Browse Articles

ZnO nanoparticles functionalized with amoxicillin: Synthesis, characterization and assessment of corrosion inhibition performance of aluminum in alkaline medium

From Planar to 3D: The Evolution of Complementary Field‐Effect Transistor for Next‐Generation Semiconductor Nodes

ABSTRACT Complementary Field‐Effect Transistor (CFET) technology is emerging as a critical point to extending Moore's Law by transitioning device scaling and integration from 2‐ to 3D architectures. Recent advancements, including silicon‐based homogeneous CFETs and van der Waals‐based heterogeneous CFETs, have demonstrated significant progress, yet a comprehensive and up‐to‐date review is absent to further advance the field. This work explores CFET fabrication methodologies, comparing the advantages and challenges of Monolithic and Sequential integration approaches, with a focus on thermal management, process complexity, and material compatibility. We highlight the critical role of layered van der Waals materials in addressing thermal constraints and enhancing gate control, leveraging their atomic‐scale thickness and unique electronic properties. Furthermore, we discuss strategies to overcome key challenges such as achieving balanced electrical characteristics, optimizing thermal management, and minimizing parasitic capacitance through innovative channel engineering, gate‐dielectric design, and structural optimization. The co‐design principles of CFET architectures are also examined, showcasing their potential in logic circuits, memory units, and computing‐in‐memory systems. This review provides a forward‐looking perspective on CFET technology, emphasizing the need for continued innovation in material‐processing‐structure co‐design and co‐optimization to unlock new frontiers in semiconductor technology.

Impact of locoregional treatments in oligometastatic squamous cell anal carcinoma.

e15502 Background: Squamous cell anal carcinoma (SCAC) is a rare malignancy with limited therapeutic options in the metastatic setting. While systemic therapy represents the standard of care, the role of curative-intent locoregional treatments (LRT) in metastatic SCAC (mSCAC) is supported by limited clinical evidence. We investigated the impact of curative-intent LRT on survival outcomes in patients (pts) with mSCAC. Methods: This retrospective, single-center study included adult pts diagnosed with oligometastatic SCAC treated at the Veneto Institute of Oncology–IRCCS (Padua, Italy) between Jan-2015 and Dec-2024. Comprehensive clinical, pathological and treatment-related data were collected. Oligometastatic disease was defined as the presence of a limited number of metastatic lesions amenable to complete LRT, as assessed by a dedicated multidisciplinary tumor board (MTB). Curative-intent LRT included surgery, radiotherapy (RT) and microwave ablation. Disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan–Meier method. Associations between clinicopathological variables and survival outcomes were evaluated using univariable and multivariable Cox proportional hazards models. To mitigate immortal time bias, curative-intent LRT was modeled as a time-dependent covariate. Results: Among over 300 cases of SCAC discussed at a dedicated MTB, 67 patients with metastatic disease were included; 27 (40.3%) underwent curative-intent LRT. Median follow-up was 58 months. Pts receiving LRT experienced a significantly prolonged OS compared with those who did not (median OS 56.3 vs 19.0 months; HR 0.22, 95% CI 0.12–0.45; p < 0.0001). This association remained significant in time-dependent analyses (HR 0.36, 95% CI 0.16–0.78; p = 0.010) and in multivariable models adjusting for metastatic timing and ECOG performance status (HR 0.18, 95% CI 0.08–0.47; p < 0.0001). Among patients receiving LRT, median DFS was 5.9 months, with a subset achieving durable disease control. In pts with synchronous metastatic disease treated with definitive concurrent chemoRT to the primary tumor, durable local control was associated with improved OS (median OS 41 vs 10 months). Conclusions: In this real-world cohort, curative-intent LRT were independently associated with prolonged OS in carefully selected pts with mSCAC. These findings support the potential value of integrating LRT into a personalized, multimodal treatment strategy guided by multidisciplinary evaluation. Prospective studies are warranted to refine patient selection, optimize treatment sequencing, and define the integration of LRT emerging systemic therapies, including immunotherapy.

Bevacizumab-based triplet versus doublet chemotherapy as first-line treatment for metastatic right-sided colon cancer: Results of the KCSG CO19-18 phase II trial.

e15562 Background: The prognostic significance of primary tumor location in colorectal cancer has recently gained attention. Previous studies have demonstrated poorer outcomes of cetuximab-based therapy in right-sided colon cancer. Therefore, we conducted a multicenter, prospective, open-label, randomized phase II trial to evaluate the efficacy of bevacizumab plus FOLFOXIRI (A-FOLFOXIRI) versus bevacizumab plus FOLFOX/FOLFIRI (A-FOLFOX/FOLFIRI) in patients with unresectable right-sided colorectal cancer with poor prognosis (KCSG CO19-18; NCT03641976). Methods: Previously untreated patients with metastatic right-sided colon cancer (cecum to splenic flexure) were enrolled. Patients were stratified by ECOG performance status (0 vs 1–2), prior adjuvant chemotherapy (yes vs no), and participating center, and randomly assigned (1:1) to receive A-FOLFOXIRI (experimental arm) or A-FOLFOX/FOLFIRI (control arm). Treatment was administered every 2 weeks for up to 12 cycles, followed by investigator-determined continuation until disease progression, withdrawal of consent, or unacceptable toxicity. Maintenance therapy with bevacizumab, fluorouracil, and leucovorin was permitted in cases of intolerance to oxaliplatin or irinotecan. The primary endpoint was the 6-month progression-free survival (PFS) rate. Secondary endpoints included median overall survival, median PFS, objective response rate (ORR), and safety. Results: From December 2018 to February 2024, 61 patients were enrolled (median age, 62.9 years). At a median follow-up of 10.6 months, A-FOLFOXIRI did not significantly improve the 6-month PFS rate compared with A-FOLFOX/FOLFIRI (100% vs 87.1%; HR, 1.05; 95% CI, 0.53–1.71; p = 0.87). Median PFS was not significantly different between the two groups (14.7 months [95% CI, 10.3–19.1] vs 16.6 months [95% CI, 7.0–26.2]). The ORR was 82.8% versus 64.6%, respectively (p = 0.245). In an exploratory subgroup analysis, among patients who did not undergo palliative resection, A-FOLFOXIRI showed numerically longer PFS and higher ORR than A-FOLFOX/FOLFIRI. In contrast, among patients who underwent palliative resection, response rates were numerically higher across both treatment arms. The overall safety profiles were manageable in both arms. Grade ≥3 neutropenia was more frequent with A-FOLFOXIRI, whereas peripheral sensory neuropathy, gastrointestinal toxicities, and hypertension were comparable or slightly more frequent with A-FOLFOX/FOLFIRI. Conclusions: A-FOLFOXIRI did not improve PFS compared with A-FOLFOX/FOLFIRI in unresectable right-sided metastatic colorectal cancer, despite numerically higher overall response rates and an acceptable safety profile, underscoring the need for further studies to define patient subsets most likely to benefit from intensified chemotherapy. Clinical trial information: NCT03641976 .

Secondary safety analysis of trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in DESTINY-Breast05: Clinical and demographic risk factors of interstitial lung disease (ILD) and radiation pneumonitis (RP).

516 Background: In DESTINY-Breast05 (NCT04622319), T-DXd showed superior efficacy vs T-DM1 in patients (pts) with human epidermal growth factor receptor 2-postive (HER2+) early breast cancer (eBC) with residual invasive disease after neoadjuvant therapy (NAT) and high risk of recurrence—a population in which radiotherapy (RT) is broadly used. Safety was consistent with the established T-DXd profile; ILD remained an important risk, although most cases were low grade. Previous T-DXd pooled analyses suggested potential associations between ILD and clinical and demographic factors. We report additional safety outcomes stratified by these risk factors. Methods: Pts with residual invasive HER2+ eBC and at high risk of recurrence after NAT were randomized 1:1 to receive T-DXd 5.4 mg/kg (n = 818) or T-DM1 3.6 mg/kg (n = 817) once every 3 weeks for 14 cycles. All pts underwent low-dose non-contrast chest computed tomography (CT) at screening. Pts who received adjuvant RT (aRT; either concurrently with or sequentially before study therapy) underwent additional low-dose CT during and after treatment completion. CT scans showing ILD or RP underwent blinded central adjudication. Results: At data cutoff (July 2, 2025), 806 pts in the T-DXd arm and 801 pts in the T-DM1 arm received ≥1 dose of treatment; no pts were ongoing study treatment. In the T-DXd arm, 93.9% of pts received aRT vs 93.6% in the T-DM1 arm. Adjudicated drug-related (adj DR) ILD rates were generally consistent across global regions (Asia, Europe, North America [NA] + Australia, and Rest of World), though numerically lower in NA + Australia for T-DXd. In both arms, adj DR ILD rates were higher in pts from Japan (n = 147) vs outside Japan (n = 1460; T-DXd: 14.9% vs 8.9%; T-DM1: 6.7% vs 1.2%), Japan vs other Asian countries (T-DXd: 14.9% vs 9.6%; T-DM1: 6.7% vs 2.1%), and in pts with baseline moderate vs normal renal impairment (T-DXd: 14.3% vs 9.7%; T-DM1: 5.0% vs 1.0%). Adj DR ILD incidence was comparable across racial subgroups. In both arms, investigator-reported RP rates were higher in pts from Japan vs outside Japan (T-DXd: 47.1% vs 27.4%; T-DM1: 45.0% vs 27.3%). Most ILD/RP events recovered or were recovering with protocol-specific management. Recovery/resolution was observed in 64.5% vs 75.0% of adj DR ILD events and 38.2% vs 43.2% of RP events in the T-DXd and T-DM1 arms, respectively. Conclusions: Adj DR ILD and RP events were mostly low grade and reversible with protocol-specific management guidelines. Adj DR ILD rates were higher with T-DXd than T-DM1 and were influenced by country and baseline renal function, consistent with prior pooled analysis. These findings are consistent with, and further characterize, the safety profile of T-DXd in post-NAT HER2+ eBC. Clinical trial information: NCT04622319 .

The GP78-Spatial Aggressiveness Index (GP78-SAI): A race-independent AI-driven biomarker for precision oncology.

e12566 Background: GP78 (AMFR) protein expression is associated with breast cancer (BC) progression and poor outcomes (PMC9310521), but traditional bulk protein quantification ignores spatial architecture within the tumor microenvironment (TME). We developed the GP78-Spatial Aggressiveness Index (GP78-SAI), and AI-integrated, spatially informed metric derived from multi-gene GP78 protein-based signatures. We hypothesized that the GP78-SAI would outperform genomics-markers, demonstrate race-independent prognostic utility, and be feasibly for use in resource-limited clinical settings. Methods: GP78-SAI was computed using spatial autocorrelation modeling across 651 breast tumor tissue microarray cores from patients with stage II-III primary invasive breast cancer treated with curative-intent surgery (diagnosed between 2005-2020) and validated using CosMx 6K plex data. Tumor cell neighborhoods were defined using k-nearest neighbors (k = 10) with row-standardized spatial weights. Ancestry-optimized multi-gene GP78 cytoplasmic signatures were derived for Black/African American (AA) compared to White/European American (EA) patient cohorts and applied across the same datasets. The resulting scoring system was designed to be computationally efficient and compatible with standard immunohistochemistry workflows. Results: GP78-SAI robustly stratified tumor aggressiveness, with significantly higher spatial clustering in high-grade (Grade 3) tumors versus low-grade (Grade 1/2) tumors. Using AA-optimized signatures, mean GP78-SAI was 0.196 in high-grade (HG) versus 0.136 in low-grade tumors (adjusted P = 0.0003); using EA-optimized signatures, mean GP78-SAI was 0.173 versus 0.126, respectively (adjusted P = 0.0064). In contrast, the single-gene AMFR marker demonstrated minimal spatial organization (mean ≈0.02) and no association with tumor grade (adjusted P = 0.77). Despite ancestry-specific signature derivation, GP78-SAI demonstrated consistent, race-independent discriminatory performance. Conclusions: GP78-SAI is a novel spatial aware AI biomarker that captures an aggressive tumor organization phenotype not detected by conventional molecular assays. By translating spatial protein architecture into a quantifiable metric, GP78-SAI improves tumor risk stratification while supporting equitable treatment prioritization. These findings support clinical integration of GP78-SAI into digital pathology workflows to advance precision oncology across diverse patient populations.

Effect of (Z)-endoxifen on estrogen receptor signaling inhibition across clinically relevant <i>ESR1</i> mutations.

e15155 Background: Activating mutations in the estrogen receptor alpha gene (ESR1) are a key mechanism of resistance to endocrine therapy in estrogen receptor–positive (ER+) breast cancer and represent an important unmet clinical need. While selective estrogen receptor degraders (SERDs) are under development for ESR1-mutant disease, the activity of (Z)-endoxifen, the active metabolite of tamoxifen, across clinically relevant ESR1 mutations has not been fully characterized. We evaluated ER signaling inhibition by (Z)-endoxifen in comparison with oral SERDs at clinically relevant concentrations. Methods: ER transcriptional activity was measured in human ER+ breast cancer cells using clinically relevant concentrations of (Z)-endoxifen (746–20 nM), elacestrant (224–56 nM), and imlunestrant (269–67.25 nM). ER signaling was quantified and expressed as percent activity relative to untreated control. Studies were conducted in ESR1 wild-type (WT) and mutant backgrounds, including Y537N, Y537S, and D538G as well as parental MCF7 cells. Results: In parental MCF-7 cells, endoxifen produced dose-dependent and statistically significant inhibition of ER signaling at all clinically relevant concentrations, reducing ER activity to 16–26% of control ( p &lt; 0.001). Elacestrant and imlunestrant also significantly suppressed ER signaling in MCF-7 cells, achieving residual activity of approximately 13–14% and 10–11%, respectively ( p &lt; 0.001). In ESR1-WT cells, all agents suppressed ER signaling to &lt; 5% of control ( p &lt; 0.001). In contrast, ESR1-mutant models demonstrated differential sensitivity. Endoxifen maintained statistically significant ER inhibition across Y537N, Y537S, and D538G mutations ( p &lt; 0.01), whereas SERDs showed reduced efficacy in mutant settings, most notably in the D538G background, where residual ER signaling remained substantially higher despite treatment ( p &lt; 0.05). Among ESR1 mutations, D538G exhibited the greatest resistance, while Y537N remained the most sensitive across therapies. Conclusions: At clinically relevant concentrations, (Z)-endoxifen demonstrates robust and consistent inhibition of ER signaling across key ESR1 mutations, including those associated with resistance to current endocrine therapies. These data support (Z)-endoxifen as a promising therapeutic approach in ESR1-mutant ER+ breast cancer and highlight its potential clinical relevance in a patient population with limited treatment options.

Adverse effects of immune checkpoint inhibitors in locally advanced head and neck squamous cell carcinoma: A meta-analysis of randomized trials.

e24179 Background: Immune checkpoint inhibitors (ICIs) have improved outcomes in recurrent and metastatic head and neck squamous cell carcinoma (HNSCC). In the locally advanced, curative-intent setting, however, their safety profile is less well defined. Several randomized trials have evaluated the addition of ICIs to standard treatment strategies for locally advanced HNSCC (LA HNSCC), but concerns regarding treatment-related toxicity remain. We conducted an updated systematic review and meta-analysis to better characterize adverse events associated with ICI-based approaches in LA HNSCC. Methods: MEDLINE and EMBASE were searched through January 10, 2026 to identify phase II and III randomized trials evaluating ICIs in LA HNSCC. Eligible studies compared ICI-containing regimens with standard-of-care therapy. Safety endpoints included treatment-related adverse events (TRAEs), serious adverse events, adverse events of special interest (AESI), immune-mediated adverse events, and treatment-related mortality. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects inverse-variance model. Results: Seven randomized trials comprising 3,605 patients were included. Overall, the addition of ICIs did not meaningfully change the rate of treatment-related adverse events, either for events of any grade (RR 1.01, 95% CI 0.97 to 1.04; p = 0.69) or for high-grade toxicity (RR 1.06, 95% CI 0.98 to 1.13; p = 0.12). Serious adverse events were observed more often in ICI-containing arms (RR 1.28, 95% CI 1.11 to 1.47; p = 0.0005), though deaths attributed to treatment-related toxicity were uncommon and similar between groups (RR 1.11, 95% CI 0.56 to 2.20; p = 0.77). Events categorized as AESI were also more frequent with ICI use (RR 1.86, 95% CI 1.23 to 2.79; p = 0.003). As anticipated, immune-mediated toxicity occurred more often with ICIs. Both any-grade immune-related adverse events (RR 1.91, 95% CI 1.30 to 2.81; p = 0.001) and high-grade immune-related adverse events (RR 3.93, 95% CI 2.07 to 7.48; p &lt; 0.001) were increased. Hypothyroidism was limited to low-grade events but occurred more frequently among ICI-treated patients (RR 2.50, 95% CI 1.53 to 3.83; p &lt; 0.001). In contrast, locoregional toxicities such as stomatitis, radiation-associated skin injury, dysphagia, xerostomia, and dysgeusia were similar across treatment arms. Conclusions: Across randomized trials, ICI-based strategies in LA HNSCC were associated with higher rates of immune-mediated adverse events, most of which were low grade. Importantly, this did not translate into higher overall or high-grade treatment-related toxicity or increased treatment-related mortality. Locoregional toxicity patterns remained comparable, supporting continued evaluation of ICIs in curative-intent treatment settings with appropriate toxicity monitoring.

Comparative analysis of mortality trends in acute versus chronic myeloid leukemia in the U.S. population with time series projection: A CDC WONDER–based study (1999–2023).

e18501 Background: Myeloid leukemias (ML) pose a significant public health concern globally and in the United States, particularly affecting older adults. Acute (AML) and chronic (CML) forms differ in clinical behavior and outcomes. This study compares mortality trends of AML and CML among the U.S. population from 1999 to 2023 and uses an autoregressive integrated moving average (ARIMA) model for predicting future trends. Methods: Data retrieved from the CDC WONDER database (1999-2023) included individuals aged ≥45 years. Mortality trends among people diagnosed with AML (C92.0) and CML (C92.1) individually were analyzed. We performed a head-to-head comparison of both groups. Age-adjusted mortality rates (AAMRs) per 100,000 population stratified by age, sex, race, Hispanic origin, U.S. Census regions, and 2013 urbanization categories were analyzed. Joinpoint regression was used to estimate Annual Percent Changes (APCs) and corresponding 95% CI. p &lt; 0.05 was considered significant. R Software (Version 4.5.0) was used for time-series projections performed using an ARIMA model based on historical trends. Results: Between 1999-2023, a total of 207,992 deaths were attributed to AML (AAMR: 6.87) while CML accounted for 27,199 deaths (AAMR: 0.93). In both AML and CML, males showed higher mortality rates than females contributing to 56.9% and 55.4% of total deaths respectively. From 1999 to 2001, males and non-Hispanics showed significant upward trends in AML mortality with APC of 5.66 (95% CI: 2.09-8.78) and 4.91 (95% CI: 2.13-7.11), respectively. While in CML, from 1999-2006 males and non-Hispanics showed a notable decline in mortality with APC of -9.23 (95% CI: -11.22 - -7.77) and -9.22 (95% CI: -12.81 - -7.15), respectively. Whites affected by AML exhibited significant rising trends in mortality from 1999-2010 with APC of 2.14 (95% CI: 0.84-7.21). For AML, the Northeast region reported the highest AAMR 6.90 whereas for CML, the highest AAMR (1.0) was observed in the Midwest. Among states, North Dakota showed the highest AAMR of 8.8 in AML-group while Wyoming recorded the highest AAMR for CML at 1.2. ARIMA-based forecasting through 2030 showed relatively stable AML rates at approximately 6.68 (95% prediction interval: 6.09–7.28), whereas CML rates declined from 0.71 to 0.57 with wider uncertainty (95% prediction interval in 2030: −0.17 to 1.32), highlighting persistent disparities. Conclusions: AML mortality rose sharply, then steadily increased before declining, whereas CML mortality fell rapidly and later plateaued. These distinct trends indicates the need for population specific interventions and evaluation of therapeutic strategies.

Golcadomide (GOLCA), a potential, first-in-class, oral CELMoD, + Pola-RCHP in patients (pts) with newly diagnosed aggressive B-cell lymphoma (a-BCL): Safety and 12-month (mo) efficacy results.

7011 Background: Up to 40% of pts with diffuse large B-cell lymphoma (DLBCL) will relapse or have refractory disease following 1L treatment (Tx) with SOC chemoimmunotherapy regimens R-CHOP or Pola-RCHP. High risk (HR) populations include those with International Prognostic Index (IPI) score 3–5 and IPI 1–2 with either ≥1 lesion ≥7 cm or baseline LDH &gt;1.3×ULN. GOLCA is a potential, first-in-class, oral CELMoD designed for the Tx of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA induces rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing and immunomodulatory activity. GOLCA 0.4 mg + R-CHOP has shown promising safety, a ≥90% minimal residual disease (MRD) negativity rate, and durable efficacy (24-mo PFS, 79%) in 1L a-BCL (Nowakowski et al, ASH 2025, 476) and is being evaluated in the Phase (Ph) 3 study GOLSEEK-1 (NCT06356129). We report initial Ph1b results with GOLCA + Pola-RCHP in 1L a-BCL. Methods: Pts aged ≥18 y with ECOG PS ≤2, IPI 0–5 (Part 2A) or 2–5 (Part 2B), and newly diagnosed a-BCL with measurable tumorous disease were included. Pts were treated with GOLCA + Pola-RCHP for six 21-day (D) cycles or until disease progression/unacceptable toxicity/study withdrawal. In dose escalation, GOLCA was dosed at 0.2 and 0.4 mg D1–7. In dose expansion, pts were randomized 1:1 to Pola-RCHP + GOLCA 0.2 or 0.4 mg. Primary endpoint: safety; efficacy was a secondary endpoint. Results: At data cutoff, 57 pts were treated with GOLCA + Pola-RCHP (0.2 mg, n=28; 0.4 mg, n=29). Median age was 63 y. Most pts had HR disease (86%) and DLBCL not otherwise specified histology (84%). For known cell of origin (COO), 47% were germinal center B cell (GCB) and 39% non-GCB by Hans algorithm. Forty-seven pts (83%) completed Tx and 52 (91%) entered the follow-up (f/u) period. Grade 3/4 Tx-emergent adverse events occurred in 95% of pts, most frequently neutropenia (86%; an on-target side effect of GOLCA) and anemia (39%). Median relative dose intensity for GOLCA and Pola-RCHP components was &gt;95%. At 15.5 mo median f/u, end of Tx (EOT) complete metabolic response (CMR) rate was 69% at 0.2 mg, 82% at 0.4 mg, and similar across COO subtypes. EOT CMR was consistent in HR pts (65% at 0.2 mg, 83% at 0.4 mg). The 12-mo DOR and PFS rates were 92% and 88% at 0.2 mg, and 96% and 96% at 0.4 mg. In pts with both pre-Tx and EOT ctDNA analysis, 65% and 83% at 0.2 and 0.4 mg achieved MRD negativity (PhasED-Seq) at EOT. Conclusions: GOLCA + Pola-RCHP demonstrated a predictable and manageable safety profile, and addition of GOLCA did not compromise median dose intensity of Pola-RCHP. GOLCA 0.4 mg + Pola-RCHP resulted in a high rate of durable CMRs, high rate of MRD negativity, and a promising 12-mo PFS rate. These data continue to show that GOLCA + SOC regimens R-CHOP and Pola-RCHP has potential to improve outcomes in 1L HR a-BCL. Clinical trial information: NCT04884035 .

High-volume patient navigator encounters and access to oncology clinical trials.

e23227 Background: Only 7% of US adults with cancer enroll in clinical trials, despite a rising number of clinical trials available. Barriers to trial participation extend beyond clinical eligibility and include social determinants of health such as logistical and insurance related factors. Timely and consistent patient navigation is needed to address these barriers. The Trial Library platform includes a navigation operating system to facilitate end-to-end support to eligible patients. Methods: he Trial Library platform was integrated in community oncology settings from January 1, 2025, to December 31, 2025. Patient referrals were captured in a HIPAA-compliant platform and triggered navigation. Navigation support included trial eligibility verification and patient care coordination, including assistance with logistical and insurance authorization-related barriers. Navigator encounters involved patients, healthcare providers, study sites, and/or insurance personnel. High navigation volume was defined as ≥ 10 navigation encounters per referral. Associations between navigation volume and patient and trial characteristics were examined using Firth penalized likelihood logistic regression. Results: The platform supported 131 patients, with a median of 7 encounters per referral (range: 1-88); 36% of referrals (47/131) required a high volume of navigation encounters. In univariable analyses, older age, male sex, and referral for interventional trials, compared to observation trials, were associated with high navigation encounter volume, whereas cancer type was not (Table). All high navigation volume encounters occurred among male patients, resulting in complete separation. Conclusions: Navigation needs varied markedly by trial type and patient characteristics, with higher utilization observed among patients referred for interventional trials. These findings highlight the importance of robust patient navigation infrastructure to address non-clinical barriers and support expansion of clinical trial access. Association of high navigation encounter volume with patient and trial characteristics. OR (95% CI) p-value Age (Continuous) 1.05 (1.01 - 1.10) 0.007 Cancer type (Hematologic vs Solid) 0.95 (0.10 - 8.24) 0.9 Sex (Female vs Male) 0.04 (0.0003 - 0.29) &lt; 0.001 Trial type (Interventional vs Observational) 5.93 (2.51 - 14.91) &lt; 0.001

Ranking neoantigens for escape-resilience rather than predicted immunogenicity: Associated changes in vaccine design.

2654 Background: Personalised neoantigen vaccines induce detectable CD8 + T cell responses for fewer than one-third of selected peptides. Current pipelines prioritise candidates by predicted immunogenicity and select peptides independently, overlooking two constraints: efficacy depends on the peptide set as a whole, and tumours adapt antigen processing under immune pressure. We developed a framework that optimises peptide combinations for resilience to tumour escape and tested whether escape-resilience predicts clinical immunogenicity. Methods: We modelled peptide susceptibility to five antigen-processing escape mechanisms: TAP downregulation, immunoproteasome-to-constitutive proteasome switching, aminopeptidase upregulation, tapasin loss, and HLA loss of heterozygosity. Selection was formulated as a minimax optimisation, maximising predicted efficacy under worst-case tumour adaptation. We analysed five neoantigen vaccine trials with per-epitope CD8 + T cell response data, consisting of 571 neoantigens, 3,806 peptides, and 174 patients. Mixed-effects models tested associations between escape-resilience and immunogenicity, adjusting for binding affinity (NetMHCpan-4.1 %rank), pMHC stability (NetMHCstabpan), mutation type, and clonality. Six hypotheses were pre-registered with Bonferroni correction. Results: Escape-resilience predicted immunogenicity independently of established features. After adjustment, vulnerability to TAP loss (OR 0.42 per SD, 95% CI 0.24–0.71, p=0.0018) and proteasome switching (OR 0.54 per SD, 95% CI 0.34–0.86, p=0.0089) were associated with failure to elicit CD8 + responses. Among peptides with comparable predicted binding affinity, escape-resilient peptides were significantly more likely to be immunogenic. Composite escape-resilience scores discriminated immunogenic from non-immunogenic peptides (AUC 0.71, 95% CI 0.66–0.76), outperforming binding affinity alone (AUC 0.58) and an affinity-stability model (AUC 0.64). Adding escape-resilience improved discrimination (ΔAUC 0.07, p=0.003). Retrospective re-ranking altered 38% (95% CI 31–45%) of vaccine compositions, replacing high-affinity but escape-vulnerable peptides with lower-affinity, processing-robust alternatives. Associations were stronger for truncal mutations (OR 2.8, 95% CI 1.6–4.9) than subclonal mutations (OR 1.4, 95% CI 0.8–2.4; interaction p=0.041), indicating that processing robustness is most consequential for clonally dominant neoantigens. Conclusions: Optimising neoantigen selection against tumour escape identifies peptides more likely to elicit CD8 + T cell responses, independent of binding affinity and stability. The stronger effects in truncal mutations suggest escape-aware ranking may be particularly valuable for durable, clone-targeted vaccination strategies. Prospective trials are needed to assess clinical impact.

Enhancing recruitment of AYAs with Hodgkin lymphoma through community partnerships: Prioritizing diverse populations.

11026 Background: Hodgkin lymphoma (HL) is one of the most common cancers affecting adolescents and young adults (AYAs). AYAs with HL aged 15-39 years are a group historically difficult to reach for research participation. Their voice is critical to enhance care. For two funded qualitative studies, the team engaged in and assessed the feasibility of a community-centered approach to recruit HL patients with 1:1 representation by age [those diagnosed as children (0-14), AYAs (15-39), and above 40 years], race and ethnicity (Black and Hispanic communities), and insurance (private, Medicaid, and uninsured populations). Methods: Recruitment was conducted exclusively through advocacy partner organizations including Blood Cancer United, Stupid Cancer, Cactus Cancer Society, and Elephants &amp; Tea. Study team patient advocates guided recruitment approach, including selecting imagery using a Black-identifying male and Hispanic-identifying female and rephrasing recruitment material language. Advocacy partners utilized their techniques for engaging AYAs, such as Instagram, website posting, email, and/or attendance at member engagement events. Recruitment to the two studies required the study participants online to 1) complete a survey on REDCap documenting their consent using a waiver and 2) provide confirmation of their HL diagnosis by uploading proof to REDCap (e.g., screenshot from their medical record containing their name, date of birth, and HL diagnosis). Results: A total of 389 patients from 46 states or US territories started their REDCap survey and completed the waiver of consent. Of those, 217 (55%) were AYAs at diagnosis and 95 ≥40 (24%). Of the total 389, 85 (22%) were Black, 39 (10%) Hispanic, 34 (9%) had Medicaid, and 12 (3%) were uninsured. 154 (40%) provided proof of diagnosis from 38 states. Of the 154 that uploaded proof of HL diagnosis, 123 (80%) were AYA and 26 (17%) ≥40 years at diagnosis. 17 (11%) were Black, 21 (14%) Hispanic, 17 (11%) with Medicaid, and 3 (2%) uninsured. Documentation was most commonly provided using an after visit summary or visit note (47%), pathology report (19%), or physician signed letter (13%). Conclusions: Partnering with advocacy organizations, particularly those serving AYAs, proved successful in exceeding recruitment goals for AYA patients. Attrition in participation was seen between waiver completion and providing confirmation of diagnosis. AYAs were more likely than adults ≥ age 40 to provide proof of confirmation of diagnosis. Recruitment met national averages for Black representation, but fell short with lower than national average estimates for representation of Hispanic survivors, those on Medicaid or uninsured. Future studies should engage underrepresented populations during the research process to understand how to plan recruitment activities in a way that prioritizes what is most important and impactful for the target population.

Distinct clinical and genomic landscape of bilateral parenchymal non–small cell lung cancer (NSCLC) using the AACR GENIE BPC database.

e20558 Background: NSCLC with bilateral lung involvement is currently staged as IV (M1a). However, patients with lung-only metastasis without lymph node (LN) involvement often exhibit atypical clinical courses. We aimed to characterize the survival and genomic signatures of this "Bilateral Parenchymal (BP)" subgroup compared to stage III and other stage IV NSCLC. Methods: From the AACR GENIE Biopharma Collaborative (BPC) cohort (N = 1,846), we analyzed a selected group of 1,156 patients with stage III or IV disease. Patients were categorized into: BP (n = 62; bilateral parenchymal only, no LN/distant metastatis), stage III (n = 388), and other stage IV (n = 706). Overall survival (OS) was estimated via the Kaplan-Meier method. Genomic alterations, including non-synonymous somatic mutations and copy number alterations, were compared across cohorts using Fisher’s Exact test with Benjamini-Hochberg correction for multiple testing. Results: The BP group was predominantly comprised of adenocarcinoma (93.5%) with a median age of 65.7 years. The median OS for the BP group was 30.7 months (95% CI, 22.4–38.9), which was significantly superior to other stage IV (21.6 months; 95% CI, 19.3–24.1; HR, 0.66; 95% CI, 0.47–0.91; p = 0.012) and comparable to stage III (33.6 months; 95% CI, 28.5–39.4; HR, 1.39; 95% CI, 0.98–1.97; p = 0.064). Genomically, the BP group exhibited a significantly lower prevalence of TP53 mutations (40.3%) compared to other stage IV (59.0%; p = 0.005) and stage III (55.7%). Notably, GNAS mutations were highly enriched in the BP group (10.5%) compared to stage III (1.7%) and other stage IV (1.6%) (p &lt; 0.001). Other enriched alterations in the BP group included NEGR1 (7.1%, p = 0.016) and ASXL2 (7.4%, p = 0.024). Conclusions: NSCLC with bilateral parenchymal involvement without LN involvement represents a unique clinical entity with a survival profile more aligned with stage III than metastatic disease. This improved prognosis is associated with a distinct genomic landscape featuring lower TP53 and higher GNAS mutation, a molecular signature frequently associated with mucinous histology. It also provides a biological rationale for exploring aggressive local therapies, such as bilateral lung transplantation.

Efficacy and safety of retifanlimab across solid tumors: A systematic review and meta-analysis.

e14585 Background: Retifanlimab is a PD-1 inhibitor with demonstrated activity in several solid tumors, including FDA approved indication in squamous cell carcinoma of the anal canal (SCAC). However, its efficacy and safety across tumor types have not been systematically synthesized. Methods: We conducted a systematic review and meta analysis of prospective trials evaluating retifanlimab in solid tumors. PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and oncology conferences were searched through January 2026. Pooled ORR and CR were estimated using random effects models. Subgroup analyses were performed by tumor type, treatment line, and regimen. Results: Nineteen studies encompassing 1,113 patients across phase I-III trials were included. Tumor types included SCAC, Merkel cell carcinoma (MCC), NSCLC, HNSCC, sarcoma, and MSI-H endometrial cancer. Pooled ORR was 57.2% (95% CI, 48.6–65.9%; I² = 87%); CR rate was 26.3% (95% CI, 19.7–32.8%). First-line treatment showed significantly higher ORR than later lines (79.8% vs 39.5%). By tumor type, higher ORRs were observed in HNSCC (74.8%), NSCLC (74.7%), MCC (69.4%), and SCAC (65.4%). Safety was consistent with PD-1 inhibitor class: any-grade irAEs in 27.8%, grade ≥3 in 6.3%. Conclusions: Retifanlimab demonstrates clinically meaningful antitumor activity across multiple solid tumors, with greatest benefit in first line treatment. Consistency of efficacy and safety signals supports ongoing development. Pooled ORR by tumor type. Tumor Studies Patients ORR (95% CI) SCAC 3 402 65.4% (40.7–90.2%) MCC 2 111 69.4% (37.2–101.6%) NSCLC 2 58 74.7% (39.1–110.3%) HNSCC 2 50 74.8% (53.3–96.4%) Sarcoma 3 88 37.5% (21.8–53.2%)

Distinct T-cell subsets as drivers of response to different neoadjuvant treatments in esophageal squamous cell carcinoma.

2638 Background: The optimal integration of immunotherapy with chemoradiotherapy (CRT) in the neoadjuvant treatment of esophageal squamous cell carcinoma (ESCC) remains unclear, largely due to limited mechanistic insight into immune determinants of response. Methods: we performed paired single-cell RNA and TCR sequencing of ESCC tumor samples collected before and after treatment across three neoadjuvant modalities—immunochemotherapy (NICT), chemoradiotherapy (NCRT), and immuno-chemoradiotherapy (NICRT)—to dissect intratumoral CD8 + T cell dynamics. Results: We identified two distinct immune response programs. In NICT responders, pre-existing immunoresponsive CXCL13 + PD-1 + CD8 + T cells underwent clonal expansion and transcriptional reprogramming into a less exhausted yet CXCL13+ progenitor-like state (CD8Tex_CXCR4), accompanied by the formation of tertiary lymphoid structures. Conversely, CRT responders exhibited depletion of the subset of CXCL13 + CD8 + T cells and enrichment of PD-1 - cytotoxic CD8Teff_NIBAN1 cells, which originated from the peripheral blood and were characterized by robust clonal expansion, high effector gene expression, and association with tumor regression. We validated the association of these two T cell subsets with distinct neoadjuvant modalities and treatment responses using public datasets and independent prospective cohorts encompassing NICT, NICRT, and NCRT. Mechanistically, conventional radiotherapy suppressed PD-1 + T cell expansion—even in the presence of ICB—while a sequential strategy of induction ICB followed by delayed radiotherapy preserved the process of clonal expansion in exhausted T cell populations and achieved superior tumor control in vivo. Conclusions: These findings reveal divergent CD8 + T cell–mediated immune programs driving response to neoadjuvant therapies in ESCC and identify CD8Teff_NIBAN1 as a key effector population following CRT. Our study provides mechanistic insight into ICB–radiotherapy interactions and supports the rational design of temporally optimized combination strategies in solid tumors.

A retrospective analysis of patients with metastatic melanoma treated with sequential metronomic temozolomide after immune therapy failure.

e21515 Background: Melanoma is a skin malignancy that results in the deaths of around 60,000 people globally per year. Although metastatic melanoma historically carried a poor prognosis, breakthroughs such as pembrolizumab, a monoclonal antibody targeted against PD-1 receptor, have led to significant improvements in therapy. Despite this, studies have shown that more than 60% of patients show resistance to anti-PD-1 therapies. Multiple mechanisms, such as lack of presentation of antigenic proteins, insensitivity to T cells, and presence of immunosuppressive cells, have been implicated in this resistance. Temozolomide, a DNA alkylating agent, has been shown in a rat glioma model to reduce the number of circulating T regulatory cells. In a recent case series, three patients with metastatic melanoma showed responsiveness to metronomic temozolomide after pembrolizumab therapy failure. This study intends to provide a retrospective chart review of patients with metastatic melanoma to evaluate different factors that could influence the use of sequential metronomic temozolomide as a treatment option in patients who did not derive benefit from initial immunotherapy. Methods: Using TriNetX, patients with metastatic melanoma who received metronomic temozolomide after immunotherapy failure and received care at the University of Iowa Health Care were identified. Patients who did not receive prior immunotherapy or had ocular melanoma were excluded from analysis. Factors analyzed include age, gender, location of melanoma, stage, location of metastasis, disease burden, and receipt of prior definitive or palliative radiation. The key outcomes investigated were progression-free survival (PFS) and overall survival (OS) using Cox regression. Results: A cohort of 73 (58% male, median age 62) patients was identified. Median PFS and OS were 1.8 and 4.6 months, respectively. On univariate analysis, increased M stage (Hazard ratio [HR]: M1b 3.27, M1c 2.53, M1d 3.55, M1a referent; p = 0.04), presence of brain metastasis (HR: 1.82; p = 0.02), and receipt of palliative radiation (HR: 1.78; p = 0.02) were significantly associated with decreased PFS. While associated with decreased PFS, they were not found to have statistically significant differences in OS. Conclusions: In patients with metastatic melanoma who received metronomic temozolomide following immunotherapy failure, advanced M stage, presence of brain metastasis, and reception of palliative radiation were shown to have statistically significant decreases in PFS. Although this study does not demonstrate any specific factors associated with improved PFS or OS, therapies for immunotherapy-refractory metastatic melanoma remain exceptionally limited, and this study can help inform the risk-benefit analysis utilized by clinicians when considering the use of temozolomide in patients with varying disease presentations.

Digital twin survival calibration to enable cross-disease interpretation of early clinical trials.

e14507 Background: Early-phase oncology programs increasingly explore multiple disease indications, yet overall survival outcomes cannot be directly compared across cancers due to fundamentally different baseline mortality patterns. This creates uncertainty when interpreting early survival signals and planning cross indication expansion. A digital twin survival model was developed that calibrates survival time across disease sites using non parametric hazard alignment, without modeling treatment-specific effects. Methods: Publicaly available overall survival data were obtained from the TCGA PanCancer survival resource via UCSC Xena. Three disease cohorts were analyzed: melanoma, non-small cell lung cancer, and renal cell carcinoma (n = 1,900 patients total). For each cohort, survival distributions were estimated non parametrically and transformed into cumulative hazard function. Digital twin survival time was generated by mapping source survival time to the target disease time scaleat matched cumulative hazard, yielding patient level counterfactual baseline survival trajectories. Translation performance was evaluated using time-wrap functions and survival curve overlays. Results: Baseline survival differed markedly across disease sites, with median overall survival of 1,175 days for melanoma, 523 days for Non small cell lung cancer, and 1,175 days for renal cell carcinoma. When translating melanoma survival to the lung cancer hazard scale, 365 days of melanoma survival corresponded to 324 days in lung cancer, and 730 days corresponded to 559 days. The median digital twin survival of melanoma patients expressed on the lung cancer time scale was 862 days. After transformation, digital twin survival closely matched the observed lung cancer survival distribution, demonstrating accurate cross-disease calibration of baseline survival distributions. Conclusions: Digital twin survival modeling provides a quantitative framework for calibrating baseline survival across disease sites without assuming equal treatment effects. This enables hazard-calibrated interpretation of early survival signal, supports indication prioritization, and informs cross- disease dose-expansion planning in early drug development. The approach is fully reproducible using public data and is applicable across therapeutic modalities.

Elevated red blood cell distribution width-to-albumin ratio and incident cancer risk: A prospective cohort study.

10575 Background: Cancer remains a leading cause of global morbidity and mortality, underscoring the need for accessible biomarkers for early detection and risk stratification. The red blood cell distribution width-to-albumin ratio (RAR) is an emerging composite index integrating markers of erythropoietic stress and nutritional status/hepatic dysfunction, often dysregulated in malignancy and systemic inflammation. Elevated RAR correlates with worse outcomes in patients with sepsis and various cancers; however, its association with incident cancer risk in large prospective cohorts remains uncharacterized. Methods: Using UK Biobank data, we conducted a prospective cohort study with 5:1 propensity score matching, yielding an analytic cohort of 112,107 participants (18,916 with elevated RAR, 93,191 with normal RAR). Elevated RAR was defined as &gt; 95th percentile (&gt; 3.48 %·dL/g) among cancer-free participants at baseline. Matching balanced groups by age, sex, ethnicity, socioeconomic status, BMI, smoking, alcohol use, diabetes, chronic kidney disease, and family history of cancer. Adjusted Cox proportional hazards regression was utilized to assess associations between elevated RAR and incident cancer. We also performed a 2-year landmark analysis to evaluate reverse causation. Hazard ratios (HRs) with 95% confidence intervals (CIs) are reported. Results: During median follow-up of 15.4 years (1.55 million person-years), 21,307 incident cancers occurred. Elevated RAR was significantly associated with 23% increased overall cancer risk (HR 1.23; 95% CI 1.18-1.27). Cancer-specific analyses revealed strongest associations for hematologic malignancies (HR 1.91; 95% CI 1.70-2.14), including acute myeloid leukemia (HR 2.22; 95% CI 1.37-3.60) and chronic myeloid leukemia (HR 2.78; 95% CI 1.23-6.31). Significant associations were also observed for gastric (HR 2.12; 95% CI 1.57-2.86), liver (HR 1.90; 95% CI 1.38-2.62), lung (HR 1.45; 95% CI 1.27-1.66), and colon cancer (HR 1.48; 95% CI 1.28-1.72). No significant association was observed for breast (HR 1.06; 95% CI 0.96-1.17) or prostate cancer (HR 0.94; 95% CI 0.84-1.05). A 2-year landmark analysis showed that the association with overall cancer risk remained robust (HR 1.19; 95% CI 1.15-1.24). Conclusions: Elevated RAR is independently associated with increased incident cancer risk, particularly for hematologic, gastrointestinal, and lung cancers. These associations persisted in 2 year landmark analyses, supporting a potential prospective relationship and motivates further evaluation of RAR, a readily calculable index from routinely obtained laboratory values, in cancer risk models.

Efficacy and safety of primary thromboprophylaxis in adult ambulatory cancer patients: A scholarly review.

e24003 Background: Venous thromboembolism (VTE) is a major complication in patients with cancer, with approximately a six-fold increased risk compared to the general population. VTE contributes significantly to morbidity and mortality, particularly in the ambulatory setting, where risk assessment and monitoring are more complex. Primary thromboprophylaxis has been shown to reduce VTE incidence but is associated with an increased risk of bleeding. Patients with cancer are subject to significant treatment burdens, both in terms of anticancer and supportive therapy. This review aimed to evaluate the efficacy and safety of primary thromboprophylaxis in adult ambulatory cancer patients, with a particular focus on VTE incidence, major bleeding, and mortality or survival outcomes. Methods: A systematic literature search was conducted across the PubMed, MEDLINE, and Embase databases for studies published between January 1, 2014, and November 14, 2024. Eligible studies were randomised controlled trials involving adult cancer patients (≥18 years) receiving primary thromboprophylaxis in the ambulatory setting. The primary outcome was VTE incidence. Secondary outcomes included major bleeding rates, mortality, and survival outcomes. Study quality was assessed using the National Health and Medical Research Council levels of evidence, the Cochrane Risk of Bias tool, and the Revised Joanna Briggs Institute Critical Appraisal tool. Results: Nine randomised controlled trials were selected for final analysis. Thromboprophylaxis significantly reduced VTE incidence in six of the trials, using either low molecular weight heparin (LMWH) or a direct oral anticoagulant (DOAC). Three studies reported significantly higher major bleeding rates associated with thromboprophylaxis, particularly with DOACs. Eight studies demonstrated no significant differences in mortality or survival outcomes between thromboprophylaxis and control groups. One biomarker-guided trial reported a reduction in short-term mortality with LMWH, but this finding was not consistently replicated. Conclusions: Primary thromboprophylaxis in ambulatory adult cancer patients effectively reduces VTE incidence but increases the risk of major bleeding and does not consistently improve mortality or survival outcomes. These findings highlight the importance of individualised risk assessment and careful patient selection. Future large-scale multicentre randomised trials with broader inclusion criteria, longer follow-up, and improved risk stratification tools are needed to optimise the balance between efficacy and safety in thromboprophylaxis for ambulatory cancer patients.