Targeting NBL1/PI3K/AKT axis to enhance the chemosensitivity and radiosensitivity of esophageal squamous cell carcinoma.

The deubiquitinase USP28 promotes esophageal squamous cell carcinoma proliferation by stabilizing ΔNp63 protein.

PRMT5-mediated arginine methylation of HSP90AA1 drives esophageal squamous cell carcinoma progression.

Radiotherapy (RT) is preferred over stent placement for dysphagia in unresectable esophageal squamous cell carcinoma (ESCC); however, low-radial-force self-expandable metallic stents (SEMS) may offer safer and more effective palliation. We aimed to compare the outcomes of RT and low-radial-force SEMS in ESCC patients. This retrospective study included patients with unresectable ESCC and dysphagia who underwent palliative RT or low-radial-force SEMS placement between 2013 and 2023. Adverse events were compared, and treatment efficacy was assessed based on changes in Dysphagia Score (DS) and the duration of maintaining DS ≤ 1 among those who achieved it. The stent and RT groups comprised 34 and 45 patients, respectively. Treatment-related adverse events of Grade ≥ 2 and ≥ 3 occurred in 29.4% and 5.8% in the stent group and 34.9% and 6.7% in the RT group, respectively, with no significant differences. After adjustment for baseline DS, the stent group showed significantly greater improvement at 1 month (p < 0.001), whereas no differences were observed at 2 or 3 months. DS ≤ 1 was achieved in 76.5% with stent and 44.4% with RT (p = 0.006). Maintenance of DS ≤ 1 was shorter with stent group when additional SEMS placement was considered an event (p = 0.006), whereas no difference was observed when additional SEMS was allowed (p = 0.898). Low-radial-force SEMS is safe and effective for dysphagia in unresectable advanced ESCC, especially when early oral intake is needed, and can help prolong oral intake if additional SEMS is allowed.

Photodynamic therapy (PDT) is a salvage endoscopic treatment option for local failure after chemoradiotherapy for esophageal squamous cell carcinoma (ESCC). PDT is usually performed using ordinary-sized conventional endoscopes (CEs); however, some patients with local failure have esophageal stenosis caused by chemoradiotherapy or endoscopic resection. In such cases, an ultra-thin endoscope (UTE) is sometimes used, but the efficacy and safety of PDT performed with UTEs (UTE-PDT) remain unclear. In this study, we compared the treatment outcomes of UTE-PDT with those of PDT using CEs (CE-PDT). This retrospective study analyzed patients who underwent talaporfin sodium-based PDT for histologically confirmed local ESCC failure between October 2015 and June 2022. Short-term outcomes, including the local complete response (L-CR) rate and adverse events, were compared between UTE-PDT and CE-PDT. In total, eight patients underwent UTE-PDT and 81 underwent CE-PDT. L-CR rates were 50.0% and 59.3% for the UTE-PDT and CE-PDT groups, respectively. The L-CR rates for lesions ≤ 20mm were 50.0% (4/8) and 63.4% (45/71) in the UTE-PDT and CE-PDT groups, and for cT1 lesions, they were 57.1% (4/7) and 63.2% (43/68), respectively. Adverse events included esophageal pain (12.5% and 39.5%) and esophageal stenosis (12.5% and 4.9%) in the UTE-PDT and CE-PDT groups, respectively; however, all were grade ≤ 2. UTE-PDT for local failure after chemoradiotherapy for ESCC showed short-term outcomes that did not differ substantially from those of CE-PDT and may represent a potential therapeutic option for patients with no alternative treatment options.

In the global phase 3 RATIONALE-306 study (NCT03783442), first-line tislelizumab plus chemotherapy showed significant overall survival (OS) benefit versus chemotherapy alone for unresectable locally advanced/metastatic esophageal squamous cell carcinoma (ESCC). We report post hoc results for the Japanese subgroup. Eligible Japanese patients were randomized (1:1) to tislelizumab 200mg or placebo every 3weeks plus chemotherapy (cisplatin plus fluoropyrimidine) and included in the Japanese analysis set. Endpoints included OS, progression-free survival (PFS), objective response rate (ORR), OS in patients with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥ 10%, and safety. Overall, 66/649 (10.2%) patients were randomized in Japan (n = 33 per arm). After a minimum follow-up of 37.9months (data cutoff November 24, 2023), tislelizumab plus chemotherapy showed improvements in median OS versus placebo plus chemotherapy (24.5 vs. 15.1months; hazard ratio [HR]: 0.75; 95% CI 0.43-1.30). An improvement in OS was also seen in patients with PD-L1 TAP score ≥ 10% (HR: 0.79; 95% CI 0.26-2.36). There was improvement in median PFS (HR: 0.77; 95% CI 0.45-1.32) and a higher ORR (63.6% vs. 45.5%) in the tislelizumab plus chemotherapy versus placebo plus chemotherapy arm, respectively. Treatment-related adverse events (TRAEs) with tislelizumab plus chemotherapy versus placebo plus chemotherapy occurred in, respectively, 45.5% versus 36.4% (any-grade) and 27.3% versus 6.1% (grade ≥ 3) of patients. No TRAE-related deaths occurred. After 3years, first-line tislelizumab plus chemotherapy demonstrated sustained efficacy and a tolerable safety profile in Japanese patients with unresectable locally advanced/metastatic ESCC, consistent with the global RATIONALE-306 population.

Posttranslational modification (PTM) is pivotal in cancer progression. However, the mechanisms, biological function, and clinical significance underlying PTM crosstalk are unclear. Here, we performed systematic analyses of 2-hydroxyisobutyrylation (Khib), phosphoproteomic, proteomic, and transcriptomic profiles from 60 esophageal squamous cell carcinoma (ESCC) samples, comprising matched normal, primary tumor, and metastatic lymph node tissues. The integrative analysis identified 4499 proteins co-modified by Khib and phosphorylation on distinct residues. Interestingly, while the two PTMs target distinct motifs across proteins, they engage common motifs within individual proteins. Functionally, Khib and phosphorylation show prevalent positive crosstalk linked to metastatic progression. Mechanistically, Khib mediates this intra-protein crosstalk by recruiting kinases and potentiating phosphorylation events. Machine learning-based artificial intelligence (AI) analysis of secreted proteins with PTM crosstalk revealed an independent and highly effective plasma signature predicting lymph node metastasis. Moreover, molecular subtyping stratified ESCC into three groups, with immunotherapy-resistant Subtype 3 associated with the worst survival. While combined treatment of integrin inhibitor cilengitide and immunotherapy exhibited targeted efficacy. By deciphering the mechanistic basis of Khib-phosphorylation crosstalk, identifying a novel plasma biomarker for lymph node metastasis, and providing a therapeutic strategy to sensitize tumors to immunotherapy, this work collectively advances the precision diagnosis and treatment of ESCC.

In Japan, endoscopic submucosal dissection (ESD) is the standard treatment for superficial esophageal squamous cell carcinoma (ESCC). Although clinical guidelines outline indications, additional treatment, and stricture prevention, real-world practice patterns remain insufficiently characterized. The present nationwide survey aimed to clarify the current endoscopic management of ESCC in Japan. A web-based, 20-item multiple-choice questionnaire was distributed to endoscopists performing upper gastrointestinal endoscopy at least weekly. Invitations were disseminated through the mailing lists of the Japan Esophageal Society and the individual mailing lists of core study members. The survey assessed diagnostic strategies, endoscopic treatment selection, indications for additional therapy after ESD, and approaches to stricture prevention. Altogether, 303 endoscopists who had performed endoscopic treatment for ESCC within the preceding year were enrolled. Most respondents reported using ESD exclusively. For clinical muscularis mucosa (MM) or shallow submucosa (SM1) lesions, treatment selection depended on circumferential extent, with ESD performed on 95.0% of patients with lesions involving < 1/2 of the circumference and ESD, chemoradiotherapy, and surgery conducted at similar frequencies for circumferential lesions. Decisions regarding additional treatment post-ESD for pathological MM or SM1 lesions were strongly influenced by lymphovascular invasion. Stricture prevention strategies varied according to the extent of mucosal defect, with steroid injection preferred for defects involving ≥ 1/2 but < 3/4 of the circumference and combined local steroid injection and oral steroids for circumferential defects. Although most practices align with guideline recommendations, substantial variability persists in areas lacking explicit guidance, highlighting the need for stronger evidence to support standardized clinical decision-making.

Fusobacterium nucleatum-induced mitophagy in macrophages supports intracellular bacterial persistence and promotes esophageal squamous cell carcinoma metastasis.

Arecoline, the primary alkaloid in areca nut, is a major risk factor for metastasis-associated progression in esophageal squamous cell carcinoma (ESCC). Epigallocatechin gallate (EGCG), a major polyphenol in green tea, has exhibited anti-cancer and anti-metastatic activity in multiple tumor models. However, the effects of EGCG on arecoline-induced metastatic behavior in ESCC have not been directly examined. In this study, we examined the effects of EGCG on arecoline-induced migration and invasion in human ESCC cells. Parental CE81T/VGH cells and a highly invasive subline, CE81T-M4, were treated with arecoline, EGCG, or their combination. Cell migration and invasion were assessed using the wound-healing and transwell assays, while changes in EGFR-related signaling and epithelial-mesenchymal transition (EMT)-associated markers were analyzed by western blotting and immunofluorescence. Arecoline increased ESCC cell motility and invasion and activated EGFR-dependent signaling, including AKT and P38 phosphorylation, accompanied by increased expression of EMT-associated markers. EGCG suppressed these effects in both parental and invasive ESCC cells. Genetic knockdown of AKT reduced P38 activation and VIMENTIN expression, supporting a role for AKT upstream of P38 in regulating EMT-related responses. The attenuation of arecoline-driven metastatic behavior in ESCC cells by EGCG is associated with alterations in EGFR-AKT-P38 signaling, supporting its potential role as a dietary or adjunctive agent in areca-associated esophageal cancer.

We evaluated whether preoperative 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) uptake in pathologically confirmed metastatic lymph node (MLN) stations stratifies prognosis in esophageal squamous cell carcinoma (ESCC). We retrospectively analyzed 134 patients who underwent FDG-PET/CT without neoadjuvant therapy. MLN stations were pathologically assessed from surgical specimens. Maximum standardized uptake value (SUVmax) >3.0 in MLN station was defined as PET-positive MLN (PP-MLN), while SUVmax ≤3.0 was defined as PET-negative MLN (PN-MLN). Recurrence-free survival (RFS) and disease specific survival (DSS) were compared between PP-MLN and PN-MLN groups. Sixty-six patients had MLNs and showed worse survival than those without MLNs (5-year RFS, 49.2% vs. 84.0%; p<0.001; 5-year DSS, 62.4% vs. 88.5%; p=0.001). Within the MLN-positive group, patients with PP-MLNs (n=21) had poorer survival than those with PN-MLNs (n=45): 5-year RFS, 21.1% vs. 61.1% (p<0.001); 5-year DSS, 28.5% vs. 77.3% (p=0.006). In multivariate analysis including preoperative cT and cN stages, PP-MLN remained independently associated with worse RFS (hazard ratio=2.27, p=0.03). FDG uptake in MLNs can stratify prognosis in ESCC. PP-MLN may serve as a practical prognostic imaging biomarker for risk stratification in node-positive ESCC.

This study aimed to investigate the spatiotemporal correlation between tumor metabolism and cancer-associated fibroblast activity using dual-tracer PET/CT, and to explore their potential association with pathologic response to neoadjuvant chemoradiotherapy (nCRT) in esophageal squamous cell carcinoma (ESCC). This retrospective analysis of a prospective trial (ChiCTR2100051599) included 48 patients with ESCC from February 2022 to August 2024. All patients underwent 68Ga-FAPI and 18F-FDG PET/CT before pre-nCRT (S1) and after nCRT (S2). Two primary metrics were used to quantify their spatial correlations by voxel-wise correlation analyses: the SUV Correlation Coefficient (SUV_R), reflecting static uptake concordance, and the Dose-Response Matrix Correlation Coefficient (DRM_R), reflecting concordance in treatment dose sensitivity. The conventional parameters derived from FAPI- and FDG- PET were also extracted: SUVmax, SUVmean, SUV_CV, SUVmaxratio, SUVmeanratio, DRMmax, DRMmedian, DRM_CV and the resistant tumor volume (V(DRM> 0.7)). The associations of these metrics with pathological tumor regression grade (TRG) were evaluated in an exploratory manner, except for DRM-related metrics. A strong voxel-wise correlation was observed between pre-nCRT FAPI and FDG uptake (S1 SUV_R = 0.80 ± 0.17), which was weaker after nCRT (S2 SUV_R = 0.51 ± 0.23). Two dose-response matrices showed a strong correlation (DRM_R = 0.82 ± 0.14). The bivariate Logistic model, integrating the post-treatment SUV_R and SUV_CV_FDG, significantly predicted pathological response (p = 0.007), achieving an optimization-corrected AUC of 0.78 (95%CI: 0.62-0.95). The pre-nCRT tumor voxel intensity and dose response constructed using either FDG or FAPI PET imaging exhibited a strong spatial correlation. In this exploratory analysis, the post-nCRT FAPI-FDG correlation coefficient was associated with pathologic response when combined with SUV_CV_FDG in a Logistic model.

The optimal extent of lymphadenectomy following neoadjuvant chemoimmunotherapy (nCIT) for esophageal squamous cell carcinoma (ESCC) remains unclear. Current recommendations are largely derived from neoadjuvant chemoradiotherapy cohorts, and their applicability in the era of immunotherapy is unclear. This study evaluated the association between lymph node dissection (LND) yield and disease-free survival (DFS) in patients with ESCC treated with nCIT. This retrospective multicenter cohort study included 465 patients with ESCC who underwent nCIT followed by radical esophagectomy at six hospitals in China between January 2019 and December 2023. The median follow-up was 40.7 months. The total number of dissected lymph nodes was analyzed in relation to DFS. The restricted mean survival time at 5 years was estimated by using random survival Forest-based models, with subgroup analyses by posttherapy pathological stage (ypT/ypN). A higher lymph node yield was associated with improved DFS, although the relationship was nonlinear and varied by pathological subgroup. In patients with ypT0-2N0 disease, DFS improved with increasing LND up to approximately 20-30 lymph nodes, after which the benefit plateaued. In patients with residual nodal disease (ypN1-3), higher lymph node yields were associated with longer DFS, with greater yields observed in more advanced disease stages. Across all subgroups, lower lymph node yields were consistently associated with inferior DFS. In this multicenter cohort of patients with ESCC treated with nCIT, lymph node yield was associated with DFS in a stage-dependent manner, suggesting its potential role as a postoperative quality indicator for surgical lymphadenectomy after nCIT.

To confirm the accurate pN0 status in patients with cT1-2N0 esophageal squamous cell carcinoma (ESCC) and recommend an optimal lymph node (LN) count for accurate nodal staging. A total of 1855 patients who underwent upfront surgery for cT1-2N0 ESCC at two tertiary academic hospitals in Korea between 1995 and 2019 were included. The probability of false-negative lymphadenectomy and the Nodal Staging Score (NSS) were calculated to assess adequate staging. The mean age was 63.4 ± 8.0years, with 93.1% male patients. The mean number of dissected LNs was 34.7 ± 14.0. The clinical T stages were cTis and cT1a 354 (19.1%), cT1b 1,053 (56.8%), and cT2 448 (24.2%). Pathological nodal upstaging occurred in 448 (24.2%) patients, with 337 (18.2%) pN1, 94 (5.1%) pN2, and 17 (0.9%) pN3. The analysis indicated that removing fewer than 33 LNs was associated with a 20% risk of missing metastatic nodes, whereas dissecting 53 nodes reduced this risk to 10%. Although overall survival improved with an increasing number of dissected LNs, the benefits plateaued beyond 33 LNs. The NSS, which indicates the likelihood that a patient with pN0 truly has no occult nodal disease, increased with the number of LNs dissected. We recommend extensive dissection of at least 33 LNs during esophagectomy for accurate staging and to minimize the risk of undetected positive LNs in early-stage ESCC.

Alcohol consumption is a common risk factor for esophageal squamous cell carcinoma (ESCC) and hepatic fibrosis. Mac-2 binding protein glycosylated isomer (M2BPGi), a sensitive marker of fibrosis, may predict postoperative skeletal muscle loss by reflecting the metabolic link between liver function and muscle maintenance. Eighty-nine patients with ESCC undergoing esophagectomy (June 2021-July 2024) with alcohol use and pretherapeutic M2BPGi levels were included; the cutoff was 0.66. Muscle mass was assessed by bioelectrical impedance analysis. The study population was stratified by M2BPGi levels into low (n = 59) and high (n = 30) groups. No significant differences were observed in sex, clinical stage, preoperative skeletal muscle mass, surgical approach, or intraoperative fluid balance. The high M2BPGi group showed lower preoperative albumin levels (4.2 vs. 4.0g/dL, p = 0.01) and higher CRP (0.1 vs. 0.4mg/dL, p < 0.01) and ICG R15 values (9.2% vs. 12.8%, p = 0.04). Although there was no difference in the incidence of complications, the decrease in skeletal muscle mass at 3months was significantly greater in the high M2BPGi group (- 7.6% vs. - 12.0%, p = 0.02). In the propensity score-matched cohort (low n = 40; high n = 20), the high M2BPGi group showed significantly greater muscle loss at 3months (- 7.5% vs. - 12.6%, p = 0.04) and a trend toward longer hospital stays (22 vs. 25.5days, p = 0.06). High pretherapeutic M2BPGi levels are independently associated with postoperative skeletal muscle loss at 3months.

The indication of feeding-stoma creation (gastrostomy/jejunostomy) in esophageal squamous cell carcinoma (ESCC) patients and its impact on survival remain unclear. We aimed to identify patient subgroups who benefit from feeding-stoma placement before concurrent chemoradiation therapy (CCRT). We did a secondary analysis of prospective cohort. A total of 260 patients with advanced ESCC who underwent CCRT between April 2008 and March 2024 were included. Tumor-occupying proportion (tumor area/total lumen area) and other tumor characteristics were measured from standardized endoscopic images. Characteristics that predict post-CCRT cachexia was identified and validated as indications of feeding-stoma creation. Post-CCRT cachexia developed in 60.7% of patients. Independent predictors of cachexia included longer tumor length and bigger tumor-occupying proportion. ROC curve found tumor length ≥ 6cm (area under ROC (AUC): 0.760, P < 0.001) and tumor-occupying proportion ≥ 70% are optimal to predict post-CCRT cachexia (AUC: 0.620, P = 0.001). Sixty-two patients (23.8%) underwent pretreatment feeding-stoma creation. In the overall cohort, feeding-stoma creation was not associated with a longer progression-free survival (PFS) or overall survival (OS). In patients with tumor-occupying proportion ≥ 70%, feeding-stoma creation was associated with reduced cachexia incidence, better treatment response (OR: 2.78, P = 0.028), longer median PFS (6 vs. 4 months, P = 0.012) and OS (11 vs. 9 months, P = 0.009). In contrast, feeding-stoma creation was not associated with an improved treatment response or survival in patients with tumor-occupying proportion < 70% or in patients with different tumor length. Tumor-occupying proportion is a novel metric that predicts cachexia and survival in advanced ESCC. Pretreatment feeding-stoma creation was associated with a better treatment response and longer survival only in patients with tumor-occupying proportion ≥ 70%, supporting its use as a selection criterion for this invasive procedure.

Refining Nodal Staging in Esophageal Squamous Cell Carcinoma with CT-based Extranodal Extension.

Chemoradiotherapy has proven effective in enabling conversion surgery (CS). However, the priority of immunochemotherapy compared with chemoradiotherapy as induction therapy for initially unresectable cT4 esophageal squamous cell carcinoma (ESCC) remains unclear. We aimed to compare the survival outcomes of CS following induction immunochemotherapy (iICT) versus induction chemoradiotherapy (iCRT) in these patients. This multi-institutional retrospective cohort study included initially unresectable cT4 ESCC patients who underwent CS after iICT or iCRT between 2019 and 2022. Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method and the log-rank-test. Univariable and multivariable analyses for prognostic factors were performed. In total, 118 patients were included: 43 in the iICT group and 75 in the iCRT group. There were no significant differences between the two groups in terms of pathological complete response rates (P = 0.637) or R0 resection rates (P = 0.885). The iICT group had a lower rate of postoperative overall recurrence (P = 0.005) and distant metastasis (P = 0.015) than the iCRT group. The OS (1-year: 90.4% vs. 76.0%; 3-year: 77.3% vs. 54.9%, P = 0.027) and DFS (1-year: 85.4% vs. 58.7%; 3-year: 73.1% vs. 39.0%, P = 0.001) rates were significantly higher in the iICT group than in the iCRT group. Multivariable Cox analysis demonstrated that the iICT regimen was independently associated with improved OS and DFS. iICT combined with CS was a safe and manageable treatment option and was associated with improved OS and DFS in patients with initially unresectable cT4 ESCC.

SPI1 mediates CST2 transcription to promote the proliferation, metastasis, and angiogenesis of esophageal cancer.

Advanced esophageal squamous cell carcinoma (ESCC) may require combined resection or result in non-curative resection, increasing the risk of severe complications related to the posterior mediastinal dead space created after esophagectomy, such as airway instability and mediastinitis. Although filling this space with the greater omentum via the posterior mediastinal route is commonly used, this approach may impair gastric conduit alignment and function due to intrathoracic negative pressure. We developed a novel technique to overcome these limitations. We retrospectively reviewed 20 patients who underwent esophagectomy with gastric conduit reconstruction and additional omental transposition using a novel "waterfall" method between 2012 and 2022. Omental transposition was selectively added in cases involving combined resection of adjacent organs or non-curative resection, in which the posterior mediastinal dead space was considered to increase postoperative complication risk. In this technique, the greater omentum is elevated to the neck with the gastric conduit via the retrosternal route and then pulled down from the anterior mediastinum to fill the posterior mediastinal dead space. Surgical outcomes, postoperative complications, and conduit-related symptoms were evaluated. Sixteen patients had cT4b disease and four had cT3 disease. Curative resection was achieved in 12 patients, while 8 underwent non-curative resection. No serious complications such as airway necrosis, airway-mediastinal fistula, or mediastinitis were observed, and no patients developed gastric conduit dysfunction. The waterfall method is a safe and feasible technique for filling the posterior mediastinal dead space after esophagectomy while preserving gastric conduit alignment and function in high-risk ESCC cases.