Browse Articles

Association of mRNA COVID-19 vaccination near immune checkpoint inhibitor initiation with outcomes: A real-world analysis.

2636 Background: Prior study showed mRNA COVID-19 vaccines can activate innate and adaptive immune pathways and have been hypothesized to “prime” anti-tumor immunity via increased tumor PD-L1 expression when administered near immune checkpoint inhibitor (ICI) initiation. We performed a real-world validation to evaluate the association between COVID-19 vaccination around ICI initiation and outcomes among patients with 4 advanced/metastatic solid tumors. Methods: Using ConcertAI Patient360 (US-based, de-identified, human-abstracted oncology EHR linked to medical/pharmacy claims and third-party mortality), we identified adults (≥18 years at diagnosis) with advanced/metastatic bladder cancer, melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) who initiated an ICI between Jan 2021 and Mar 2024. Exposure was receipt of ≥1 mRNA COVID-19 vaccine within 100 days of ICI initiation. Exposed patients were propensity score–matched 1:1 to unexposed patients on demographics (age, sex, race, ethnicity) and clinical factors (baseline steroid use, ICI initiation year, Charlson Comorbidity Index, ECOG performance status, BMI, and tumor type). Real-world OS (rwOS) and real-world PFS (rwPFS) were estimated by Kaplan-Meier; hazard ratios (HRs) were estimated using univariate Cox models (post-match) and multivariable Cox models (residual confounding sensitivity), overall and by tumor type. Results: Among 7085 eligible patients, 1,513 were vaccinated around ICI initiation. After matching, 3,018 patients (1,509 per group) had evaluable time-to-event data and were included in Kaplan-Meier and Cox analyses (tumor mix: NSCLC 73.6%, RCC 11.7%, bladder 8.5%, melanoma 6.3%). Overall, vaccination was associated with improved rwOS and rwPFS: median rwOS 19.52 vs 15.31 months (p<0.001) and median rwPFS 7.95 vs 6.37 months (p=0.002). Univariate Cox models favored vaccination for rwOS (HR 0.82; 95% CI 0.75–0.90; p<0.001) and rwPFS (HR 0.88; 95% CI 0.81–0.95; p=0.002), with consistent findings in multivariable models (rwOS HR 0.81; 95% CI 0.74–0.89; p<0.001; rwPFS HR 0.87; 95% CI 0.80–0.95; p=0.001). Twelve-month rwOS was 64.87% vs 54.45% (vaccinated vs unvaccinated). By tumor type, univariate (post-match) associations were directionally favorable and strongest in NSCLC (rwOS HR 0.79; 95% CI 0.71–0.87; p<0.001; rwPFS HR 0.85; 95% CI 0.77–0.93; p<0.001). Similar, non-significant trends were observed in smaller bladder and RCC cohorts; melanoma showed no association with rwOS. Conclusions: In this large propensity score–matched real-world cohort of ICI-treated patients, COVID-19 vaccination within 100 days of ICI initiation was associated with significant improvements in rwOS and rwPFS, particularly in NSCLC. Prospective validation and randomized clinical trials are warranted to confirm these findings.

Efficacy and safety of HLX43 (anti–PD-L1 ADC) in patients with advanced non–small cell lung cancer.

8512 Background: HLX43 (a PD-L1 ADC) has demonstrated encouraging efficacy with a manageable safety in a phase 1 study. Here, we present the pooled findings from patients with NSCLC in a phase 1 study (HLX43-FIH101) as well as a global phase 2 study investigating HLX43 in NSCLC (HLX43-NSCLC201). Methods: The phase 1 study included a dose-escalation phase in patients with advanced solid tumors (0.5–4.0 mg/kg Q3W), followed by a dose-expansion phase in patients with advanced or metastatic NSCLC at doses of 2.0, 2.5, and 3.0 mg/kg Q3W. The phase 2 study was conducted in NSCLC and comprised two parts: Part A was dose-exploration for patients who had failed prior first-line therapy and had no actionable genomic alterations, to receive HLX43 at 2.0 or 2.5 mg/kg Q3W; Part B was dose-expansion in which patients received HLX43 at the recommended dose determined from Part A. This analysis integrated data from heavily pretreated NSCLC patients enrolled across both studies. Efficacy and safety outcomes were evaluated in the pooled population. Results: As of December 31, 2025, 205 patients were enrolled and received HLX43 at 1 mg/kg (n = 3), 2 mg/kg (n = 89), 2.5 mg/kg (n = 85), 3 mg/kg (n = 23), and 4 mg/kg (n = 5). Patients received a median of 2 lines of prior antitumor therapy (range, 1–9). Among the 161 response-evaluable patients (2, 69, 64, 21, and 5 in the 1, 2, 2.5, 3, and 4 mg/kg groups, respectively), the investigator-assessed ORR was 31.1%. In the 2.0 mg/kg group, investigator-assessed ORR was 36.4% for squamous NSCLC (n = 33); among these patients, ORR was 40.0% for those who previously failed docetaxel (n = 15). ORR was 47.4%, and 50.0% for patients with EGFR-wildtype (n = 19), and EGFR-mutant (n = 16) nonsquamous NSCLC receiving HLX43 at 2.5 mg/kg. Biomarker exploratory analyses showed that efficacy was not associated with PD-L1 expression, with ORRs of 30.1% and 32.1% in patients with PD-L1-positive (n = 83) and PD-L1-negative tumors (n = 78), respectively. Overall, 199 (97.1%) patients experienced treatment-related adverse events (TRAEs), of whom 88 (42.9%) had grade ≥3 in severity. Most common Grade ≥3 TRAEs (incidence ≥10%) included lymphocyte count decreased (n = 47, 22.9%), white blood cell count decreased (n = 27, 13.2%), anemia (n = 25, 12.2%), and neutrophil count decreased (n = 23, 11.2%). TRAEs led to treatment discontinuation in 17 (8.3%) patients. Conclusions: HLX43 exhibited promising efficacy in patients with heavily pretreated advanced NSCLC, regardless of histology subtypes, and PD-L1 expression, along with manageable tolerability. Further investigation is warranted. Clinical trial information: NCT06115642 (HLX43-FIH101-phase 1 study), NCT06907615 (HLX43-NSCLC201- phase 2 study).

Impact of clonal hematopoiesis on clinical outcomes in patients undergoing CAR T-cell therapy: A systematic review and meta-analysis.

e19011 Background: Clonal hematopoiesis (CH) is characterized by the expansion of hematopoietic cell clones harboring somatic mutations in genes associated with hematologic malignancies and has been linked to immune dysregulation and pro-inflammatory signaling. Given the immune-dependent mechanisms of chimeric antigen receptor (CAR) T-cell therapy, CH has emerged as a potential modifier of treatment response and toxicity; however, available evidence remains heterogeneous and inconclusive. Methods: We conducted a systematic review and meta-analysis of observational studies evaluating the impact of CH on outcomes following CAR T-cell therapy. PubMed, Embase, and the Cochrane Library were searched from inception through June 2025 (PROSPERO: CRD420251105655). Outcomes included overall response rate (ORR), complete response (CR), overall survival (OS), progression-free survival (PFS), cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), and post-treatment cytopenias. Random-effects models were used to pool risk ratios (RR) and hazard ratios (HR) with 95% confidence intervals (CI). Subgroup analyses were conducted for lymphoma and multiple myeloma (MM). Results: Nine observational studies comprising 702 patients were included; 291 patients (41.5%) had CH. Predominant underlying malignancies were lymphoma (n = 511) and MM (n = 186). Compared to patients without CH, those with CH demonstrated higher ORR (RR 1.20; 95% CI 1.07–1.35) and CR (RR 1.24; 95% CI 1.01–1.51) following CAR T-cell therapy, without corresponding improvements in OS (HR 0.94; 95% CI 0.66–1.34) or PFS (HR 0.86; 95% CI 0.66–1.12). Overall, CH was not associated with increased incidence or severity of CRS (RR 1.09; 95% CI 0.95–1.24) or ICANS (RR 1.12; 95% CI 0.89–1.43), although an exploratory lymphoma-restricted analysis suggested a higher incidence of grade III–IV ICANS (RR 1.66; 95% CI 1.03–2.65). Post-treatment cytopenias were heterogeneously reported and synthesized narratively, with greater hematopoietic support requirements observed in MM cohorts. Conclusions: These findings support the safe use of CAR T-cell therapy in patients with CH and highlight the need for prospective studies to clarify mutation-specific effects and long-term outcomes.

Characterization of extracolonic cancers in individuals with Lynch syndrome: A Canadian population-based cohort.

e22658 Background: While increased risk of colorectal cancer (CRC) is well established in individuals with Lynch syndrome (LS), North American population-based data on extracolonic cancers (ECCs), especially with some gene variants, remains limited. Better understanding of ECCs in LS may improve screening, care and outcomes. Manitoba has a provincial registry of individuals with mismatch repair (MMR) germline pathogenic variants (GPVs), and a multidisciplinary clinic for individuals with LS, focused on screening, surveillance and risk-reduction strategies. The aims of this study are: (1) characterize ECCs in LS; (2) evaluate impact of clinic practices on individuals with LS. Methods: We conducted a retrospective cohort study of individuals with GPVs enrolled in the Manitoba LS registry between 1999 and 2023. Clinical and pathological data were obtained from provincial cancer and genetics databases. Outcomes included ECC type, age at diagnosis, stage, tumor MMR/MSI testing, mode of cancer detection, enrollment in LS clinic and associated screening/surveillance tests. Descriptive statistics were used. Results: 124 individuals with GPVs had 192 ECCs. Impacted GPVs were: 28.1% MLH1, 27.4% MSH2, 23.4% MSH6, 17.7% PMS2, 3.2% EPCAM. Mean age of diagnosis was 57 (SD 12.6). Common cancers were: endometrial (34.9%), genitourinary tract (8.9%) ovarian (6.3%), small bowel/stomach (5.7%), sebaceous (4.2%), hepatobiliary (2.6%). Fifty (40%) individuals had >2 ECC diagnoses. The majority of ECCs were diagnosed following symptomatic presentation (56.8%) and 8.7% were advanced or metastatic stage at diagnosis. 68 (35.4%) ECCs had tumor MMR or MSI testing and 6 (3.1%) received immunotherapy. Among individuals with ECCs, 66.1% were followed in the LS clinic. Clinic-followed individuals had higher uptake of ECC screening than those not followed (89.0% vs 66.7%), although few tests were associated with a cancer diagnosis (12%). Conclusions: While ECCs in LS are less common than CRC, they are clinically significant, particularly when of advanced stage or if limited treatment options exist. In our cohort, tumour MMR/MSI testing and receipt of immunotherapy was low, highlighting areas for improvement. Higher screening uptake among clinic-followed individuals may support a centralized care model. This underscores the need for prospective studies to optimize ECC screening and evaluate outcomes.

Clinical outcome of Asian and non-Hispanic White patients with colorectal cancer in a NCI-designated cancer center serving a diverse catchment area.

e15710 Background: Traditionally, research on the epidemiology and outcomes in minorities in the United States has primarily focused on differences between Non-Hispanic White (NHW) and Non-Hispanic Black (NHB) and Hispanic populations, with a lower emphasis on Asians, a gradually increasing demographic in the US. Recent literature suggests the rate of colorectal cancer (CRC) screening among Asian Americans remains low, despite an increasing rate of CRC diagnoses within this population. The differences between the disease courses of Asian and NHW patients are not well-characterized. In this study, we aimed to examine the diagnosis, treatment, and survival of Asian and NHW patients diagnosed with CRC. Methods: This was a retrospective, observational IRB-approved study of Asian and NHW patients treated for CRC at a single NCI-designated comprehensive cancer center. Descriptive variables were collected including demographics (age at diagnosis, gender, race/ethnicity), disease characteristics (stage at diagnosis, anatomical site of primary cancer, mutations), treatment (surgery, radiation, neo-adjuvant/adjuvant therapy, lines of treatment for advanced disease), and survival. The primary outcome was overall survival (OS) from time of stage IV diagnosis to death or last follow-up. Statistical analysis was performed using R software and GraphPad Prism, and Log-Rank tests were used to determine differences in OS between the two cohorts; patients were considered dead or censored if alive or status was unknown. Results: 122 patients were included in the study: Asian (n = 60) and NHW (n = 62). The overall survival data included 68% (n = 83) alive at last follow up, 28.7% (n = 35) deceased, and 3.3% (n = 4) unknown; this was consistent across both cohorts. Median age at initial diagnosis (years) of Asians was younger, but not significantly different [Asian 61, NHW 66; p = 0.279]; the same was observed for the median age (years) at stage IV diagnosis [Asian 60, NHW 68; p = 0.222]. Asian patients had a lower proportion of stage IV disease at initial diagnosis [Asian 30%, NHW 45%; p = 0.123]; however, NHW patients were significantly more likely to have stage IV CRC at any time during their disease course [Asian 37%, NHW 61%; p = 0.011]. There was no statistically significant difference in median OS (years) to death or last follow up from time of initial diagnosis [Asian 4.89, NHW 4.79; HR 0.88, p = 0.72], and for the primary outcome of median OS (years) from time of stage IV diagnosis to death or last follow up [Asian 3.03, NHW 2.87; HR 0.91, p = 0.934]. Conclusions: Asian and NHW patients have similar overall survival and ages at initial and stage IV diagnosis, but NHW are significantly more likely to have stage IV disease. Given their increasing presence in US society, more in-depth analysis of Asian populations with CRC is warranted to determine any disparities in screening, treatments, and outcomes.

Biologic and clinical implications of HPV genome state variation in oropharyngeal cancers.

6076 Background: HPV integration enhances carcinogenesis by ensuring viral DNA retention and increasing E6/E7 expression. Though HPV usually integrates in cervical cancer, DNA episomes persist in ~50% of HPV+ oropharyngeal cancers (OPCs), and prior studies relating integration to clinical outcomes are contradictory. Defining molecular traits and clinical behavior of episomal vs. integrated OPCs is impeded by the complexity of HPV genome states, which defy classification by any one assay. Here we classified HPV states based on concordance between HPV-host fusion mRNA detection (suggesting integration) and E6/E7 levels. Gene expression and clinical outcomes were compared among groups to seek biomarkers allowing therapeutic personalization. Methods: Samples were curated from 851 therapy-naïve HPV+ OPCs receiving robotic surgery at a single institution (2007-2020). RNA sequencing was performed on 50 HPV+ OPCs that later recurred (cases) and 50 that were cured (controls). Groups were matched for stage, smoking, and adjuvant therapy. OPCs were deemed likely episomal if absence of HPV-host fusion mRNA was accompanied by E6/E7 levels in the bottom tertile and likely integrated if fusion mRNA presence coincided with E6/E7 in the top tertile. These two OPC subsets were defined as E6/E7-concordant and the rest as E6/E7-discordant. Molecular traits were analyzed as previously (Sannigrahi MK et.al, JNCI 2025 117:7) using GSEA of Hallmark pathways and by two scores derived by GSVA of host mRNAs that potently stratified recurrence risk across multiple HPV+ OPC cohorts: (1) an immune suppression score (ISS) measuring reduced anti-tumor immunity and (2) a t umor progression score ( TPS ) capturing aggressive tumor cell-intrinsic traits. Results: In the overall cohort (n=100), the fusion (+) OPCs (n=49) had increased risk of recurrence (OR 2.90, 95% CI=1.27-6.64, p=.01). Whereas E6/E7 levels alone did not stratify recurrence risk, combining it with fusion status optimized prediction: the likely integrated OPCs (n=23) had high recurrence risk vs. likely episomal OPCs (n=24) (OR=3.81, 95% CI=1.13-12.82, p=.03) despite similar clinical characteristics in both groups. Time to recurrence was also shorter in likely integrated vs. episomal subsets (p=.02). By contrast, fusion read status did not stratify recurrence risk in the E6/E7-disconcordant OPCs (n=53). Adverse gene expression features were upregulated in likely integrated vs. likely episomal OPCs, as reflected in increased TPS (p=.04) and ISS (p=.04). These differences were absent in fusion (+) tumors of the E6/E7-discordant group. Conclusions: Our findings offer the most compelling evidence to date supporting independent association of HPV integration with adverse tumor biology and recurrence risk in OPCs. Jointly considering HPV-host fusion mRNAs and E6/E7 levels may guide the molecular biomarker development needed to personalize therapy based on HPV genome state.

Adjuvant abemaciclib in pN2-3 patients with HR+/HER2− early breast cancer: Real-world outcomes from Moscow centers.

e12535 Background: Adjuvant abemaciclib (adA) plus endocrine therapy (ET) resulted in a statistically and clinically significant improvement in invasive disease-free survival (iDFS) and overall survival (OS) compared with ET alone in patients with high-risk HR+ HER2- early breast cancer (BC). Although efficacy was established in the monarchE trial, real-world evidence, particularly in high-risk subgroups such as node-positive (pN2-3) disease, remains limited. This multicenter observational study assessed adA outcomes in routine practice. Herein, we present an updated analysis of the pN2-3 subgroup, associated with the poorest prognosis. Methods: This retrospective analysis included 160 patients with HR+/HER2- BC receiving adA plus ET across Moscow centers, of whom 135 had pN2-3 disease. The primary endpoint was iDFS. Secondary endpoints included safety, treatment duration, and discontinuation reasons. Data cutoff was November 2025 (median follow-up, 24.0 months). Results: Median age was 51.6 years (range, 27-74); 44.4% were premenopausal. Histologic subtypes included lobular (15.6%; n = 21), invasive ductal/non-specific (77.0%; n = 104), and other (7.4%; n = 10). Tumor grades were G1 (5.2%), G2 (62.2%), and G3 (32.6%). Prior chemotherapy comprised neoadjuvant (60.7%) and adjuvant (39.3%) regimens. Baseline ET included aromatase inhibitors (89.6%), switch from tamoxifen to aromatase inhibitors (9.6%), and tamoxifen continuation (0.8%). Eight progression events (5.9%) occurred: locoregional recurrence (n = 2) and distant metastases (n = 6). iDFS rates were 100.0%, 94.7%, and 93.5% at 12, 24, and 36 months, respectively. At cutoff, 55 patients (40.7%) continued treatment and 49 (36.3%) completed planned duration. Discontinuations were due to toxicity (n = 14; 10.4%), progression (n = 8; 5.9%), patient refusal (n = 7; 5.2%), and other (n = 2; 1.5%). Among toxicity-related discontinuations, neutropenia ≥G2 occurred in 5, G3 anemia in 1, G1-2 diarrhea in 5, and G2 rash in 2. Conclusions: In this high-risk pN2-3 cohort with HR+/HER2- early BC, adjuvant abemaciclib yielded favorable real-world efficacy, with iDFS rates of 100.0%, 94.7%, and 93.5% at 12, 24, and 36 months. The safety profile was manageable via dose adjustments, enabling long-term treatment in most patients. These findings affirm abemaciclib's role in routine high-risk settings.

Association of <i>ALOX12B</i> gene alterations with TMB and immune checkpoint inhibitor (ICI) outcomes.

e14546 Background: ALOX12B encodes 12R-lipoxygenase (12R-LOX), an arachidonic-acidlipoxygenase that generates fatty-acid hydroperoxides and downstream lipid signalingintermediates. Arachidonic-acid–derived lipid mediators can shape antitumor immunity bymodulating myeloid and T-cell programs within the tumor microenvironment. As a result LOX-pathway perturbations may influence ICIsensitivity. Despite this rationale, the relevance of ALOX12B to antitumor immunity and ICIoutcomes has not been systematically defined. We therefore tested whether ALOX12Balterations identify a subgroup with enhanced clinical benefit from ICI therapy. Methods: In cBioPortal’s “TMB and Immunotherapy (MSK, Nat Genet 2019)” cohort, tumorswere grouped as ALOX12B-altered (n = 24; mutations/structural variants) or unaltered(n = 1,637). Non-synonymous tumor mutation burden (mut/Mb) was compared betweengroups. Overall survival (OS) from ICI initiation was assessed by Kaplan–Meier and log-rank ,subtypes including melanoma and colorectal cancer (CRC) subsets. Co-alterations weresummarized. TIMER3 Mutation and Immunotherapy_outcome modules were used fororthogonal immune-infiltration and independent ICI outcome support. Results: ALOX12B alterations occurred in 24/1,661, enriched in melanoma (12/24) and CRC(4/24). Altered tumors had markedly higher TMB (median 43.37 vs 5.87 mut/Mb; p = 1.72×10^-9).Overall survival (OS, months) favored ALOX12B-altered tumors across cancers (median58.0 vs 18.0 months; p = 0.036), in melanoma ( 58.0 vs 42.0 months; p = 0.204), and in CRC(median not reached vs 15.0 months; p = 0.0309). Most Frequent co-alterations includedTERT (67%) and EPAS1 (60%). TIMER3 Mutation-module analysis linked ALOX12B mutation to higher T-cell–relatedinfiltration signatures—particularly CD8+ and cytotoxic/exhausted T-cell programs—acrossmultiple deconvolution methods, including ImmuCellAI, xCell, ABIS, CIBERSORT-ABS,quanTIseq, and the TIMER algorithm (nominal p&amp;lt;0.05).In the TIMER3Immunotherapy_outcome module, higher ALOX12B expression was associated with bettersurvival after ICI treatment in glioblastoma patients (GBM_PRJNA482620; Cox coefficient =−2.11, p = 0.035). Conclusions: ALOX12B alterations define a rare, hypermutated subgroup with improved survivalfollowing immune checkpoint inhibition. Across complementary analyses, ALOX12B-altered tumors demonstrate a strong TMB signal and supportive immune-contexture features, includingCD8/Treg-related infiltration indicators, together suggesting that ALOX12B status may serve asa robust biomarker of ICI benefit. These findings warrant deeper mechanistic study andvalidation in larger, tumor-specific immunotherapy datasets with multivariable modeling toconfirm independent predictive value and establish clinical applicability.

Types of genotypes in progressive familial intrahepatic cholestasis and liver transplantation: A meta-analysis of observational studies

Background Progressive familial intrahepatic cholestasis (PFIC) refers to a group of inherited cholestatic liver diseases that affect children, often leading to liver failure and requiring liver transplantation (LT). Many studies have established correlations between the effect of the causal gene variant types and the severity of the PFIC phenotype, the treatment considered, or its outcomes in patients. Nevertheless, no selection criteria for LT based on genotypes have been adopted for patients affected by this group of diseases. Therefore, we conducted a meta-analysis to investigate the association between the main PFIC subtype genotypes and the treatment with LT. Methods Online databases were searched for articles on PFIC1–4 and LT. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The genotypes of patients were extracted from the included studies and categorized into a group of cases, harboring null genotypes, and a group of controls, harboring non-null genotypes. The relationship between the genotype type and LT outcome was expressed as an OR by assessing the LT event among the case group and the control group. Results Eighteen studies involving 420 PFIC patients were included. A random-effects model was used to assess the OR. Overall, we observed a close relationship between the PFIC null genotype and the LT event; OR=2.79 (95% CI:1.63 to 4.77; p &lt; 0.001). Subgroup analysis according to the PFIC subtype showed the same effect. Conclusions Our results provide evidence of a potential association between null genotypes in PFIC diseases and the indication of LT as a treatment. Further trials are needed to confirm our results and guide decisions regarding personalized and early preventive LT. Research protocol registration https://doi.org/10.17605/OSF.IO/MNQWB

Oxygen Vacancy‐Driven Dual‐Site Pd‐TiO ₂ Sonocatalyst for Amplified Reactive Oxygen Species Generation and Sonocatalytic Therapy

ABSTRACT Ultrasound (US)‐triggered reactive oxygen species (ROS) generation by nano‐sonocatalysts is vital for sonocatalytic therapy. However, the therapeutic effect is hindered by the low ROS generation yield owing to sluggish charge transfer and elusive active sites. Herein, in situ oxygen vacancies (Vo)‐engineered Pd‐TiO 2 sonocatalysts with spatially separated dual reactive sites are developed, which optimize charge kinetics and amplify ROS generation. Mechanism studies revealed that US‐induced Vo serves as an electron pump, activating the Pd–O–Ti transport channel, lowering interfacial barriers and steering electron migration from TiO 2 to Pd. This ordered charge redistribution tunes the d ‐band center of Pd, designating electron‐rich Pd sites as the primary active center for O 2 adsorption and activation to produce singlet oxygen ( 1 O 2 ). Concurrently, Vo‐mediated reconstruction of Ti 3d states strengthens orbital coupling with H 2 O at the Pd–O–Ti interface, dominating the activation of H 2 O to promote the generation of hydroxyl radical (•OH). This dual‐site configuration effectively lowers the activation energy barriers, which increases the rate constants of 1 O 2 and •OH generation by 5.0‐fold and 2.7‐fold, respectively, and ultimately achieving an 87.5% tumor inhibition efficiency. This work provides molecular insights into the charge transfer cascade and critical active centers in US‐activated Pd‐TiO 2 , offering a rational paradigm for designing high‐performance sonocatalysts.

Nano-Arbortristoside-A: A targeted approach to enhance therapeutic efficacy in the treatment of leishmaniasis

Dynamic Polarization‐Dependent Multicolor 3D Holography Based on Inverse‐Designed Single‐Cell Nanoprinting Metasurface

ABSTRACT With the pursuit of vivid display based on a light‐weight device, researchers draw more attention to multifunctional 3D display metasurface. Traditionally, polarization is not considered in single‐wavelength and full color 3D holography, which leads to the lack of an important channel in display and information storage. In this paper, a gradient descent algorithm is introduced to combine the polarization in single‐wavelength and full color 3D holography, the renewed algorithm greatly promotes the achievement of single‐wavelength and full color 3D holography. To make optimization less parameters, geometry phase‐only design strategy was adopted to acquire different holographic images under different polarizations. To make full color 3D holography display vividly, electrically‐driven liquid crystals (LCs) are introduced to acquire random combination of wavelengths in red, green, and blue regions to obtain 42 different holographic images in the experiment. Furthermore, ten wavelength‐based hyperspectral polarization‐dependent 3D holography with 60 channels is also demonstrated in simulation. For commercialization, a high‐refractive‐index TiO 2 particle‐doped resin‐based nanoprinting metasurface is introduced to make our designs come into practice on a large scale. Our efforts perfectly combine the modern design method and high‐throughput nanoprinting, paving the way for large applications of dynamic multiplexed 3D display via light‐weight, high‐throughput nanoprinting metasurface and LCs.

Digital Microneedles for Multiplexed Transdermal Sensing via Fluorescent QR Codes

ABSTRACT Real‐time biochemical sensing is essential for precision medicine, yet current wearable and transdermal biosensors suffer from signal drift, calibration demands, and limited multiplexing capabilities in vivo. Here, we introduce digital fluorescent microneedles that translate analyte concentrations into scannable QR codes via threshold‐activated probes. Each microneedle functions as a fluorescent binary switch, turning “on” only above a defined analyte threshold, thereby eliminating the need for calibration and enhancing robustness against tissue heterogeneity and environmental noise. The microneedles feature a biodegradable, mechanically optimized “baby‐bottle” design that enables reliable skin penetration and controlled tip detachment. Central to this concept is the rational engineering of fluorescent probes with discrete activation thresholds, which—when embedded in microneedles—produce stepwise readouts spanning physiopathological ranges of pH (4.5–8.5) and glucose (1–10 mM). By tuning probe loading, we achieve reproducible threshold activation, enabling fully digital, multiplexed detection of pH and glucose in skin with classification accuracies of 93% and 85%. This digital encoding concept is broadly extensible to diverse probes and biomarkers, providing a scalable route to calibration‐free, multiplexed biosensing in vivo. The QR‐based output delivers a direct, quantitative representation of biochemical information, facilitating decentralized diagnostics and integration into digital health workflows. Together, these advances establish digital microneedles as a versatile and clinically relevant platform for transdermal biosensing.

Application and performance of bentonite–leonardite mixture for feed-derived nitrogen removal in freshwater aquaculture systems

Correction: PKM2 inhibitor suppresses kidney fibrogenesis by disrupting YAP-TEAD-CCN2 transcriptional signaling following ischemia–reperfusion injury

Diagnostic performance of serum PIVKA-II alone and in combination with AFP for hepatocellular carcinoma: A comparative retrospective study.

e15064 Background: Protein-Induced by Vitamin K Absence-II (PIVKA-II), being mechanistically linked to Hepatocellular carcinoma (HCC) pathogenesis, is considered a more specific biomarker than alpha-fetoprotein (AFP) and other diagnostic tools that often struggle to distinguish HCC from background liver pathology. This study evaluated the diagnostic performance of PIVKA-II alone and in combination with AFP, compared to AFP. Methods: AFP and PIVKA-II levels were measured in patients with biopsy-proven HCC, non-HCC liver malignancies, and benign liver diseases. Statistical analyses included non-parametric group comparisons, Spearman’s correlation, and receiver operating characteristic (ROC) analysis, optimal cut-offs, sensitivity, and specificity. Logistic regression was applied to assess combined diagnostic efficacy. Results: Among 128 participants (mean age:55.2±13.1y), AFP was assessed in 45 HCC, 51 non-HCC malignancies, and 32 benign cases, while PIVKA-II was measured in 20, 16, and 8 cases, respectively. Both biomarkers were significantly elevated in HCC compared with controls (P&lt;0.001). PIVKA-II showed better diagnostic-performance (AUC=0.956) compared with AFP (AUC=0.815) for distinguishing HCC from non-HCC malignancies, though not statistically significant (P=0.222). PIVKA-II significantly outperformed AFP in differentiating HCC from benign liver disease (AUC=0.906 vs. 0.796; P=0.025). Optimal diagnostic thresholds were 105.8mAU/ml for PIVKA-II (sensitivity:95%, specificity:87.5%) and 33.6ng/ml for AFP (sensitivity:68.9%, specificity:86.3%). Combining AFP with PIVKA-II did not improve diagnostic accuracy beyond PIVKA-II alone, and no significant correlation was observed between AFP and PIVKA-II levels in HCC (r=0.371, P=0.108). Conclusions: PIVKA-II demonstrated superior diagnostic utility over AFP, particularly against benign liver disease. AFP did not improve diagnostic-accuracy, suggesting that PIVKA-II alone, with appropriately defined cut-off, may serve as a reliable biomarker. Summary of the diagnostic performance of serum AFP and PIVKA-II levels. Comparison Biomarker AUC (95% CI) Optimal Cut-off Sensitivity (95% CI) Specificity (95% CI) Z test (against AFP alone) HCC vs non-HCC liver malignancies AFP 0.815 (0.726, 0.903) 33.55 ng/ml 68.9% (54.26% to 80.55%) 86.3% (73.97% to 93.50%) - PIVKA-II 0.956 (0.894, 1.019) 105.80 mAU/ml 95.0% (88.7% to 98.4%) 87.5% (0.8530 to 0.8941) P=0.222 AFP+PIVKA-II combined 0.956 (0.894, 1.019) - 95.0% (88.7% to 98.4%) 87.5% (0.8530 to 0.8941) P=0.222 HCC vs benign liver conditions AFP 0.796 (0.695, 0.897) 28.00 ng/ml 68.9% (54.2% to 80.55%) 87.5%(71.32% to 95.64%) - PIVKA-II 0.906 (0.791, 1.021) 65.00 mAU/ml 100% (81.02% to 100%) 62.5%(30.38% to 86.51%) P=0.025 AFP+PIVKA-II combined 0.906 (0.791, 1.021) - 100% (81.02% to 100%) 62.5%(30.38% to 86.51%) P=0.025

Phase I trial of the anti-CAPRIN1 antibody TRK-950 alone or with nivolumab in Japanese patients with advanced solid tumors.

2525 Background: CAPRIN-1 is expressed on the tumor-cell membrane across many solid cancers but not on normal cells. TRK-950 is a first-in-class humanized IgG1 that mediates antibody-dependent cellular phagocytosis and cytotoxicity. A series of pre-clinical studies demonstrates its potency and safety. In the phase I study of TRK-950 monotherapy (NCT02990481) in US and France, it appears safe and well tolerated. No DLT was observed and MTD was not reached at doses of 3-30mg/kg IV weekly. Here, we evaluated safety/tolerability, pharmacokinetics (PK), and preliminary antitumor activity in Japanese patients with advanced solid tumors. Methods: Open-label, single-center, dose-escalation study in Japan (NCT05423262). Part 1 evaluated TRK-950 at 5 or 10 mg/kg IV weekly in patients with locally advanced or metastatic solid tumors. Part 2 evaluated TRK-950 at 10 mg/kg weekly or 20 mg/kg every 2 weeks in combination with nivolumab 240 mg every 2 weeks in patients with locally advanced or metastatic solid tumors who were eligible for standard nivolumab monotherapy. Primary endpoints were safety/tolerability (DLT; Treatment-related AEs per CTCAE v5.0). Secondary endpoints included PK, immunogenicity, and antitumor activity by RECIST v1.1. Results: Thirteen patients were treated (Part 1 n=7; Part 2 n=6). No DLTs occurred and the MTD was not reached; both monotherapy and combination regimens were well tolerated. TRK-950 PK was consistent with IgG1; exposures were comparable between 10 mg/kg weekly and 20 mg/kg every 2 weeks, with no meaningful PK interaction with nivolumab. In Part 1, a partial response was achieved in a patient with melanoma achieved a partial response, and the response was sustained for an extended period. In Part 2, no response were observed. Conclusions: TRK-950, as monotherapy and with nivolumab, was safe and tolerable in Japanese patients with advanced solid tumors. Durable antitumor activity with monotherapy supports continued development. Both the 10 mg/kg weekly and the more convenient 20 mg/kg biweekly dosing regimens of TRK-950 in combination with nivolumab were safely administered, supporting the potential for further development of this combination. Clinical trial information: NCT0542326 .

Real-world efficacy of cetuximab after immune checkpoint inhibitor and platin failure in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): A 10-year retrospective study in 124 patients.

e18025 Background: In R/M HNSCC, cetuximab monotherapy historically yields an objective response rate (ORR) of 13%. Emerging data, including the INTERLINK-1 trial with 20% of ORR, suggest an IO-priming effect where prior immunotherapy (IO) enhances subsequent anti-EGFR sensitivity. We evaluated the real-world efficacy and prognostic factors of cetuximab following IO failure in a large HNSCC cohort. Methods: Since 2015, we retrospectively analyzed all medical records of patient treated with cetuximab in a single institution, the Centre Leon Berard in France, who were in failure after IO (pembrolizumab, nivolumab, ipilimumab, atezolizumab, tremelimumab, lirimumab, FS-118 or durvalumab) and platin for R/M HNSCC. Off-label panitumumab after hypersensitivity to cetuximab, or combination with monalizumab (based on the negative results of the INTERLINK-1 trial) were allowed. Patients were naive of anti-EGFR for R/M HNSCC ORR was analyzed by RECIST 1.1. PFS and OS were calculated from the first administration of cetuximab to the progression or death. Results: Between 2015 and 2025, 124 patients met the criteria. The median age was 65 years, with a majority of males (76.6%) and former smokers (74.2%). At the start of cetuximab, 47.6% of patients had an ECOG-PS ≥ 2. Cetuximab treatment was 2nd-line (45), 3rd-line (73), or 4th-line (6). Overall median PFS was 3.7 months (95% CI: 2.5-4.4) and median OS 7.1 months (95% CI: 6.0-9.3). Median OS was significantly better for ECOG-PS 0-1 (8.9 months; 95% CI: 7.0-12.1) compared to PS 2-3 (5.9 months; 95% CI: 3.6-8.9). At two months, ORR was 32.3% (95% CI: 24.0-40.5) and DCR 59.7% (51.0-68.3), including 5 CR (4.0%) and 35 PR (28.2%). Poor outcomes were linked to prior cetuximab-radiotherapy potentiation and pure metastatic disease. Prior taxane exposure or response to IO were favorable markers. Subgroup analyses do not appear to indicate any effect of the interval between cetuximab and IO. Grade ≥ 3 toxicities occurred in 16 patients; 5 severe allergies required switching to panitumumab. Conclusions: This study reports a high ORR of 32.3%after use of IO, significantly exceeding historical data. No impact of the time interval between IO and cetuximab was observed and ancillary studies are needed to undestand this higher ORR. That supports ongoing trials exploring IO and anti-EGFR combinations. Prior taxane use and IO response emerged as favorable prognostic markers. Median overal survival of patients with PS0-1 is 8.9 months and is confirmed as a standard treatment after platin and IO.

Integrating overall survival and quality of life to rank first-line therapies for advanced urothelial carcinoma.

e16588 Background: While survival advantages of first-line therapies for locally advanced or metastatic urothelial carcinoma (la/mUC) are well established, it remains unclear whether treatments with superior overall survival (OS) also provide the most favorable integrated, patient-centered benefit when early health-related quality of life (HRQoL) is considered. We performed a joint evaluation of OS and HRQoL across first-line la/mUC regimens using an integrated network meta-analytic framework. Methods: We performed a network meta-analysis of randomized trials evaluating first-line systemic therapies for la/mUC. OS was synthesized using hazard ratios and ranked using surface under the cumulative ranking curve (SUCRA). HRQoL was assessed using mean change from baseline in EORTC QLQ-C30 Global Health Status (GHS) at approximately 12 weeks, harmonized across trials using the closest available assessment. HRQoL effects were ranked using SUCRA. OS and HRQoL were jointly integrated using the minimum distance criterion (MDC), defined as the minimum distance from the ideal point (OS SUCRA = 1, HRQoL SUCRA = 1), with equal weighting of both outcomes. Analyses focused on enfortumab vedotin plus pembrolizumab, nivolumab plus gemcitabine-cisplatin, and platinum chemotherapy. Results: Enfortumab vedotin plus pembrolizumab ranked highest for OS (OS SUCRA = 0.9997) and demonstrated favorable early HRQoL preservation (GHS SUCRA = 0.97). Nivolumab plus gemcitabine-cisplatin showed intermediate OS benefit (OS SUCRA = 0.64) with substantially lower early HRQoL preservation (GHS SUCRA = 0.20). Platinum chemotherapy ranked lowest for OS (OS SUCRA = 0.02) despite modest early HRQoL preservation (GHS SUCRA = 0.18). When OS and HRQoL were jointly considered, enfortumab vedotin plus pembrolizumab ranked closest to the ideal treatment (MDC = 0.03), followed by nivolumab plus gemcitabine-cisplatin (MDC = 0.88) and platinum chemotherapy (MDC = 1.27). Conclusions: Survival benefit alone does not define optimal first-line therapy in la/mUC. When survival and early quality of life are jointly considered, enfortumab vedotin plus pembrolizumab emerges as the regimen with the most favorable integrated patient-centered benefit, highlighting the importance of incorporating quality-of-life outcomes into comparative treatment evaluation. Integrated ranking of first-line therapies for advanced urothelial carcinoma using the minimum distance criterion (MDC). Treatment OS SUCRA HRQoL SUCRA (GHS) MDC Enfortumab vedotin + pembrolizumab 0.9997 0.97 0.03 Nivolumab + gemcitabine-cisplatin 0.64 0.20 0.88 Platinum chemotherapy 0.02 0.18 1.27 OS SUCRA: Overall survival ranking (higher = better). HRQoL SUCRA: Ranking based on EORTC QLQ-C30 Global Health Status at ~12 weeks (higher = better). MDC: Distance from the ideal point (OS SUCRA = 1; HRQoL SUCRA = 1); lower values indicate better integrated outcomes.

Temporal trends and disparities in sudden cardiac death among pancreatic cancer patients in the United States.

e16438 Background: In patients with pancreatic cancer, sudden cardiac death (SCD) is an overlooked terminal event. There is an absence of population-level data characterizing its burden and disparities. We looked at national trends as well as regional and demographic differences in SCD among Americans who died from pancreatic cancer. Methods: The CDC WONDER Multiple Cause of Death database (1999–2020) was examined. ICD-10 code C25 was used to identify deaths from pancreatic cancer as the underlying cause of death. Contributing cause codes I46.1, I46.9, I49.0, I21 to I24, R96, and R96.1 were used to define SCD. Descriptive analyses were carried out to measure the mortality burden and its distribution by age, sex, race, and state. The 2000 U.S. population was used to standardize age-adjusted mortality rates (AAMRs). Results: Among those who died from pancreatic cancer, 34,489 deaths were linked to SCD. The crude mortality rate was 3.17 per 100,000, with a range of 0.1 to 12.2 and a median of 1.8. The burden of SCD rose with age, reaching a peak among those between the ages of 75 and 84, while those between the ages of 25 and 34 had the fewest deaths. SCD-associated mortality was consistently higher in men than in women. There were clear racial differences: White decedents had significantly lower rates, while Black or African American decedents had the highest AAMRs, followed by Asian or Pacific Islander people. There was noticeable regional variation: the highest average AAMRs were found in New York, California, Mississippi, Georgia, and Connecticut, while the lowest were found in Illinois, Michigan, Texas, North Carolina, and Pennsylvania. Although disparities remained across demographic and geographic strata, overall SCD-associated mortality showed a declining temporal pattern. Conclusions: Among people who die from pancreatic cancer, sudden cardiac death is a substantial and unevenly distributed factor in mortality. Persistent disparities by age, sex, race, and state indicate an increased focus on cardiovascular risk assessment, cardio-oncology integration, and end-of-life cardiac monitoring in this high-risk population. Descriptive characteristics of sudden cardiac death among pancreatic cancer decedents, united states, 1999–2020. Characteristic Deaths, n (%) Total sudden cardiac death–associated deaths 34,489 (100) Sex Male Higher proportion Female Lower proportion Age Group (years) 25–34 Lowest 35–44 Low 45–54 Moderate 55–64 Increased 65–74 High 75–84 Highest ≥85 Slightly lower than 75–84 Race White Lower burden Black or African American Highest burden Asian or Pacific Islander Elevated American Indian/Alaska Native Variable / sparse State-Level Mortality (Mean Age-Adjusted Rates) Highest-burden states New York Highest California High Mississippi High Georgia High Connecticut High Lowest-burden states Illinois Lowest Michigan Low Texas Low North Carolina Low Pennsylvania Low