BACKGROUND:Nivolumab is effective in treating patients with esophageal squamous cell carcinoma (ESCC). The efficacy of nivolumab in combination with neoadjuvant chemoradiotherapy (CRT) remains unclear. METHODS:In this phase II trial with Simon's 2-stage design, neoadjuvant nivolumab, paclitaxel, and cisplatin were administered with radiotherapy followed by esophagectomy to patients with locally advanced ESCC. The primary endpoint was pathological complete response (pCR). The secondary endpoints were feasibility, safety, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). RESULTS:A total of 17 patients were enrolled in stage I. Fourteen patients received esophagectomy, with pCR achieved in 4, below the criterion for continuing to stage II. All grade and ≥grade 3 treatment emergent adverse events (TEAEs) occurred in 15 and 4 patients, respectively. Immune-related TEAEs occurred in 7; none were ≥ grade 3. The median durations of RFS, PFS, and OS were 8, 12, and 25 months, respectively. Patients with high expression of PD-L1 had higher pCR rate (100% vs 18%, P = 0.019). CONCLUSIONS:Nivolumab in combination with neoadjuvant CRT is safe for patients with locally advanced ESCC, and may be beneficial in those with high PD-L1 expression. CLINICAL TRIAL REGISTRATION:NCT05130684.

BACKGROUND:C-C motif chemokine ligand-2 (CCL2)-C-C motif chemokine receptor-2 (CCR2) axis plays critical roles in hepatocellular carcinoma (HCC) progression and in shaping immune responses following radiotherapy (RT). However, its contribution to radio-resistance and the underlying mechanism remain poorly understood. METHODS:CCL2 and CCR2 expressions were analyzed in paired pre-/post-RT HCC tumor samples from patients exhibiting differential responses to RT. In parallel, we assessed CCL2 secretion, infiltration of CCR2-expressing myeloid cells, and tumor-associated macrophage (TAM) subsets, including the subpopulations expressing NOS2, in two murine HCC models: radioresistant BNL and radiosensitive Hepa1-6 allografts. RESULTS:Despite similarly elevated CCL2 levels and comparable induction of immunogenic cell death indicated by calreticulin exposure, CCR2+ myeloid cells were recruited in significantly greater abundance in RT-resistant than RT-responsive tumors, both in human tumors and murine allografts. Following RT, there was a significantly greater increase in NOS2-expressing M1-like TAMs in Hepa1-6 than BNL tumors. Ex vivo experiments demonstrated that the TAMs isolated from irradiated Hepa1-6 tumors suppressed tumor proliferation, promoted CD8+ T-cell infiltration, and improved tumor control compared to TAMs from non-irradiated tumors. In vitro co-culture assays demonstrated CCR2+ myeloid cells attenuated NOS2 expression in M1-like macrophages, suggesting a suppressive effect on their pro-inflammatory phenotype. Furthermore, pharmacologic blockade of CCR2+ cells using a CCR2 antagonist restored NOS2 expression, enhanced radiosensitivity, and improved tumor control in radioresistant BNL models. CONCLUSIONS:CCR2+ myeloid cells suppress NOS2-mediated antitumor responses in HCC following RT. Targeting RT-recruited CCR2+ myeloid cells may offer a promising radiosensitizing strategy to overcome therapeutic resistance in HCC.

PURPOSE:Radiotherapy (RT) for thymic tumors often involves cardiac exposure. We evaluated the association between cardiac substructure dosimetry and post-RT arrhythmia. MATERIALS AND METHODS:This retrospective study included patients with thymic cancer or thymoma who underwent curative-intent radiotherapy between 2016 and 2024 and had available treatment plans. Cardiac substructures were auto-contoured, and mean doses, V5Gy, and V30Gy were calculated. Receiver operating characteristic curve analysis identified cutoff values for cardiac substructure dosimetric parameters. Univariate and multivariate analyses were performed using a competing risk model. RESULTS:Among 100 patients (median follow-up, 47 months), 19 (19%) developed substantial arrhythmic events after thoracic radiotherapy. The 1-, 2-, and 5-year cumulative incidences of arrhythmia, adjusted for the competing risk of death, were 5.1%, 8.9%, and 24.4%, respectively. Patients with arrhythmic events had higher baseline World Health Organization (WHO) cardiovascular disease (CVD) risk scores and higher cardiac doses, including mean whole-heart, left atrium, left ventricle, and right ventricle doses. Receiver operating characteristic curve analysis identified predictors of arrhythmia: WHO CVD risk score > 6%, mean whole-heart dose > 2594 cGy, mean left atrium dose > 2388 cGy, mean left ventricle dose > 730 cGy, and mean right ventricle dose > 1236 cGy. In multivariate analysis, WHO CVD risk score and mean whole-heart dose remained independent predictors of arrhythmic events. CONCLUSIONS:Substantial arrhythmic events after radiotherapy for thymic cancer or thymoma were associated with the baseline WHO CVD risk score and mean whole-heart dose. Implementing stricter cardiac dose constraints is essential to mitigate long-term toxicity in this potentially long-surviving cohort.

Abstract Topic Esophageal Cancer: New Diagnostic Modalities (Including PET, PET-CT, New Tracers) Background We evaluated whether serial 18F-FDG PET–derived metabolic changes in tumor and host response are associated with pathologic complete response (pCR) and survival in patients with locally advanced resectable esophageal squamous cell carcinoma (ESCC), addressing the limited ability of baseline-to-preoperative PET response to detect substantial residual disease and to differentiate viable tumor from post-treatment inflammation. Methods We enrolled 38 patients from 2 phase II clinical trials (NCT03623737 and NCT05130684) with locally advanced, resectable ESCC who underwent serial 18F-FDG PET/CT at three predefined time points: initial staging (PET1), approximately 3 weeks after completion of neoadjuvant concurrent chemoradiotherapy (PET2), and before surgery (PET3). Tumor metabolic parameters, including maximum standardized uptake value (SUVmax), metabolic tumor volume, and total lesion glycolysis, were quantified at each scan. Host-response metabolic activity was assessed using spleen-to-liver uptake ratio, bone marrow SUV, and subcutaneous and visceral adipose tissue SUVs. Both single–time point measurements and interval-based relative percentage changes were calculated across PET1–PET2, PET2–PET3, and PET1–PET3. Associations between serial PET-derived tumor and host-response metrics with pCR and survival outcomes were evaluated using appropriate regression and survival analyses. Logistic and Cox regression were used to model pCR and overall survival (OS), respectively. Results Among 38 enrolled patients, 35 underwent surgical resection; three were excluded from surgery due to esophagopulmonary fistula, intraoperative pleural seeding, or interstitial lung disease. pCR was achieved in 13 patients. The interval between PET2 and PET3 differed significantly between groups, whereas other clinical characteristics were balanced. Single–time point PET-derived tumor and host metabolic parameters showed no significant group differences. In contrast, relative changes in tumor SUVmax and visceral adipose tissue SUV from PET2 to PET3 were significantly associated with pCR (both p<0.05). On logistic regression, both parameters independently predicted pCR, with and without adjustment for the PET2–PET3 interval. A combined tumor–host model improved discrimination compared with single-parameter models; however, only tumor SUVmax change remained independently significant. During a median follow-up of 660 days, 10 deaths occurred. Tumor SUVmax change from PET2 to PET3 was a significant prognostic factor (HR 1.02, 95% CI 1.004–1.03; P=0.01). Conclusion Dynamic tumor metabolic change between post-chemoradiotherapy and preoperative PET (PET2–PET3) is a major determinant of pCR in locally advanced resectable esophageal squamous cell carcinoma. Incorporation of host metabolic metrics enhances overall model discrimination, supporting a complementary biologic role. Importantly, dynamic tumor metabolic change from PET2 to PET3 also serves as an independent predictor of OS, underscoring the clinical value of longitudinal PET assessment.

BACKGROUND:With the growing adoption of stereotactic spine radiosurgery (SSRS), precise target delineation is essential. The International Spine Radiosurgery Consortium (ISRC) has proposed contouring guidelines covering both the tumor and adjacent structures, termed the elective field (EF). We designed this randomized trial comparing EF and involved field (IF)-contouring strategy to determine which yielded the lowest protocol-specified failure rate. METHODS:Patients with spinal metastases not requiring surgery were randomized 1:1 to receive 16 Gy in a single fraction via EF or IF SSRS. EF followed ISRC recommendations. IF comprised the gross tumor volume with an 8-mm isotropic intraosseous margin. We aimed to reject failure rates >10% at 6 months. Treatment failure was defined as grade ≥3 treatment-related toxicity or local progression. RESULTS:Between August 2019 and May 2024, 106 patients (164 segments) were analyzed. Fifty-two and 54 patients were randomized to EF and IF, respectively. The median follow-up was 41.6 months. At 6 months, the cumulative incidence of treatment failure (CIF) met the acceptability criteria (per-patient: EF 3.8% vs IF 7.5%, P = .42). By 12 months, EF group showed low CIF, both per-patient (3.8% vs 13.5%) and per-segment (2.6% vs 11.8%). CIF curves differed significantly between groups (Gray's test, per-patient: P = .03, per-segment: P = .02). In the IF group, two-thirds of the out-of-field or marginal recurrences could be enclosed by the EF contouring strategy. CONCLUSIONS:EF and IF SSRS met the criteria for acceptable CIF at 6 months. With longer follow-up, EF demonstrated lower failure rates. ISRC contouring guidelines should be the standard practice.

4084 Background: Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy is standard treatment for patients with resectable locally advanced ESCC. A direct comparison of taxane/platinum nCRT versus PF nCRT in prospective randomized clinical trials has never been reported. Methods: This is a single-center, open-label, randomized phase II/III trial (registered as NCT0623737 at ClinicalTrial.gov). Patients with locally advanced ESCC (T3/4aN0M0 or T1-3N1-3M0 per AJCC 7 th ed.) were randomized 1:1 to TP (paclitaxel 50 mg/m2 weekly plus cisplatin 30 mg/m2 weekly for 5 weeks) or PF (cisplatin 75 mg/m2 day 1 plus 5-FU 1,000 mg/m2 days 1-4 on weeks 1 and 5) chemotherapy with concurrent radiotherapy 45 Gy/25 fractions. Esophagectomy was performed 6 to 10 weeks after completing CRT. Primary endpoint was pathological complete response (pCR) rate for phase II part. If significant pCR benefit of TP versus PF nCRT was found in phase II part, the trial would continue enrolment for the phase III part with overall survival as primary endpoint. Results: From Mar 2017 to Jul 2025, 128 patients were enrolled in the phase II part; 6 withdrew before treatment. The intention-to-treat (ITT) population included 122 patients (61 patients per arm); median age was 61 (35-77) years with TP and 58 (39-77) with PF; 90% and 89% were male, respectively. Esophagectomy was performed in 51/61 (84%) vs. 49/61 (80%), and R0 resection was achieved in 43/51 (84%) vs. 36/49 (73%) ( p =0.183), respectively. The pCR rate per ITT population was 23/61 (37.7%) with TP vs 17/61 (27.9%) with PF ( p =0.247). The difference of pCR rate did not meet the boundary to continue the trial to the phase III part. Median overall survival was 54 vs 43 months (HR 0.76; p =0.284) and median progression-free survival was 33 vs 25 months (HR 0.74; p =0.193) for TP vs PF. Median recurrence free survival was not reached in both arms. Grade 3-4 adverse events during nCRT occurred in 29/61 (47.5%) with TP and 40/61 (65.6%) with PF ( p =0.045); most common grade ≥3 events were leucopenia (23.0% vs 32.8%), esophagitis (11.5% vs 29.5%), and dysphagia (14.8% vs 27.9%). Postoperative 90-day mortality was 0% in both arms. Conclusions: TP-nCRT did not significantly improve pCR versus PF-nCRT in patients with locally advanced ESCC. Clinical trial information: NCT0623737 . Efficacy and safety outcomes for TP-nCRT versus PF-nCRT. TP PF Statistics ITT, n 61 61 - Resection, n (%) 51 (84) 49 (80) p =0.638 R0 resection rate (%) 43/51 (84) 36/49 (73) p =0.183 pCR (ITT) rate (%) 23/61 (37.7) 17/61 (27.9) p =0.247 pCR (resected population) rate (%) 23/51 (45.1) 17/49 (34.7) p =0.288 OS, median (mo) 54 43 HR 0.76; p =0.284 PFS, median (mo) 33 25 HR 0.74; p =0.193 Grade 3-4 AEs during nCRT, n (%) 29 (47.5%) 40 (65.6%) p =0.045 Postoperative 90-day mortality 0 0 -

Submarine groundwater discharge (SGD) serves not only as an additional source of water, nutrients, and other associated solutes from the land to the sea, but also as a potential freshwater resource, especially under drought conditions. Therefore, it is crucial to quantify SGD and characterize its seasonal and temporal variations. However, sparse studies have examined SGD during a drought period. In this study, we investigated the seasonal SGD in Taiwan in an extreme drought year (2021). Water samples, including coastal seawater, groundwater and riverine/ drainage water, collected from the northwestern coast of Taiwan during dry (May-October) and wet (November-April) seasons were analyzed for radium isotopes (Ra-223, Ra-224(ex), and Ra-228) and stable isotopes (delta O-18 and delta D). Coupled short-lived radium isotopes (Ra-223 and Ra-224(ex)) in coastal seawater at four selected sites were used to calculate the Ra-derived apparent age of coastal seawater, which can represent the amount of time that a water mass spent in our boundary-defined box (i.e., residence time), and the averages displayed slightly higher in the dry season (6.48 +/- 2.63 days) than in the wet season (4.69 +/- 2.40 days). Based on a mass balance model of Ra-224(ex), SGD in the wet season (841.47 +/- 156.61 cm d(-1)) was 2.7 times that in the dry season (391.34 +/- 79.59 cm d(-1)). In addition, the similarity in the averaged activity ratios of Ra-224(ex) to Ra-223 in shallow (depth <= 20 m) and deep (depth >20 m) groundwater and the good linear relationship between delta O-18 and delta D values might indicate the same origin for shallow groundwater and deep one, probably the deep aquifer contributed to SGD in the coastal area. This study provides rare observation data and valuable results related to the seasonal variation of SGD in northwestern coastal Taiwan in an extreme drought year. Importantly, it offers new insights into the contribution of groundwater from deep aquifers under drought conditions. The results can serve as an important reference for understanding the effects of drought conditions on the seasonal variation of SGD, thereby enhancing our understanding of SGD under contrasting hydrological conditions.

INTRODUCTION:Limited linkage between epidermal growth factor receptor (EGFR) mutations and recurrence-predictive radiomic signatures restricts the application of radiomics-guided therapy for brain metastases (BMs) from non-small-cell lung cancer (NSCLC). This study aimed to establish an EGFR-associated radiomic signature (EGFR-RS), compare its consistency with that of conventional whole radiomic features-based radiomic signature (WF-RS), and evaluate its efficacy in predicting local recurrence for BMs treated with radiosurgery. METHODS:Brain magnetic resonance (MR) and computed tomography (CT) images of NSCLC patients with BMs undergoing radiosurgery between 2008 and 2020 were examined. The least absolute shrinkage and selection operator was utilized to select features and develop signatures. Discriminative abilities were assessed using the area under the curve, while univariable and multivariable competing risk regression determined predictors and established a clinical-radiomic model. RESULTS:In total, 318 patients with 759 BMs were enrolled. The EGFR-RS, incorporating 11 MR and six CT EGFR-associated prognostic radiomic features, displayed better consistency, and superior predictive performance than the WF-RS, with C-indices of 0.746 (95 %CI 0.616, 0.876) in the test cohort, compared with 0.655 (95 %CI 0.527, 0.784) for the WF-RS. Multivariable analysis indicated EGFR-RS as the sole significant predictor of local recurrence in both the discovery and test sets (P < 0.001, hazard ratio [HR] = 2.75; and P = 0.01, HR = 2.13, respectively). The clinical-radiomic model (EGFR-RS + EGFR mutation status + BM size) outperformed the clinical model in identifying high-risk lesions with local recurrence (discovery: P < 0.001; HR = 4.54; test: P = 0.002; HR = 5.1). CONCLUSION:The multimodal EGFR-RS, demonstrating better consistency than the WF-RS, effectively predicted the local recurrence of NSCLC BMs.

BACKGROUND CONTEXT: Stereotactic spine radiosurgery (SSRS) shows potentials of better tumor and pain control for limited spinal metastases. However, the optimal schedule of SSRS is not well established and has never been investigated in a prospective randomized trial. PURPOSE: To compare 2 SSRS schedules to determine which results in the lowest rate of Grade 3 or higher protocol-specified adverse events at 4 months. STUDY DESIGN: A prospective randomized Phase II trial. PATIENT SAMPLE: Patients with biopsy-proven nonhematogenous malignancy and limited unirradiated spine metastases not requiring upfront spine surgery were eligible. Between November 2015 and April 2019, 69 patients were randomly assigned, yielding a total cohort of 63 analyzable patients with 79 treated spinal segments. OUTCOME MEASURES: Primary outcomes were the 4-month Grade 3 or higher adverse events determined by the Common Toxicity Criteria for Adverse Events version 4.0 (CTCAE) definitely, probably, or possibly related to single fraction or multiple fractions spine SSRS. METHODS: All patients at a single tertiary medical center who had radiographic evidence of limited spine metastases not requiring upfront spinal surgery were randomized to receive 16 Gy in SF or 24 Gy in 3 fractions. A posthoc analysis was performed to assess the cumulative incidences and prognostic factors of local progression (LP) and vertebral compression fracture (VCF) by the Fine and Gray competing risk model. RESULTS: Sixty-three patients (29 with 38 spinal segments in the SF arm and 34 with 41 spinal segments in the MF arm) were analyzed. Median follow-up was 16.6 months. At 4 months, none of the patients in the SF arm and 1 patient in the MF arm experienced protocol-specified grade 3 or higher toxicity. The 1-year cumulative incidence of LP was 2.6% for the SF arm and 4.9% for the MF arm, respectively. The 1-year cumulative incidence of VCF was 7.9% and 10.1% for the SF arm and the MF arm, respectively. CONCLUSIONS: Both single-fraction and multifraction SSRS are safe. There was no difference in cumulative incidence of LP or VCF between 2 dose-fractionation schedules. Single-fraction SSRS is more efficient and provides the most acceptable outcome profile for all assessed endpoints. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Purpose: We aimed to identify the impact of conversion surgery to survival in patients with stage IV esophageal cancer who have a stabilized disease and good treatment response before surgery. Patients and Methods: This retrospective study included patients with esophageal cancer M1 disease treated at a tertiary medical center from April 2002 to June 2021. For patients with a good clinical response to chemoradiation and well-controlled metastatic lesions, esophagectomy and lymphadenectomy were performed. A propensity score-matching (PSM) study with a 1:2 ratio and based on patient age, tumor stage, and metastasis status was conducted for verifying the results. Results: We enrolled 162 patients, including 124 treated with concurrent chemoradiation therapy (CCRT) alone and 38 treated with CCRT followed by esophagectomy. A total of 114 patients were analyzed using PSM, including 76 patients treated with CCRT alone and 38 patients treated with CCRT and surgery. The 3- and 5-year OS was 24.6% vs. 2.8% and 12.3% vs. 1.4% (p = 0.006), and PSM was 24.6% vs. 4.6% and 12.3% vs. 2.3% (p = 0.033) for those with or without esophagectomy, respectively. Multivariate analysis revealed surgery with esophagectomy as an independent prognostic factor for OS with odd ratios (95% confidence interval [CI]) of 1.91 (1.23–2.95) (p = 0.004). Conclusions: Surgical resection following CCRT holds a potential survival benefit for the patients with a favorable response to CCRT for patients with stage IV esophageal cancer.

TPS4213 Background: Locally advanced esophageal squamous cell carcinoma (ESCC) is indicated for multi-modalities treatment strategies, including a neoadjuvant chemoradiotherapy (CRT) followed by surgery. While the CROSS trial established neoadjuvant CRT as a standard of care, distant metastasis remains a significant cause of treatment failure. Immune checkpoint inhibitors (ICIs) have demonstrated survival benefits in advanced or metastatic ESCC, and adjuvant nivolumab has shown efficacy following neoadjuvant CRT in locally advanced ESCC. Integrating ICI earlier in the treatment sequence through total neoadjuvant therapy may enhance the immune response against the primary tumor and the hidden metastases and potentially lead to improved survival outcomes. This phase II study evaluates induction immunochemotherapy followed by CRT before surgery in locally advanced ESCC. Methods: This is a single-center, single-arm, phase II study enrolling 50 patients with histologically confirmed ESCC (T3/4aN0M0 or T1-4aN1-3M0 according to the AJCC Cancer Staging System 8th ed). Eligible patients must have primary intrathoracic esophageal tumor ≤10 cm in length and ≤5 cm in radial diameter, an ECOG performance status of 0-1, and adequate organ function. Patients will receive induction immunochemotherapy consisting of tislelizumab (200 mg every 3 weeks), paclitaxel (175 mg/m² every 3 weeks), and cisplatin (75 mg/m² every 3 weeks) for two cycles. This is followed by CRT consisting of radiotherapy (45 Gy in 25 fractions, 1.8 Gy/day, 5 days/week) plus chemotherapy with weekly paclitaxel (50 mg/m²) and cisplatin (30 mg/m²) for 5 weeks. Esophagectomy will be performed 6 to 8 weeks after completing CRT. The primary endpoint is pathologic complete response (pCR) rate, defined as no residual tumor in the resected primary site and lymph nodes. We hypothesize that the pCR rate will increase from 35% (the historical control) to 55%. Based on a binomial precision design, the study is of 80% power and a unilateral α error of 0.05 to detect a statistically significant difference in pCR rate. Secondary endpoints include major pathological response rate, R0 resection rate, disease-free survival, event-free survival, distant metastasis-free survival, overall survival and safety. The study starts patient enrollment in March 2025 (registered at ClinicalTrials.gov as NCT06764355). Clinical trial information: NCT06764355 .

BACKGROUND:The Skeletal Oncology Research Group machine-learning algorithm (SORG-MLA) was developed to predict the survival of patients with spinal metastasis. The algorithm was successfully tested in five international institutions using 1101 patients from different continents. The incorporation of 18 prognostic factors strengthens its predictive ability but limits its clinical utility because some prognostic factors might not be clinically available when a clinician wishes to make a prediction. QUESTIONS/PURPOSES:We performed this study to (1) evaluate the SORG-MLA's performance with data and (2) develop an internet-based application to impute the missing data. METHODS:A total of 2768 patients were included in this study. The data of 617 patients who were treated surgically were intentionally erased, and the data of the other 2151 patients who were treated with radiotherapy and medical treatment were used to impute the artificially missing data. Compared with those who were treated nonsurgically, patients undergoing surgery were younger (median 59 years [IQR 51 to 67 years] versus median 62 years [IQR 53 to 71 years]) and had a higher proportion of patients with at least three spinal metastatic levels (77% [474 of 617] versus 72% [1547 of 2151]), more neurologic deficit (normal American Spinal Injury Association [E] 68% [301 of 443] versus 79% [1227 of 1561]), higher BMI (23 kg/m 2 [IQR 20 to 25 kg/m 2 ] versus 22 kg/m 2 [IQR 20 to 25 kg/m 2 ]), higher platelet count (240 × 10 3 /µL [IQR 173 to 327 × 10 3 /µL] versus 227 × 10 3 /µL [IQR 165 to 302 × 10 3 /µL], higher lymphocyte count (15 × 10 3 /µL [IQR 9 to 21× 10 3 /µL] versus 14 × 10 3 /µL [IQR 8 to 21 × 10 3 /µL]), lower serum creatinine level (0.7 mg/dL [IQR 0.6 to 0.9 mg/dL] versus 0.8 mg/dL [IQR 0.6 to 1.0 mg/dL]), less previous systemic therapy (19% [115 of 617] versus 24% [526 of 2151]), fewer Charlson comorbidities other than cancer (28% [170 of 617] versus 36% [770 of 2151]), and longer median survival. The two patient groups did not differ in other regards. These findings aligned with our institutional philosophy of selecting patients for surgical intervention based on their level of favorable prognostic factors such as BMI or lymphocyte counts and lower levels of unfavorable prognostic factors such as white blood cell counts or serum creatinine level, as well as the degree of spinal instability and severity of neurologic deficits. This approach aims to identify patients with better survival outcomes and prioritize their surgical intervention accordingly. Seven factors (serum albumin and alkaline phosphatase levels, international normalized ratio, lymphocyte and neutrophil counts, and the presence of visceral or brain metastases) were considered possible missing items based on five previous validation studies and clinical experience. Artificially missing data were imputed using the missForest imputation technique, which was previously applied and successfully tested to fit the SORG-MLA in validation studies. Discrimination, calibration, overall performance, and decision curve analysis were applied to evaluate the SORG-MLA's performance. The discrimination ability was measured with an area under the receiver operating characteristic curve. It ranges from 0.5 to 1.0, with 0.5 indicating the worst discrimination and 1.0 indicating perfect discrimination. An area under the curve of 0.7 is considered clinically acceptable discrimination. Calibration refers to the agreement between the predicted outcomes and actual outcomes. An ideal calibration model will yield predicted survival rates that are congruent with the observed survival rates. The Brier score measures the squared difference between the actual outcome and predicted probability, which captures calibration and discrimination ability simultaneously. A Brier score of 0 indicates perfect prediction, whereas a Brier score of 1 indicates the poorest prediction. A decision curve analysis was performed for the 6-week, 90-day, and 1-year prediction models to evaluate their net benefit across different threshold probabilities. Using the results from our analysis, we developed an internet-based application that facilitates real-time data imputation for clinical decision-making at the point of care. This tool allows healthcare professionals to efficiently and effectively address missing data, ensuring that patient care remains optimal at all times. RESULTS:Generally, the SORG-MLA demonstrated good discriminatory ability, with areas under the curve greater than 0.7 in most cases, and good overall performance, with up to 25% improvement in Brier scores in the presence of one to three missing items. The only exceptions were albumin level and lymphocyte count, because the SORG-MLA's performance was reduced when these two items were missing, indicating that the SORG-MLA might be unreliable without these values. The model tended to underestimate the patient survival rate. As the number of missing items increased, the model's discriminatory ability was progressively impaired, and a marked underestimation of patient survival rates was observed. Specifically, when three items were missing, the number of actual survivors was up to 1.3 times greater than the number of expected survivors, while only 10% discrepancy was observed when only one item was missing. When either two or three items were omitted, the decision curves exhibited substantial overlap, indicating a lack of consistent disparities in performance. This finding suggests that the SORG-MLA consistently generates accurate predictions, regardless of the two or three items that are omitted. We developed an internet application ( https://sorg-spine-mets-missing-data-imputation.azurewebsites.net/ ) that allows the use of SORG-MLA with up to three missing items. CONCLUSION:The SORG-MLA generally performed well in the presence of one to three missing items, except for serum albumin level and lymphocyte count (which are essential for adequate predictions, even using our modified version of the SORG-MLA). We recommend that future studies should develop prediction models that allow for their use when there are missing data, or provide a means to impute those missing data, because some data are not available at the time a clinical decision must be made. CLINICAL RELEVANCE:The results suggested the algorithm could be helpful when a radiologic evaluation owing to a lengthy waiting period cannot be performed in time, especially in situations when an early operation could be beneficial. It could help orthopaedic surgeons to decide whether to intervene palliatively or extensively, even when the surgical indication is clear.

Introduction: The management of early stage NSCLC is evolving with new therapies. Given the lack of guidelines for Asia Pacific, understanding the different factors affecting treatment decisions is key to effective clinical practice. This cross-sectional study describes management patterns for early stage NSCLC in six territories across the region and identifies factors influencing treatment choices. Methods: From June 2022 to July 2023, we recruited lung cancer specialists from public and private health care systems in Australia, Hong Kong, South Korea, Singapore, Taiwan, and Vietnam to complete a survey on treatment considerations in early stage NSCLC among three patient groups based on American Joint Committee on Cancer disease staging. Results: Among 505 physicians screened, 212 were eligible for our study. They frequently screened high-risk individuals. Biomarker testing was common as part of diagnosis and at disease recurrence. Surgery followed by adjuvant chemotherapy, definitive concurrent chemoradiation, and definitive chemoradiation followed by immunotherapy were mostly recommended, depending on disease stage and presence of oncogenic alteration. Variations were observed among territories and specialties. Cisplatin was preferred over carboplatin for both neoadjuvant and adjuvant therapies. Physicians were more likely to prescribe neoadjuvant or adjuvant treatments for patients with lower Eastern Cooperative Oncology Group performance status and/or higher nodal stage. Conclusions: This study revealed that management of early stage NSCLC across Asia Pacific largely follows international guidelines at the time of survey; however, variations exist. Our findings provide useful insights into real-world management patterns in the region and will be valuable in helping clinicians make informed management decisions.

Introduction The management of early-stage non-small-cell lung cancer (NSCLC) is evolving with new therapies. Given the lack of guidelines for Asia Pacific, understanding the different factors affecting treatment decisions is key to effective clinical practice. This cross-sectional study describes management patterns for early-stage NSCLC in six territories across the region and identifies factors influencing treatment choices. Methods From June 2022 to July 2023, we recruited lung cancer specialists from public and private healthcare systems in Australia, Hong Kong, South Korea, Singapore, Taiwan, and Vietnam to complete a survey on treatment considerations in early-stage NSCLC among three patient groups based on American Joint Committee on Cancer disease staging. Results Among 505 physicians screened, 212 were eligible for our study. They frequently screened high-risk individuals. Biomarker testing was common as part of diagnosis and at disease recurrence. Surgery followed by adjuvant chemotherapy, definitive concurrent chemoradiation, and definitive chemoradiation followed by immunotherapy were mostly recommended, depending on disease stage and presence of oncogenic alteration. Variations were observed among territories and specialities. Cisplatin was preferred over carboplatin for both neoadjuvant and adjuvant therapies. Physicians were more likely to prescribe neoadjuvant or adjuvant treatments for patients with lower Eastern Cooperative Oncology Group performance status and/or higher nodal stage. Conclusions This study showed that management of early-stage NSCLC across Asia Pacific largely follows international guidelines at the time of survey; however, variations exist. Our findings provide useful insights into real-world management patterns in the region and will be valuable in helping clinicians make informed management decisions.

In a phase II trial (neo-NTP-CRT, NCT05130684), the efficacy of adding nivolumab to paclitaxel and cisplatin-based neoadjuvant chemoradiotherapy (CRT) was tested in patients with locally advanced esophageal squamous cell carcinoma (ESCC) (n=17). The study reported a pathological complete response (pCR) rate of 24%, a median relapse-free survival and overall survival (OS) of 8 and 16 months, respectively. We conducted this exploratory analysis to investigate the potential immune-related biomarkers. Pretreatment endoscopy-biopsied tumor tissues were analyzed. Immunohistochemistry (IHC) was used to measure PD-L1 expression by clone SP142 (Ventana, Tucson, AZ, USA) on tumor cells (PD-L1-TC), immune cells (PD-L1-IC), and combined positive score (CPS), and to define mature tertiary lymphoid structure (mTLS) according to CD20 and CD23 expression (n=16). The expression of immune-related genes in ESCC tumor tissues was quantitated by PanCancer Immune Profiling and analyzed by nCounter® Analysis System (nanoString, Seattle, WA, USA) (n=12). 12-chemokine TLS signature was also analyzed. The association of PD-L1-TC, PD-L1-IC, CPS, mTLS, and TLS signature with pCR was examined by Chi-square test; the association with OS was examined by log rank test. The differences of various immune cells and immune-related functions between patients with and without pCR was investigated by t-test. pCR rate was significantly higher in the patients with positive PD-L1 TC (100% vs 18%, p=0.019), high PD-L1 IC (100% vs 18%, p=0.019), and CPS≥5 (100% vs 10%, p=0.0006), and trended to be higher in patients with mTLS (50% vs 14%, p=0.19) and higher 12-chemokine TLS signature (75% vs 17%, p=0.077). OS trended to be longer in patients with positive PD-L1 TC (median: not reached vs 15 months; HR: 0.24, p=0.05) and CPS≥5 (median: 26 vs 15 months; HR: 0.19, p=0.069), and patients with high PD-L1 IC had numerically longer OS (median: 25 vs 16 months; HR: 0.42, p=0.38). mTLS was not associated with OS (median: 25 vs 25 months; HR: 0.91, p=0.88); however, patients with higher 12-chemokine TLS signature had better OS (median: 25 vs 14 months; HR: 0.23, p=0.042). The analysis of immune-related gene expression revealed patients with pCR had significantly higher abundance of TILs, lower amounts of Treg, exhausted CD8 T cells, and macrophages. Significantly higher B cell function, cytotoxicity function, and Toll-like receptor function was found in tumors of pCR patients. We found that PD-L1 expression and 12-chemokine TLS signature may be a potential predictor of the response to neoadjuvant nivolumab plus paclitaxel and cisplatin-based CRT. (grants: NCTRC200909, MOST 108-2314-B-002-076-MY3, MOHW 111-TDU-B-221-114006) Ta-Chen Huang, Jhe-Cyuan Guo, Chia-Chi Lin, Hung-Yang Kuo, Chien-Huai Chuang, Jason Chia-Hsien Cheng, Feng-Ming Hsu, Jang-Ming Lee, Pei-Ming Huang, Chih-Hung Hsu. Exploration of potential biomarkers associated with treatment outcomes in locally advanced esophageal squamous cell carcinoma patients receiving neoadjuvant nivolumab plus paclitaxel and cisplatin chemoradiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 744.

Purpose/Objective(s) Metastatic esophageal squamous cell carcinoma (MESCC) poses a significant treatment challenge, with limited responses to conventional chemotherapy. Emerging evidence suggests the promising efficacy of incorporating immune checkpoint inhibitors into standard chemotherapy. Furthermore, studies suggested radiotherapy (RT) might improve the outcomes for patients with MESCC, and preclinical research also demonstrated RT potentially modulates anti-tumor immune response. This study explores the efficacy and safety of integrating Avelumab (Ave) with platinum/5-fluorouracil (PF) chemotherapy and radical hypofractionated radiotherapy (CRT) in treating MESCC, hypothesizing the synergistic and abscopal effects that could translate to clinical benefits. Materials/Methods In this prospective phase II trial, patients with biopsy-proven non-T4 MESCC, satisfactory performance status, and adequate organ function were eligible. The protocol systemic therapy regimen consisted of cisplatin or carboplatin plus 5-fluorouracil administered every 4 weeks for up to six cycles, alongside Avelumab (10 mg/kg) biweekly. Radiotherapy was delivered to the primary tumor and adjacent metastatic nodes with a total dose of 45 Gy in 15 fractions. Treatment efficacy was evaluated using RECIST 1.1 and iRECIST, while adverse events were assessed via CTCAE. The primary endpoint was the overall radiographic response rate at 6 months after treatment starts, with survival outcomes analyzed using the Kaplan-Meier method. Results From 2019 to 2022, 33 patients were screened and 26 were enrolled to receive the protocol treatment. The study cohort predominantly featured male participants (92%) with the most common metastasis sites being bone (73%), followed by lung and liver (each 65%), and distant nodes (54%). Most patients (77%) had oligo-metastatic disease (metastatic number < 5). All patients completed RT while 15 (58%) received ≥ 5 cycles of protocol systemic therapy. Only two patients halted Ave use due to grade 3 immune-related adverse events. At 6 months, 20 patients were eligible for response evaluation and the radiographic response rate was 75% (95% confidence interval 54%–96%). The median overall survival was 13.3 months (95% confidence interval 9.1–17.5 months) while the median progress-free survival was 6 months (95% confidence interval 3.3–8.7 months). At the last follow-up, 4 patients remained alive and progression-free for more than 30 months after protocol treatment. Conclusion The initial findings indicate that Ave-PF-CRT is a feasible and potentially effective treatment for MESCC, with manageable toxicity, acceptable compliance, and clinical benefits. Notably, a subset of MESCC patients could achieve long-term disease control after Ave-PF-CRT. This approach warrants further validation in larger cohorts to confirm its efficacy and safety.

INTRODUCTION:This study explored the failure pattern and clinical outcomes in patients with ependymoma undergoing radiotherapy. METHODS:Between January 2004 and June 2022, we included 32 patients with ependymoma who underwent radiotherapy as part of the multimodality treatment at our institution. Of these, 27 (84.4%) underwent adjuvant radiotherapy, four received radiotherapy after local recurrence, and one received definitive CyberKnife radiotherapy (21 Gy in three fractions). The median prescribed dose was 54 Gy in patients who received conventional radiotherapy. We analyzed the local progression-free survival (LPFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), overall survival (OS), and potential prognostic factors. RESULTS:The median age was 29.8 years. Approximately 28.1% were pediatric patients. Fifteen tumors (46.9%) were World Health Organization (WHO) grade II, 10 (31.3%) were WHO grade III, and seven (22.8%) were WHO grade I. Among them, 15 patients (46.9%) had posterior fossa tumors, 10 (31.3%) had supratentorial tumors, and seven (22.8%) had spinal tumors. Of the 31 patients who underwent upfront surgical resection, 19 (61.3%) underwent gross total resection or near-total resection. Seventeen of 19 patients with first failures (89.5%) had isolated local recurrences. Of the 19 patients with disease progression, 11 (57.9%) were disease free or had stable disease after salvage therapy, and five (26.3%) had disease-related mortality. Most of the first local recurrences after radiotherapy occurred infield (13 of 16, 81.3%). The 5-year LPFS, DMFS, PFS, and OS rates were 48.5%, 89.6%, 45.1%, and 88.4%, respectively, at a median follow-up of 6.25 years. Subtotal resection was associated with poorer LPFS and PFS in patients with intracranial ependymoma (hazard ratio = 3.69, p = 0.018, for LPFS; hazard ratio = 3.20, p = 0.029, for PFS). CONCLUSION:Incorporating radiotherapy into multimodal treatment has led to favorable outcomes in patients with ependymoma, and the extent of resection is a prognostic factor for the local control of intracranial ependymoma.

This study focused on the chemistry of sedimentary pore fluids to clarify hydrothermal fluid migrating within sediments at the Geolin Mounds (GLM) and Mienhua Volcano (MHV) hydrothermal fields, southernmost Okinawa Trough, where are characterized by covering of thick sediment. The significant downward decrease in Mg2+ (low to 23.3 mmol L-1) and concurrent increase in Li+ (up to 2,269 mu mol L-1) in sedimentary pore fluids implied a substantial influence of hydrothermal fluid, which might be associated with high-temperature (>350 degrees C) rock/sediment-fluid interaction. The best fitting of the 1-D advection-diffusion equation to pore-fluid Cl-, Mg2+, and Li+ concentrations further evidenced the upward hydrothermal through sediments with rates of 0.13 similar to 124 cm yr(-1). The apparently Cl-depleted and slightly Cl-enriched pore fluids in the GLM and MHV hydrothermal fields supported the occurrence of subseafloor phase separation and classified their hydrothermal fluids into vapor-rich and brine-rich phases, respectively. The low pH values (pH = 5.67 similar to 6.21) with downward increasing trends of pore-fluid dissolved inorganic carbon (DIC, up to 60 mmol L-1) and its heavy isotopic compositions (delta C-13(DIC) = +2.5 similar to +7.0 parts per thousand) inferred in-situ liquid CO2-impregnated sedimentary circumstance in the GLM and MHV hydrothermal fields. This sedimentary environment, as demonstrated, enhanced the chemical weathering of silicate and carbonate minerals, resulting in the elevated concentrations of Ca2+ and K+ in pore fluids. It highlights the impact of acidic and in-situ CO2-saturated fluids within sediments on geochemical alterations of bulk solids/sediments and interstitial fluids.