Browse Articles

A patient-tailored protein marker blood test for monitoring treatment response and postoperative recurrence across multiple cancers.

e15047 Background: ctDNA-based minimal residual disease (MRD) assays are increasingly used for post-treatment surveillance but remain costly and technically complex, limiting adoption, particularly in low- and middle-income countries (LMICs). Protein tumor markers (PTMs) are inexpensive and widely available but lack disease specificity and are limited by inter-patient heterogeneity. We developed OncoGraph, a patient-tailored approach that identifies abnormally elevated PTMs at baseline and tracks their longitudinal dynamics for individualized monitoring of recurrence risk and treatment response. Methods: Pretreatment blood samples were analyzed using OncoSeek, a validated multi-cancer early detection assay quantifying a standardized PTM panel (e.g., AFP, CEA). PTMs exceeding predefined thresholds were designated as patient-specific markers and serially monitored after curative surgery or during systemic therapy. Postoperative surveillance in liver cancer and lung cancer used PTM changes at one month after surgery to MRD, while treatment monitoring in advanced lung cancer and lymphoma used PTM dynamics after two treatment cycles to evaluate response and outcomes. Results: In liver cancer, 18/30 patients (60.0%) had elevated baseline PTMs. Three of 18 (16.7%) showed insufficient postoperative PTM decline (<25%) and all recurred within 95 days, with a shorter RFS than patients achieving significant PTM reduction (≥25%) (median RFS, 42 vs 385 days; HR=3.5; P<0.05). Among surgically treated lung cancer patients, 16/23 (69.6%) had elevated baseline PTMs. One patient with insufficient PTM decline recurred at 186 days, whereas patients with significant PTM reduction (15/16, 93.8%) had a median RFS of 336 days (HR=5.3; P=0.07). In advanced lung cancer, 21/23 patients (91.3%) exhibited elevated baseline PTMs. After two treatment cycles, six (28.6%) patients with insufficient PTM decline (<25%) had significantly shorter PFS than those with marked PTM reduction (15/21, 71.4%) (median PFS, 177 vs 434 days; HR = 3.6; P < 0.01), with a trend toward inferior OS (median OS, 431 vs. 922 days; HR = 2.5; P = 0.07). In lymphoma, baseline-abnormal PTMs were observed in 16/116 patients (13.8%). After two treatment cycles, four (25.0%) patients with insufficient PTM reduction (<50%) was associated with poorer PFS (HR = 6.2; P = 0.13) and inferior OS compared with greater PTM decline (12/16, 75.0%) (median OS, 506 days vs not reached; HR = 5.3; P = 0.06). Conclusions: OncoGraph enables patient-tailored PTM-based monitoring by addressing the limitations of conventional method. Early PTM dynamics correlated with postoperative recurrence risk and treatment outcomes across multiple cancers. Given its low cost, minimal technical requirements, and broad applicability, OncoGraph represents a scalable blood-based monitoring strategy, particularly suitable for LMIC.

Racial and ethnic differences in breast-conserving surgery after neoadjuvant chemotherapy for HER2-positive and triple-negative breast cancer.

e13724 Background: Neoadjuvant chemotherapy (NACT) increases eligibility for breast-conserving surgery (BCS) among patients with stage II–III breast cancer, particularly those with HER2-positive and triple-negative breast cancer (TNBC). Despite equivalent oncologic outcomes between BCS and mastectomy, racial and ethnic disparities in surgical management persist. Data examining racial and ethnic differences in receipt of BCS following NACT remains limited. We examined the association between race and ethnicity and the odds of undergoing BCS after NACT. Methods: The National Cancer Database was used to identify female patients with stage II or III HER2-positive or triple-negative breast cancer diagnosed between 2013 to 2022 who received NACT followed by surgery. Patients were categorized by race and ethnicity, and the primary outcome was receipt of BCS versus mastectomy. Demographic, clinical, and treatment variables were compared using Chi-square tests and one-way ANOVA, as appropriate. Multivariable logistic regression was used to examine the association between race/ ethnicity and the odds of undergoing BCS, adjusting for age, year of diagnosis, clinical stage, subtype, insurance status, geographic region, facility type, and comorbidity score. Odds ratios with 95% confidence intervals were reported. Results: Among 255,735 women who met inclusion criteria, 65.4% were non-Hispanic White, 19.5% Black, 9.3% Hispanic, 5.3% Asian or Pacific Islander, and 0.4% American Indian or Alaskan Native. The cohort included 65.3% with stage II disease and 34.7% with stage III; 66.7% had TNBC and 33.3% HER2-positive disease. Following NACT, 60.1% underwent mastectomy and 39.9% underwent BCS. Compared with Non-Hispanic White women, Black (OR 1.26, 95% CI 1.15-1.38) and Hispanic (OR 1.23, 95% CI 1.04-1.46) women had higher odds of receiving BCS, whereas Asian and Pacific Islanders had lower odds (OR 0.73, 95% CI 0.56-0.94) (Table 1). Older age, stage II disease, lower comorbidity score, treatment in New England, and more recent diagnosis year were independently associated with significantly higher odds of receiving BCS. On moderation analysis, clinical stage did not modify the association between race/ ethnicity and receipt of BCS. Conclusions: Patterns of surgical management following NACT vary by race and ethnicity. Black and Hispanic women had higher odds of undergoing BCS compared with Non-Hispanic White women, whereas Asian and Pacific Islander women had lower odds, independent of key covariates. Further research is needed to elucidate the underlying factors contributing to these differences. BCS Adjusted OR (95% CI) p-value Race/ Ethnicity: Non-Hispanic White Reference Black 1.26 (1.15 - 1.38) <0.001 Asian or Pacific Islander 0.73 (0.56 - 0.94) 0.016 American Indian or Alaskan Native 0.81 (0.60 - 1.09) 0.169 Hispanic 1.24 (1.04 - 1.46) 0.016

Siltuximab for the prevention of severe immune-related adverse events during immune checkpoint inhibitor rechallenge in advanced cancer: First interim analysis of the CIRES trial.

e24146 Background: Immune checkpoint inhibitors (ICI) predisposes patients to unpredictable irAEs. Many patients who had irAEs require ICI reinduction to control their cancer. The CIRES trial evaluates siltuximab, an anti-interleukin-6 (IL-6) antibody, to prevent severe irAEs during reinduction, because IL-6 signaling is central to irAE pathogenesis. We report the first pre-planned interim analysis for safety (NCT06470971). Methods: Adults (ECOG ≤2) with advanced cancers and prior severe irAEs [defined as ≥grade (G) 2 requiring ICI discontinuation and prednisone ≥0.5 mg/kg/day or equivalent] were eligible after recovery to ≤G1. Patients with ≥G3 myocarditis and encephalitis were excluded. The primary endpoint is the rate of recurrent or new severe irAE. Siltuximab (11 mg/kg q3w or 15 mg/kg q4w) was given up to 6 months with anti–PD-1 therapy. The protocol has a stopping criteria for severe irAEs in ≥3/10 patients. Results: Among the first 10 patients (Table 1), with a median follow-up of 14.7 months, no severe irAEs were observed. All irAEs were either G2 with fatigue (n = 1) and uveitis/scleritis (n = 1) or G1 with thyroid dysfunction being the most frequent (n = 4), hepatitis, fatigue, myalgia, arthralgia, and eosinophilia (1 each). Treatment-related adverse events (TRAEs) included G3 duodenal stenosis (n=1); G2 lymphopenia (n=4), mucositis, hypertension, thrombocytopenia, and hyperlipidemia (1 each); and non-clinically significant G1. At 6 months, best RECIST v1.1 responses were stable disease (n = 4) and progressive disease (n = 5); one had no measurable disease and remained without evidence of disease. Three patients continued ICI after completing the protocol without further irAEs. Conclusions: At this safety interim analysis, no recurrent or new severe irAEs were observed, indicating an encouraging signal for the efficacy of siltuximab to reduce the severity of irAE from anti–PD-1 therapy. Disease stabilization was observed in 40% of patients. Enrollment is ongoing. Clinical trial information: NCT06470971 . Patient characteristics. Demographics Histology n Prior Treatment n Prior IrAEs (Grade) n Median Age 66.2 Years RCC 3 ICI+TKI 3 Hepatitis (2&3) 3 Female 4 (40%) UC 2 ICI Monotherapy 2 Pneumonitis (2&3) 2 NSCLC 1 Dual ICI 2 Colitis (3) 1 Rechallenge ICI NET 1 ICI + Chemotherapy 2 Pancreatitis (3) 1 Nivolumab 6 PDAC 1 ICI + ADC 1 Myositis (2) 1 Pembrolizumab 4 Melanoma 1 Meningitis (3) 1 CIDP (3) 1 ADC, antibody drug conjugate; CIDP, chronic inflammatory demyelinating polyneuropathy; ICI, immune checkpoint inhibitor; NET, neuroendocrine tumor; NSCLC, non–small cell lung cancer; PDAC, pancreatic ductal adenocarcinoma. RCC, renal cell carcinoma; UC, urothelial carcinoma.

Initial findings from the PROMISE Registry, a US decentralized, prospective prostate cancer genetic registry.

10610 Background: The role for genetic testing (GT) for prostate cancer (PCa) patients (pts) has expanded to find pts with germline pathogenic variants (PV) for therapeutic opportunities given FDA-approvals for PARP inhibitors in metastatic PCa as well as understanding familial cancer risk and opportunities for tailored screening and risk reduction. The PROMISE Registry (NCT04995198) was set up as a genetic registry to partner with PCa pts for rapid access to a new standard of care given insurance coverage and clinical implementation were initially major barriers. A second goal is to characterize disease features and treatment outcomes to inform management and provide updates about novel therapeutic clinical trials, both of which remain important to rare genetic variant carriers. Methods: PROMISE is a US decentralized prospective PCa genetic registry initiated in 2021 with initial phase to enroll and provide clinical-grade germline genetic testing (30 gene cancer-specific panel) to 5,000 PCa pts to identify ~500 PCa pts with variants of interest (pathogenic variants, PV, and variants of uncertain significance, VUS) in DNA repair genes for long-term clinical follow-up of 15 years (LTFU). Here, we report the initial phase testing results and identification of the LTFU cohort. Study design and enrollment strategy have been reported separately. Results: Between 2021-2026, 7,275 pts with any stage PCa across 50 US states self-consented to PROMISE, of which 5,674 (78%) of pts completed genetic testing, indicating feasibility of patient-directed, decentralized enrollment. We have identified 495 (8.7%) pts for LTFU. Baseline data is reported for n=367 (Table 1, will be updated at time of presentation). The most frequently observed PV/LPV variants being in CHEK2 (25%) , BRCA2 (23%) , ATM (12%) , and BRCA1 (4.6%). At the time of PCa diagnosis, the majority of LTFU pts had non-metastatic disease, with 47% of pts with Gleason>7, median PSA of 5 ng/mL, and median time from diagnosis to PROMISE GT of 25 months. Conclusions: PROMISE is a nationwide decentralized PCa genetic registry that has completed initial goal to recruit 5,000 PCa pts to offer germline genetic testing and recruit a cohort of 500 for LTFU. Data about diagnosis characteristics are reported, and analysis of ongoing disease course, treatment response/outcomes and overall survival is being collected. Clinical trial information: NCT04995198 . Long-term follow-up participant demographics. Characteristic Overall, N = 367 Age at Diagnosis (yrs) 63 (57, 69) Race N = 361 (6, nr) Asian, American Indian or Alaska Native, Multiracial, Other 22 (6.0%) Black or African American 22 (6.0%) White 317 (86%) Disease State at Diagnosis N = 348 (19, nr) Metastatic 46 (13%) Non-metastatic 302 (87%) Time from Diagnosis to PROMISE GT (months) 25 (4, 82) Gleason Score N = 280 (87, nr) </= 7 148 (53%) >7 132 (47%) PSA At Diagnosis (ng/mL) 5 (0, 10) (88, nr) Subjects with baseline data entered. nr=not reported. Median (Q1, Q3); n (%).

Molecular testing, first-line treatment patterns, and survival in metastatic non–small cell lung cancer in Colombia: The RECAPC multicenter registry.

e20670 Background: Real-world Latin American NSCLC cohorts that jointly capture molecular testing, insurance coverage, treatment exposure, and time-to-event outcomes remain limited. We summarized the Colombian RECAPC registry using prespecified, reproducible endpoint definitions. Methods: Registry-based multicenter observational cohort of adults with NSCLC treated across 11 Colombian centers (5 cities) from December 15, 2000, through August 15, 2025; data cutoff October 6, 2025. Primary outcome was overall survival (OS). Progression-free survival (PFS) used patient-level progression dates; when unavailable, a prespecified real-world endpoint based on treatment-line dates (time to next treatment or discontinuation) was applied. OS and PFS were estimated with Kaplan–Meier methods; median follow-up was estimated with reverse Kaplan–Meier. Cox regression evaluated associations with OS and PFS. Results: Among 879 patients, 53% were women and mean age was 71 years (SD, 12); 585 (67%) had metastatic disease. In the full cohort, testing rates were 69% for EGFR, 57% for ALK, and 38% for ROS1; alterations were identified in 180 (20%), 72 (8.2%), and 19 (2.2%) patients, and other actionable variants in 58 (6.6%). Among metastatic patients (N = 585), 244 (42%) had a documented actionable alteration, 235 (40%) were no-driver, and 106 (18%) had unknown driver status. Median follow-up was 28 months; median OS was 22 months (95% CI, 19–28) and median PFS was 14 months (95% CI, 12–17). In patients with a molecular result documented in the medical record (OS-evaluable subset, n = 302), median OS was 36 months in driver-altered tumors versus 17 months in no-driver tumors (log-rank P < 0.001). First-line therapy (mutually exclusive, based on the initial-regimen field) was chemotherapy alone in 229 (39.1%), chemotherapy plus immunotherapy in 117 (20.0%), immunotherapy alone in 37 (6.3%), targeted therapy in 152 (26.0%), and no systemic therapy in 50 (8.5%). Median PFS was 19 months for EGFR (n = 113; P = 0.021 vs no-driver), 26 months for ALK (n = 54; P < 0.001), 19 months for ROS1 (n = 13; P = 0.28), 24 months for other actionable variants (n = 41; P = 0.034), and 12 months for no-driver tumors (n = 161). In multivariable models, ECOG ≥2 (HR, 3.23; 95% CI, 1.97–5.30) and age ≥75 years (HR, 2.02; 95% CI, 1.15–3.56) were associated with shorter OS; for PFS, ECOG ≥2 (HR, 1.68; 95% CI, 1.20–2.36) and > 3 metastatic sites (HR, 2.07; 95% CI, 1.29–3.33) were associated with shorter PFS, while pembrolizumab monotherapy was associated with longer PFS (HR, 0.60; 95% CI, 0.43–0.84). Conclusions: RECAPC provides national real-world metastatic NSCLC data integrating molecular epidemiology, payer type, treatment patterns, and reproducible endpoints.

Patient and caregiver knowledge and understanding of acute myeloid leukemia and satisfaction with oncologist communication.

e24104 Background: Acute myeloid leukemia (AML) is primarily diagnosed in older adults who often need caregiver support. Thus, oncologists need to communicate complex prognosis and treatment options to both patients and caregivers. However, satisfaction with oncologist communication and its impact on older adults and caregivers are not well-understood. Methods: This cross-sectional secondary analysis of a decisional intervention trial assessed disease knowledge, disease understanding, and communication satisfaction of patients ages 60 or older with newly diagnosed AML and their caregivers. Disease knowledge was defined as percent accuracy on an investigator-developed true/false quiz on AML risks and treatment. Disease understanding was defined as patient or caregiver response concordance with the oncologist’s multiple-choice estimates of cure probability and life expectancy. Communication satisfaction was assessed using the 36-item PCC-Ca-36 for patients or the 6-item PCC-Ca-6 for caregivers. PCC-Ca-36 includes six core functions: exchanging information, fostering healthy relationships, making decisions, responding to emotions, enabling patient self-management, and managing uncertainty. We summarized descriptive results of the 3 measures; multivariable logistic regression models assessed associations among measures, adjusting for sociodemographic factors. Results: We included 79 patients, 45 caregivers, and 8 oncologists. Disease knowledge was high (78% for patients and 84% for caregivers), but disease understanding was low. Patient-oncologist exact concordance was 28% for cure probability and 19% for life expectancy while caregiver-oncologist was 39% and 24%. While oncologists indicated only 3% of patients had > 50% cure probability, 38% of patients and 30% of caregivers responded as such. Similarly, oncologists indicated no patient had a life expectancy above 5 years, but 48% of patients and 30% of caregivers responded as such. Communication satisfaction was high with a mean PCC-Ca-36 of 4.2/5.0 (SD 0.6) for patients and a mean PCC-Ca-6 of 4.0/5.0 (SD 0.7) for caregivers. Patients scored the functions of enabling patient self-management (3.9/5.0) and managing uncertainty (3.9/5.0) the lowest. While communication satisfaction was not significantly associated with disease knowledge or understanding, the “making decisions” core function was positively associated with patient disease knowledge (p=0.06). Patient PCC-Ca-36 was positively associated with caregiver PCC-Ca-6 (p=0.03). Conclusions: While patients and caregivers had similar levels of satisfaction with oncologist communication, this satisfaction was not associated with disease knowledge or understanding. Communication interventions should focus on improving disease understanding and shared decision-making, enabling patient self-management, and managing uncertainty.

Association of response with survival in patients with relapsed/refractory high-risk neuroblastoma: A report from NANT Consortium.

10033 Background: Patients with relapsed/refractory (RR) high-risk neuroblastoma (HR-NB) have poor survival. Tumor response may be an early predictive endpoint, though response may not reflect long term survival. We evaluated the association between NANT Response Criteria (NANTRC) v1.2/2.0 with event-free survival (EFS) and overall survival (OS) in patients with RR-NB treated on contemporary NANT Phase 1/2 trials. Methods: Patients enrolled on 8 NANT trials from 2013 to 2022 were included. For patients enrolled on more than one trial, the first trial data was included. NANTRC were utilized to grade individual response components (soft tissue [ST], bone/MIBG, bone marrow [BM]) and overall response (complete [CR], partial [PR], minor [MR] response, stable disease [SD], or progressive disease [PD]). Patient/tumor characteristics, prior therapy and relapse, and disease at enrollment were analyzed for association with best overall response (BOR). Component and BOR were analyzed for association with EFS and OS from trial treatment initiation. EFS and OS were compared with the log-rank test and estimated by the Kaplan-Meier methods. Results: Among 244 patients, 3-year OS was 52% (95% confidence interval [CI] 46-58%), and EFS was 22% (95% CI 14-32%). OS differed significantly by best overall response (p<0.001), driven primarily by inferior outcomes of patients with PD. The 3-year OS was 16% (95% CI 9-29%) for patients with PD. Patients achieving objective response (CR/PR/MR) had an OS of 63% (95% CI 55-74%) and EFS 25% (95% CI 15-43%), while those achieving disease control (CR/PR/MR/SD) had very similar OS of 63% (95% CI 57-71%) and EFS 29% (95% CI 20-43%). Among patients with response of CR, PR, MR, or SD, OS and EFS were not significantly different. For individual components, a similar impact on OS was seen for PD vs no PD (all p<0.001), with BOR of PD in MIBG/bone and ST having OS <10%. Patients lacking either BM or bone/MIBG involvement (but not ST) at baseline and remained not involved in those components demonstrated superior OS (both p<0.001). Patients with BOR of PD had shorter time from diagnosis to first progression (median of 1.4 vs 1.8 years, p=0.035), and higher incidence of MYCN -amplified disease (46% vs. 14%, p<0.001) and prior history of progression (95% vs 73%, p<0.001). Conclusions: In RR-HRNB treated on contemporary NANT trials, BOR of PD is associated with inferior OS. Patients achieving disease control (CR/PR/MR/SD) experienced comparable outcomes regardless of response achieved. These findings support disease-control as a clinically meaningful efficacy endpoint for early-phase neuroblastoma trials. 3-year survival by component response. Component Response N OS % (95% CI) EFS* % (95% CI) BM Non-PD 100 47 (38, 58) 17 (7, 38) PD 18 29 (14, 61) - Bone/MIBG Non-PD 180 59 (52, 66) 22 (13, 35) PD 30 7 (2, 26) - ST Non-PD 142 61 (53, 70) 28 (18, 44) PD 35 9 (3, 25) - *EFS censored at time of new therapy.

Comparative analysis of mitochondrial free radical markers in endometrioid adenocarcinoma and an experimental model.

e17627 Background: Endometrial cancer (EC) is the sixth most common cancer worldwide. In postmenopausal women, adipose tissue converts androgens to estrogens. Estrogen has antioxidant functions, protecting cancer cells from reactive oxygen species. Mitochondria can be exposed to free radicals, leading to increased DNA mutations. This paper presents clinical and experimental data from a comparative study, drawing parallels between alterations in free radical processes observed in the mitochondria of uterine and tumor cells from female patients and rats. The aim was to study parameters of free radical processes in the mitochondria of endometrioid adenocarcinoma (EA) cells from gynecologic oncology patients and in the mitochondria of intrauterine Guérin carcinoma cells in rats. Methods: The study included 42 patients who underwent surgery for EA and 14 patients with uterine fibroids (source of intact endometrium). Among the EA patients, 16 had well-differentiated (G1), 12 had moderately differentiated (G2), and 14 had poorly differentiated (G3) EA. The mean age of EA patients was 60.8±2.9 years; for those with fibroids, it was 49.4±2.5 years. Patients did not receive neoadjuvant therapy. The experimental part utilized biological material from 15 outbred laboratory female rats (250±25 g) with modeled intrauterine growth of Guérin carcinoma. In mitochondria isolated from tumor tissue and intact uterine tissue, concentrations of mitochondrial superoxide dismutase (SOD-2), malondialdehyde (MDA), diene conjugates (DC), and oxidative DNA/RNA modification products were determined using enzyme-linked immunosorbent assay (ELISA). Protein was measured via the Lowry method. Statistical analysis used parametric and nonparametric tests with adjustments for multiple comparisons. Results: In patients, mitochondria from G1 EA cells showed high levels of MDA and DC, which were 2.3-fold and 2.9-fold higher, respectively, compared with intact endometrium. In G2 tumors, MDA levels were 3.2 times higher, and DC levels were 2.7 times higher than in intact mitochondria. G3 tumors exhibited a 1.6-fold increase in DNA damage (p<0.05), along with 2.4-fold, 3.0-fold, and 3.4-fold increases in MDA, DC, and SOD-2 concentrations, respectively, versus intact tissue. In female rats, tumor mitochondria exhibited changes analogous to those in EA patients: MDA increased 1.6-fold (p<0.05), DC 1.5-fold (p<0.05), SOD-2 2.4-fold, and DNA damage 1.6-fold (p<0.05) compared with intact uterine tissue values. Conclusions: Oxidative stress and mitochondrial dysfunction in malignant cells from patients indicate a pathogenetic feature dependent on the degree of tumor differentiation. The experimental model confirms the association between free radical processes and mitochondrial alterations, likely contributing to the pathogenetic mechanism of uterine carcinoma.

Interplay of the IGFBP-3 polymorphism and serum levels of IGF-1/IGFBP-3 with hormone receptor subtypes in patients with breast cancer among Palestinian women

Breast cancer remains a global public health challenge. This study aimed to investigate the relationships between serum levels of insulin-like growth factor binding protein 3 (IGFBP-3), insulin-like growth factor 1 (IGF-1), the IGFBP-3 A-202C polymorphism and hormone receptor subtypes: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) with respect to breast cancer risk in Palestinian women. A cross-sectional study was conducted on 112 newly diagnosed, histopathologically confirmed breast cancer patients. Data collection included structured interviews and laboratory analyses, including biochemical, genetic, and immunohistochemical assessments. The tumor tissue samples were analyzed for ER, PR, and HER-2 status. SPSS version 28 was used for all data analysis. A high prevalence of hormone receptor positivity was observed. Among the breast cancer patients, 87.5% were ER positive and 84.8% were PR positive. A total of 75.9% were HER-2 negative. The IGFBP-3 A-202C genotype is significantly associated with PR and combined ER/PR positivity ( p  = 0.020). Patients with ER(+)/PR(+) status had significantly higher serum IGF-1 and IGFBP-3 levels ( p  ≤ 0.001), with IGF-1 levels positively correlated with hormone receptor status ( r s  = 0.232, p  ≤ 0.001) and advanced disease stages, moderately with Stage III ( r s  = 0.191, p  ≤ 0.001) and weakly correlated with Stage IV ( r s  = 0.119, p  = 0.029). These findings suggest that IGF-1 and IGFBP-3 may have potential as candidate biomarkers for breast cancer risk and progression. Integrating genetic, biochemical, and hormone receptor status provides novel insights into breast cancer biology and may support future research on personalized prevention and treatment strategies, particularly in resource-limited settings such as the Gaza Strip.

The chemo-biochemical convergence in nanomedicine: A review of tailored therapeutic strategies

STING signalling as a mediator between lipid metabolism and innate immunity

Metamaterial Antennas Enhance MRI of the Eye and Occipital Brain (Adv. Mater. 32/2026)

Brush‐on‐Brush Architecture Enables Durable and Reversible Aptamer Therapeutics With Minimal PEG Associated Immunogenicity

ABSTRACT We present a “Brush‐on‐Brush” (BOB) nanocarrier as a next‐generation alternative to PEGylation for nucleic acid aptamer therapeutics. This architecture, comprising aptamers and dense brush‐shaped oligo(ethylene glycol) (b‐OEG) side chains co‐grafted onto a peptide backbone, was validated using the thrombin‐binding HD1 aptamer. BOB‐HD1 exhibited exceptional nuclease resistance, retaining >40% integrity after 2 h of S1 nuclease exposure (versus complete degradation of free aptamer within 3 min), while fully preserving G‐quadruplex folding, thrombin‐binding activity, and antidote‐mediated reversibility. In mice, BOB‐HD1 achieved a 7.5‐fold increase in systemic exposure and sustained anticoagulation for 4 h, compared to <20 min for unmodified or linearly PEGylated aptamer. Critically, unlike linear PEG conjugates that induced anti‐PEG antibodies and accelerated blood clearance upon repeated dosing, BOB‐HD1 induced no detectable anti PEG IgM or IgG responses under the tested conditions and maintained full efficacy upon repeated administration. This dense brush architecture thus addresses key stability, clearance, and PEG associated immunogenicity barriers that have impeded aptamer clinical translation, offering a versatile and controllable platform for durable aptamer therapeutics while minimizing detectable anti PEG antibody responses under the tested conditions.

A hybrid knowledge-based and evolutionary framework for fault diagnosis and optimization in power systems

Abstract This paper presents a hybrid artificial intelligence framework designed to improve the diagnosis of error and subsequent optimization of operational efficiency in complex energy systems. By integrating knowledge-based systems with evolutionary algorithms, we address the critical need for fast and accurate fault identification as a prerequisite for maintaining the reliability of the network. Knowledge-based components use expert rules to precisely determine the locations and types of errors, and then dynamically limit genetic algorithms (GAs) to optimize restoration strategies such as load reduction and network reconfiguration. Performance metrics reported in this study were obtained from multiple independent simulation trials conducted under varying fault locations and noise conditions. The proposed framework achieved higher fault-diagnosis accuracy with an average detection latency of less than 55.65 ms by performing comprehensive simulations of the IEEE 30-bus and 118-bus systems, across different test conditions. By intelligently reducing the search space, the hybrid approach reduces the total system recovery time to less than 1.0 s, a significant improvement over the independent evolutionary methods that require more than 5.0 s. In addition, the optimization module successfully limited load loss to less than 5%, surpassing traditional methods by more than 50% in terms of service continuity. Robustness analysis confirmed diagnostic accuracy of more than 98% even below the signal-to-noise ratio of 20 dB, and IEEE 118 bus scale-up test showed a 38% to 47% increase in computational efficiency compared to standalone particle swarm optimization (PSO). These results highlight the performance of the framework and the practical application of critical energy infrastructure management with real-time, resilient management.

Meeting report on FASEB protein arginine methylation: mechanism to therapeutics

CXCL12 ⁺ pericytes as drivers of lymphatic dissemination in pancreatic cancer: Integrated single-cell and spatial analysis.

4126 Background: Pancreatic ductal adenocarcinoma (PDAC) exhibits poor prognosis largely due to early lymph node metastasis, yet the cellular and molecular mechanisms governing lymphatic dissemination remain incompletely understood. Methods: We integrated multi-omics approaches including single-cell RNA sequencing (scRNA-seq) of 19 PDAC samples, spatial transcriptomics of 6 specimens, bulk RNA sequencing of 174 cases, and multiplex immunofluorescence of 166 clinical samples stratified by lymph node metastasis status. Cell-cell communication analysis, trajectory inference, and functional validation were performed to elucidate pro-metastatic mechanisms. Results: Single-cell profiling of 145,283 cells revealed substantial cellular heterogeneity, with fibroblasts and pericytes serving as dominant signaling hubs within the tumor microenvironment. Lymph node metastasis-positive (pLNM) tumors exhibited enhanced stromal-epithelial crosstalk mediated by PTN and ANGPT pathways. We identified invasive epithelial subpopulations (Epi_MUC5AC_CD24 and Epi_NEAT1_MALAT1) significantly enriched in pLNM samples, characterized by activation of EMT and invasion-related programs. Critically, high-resolution subclustering uncovered a CXCL12-expressing pericyte subset (PCs_CXCL12) preferentially expanded in metastatic tumors. Multiplex immunofluorescence validation in 166 specimens demonstrated that CXCL12+ pericyte infiltration correlated with perineural invasion, lymph node metastasis, advanced TNM stage, and inferior survival outcomes. Multivariate analysis established CXCL12+ pericyte score as an independent prognostic factor for both disease-free and overall survival. Mechanistically, we identified MYC as the master transcriptional regulator driving CXCL12 secretion in pericytes. Functional studies revealed that MYC-driven pericyte-derived CXCL12 promoted PDAC cell proliferation, invasion, and EMT. Spatial transcriptomics demonstrated co-localization of MYC, CXCL12, and its receptor CXCR4 in perineural pericyte niches. Orthotopic xenograft models confirmed that pericyte-specific Myc depletion significantly reduced tumor growth, CXCL12+ pericyte density, and tumor-associated lymphangiogenesis. Conclusions: This study establishes the pericyte MYC-CXCL12 axis as a critical driver of PDAC lymphatic metastasis through promotion of tumor cell invasion, EMT, and lymphangiogenesis. CXCL12+ pericytes represent a novel prognostic biomarker and potential therapeutic target for preventing lymph node metastasis in PDAC patients.

Enrichment of the germline <i> NLRC5 ^Pro191Leu </i> variant in patients with immune checkpoint inhibitor–induced hepatitis.

2660 Background: Immune checkpoint inhibitor–induced hepatitis (ICI-hepatitis) is a clinically significant immune-related adverse event (irAE) that may require treatment interruption and immunosuppressive therapy. Predictors of susceptibility to irAEs remain poorly defined. NLRC5 is a key regulator of MHC class I antigen presentation and CD8⁺ T-cell–mediated immune activation. We previously identified a germline missense variant at the NLRC5 gene ( NLRC5 Pro191Leu ) that is associated with ICI-related endocrinopathies, and increased expression of downstream genes involved in antigen presentation. Our purpose was to determine whether the variant has a broader role in immune-related toxicity. Methods: We evaluated the prevalence and clinical associations of the germline NLRC5 Pro191Leu variant in patients with grade ≥2 ICI-hepatitis. Sanger sequencing was performed to assess the NLRC5 Pro191Leu (rs74439742) germline variant. Hepatitis severity was graded according to CTCAE criteria. Clinical data included irAE co-occurrence, duration of corticosteroid therapy, and requirement for additional immunosuppression. Variant prevalence was compared with the general population using data from the 1000 Genomes Project. Results: Among 39 patients with ICI-hepatitis, the cohort was predominantly composed of patients with metastatic melanoma receiving ipilimumab plus nivolumab. The variant was significantly enriched in the ICI-hepatitis cohort compared with the general population (30.0% vs 12.8%; p = 0.007, odds ratio [OR] = 2.9). Variant carriers also more frequently developed co-occurring endocrine irAEs, particularly thyroid dysfunction and hypopituitarism. Conversely, co-occurrence of hepatitis and colitis was more frequent among wild-type patients (p = 0.06, OR = 7.6), suggesting distinct immunopathogenic toxicity patterns. The severity of hepatitis was assessed by a composite outcome of maximal grade 4 hepatitis and prolonged steroid use (≥120 days). Variant carriers showed a trend toward increased hepatitis severity that did not reach statistical significance (Fisher’s exact p = 0.06; OR = 4.9). Conclusions: Germline NLRC5 Pro191Leu is significantly more common in patients who develop ICI-hepatitis than in the general population and is associated with distinct immune-related toxicity patterns. This suggests that host genetic factors may inform toxicity surveillance and early management strategies. Larger multi-center studies are needed to validate these observations and define the clinical utility of NLRC5 Pro191Leu as a predictor of immune-related toxicity risk. Prevalence of NLRC5 Pro191Leu variant in the ICI-hepatitis cohort. Group NLRC5 WT, n (%) NLRC5Pro191Leu , n (%) ICI-hepatitis cohort (n=39) 27 (70.0) 12 (30.0) Odds ratio 2.9 p value 0.007 General population (1000 Genomes Project) (n=694) 605 (87.2) 89 (12.8)

A retrospective analysis of concomitant opioid usage with immunotherapy in recurrent/metastatic head and neck squamous cell carcinoma.

e18103 Background: Cancer-related pain is a significant consequence of disease for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. Pain severity contributes to a high opioid burden for this patient population. Recent studies have shown that opioids are immunosuppressive, diminishing the efficacy of immunotherapy (IO), which is the standard of care for R/M HNSCC. The prognostic impact of the concomitant use of opioids in R/M HNSCC patients receiving IO remains unclear. In this study, we aimed to analyze whether the use of opioids along with IO in patients with R/M HNSCC impacts clinical outcomes. Methods: This was a retrospective, IRB-approved study that examined R/M HNSCC patients at a single NCI-designated comprehensive cancer center treated with IO from 2022–2025. Patients were divided into two groups: those who used opioids while on first-line IO (Opioids) and those that did not (Controls). Descriptive variables including demographic and clinical characteristics (age, gender, race/ethnicity, histology, metastatic sites, PD-L1 and HPV status), IO treatment (type, therapy duration, use of other biologic treatment), and opioid usage (type, dose in morphine milligram equivalency [MME], therapy duration) were collected. Primary outcome was overall survival (OS) from time of start of IO therapy to death or date of last follow up. Statistical analysis was descriptive and OS was analyzed using GraphPad Prism v 10 and the Gehan-Breslow-Wilcoxon test. Results: Among 45 R/M HNSCC patients, 24 were treated with first-line IO without opioid use (Controls) and 21 were treated with opioids and IO concurrently (Opioids). Median age at diagnosis of R/M disease was 65 (Opioids 63; Controls 66). Gender and race/ethnicity were consistent across groups and most commonly Non-Hispanic White (N=21, 35%) and male (N=35, 58.3%). Most patients had ECOG performance status (PS) of 0 (N=16, 36%) or 1 (N=19, 42%). Oral cavity (49%) and oropharyngeal (29%) were the most prevalent primary sites; 56% of the oropharyngeal group were p16 positive. 28 patients had a known PD-L1 combined positive score (CPS) ≥ 1. Patients were treated with single-agent IO (N=23, 51%) or with another therapy (plus chemotherapy N=21, 47%; plus biologic N=1, 2%). Pembrolizumab (N=35, 78%) and nivolumab (N=8, 18%) were the most common IO. Median time on IO was 133 days for Controls and 120 days for Opioids. The Opioids group had a median total MME per patient of 5499 (range 30-59130; median dosage of 45 MME/day). Median OS (months) was statistically significantly different between both groups (Opioids 9.3; Controls 27.1; p=0.04). Conclusions: This study showed a significant difference in survival in R/M HNSCC patients taking opioids with IO compared to patients not exposed to opioids. Further investigation is needed to understand the potential effects conferred by opioid use in R/M HNSCC patients on IO.

Impact and prognosis of pembrolizumab combination in neoadjuvant chemotherapy for triple-negative breast cancer: A single-center retrospective study.

e12507 Background: The addition of pembrolizumab (PEM) to neoadjuvant chemotherapy (NAC) has been shown to significantly improve pathological complete response (pCR) rates in patients with early-stage triple-negative breast cancer (TNBC). However, long-term prognostic outcomes in real-world clinical practice, specifically for patients who achieve pCR, have not been sufficiently verified. This study evaluated the efficacy and safety of PEM-combined regimens, with a specific focus on the prognostic implications for patients achieving pCR. Methods: We analyzed 219 patients with TNBC who underwent NAC at our institution between 2009 and 2025. Patients were categorized into a conventional chemotherapy group (TN-historical; n=170) and a pembrolizumab combination group (TN-PEM; n=49). Primary endpoints included pCR rates, disease-free survival (DFS), and overall survival (OS). A subgroup analysis was performed on 100 patients who achieved pCR (TN-historical: n=67; TN-PEM: n=33) to evaluate recurrence patterns and post-recurrence survival. Statistical analyses were performed using Fisher's exact test, the Kaplan-Meier method, and the Log-rank test. Results: The overall pCR rate was significantly higher in the TN-PEM group compared to the TN-historical group (67.3% vs. 39.4%; p=0.001). However, among patients who achieved pCR, long-term outcomes were unexpectedly inferior in the immunotherapy cohort. The 5-year DFS rate for pCR achievers was 81.8% in the TN-PEM group versus 96.6% in the TN-historical group (p=0.002). Similarly, the 5-year OS rate was significantly lower in the TN-PEM group (76.9% vs. 100.0%; p=0.001). The recurrence rate among pCR cases was significantly higher in the TN-PEM group (15.2% [5/33]) compared to the TN-historical group (1.5% [1/67]; p=0.014). Notably, 80% of recurrences in the TN-PEM group involved liver metastases. The clinical course after recurrence in the TN-PEM group was aggressive, with a median time from recurrence to death of only 2.7 months. Conclusions: While the addition of pembrolizumab to NAC significantly improves pCR rates in TNBC, our data suggest a paradoxical risk of early and aggressive recurrence even after achieving pCR. Recurrences in the PEM-treated cohort were characterized by a high incidence of liver metastasis and rapid disease progression, suggesting potential acquired resistance mechanisms following immunotherapy. These findings underscore the necessity for rigorous surveillance and the development of novel therapeutic strategies for patients treated with immune checkpoint inhibitors, regardless of pathological response status.

Lung cancer stage prediction using longitudinal CT imaging compared with single-timepoint assessment.

8018 Background: Lung cancer staging guides treatment decisions but is based on single-timepoint imaging, treating tumors as static entities. Screening programs routinely acquire serial low-dose CTs (LD-CTs), yet this longitudinal information is not used for staging. We hypothesized that modelling temporal change would capture tumor evolutionary dynamics predictive of stage beyond volume change alone, reframing staging as a process rather than a snapshot. Methods: We identified 236 NLST participants with biopsy-confirmed lung cancer and three pre-treatment LD-CTs (median interval 12 months). Reference staging used AJCC 7th edition criteria, pathologic where available and otherwise clinical, for overall stage (I–IV) and T and N components. We developed a longitudinal 3D residual network with dual attention and interval-aware temporal encoding, trained using nested five-fold cross-validation. Volume doubling time (VDT) was computed to assess whether temporal features provided information beyond growth rate. The primary endpoint was macro-AUC for overall stage. Secondary endpoints included balanced accuracy, weighted κ, calibration (ECE, Brier score), and decision-curve net benefit. External validation is ongoing in NLSTseg (n = 605) and NSCLC Radiogenomics (n = 211). Results: The longitudinal model outperformed a single-timepoint baseline, achieving a macro-AUC of 0.86 versus 0.82, Δ +0.04, p &lt; 0.05. Improvements were greatest for N-stage (Δ +0.13) and T-stage (Δ +0.11). Compared with a recent foundation model approach (DINOv2 + ABMIL), the model showed superior N-stage discrimination (AUC 0.86 vs 0.70). Temporal features remained independently predictive after adjustment for VDT, indicating capture of biological signal beyond growth rate. Attention maps consistently highlighted lesion margins and peritumoral regions across timepoints, consistent with invasive behavior. Performance was stable across sex, age, and smoking subgroups, and inference was feasible on standard CPUs. Conclusions: Modelling longitudinal change across serial LD-CTs captures tumor evolutionary dynamics that predict lung cancer stage independently of growth rate. This reframes staging as a dynamic, evolution-aware process and provides a practical route for integrating artificial intelligence into screening workflows where serial imaging is already available. External validation is underway.