Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is the standard of treatment for esophageal cancer (EC). Early prediction of tumor response is critical for optimizing surgical planning and improving overall patient outcomes. While longitudinal PET/CT is routinely used for clinical evaluation, effectively leveraging it for tumor response prediction remains a challenge. Existing methods suffer from two primary limitations: the inability to fully capture multimodal dynamic changes within longitudinal PET/CT, and the inefficient utilization of longitudinal tumor change for response prediction. To address these issues, we propose PTFsNet, a model designed to mimic the clinical workflow of radiologists, who first fuse PET/CT images and subsequently compare tumor changes between pre- and post-nCRT scans. First, we introduce a fusing-contrasting framework incorporating Cross-Modal Fusing Attention (CMFA) and Longitudinal Contrasting Attention (LCA) modules. These modules fuse PET metabolic activity with CT anatomical structure and contrast pre- and post-nCRT tumor changes, thereby effectively extracting multimodal dynamic information. Second, we propose a Multiscale Tumor-Aware Contrastive Learning strategy (MTACL). Leveraging the prior of non-response in pre-nCRT tumors, we constrain feature similarity based on pathological complete response (pCR) status: enforcing lower pre/post-nCRT feature similarity for pCR patients and higher similarity for non-pCR patients. This allows the model to learn longitudinal feature patterns associated with distinct response outcomes. Furthermore, to mitigate interference from post-radiation inflammation, we employ a multi-task learning framework incorporating tumor segmentation, restricting the contrastive learning within the tumor region to enhance prediction robustness. Evaluated on multi-center longitudinal esophageal cancer PET/CT dataset, PTFsNet outperforms existing methods in both response prediction and tumor segmentation, demonstrating superior generalization capabilities.

PURPOSE:The management of thymoma patients with pleural dissemination remains challenging. We conducted a prospective phase 2 study to investigate the safety and efficacy of surgery followed by entire hemithoracic radiotherapy (EHRT) in these patients. MATERIALS AND METHODS:Thymoma patients with pleural dissemination (de novo or recurrent) were enrolled. After macroscopic resection, intensity-modulated radiotherapy (IMRT) of 14 Gy in 14 fractions was delivered to the entire hemithorax. An additional dose of 30 Gy in 15 fractions was delivered to the mediastinal tumor bed if the stage of the primary tumor was higher than T2. RESULTS:Between April 2020 and December 2021, 71 patients completed the study protocol. There were 30 male and 41 female patients, with a median age of 46 years (range, 26-75). There were 32 de novo cases and 39 recurrent cases. During a median follow-up of 57 months, two patients (2.8%) died: one from disease progression and the other from heart disease. A total of 34 patients (47.9%) developed disease progression, including pleural recurrence inside the radiation field (n=24) and outside the field (n=10). The median progression-free survival (PFS) was 50 months (95% CI, 45.95-54.39). The 3-year and 5-year PFS were 68.9% (95% CI, 56.7%-78.3%) and 50.8% (95% CI, 38%-62.3%), respectively. The 3- and 5-year recurrence-free survival rates (defined as no relapse inside the radiation field) were 78.8% (95% CI, 67.4%-86.7%) and 66.5% (95% CI, 53.3%-76.7%), respectively. The 5-year overall survival (OS) was 98.6%. Nausea, fatigue, and vomiting were the most frequent toxicities, and most were mild in severity. CONCLUSIONS:Surgical resection followed by EHRT is a safe treatment approach for thymoma patients with pleural dissemination, yielding promising local control. The optimal dose and target volume of radiotherapy warrant further investigation.

The ESTRO/EORTC classification categorizes oligometastatic disease (OMD) into de-novo, repeat, and induced OMD based on prior disease history and treatment status. However, its prognostic relevance in lung cancer patients treated with stereotactic ablative radiotherapy (SABR) remains incompletely characterized in real-world settings. This study evaluated the ESTRO/EORTC classification and two simplified binary stratification approaches derived from its decision framework. This single-center retrospective study included 648 lung cancer patients with 1–5 metastases treated with SABR between 2015 and 2021. Patients were categorized according to the ESTRO/EORTC classification. Two simplified binary stratification approaches derived from the ESTRO/EORTC decision framework were additionally explored: (1) a history-based approach distinguishing patients with prior polymetastatic disease from those without, and (2) a therapy-dependent progression approach distinguishing oligometastatic progression during active systemic therapy from other OMD states. Survival outcomes were analyzed using Kaplan-Meier and Cox regression, and prognostic discrimination was assessed using Harrell’s C-index. With a median follow-up of 54.5 months, 325 deaths and 552 progression events were observed. Induced OMD was associated with significantly worse outcomes compared with de-novo OMD (OS: 35.7 vs. 68.9 months; PFS: 8.6 vs. 15.5 months; both p < 0.001) and repeat OMD (OS: 35.7 vs. 60.2 months; PFS: 8.6 vs. 14.4 months; both p < 0.001). No significant differences were observed between de-novo and repeat OMD. The therapy-dependent progression stratification approach demonstrated distinct survival separation (median OS 34.4 vs. 86.4 months; PFS 8.4 vs. 16.4 months; both p < 0.001), although the difference in discriminatory performance was modest (C-index 0.596 for OS) compared with the ESTRO/EORTC classification (0.565) and the history-based approach (0.563). Differences in discriminatory performance were modest and not statistically significant after multiple-testing correction and bootstrap resampling. The ESTRO/EORTC classification is associated with survival outcomes in lung cancer patients with OMD treated with SABR, with induced OMD conferring the poorest prognosis. Simplified binary stratification approaches derived from this framework may provide a pragmatic and clinically accessible approach for risk stratification. These approaches should be considered complementary to, rather than replacements for, the full ESTRO/EORTC classification. Prospective validation is warranted.

2638 Background: The optimal integration of immunotherapy with chemoradiotherapy (CRT) in the neoadjuvant treatment of esophageal squamous cell carcinoma (ESCC) remains unclear, largely due to limited mechanistic insight into immune determinants of response. Methods: we performed paired single-cell RNA and TCR sequencing of ESCC tumor samples collected before and after treatment across three neoadjuvant modalities—immunochemotherapy (NICT), chemoradiotherapy (NCRT), and immuno-chemoradiotherapy (NICRT)—to dissect intratumoral CD8 + T cell dynamics. Results: We identified two distinct immune response programs. In NICT responders, pre-existing immunoresponsive CXCL13 + PD-1 + CD8 + T cells underwent clonal expansion and transcriptional reprogramming into a less exhausted yet CXCL13+ progenitor-like state (CD8Tex_CXCR4), accompanied by the formation of tertiary lymphoid structures. Conversely, CRT responders exhibited depletion of the subset of CXCL13 + CD8 + T cells and enrichment of PD-1 - cytotoxic CD8Teff_NIBAN1 cells, which originated from the peripheral blood and were characterized by robust clonal expansion, high effector gene expression, and association with tumor regression. We validated the association of these two T cell subsets with distinct neoadjuvant modalities and treatment responses using public datasets and independent prospective cohorts encompassing NICT, NICRT, and NCRT. Mechanistically, conventional radiotherapy suppressed PD-1 + T cell expansion—even in the presence of ICB—while a sequential strategy of induction ICB followed by delayed radiotherapy preserved the process of clonal expansion in exhausted T cell populations and achieved superior tumor control in vivo. Conclusions: These findings reveal divergent CD8 + T cell–mediated immune programs driving response to neoadjuvant therapies in ESCC and identify CD8Teff_NIBAN1 as a key effector population following CRT. Our study provides mechanistic insight into ICB–radiotherapy interactions and supports the rational design of temporally optimized combination strategies in solid tumors.

Background: In neoadjuvant chemoradiotherapy (NCRT), only 1/3 of patients with esophageal squamous cell carcinoma (ESCC) achieve pathologic complete response (pCR). Here, we aimed to depict the biological landscape of ESCC with different responses to NCRT and identify biomarkers to facilitate clinical decisionmaking. Methods: Tumor specimens before NCRT were obtained for whole exome sequencing (WES), RNA sequencing, and data-independent acquisition (DIA) mass spectrometry. Genomic data were analyzed for significantly mutated genes (SMGs), copy number alterations, microsatellite instability (MSI), tumor mutation burden (TMB), and mutational signatures. Transcriptomic and proteomic data were used to examine differentially activated pathways. Gene set enrichment analysis (GSEA) and ActivePathways were used for single omics and joint multiomics analyses, respectively. Treatment-resistance biomarkers were identified and confirmed in a separate cohort using immunohistochemistry (IHC). Results: FBXW7 mutation (Fisher's exact test, P=0.03) and 9p21.3 cytoband loss (q-value =0.001) are the significant genetic variations in the pCR group. Combined transcriptomic and proteomic analyses revealed that the type I interferon signaling pathways and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathways were enriched in non-pCR tumors. A biomarker panel of 12 proteins predictive of nonpCR tumors was identified, 10 of which were verified using multiplex IHC (mIHC) in an independent cohort. Conclusions: We described the multiomic biological characteristics of ESCC with distinct responses to NCRT and proposed a panel of proteins as predictive biomarkers for non-pCR patients.

Background:Non-small cell lung cancer (NSCLC) patients undergoing postoperative radiotherapy (PORT) after lung resection present a unique challenge due to anatomical changes and reduced baseline lung capacity. Standard dosimetric constraints established for intact lungs may not be applicable. This study aims to identify key risk factors and develop a model for predicting grade ≥ 2 (G2+) radiation pneumonitis (RP) through a secondary analysis of a prospectively collected cohort of NSCLC patients treated with PORT following lobectomy or sleeve resection. Methods:Data from patients with completely resected stage T1-3N2M0 (7th Edition) NSCLC receiving PORT were drawn from two prospective, multicenter, randomized trials (NCT02977169, NCT02974426) initiated in 2016. The endpoint was G2+ RP (Common Terminology Criteria for Adverse Events v5.0) within one year after radiotherapy. Least absolute shrinkage and selection operator (LASSO) regression, univariable and multivariable Cox proportional hazards models were utilized to identify contributing parameters. A nomogram for G2+ RP was developed and validated using the concordance index (C-index), time-dependent C-index curves, calibration curves, and decision curve analysis. Results:Of the 178 eligible patients, 21 developed G2+ RP, with a 12-month cumulative incidence of 11.8%. Age ≥67 years, the percentage of lung volume exceeding 13 Gy (V13) of the lung ≥25%, and the absolute lung volume spared from a 5 Gy dose (VS5) <1,230 cc were key risk factors for G2+ RP. The predictive model integrating age, V13, and VS5 achieved the bootstrap-corrected C-index of 0.757. Additionally, patients could be further stratified into low-risk (0 or 1 risk factor) and high-risk (2 or 3 risk factors) groups, with cumulative G2+ RP incidences of 6.6% and 29.3%, respectively (P<0.0001). Exploratory V13 thresholds were also proposed to help limit the incidence of G2+ RP. Conclusions:The combination of age (≥67 years), V13 (≥25%), and VS5 (<1,230 cc) effectively estimated the risk of G2+ RP in NSCLC patients receiving PORT after lung resection. Our findings underscore the importance of preserving a sufficient volume of normal lung tissue from low-dose exposure to ensure safety in patients with reduced lung reserve. Given the relatively limited number of events in our analysis, these findings are exploratory and require validation in larger, prospective cohorts.

Background and purpose: We aimed to assess the benefits of postoperative radiotherapy (PORT) in completely resected patients with pathologic stage IIIA(N2) non-small cell lung cancer (NSCLC) with a high risk of locoregional recurrence (LRR). Materials and methods: A prospective, randomized trial was conducted starting in July 2016 to explore the optimal timing of PORT in high-LRR-risk patients with completely resected IIIA(N2) NSCLC (NCT02974426). Patients were identified as high-LRR-risk patients via the prognostic index (PI) model and were randomly assigned to PORT-first or PORT-last treatment. To evaluate PORT for high-LRR-risk patients, all patients in this trial constituted the PORT cohort, whereas high-LRR-risk patients without PORT were selected from a retrospective cohort as the non-PORT cohort. Propensity score-matched (PSM) analyses were conducted to compare overall survival (OS), disease-free survival (DFS), locoregional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS). Results: Between 2016 and 2022, 132 patients were included in the trial, with a median follow-up of 49.3 months. The 3-year OS rate was 83.2 %, and the 3-year DFS rate was 35.0 %. Among these patients, 122 patients (92 %) received planned PORT. For 132 intention-to-treat patients, PSM analysis with the non-PORT cohort (n = 307) resulted in 130 matched pairs. The results revealed that PORT improved LRFS (3-year LRFS, 77.6 % vs. 57.3 %; p = 0.00014), DFS (3-year DFS, 35.2 % vs. 28.6 %; p = 0.038), and OS (3-year OS, 83.0 % vs. 60.7 %; p = 0.00017), with no difference in DMFS (p = 0.17). Conclusion: PORT could increase local control, DFS, and OS in high-LRR-risk patients with completely resected IIIA(N2) NSCLC. Future research should utilize multidimensional data to pinpoint more precise subgroups benefiting from PORT, with prospective trials validating these findings.

With the advancement of immunotherapy, neoadjuvant immunochemotherapy has emerged as an effective approach for treating locally advanced esophageal squamous cell carcinoma (LA‐ESCC). However, whether radiotherapy can serve as a reliable organ‐preserving alternative following induction immunochemotherapy (IICT), and which patient subgroups benefit most, remains uncertain. In this retrospective study, 388 patients with LA‐ESCC were analyzed, including 299 who underwent surgery and 89 who received radiotherapy after IICT. Responses to immunochemotherapy were classified as major pathologic response (MPR) or non‐MPR based on pathologic examination for surgical patients and a previously developed MPR predictive model for radiotherapy patients. Survival outcomes were assessed using the Kaplan–Meier method, while prognostic factors were evaluated through Cox regression analyses. Propensity score matching (PSM) was used to minimize confounding factors. Surgery was associated with better progression‐free survival (PFS) compared to radiotherapy ( p = 0.002 before PSM; p = 0.017 after PSM), but no significant difference in overall survival (OS) was observed ( p = 0.144 before PSM; p = 0.241 after PSM). Among MPR patients, radiotherapy achieved PFS and OS outcomes similar to surgery (PFS: p = 0.136; OS: p = 0.255) after PSM. Failure patterns differed, with local or regional recurrence being more common in the radiotherapy group, while distant metastasis was prevalent in surgery patients. Major postoperative complications occurred in 9.36% of surgery patients, and 11.2% of radiotherapy patients had grade 3–4 adverse events. These findings indicate that radiotherapy could be a safe and effective organ‐preserving alternative for LA‐ESCC patients, especially those achieving MPR, offering more personalized and less invasive treatment options while maintaining quality of life.

PURPOSE:Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy remains standard for locally advanced esophageal squamous cell carcinoma (ESCC). However, accurately predicting pathological complete response (pCR) and treatment outcomes remains challenging. This study aimed to develop and validate a multidimensional deep ensemble learning model (DELRN) using pretreatment CT imaging to predict pCR and stratify prognostic risk in ESCC patients undergoing nCRT. METHODS:In this multicenter, retrospective cohort study, 485 ESCC patients were enrolled from four hospitals (May 2009-August 2023, December 2017-September 2021, May 2014-September 2019, and March 2013-July 2019). Patients were divided into a discovery cohort (n = 194), an internal cohort (n = 49), and three external validation cohorts (n = 242). A multidimensional deep ensemble learning model (DELRN) integrating radiomics and 3D convolutional neural networks was developed based on pretreatment CT images to predict pCR and clinical outcomes. The model's performance was evaluated by discrimination, calibration, and clinical utility. Kaplan-Meier analysis assessed overall survival (OS) and disease-free survival (DFS) at two follow-up centers. RESULTS:The DELRN model demonstrated robust predictive performance for pCR across the discovery, internal, and external validation cohorts, with area under the curve (AUC) values of 0.943 (95 % CI: 0.912-0.973), 0.796 (95 % CI: 0.661-0.930), 0.767 (95 % CI: 0.646-0.887), 0.829 (95 % CI: 0.715-0.942), and 0.782 (95 % CI: 0.664-0.900), respectively, surpassing single-domain radiomics or deep learning models. DELRN effectively stratified patients into high-risk and low-risk groups for OS (log-rank P = 0.018 and 0.0053) and DFS (log-rank P = 0.00042 and 0.035). Multivariate analysis confirmed DELRN as an independent prognostic factor for OS and DFS. CONCLUSION:The DELRN model demonstrated promising clinical potential as an effective, non-invasive tool for predicting nCRT response and treatment outcome in ESCC patients, enabling personalized treatment strategies and improving clinical decision-making with future prospective multicenter validation.

To develop a deep learning (DL) model for predicting disease-free survival (DFS) in clinical stage I lung cancer patients who underwent surgical resection using pre-treatment CT images, and further validate it in patients receiving stereotactic body radiation therapy (SBRT). A retrospective cohort of 2489 clinical stage I non-small cell lung cancer (NSCLC) patients treated with operation (2015–2017) was enrolled to develop a DL-based DFS prediction model. Tumor features were extracted from CT images using a three-dimensional convolutional neural network. External validation was performed on 248 clinical stage I patients receiving SBRT from two hospitals. A clinical model was constructed by multivariable Cox regression for comparison. Model performance was evaluated with Harrell’s concordance index (C-index), which measures the model’s ability to correctly rank survival times by comparing all possible pairs of subjects. In the surgical cohort, the DL model effectively predicted DFS with a C-index of 0.85 (95

Background:The heterogeneity of locally advanced non-small cell lung cancer (LA-NSCLC) has led to varied treatment strategies. Before the immunotherapy era, definitive chemoradiotherapy (CRT) was the standard for inoperable patients. This real-world study evaluates the role of thoracic radiotherapy (RT) in patients receiving first-line immunotherapy-based treatment. Methods:This retrospective analysis included stage III NSCLC patients from January 2018 to December 2022 who were inoperable or declined surgery and received immunotherapy. Treatment patterns, survival outcomes, and failure modes were assessed. Real-world overall survival (OS), progression-free survival (PFS), and local recurrence-free survival (LRFS) were analyzed using Kaplan-Meier methods. Results:Among 410 eligible patients, 173 received RT (RT group), while 237 underwent chemoimmunotherapy (CIT) alone (non-RT group). The RT group demonstrated significantly longer median OS (55.5 vs. 26.6 months) and PFS (21.3 vs. 14.1 months) compared to the non-RT group (P<0.001). Patients receiving ≤4 CIT induction cycles before RT had improved outcomes versus >4 cycles (P=0.04). No survival difference was observed between RT doses of 50 Gy and 60 Gy. Conclusions:This study confirms that thoracic RT remains essential for inoperable LA-NSCLC in the immunotherapy era. An exploratory analysis suggests that a potential strategy could involve ≤4 cycles of CIT induction followed by concurrent CRT (cCRT) and immune checkpoint inhibitor maintenance. These findings encourage further investigation into RT integration within multimodal treatment, with 50-60 Gy appearing potentially comparable in selected patients.

To evaluate the feasibility of multi-parameters combined simplified intensity-modulated radiation therapy (sIMRT) planning in thoracic tumors and provide guidance for clinical practice. A total of 34 patients with thoracic tumors who underwent radiotherapy during 2019 to 2020 in our hospital were retrospectively analyzed. The same experienced medical physicist designed the sIMRT planning. The sIMRT planning limited the maximum number of segments per beam-field, the minimum segment area, and the minimum number of segment monitor units (MU), remaining consistent with the conventional intensity-modulated radiation therapy (IMRT). Comparative analysis of the difference in the irradiation dose to the tumor target area, and organs at risk, and delivery validate between 2 groups. The sIMRT slightly increased the tumor target area irradiation dose, but the homogeneity index was similar when compared with IMRT ( P > .05). The sIMRT planning significantly reduced the low dose-volume area of the lungs (left lung, V 5 : 2.5%; right lung, V 5 : 3.1%; V 10 : 1.8%; lungs, V 5 : 3.2%; V 10 : 1.5%, P < .05) and significantly increased the high dose-volume area of the lungs, heart, and esophagus, while meeting the clinical dose-restriction requirements. Moreover, the planning delivery validation showed that significantly reduced the treatment time (6.5 ± 1.9 minutes vs 8.8 ± 2.0 minutes, P < .0001) and total MU (386.3 ± 109.4 MU vs 406.3 ± 107.9 MU, P < .05). This simplified sIMRT method can meet the requirements of thoracic tumors radiotherapy planning, and has higher time effectiveness. In the future, it needs to be further explored in clinical practice.

BACKGROUND:Neoadjuvant immunochemotherapy has demonstrated promising efficacy in locally advanced esophageal squamous cell carcinoma (ESCC), yet the role of adjuvant therapy remains unclear. This study aimed to develop a pathologic classification scheme to distinguish postoperative outcomes and explore the potential benefit of adjuvant therapy. METHODS:This study retrospectively collected data on patients with locally advanced ESCC who underwent radical esophagectomy after neoadjuvant immunochemotherapy between 2019 and 2022. The primary outcome was recurrence-free survival (RFS), and secondary outcomes included recurrence patterns, overall survival, locoregional recurrence-free survival, and distant metastasis-free survival. The Kaplan-Meier method was used to plot survival curves, propensity score matching was used to match different groups, and Cox proportional hazards models identified factors affecting prognosis. RESULTS:Among 333 eligible patients, the overall pathologic complete response (pCR) rate was 25.8%. With a median follow-up of 23.8 months, the 1-year and 2-year RFS rates were 77.0% and 63.2%, respectively. Multivariable analysis identified ypN as the primary factor influencing RFS, while both ypN and MPR status were key determinants of recurrence patterns. A classification approach based on MPR and ypN status was developed to distinguish patient subgroups with different RFS and recurrence patterns. Patients with ypN0 had a favorable prognosis. In ypN+ patients, MPR was linked to more locoregional recurrences, while non-MPR cases showed mainly distant metastases. Among MPR ypN+ patients, adjuvant therapy was associated with improved RFS (hazard ratio, 0.38; 95% confidence interval, 0.15- 0.93; P = .028). CONCLUSIONS:The MPR-ypN-based classification distinguishes postoperative outcomes and suggests that MPR ypN+ patients may derive benefit from adjuvant therapy.

PURPOSE:To develop and validate a dosiomics and radiomics model based on three-dimensional (3D) dose distribution map and computed tomography (CT) images for the prediction of the post-radiotherapy (post-RT) neutrophil-to-lymphocyte ratio (NLR).METHODS:This work retrospectively collected 242 locally advanced non-small cell lung cancer (LA-NSCLC) patients who were treated with definitive radiotherapy from 2012 to 2016. The NLR collected one month after the completion of RT was defined as the primary outcome. Clinical characteristics and two-dimensional dosimetric factors calculated from the dose-volume histogram (DVH) were included. A total of 4165 dosiomics and radiomics features were extracted from the 3D dose maps and CT images within five different anatomical regions of interest (ROIs), respectively. Then, a three-step feature selection method was proposed to progressively filter features from coarse to fine: (i) model-based ranking according to individual feature's performance, (ii) maximum relevance and minimum redundancy (mRMR), (iii) select from model based on feature importance calculated with an ensemble of several decision trees. The selected feature subsets were utilized to develop the prediction model with GBDT. All patients were divided into a development set and an independent testing set (2:1). Five-fold cross-validation was applied to the development set for both feature selection and model training procedure. Finally, a fusion model combining dosiomics, radiomics and clinical features was constructed to further improve the prediction results. The area under receiver operating characteristic curve (ROC) were used to evaluate the model performance.RESULTS:The clinical-based and DVH-based models showed limited predictive power with AUCs of 0.632 (95% CI: 0.490-0.773) and 0.634 (95% CI: 0.497-0.771), respectively, in the independent testing set. The 9 feature-based dosiomics and 3 feature-based radiomics models showed improved AUCs of 0.738 (95% CI: 0.628-0.849) and 0.689 (95% CI: 0.566-0.813), respectively. The dosiomics & radiomics & clinical fusion model further improved the model's generalization ability with an AUC of 0.765 (95% CI: 0.656-0.874).CONCLUSIONS:Dosiomics and radiomics can benefit the prediction of post-RT NLR of LA-NSCLC patients. This can provide a reference for evaluating radiotherapy-related inflammation.

Background: We aimed to assess the value of stereotactic body radiotherapy (SBRT) delivered under the situation of controlled or progressed disease during ICI therapy in advanced or recurrent NSCLC. Methods: We retrospectively collected patients with advanced or recurrent NSCLC who received SBRT concurrently with ICI in our institution between January 2017 and December 2021. Patients were divided into two groups, including those for whom SBRT was delivered initially or to the residual tumors during the first- or later-line ICI treatment (Group 1), and those for whom SBRT was given to the progressed tumors irrespective of first- or later-line ICI treatment (Group 2). Results: A total of 144 patients were included. With median follow-up duration of 25.6 (range: 3.6 to 56.2) months, median progression-free survival (PFS) was 13.7 (95 % CI: 10.4 to 17.1) months and median overall survival (OS) was 52.8 [95 % CI: 30.6 to not available (NA)] months. In Group 1 (n = 78), median PFS was 17.9 (95 % CI: 14.5 to 29.8) months while median OS was not reached and 5-year OS rate was 61.2 %. In Group 2 (n = 66), median PFS was 8.0 (95 % CI: 6.0 to 13.1) months and median OS was 30.6 (95 % CI: 21.5 to NA) months. Conclusions: SBRT combined with ICI demonstrated favorable survival for advanced or recurrent NSCLC, delivered in a controlled-disease situation as well as to progressed diseases with salvage-intent. Future prospective studies are warranted to investigate the optimal SBRT dose regimen and appropriate combination strategy to synergize ICI.

Neoadjuvant therapy followed by surgery is a common clinical strategy for operable non-small cell lung cancer (NSCLC), and the mainstream neoadjuvant therapies include chemoimmunotherapy, targeted therapy, and chemotherapy. However, there is a lack of studies to report the difference in benefits between these treatment modalities in the same institution. Therefore, this study aimed to depict the short-term efficacy of radiology and pathology achieved by different therapies and their impact on long-term survival as well as the underlying clinical significance. A total of 243 NSCLC patients who underwent different neoadjuvant therapies were eligible for inclusion. Demographic, radiological, and pathological features of patients were recorded. The event-free survival (EFS) outcome was analyzed using Kaplan-Meier analysis. The objective response rates (ORR) of primary tumor in the chemoimmunotherapy, targeted therapy, and chemotherapy cohorts were 48.95 %, 57.58 %, and 34.09 % respectively, major pathological response (MPR) rates were 58.74 %, 15.15 %, and 20.83 % (P<.0001), and pathological complete response (pCR) rates were 41.26 %, 0 %, and 11.11 % (P<.0001). For consistency between imaging and pathological evaluation, Cohen's Kappa were 0.275, 0.233, and 0.330. The EFS of MPR group was significantly longer than that of non-MPR group in the chemoimmunotherapy and chemotherapy cohorts (P=.0077**&.0343*, HR=0.3287&0.3715), but this improvement was not observed in the targeted therapy cohort. Neoadjuvant chemoimmunotherapy often underestimates pathological efficacy in imaging but shows consistent long-term outcomes. Neoadjuvant chemotherapy with moderate overall effectiveness has a significant correlation between short-term benefits and reduced recurrence. Neoadjuvant targeted therapy shows remarkable short-term imaging improvements but often fails to convert into sustained long-term survival.

Background: Chemotherapy plus immunotherapy has become the standard first-line treatment of advanced or metastatic esophageal squamous cell carcinoma (ESCC), but median duration of response is only 7.0–8.3 months and progression-free survival (PFS, ∼6 months) is still far from satisfactory. We aim to evaluate whether early involvement of radiotherapy might improve the treatment outcome if objective response to first-line chemo-immunotherapy was observed in locally advanced or metastatic ESCC. Methods: Patients were retrospectively collected from 3 institutions in China. Patients with histopathologically confirmed diagnoses of locally advanced or metastatic ESCC were identified, who objectively responded to first-line chemo-immunotherapy (complete or partial response, or stable disease) and also received radiotherapy of primary lesions with radiation dose of over 40 Gy, with or without radiotherapy of metastatic lesions before the first disease progression. Results: A total of 72 eligible patients were identified. With median follow-up duration of 14.6 (range, 7.1–34.8) months, median progression-free survival (PFS) and overall survival (OS) were 13.5 (95 % CI,10.4-NA) months and 31.8 (95 % CI, 23.0-NA) months, respectively. Median duration from initiation of chemo-immunotherapy to radiotherapy was 2.9 (range, 0–15.1) months. Besides lower tumor burden as a significant factor of better treatment outcome, radiation dose ≥ 50 Gy was associated with superior PFS, while OS might be mainly related to tumor response to the induction chemo-immunotherapy. A low incidence of Grade 3 or above treatment-related adverse events were observed (19 %), and no treatment-related death occurred. Conclusion: Our multi-center retrospective study showed survival benefit brought by early involvement of radiotherapy after first-line chemo-immunotherapy for patients with locally advanced or metastatic ESCC. However, further investigation is warranted in future prospective, controlled trials to assess the value of radio-immunotherapy in advanced or metastatic ESCC.

Radiation-induced heart disease (RIHD) is a severe delayed complication of thoracic irradiation (IR). Endonuclease/exonuclease/phosphatase family domain-containing 1 (EEPD1) plays an important role in DNA damage repair, but its role in RIHD is less known. In this study, EEPD1 global knockout mice, C57BL/6J mice, and C57BL/6J mice overexpressing EEPD1 are treated with radiation at a total dose of 20 Gy or 0 Gy. After 9 weeks, echocardiography is used to assess cardiac hypertrophy and apoptosis. The results show that EEPD1 deletion exacerbates radiation-induced cardiac hypertrophy and apoptosis, while EEPD1 overexpression has the opposite effect. Further mechanistic investigations reveal that EEPD1 interacts with FOXO3A and destabilizes it by catalyzing its deubiquitination. Inhibition of FOXO3A ameliorates cardiac hypertrophy and apoptosis after EEPD1 knockdown. Thus, EEPD1 protects against radiation-induced cardiac hypertrophy and apoptosis via destabilization of FOXO3A, which may offer new insight into therapeutic strategies for RIHD.

Patients with EGFR-mutated non-small cell lung cancer (NSCLC) respond poorly to immune checkpoint inhibitors (ICIs). It has been reported that the number of CD8+ T cells is reduced in EGFR-mutated NSCLC. However, the extent of heterogeneity and effector function of distinct populations of CD8+ T cells has not been investigated intensively. In addition, studies investigating whether a combination of radiotherapy and ICIs can improve the efficacy of ICIs in EGFR-mutated lung cancer are lacking. Single-cell RNA sequencing (scRNA-seq) was used to investigate the heterogeneity of CD8+ T cell populations in EGFR-mutated NSCLC. The STING pathway was explored after hypofractionated radiation of EGFR-mutated and wild-type cells. Mice bearing LLC-19del and LLC-EGFR tumors were treated with radiotherapy plus anti-PD-L1. The scRNA-seq data showed the percentage of progenitor exhausted CD8+ T cells was lower in EGFR-mutated NSCLC. In addition, CD8+ T cells in EGFR-mutated NSCLC were enriched in oxidative phosphorylation. In EGFR-mutated and wild-type cells, 8 Gy × 3 increased the expression of chemokines that recruit T cells and activate the cGAS-STING pathway. In the LLC-19del and LLC-EGFR mouse model, the combination of radiation and anti-PD-L1 significantly inhibited the growth of abscopal tumors. The enhanced abscopal effect was associated with systemic CD8+ T cell infiltration. This study provided an intensive understanding of the heterogeneity and effector functions of CD8+ T cells in EGFR-mutated NSCLC. We showed that the combination of hypofractionated radiation and anti-PD-L1 significantly enhanced the abscopal responses in both EGFR-mutated and wild-type lung cancer by activating CD8+T cells in mice.

Abstract Background Concurrent chemoradiotherapy is the cornerstone treatment for locally advanced esophageal cancer. Immunochemotherapy, established as the standard treatment for advanced esophageal cancer, concurrently exhibits excellent short-term efficacy in the neoadjuvant stage. Combining concurrent chemoradiotherapy with immunochemotherapy may enhance control over primary tumor and metastatic lymph nodes, potentially improving patients’ outcomes and survival. Therefore, comparing the pros and cons of these two treatment modalities in controlling primary lesions and lymph node metastasis is crucial for guiding clinical treatment. Methods Our study enrolled a total of 137 patients with esophageal squamous cell carcinoma (ESCC) who underwent neoadjuvant immunochemotherapy (NICT) and 151 ESCC patients who underwent neoadjuvant chemoradiotherapy (NCRT) between January 2019 and March 2022. We documented baseline patient characteristics, including clinical TNM stage, tumor location, and clinical metastatic lymph nodes, as well as pathologic outcomes such as pathological stage, pathologic complete response (pCR), tumor regression grade (TRG), and pathological metastatic lymph nodes. To balance baseline patient characteristics, we employed inverse probability of treatment weighting (IPTW) to adjust for confounding in different neoadjuvant treatment groups. Results After balancing baseline characteristics, there was no statistically significant difference in pathologic outcomes, including pCR rate, major pathologic response rate, TRG, yp-TNM stage, and R0 resection rate between NCRT and NICT. However, patients with clinical N2-3 stage (OR 2.66; 95% CI 1.05 to 6.79) or lower thoracic esophageal tumors (OR 2.31; 95% CI 1.05 to 5.04) had a higher chance of achieving pCR after NICT compared to NCRT. For patients undergoing NICT, the ypN0 rates for clinically N0 patients were 100.0% (5/5), while only 65.0% (13/20) of clinical N0 patients achieved ypN0 in the NCRT group. Even after adjusting for differences in clinical stage, tumor location, and baseline lymph node metastasis rates in various locations, the NICT group still demonstrated a lower rate of abdominal lymph node metastasis during surgery (p=0.030). Conclusion In comparison to concurrent chemoradiotherapy, immunochemotherapy exhibits comparable overall disease control for primary lesions and lymph node metastasis. Notably, patients with clinical N2-3 and lower thoracic esophageal cancer may derive greater benefits from NICT. The potential of immunochemotherapy in enhancing the effectiveness of chemoradiotherapy is evident in its ability to improve the control of occult metastatic lymph nodes and reduce abdominal lymph node metastasis.