognosis. However, if recurrence occurs in multiple regions, the oncological efficacy of surgery may be limited. Radiotherapy/chemoradiotherapy can be employed for unresectable or recurrent cases, as well as for selected cases in neo- or adjuvant settings. Dose escalation and toxicity are potential issues with conventional three-dimensional conformal radiotherapy; however, more precise therapeutic efficacy can be obtained using technical modifications with improved targeting and conformality, or with the use of proton beam therapy. The introduction of immune checkpoint inhibitors, including pembrolizumab or nivolumab, in addition to chemotherapy, has been shown to improve the overall survival in unresectable, advanced/recurrent cases. For patients with lymph node recurrence in multiple regions, chemotherapy (5-fluorouracil [5-FU] plus cisplatin) and combination therapy with nivolumab and ipilimumab have shown comparable oncological efficacy. Further prospective studies are needed to improve the treatment outcomes in patients with esophageal cancer with locoregional recurrence.

Unbalances in the gut microbiota have been proposed as a possible cause of esophageal cancer (ESCA), yet the exact causal relationship remains unclear.

To investigate the potential causal relationship between the gut microbiota and ESCA with Mendelian randomization (MR) analysis.

Genome-wide association studies (GWASs) of 207 gut microbial taxa (5 phyla, 10 classes, 13 orders, 26 families, 48 genera, and 105 species) and 205 gut microbiota metabolic pathways conducted by the Dutch Microbiome Project (DMP) and a FinnGen cohort GWAS of esophageal cancer specified the summary statistics. To investigate the possibility of a mediation effect between the gut microbiota and ESCA, mediation MR analyses were performed for 1091 blood metabolites and 309 metabolite ratios.

MR analysis indicated that the relative abundance of 10 gut microbial taxa was associated with ESCA but all the 12 gut microbiota metabolic pathways with ESCA indicated no statistically significant association existing. Two blood metabolites and a metabolite ratio were discovered to be mediating factors in the pathway from gut microbiota to ESCA.

This research indicated the potential mediating effects of blood metabolites and offered genetic evidence in favor of a causal correlation between gut microbiota and ESCA.

Describe the accurate locations of lymph node recurrence (LNR) of Chinese patients with postoperative thoracic esophageal squamous cell carcinoma (ESCC) is essential for determining the need for further surveillance protocols and treatments. The authors aimed to evaluate the patterns of postoperative ESCC and its current risk stratification with LNR.

This population-based cohort study included a retrospective review of the medical records and image material of patients with ESCC who underwent LNR after radical surgery between January 2013 and September 2022, with a median follow-up time of 5.71 years. Clinical features were extracted from these records, and survival analysis was performed. The primary endpoint was the accurate location and range of LNR according to the nomenclature of the Japanese Society for Esophageal Diseases. The second endpoints was to explore the related factors of recurrence range and overall survival.

A total of 3268 lymph node regions were recurrence from 1129 patients, with a mean of 2.89 regions per patient. No.104, 106, and 107 was the most common recurrence of thoracic ESCC with an LNR rate higher than 15%. In upper thoracic ESCC, No.105 was a common recurrence site and abdominal LNR was rare. In lower thoracic ESCC, retroperitoneal lymph node was a unique regions (15.4%). Anastomotic recurrence is an important recurrence pattern in patients with postoperative esophageal cancer, with an incidence of 24.5%. Rates of LNR in range of lymph node dissection was low (13.9%). The median time of LRT was 20.0 (1.5-184.0) months. High range of recurrence was associated with significantly poorer OS in patients. Multiple linear regression analysis identified demonstrated N stage, tumor differentiation, adjuvant radiotherapy, and total lymph nodes removed were association with recurrence range for patients.

Supraclavicular and upper mediastinums lymph nodes were common recurrence site for ESCC patients, and careful initial staging and surveillance are needed. Thorough lymph node dissection may reduce the range of regional recurrence.

Radiation therapy is an effective treatment modality in the management of patients with esophageal cancer regardless of tumor location (proximal, middle, or distal esophagus) or histology (squamous cell vs adenocarcinoma). The addition of neoadjuvant CRT to surgery in patients who are surgical candidates has consistently shown a benefit in terms of locoregional recurrence, pathologic downstaging, and overall survival. For patients who are not surgical candidates, CRT has a role as definitive treatment.

Treatment options for recurrent esophageal cancer (EC) previously treated with radiation therapy (RT) are limited. Reirradiation (reRT) with proton beam therapy (PBT) can offer lower toxicities by limiting doses to surrounding tissues. In this study, we present the first multi-institutional series reporting on toxicities and outcomes after reRT for locoregionally recurrent EC with PBT.

Analysis of the prospective, multicenter, Proton Collaborative Group registry of patients with recurrent EC who had previously received photon-based RT and underwent PBT reRT was performed. Patient/tumor characteristics, treatment details, outcomes, and toxicities were collected. Local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Event time was determined from reRT start.

Between 2012 and 2020, 31 patients received reRT via uniform scanning/passive scattering (61.3%) or pencil beam scanning (38.7%) PBT at 7 institutions. Median prior RT, PBT reRT, and cumulative doses were 50.4 Gy (range, 37.5-110.4), 48.6 Gy (relative biological effectiveness) (25.2-72.1), and 99.9 Gy (79.1-182.5), respectively. Of these patients, 12.9% had 2 prior RT courses, and 67.7% received PBT with concurrent chemotherapy. Median follow-up was 7.2 months (0.9-64.7). Post-PBT, there were 16.7% locoregional only, 11.1% distant only, and 16.7% locoregional and distant recurrences. Six-month LC, DMFS, and OS were 80.5%, 83.4%, and 69.1%, respectively. One-year LC, DMFS, and OS were 67.1%, 83.4%, and 27%, respectively. Acute grade ≥3 toxicities occurred in 23% of patients, with 1 acute grade 5 toxicity secondary to esophageal hemorrhage, unclear if related to reRT or disease progression. No grade ≥3 late toxicities were reported.

In the largest report to date of PBT for reRT in patients with recurrent EC, we observed acceptable acute toxicities and encouraging rates of disease control. However, these findings are limited by the poor prognoses of these patients, who are at high risk of mortality. Further research is needed to better assess the long-term benefits and toxicities of PBT in this specific patient population.

Esophageal squamous cell carcinoma (ESCC) is an aggressive and fatal malignancy that leads to epithelial cancer. The association between epithelial cell heterogeneity, prognosis, and immune response in this cancer remains uncertain. This study aimed to investigate epithelial cell heterogeneity in ESCC and develop a predictive risk model using the identified cell types.

Single-cell RNA sequencing (scRNA-seq) and differential ESCC gene data were accessed from the Gene Expression Omnibus. Functional enrichment analysis, inferCNV, cell development trajectories, and intercellular communication were analyzed following epithelial cell characterization. Differentially expressed ESCC (n = 773) and epithelial cell marker genes (n = 3407) were intersected to obtain core genes, and epithelial cell-related prognostic genes were identified. LASSO regression analysis was used to construct a prognostic model. The external dataset GSE53624 was used to further validate the stability of the model. Drug sensitivity predictions, and immune cell infiltration were analyzed. Molecular docking clarified the possible therapeutic role of β-sitosterol in ESCC. Finally, wound healing assay, cell colony, and transwell assay were constructed to detect the effects of the core gene PDLIM2 on ESCC cell proliferation, invasion, and migration.

Eight cell clusters were identified, and epithelial cells were categorized into tumor and paratumor groups. The tumor group possessed more chromosomal variants than the paratumor group. Epithelial cells were associated with multiple cell types and significantly correlated with the Wnt, transforming growth factor, and epidermal growth factor signaling pathways. From 231 intersected genes, five core genes were screened for use in the risk model: CTSL, LAPTM4B, MYO10, NCF2, and PDLIM2. These genes may contribute to the cancerous transformation of normal esophageal epithelial cells and thereby act as biomarkers and potential therapeutic targets in patients with ESCC. β-Sitosterol furthermore displayed excellent docking potential with these genes. Meanwhile, further experiments demonstrated that the gene PDLIM2 plays a major role in the progression of oesophageal squamous carcinoma.

We successfully developed a risk model for the prognosis of ESCC based on epithelial cells that addresses the response of ESCC to immunotherapy and offers novel cancer treatment options.

About 40% of esophageal squamous cell carcinoma (ESCC) patients experienced recurrence after neoadjuvant chemoradiotherapy (nCRT) plus esophagectomy. While limited information was available on recurrence risk stratification in ESCC after neoadjuvant treatment. Our previous study showed ypN status was a reliable tool to differentiate and predict the prognosis in the recurrent population. Here, we evaluated recurrence timing and patterns in ESCC patients, taking into consideration lymph node status after nCRT.

A total of 309 ESCC patients treated with nCRT plus esophagectomy between 2018 and 2021 were enrolled in this observational cohort study. Lymph node status was recorded by the pathologist according to the surgical specimens. We retrospectively investigated the timing and patterns of recurrence and the prognoses in ESCC patients, taking into consideration lymph node status after nCRT.

After nCRT plus surgery in ESCC patients, lymph node metastasis was associated with unfavorable clinicopathological factors and high risks of recurrence. In the recurrent subgroup, ypN+ patients experienced earlier recurrence, especially for locoregional recurrence within the first year. Moreover, ypN+ patients had poorer prognosis. However, the recurrence patterns in the ypN- and ypN+ groups were similar. Besides, there were no significant differences in surgery to recurrence, recurrence to death, or overall survival among patients with locoregional or distant recurrence for overall patients and within ypN- or ypN+ groups.

Lymph node metastasis was correlated with unfavorable clinicopathological factors and high risks of recurrence. Despite a similar recurrence pattern in the recurrent subgroup between the ypN- and ypN+ groups, ypN+ patients exhibited earlier recurrence and a worse prognosis.

This study aims to report the 2-year outcomes of patients with clinical stage N2-3 esophageal squamous cell carcinoma who received neoadjuvant chemotherapy and immunotherapy followed by surgery from a phase 2 NICE trial.

Eligible patients with clinical stage N2-3 esophageal squamous cell carcinoma were screened and enrolled, then treated with regimen of nab-paclitaxel (100 mg/m2, days 1, 8, 15), carboplatin (area under the curve = 5, day 1), camrelizumab (200 mg, day 1) of two 21-day cycles and esophagectomy 4 to 6 weeks after the last chemotherapy. Oncologic outcomes, recurrence patterns, overall survival (OS), and recurrence-free survival (RFS) were explored.

From November 20, 2019, to December 22, 2020, 60 patients were recruited. After a median follow-up of 27.4 months, disease recurrence was observed in 19 (37.3%) patients, with 5 (9.8%) locoregional recurrence, 9 (17.6%) distant metastasis, and 5 (9.8%) combined recurrence. Lung was the most commonly involved metastatic site. The median time to recurrence was 10.8 months (interquartile range, 7.5-12.7 months). The 2-year OS and RFS rates were 78.1% and 67.9%, respectively. Patients who achieved major pathologic response (MPR) had a significantly greater 2-year OS rate (91.4% vs 47.7%; P < .001) and RFS rate (77.1% vs 45.9%; P = .003). On multivariable analysis, MPR was indicated as an independent prognostic factor for disease recurrence (hazard ratio, 0.39; 95% confidence interval, 0.21-0.82; P = .029).

In patients receiving neoadjuvant chemotherapy and immunotherapy, distant metastasis remains the predominant recurrence pattern. MPR is associated with lower recurrence and better survival. Long-term results derived from randomized controlled trials are further required.

ChiCTR1900026240.

Neoadjuvant chemoradiation therapy (NCRT) for cT1b esophageal cancer is not recommended despite the risk of pathologic upstaging with increased depth of penetration. We aimed to (1) define the rate of and factors associated with pathologic upstaging, (2) describe current trends in treatments, and (3) compare overall survival (OS) with and without NCRT for surgically resected cT1b lesions.

We used the 2020 National Cancer Database to identify patients with cT1b N0 esophageal cancer with or without pathologic upstaging who underwent removal of their tumor. We built multivariable logistic regression models to assess factors associated with pathologic upstaging. Survival was compared using log-rank analysis and modeled using multivariable Cox proportional hazards regressions.

Out of 1106 patients with cT1b esophageal cancer, 17.3% (N = 191) had pathologic upstaging. A higher tumor grade (P = 0.002), greater tumor size (P < 0.001), and presence of lympho-vascular invasion (P < 0.001) were associated with pathologic upstaging. 8.0% (N = 114) of patients were treated with NCRT. Five-y OS was 49.4% for patients who received NCRT compared to 67.2% for upfront esophagectomy (P < 0.05). Pathologic upstaging was associated with decreased OS (pathologic upstaging 43.7% versus no pathologic upstaging 67.7%) (hazard ratio 2.12 [95% confidence interval, 1.70-2.65; P < 0.001]). Compared to esophagectomy, endoscopic local tumor excision was associated with a decreased OS (hazard ratio 1.50 [95% confidence interval, 1.19-1.89; P = 0.001]).

Pathologic upstaging of cT1b lesions is associated with decreased OS. Esophagectomy is associated with a survival benefit over endoscopic local tumor excision for these lesions. NCRT is not associated with an increase in OS in cT1b lesions compared to upfront esophagectomy.

Choosing the appropriate treatment for elderly patients with esophageal cancer remains a contentious issue. While surgery is still a valid option, we aimed to identify predictors and outcomes in elderly esophagectomy patients with esophageal cancer.

We analyzed characteristics, surgical outcomes, survival rates, cause-specific mortality, and recurrence in 120 patients with stage I-IV esophageal cancer. Univariate and multivariate analyses were used to identify risk factors for event-free survival (EFS) and overall survival (OS).

The median follow-up period was 31 months, with 5-year overall survival (OS) and event-free survival (EFS) rates standing at 45.2% and 41.5%, respectively. Notably, lower body mass index (BMI ≤ 22 kg/m2) and reduced preoperative albumin levels (pre-ALB < 40 g/L) led to a significant decrease in OS rates. Postoperative pulmonary complications resulted in higher in-hospital and 90-day mortality rates. After about 31 months post-surgery, the rate of cancer-specific deaths stabilized. The most common sites for distant metastasis were the lungs, supraclavicular lymph nodes, liver, and bone. The study identified lower BMI, lower pre-ALB levels, and postoperative pulmonary complications as independent risk factors for poorer EFS and OS outcomes.

Esophagectomy remains a safe and feasible treatment for elderly patients, though the prevention of postoperative pulmonary infection is crucial. Factors such as lower BMI, lower pre-ALB levels, advanced tumor stage, postoperative pulmonary complications, and certain treatment modalities significantly influence the outcomes in elderly esophagectomy patients. These findings provide critical insights into the characteristics and outcomes of this patient population.