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Prediction of hematotoxicity using CT-derived body composition in rectal cancer patients receiving immunotherapy-based total neoadjuvant therapy.

3599 Background: Immunotherapy-based total neoadjuvant therapy (iTNT) is a promising strategy to enhance complete response rates and facilitate organ preservation in locally advanced rectal cancer (LARC). However, it is linked to a considerable incidence of severe hematotoxicity, while reliable predictive biomarkers are lacking. Body composition, reflecting nutritional status, has been linked to treatment-related toxicity, but its relationship with iTNT toxicity remains unclear. This study aimed to investigate the association between body composition and hematotoxicity of iTNT and to develop a predictive model. Methods: A cohort of 204 LARC patients treated with iTNT was included for model development, with internal training and validation via five-fold cross-validation. Additionally, 43 metastatic rectal cancer patients treated with the same regimen served as the external validation cohort. Body composition parameters were obtained from pretreatment CT images at L3. LASSO regression was applied to select variables and four machine learning (ML) algorithms including logistic regression, random forest (RF), support vector machine (SVM), and extreme gradient boosting (XGBoost) were developed. Results: 33.8% of the discovery cohort experienced grade 3-4 hematotoxicity. Among baseline characteristics, skeletal muscle index (SMI) showed the most significant correlation with toxicity. The cut-offs for SMI, determined by optimal stratification, were 50.0 cm²/m² for males and 39.6 cm²/m² for females. Patients with low SMI had a higher incidence of severe toxicities ( P < 0.001). Seven features were included in the ML models: age, body mass index (BMI), SMI, subcutaneous adipose tissue index (SATI), subcutaneous adipose tissue attenuation (SAT_HU), visceral adipose tissue index (VATI), and skeletal muscle attenuation (SM_HU). The predictive performance of the models is summarized in the following table. Overall, the SVM model showed the highest discriminative performance and robust generalizability. Conclusions: SMI was significantly associated with hematotoxicity during iTNT. A CT-based machine learning model was developed and validated to predict hematotoxicity, with the SVM model showing the most robust performance (AUC > 0.85) to guide clinical decision-making. Cohort Model Accuracy Sensitivity Specificity AUC Internal validation SVM 0.850 ± 0.024 0.849 ± 0.021 0.833 ± 0.027 0.881 ± 0.019 RF 0.755 ± 0.037 0.749 ± 0.037 0.777 ± 0.032 0.803 ± 0.033 Logistic regression 0.704 ± 0.048 0.672 ± 0.055 0.720 ± 0.048 0.730 ± 0.033 XGBoost 0.796 ± 0.024 0.769 ± 0.038 0.788 ± 0.036 0.814 ± 0.027 External validation SVM 0.821 ± 0.034 0.829 ± 0.026 0.800 ± 0.019 0.858 ± 0.029 RF 0.713 ± 0.030 0.723 ± 0.051 0.734 ± 0.043 0.750 ± 0.038 Logistic regression 0.666 ± 0.034 0.652 ± 0.044 0.649 ± 0.027 0.671 ± 0.037 　 XGBoost 0.751 ± 0.046 0.714 ± 0.038 0.744 ± 0.031 0.779 ± 0.044

Determinants of digital health literacy among health professionals: Evidence from public and private hospitals in Eastern Ethiopia

Background Digital health literacy has become essential for effective clinical practice as healthcare systems increasingly adopt digital technologies. However, many low- and middle-income settings continue to face substantial gaps in digital readiness among the health workforce. Despite growing national initiatives to expand digital health in Ethiopia, evidence on digital health literacy among healthcare professionals in the eastern part remains limited. Therefore, this study aimed to assess the level of digital health literacy and its determinants among healthcare professionals in Eastern Ethiopia. Methods A cross-sectional study was conducted from May 1–30, 2025, among 401 randomly selected healthcare professionals working in three public and private hospitals. Data were collected using a structured questionnaire based on the European Digital Competence framework and analyzed using STATA (V17.0). Multivariable logistic regression was used to identify independent predictors of digital health literacy with significance set at p < 0.05. Results Out of 401 participants, 50.6% (95% CI: 45.62–55.62) of health professionals had adequate digital health literacy. Internet access (AOR = 3.89, 95% CI: 1.21–12.47), digital technology training (AOR = 6.24, 95% CI: 3.46–11.26), higher perceived usefulness (AOR = 2.87, 95% CI: 1.51–5.46), perceived ease of use (AOR = 1.90, 95% CI: 1.02–3.57), and good computer literacy was significant predictors of adequate digital health literacy (AOR = 3.11, 95% CI: 1.71–5.68). Conclusion Digital health literacy among healthcare professionals in the Harari region is relatively low compared to global standards. Strengthening digital infrastructures, expanding structured digital trainings, and creating user-friendly digital environment are essential to improve digital health literacy.

Correlating dopant-induced lattice modifications with optical and magnetic properties in Ni²⁺-doped TiO₂ nanostructures

Molecular Polarization‐Driven Synergistic Interface Engineering for High‐Performance Perovskite Solar Cells

ABSTRACT The performance of inverted perovskite solar cells (PSCs) is often impeded by severe non‐radiative recombination and carrier transport losses at the self‐assembled monolayer (SAM)/perovskite interface, arising from inhomogeneous SAM distribution and weak interfacial bonding with the perovskite layer. To address these challenges, we introduce a universal synergistic interface engineering strategy employing 2‐aminopyrimidine‐4‐carboxylic acid (m‐APCA), a meta‐substituted molecule featuring asymmetric bifunctional groups on its pyrimidine ring. These groups induce substantial molecular polarization, amplifying the dipole moment and reinforcing intermolecular π–π interactions with SAMs, thereby mitigating SAM aggregation and ensuring uniform substrate coverage. Concurrently, the strong dipole field and bifunctional chemistry of m‐APCA enable robust chemical bonding with the perovskite layer, acting as nucleation sites that regulate grain growth and passivate buried interfacial defects. This dual‐action approach reduces interfacial energy barriers and enhances hole transport efficiency, achieving very high efficiencies of 26.77% (certified at 26.71%), 26.08%, and 24.17% for small‐area (normal bandgap), centimeter‐scale (normal bandgap), and wide‐bandgap PSCs, respectively. Notably, optimized PSCs demonstrate exceptional operational stability, retaining 96% of initial efficiency after 1200 h of continuous maximum power point tracking.

Quasi-static and dynamic mechanical properties of functionally graded triply periodic minimal surface structures and their application exploration in interior design

The role of HIF-1α in innate immune mechanisms and autoimmunity: A double-edged sword

Empowering educators: An international virtual mentorship program for hematology/oncology medical educators.

9036 Background: Mentorship is a cornerstone of physician career development, linked to improved well-being, job satisfaction, research productivity, and faculty retention. Clinician educators often cite lack of mentorship as a major barrier to career advancement. We developed and piloted a year-long virtual mentorship program (VMP) with the American Society of Clinical Oncology (ASCO) for hematology/oncology (H/O) career development in medical education. Methods: We piloted the program during the 2024-2025 ASCO VMP cycle. Mentors and mentees applied via survey and were matched by committee members based on interests and goals. Each pair was required to complete a mentorship plan, including goals in three domains: professional development/course work, administrative/leadership experience, and scholarly output. We conducted an anonymous retrospective survey of participants via Qualtrics upon cycle completion. Surveys assessed: meeting cadence, satisfaction, goal attainment, and perceptions of career trajectory. Confidence in mentoring and knowledge growth related to pursuing a medical education career were assessed using a 5-point Likert scale with retrospective pre–post ratings. Paired scores were analyzed using the Wilcoxon signed-rank test after excluding ties. Results: Thirty-eight mentors and 42 mentees participated in the pilot. Survey response rate was 40% (mentors: 36.8%, mentees: 42.9%). Most met monthly (mentors: 35.7%, mentees: 44.4%) or every 2-3 months (mentors: 42.9%, mentees: 38.9%). Satisfaction was high (mentors: 71.4% “very satisfied,” 21.4% “satisfied”; mentees: 66.7% “very satisfied,” 27.8% “satisfied”), and nearly all would recommend the program (mentors: 100%, mentees 94.4%). The mentorship plan was discussed by all, with the majority reporting goal achievement (mentors: 92.9%, mentees: 88.9%). Most plan for ongoing mentoring after cycle completion (mentors: 78.6%, mentees: 72.2%). All respondents reported improved perceptions of career trajectory, with all mentors and 92.9% of mentees expressing greater interest in medical education careers and all noting a higher perceived likelihood of success. Mentors’ confidence in mentoring increased by a mean of 0.29 on a 5-point scale, but the Wilcoxon test was non-significant (p = 0.22). Mentees’ knowledge of medical education careers increased significantly with a mean gain of 0.57 (p = 0.016). Conclusions: Our pilot medical education VMP was highly valued, with strong satisfaction, widespread goal attainment, improved perceptions of career trajectory, and plans for sustained relationships beyond the defined mentorship period. These findings support virtual mentorship as a feasible strategy for clinician educator career development within H/O. Collaboration with and organizational support from professional societies will be essential for scalable, sustainable program development.

Long-term efficacy and safety of first-line (1L) nivolumab plus relatlimab (NIVO + RELA) versus NIVO plus ipilimumab (NIVO + IPI) in advanced melanoma: An updated indirect treatment comparison (ITC) with 5-year follow-up data.

9530 Background: An ITC comparing NIVO + RELA and NIVO + IPI, approved dual immunotherapy treatment options for patients (pts) with advanced melanoma, was previously conducted using pt-level data from the pivotal RELATIVITY-047 (RELA-047; NIVO + RELA vs NIVO) and CheckMate 067 (CM-067; NIVO + IPI or NIVO vs IPI) trials (Long JCO 2024). Here we present updated results using 5-year follow-up data from RELA-047. Methods: Inverse probability of treatment weighting was used to adjust for cross-trial imbalances in baseline characteristics. CM-067 follow-up was truncated to best align with the follow-up length in RELA-047. Progression-free survival (PFS) per investigator (INV), confirmed objective response rates (ORRs) per INV, overall survival (OS), and melanoma-specific survival (MSS) were analyzed. Outcomes were also evaluated across key subgroups. The weighted NIVO arms from each trial were compared for validation. Results: After weighting, key baseline characteristics were balanced for NIVO + RELA (n = 339) and NIVO + IPI (n = 297). Outcomes after weighting were similar between NIVO + RELA and NIVO + IPI (hazard ratio [HR] [95% CI]: PFS, 1.10 [0.90–1.34]; OS, 0.96 [0.77–1.20]; MSS, 0.88 [0.68–1.12]; table). Grade 3–4 treatment-related adverse event (TRAE) rates were numerically lower with NIVO + RELA than with NIVO + IPI (23% vs 62%, respectively). Across subgroups, efficacy appeared similar between treatments, although trends favoring NIVO + IPI were observed for ORRs among pts with BRAF mutant disease (59% vs 48%) or serum lactate dehydrogenase > 2× the upper limit of normal (33% vs 12%). Among pts progression-free at 3 years, both NIVO + RELA and NIVO + IPI were associated with sustained benefit, with 5-year OS of 96% and 94% and MSS of 100% and 98%, respectively. Conclusions: Consistent with earlier findings, this updated ITC with a 5-year minimum follow-up from RELA-047 suggests that 1L treatment with NIVO + RELA may have efficacy comparable to NIVO + IPI in pts with advanced melanoma, overall and across most, but not all, subgroups. Results should be interpreted with caution because of differences in study design and the evolving treatment landscape over time. Efficacy outcomes after weighting. NIVO + RELA (n = 339) NIVO + IPI (n = 297) HR/OR (95% CI) a NIVO RELA-047 (n = 338) NIVO CM-067 (n = 288) HR/OR (95% CI) b Median PFS per INV, mo (95% CI) 12.0 (8.2–17.1) 11.2 (8.5–18.1) 1.10 (0.90–1.34) 6.7 (4.6–10.2) 5.7 (3.9–9.1) 0.96 (0.79–1.16) Confirmed ORR per INV, % 48 50 0.92 (0.73–1.15) 40 40 0.99 (0.78–1.26) Median OS, mo (95% CI) 64.2 (38.6–NR) 61.4 (37.1–NR) 0.96 (0.77–1.20) 34.7 (27.3–47.3) 35.7 (26.4–52.7) 1.04 (0.85–1.28) Median MSS, mo (95% CI) NR (NR–NR) NR (61.4–NR) 0.88 (0.68–1.12) 51.2 (34.7–NR) 44.8 (32.3–NR) 1.00 (0.80–1.25) a NIVO + RELA vs NIVO + IPI. b NIVO arms. NR, not reached; odds ratio, OR.

AndroMETa-Lung-713: A phase 2/3 study of telisotuzumab adizutecan (ABBV-400, Temab-A) vs standard of care (SOC) in patients with epidermal growth factor receptor ( <i>EGFR</i> )–mutated non–small cell lung cancer (NSCLC).

TPS8661 Background: Patients with advanced EGFR -mutated NSCLC routinely receive third-generation EGFR TKIs in first-line therapy, such as osimertinib or lazertinib, either as monotherapy or in combination with other agents. Following progression, available options primarily include platinum-doublet chemotherapy or amivantamab + chemotherapy, with country-specific approvals for additional agents including antibody-drug conjugates (ADCs). MET gene amplification and c-Met protein (also known as MET protein) overexpression are established mechanisms of acquired resistance to osimertinib. Temab-A is a c-Met–directed ADC composed of the telisotuzumab antibody linked to a potent topoisomerase 1 inhibitor payload and is designed to selectively target c-Met–expressing tumors. In the first-in-human study (NCT05029882), Temab-A demonstrated manageable safety and encouraging efficacy in heavily pretreated EGFR -mutated NSCLC (confirmed objective response rate [ORR] 63%; median duration of response 9.8 months; median progression-free survival [PFS] 10.9 months) (Camidge. JCO 2025;43: abstract 8512). Methods: AndroMETa-Lung-713 (NCT07155187) is a global, open-label, randomized phase 2/3 study enrolling adults with locally advanced or metastatic non-squamous EGFR -mutated NSCLC after progression on 1 prior third-generation EGFR TKI administered in the adjuvant, locally advanced, or metastatic setting, as monotherapy or in combination with other agents. Key eligibility criteria include ECOG PS 0–1, measurable disease per RECIST v1.1, exon 19 deletion or exon 21 L858R mutation, and provision of tumor tissue for c-Met protein immunohistochemistry. In phase 2, approximately 80 patients will be randomized 1:1 to Temab-A dose 1 or dose 2 IV every 3 weeks (Q3W) to select the recommended phase 3 dose (RP3D) on the basis of safety, efficacy, pharmacokinetics (PK), and available biomarker data. In phase 3, approximately 350 patients will be randomized 1:1 to Temab-A RP3D or investigator’s-choice SOC (platinum-doublet chemotherapy or amivantamab + chemotherapy). Treatment continues until disease progression, intolerable toxicity, or other protocol-defined discontinuation criteria are met. The primary endpoints are ORR in phase 2 and PFS in phase 3, assessed by blinded independent central review. Tumor assessments are performed Q6W for 2 years, then Q12W. Assessment of PK, immunogenicity, and exploratory biomarker analyses, including c-Met protein expression levels and ctDNA dynamics, will be conducted. Clinical trial information: NCT07155187 .

Exosomal miRNA signatures as predictors of response to neoadjuvant FOLFIRINOX and GEM/nab-paclitaxel in resectable pancreatic cancer: The PRECEPT study.

4223 Background: Neoadjuvant chemotherapy (NAC) with FOLFIRINOX or gemcitabine plus nab-paclitaxel (GEM/nab-PTX) is widely used for resectable and borderline-resectable pancreatic ductal adenocarcinoma (PDAC). However, 10–20% of patients experience disease progression or severe toxicity during NAC, leading to loss of opportunity for curative resection. Given substantial differences in treatment responsiveness between regimens, reliable regimen-specific predictive biomarkers are needed to improve preoperative risk stratification and treatment selection. The PRECEPT trial (NCT07226154) aims to develop circulating exosomal microRNA (exo-miRNA)–based predictors of NAC response. Methods: Pre-treatment plasma samples were collected from patients with resectable or borderline-resectable PDAC prior to NAC. Exo-miRNAs were profiled by small RNA sequencing in a discovery cohort of 49 patients (FOLFIRINOX, n = 31; GEM/nab-PTX, n = 18) to identify regimen-specific candidate exo-miRNAs, which were subsequently quantified by qRT-PCR in a validation cohort of 73 patients (FOLFIRINOX, n = 43; GEM/nab-PTX, n = 30). Regimen-specific miRNA panels were constructed using stepwise selection followed by Firth penalized logistic regression. To benchmark against conventional biomarkers, multivariable Firth logistic regression models including the panel score and baseline CA19-9 were performed to evaluate the incremental predictive value of the exo-miRNA panels. Predictive performance was assessed by receiver operating characteristic (ROC) analysis. Results: In the discovery cohort, exo-miRNA signatures achieved areas under the curve (AUC) of 0.953 for the FOLFIRINOX panel and 1.000 for the GEM/nab-PTX panel. In the qRT-PCR validation cohort, performance remained robust (AUC 0.835 and 0.882, respectively). Higher panel scores were significantly associated with non-response to NAC ( p &lt; 0.01). In multivariable analyses, the exosome-derived miRNA panels provided predictive information beyond CA19-9 and remained independent predictors of treatment non-response in both therapeutic cohorts, demonstrating incremental value over conventional biomarkers. Both panels showed high sensitivity with low false-negative rates, supporting their clinical utility in identifying patients unlikely to benefit from neoadjuvant chemotherapy for each regimen. Conclusions: We developed two regimen-specific circulating exo-miRNA panels capable of predicting response to FOLFIRINOX and GEM/nab-PTX prior to treatment initiation. These panels provide predictive information beyond CA19-9 and may support individualized NAC selection, risk-adapted treatment planning, and improved preoperative decision-making in resectable PDAC. Clinical trial information: NCT07226154 .

Moving Beyond Imaging in metastatic castration-resistant prostate cancer: Liquid biopsy cfNA profiling of <i>PTEN-FANCD2-POLQ</i> as molecular signatures of response to 177Lu-PSMA-617.

e17050 Background: 177Lu-PSMA-617 radioligand therapy (RLT) has demonstrated efficacy in metastatic castration-resistant prostate cancer (mCRPC), although clinical benefit remains heterogeneous. We hypothesize that loss of PTEN leads to the functional impairment of FANCD2 -mediated high-fidelity DNA damage repair (DDR). In this deficient landscape, mCRPC cells become hyper-dependent on POLQ , which governs the error-prone Microhomology-Mediated End Joining (MMEJ) pathway. This "pathway switching" may sensitize mCRPC cells to RLT-induced DDR. We investigated whether baseline clinical factors and cell-free nucleic acid (cfNA) molecular profiles could refine patient selection and predict biochemical response. Methods: Consecutive mCRPC, PSMA-positive, patients treated with 177Lu-PSMA-617 every 6 weeks, from May to October 2025, were included. Baseline clinical data [Body Mass Index (BMI) Neutrophil-to-Lymphocyte Ratio (NLR), NRS pain scale, and time to CRPC)] were collected. Liquid biopsies were obtained after 3 cycles. Gene expression of PTEN , POLQ , and FANCD2 was quantified via ddPCR from plasma-derived cfNA. Biochemical response (BR) was defined as a ≥50% PSA decline. Results: Among 31 evaluable patients, 16 were responders (R) and 15 non-responders (NR). R showed lower baseline BMI (25.2 vs 26.8 months), NLR (2.6 vs 3.5), and NRS (5 vs 7), with a significantly longer time to CRPC (23 vs 13). Liquid biopsy showed lower median cfDNA levels in R (0.35 vs 1.57 ng/µL). Notably, a distinct DDR signature was associated with BR: R exhibited significantly lower median expression of PTEN (11.74 vs 14.83; p = 0.005) and FANCD2 (2.99 vs 13.65; p = 0.03), while POLQ expression was markedly elevated or uniquely detectable in R (range 0–27.23) compared to NR (0–0.83). This molecular signature suggests that the downregulation of PTEN and FANCD2 induces a homologous recombination deficiency state, providing a compensatory activation of the error-prone POLQ -mediated MMEJ pathway. Conclusions: A cfNA profile characterized by reduced FANCD2/PTEN and increased POLQ expression identifies a "synthetic vulnerability" signature of high genomic instability where the loss of high-fidelity repair mechanisms renders the tumor highly susceptible to RLT. These findings support futher study of PTEN-FANCD2-POLQ axis as predictive biomarker in larger cohorts, and the development of combination strategies targeting the DDR axis.

Four cycles of tislelizumab plus GP regimen as neoadjuvant therapy for high-risk (T4/N3) locally advanced nasopharyngeal carcinoma.

6089 Background: The efficacy of standard chemoradiotherapy for locally advanced nasopharyngeal carcinoma (LANPC) is still unmet need, especially for stage Ⅳa(T4/N3, AJCC 8th) NPC. The efficacy and safety of the 4 cycles neoadjuvant chemotherapy strategy in stage N2-3 LANPC has been confirmed. Meanwhile, immunotherapy has showed favorable tumor response and survival benefit for patients with LANPC. Therefore, this study investigated the efficacy and safety of four cycles tislelizumab plus GP regimen as neoadjuvant therapy for high-risk LANPC. Methods: Patients with stage IVa (T4/N3, AJCC 8th) NPC were enrolled and treated with neoadjuvant therapy (gemcitabine, 1000 mg/m 2 , on days 1 and 8, cisplatin, 80 mg/m 2 , on day 1, tislelizumab 200mg, on day 1) every 3 weeks for 4 cycles followed by standard concurrent chemoradiotherapy. The primary endpoint was complete response (CR) rate after neoadjuvant therapy. Secondary endpoints included overall response rate (ORR) after neoadjuvant therapy, disease-free survival, overall survival, and tolerance. Results: From February 2022 to June 2022, 25 patients were enrolled and 24 evaluable patients (median age 49 years old; 15 men [62.5%]) completed protocol-specified 4 cycles neoadjuvant therapy without delaying radiotherapy. 1 patient was withdrawn from the trial due to treatment of acute viral parotitis. The CR rate was 50% (12/24), achieving the predefined endpoint. The ORR of all evaluable patients was 91.7%. By the cut-off date of Jan 15 th 2026, the median follow-up time was 44.8 months. The median disease-free survival was not reached and 36-month disease-free survival was 91.7%(95% CI 70.6%–97.8%). Two patients died of diseases not related to nasopharyngeal carcinoma and treatment, while the other patients still have no disease progression. 13 (52%) of 25 patients had grade 3-4 acute treatment-related adverse events (TRAE). Grade 1-2 immune-related adverse events (irAE) was recorded in 18 patients (72%). No grade 3-4 irAEs occurred. 3 (12%) of 25 patients had long-term TRAEs. Conclusions: Four cycles of tislelizumab plus GP regimen as neoadjuvant therapy demonstrated promising tumor response, long-term survival benefit and manageable safety profile in high-risk LANPC patients. Clinical trial information: ChiCTR2200056941.

Neoadjuvant mitomycin C plus carboplatin followed by paclitaxel vs. standard doxorubicin–cyclophosphamide followed by paclitaxel–carboplatin in BRCA1/2-associated breast cancer.

620 Background: Triple-negative breast cancer (TNBC) associated with BRCA1/2 mutations is an aggressive disease subtype characterized by high sensitivity to chemotherapy. Accumulating evidence suggests the efficacy of mitomycin C, both as monotherapy and in combination with platinum agents, in BRCA1/2-driven tumors. This clinical study aimed to compare mitomycin C–based chemotherapy regimens with standard neoadjuvant chemotherapy in patients with BRCA1/2-associated TNBC. Methods: A total of 52 patients with BRCA1/2 pathogenic variants and TNBC stage T1-3N0-3M0 were enrolled. Patients were randomized to an experimental arm (n=26) receiving mitomycin C (10 mg/m²) plus carboplatin (AUC 5) (MCbP) for four cycles followed by weekly paclitaxel (80 mg/m²) for 12 cycles (MCbP-T), or to a control arm (n=26) receiving doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²) (AC) for four cycles followed by weekly paclitaxel (80 mg/m²) plus carboplatin (AUC2) for 12 cycles (AC-TCbP). Treatment efficacy was assessed according to RECIST criteria and the rate of pathological complete response (pCR) after surgery. Results: After four cycles of MCbP/AC, clinical complete response (cCR) was observed more frequently in the MCbP group compared with the AC group (58% vs 7.7%; p = 0.0002). Upon completion of neoadjuvant chemotherapy, cCR remained significantly higher in the experimental arm (65.4% vs 42%; p = 0.037). The pCR rate was 81% versus 62% (p = 0.12), while Miller–Payne grade V pathological response was achieved in 77% and 65% of patients, respectively (p = 0.084). During a 26-month follow-up, adverse events occurred in 3.8% of patients in the experimental group and 12% in the control group; one death was reported only in the AC-TCbP arm (p = 0.6). Grade III leukopenia and neutropenia were more frequent in the AC-TCbP group (42% and 46%) compared with MCbP-T (4% and 8%; p = 0.002 and p = 0.003, respectively). Thrombocytopenia of any grade occurred more frequently in the MCbP-T group (36% vs 0%; p &lt; 0.001). Grade II alopecia was observed in all patients in the control group and in none of the MCbP-T patients (p &lt; 0.001). Conclusions: In BRCA1/2-associated TNBC, the MCbP-T regimen demonstrates efficacy comparable to standard anthracycline-based chemotherapy with platinum agents, while providing a more favorable safety profile and a lower incidence of adverse events.

Pilocytic astrocytoma: An NCDB analysis of contemporary clinical and socioeconomic patterns.

e14082 Background: Pilocytic astrocytoma (PA) is a rare, low grade glioma, most commonly found in the cerebellum of pediatric and young adult patients. PA is histologically characterized by biphasic astrocytes with pilocytic morphology. Prognosis is favorable, with prior studies demonstrating a 10-year survival rate of 95% following gross total surgical resection. Given the rarity of PA, large-scale population-level data describing contemporary trends remain limited. This study addresses this gap by analyzing a substantially larger cohort of PA patients from the National Cancer Database (NCDB) with data extending through 2020 to better characterize contemporary clinical, socioeconomic, and demographic trends in PA patients. Methods: A retrospective cohort study was performed using the 2004-2020 NCDB to identify patients with histologically confirmed PA (ICD-O-3 Code: 9421). Demographic variables, including sex, race, Hispanic origin, insurance status, median household income, treatment facility type and location, and year of diagnosis, were analyzed through descriptive statistics. Incidence trends were determined via regression analysis. Results: This study identified 10,653 PA patients, with a stable annual incidence from 2004 to 2020 (R² = 0.10). Mean age at diagnosis was 20.6 years (IQR: 22). The cohort showed a slight male predominance (51.6%) and most patients were White (81.0%) and non-Hispanic (85.2%). A plurality were found in the highest income quartile (&gt;$74,063; 36.6%). Most were privately insured (62.3%), followed by Medicaid (24.3%) and Medicare (4.9%). Nearly half (49.4%) of the patients resided in metropolitan areas with populations &gt;1 million. Treatment was common at academic or research programs (54.4%), followed by community cancer programs (24.5%). A majority of patients (88.2%) had no comorbidities, demonstrated by a Charlson–Deyo score of 0. Clinically, the cerebellum was the most common primary tumor site (28.3%). Surgical resection was performed in 87.0% of cases and 78.8% of patients survived ≥ 90 days postoperatively. Primary radiation and primary chemotherapy were administered in 11.5% and 11.4% of patients, respectively. Mean tumor size was 39.2 mm (SD: 30.1). Two, five, and ten year survival rates were 96%, 92%, and 88%, respectively. Mean overall survival was 16 years (95% CI: 15.9–16.2). Conclusions: This study provides updated population-level data on contemporary clinical and sociodemographic trends in PA, addressing an existing gap in literature. Most patients were White, privately insured, resided in high-income metropolitan areas, and were treated at academic centers. The cerebellum was the most common primary site and long-term survival was favorable, consistent with prior studies. Additional population-level analyses incorporating more diverse sociodemographic data are needed to further validate these prognostic influences in PA patients.

Influence of pirfenidone on checkpoint inhibitor pneumonitis and antitumor efficacy in NSCLC: A multicenter study and mechanistic exploration.

2609 Background: Checkpoint inhibitor pneumonitis (CIP) is a major fatal immune-related adverse events (irAEs) in immune checkpoint inhibitor (ICI) therapy, accounting for ~35% of fatal irAE-related deaths. Patients with pre-existing interstitial lung disease (ILD) face markedly higher CIP risk and are routinely excluded from ICI treatment, depriving them of antitumor benefits. Current first-line glucocorticoid therapy for CIP are limited by inadequate efficacy in fibrotic-stage or steroid-resistant CIP and impaired ICI activity. As a drug-induced interstitial pneumonitis, CIP shares pathological similarities with ILD. Pirfenidone, an approved ILD drug, showed potential efficacy in CIP case reports, but its systematic clinical value and mechanisms remain unvalidated. This study aimed to elucidate pirfenidone's role in full-cycle CIP management and its synergistic antitumor effect with ICIs. Methods: A multicenter retrospective study enrolled advanced non-small cell lung cancer (NSCLC) patients receiving first-line ICI-based therapy from three hospitals between 2018 and 2024, stratifying into pirfenidone+ICI+chemotherapy (Pirf+ICI+chemo) and ICI+chemotherapy (ICI+chemo) groups. Primary endpoint was CIP incidence, secondary endpoints objective response rate (ORR) and progression-free survival (PFS). For mechanistic studies, bleomycin and ICI were administered to spontaneous NSCLC mice to mimic clinical ICI treatment in ILD-high-risk patients, generating a CIP mouse model. Lung scRNA-seq defined pirfenidone's role in CIP management and synergistic antitumor activity. Results: Of 141 enrolled patients, Pirf+ICI+chemo had significantly lower CIP incidence vs. ICI+chemo (34.01% vs. 59.57%, p =0.0070), with synergistic antitumor effects manifested as higher ORR (78.72% vs. 60.64%, p =0.0376), and longer median PFS (9.97 vs. 5.47 m, p =0.0120). CIP shows a biphasic inflammation-fibrosis pathology. scRNA-seq of 62,335 lung cells identified ISG + aged neutrophils (ISG + Na) as the key pathogenic driver of CIP progression. ICI-induced excessive immune activation triggers lung damage, activating the IFN-I-IRF9/STAT1 axis to promote ISG + Na differentiation. These cells secrete IL-6, IL-8, TNF-α to amplify inflammation, and TGF-β to induce fibroblast proliferation and activation, all of which pirfenidone blocks, supporting its full-cycle CIP efficacy mechanistically. Animal experiments further confirmed pirfenidone's robust efficacy in CIP prevention, treatment and synergistic antitumor activity with ICI. Conclusions: Pirfenidone reduces CIP incidence and synergizes with ICI therapy to enhance antitumor efficacy. Mechanistically, it targets IFN-I-IRF9/STAT1-ISG + Na axis for dual clinical benefits. These findings confirm pirfenidone as a translatable strategy to balance CIP control and antitumor activity.

Prediction of survival outcome in clinical stage II-III non-small cell lung cancer undergoing neoadjuvant chemoimmunotherapy: Role of ypN status vs PCR.

8056 Background: After FDA approval in 2022, neoadjuvant chemoimmunotherapy has become the standard of care for patients with non-small cell lung cancer (NSCLC) due to improved survival outcomes. Pathologic complete response (pCR) is often used as a predictor of patient survival following treatment. However, the role of posttreatment pathological nodal status (ypN) as a treatment predictor remains undefined. This study evaluates the predictive significance of ypN in comparison to established treatment predictors, such as pCR. Methods: Patients with clinical stage II-III NSCLC diagnosed in 2022 (n=29,017) who underwent neoadjuvant chemoimmunotherapy and resection (n=1,175) were identified using the National Cancer Database. Those with missing pCR data (n=16), pCR in tumor only (n=18), and those who died within one month of diagnosis were excluded. Chi-square tests were used for comparisons between groups. Survival analysis was performed using the Kaplan-Meier method, along with univariate and multivariable Cox proportional models. All tests were two-sided, and the statistical significance level used was 0.05. Results: The final cohort consisted of 720 patients divided into three groups: pCR-both (pCRb; ypT0N0; n=217; 30.1%), pCR-node (pCRn; ypN0; n=265; 36.8%), and residual viable in both (RVb; n=238; 33.1%). The pCRb group had a higher proportion of squamous cell carcinoma compared to the pCRn group (47% vs 34%, p&lt;0.001). pCRn patients demonstrated a slightly higher rate of positive surgical margins (3% vs 1%, p=0.03) and subsequent use of adjuvant radiotherapy compared with pCRb (3% vs 1%, p=0.03). Kaplan-Meier analyses and Cox proportional hazards models showed similar overall survival (OS) between pCRb and pCRn groups (HR=1.37; p=0.363), while both had significantly higher OS compared with RVb (HRs 0.26 and 0.36; p&lt;0.0001 for both). Subgroup analysis by number of examined lymph nodes showed comparable OS between pCRb and pCRn in patients with ≥10 lymph nodes examined (LN≥10; HR=1.36; p=0.47) and in those with &lt;10 nodes examined (LN&lt;10; HR=1.50; p=0.40). Conclusions: In clinical stage II-III NSCLC treated with neoadjuvant chemoimmunotherapy followed by resection, pCRb and pCRn demonstrated similar rates of OS, highlighting the significance of post-treatment pathological nodal status (ypN) as a potential predictor of OS in this population. Since pCRb requires invasive tissue sampling, using ypN as a predictor of OS would allow for more efficient risk stratification with overall less invasive testing.

Resection and intracranial implant of (Z)- <i>n</i> -butylidenephthalide wafer followed by temozolomide as treatment for recurrent glioblastoma: A randomized phase IIb/III trial.

TPS2097 Background: Glioblastoma, an isocitrate dehydrogenase (IDH)–wildtype diffuse glioma, remains highly lethal despite standard therapy, and the absence of an effective treatment at recurrence highlights a critical unmet clinical need. (Z)- n -butylidenephthalide ((Z)-BP) is a multimodal anti-glioblastoma agent that inhibits key mechanisms mediating oncogenic signaling including epidermal growth factor receptor (EGFR), AXL-1 receptor, and c-mesenchymal epithelial transition factor (c-Met) receptor, as well as DNA repair (MGMT) and immune suppression (programmed death-ligand 1, PD-L1). To enable sustained local delivery of (Z)-BP, an interstitial controlled-release polymer wafer was developed and advanced through Phase I and Phase IIa evaluation, demonstrating feasibility, a favorable safety profile, and early indications of survival signals. Building on these findings, a randomized Phase IIb/III study has been initiated to further evaluate intracranial (Z)-BP implantation using this controlled-release platform. Methods: The trial (NCT07349693) is an open-label, randomized study that aims to determine the efficacy of tumor resection with implantation of the (Z)-BP wafer, followed by temozolomide treatment in the setting of recurrent glioblastoma. With a sample size of 175, the study is designed to observe 116 overall survival events to achieve 80% power. Eligible adults must have histologically confirmed glioblastoma at first or second recurrence following standard first-line therapy and maintain a Karnofsky Performance Status ≥ 70. Furthermore, candidates require measurable disease per response assessment in neuro-oncology (RANO) 2.0 criteria (lesion ≥ 1 cm) that is deemed suitable for gross total resection. Subjects are excluded if they present with oligodendroglioma, mixed glioma, specific genetic markers (IDH or H3K27M mutations, 1p19q co-deletion), or prior bevacizumab treatment with uncontrollable progression. Patients with MRI findings showing multi-focal disease, diffuse dissemination, lesions &gt; 6 cm, or tumor locations deemed unsuitable for safe resection and wafer implantation will also be excluded. Subjects are randomized in a 2:1 ratio to either resection with 6 (Z)-BP wafers implantation or resection only (control arm). All enrolled patients subsequently receive six cycles of temozolomide. The primary endpoint is median overall survival (OS). Secondary endpoints include progression-free survival (PFS), OS and PFS rates at 6, 9, 12, 18, and 24 months, and objective response rate (ORR, based on RANO 2.0). Exploratory objectives include assessing plasma concentrations of (Z)-BP and its metabolite, quality of life (EORTC QLQ-C30), and survival analyses stratified by molecular subgroups (EGFR, AXL, c-Met, MGMT, and PD-L1 expression). The enrollment is expected in Q2 2026. Clinical trial information: NCT07349693 .

Age as a surrogate: Mortality and vascular risk in gastrointestinal stromal tumor after frailty and comorbidity adjustment.

e23516 Background: Older adults with gastrointestinal stromal tumor (GIST) have worse survival than younger patients, typically attributed to comorbidity, frailty, or treatment selection rather than age itself. Because prior studies have not isolated the independent effect of age, we conducted an age-stratified cohort study across multiple thresholds using propensity score matching adjusted for validated comorbidity and frailty indices. Methods: We performed a retrospective cohort study using TriNetX (111 healthcare organizations). Incident GIST was identified using ICD-10-CM code C49.A and ICD-O-3 morphology codes 8936/0, 8936/1, and 8936/3 (2018-2022), with a 2-year washout period. Patients with prior malignancies or palliative care were excluded. Four prespecified comparisons were analyzed: ≥65 vs ≤64 years (primary), ≥65 vs 50-64, 50-64 vs ≤49, and ≥65 vs ≤49 years. Cohorts had 1:1 propensity score matching incorporating variables derived from the Charlson Comorbidity Index and Hospital Frailty Risk Score, including demographics, cardiovascular/metabolic comorbidities, renal/pulmonary disease, anemia, substance use, and frailty-related diagnoses. Outcomes assessed from 90 days post-diagnosis included mortality, stroke, acute myocardial infarction (AMI), venous thromboembolism (VTE), healthcare utilization, and tyrosine kinase inhibitor (TKI) exposure. Results: After matching, sample sizes were: ≥65 vs ≤64 (n = 847 pairs), ≥65 vs 50-64 (n = 778), 50-64 vs ≤49 (n = 311), and ≥65 vs ≤49 (n = 234). Despite exhaustive adjustment, patients ≥65 years demonstrated significantly higher mortality versus ≤64 years (OR 1.99 [1.39-2.85], p &lt; 0.001; survival 83.2% vs 89.9%), composite stroke (OR 2.10 [1.23-3.56]), ischemic stroke (OR 2.45 [1.33-4.52]), and AMI (OR 1.85 [1.06-3.23]). Similar patterns were observed for ≥65 vs 50-64 (mortality OR 1.81 [1.23-2.65]; stroke OR 1.96 [1.16-3.31]). Mortality and cardiovascular outcomes could not be analyzed for comparisons involving ≤49 years due to limited events; however, healthcare utilization and TKI exposure showed no significant differences across all four comparisons, including ≥65 vs ≤49 (ED/inpatient OR 0.69 [0.34-1.43]) and 50-64 vs ≤49 (TKI OR 1.13 [0.52-2.46]). Conclusions: Older adults with GIST have higher mortality and cerebrovascular/cardiovascular event rates than younger patients, even after rigorous adjustment for comorbidity and frailty. These differences persist despite similar post-diagnosis healthcare utilization and TKI exposure, arguing against treatment underuse as the primary driver. Risk increased progressively with advancing age, demonstrating a graded age-related effect and suggesting age itself contributes independently to adverse outcomes beyond measured comorbidity and frailty.

Adjuvant immune checkpoint inhibitors combined with chemotherapy and lenvatinib for biliary tract cancer after curative resection: A single-center retrospective study.

e16269 Background: Surgery is the cornerstone of curative treatment for biliary tract cancer (BTC), yet only about 30% of patients qualify for resection. Even after surgery, the 3-year recurrence rate approaches 80%, and the BILCAP study shows up to 50% recurrence despite adjuvant therapy. Thus, more effective adjuvant strategies are urgently needed to reduce recurrence after curative therapy. Recent TOPAZ-1 and KN966 results demonstrate that immune checkpoint inhibitors (IO) plus chemotherapy improve BTC survival, while studies of IO combined with GEMOX and lenvatinib show promising efficacy. These data support further evaluation of IO plus chemotherapy and lenvatinib as adjuvant treatment post-surgery. Methods: This single-center, retrospective study enrolled patients with BTC who underwent curative surgery (R0/R1 resection) between July 2021, and December 2025. Eligible patients received adjuvant therapy consisting of immune checkpoint inhibitors (IO) in combination with chemotherapy (GEMOX, capecitabine, or S-1) and lenvatinib, administered according to guideline-recommended dosing. The primary endpoint was relapse-free survival (RFS), while secondary endpoints included overall survival (OS) and safety. Results: A total of 25 patients were included, among whom 16 (64%) were male; the median age was 61 years (range, 42–73). ECOG performance status was 0 in 22 patients (88%) and 1 in 3 patients (12%). Diagnoses included intrahepatic cholangiocarcinoma in 10 cases (40%), extrahepatic cholangiocarcinoma in 9 cases (36%), and gallbladder cancer in 6 cases (24%). Disease stage was stage I in 13 patients (52%), stage II in 3 (12%), stage III in 6 (24%) and stage IV in 3 (12%). Lymph node status was N− in 18 patients and N+ in 7 patients. The proportion of R0 resections was 76%. Treatment regimens included immunotherapy (durvalumab, sintilimab, toripalimab, etc.) plus GEMOX and lenvatinib in 11 patients; immunotherapy plus capecitabine and lenvatinib in 9 patients; and immunotherapy plus S-1 and lenvatinib in 5 patients. The median follow-up duration was 11.7 months. The median number of IO cycles was 10 (range, 1–34), and the median number of chemotherapy cycles was 6 (range, 1–8). Median RFS was 14.8 months, and the 1-year OS rate was 94.74%. Adverse events occurred in 9 patients (36%), with grade ≥3 treatment-related events observed in 20%. Common AEs included myelosuppression, elevated liver enzymes, and hypothyroidism. Conclusions: Adjuvant IO-based therapy with chemotherapy and lenvatinib may delay recurrence after curative resection of BTC, with a favorable safety and tolerability profile. Further prospective studies are warranted to confirm these findings and optimize adjuvant strategies in BTC.

EA3231: A randomized phase III study of BRAF-targeted therapy vs cabozantinib in RAI-refractory differentiated thyroid cancer with <i>BRAF</i> V600Em.

TPS6140 Background: About half of patients with RAIR advanced differentiated thyroid cancer (DTC) harbor a mutation in BRAF V600E. Although multiple systemic therapies are now approved, optimal treatment sequencing remains undefined for patients with BRAF V600Em RAIR DTC. Given the indolent natural history of this disease and often prolonged exposure to oral therapies with significant toxicity, comparative data on efficacy and tolerability of second-line therapy is a clear unmet need. Methods: EA3231 (NCT06475989) is a NCTN cooperative group randomized phase III study in patients with BRAF V600Em RAIR DTC who have progressed on prior multikinase inhibitor therapy such as lenvatinib or sorafenib. Patients will be randomized 1:1 to BRAF-targeted therapy (dabrafenib and trametinib) or cabozantinib, all of which are FDA-approved agents in this setting. The primary objective is to compare progression-free survival (PFS) between dabrafenib/trametinib vs cabozantinib, with secondary objectives including overall response rate, overall survival, PFS2, and safety and tolerability. We hypothesize that BRAF-directed therapy will be associated with improved PFS and tolerability compared to cabozantinib. Our target accrual is 120 patients; this sample size will provide 83% power to detect a HR of 0.60 (corresponding to a median PFS of 12 months) compared to an estimated median PFS of 7.2 months in the cabozantinib arm. This study was activated in late 2024, and has enrolled 8/120 patients as of 1/2026. Clinical trial information: NCT06475989 .