This secondary analysis of a randomized clinical trial reports the long-term survival rates and cancer- and noncancer-related causes of death associated with concurrent chemoradiotherapy with S-1 in older patients in China. QuestionIs concurrent chemoradiotherapy (CCRT) with S-1 associated with differences in survival compared with radiotherapy alone in older patients with esophageal cancer (EC)?FindingsIn this secondary analysis of a randomized clinical trial involving 298 patients with EC, the first prospective long-term data (median follow-up of 87 months) on treatment outcomes were reported. Patients in the CCRT with S-1 group showed significantly better overall survival than those in the RT-alone group, and long-term follow-up revealed no increase in noncancer-related mortality among patients receiving CCRT with S-1.MeaningThese results support CCRT with S-1 as an effective and tolerable treatment option for older patients with EC, addressing the critical evidence gap for this underrepresented population. ImportanceMost older patients with esophageal cancer (EC) are unable to complete standard platinum-based concurrent chemoradiotherapy (CCRT) due to reduced organ reserve, comorbidities, and malnutrition. A new treatment option-CCRT with S-1-has been found to have high efficacy and fewer toxic effects for this population, yet long-term data supporting its use remain limited.ObjectiveTo evaluate the long-term outcomes of CCRT with S-1 vs radiotherapy (RT) alone in older patients with EC.Design, Setting, and ParticipantsThis secondary analysis of a phase 3 randomized clinical trial conducted at 23 centers in China was not prespecified in the trial protocol. Patients aged 70 to 85 years with histologically confirmed EC were enrolled between June 1, 2016, and August 31, 2018. Data cutoff date was February 1, 2025, with an additional follow-up of 54 months beyond the primary analysis. Data were analyzed from February 1 to April 1, 2025.InterventionsPatients were randomly assigned 1:1 to receive CCRT with S-1 consisting of 54 Gy in 30 fractions with S-1, 70 mg/m2 per day on days 1 to 14 and 29 to 42, or RT alone consisting of 60 Gy in 30 fractions, 2.0 Gy per day 5 days per week.Main Outcomes and MeasuresThe primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), cause-specific mortality, cumulative incidence of death from EC or other reasons, and cumulative incidences of locoregional or distant metastasis during treatment or relapse after treatment.ResultsA total of 298 patients (median [IQR] age, 77 [74-79] years; 180 males [60.4%]) were enrolled. There were 151 patients (50.7%) clinically diagnosed with stage III to IV disease. With a median (IQR) follow-up of 87 (85-92) months, the median OS was 24.7 (95% CI, 21.2-37.6) months in the CCRT group and 15.1 (95% CI, 12.4-18.6) months in the RT group (hazard ratio [HR], 0.69; 95% CI, 0.53-0.90; P = .005). The 5-year OS rates were 33.5% (95% CI, 26.7%-42.1%) and 24.4% (95% CI, 18.3%-32.4%) for the CCRT and RT groups, respectively; the 8-year OS rates were 26.2% and 16.1%, respectively. The median PFS was 18.7 (95% CI, 13.1-25.8) months in the CCRT group and 9.2 (95% CI, 7.9-12.7) months in the RT group (HR, 0.69; 95% CI, 0.54-0.90; P = .005). Cause-specific analyses showed reduced EC-related mortality with CCRT (HR, 0.67; 95% CI, 0.50-0.89; P = .005), with 8-year absolute risks of 58.5% vs 72.9%, respectively, and no excess noncancer-related mortality.Conclusions and RelevanceIn this secondary analysis of a randomized clinical trial, long-term results showed that CCRT with S-1 was associated with a sustained survival benefit compared with RT alone, without increased noncancer-related mortality. This finding supports CCRT with S-1 as the preferred regimen for patients aged 70 to 85 years with EC.Trial RegistrationClinicalTrials.gov Identifier: NCT02813967
Despite promising data showing that circulating tumour DNA (ctDNA) dynamics during treatment can inform real-time tumour response and recurrence risk1, how best to translate these insights into actionable clinical decision-making remains unclear. Here we report results from the EP-STAR trial-a multi-centre, ctDNA-driven, risk-adapted, non-randomized phase II study ( NCT04072107 ; ClinicalTrials.gov) testing whether a risk-adaptive treatment (RAT) strategy guided by on-treatment ctDNA dynamics can meaningfully improve survival, using nasopharyngeal carcinoma as a model. Eligible patients were enrolled and began treatment with standard-of-care gemcitabine-cisplatin neoadjuvant chemotherapy (GP-NAC; the P in this abbreviation stands for platinum)2, followed by RAT or standard-of-care chemoradiotherapy guided by ctDNA clearance trajectory during GP-NAC. Protocol-eligible patients who did not receive RAT, drawn from a prospectively registered ctDNA biomarker cohort ( NCT03855020 )3, served as a non-randomized, contemporaneous no-RAT external cohort. The primary end-point was failure-free survival (FFS) in the RAT group. After a median follow-up of 47.3 months, the 3-year FFS was 89.1% (83.2-95.0%) in the RAT group (n = 110). Patients who received RAT showed significantly improved FFS (P = 0.003, log-rank test) compared with the no-RAT external cohort (hazard ratio = 0.41 [0.23-0.75]; P = 0.004, Cox regression model). The RAT strategy was well-tolerated with no treatment-related deaths. Collectively, these data show that a ctDNA-driven RAT paradigm could be a promising strategy to improve survival, challenging the conventional fixed-course, static treatment approach.
Primary breast cancer (PBC) with axillary lymph node metastasis (ALNM+) is associated with distinct clinical outcomes, including reduced survival (The Cancer Genome Atlas/Foshan cohorts, P < 0.05) and an attenuated response to anti-programmed cell death protein 1 antibody/anti-programmed death-ligand 1 antibody (anti-PD-1/anti-PD-L1) therapy. Through ALNM-stratified single-cell RNA sequencing profiling, we identified 3 hallmark immune subsets in ALNM+ PBC: (a) proliferative MKI67+ T cells, (b) exhausted GZMA+ CD8+ T cells, and (c) CCL13/CXCL10/TOP2A+ macrophages. Cross-modal integration of metastasis–epithelial–mesenchymal transition (EMT) signatures with Mendelian colocalization analysis prioritized TFF3 as a central mechanistic regulator. We validated malignant-cell-specific TFF3 expression across pan-cancer single-cell profiles and in PBC lineages. Integration of Mendelian colocalization signatures with pan-cancer spatial atlases established the TFF3 oncogene as a regulator of spatial EMT programs. Radiogenomic modeling that incorporated machine-learning-derived computed tomography features identified a TFF3-based radiomics risk score. Spatial multi-omics analyses—including bulk RNA sequencing, proteomics, and spatial transcriptomics—established a correlation between TFF3 expression and both MAPK signaling activation and EMT markers. Functional validation demonstrated that TFF3 plays a dual role as an amplifier of the MAPK–EMT axis and a modulator of immune checkpoints. Critically, the prometastatic phenotype driven by TFF3 was rescued upon pharmacological inhibition of MAPK signaling, providing direct evidence of this mechanistic link. In vivo xenograft models confirmed that TFF3 knockdown suppressed metastasis. Pharmacogenomic screening identified 6-mercaptopurine as a novel TFF3 antagonist, which exhibited dose-dependent inhibition of the MAPK–EMT axis. Furthermore, the antimigratory effect of 6-mercaptopurine was reversed by TFF3 overexpression, confirming the functional specificity of this drug–target interaction. Notably, tumors with high TFF3 expression (TFF3hi) exhibited elevated resistance to PD-1 inhibitors but heightened sensitivity to MAPK inhibitors, suggesting a potential theranostic framework for ALNM stratification.
Automatic generation of radiology reports seeks to reduce clinician workload while improving documentation consistency. Existing methods that adopt encoder-decoder or retrieval-augmented pipelines achieve progress in fluency but remain vulnerable to visual-linguistic biases, factual inconsistency, and lack of explicit multi-hop clinical reasoning. We present NeuroSymb-MRG, a unified framework that integrates NeuroSymbolic abductive reasoning with active uncertainty minimization to produce structured, clinically grounded reports. The system maps image features to probabilistic clinical concepts, composes differentiable logic-based reasoning chains, decodes those chains into templated clauses, and refines the textual output via retrieval and constrained language-model editing. An active sampling loop driven by rule-level uncertainty and diversity guides clinician-in-the-loop adjudication and promptbook refinement. Experiments on standard benchmarks demonstrate consistent improvements in factual consistency and standard language metrics compared to representative baselines.
OBJECTIVE:This study investigates the efficacy of metastatic lesion radiotherapy (MLRT) in patients with de novo metastatic nasopharyngeal carcinoma (dmNPC). MATERIALS AND METHODS:This study included patients with dmNPC from four institutions. To ensure comparability between groups, propensity score matching (PSM) was employed. Overall survival (OS) rates were assessed using the Kaplan-Meier method and compared using the log-rank test. Prognostic factors were identified through univariate and multivariate Cox hazard analyses. Subgroup analyses were conducted to evaluate the effects of MLRT on specific patient populations. RESULTS:We analyzed data from 1,503 patients with dmNPC. Following PSM analysis, 122 patients were included in the MLRT group, while 366 patients comprised the non-MLRT group. Patients who received MLRT exhibited significantly better OS compared to those who did not, both in the matched cohort (3-year OS rate: 79.0% vs. 65.8%) and in the original cohort. In multivariate analyses, MLRT was identified as an independent favorable predictor of OS, with a hazard ratio of 0.64. Results from the subgroup analyses demonstrated that MLRT effectively treated patients with bone metastases, oligo-metastases, 5 or fewer metastatic lesions, and those with undetectable EBV DNA2-6 cycles. Furthermore, higher total radiation doses of MLRT (biologically effective dose (BED) > 72 Gy, corresponding to an equivalent dose in 2-Gy fractions (EQD2) > 60 Gy) were associated with improved OS. CONCLUSIONS:MLRT provides survival advantages for patients diagnosed with dmNPC, particularly for those with a limited metastatic burden. The BED exceeding 72 Gy (EQD2 exceeding 60 Gy) was found to yield greater survival benefits.
