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Synthesis of Fe3O4-NPs using Ziziphus spina-christi(L) and Azadirachta indica leave extract and study of its biological activity

Glucose‐Oxidase Conjugated Cerium Oxide‐Based Super Nanozyme for Rapid MRSA Eradication and Wound Closure

ABSTRACT The global rise of antibiotic‐resistant pathogens poses a serious challenge to public health, particularly in the healing of infected chronic wounds. Innovative, safe, and therapeutically adaptive strategies are urgently required to combat antimicrobial resistance (AMR) pathogens. A glucose‐oxidase conjugated cerium oxide nanoparticle (CeO 2 NPs‐GOx)‐based nanozyme displaying oxidase‐mimetic activity at physiological pH and wound exudate is developed. The conjugate displays potent antibacterial activity and eradication of β‐lactamase‐producing clinical isolates of methicillin‐resistant Staphylococcus aureus (MRSA) by producing superoxide and hydroxyl radicals in the presence of adenosine triphosphate (ATP) and glucose. Microscopic imaging, lactate dehydrogenase (LDH) release and lipid peroxidation assays revealed compromised bacterial cell wall structure and release of cytoplasmic contents due to the continuous production of free radicals. The in vivo MRSA‐infected wound data showed that application of CeO 2 NPs‐GOx led to infection clearance within a week, as well as better wound closure than vancomycin. Upon CeO 2 NPs‐GOx treatment, wound tissues undergo enhanced re‐epithelialization, collagen deposition, and angiogenesis, while reduced production of pro‐inflammatory cytokines (IL‐6, TNF‐α, and IL‐1β). CeO 2 NPs‐GOx exposure displayed almost no accumulation rather rapid clearance of nanozymes from the body. Overall, this study establishes CeO 2 NPs‐GOx as an effective antibacterial nanozyme, integrating ATP‐assisted oxidase‐mimetic activity, exhibiting reactive oxygen species (ROS)‐mediated elimination of MRSA infection from wounds. Thus, the developed novel CeO 2 NPs‐based nanozyme offers an alternative to antibiotics for clinical translation and effective control of AMR spread.

Metamaterial Antennas Enhance MRI of the Eye and Occipital Brain

ABSTRACT A metamaterial‐integrated radio frequency antenna (MTMA), implemented in planar and bend configurations, enables high‐resolution MRI of the eye, orbit, and occipital brain at 7.0 T. Its dual‐layer co‐planar architecture integrates a two‐channel transceive loop with a metamaterial layer composed of subwavelength epsilon‐negative unit cells. These unit cells were custom‐designed based on classical split‐ring resonators for operation at 7.0 T. Electromagnetic simulations, including human voxel models, guided the design and characterization of the MTMA's electromagnetic behavior. Both MTMA configurations were benchmarked against conventional loop coil arrays in phantoms and in vivo for experimental validation, demonstrating enhanced transmit (B 1 + ) efficiency and receive sensitivity enabled by the metamaterial layer through resonant near‐field coupling. MRI safety was verified through SAR simulations, bio‐thermal modeling, Magnetic Resonance thermometry, and fiber‐optic sensors, confirming compliance with safety guidelines. The Bend‐MTMA enabled in vivo human MRI of the eye and orbit in healthy volunteers, including B 1 + mapping, and provided diagnostic T 1 ‐ and T 2 ‐weighted imaging in volunteers with retinal pathology and sinus cysts, demonstrating clinical applicability. The Planar‐MTMA enabled occipital lobe MRI in human volunteers, achieving superior signal coverage and transmit performance. The modular unit cell design enables tuning across MRI magnetic field strengths, establishing a clinically translatable metamaterial‐integrated antenna platform for ocular and neurological imaging.

Biology-driven lead-time considerations for endocrine therapy de-escalation in elderly patients with favorable breast cancer.

e12726 Background: Small breast cancers are generally assumed to have a favorable prognosis because of their limited size. However, whether small tumor size itself confers a good prognosis or merely reflects indolent tumor biology remains unclear. This distinction is particularly relevant when considering treatment de-escalation in elderly patients with hormone receptor–positive breast cancer. Methods: We retrospectively analyzed 1,058 patients with surgically treated invasive breast cancer (cohort 1), including 944 patients with HER2-negative disease (cohort 2), treated between 2007 and 2020. Tumors were classified into favorable, intermediate, and unfavorable prognostic groups based on estrogen receptor (ER), progesterone receptor (PR), and nuclear grade (NG). Tumor size distribution, age distribution, and breast cancer–specific survival (BCSS) were evaluated across groups. The impact of adjuvant endocrine therapy was explored in the favorable subgroup. Results: Biologically favorable tumors were disproportionately represented among small tumors, whereas unfavorable tumors were more prevalent among larger tumors. Favorable tumors demonstrated excellent long-term BCSS regardless of tumor size, and patients with larger favorable tumors had better outcomes than those with smaller unfavorable tumors. The distribution of favorable tumor biology was similar across age groups, suggesting that biological indolence is not age-dependent. In the favorable subgroup, no significant difference in BCSS was observed between patients who did and did not receive adjuvant endocrine therapy, although this analysis was limited by its retrospective and non-randomized nature. Conclusions: Our findings suggest that small tumor size is more likely a consequence of favorable tumor biology than an independent determinant of prognosis. When tumor biology is considered alongside patient age and life expectancy, selected elderly patients with favorable, hormone receptor–positive breast cancer may derive limited absolute benefit from adjuvant endocrine therapy. These results support a biology- and time-informed framework for individualized treatment decision-making and warrant prospective evaluation of endocrine therapy de-escalation strategies.

Genomically personalized radiation dose de-escalation: A phase II basket radiation study in patients with pathogenic mutations in <i>ATM</i> .

3015 Background: ATM (ataxia-telangiectasia mutated) is a key DNA damage response gene, and pathogenic variants are known to cause a rare hereditary syndrome notable for extreme radiosensitivity. Somatic ATM inactivation is associated with markedly improved tumor control following RT. We hypothesized that ATM -mutant tumors could achieve effective local control with substantially lower RT doses, reducing normal tissue toxicity. This concept of genomically personalized radiation dose de-escalation was tested in a phase II trial. Methods: We conducted a single-arm phase II trial of low-dose RT in patients with metastatic solid tumors harboring pathogenic ATM mutations. Eligible patients had radiographic progression suitable for palliation and all patients received 4Gy x 2 fractions- 60% reduced compared to conventional 4Gyx5 palliation- delivered to a target lesion. The primary endpoint was 6-month local failure rate (radiographic progression or re-irradiation) and benchmarked against historical local failure control rates of 82% for 4Gyx5 standard palliation, with pre-specified analysis conducted at this initial dose level. Toxicity was graded by CTCAE criteria. Results: Twenty-one patients (across 9 histologies; 3 germline ATM , 18 somatic) were enrolled. At 6 months, 12 patients were evaluable; 10 of 12 (83.3%) achieved local control with the 4Gyx2 regimen. Notably, this included a 4.4cm angiosarcoma with a complete response by 6 months- an exceptional outcome with such a low dose. Two patients (16.7%) had local failure by 6 months. Both of these tumors retained ATM protein expression by immunohistochemistry and harbored concurrent pathogenic TP53 mutations. In contrast, molecular analysis confirmed biallelic ATM loss in four patients, including the top three responders. No grade ≥2 toxicities or other significant RT-related side effects were observed. Conclusions: ATM -mutant tumors were effectively controlled with markedly reduced RT dose (4Gyx2), achieving local control in 83% of lesions at 6 months, comparable to historical response rates with standard palliation (4Gyx5), but with minimal toxicity. Additionally, FACETS analysis showed a stronger correlation with treatment response than germline vs. somatic mutation status, suggesting that FACETS analysis could be more informative in determining eligibility criteria for future clinical trials. These preliminary findings establish ATM as a novel biomarker for personalized RT dose de-escalation and compel further investigation into ATM as a therapeutic target. Clinical trial information: NCT05010031 .

Global and regional economic burden of alcohol-attributable cancers: A benchmarking analysis.

e23105 Background: Alcohol consumption is responsible for 6–8% of global cancer deaths, but comprehensive regional economic estimates are lacking. We quantified direct and indirect economic burdens of alcohol-related cancers worldwide using GBD 2023 data. Methods: Alcohol-attributable cancer burden was assessed for all cancer types across 189 countries using the GBD 2023 comparative risk assessment framework. Major sites included colorectal (30.8% of total alcohol-related cases), liver (28.4%), breast (18.7%), and esophageal (14.6%). Population-attributable fractions (PAF) were derived from pooled estimates of 2,281 epidemiologic studies. Direct medical costs encompassed diagnostics, chemotherapy, radiotherapy, surgery, and palliative care; indirect costs included productivity losses from premature mortality and morbidity. Expenditures were adjusted by regional GDP per capita. Results: In 2023, alcohol-related cancers caused 842,000 deaths globally (8.1% of all cancer mortality), resulting in 18,400,000 DALYs. Total annual direct medical costs were $156 billion USD, while indirect costs from lost productivity and informal care reached $198 billion USD. Liver cancer imposed the greatest annual direct economic burden ($67.4 billion), followed by colorectal ($52.1 billion), breast ($23.8 billion), and esophageal cancer ($21.4 billion). Low- and middle-income countries (LMICs) accounted for 61% of global alcohol-related cancer deaths but received only 28% of direct healthcare expenditures. In contrast, high-income countries spent an average of $89,400 per patient versus $6,200 in low-income settings. Between 2000 and 2023, alcohol-attributable cancer burden rose by 54% globally, surpassing the growth in all-cancer burden (37%). Countries with active alcohol reduction policies (e.g., Australia, Canada, Nordic countries) exhibited 8–12% lower incidence of alcohol-attributable cancers compared to those without such policies. Regional mortality hotspots were identified in Eastern Europe and Southern Africa, where alcohol-related cancers comprised 18–24% of all cancer deaths. Modeling suggests that implementing alcohol taxation and expanding treatment access in LMICs could prevent approximately 184,000 alcohol-related cancer deaths annually. Conclusions: Alcohol-related cancers are responsible for over $350 billion USD in annual global economic losses, with a rapidly rising burden in LMICs and pronounced treatment disparities. Policy-based reductions in harmful alcohol use are urgently needed to mitigate preventable deaths and improve global cancer control.

The TIME trial: Phase II randomized controlled trial of time-of-day–specified nivolumab and ipilimumab for advanced melanoma.

TPS2677 Background: Nivolumab/ipilimumab is standard of care for advanced melanoma patients based on Phase III randomized data from the CheckMate 067 trial. The recent 10-year outcomes results were reported with a melanoma specific survival for Nivolumab/ipilimumab of 52%. These data are very encouraging, but 50% of patients still succumb to their disease by 10-years. Preclinical data suggests that the circadian rhythm may influence the anatomic localization, function and activity of T cells, the target of immunotherapy. More T cells in the tumor or tumor-draining lymph node during initial immunotherapy administration may improve clinical responses and long-term outcomes. To investigate this idea, we performed a retrospective analysis, the MEMOIR study, finding that more evening infusions of immunotherapy were associated with significantly worse progression free and overall survival for metastatic melanoma patients. These findings have now been reproduced in other cancer histologies, in a larger meta-analysis, and in pre-clinical mechanistic studies. Considering these data, we hypothesize that evening infusions of immunotherapy will have worse progression free survival than either morning or midday infusions. Methods: The TIME trial is a three-arm phase II study of time-of-day specified administration of standard dose nivolumab/ipilimumab for metastatic melanoma. For newly diagnosed metastatic melanoma patients enrolled on study, they will be randomized to receive 4 cycles every 3 weeks of nivolumab/ipilimumab between 8:00-11:00 (Arm A), 11:00-14:00 (Arm B), or 14:00-17:00 (Arm C). Following these 4 cycles, they will receive standard of care maintenance nivolumab in a time-of-day agnostic fashion. Eligible patients must have stage IV unresectable cutaneous, acral or mucosal melanoma, no prior immunotherapy within 1 year, ECOG performance status of 0-1, age ≥ 18, no symptomatic or hemorrhagic brain metastases with none greater than 2 cm. The primary objective is to determine whether progression free survival for Arm A or Arm B is superior to Arm C. Secondary objectives include assessments of adverse events, melanoma specific survival and overall survival. We will evaluate the immune profiles of blood and tumor to assess the impact of time of drug administration on the circulating immune responses and the tumor immune microenvironment. 99 patients will be enrolled to detect a HR of 0.50 with at least 80% power and a Type 1 error rate of 0.1 (2-sided) for a comparison of A vs. C, and B vs. C. The study is open at Emory and has enrolled 3 patients; the study is undergoing regulatory review at MGH and Cedars-Sinai. Clinical trial information: NCT07155317 .

A prospective observational study to compare the efficacy, time toxicity, and cost of conventional 3+7 regimen versus azacitidine + venetoclax (AZA + VEN) as induction therapy in patients with acute myeloid leukemia (AML).

6511 Background: In low-middle income countries, 3+7 induction therapy for AML is associated with high induction mortality (7-40%), more so in patients with infections at diagnosis. Given the activity of AZA+VEN, a considerable proportion of patients with high-risk features (infections at diagnosis, poor-risk AML, poor performance status, multiple comorbidities, elderly) or long-waiting for admission to start induction are treated with AZA+VEN and 3+7 regimen use is limited to young, fit and good/intermediate risk groups. However, it is important to understand if use of AZA+VEN in this setting provides similar efficacy and is safe without increasing the cost of therapy and time-toxicity as defined by the contact days with healthcare system. Ideally a randomized controlled trial is needed to answer this question, however physicians’ unwillingness to randomize patients at high-risk of induction mortality to 3+7 regimen would challenge the feasibility of such trial. Methods: A prospective observational study enrolled consecutive de-novo AML patients aged ≥18-years after written informed consent who were planned for treatment by a multi-disciplinary joint clinic with either 3+7 or AZA+VEN. The primary endpoint was induction mortality, with secondary endpoints of grade 3/4 toxicity, treatment cost, time toxicity, complete response/complete response rate with incomplete count recovery rates (CR/CRi) assessed after one course. Results: 154 participants were included (3+7 -73, AZA+VEN-83). Median age was 35 years in 3+7 as compared to 44 years in Aza-Ven group. The AZA+VEN group was enriched for high-risk features – ECOG PS ≥2 (10.9% vs 33.3%), baseline fungal pneumonia (4.1% vs 50%), poor-risk profile as per ELN 2022(12.3% vs 24.7%). The primary reasons for starting AZA+VEN were active infection (65.4%), poor-risk disease (28.4%), delay in admission (16%), and poor performance status (8.6%). Induction mortality was comparable between 3+7 and AZA+VEN (8.2% vs 7.5%). Toxicities were higher with 3+7; febrile neutropenia (95.9% vs 79.7%), new-onset bacterial infections (49.3% vs 19.0%) with multidrug resistant bacterial sepsis (32.9% vs 9.1%), and new-onset fungal pneumonia (27.4% vs 15.2%). The median treatment cost was higher with 3+7 (227,790 INR) compared to AZA+VEN (184,694 INR). Time toxicity (26.0±0.8 vs 19.0±0.9 days) and duration of hospitalization (26.0±0.9 vs 18.0±2.1 days) were higher in the 3+7. CR/CRi rates were higher with 3+7 (80.6% vs 57.1%), including higher CR (52.2% vs 27.1%) and flow-MRD negativity (71.6% vs 41.9%) driven by the favorable risk profile in this group. Conclusions: The study demonstrated that AZA+VEN in patients who are at high-risk of induction mortality provides a valuable alternative with better safety and reduced financial burden and time toxicity.

Real-world time-to-event detection of immune-related adverse events from electronic health records using clinical natural language processing.

e13650 Background: Immune-related adverse events (irAEs) are a major challenge in immune checkpoint inhibitor (ICI) therapy. In real-world practice, irAEs are often documented in unstructured clinical narratives, limiting systematic surveillance. We evaluated the feasibility of detecting irAEs from clinical narratives in electronic health records (EHRs) using a natural language processing (NLP) pipeline in a large real-world cohort. Methods: We conducted a retrospective cohort study using EHR data from a single tertiary hospital (2004–2023). Among 177,535 patients, 57,658 had cancer. Patients with cancer prescribed ICIs were compared to patients with cancer without documented ICI prescriptions using 1:1 nearest-neighbor propensity score matching. Clinical narratives were analyzed using MedNERN-CR-JA, a BERT-based Japanese medical NLP pipeline, to extract irAE-labeled entities. The primary outcome was time to first NLP-detected irAE per patient, defined as the earliest documentation of either an organ-attributed irAE entity or a generic “irAE” mention. Time-to-event analyses were performed using Kaplan–Meier and Cox proportional hazards models. All clinical notes from the matched cohort were manually reviewed at the note level as a reference standard by a trained pharmacy student and an oncology-certified pharmacist, then aggregated to patient-level classifications and assessed for misclassification, with correction of misclassified cases and qualitative error analysis. Results: After matching, 1,160 patients were included in each group. NLP-detected irAEs occurred in 18.8% of ICI-treated patients, compared with 0.9% in matched patients with cancer without documented ICI prescriptions, consistent with known real-world irAE frequencies, and were strongly associated with ICI exposure (hazard ratio: 23.72, 95% confidence interval: 12.94–43.48). Organ-specific irAEs explicitly mentioned in clinical narratives were identifiable using the NLP pipeline, and irAEs normalized as non-organ-specific entities could be retrospectively mapped to specific organs through manual chart review. Manual review revealed few false-positive patient classifications, mainly due to differential diagnoses or precautionary statements without active symptoms. Conclusions: Clinical NLP enables scalable, real-world detection of irAEs from unstructured EHR narratives and efficient identification of an irAE-enriched cohort, substantially reducing the population requiring detailed review. This framework supports robust time-to-onset analyses and facilitates future investigations of longer-term outcomes, such as symptom resolution, that typically require extended follow-up. These results support the feasibility of NLP-based irAE surveillance and its potential role in scalable, real-world safety evaluations of ICI therapy.

Liver transplantation for unresectable colorectal liver metastases: A systematic review and meta-analysis of survival outcomes.

e15548 Background: Patients with unresectable colorectal liver metastases (uCRLM) have limited long-term survival with conventional systemic and locoregional therapies. Liver transplantation (LT) has re-emerged as a potential curative strategy in highly selected patients, but comparative evidence remains fragmented. We performed a systematic review and meta-analysis to evaluate survival outcomes of LT compared with best alternative non-transplant therapies (BAT) in uCRLM. Methods: PubMed, Embase, and Cochrane CENTRAL were systematically searched from inception through November 2025 for studies including adults with uCRLM treated with LT. Randomized and non-randomized comparative studies and non-comparative cohorts were eligible. Overall survival (OS) was the primary outcome. Hazard ratios (HRs) were pooled using a random-effects model. Risk of bias was assessed using RoB 2 for randomized trials and ROBINS-I for non-randomized studies. A leave-one-out sensitivity analysis was performed. Results: Seventeen studies met inclusion criteria, including one randomized controlled trial and sixteen non-randomized studies. Three comparative studies (TransMet 2024, Serenari 2025, Byrne 2024) provided data suitable for meta-analysis. LT was associated with significantly improved OS compared with BAT (pooled HR 0.45, 95% CI 0.28–0.72; P = 0.0009), with low statistical heterogeneity (I² = 3%). Sensitivity analysis identified the TransMet trial as the primary contributor to statistical significance; exclusion of this study attenuated the effect (HR 0.64, 95% CI 0.30–1.35). Non-comparative cohorts consistently reported favorable outcomes, with 1-year OS approaching 100% and 5-year OS ranging from 60% to 83% in biologically selected populations. Despite high overall survival, recurrence remained common, with disease-free survival typically limited to 8–17 months, predominantly involving lung-dominant relapse patterns. Conclusions: In selected patients with uCRLM, liver transplantation is associated with significantly improved overall survival compared with non-transplant strategies. These findings support LT as a viable treatment option in carefully selected patients, while underscoring the importance of biological selection and prospective validation. Comparative Overall Survival Outcomes in Studies Included in the Meta-analysis. Study (Year) Study Design Comparator Patients (LT / Control) Outcome Effect Estimate TransMet (2024) Randomized controlled trial Chemotherapy 45 / 45 Overall survival HR 0.37 (95% CI 0.21–0.65) Serenari (2025) Prospective cohort ALPPS 13 / 21 Overall survival HR 1.40 (95% CI 0.63–3.09) Byrne (2024) Prospective cohort Best alternative therapy 20 / 13 Overall survival HR 0.23 (95% CI 0.02–2.25) Pooled estimate Random-effects model — — Overall survival HR 0.45 (95% CI 0.28–0.72) HR &lt;1 favors liver transplantation.

Febrile neutropenia prophylaxis with prolonged G-CSF in elderly cancer patients: Analysis from the EMPREREAL study.

e13773 Background: Guidelines consider age ≥ 65 years a key factor in recommending primary prophylaxis with granulocyte colony-stimulating factors (G-CSFs) for patients receiving chemotherapy regimens with an intermediate risk (10-20%) of febrile neutropenia (FN). There is limited evidence on neutropenia outcomes in elderly patients receiving prolonged G-CSF. We report a prespecified analysis of elderly patients from the EMPEREAL study assessing chemotherapy-induced neutropenia (CIN) of any grade, FN, and dose-limiting neutropenia (DLN). Methods: EMPEREAL is an observational prospective cohort study of 2384 cancer patients receiving chemotherapy (CT) and primary FN prophylaxis with prolonged G-CSF empegfilgrtastim. Patients were followed up for up to five cycles of CT. Number and proportion of patients with FN, CIN of grade 4, grade 3-4, grade 1-4 and DLN in the elderly cohort are presented. Results: The EMPEREAL study included 634 patients (26.6%) aged ≥65 years. Their mean age was 69 years, 65/634 (10.3%) were aged ≥75 years, 2/634 (0.3%) were aged ≥85 years. 468/634 (73.8%) were females. Primary sites for the malignancies included breast cancer (51.4%), digestive cancer (24.0%), lung cancer (8.5%). Most patients (93.8%) had ECOG 0–1. One-third of the patients (31.2%) had received previous systemic therapy. About half (52.5%) pts had a regimens with 10–20% FN risk and 38,5% pts had a regimens with ≥20% risk, Included dose-dense regimens in 12,4 %. 598/634 (94.3%) had at least one risk factors for FN additional to age (median number of additional risk factors was 2): advanced stage (22.9%), female gender (73.8%), Hb &lt; 12 g/dL (26.0%), previous radiation therapy (8.2%), renal or liver failure or heart disease (48.6%), malnutrition (4.4%), history of febrile neutropenia (3.0%). There were no data on neutropenia available for 57/634 (9.0%) patients. FN, CIN of any grade and DLN were registered in 0/577 (0%), 61/577 (15.1%) and 6/577 (1.6%), respectively (Table 1). Conclusions: These results support the effectiveness of primary prophylaxis with empegfilgrastim in routine practice for elderly patients. Clinical outcomes at the patient level. FN 0 (0.0%) CIN grade 4 6 (1.6%) CIN grade 3-4 7 (1.8%) CIN grade 1 through 4 61 (15.1%) DLN 6 (1.6%)

Temporal trends in early-phase oncology trials in Brazil.

e23427 Background: With improvements in regulatory frameworks, early-phase oncology research is increasingly expanding into Latin America, particularly Brazil. Beyond capacity expansion, conducting Phase I trials in Brazil enables the enrollment of a highly diverse and historically underrepresented population, potentially enhancing the generalizability of early safety and efficacy signals. This study aimed to characterize the landscape and temporal trends of early-phase oncology drug development in Brazil. Methods: We searched the ClinicalTrials.gov database from inception through December 13, 2025, for Phase I and Phase I/II clinical trials with “cancer” listed as a condition and at least one study site in Brazil. For each trial, we manually identified all listed research facilities and extracted historical version updates to determine recruitment start and end dates for each site. We calculated facility-days (number of facilities multiplied by recruitment days) for each time frame and study-days (number of studies multiplied by recruitment days) for each trial site. Temporal trends were evaluated across four periods (2005–2010, 2011–2015, 2016–2020, and 2021–2025) using Cochran–Armitage tests, while differences between periods were assessed using Kruskal–Wallis and Fisher exact tests. Results: Of 135 cancer trials identified (44 Phase I and 91 Phase I/II), duplicates, non-cancer trials, and trials whose listed locations were never recruiting were excluded. The final cohort comprised 86 trials, including 30 Phase I and 56 Phase I/II trials. A positive temporal trend was observed in both the number of trials and median facility-days across study periods, increasing from 4 trials in 2005–2010 to 9 in 2011–2015, 17 in 2016–2020, and 56 in 2021–2025. Median facility-days rose significantly from 376 days in 2005–2010 to 1.568 days in 2021–2025 (p = 0.031). Trials were predominantly concentrated in the Southeast (93%) and South (71%) regions. ICESP/HC-FMUSP was the leading site, with 11.366 days of open accrual, followed by the Instituto Nacional de Câncer with 11.174 study-days. Subgroup analysis of Phase I trials (N = 30) mirrored these trends, increasing from 2 trials in 2005–2010 to 17 in 2021–2025, with a corresponding rise in facility-days (p = 0.021). Conclusions: Early-phase oncology trials in Brazil have increased over time, particularly in the last five years, reflecting growing national capacity for early-phase clinical research and an expanding role in the global oncology drug development landscape.

Distribution and density of tertiary lymphoid structures as predictors of clinical outcomes and immunotherapy responses in gallbladder cancer.

4127 Background: Gallbladder cancer (GBC) is an aggressive malignancy with limited treatments and is often immunologically “cold.” Tertiary lymphoid structures (TLS) are key regulators of antitumor immunity, but their spatial heterogeneity and clinical impact in GBC remain unknown. This study explores how TLS distribution and maturation influence outcomes and immunotherapy response in GBC. Methods: We analyzed 99 GBC patients who underwent curative resection (2015–2020). H&amp;E and multiplex immunohistochemistry(mIHC) identified TLS number, maturation, and spatial distribution. TLS were categorized into intratumoral (T) and peritumoral (P) regions. Novel TLS scores (T score, P score) were developed to quantify TLS abundance and correlate with overall survival (OS). Pre-treatment samples from anti-PD-1-treated advanced GBC patients were assessed for TLS association with immunotherapy response. Patient-derived xenograft (PDX) models were used to compare tumor progression and anti-PD-1 efficacy between TLS-high and TLS-low groups. Results: T score correlated with improved OS (p &lt; 0.001), while P score negatively correlated with OS (p &lt; 0.001). Intratumoral TLS contained more Fol-I/Fol-II structures; peritumoral TLS were predominantly Agg (p &lt; 0.001). Responders to immunotherapy had higher intratumoral TLS scores (median 2.5 vs. 0.5, p &lt; 0.01), TLS numbers (8.0 vs. 3.0/ROI, p &lt; 0.05), and TLS area (29.0% vs. 12.0%, p &lt; 0.05). Intratumoral TLS showed higher CD8⁺ T cells, CD4⁺ T cells, and Tfh cells (all p &lt; 0.05), whereas peritumoral TLS were enriched in Tregs (p &lt; 0.01). Higher T scores linked with increased CD8⁺ T cells, Tfh cells, CD21⁺CD23⁺ FDC, and LAMP3⁺ DCs, but decreased Tregs and M2 macrophages (all p &lt; 0.05). An immune classification based on T/P scores stratified patients into four prognostic subgroups with distinct OS (p &lt; 0.001). In PDX models, TLS-high tumors progressed slower (p &lt; 0.05) and responded better to anti-PD-1 therapy(p &lt; 0.01). Conclusions: TLS spatial distribution in GBC exerts opposing prognostic effects: intratumoral TLS promote antitumor immunity, while peritumoral TLS may support tolerance. TLS-high tumors show greater sensitivity to immunotherapy. A TLS-based immune classification may guide personalized treatment.

Generalized integral transform technique (GITT) in tumor dynamics: A technical qualitative review for translational oncology.

e13645 Background: Mathematical models of tumor growth, invasion, cell–matrix interactions, and therapeutic response commonly rely on nonlinear partial differential equations (PDEs), which become analytically and numerically challenging under realistic geometry, heterogeneity, anisotropy, and treatment forcing. The Generalized Integral Transform Technique (GITT) provides a semi-analytical framework that projects PDEs onto eigenfunction bases, reducing them to coupled ordinary differential equations (ODEs) while preserving spatial structure and improving analytical transparency in tumor modeling. Methods: A technical narrative review examined GITT-based tumor models, including avascular or vascular growth (41%), chemotaxis/haptotaxis-driven invasion (28%), tumor–immune interactions (19%), and intra- or extracellular drug transport (12%). Qualitative synthesis with descriptive quantitative analysis evaluated the impact of modal projection on PDE restructuring, dimensionality reduction, and interpretable temporal dynamics; Pearson correlation assessed associations among modal truncation efficiency, numerical stability, computational cost, and accuracy preservation. Results: GITT application was consistently associated with methodological advantages. Improved numerical stability in nonlinear regimes was reported in 87% of studies (95% CI 79–93), and reduced computational cost without loss of spatial resolution in 70% (95% CI 60–79). In invasion models, 82% (95% CI 73–90) achieved clearer representation of anisotropy and directional migration. Among tumor–immune and therapy-response models, 74% (95% CI 63–83) enabled improved discrimination of elimination, equilibrium, and escape regimes through dominant spectral modes. Models incorporating fractional operators demonstrated stable behavior in all cases (100%; 95% CI 88–100). Modal truncation efficiency correlated positively with numerical stability (r = 0.58, p &lt; 0.01) and negatively with computational cost relative to accuracy preservation (r = −0.46, p &lt; 0.05). Conclusions: GITT emerges as a robust semi-analytical approach in tumor modeling, enhancing numerical stability, reducing computational burden, and preserving spatial fidelity. Modal decomposition facilitates interpretation of nonlinear dynamics and biologically relevant mechanisms, supporting GITT as a mature tool for comparative and multiscale analyses of tumor dynamics. Summary of GITT contributions in tumor modeling. Component Role GITT Contribution Geometry Spatial constraints Eigenfunction encoding PDEs Transport and reactions Conversion to ODEs Modal structure Space–time separation Stability and interpretability Nonlinearity Growth and taxis Modal coupling Therapy Drug and immune effects Semi-analytical assessment

Indirect comparison of nivolumab-ipilimumab versus chemotherapy (Chemo) and/or immunotherapy in dMMR/MSI-H metastatic colorectal cancer (mCRC) using reconstructed individual patient data (IPD).

3579 Background: In patients with dMMR/MSI-H mCRC, phase III randomized trials have established immune checkpoint (IO) inhibition as a key first-line strategy. In KEYNOTE-177, pembrolizumab demonstrated superior outcomes vs chemo, supporting an IO-first approach. In CheckMate 8HW, nivolumab plus ipilimumab (Nivo+Ipi) outperformed both nivolumab and chemo, demonstrating benefit from dual checkpoint blockade. In contrast, COMMIT evaluated FOLFOX plus bevacizumab plus atezolizumab and reported improved outcomes vs atezolizumab monotherapy. Despite these advances, a direct head-to-head comparison between Nivo+Ipi and chemo-IO remains unavailable. We addressed this unmet question by reconstructing IPD from published Kaplan-Meier (KM) curves to enable an indirect cross trial comparison. Methods: Published PFS KM curves were digitized to pseudo-IPD. To mitigate cross-trial differences, arms were divided into four groups: Nivo+Ipi (CheckMate 8HW; n=171), chemo-IO (COMMIT; n=38), IO monotherapy [pembrolizumab (KEYNOTE-177; n=153), nivolumab (CheckMate 8HW; n=170), atezolizumab (COMMIT; n=40); n=363], and chemo (standard arms in KEYNOTE-177/CheckMate 8HW; n=238). The primary estimand was PFS restricted mean survival time (RMST) at τ=24 months. As a late-benefit sensitivity analysis, RMST was also estimated at τ=48 months where ≥10% patients remained at risk, to limit instability from sparse tails. KM comparisons (log-rank and Cox HR) were derived from reconstructed pseudo-IPD. Results: At τ=24 months, Nivo+Ipi improved PFS RMST vs chemo (18.87 vs 10.33 months; ΔRMST +8.54, 95% CI 6.78-10.31; p&lt;0.001) and vs IO monotherapy (18.87 vs 14.61 months; ΔRMST +4.26, 95% CI 2.54-5.99; p&lt;0.001). Chemo-IO improved RMST vs chemo (16.92 vs 10.33 months; ΔRMST +6.59, 95% CI 3.59-9.60; p&lt;0.001). In the key indirect comparison, Nivo+Ipi vs chemo-IO did not show a statistically significant RMST difference (18.87 vs 16.92 months; ΔRMST +1.95, 95% CI -1.14-5.04; p=0.217). In contrast, the late-benefit (τ=48 months) analysis demonstrated a statistically significant advantage for Nivo+Ipi (RMST 35.00 vs 27.71 months; ΔRMST +7.29, 95% CI 0.08-14.49; p=0.048). KM-derived estimates were consistent with these patterns: Nivo+Ipi outperformed chemo (p&lt;0.001) and IO monotherapy (p&lt;0.001), and chemo-IO outperformed chemo (p&lt;0.001). Compared with chemo-IO, Nivo+Ipi was associated with numerically longer PFS (NE vs 30.2 months; HR 0.62, 95% CI 0.36-1.05; p=0.073). Conclusions: Nivo+Ipi and chemo IO substantially improved 24-month PFS RMST vs chemo and IO monotherapy, with similar outcomes. Nivo+Ipi showed a significant advantage over chemo-IO at 48 months, consistent with a sustained late PFS effect. Findings are hypothesis-generating given cross-trial heterogeneity and reconstruction-related bias.

Tislelizumab combined with donafenib and GEMOX as first-line treatment for advanced biliary tract cancer: A single-arm, phase II study.

4110 Background: Advanced biliary tract cancer (BTC) progresses rapidly and has a poor prognosis, with a 5-year survival rate of less than 5%. Gemcitabine and oxaliplatin (GEMOX) plus tislelizumab and donafenib as the first-line treatment for advanced BTC has confirmed good safety and preliminary efficacy in our phase I study (NCT04979663). This study aimed to further evaluate the efficacy and safety of GEMOX plus tislelizumab and donafenib. Methods: This is a single-arm, phase II trial (NCT05668884). Patients were enrolled if they were 18-75 years old, had stage III/IV cancer (AJCC 8th Edition), were Child-Pugh A/B, had an ECOG PS of 0-1, and had received no prior systemic therapy or tumor-related surgery. Patients were administrated with tislelizumab (200 mg IV on d1 Q3W), donafenib (200mg PO BID) and GEMOX (Q3W up to 8 cycles: gemcitabine 1000 mg/m² IV on d1 and 8, oxaliplatin 100 mg/m² IV on d1). Treatment continued until disease progression or unacceptable toxicity or withdrawal of consent whichever occurred first. The primary endpoint was the objective response rate (ORR) assessed by RECIST v1.1. Results: From December 2022 to October 2025, 47 patients were enrolled with a mean age of 60.8 (18 females and 29 males), 35 patients had intrahepatic cholangiocarcinoma, 11 patients had gallbladder carcinoma and 1 patient had perihilar cholangiocarcinoma. The ORR and the disease control rate (DCR) by RECIST 1.1 were 38.3% (18/47) and 93.6% (44/47), respectively. 2 patients underwent subsequent surgery after first-line treatment. The median PFS was 12.1 months (95%CI: 5.1-19.1), 1-year survival rate was 57% (95%CI: 38-76). All patients had treatment-related adverse events (TRAEs), the incidence of grade 3-4 TRAEs was 46.8%, the most common grade 3-4 TRAEs were rash (6/47,12.8%), thrombocytopenia (5/47,10.6 %) and fever (3/47, 6.4%). No grade 5 TRAEs were observed . Conclusions: GEMOX plus tislelizumab and donafenib as a first line treatment option for advanced BTC patients shows favorable efficacy and tolerability. Clinical trial information: NCT05668884 .

Clinical risk factors and outcomes of tumor lysis syndrome in hospitalized patients with malignancy.

e18635 Background: Tumor lysis syndrome (TLS) is a serious oncologic emergency that can occur in both hematologic and solid malignancies. Contemporary real-world data describing which clinical factors are associated with TLS and which factors drive mortality once TLS occurs are limited. Methods: We analyzed adult hospitalizations with TLS in the National Inpatient Sample (2016–2021) using ICD-10 codes. Survey-weighted analyses described baseline characteristics and outcomes. Multivariable survey-weighted logistic regression was used to identify independent predictors of in-hospital mortality, adjusting for age, sex, race, payer, income quartile, acute kidney injury (AKI), chronic kidney disease (CKD), hyperuricemia, dehydration, sepsis, metastatic disease, and hospital characteristics. Results: An estimated 88,280 hospitalizations with TLS were identified; 82.2% occurred in patients with hematologic malignancies and 17.8% in those with solid tumors. Patients with TLS commonly had acute kidney injury (AKI) and sepsis, and solid-tumor TLS was frequently associated with metastatic disease. Crude in-hospital mortality among patients with TLS was 27.8% in solid tumors and 14.9% in hematologic malignancies (p&lt;0.001). After multivariable adjustment, the strongest independent predictors of in-hospital mortality were sepsis (adjusted odds ratio [aOR] 4.67, 95% CI 4.29–5.09, p&lt;0.001), AKI (aOR 3.66, 95% CI 3.26–4.12, p&lt;0.001), and metastatic disease (aOR 1.48, 95% CI 1.28–1.72, p&lt;0.001). Compared with solid tumors, TLS associated with hematologic malignancies was independently associated with lower mortality (aOR 0.69, 95% CI 0.60–0.80, p&lt;0.001). TLS associated with hematologic malignancies resulted in longer hospitalizations (mean length of stay 15.4 vs 10.2 days, p&lt;0.001) and higher total charges (mean $256,980 vs $148,140, p&lt;0.001). After adjustment, malignancy type was not independently associated with dialysis (aOR 1.06, p=0.54), ICU-level care (aOR 1.30, p=0.10), mechanical ventilation (aOR 0.81, p=0.13), or non-home discharge (aOR 0.95, p=0.40). Conclusions: Among hospitalized patients with TLS, sepsis, acute kidney injury, and metastatic disease are the dominant drivers of mortality, regardless of malignancy type. Although TLS occurs more frequently in hematologic malignancies, TLS associated with solid tumors carries a substantially higher risk of death. Early identification and aggressive management of high-risk patients may improve outcomes.

Initial analysis of adoptive neoantigen-specific T-cell immunotherapy for MGMT-unmethylated glioblastoma (TVI-AST-008): Signals amid control arm attrition.

2042 Background: MGMT-unmethylated (MGMT-u) glioblastoma (GBM) confers resistance to alkylating agents and poor overall survival (OS). Limited options beyond Standard of Care (SOC) drive patient pursuit of experimental therapies, complicating randomized controlled trials (RCTs). TVI-AST-008 evaluates safety and efficacy of adding autologous neoantigen-specific T-cell immunotherapy to SOC in this high-risk population. Methods: In this prospective RCT, newly diagnosed MGMT-u GBM patients were randomized 1:1 post-resection to Immunotherapy + SOC or SOC alone, stratified by age, residual tumor, and sex. The investigational arm used patient tissue to manufacture an autologous vaccine and undergo tumor cell vaccination to induce antigen-specific priming. Following leukapheresis, harvested lymphocytes undergo ex vivo T-cell activation/expansion (TVAX). On completion of SOC (radiation/temozolomide), manufactured cells undergo adoptive transfer with low-dose IL-2. Primary endpoint: OS. Results: As of September 2025, 21 subjects (median age 60) were randomized: Treatment (n=11) or Control (n=10). Control arm retention was challenging: 4/10 withdrew post-randomization to pursue other experimental therapies, leaving 6 evaluable Controls. Six Treatment subjects completed infusion. Despite limited statistical power, survival divergence emerged: mean OS for Controls (n=6) was 6.6 months versus 10.6 months for infused Treatment patients (n=6), with survivors followed at a median of 14 months (2 died at 9 and 10 months). Safety was favorable; adverse events were Grade 1–2 (pyrexia, rash) consistent with immune activation. No SAEs attributed to the investigational product. Conclusions: Early TVI-AST-008 data suggest adoptive neoantigen-specific immunotherapy is feasible, safe, and early signals suggest possible improved survival in MGMT-u GBM. High post-randomization withdrawal in Controls highlights challenges of SOC-controlled trials in this setting. Future validation may require synthetic controls or crossover allowances to ensure trial viability. Clinical trial information: NCT05685004 .

Lymphopenia in breast cancer and association with clinical outcomes: An analysis from over 30,000 patients.

640 Background: Lymphopenia is an independent prognostic factor for overall survival in patients with solid tumors. Low circulating lymphocytes represents impaired adaptive immunity, which can compromise antitumor immune responses and increase the risk of treatment-related toxicity. Despite having an ICD-10 code (D72.810), lymphopenia as a diagnosis might be often underrecognized and overlooked. We aimed to analyze the prevalence and concordance of lab-defined lymphopenia with the clinical diagnosis and the association of lab-defined lymphopenia with clinical outcomes in a large cohort of patients with breast cancer. Methods: We identified patients with breast cancer between 1/1/2011-12/31/2024 in a single institution using ICD-10 codes. Stage and subtype was determined using ICD codes, with recurrence defined by any ICD code for metastatic disease at least 6 months after initial diagnosis. Lab-defined lymphopenia was defined by absolute lymphocyte count (ALC) &lt;1000 cells/µL. Baseline and on-treatment lymphopenia using ICD codes was compared to lab-defined baseline and on-treatment lymphopenia using Cohen’s κ concordance statistic (0-1). Univariate logistic regression was performed to evaluate the association of lab-defined lymphopenia with recurrence. Overall mortality was analyzed using Cox proportional hazards regression. Results: 36,496 patients with breast cancer were included in the analysis. Most (89.7%) patients had early-stage breast cancer and estrogen receptor (ER)-positive disease (50.5%). At breast cancer diagnosis, 2,368 (6.5%) patients had lab-defined lymphopenia and 56 (0.02%) had lymphopenia diagnoses, demonstrating significantly low concordance by ICD codes (κ = 0.0268). Similarly, on-treatment lymphopenia was also discordant by ICD codes, with lab-defined on-treatment lymphopenia occurring in 5,564 (15.2%) of patients and 257 (0.7%) by ICD codes (κ = 0.0459). In early-stage breast cancer, baseline lab-defined lymphopenia was associated with increased risk of recurrence (OR 1.74; 95% CI 1.42-2.06; p&lt;0.001) and increased risk of mortality (HR 2.13; 95% CI 1.92-2.37; p&lt;0.001). In the metastatic setting, baseline lab-defined lymphopenia was associated with increased risk of mortality (HR 1.50; 95% CI 1.32-1.69; p&lt;0.001). Multivariable analysis demonstrated that lab-defined lymphopenia at diagnosis was associated with increased mortality (HR 2.47; 95% CI 2.01-3.02, p&lt;0.001), after adjusting for ER status, stage, and type of treatment. Conclusions: Lymphopenia is significantly underdiagnosed during breast cancer treatment, and is independently associated with increased risk of recurrence and death. These findings highlight the need for improved recognition of lymphopenia as a prognostic factor and tailored strategies to augment systemic immunity and potentially improve long-term outcomes for patients.

Implementing flexible and adapted follow-up strategies in a patient-centric, phase II trial of first-line lorlatinib for advanced ALK-positive non–small cell lung cancer (CTONG2203).

e13545 Background: We initiated the first patient-centric, multicenter, phase II trial (CTONG2203, NCT 06092086) to investigate the efficacy and safety of first-line lorlatinib and other TKIs in advanced ALK-positive non-small cell lung cancer. The follow-up schedule of treatment intervention cohorts aligns with that of the CROWN study, requiring patients to undergo frequent on-site visits over a prolonged observation period. Approximately 30% of subjects expressed a preference for reduced visit frequency, with two withdrawals due to this demanding schedule. Methods: We have made appropriate adjustments to the follow-up procedures while preserving the reliability and validity of the study results. For subjects who have received 24 months of study treatment with efficacy benefit, investigators may extend the interval of response evaluation from 8 weeks to 12 weeks. Pre-adjustment data analysis validated that the extended interval does not compromise efficacy assessment. During visit cycles in which efficacy evaluation is not required, patients may have laboratory tests performed at local hospitals (qualified through prior verification of test standardization and result consistency with study sites) and sent the results to the investigators for assessment and archiving (imaging examinations must be conducted at the study site to ensure unified evaluation standards). In a multicenter setting, the follow-up site may be relocated—upon confirming consistency across sites in medical resources, detection capacity, and follow-up procedures. as well as and documented informed consent—to accommodate changes in subjects' work or domicile. All adapted measures were approved by the medical ethics committee to ensure they adhered to the trial’s scientific objectives and did not introduce bias into the results. Results: Participants reported that these modifications significantly reduced their travel and time costs associated with follow-up visits. No more patients dropped out due to visit-related burden. About 25% of the subjects have undergone laboratory tests at local hospitals, and comparative analysis with site-based tests showed no statistically significant differences (P &gt; 0.05), confirming that local testing did not compromise data accuracy or safety assessments. In accordance with the aforementioned adjusted protocol, one subject will relocate from the Nanchang center to the Guangzhou center due to a job change, while another will transfer from the Guangzhou center to the Fuzhou center for closer proximity to her resident. Conclusions: By incorporating patient feedback to create adaptable visit schedules, patient-centric trials can optimize long-term monitoring without compromising data integrity and accuracy, offering valuable insights for future trial design. Clinical trial information: NCT06092086 .