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Background The standard treatment for elderly patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is definitive chemoradiotherapy with S-1. However, the 3-year overall survival (OS) is limited to approximately 40%. Tislelizumab is the first- and second-line standard treatment for advanced ESCC with tolerable toxicity. In this study, we aimed to explore a new curative strategy for locally advanced unresectable ESCC in the elderly by combining tislelizumab with chemoradiotherapy. Methods This study is an open-label, multicenter, investigator-initiated phase II clinical trial in older patients with inoperable locally advanced ESCC evaluating tislelizumab plus concurrent chemoradiotherapy compared with concurrent chemoradiotherapy. The main inclusion criteria were pathological confirmation of locally advanced inoperable ESCC at clinical cT1N2-3M0 or cT2-4bN0-3M0 (stage II–IVA), age ≥ 70 years, absence of previous systemic anti-tumor therapy, and adequate organ function. A total of 136 patients will be recruited from approximately seven centers (in Tianjin, Chengdu, Taiyuan, Zhengzhou, Shijiazhuang, Changsha, Nanjing) over a period of 18 months and randomized in a 1:1 ratio to receive tislelizumab in combination with concurrent chemoradiotherapy (tislelizumab + S-1 + radiotherapy) or concurrent chemoradiotherapy (S-1 + radiotherapy). The efficacy and safety of the treatment will be evaluated during the therapy and follow-up period until disease progression, death, or the end of the trial. The primary study endpoint was investigator-assessed progression-free survival (PFS), and secondary study endpoints were OS, objective response rate (ORR), duration of remission (DOR), and safety. Fresh or archival tumor tissues and peripheral blood samples will be used in exploratory studies. Discussion This study is the first “programmed death-1 (PD-1) inhibitor combined with concurrent chemoradiotherapy” for elderly patients with inoperable locally advanced ESCC (NCT06061146). The synergistic efficacy of combined definitive concurrent chemoradiotherapy with tislelizumab is expected to result in survival benefits for elderly patients with inoperable locally advanced ESCC. Because S-1 plus concurrent radiotherapy is the standard treatment option for locally advanced ESCC in older patients, the combination of definitive concurrent chemoradiotherapy and tislelizumab has the potential to change the standard ESCC therapeutic strategy with comparable safety. Trial registration ClinicalTrials.gov NCT06061146.Registered 9/10/2023.

The spatial distribution of tumor-infiltrating T cells and its dynamics during chemoradiotherapy combined with PD-1 blockade is little known in esophageal squamous cell carcinoma (ESCC). We applied the multiplex immunofluorescence method to identify T cells (CD4 , CD8 T cells, and their PD-1 or PD-1 subsets) and myeloid-derived cells (CD11c dendritic cells, CD68 macrophages, and their PD-L1 subpopulations) in paired tumor biopsies ( = 36) collected at baseline and during combination (40 Gy of radiation) from a phase Ib trial (NCT03671265) of ESCC patients treated with first-line chemoradiotherapy plus anti-PD-1 antibody camrelizumab. We used the FoundationOne CDx assay to evaluate tumor mutational burden (TMB) in baseline tumor biopsies ( = 14). We dynamically assessed the nearest distance and proximity of T-cell subsets to tumor cells under combination and estimated the association between T-cell spatial distribution and combination outcome, myeloid-derived subsets, TMB, and patient baseline characteristics. We found that the tumor compartment had lower T-cell subsets than the stromal compartment but maintained a comparable level under combination. Both before and under combination, PD-1 T cells were located closer than PD-1 T cells to tumor cells; T cells, dendritic cells, and macrophages showed the highest accumulation in the 5-10-μm distance. Higher CD4 T cells in the tumor compartment and a shorter nearest distance of T-cell subsets at baseline predicted poor OS. Higher baseline CD4 T cells, dendritic cells, and macrophages were associated with worse OS in less than 10-μm distance to tumor cells, but related with better OS in the farther distance. Higher on-treatment PD-1-positive-expressed CD4 and CD8 T cells within the 100-μm distance to tumor cells predicted longer OS. T cells, dendritic cells, and macrophages showed a positive spatial correlation. Both high TMB and smoking history were associated with a closer location of T cells to tumor cells at baseline. We firstly illustrated the T-cell spatial distribution in ESCC. Combining chemoradiotherapy with PD-1 blockade could improve the antitumor immune microenvironment, which benefits the treatment outcome. Further understanding the precision spatiality of tumor-infiltrating T cells would provide new evidence for the tumor immune microenvironment and for the combination treatment with immunotherapy.

Objective This study evaluated the 8th edition American Joint Committee on Cancer (AJCC) staging system for esophageal squamous cell carcinoma (ESCC) and developed an improved staging framework using automated recursive partitioning analysis (autoRPA). Methods This retrospective study included 2773 ESCC patients treated with definitive intensity-modulated radiation therapy (IMRT) or chemo-IMRT across 8 Chinese centers (2001–2019). Kaplan‒Meier curves and log-rank tests were used to assess overall survival (OS). AutoRPA-derived stage groupings were optimized via the revised T/N criteria. The proposed staging was compared with the 8th edition AJCC staging via hazard discrimination, consistency, sample balance, and predictive accuracy. Results The 3-year, and 5-year rates for the entire cohort were 43.5%, and 34.0%, respectively. The AJCC T4a/T4b stages exhibited overlapping OS curves, prompting their consolidation into a single T4 stage. While the AJCC N2 and N3 stages showed overlapping OS curves, supraclavicular lymph node (SLN) metastasis independently predicted worse OS than N2, with outcomes similar to those of N3. Location-based SLN classification further refined nodal staging, with cervical esophageal-SLN metastasis classified as N1, upper thoracic-SLN metastasis as N2, and middle or lower thoracic-SLN metastasis as N3, yielding distinct OS stratification. The autoRPA-derived staging outperformed the 8th edition AJCC staging in hazard consistency, sample balance, and predictive accuracy, with RPA-I exhibiting distinctly sharper OS curves than other stages. Conclusion Combining T4a/T4b and SLN subclassification enhanced prognostic precision in ESCC, with the autoRPA staging demonstrating superior hazard consistency, sample balance, and predictive accuracy compared to the 8th edition AJCC staging, thereby guiding therapeutic strategies.