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Pain response with stereotactic body radiation therapy versus conventional external beam radiotherapy for spinal metastases: An updated GRADE-assessed systematic review and meta-analysis of randomized controlled trials.

e15149 Background: Stereotactic body radiation therapy (SBRT) allows for dose-escalated ablative treatment of spinal metastases compared to conventional external beam radiotherapy (cEBRT). We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare efficacy and safety outcomes, incorporating recent phase 3 data. Methods: PubMed, EMBASE, and Cochrane Library were searched for RCTs comparing SBRT and cEBRT for spinal metastases. Endpoints included overall pain response (3 and 6 months), complete pain response (3 and 6 months), local progression, overall survival (OS), and vertebral compression fracture (VCF). Risk of bias and certainty of evidence were assessed using Cochrane tools and GRADE. Data were pooled using random-effects models. Results are reported as risk ratios (RRs) for dichotomous outcomes and hazard ratios (HRs) for time-to-event outcomes, with 95% confidence intervals (CIs). Heterogeneity was assessed using the statistic. Results: Four RCTs were identified. SBRT was associated with a statistically significant improvement in complete pain response at 3 months (RR 2.23, 95% CI 1.46–3.41). This benefit was not statistically significant at 6 months (RR 1.77, 95% CI 0.73–4.28). For overall pain response, there was no difference at 3 months (RR 1.11, 95% CI 0.73–1.68), but SBRT showed superiority at 6 months (RR 1.34, 95% CI 1.05–1.70). No significant differences were observed in local progression (RR 0.53, 95% CI 0.22–1.24), overall survival (HR 0.93, 95% CI 0.75–1.16), or the risk of vertebral compression fracture (RR 0.95, 95% CI 0.56–1.62). Conclusions: SBRT for spinal metastases demonstrates superior efficacy in achieving complete pain response at 3 months and sustained overall pain response at 6 months compared to cEBRT. Safety profiles regarding VCF and survival outcomes remain comparable. These findings support SBRT as a preferred modality for maximizing palliative durability in select patients. Outcome Time Point Effect Size (95% CI) P-Value Heterogeneity (I2) Favors Complete Pain Response 3 Months RR 2.23 (1.46–3.41) 0.0002 0% SBRT Complete Pain Response 6 Months RR 1.77 (0.73–4.28) 0.21 69% Neutral OverallPain Response 3 Months RR 1.11 (0.73–1.68) 0.64 79% Neutral OverallPain Response 6 Months RR 1.34 (1.05–1.70) 0.02 20% SBRT Local Progression NA RR 0.53 (0.22–1.24) 0.14 41% Neutral Overall Survival NA HR 0.93 (0.75–1.16) 0.53 0% Neutral Vert. Compression Fracture NA RR 0.95 (0.56–1.62) 0.85 39% Neutral

The approaches, theories, models, frameworks, and methods in designing toolkits to support healthcare providers in health behaviour change: A scoping review protocol

Objective The scoping review aims to map the existing literature on the approaches, theories, frameworks, models and methods that have been used in the development of toolkits to support HCPs in health behaviour change. Introduction Lifestyle behaviours are associated with a range of health outcomes, including comorbidities, health utilization, and quality of life. Healthcare providers (HCPs) are key figures in supporting various clinical populations to change these behaviours but are often hindered by external factors. It is important to develop evidence-based tools that support the needs of HCPs for health behaviour change. Toolkits inform and provide guidance for HCPs to bridge the evidence to practice gap in a variety of areas, including health behaviour. However, there is a lack of information as to how these toolkits should be developed. This review aims to fill this gap by mapping the existing literature on how toolkits to support HCPs in health behaviour change have been developed. Methods This scoping review will follow the Joanna Briggs Institute (JBI) methodology and reporting will follow the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for scoping review (PRISMA-ScR). The search will be conducted across MEDLINE, Embase, Emcare, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, and Scopus. Screening and data extraction will be conducted independently and in duplicate, with any disagreements resolved through discussion and involvement of a third reviewer. Data will be extracted from studies using a tool developed by the reviewers, guided by the JBI template. For synthesis, quantitative data will be reported descriptively and a conventional content analysis will be undertaken for qualitative data. Inclusion Criteria This scoping review will include studies published in peer-reviewed academic journals in English from any geographical area focusing on the development of a toolkit for HCPs involved in health behaviour change.

Microwave plasma CVD growth and characterization of polycrystalline diamond films on β-Ga2O3

The integration of diamond with β-Ga2O3 presents a promising pathway to enhance thermal management in high-power electronic devices, where the inherently low thermal conductivity of β-Ga2O3 can lead to localized self-heating and elevated junction temperatures. In this work, we demonstrate a scalable, low-damage approach to integrate polycrystalline diamond films on (010) β-Ga2O3 substrates via microwave plasma chemical vapor deposition, employing dielectric interlayers and polymer-assisted electrostatic nanodiamond seeding to systematically evaluate the impact of growth conditions on film morphology, grain evolution, phase purity, and optical characteristics. At the growth temperature of 800 °C, progressive grain coarsening is observed with extended deposition, with lateral grain size increasing from 37.6 nm (53 nm thickness) to 192.5 nm for an 886 nm film. This microstructural evolution is accompanied by narrowing of the diamond Raman peak and a monotonic increase in sp3-phase fraction from 95.9% to as high as 98.9%, indicating continued suppression of non-diamond carbon with prolonged growth. Comparison of SiO2 and SiNx interlayers under identical growth conditions shows only marginal differences in grain size and phase purity, indicating limited interlayer influence once high nucleation density is established. Importantly, diamond films exhibiting >96% sp3-phase content were achieved at substrate temperatures as low as 480 °C, highlighting the viability of diamond-on-Ga2O3 integration under reduced thermal budgets. These findings establish a robust, scalable platform for integrating diamond on β-Ga2O3, supporting the development of next-generation power and RF devices with improved thermal management.

Tyrosinase inhibitors: Molecular mechanisms, therapeutic potentials, and translational applications in dermatology and beyond

Wooden‐Monolithic Catalytic Microreactors: Construction Strategy, Structural Regulation, and Advanced Energy and Environmental Applications

ABSTRACT The increasing demands for sustainable catalysis and carbon neutrality are driving the need for the development of green, scalable, and multifunctional reaction platforms. This review establishes the conceptual framework for wood as a structurally preserved monolithic microreactor for catalysis and reaction‐based processes. The relationships between wood architecture, physicochemical properties (porosity, channel size, tortuosity, thickness, tailored surface chemistry), as well as catalytic performance (mass transport efficiency, directional electron transfer, catalyst immobilization, and confinement‐modulated reaction pathways) are summarized to elucidate the structure‐function correlations governing reactivity and durability. This review represents the first example to systematically analyze wood as a monolithic, structurally preserved, reaction‐governing scaffold for catalysis and reaction‐based processes. Applications in catalytic conversion, solar steam generation, environmental energy harvesting (e.g., moisture‐electric generators for wearable electronics), and gas‐phase reactions demonstrate the versatility of these systems. Especially, we deeply analyze how the wood structure governs the catalytic performance in these advanced applications. Besides, we compare the cost, sustainability, and some other factors of wooden microreactors with other monolithic platforms (e.g., ceramic foams, metallic structures, polymeric scaffolds). Finally, current challenges for rational design and scalable implementation are proposed in perspective of sustainable catalysis and energy conversion.

Study on the multi-source response characteristics and damage evolution mechanisms of graphene-modified concrete

Structural basis of phosphodiesterase-5 conformational organization revealed by a PDE6/PDE5 chimera

Comparative enumeration of circulating tumor cells with PD-L1 overexpression using anti-EpCAM antibody to N-cadherin in solid cancers.

e14530 Background: Minimal cellular residual disease (MCRD) with PD-L1 expression on Circulating tumor cells (CTCs), is highly evidenced for possible aggressive diseases systemically. CTCs captured using N-cadherin - a calcium dependent transmembrane glycoprotein targets epithelial–mesenchymal transition (EMT) tumor cells. Difference in phenotypic specificity, as EpCAM likely misses CTCs that have undergone EMT, while N-cadherin enables detection of these aggressive, invasive cells. Thus, N-cadherin–based CTC capture is more effective for identifying metastasis-prone CTCs. Using both markers together may improve overall CTC capture efficiency to provide a more comprehensive landscape of tumor heterogeneity and disease progression. We show the comparative and paired outcome of CTC capture using both anti EpCAM antibodies versus N-Cadherin across solid cancers. Methods: Retrospectively we compared 33 patients with different stages, breast, rectal, colon, prostate, lung, etc. cancer patients. CTCs were detected using an affinity marker-independent isolation platform to avoid EpCAM bias. CTCs were isolated using a marker-independent, anti EpCAM+ ve, and N-cadherin +ve platform OncoDiscover platform approved by CDSCO using in 1.5 mL of peripheral blood. CTCs were confirmed with CK18+, DAPI+ and CD45− and PD-L1+ expression using automated Zeiss microscopy. Anti EpCAM+ and N-cadherin +ve CTCs were classified using validated intensity thresholds, and concordance/discordance rates, cluster frequency, and mean distribution of CTCs. Results: OncoDiscover platform EpCAM and N-Cadherin expression showed an overall concordance of 60.61% and a discordance of 39.39%, indicating EMT-related phenotypic divergence. The mean CTC counts were comparable between anti EpCAM positive and N-Cadherin positive samples (0.66 and 0.70 per sample, respectively). Among EpCAM-positive CTCs, 42.85% CTCs expressed PD-L1, whereas PD-L1 positivity was lower and present in 30.30% of N-Cadherin–positive CTCs. Importantly, 04 N-Cadherin+/EpCAM– PD-L1 positive CTCs were identified, which were not captured by EpCAM affinity; conversely, 06 EpCAM+/PD-L1+ CTCs lacked N-Cadherin expression. Notably, CTC clusters were found in 12.12% of EpCAM+ cases and 6.06% of N-Cadherin +ve cases. Collectively, these findings demonstrate that dual-marker profiling improves detection sensitivity relative to single-marker interrogation. Conclusions: Using both EpCAM and N-Cadherin together improved CTC capture efficiency. However N-cadherin based CTC capture is more implicative in identifying metastasis-prone CTCs. The dual affinity accounts for CTCs for MCRD surveillance for the presence of disease systemically and indicative for the progression of micro-metastasis.

Real-world concordance of tumor mutational burden (TMB) between blood (circulating tumor DNA) and tissue, and its association with immunotherapy response.

2580 Background: Tissue-derived tumor mutation burden (tTMB) ≥10 mutations/Mb is a histology-agnostic predictive biomarker for the immune checkpoint inhibitor (ICI) pembrolizumab. It is unknown if circulating tumor DNA–derived TMB (bTMB) is also predictive and current ASCO guidelines recommend against using bTMB alone. Concordance between tTMB and bTMB is only moderate, with reported Pearson correlation coefficients between 0.54-0.70. In prior studies, bTMB was a median 2.4-fold greater than tTMB in matched samples. This study evaluated the correlation and predictive accuracy of immunotherapy response of bTMB vs. tTMB in solid tumors. Methods: 221 patients with solid tumors were included from the Cleveland Clinic genomics repository who had at least one tTMB and one bTMB result between July 1, 2021, and July 1, 2025. High TMB was defined as tTMB ≥10 mutations/Mb. For bTMB, thresholds of ≥10 and ≥16 mutations/Mb were evaluated, as prior studies suggest a bTMB threshold of 16 for Guardant 360 may be comparable to a tTMB of 10. Correlation between bTMB and tTMB was assessed using Pearson’s correlation coefficient. Among patients treated with ICIs, treatment response and time to treatment failure (TTF) were analyzed using both bTMB thresholds and compared with tTMB. Results: Among the 221 patients included in the analysis, 80 received ICIs. Median bTMB was 2.3-fold higher than matched tTMB. A strong positive linear correlation was observed between bTMB and tTMB both among patients who received ICIs (R² = 0.845, p < 0.001) and across the full cohort of 221 patients (R² = 0.818, p < 0.001). High tTMB was associated with numerically longer TTF in those with both low bTMB (median 21.3 months) and high bTMB (median 15.2 months), as shown in Table 1. Those with high tTMB/low bTMB had numerically longer median TTF compared to those with low tTMB/high bTMB (21.3 vs. 7.0 months). Increasing the bTMB threshold from 10 to 16 was associated with improved median TTF from 3.5 to 7.0 months among patients with low tTMB. Conclusions: This study confirms that bTMB values are consistently higher than tTMB and demonstrates a strong positive correlation between the two measures. Raising the bTMB threshold appears to improve prediction of immunotherapy response in patients with low tTMB. However, tTMB continued to show evidence of predictive value for response to ICIs regardless of bTMB, although these subgroup analyses were limited by small sample sizes. Larger, disease-specific studies are needed to better define the independent clinical utility of bTMB. Time to treatment failure in TMB-high vs. TMB-low patient pairs. bTMB -10=H bTMB -16=H Median TTF (months) Median TTF (months) tTMB-L, bTMB-L(n=35) 4.9 tTMB-L, bTMB-L(n=51) 3.9 tTMB-H, bTMB-L(n=3) 21.3 tTMB-H, bTMB-L(n=4) 21.3 tTMB-L, bTMB-H(n=32) 3.5 tTMB-L, bTMB-H(n=16) 7.0 tTMB-H, bTMB-H(n=10) 10.2 tTMB-H, bTMB-H(n=9) 15.2

CS2009, a novel PD-1/VEGF/CTLA-4 trispecific antibody, in patients with advanced solid tumors: Updated results from an open-label, multicenter, phase 1 first-in-human study.

2521 Background: CS2009 is a first-in-class trispecific antibody targeting PD-1, VEGF and CTLA-4. Initial data from this phase 1 study showed a favorable safety profile and encouraging antitumor activity. Here, we report updated safety and efficacy results in 98 patients. Methods: This ongoing, open-label, multicenter, phase 1 dose-escalation trial enrolled patients with advanced solid tumors who progressed on standard therapy or had no available standard therapy. CS2009 was administered intravenously every 3 weeks at 6 dose levels ranging from 1 to 45 mg/kg. Dose escalation followed an accelerated titration design at the first dose level and a 3+3 design thereafter. In parallel, additional patients were backfilled to selected dose levels deemed safe to further evaluate safety and efficacy. Primary objectives include safety, tolerability and determination of the maximum tolerated dose (MTD)/tentative recommended phase 2 dose (RP2D). Secondary and exploratory objectives include pharmacokinetic/pharmacodynamic profile and preliminary efficacy per RECIST v1.1, etc. Results: As of January 4, 2026, 98 patients (55.1% male; median age 61 [range 19-80] years; 54.1% Asian, 43.9% White) had received CS2009 across 6 dose levels, with half (49/98) remaining on study treatment. Tumor types included non-small cell lung cancer (NSCLC, n = 49), ovarian cancer (n = 12), soft tissue sarcoma (n = 9), renal cell carcinoma (RCC, n = 6), triple-negative breast cancer (TNBC, n = 6), colorectal cancer (n = 4), and others. Most (98.0%) patients received at least one prior line of systemic anti-cancer therapy. No dose-limiting toxicities (DLTs) occurred; MTD was not reached. The incidences of any-grade and grade ≥3 treatment-related adverse events (TRAEs) were 69.4% and 20.4%, respectively. The most common (≥10%) TRAEs were pruritus (n = 14, 14.3%), alanine aminotransferase increased (n = 11, 11.2%) and aspartate aminotransferase increased (n = 10, 10.2%). Five (5.1%) patients discontinued treatment due to TRAEs. There were no treatment-related deaths. Encouraging antitumor activity was observed across multiple tumor types that have received heavy prior treatment including PD-1/PD-L1 inhibitors or antiangiogenesis therapies where appropriate, including NSCLC without known actionable oncogenic alterations (n = 27), soft tissue sarcoma (n = 9), non-clear cell RCC (n = 5), and TNBC (n = 6) with ORR of 18.5%, 33.3%, 20.0%, 16.7%, respectively, and DCR of 74.1%, 66.7%, 100.0%, 50.0%, respectively (detailed and updated data to be presented at the conference). Conclusions: CS2009 demonstrated a manageable safety profile and promising antitumor activity in heavily pretreated patients with advanced solid tumors, which warrants further clinical development in an ongoing phase 2 study in nine tumor types. Clinical trial information: NCT06741644 .

Age-associated genomic instability and inflammatory pathway activation: A pan-cancer multi-omics analysis of the TITANIA framework.

2583 Background: Aging is associated with increased cancer incidence and altered tumor biology, yet molecular mechanisms underlying age-related differences remain poorly characterized at the multi-omics level. We hypothesized that elderly patients may exhibit coordinated increases in genomic instability and inflammatory pathway activation. Methods: We performed integrated multi-omics analysis comprising whole genome sequencing, RNA sequencing, and data-independent acquisition mass spectrometry-based proteomics on 153 treatment-naive patients across six cancer types (colorectal cancer n=52, gastric n=19, kidney n=32, non-small cell lung cancer n=27, ovarian n=19, liver n=4). The TITANIA study provided matched tumor and normal tissue specimens with standardized collection protocols (median cold ischemia time: 12 minutes). Patients were stratified by age (≤60 years, n=40; >60 years, n=113). Inflammation scores were calculated using ssGSEA of six Hallmark inflammatory pathways. Tumor microenvironment subtypes were identified using xCell deconvolution followed by k-means clustering (k=3). Results: Tumor mutation burden (TMB) showed a significant positive correlation with age (Spearman ρ=0.334, P<0.001), with elderly patients demonstrating higher median TMB than younger patients (4.55 vs 2.84 mut/Mb, P<0.001). Inflammation scores showed positive correlations with age in tumor tissues at both RNA (ρ=0.223, P=0.01) and protein (ρ=0.233, P=0.005) levels. Normal tissue inflammation correlated with paired tumor TMB (RNA: ρ=0.283, P=0.027; Protein: ρ=0.387, P<0.001), raising the possibility that systemic inflammaging may be associated with tumor genomic instability. TME clustering identified three subtypes: Immune-Hot (n=14), Immune-Cold (n=92), and Vascular-Rich (n=30). Notably, all patients in the Immune-Hot cluster were elderly (>60 years). TMB positively correlated with B cells, neutrophils, and M1 macrophages, while negatively correlated with stromal score and endothelial cells. The EPITHELIAL_MESENCHYMAL_TRANSITION pathway showed potential as a prognostic marker at both omics levels (C-index: RNA 0.63, Protein 0.61), though further validation is warranted. Conclusions: This pan-cancer multi-omics analysis demonstrates age-dependent genomic instability coupled with inflammatory pathway activation in both tumor and normal tissues, consistent with the inflammaging hypothesis. The novel finding that normal tissue inflammation correlates with tumor TMB suggests systemic inflammaging may contribute to tumor evolution, with potential implications for age-adapted immunotherapy strategies.

Real-world analysis of adjuvant abemaciclib in high-risk HR+/HER2− early breast cancer.

e12529 Background: Abemaciclib in combination with adjuvant endocrine therapy (ET) improves invasive disease-free survival (IDFS) and is standard of care for patients (pts) with high-risk hormone receptor–positive (HR+), HER2-negative early breast cancer (EBC) based on the monarchE trial. Given the prolonged two-year treatment course, evaluation of real-world tolerability provides insight into its use in clinical practice. We examined toxicities and treatment patterns among patients treated with adjuvant abemaciclib. Methods: We conducted a retrospective single-institution analysis, after IRB approval, of pts with HR+/HER2− EBC treated with adjuvant abemaciclib between 2021 and 2024. Demographic, clinical, pathologic, treatment, and toxicity data were abstracted from the electronic medical record. Outcomes were summarized using descriptive statistics. Results: Thirty-nine pts were included in the analysis. Pts were all female, with a median age of 52.9 years (IQR 45.9–62.3). Most pts were White and non-Hispanic (97%), and 62% were postmenopausal. All tumors were ER-positive/HER2-negative; 15% had progesterone receptor expression < 1%. Pathologic stage was III in 51% and II in 49%. All pts received adjuvant ET with aromatase inhibitors; ovarian suppression was used in 26%. Germline BRCA1/2 mutations were identified in two pts. Most pts received adjuvant chemotherapy (85%), with no neoadjuvant chemotherapy use. Eligibility for adjuvant abemaciclib was based on ≥4 positive lymph nodes in 44% of pts and 1–3 positive nodes with additional high-risk features in 56% (including grade 3 disease in 26%, Ki-67 ≥20% in 20%, and/or tumor size ≥5 cm in 10%). Most pts initiated abemaciclib at 150 mg twice daily (92%), with a median treatment duration of 24 months (IQR 18–24). Adverse events (AEs) of any grade occurred in 64% of pts (vs 98% in monarchE). Dose reductions and toxicity-related discontinuation occurred in 56% and 24% of pts, respectively (vs ~48% and 16.6% in monarchE). The most common AE was diarrhea (38% vs 82% in monarchE), followed by fatigue (18% vs 39%), abdominal pain (10%), nausea (10%), and vomiting (8%). Acute kidney injury occurred in 10% of pts and alopecia in 5%, with one thrombotic event observed. No neutropenia was reported (vs 45% in monarchE). Median follow-up was 39.4 months; all pts were alive at last follow-up, with one local recurrence, precluding meaningful IDFS and OS analyses. Conclusions: In this real-world cohort, adjuvant abemaciclib was associated with higher rates of dose modifications and treatment discontinuation compared to rates reported in the monarchE trial. Adverse events were consistent with prior reports, with lower rates of common toxicities and no observed neutropenia. These findings underscore the challenges of maintaining a two-year treatment course in routine practice. Longer follow-up and larger cohorts are needed to better characterize recurrence and survival outcomes.

Long-term mortality trends from pancreatic cancer and associated second malignancies in the U.S., 1999 to 2023: A CDC WONDER analysis.

e16369 Background: Pancreatic CA and secondary malignancies are major contributors to U.S. mortality. Methods: CDC WONDER data for U.S. adults (≥65 years) from 1999-2023 were analyzed. Age-adjusted mortality rates (AAMRs) per 100,000 were calculated according to population size, year, location of death, age, race, level of urbanization, state, and census region from 1999-2023. Joinpoint regression was used to estimate the average annual percentage change (AAPC) with 95% confidence intervals to assess statistical significance. The ICD-10 codes for pancreatic cancer were C25 and C77, C78, and C79.0–C79.8 for secondary malignancies. Results: Pancreatic CA and secondary malignancies caused 69,411 deaths. AAMRs ranged from 4.97 in 1999 to 11.3 in 2023 per 100,000, and the AAPC was 3.45%. From 1999-2008, AAMR showed a significant decline (APC: -3.09 (95% CI: -3.78 to -2.38)), followed by a significant rise up to 2013 (APC: 4.92 (95% CI: 2.46 to 7.44)) until 2016 (APC: 13.54 (95% CI: 6.41 to 21.15)) and continued to rise until 2023 (APC: 7.04 (95% CI: 6.39 to 7.69]). Males (AAMR: 7.79; 35,211 deaths) had an elevated AAMR per 100,000 and higher mortality than females (AAMR: 5.85; 34,200 deaths). From 1999-2008, males and females exhibited a decline in AAMR, with associated APCs of -3.17 and -3.31, respectively, followed by a sharp increase till 2013-2014, till 2016-2017, and continued to rise until 2023. NH Black (7.21) and NH White (6.21) showed the highest AAMRs, followed by Hispanic (5.26), and NH Asians (4.14) showed the lowest. The number of NH Asians experienced a sharp rise after 2012 (APC: 8.78). NH Black showed a decline from 1999-2008 (APC: -5.03), followed by a rise from 2008-2023 (APC: 6.43). NH Whites mirrored the overall trend, with an AAPC of 3.71%. Hispanics showed an early decline, followed by a significant increase, with an overall AAPC of 2.44%. A consistent upward trend in the crude mortality rate per 100,000 for all age groups was observed. Registered deaths were highest in the 75–84 years age group, followed by 85+ years and 65–74 years. The AAMR declined from 1999-2008 in metropolitan areas (APC: -2.99) and from to 1999-2009 in non-metropolitan areas (APC: -3.35) and increased through 2020, with AAMR 9.43 for nonmetropolitan areas and 9.20 for metropolitan areas. The Midwest (12.21) and West (12.18) showed the highest AAMRs in 2023, followed by the South (11.85). Northeast displayed the lowest AAMR (8.27) and AAPC (1.74%) with a later period of increase in 2009. The western region experienced the most rapid increase over the entire period (AAPC: 4.50%). California, Texas, and Florida showed the largest number of cumulative death counts from 1999-2023. Conclusions: Mortality from pancreatic CA and secondary malignancies has risen substantially among older adults, with persistent sex, racial, and geographic disparities, indicating the need for health equity-focused interventions.

Fezolinetant for the management of vasomotor symptoms in patients with breast cancer.

e12521 Background: Approximately 70% of breast cancers are hormone receptor (HR)–positive, for which endocrine therapy (ET) is a cornerstone of treatment. However, up to one-third of patients discontinue ET due to adverse events, most commonly vasomotor symptoms (VMS). Fezolinetant, a neurokinin 3 receptor antagonist approved in 2023 for menopausal VMS, has not been studied in patients with breast cancer. Given the need for nonhormonal options for the management of VMS, we conducted an observational, survey-based study evaluating the use of fezolinetant in patients with breast cancer. Methods: This is a single-institution, observational cohort study of adults (≥18 years) with stage 0–IV breast cancer receiving ET who were prescribed fezolinetant for ≥4 weeks for VMS. Patients receiving ET for non-malignant high-risk lesions were excluded. Participants completed a one-time phone interview or REDCap survey assessing symptom severity, treatment response, time to improvement, adverse effects, treatment preference, and financial toxicity. Clinical data were abstracted from the electronic medical record. Outcomes were summarized using descriptive statistics. This study was IRB approved, and all patients provided informed consent. The data was monitored and reviewed for completeness and accuracy. Results: Of the 70 patients screened, 34 were enrolled. Mean age was 52.5 ± 10.3 years; all participants were female, 88.2% White, and 32.4% Hispanic/Latino. Most patients had invasive breast cancer (94.1%) with early-stage disease. Baseline symptom burden was high, with 79.4% reporting severe hot flashes and 90.9% experiencing ≥4 episodes daily. Prior unsuccessful therapeutic (prescribed or over-the-counter) management attempts were common (64.7%). Following fezolinetant initiation, 97.1% reported improvement in hot flashes, with 76.5% noting significant improvement and 76.5% reporting improvement in both frequency and severity. Symptom relief occurred within one week for 70.6% of patients. Fezolinetant was well tolerated, with most patients reporting no adverse effects and 91.2% planning to continue therapy. Insurance authorization challenges and high copays were reported in 26.5% and 32.4%, respectively. Conclusions: In this real-world observational cohort of patients receiving endocrine therapy, hot flashes were common, severe, and frequently refractory to prior interventions. Initiation of fezolinetant was associated with rapid, clinically meaningful improvement in hot flash frequency and severity, with high tolerability and treatment continuation. These findings support the feasibility and potential benefit of fezolinetant for the management of endocrine therapy–associated vasomotor symptoms in patients with breast cancer and warrant prospective investigation.

Independent validation of a model to predict early favorable PSA response (NADIR model) in enzalutamide-treated patients of the ARCHES trial.

5082 Background: Our group recently trained and independently validated a multivariable logistic regression model (NADIR model) to predict early favorable PSA response (≤0.2 ng/mL) in metastatic hormone sensitive prostate cancer (mHSPC) patients (pts) within 6 months of treatment initiation with androgen receptor pathway inhibitor (ARPI). In this work, we independently validated the NADIR model in the enzalutamide (enza) treated patients from the ARCHES trial. Methods: ARCHES is a phase III randomized controlled trial where patients with mHSPC were randomly assigned to ADT versus ADT plus enzalutamide. The locked model was applied to patients in the enza arm and model discrimination was assessed using area under the receiver operating curve (AUC) with 95% confidence intervals (CI) from 5000 bootstrap iterations. Additional performance metrics included Index of prediction accuracy (IPA) relative to null model, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and positive likelihood ratio (PLR) and negative likelihood ratio (NLR). A Cox proportional hazard model was applied in a 6-month landmark population to determine the hazard of death in middle and lower tertile relative to upper tertile when stratified by tertiles of predicted probability from the NADIR model. Results: 1125 patients with non-missing data were included in this independent validation cohort of whom 559 patients were treated with enza. Approximately 64% (n=360) achieved PSA ≤0.2 ng/mL within 6 months of treatment initiation. The AUC was 0.80 [95% CI 0.76-0.83] and IPA was 23%. The sensitivity, specificity, PPV, NPV, PLR, and NLR were 0.82 [0.77-0.86], 0.56 [0.49-0.63], 0.77 [0.72-0.81], 0.63 [0.55-0.70], 1.85 [1.57-2.17], and 0.33 [0.26-0.42], respectively. The early favorable PSA response rates in patients stratified by decreasing order of tertiles of predicted probability of PSA response from the NADIR model were 92% [88-96], 64% [57-71], and 37% [30-45], respectively. Compared to those in the upper tertile, patients in the middle tertile (HR 1.97 [1.33-2.91]) and lower tertile (HR 2.18 [1.48-3.21]) had significantly worse OS. Among patients with <3 months of ADT before ARPI initiation, the AUC was 0.79 [0.75-0.83] with IPA of 22%. Conclusions: In this independent validation using the ARCHES trial, the NADIR model showed strong discriminatory performance and effectively stratified enzalutamide-treated patients by early favorable PSA response and overall survival. With prospective validation, this model may provide a useful tool for early prognostication in patients with mHSPC receiving ARPI therapy.

Metabolic signatures of response: 2-hydroxybutyric acid as a biomarker in melanoma patients receiving ipilimumab–nivolumab.

9521 Background: 2-Hydroxybutyric acid (α-HB) is an established biomarker in metabolic disease of insulin resistance and oxidative stress but its role in immuno-oncology remains unclear. This study conducted an exploratory analysis to evaluate whether α-HB could be used as a biomarker in advanced melanoma patients treated with ipilimumab-nivolumab, and its association with treatment response and toxicity. Methods: In this single-center retrospective study, 36 patients with unresectable/metastatic melanoma received ipilimumab-nivolumab. α-HB levels were measured by targeted mass spectrometry and measured relative metabolomic signal intensities. Descriptive statistics assessed α-HB across subgroups defined by age, sex and BRAF status. Associations between α-HB and grade ≥3 immune-related toxicity, treatment response, and survival at last contact were tested using univariable logistic regression with α-HB entered as a continuous predictor (log2-transformed). Prespecified sensitivity analyses dichotomized α-HB at the median (1.13) and 75th percentile (1.55). For mortality, we additionally derived an exploratory ROC-based Youden threshold to define a “high α-HB” group and report diagnostic performance (specificity, PPV, NPV) and odds ratios. Results: Median age was 53.5; 63.9% were male; 80.6% had cutaneous melanoma; 33.3% were BRAF-mutant; 80.6% received first-line therapy. Baseline α-HB was lower in patients who developed grade ≥3 toxicity (mean 1.01 vs 1.54; p=0.013) and in responders (1.09 vs 1.60; p=0.021), while it was higher among those who died (1.49 vs 1.06; p=0.045). In logistic models using log2-transformed α-HB, each doubling in α-HB was associated with reduced odds of grade ≥3 toxicity (OR 0.165, 95%CI 0.036–0.744; p=0.019) and response (OR 0.268; 95% CI 0.075–0.961; p=0.043; AUC = 0.79; HL p=0.803, where higher p indicates better fit), consistent with lower α-HB marking both toxicity and response. Higher α-HB trended toward increased death risk (OR 3.3 per doubling; p=0.066). Using a Youden-derived cutoff (α-HB ≥1.58), high α-HB defined a high-risk subgroup (OR 10.0; 95% CI 1.09–91.4; p=0.041) with high specificity for death (94%); PPV 89% and NPV 56%. Conclusions: Elevated α-HB was associated with reduced response, lower incidence of immune-related toxicity, and higher rates of death, suggesting a metabolically suppressed immune phenotype. Further validation is needed to determine whether metabolic interventions could improve immunotherapy outcomes in selected patients.

CD103 ^⁺ CD8 ^⁺ T cells in malignant pleural effusion as a clinically applicable biomarker for immunotherapy response in advanced lung cancer.

e20535 Background: Malignant pleural effusion (MPE) in advanced lung cancer is associated with poor outcomes and limited benefit from immune checkpoint blockade (ICB). A practical biomarker from an easily accessible source is needed to guide treatment. CD103 identifies tissue-resident memory CD8⁺ T cells (Trm), which are pivotal in antitumor immunity, but their predictive value in MPE has not been established. Methods: Single-cell RNA and T-cell receptor (TCR) sequencing were performed on matched primary tumors, pleural metastases, MPE, and blood from 7 patients. Intratumorally expanded CD8⁺ T cells (int-T8) were characterized. CD103⁺CD8⁺ T cells in MPE were quantified by flow cytometry in an expanded cohort (N=35) and correlated with mutational status. Their association with ICB response was validated in an independent retrospective cohort (N=23) using multiplex immunohistochemistry and survival analysis. Results: Intratumorally expanded CD8⁺ T cells displayed a Trm phenotype (CD103⁺, PD-1⁺, CD39⁺). TCR analysis confirmed that CD103⁺CD8⁺ T cells in MPE were clonally derived from these tumor-specific Trm. The proportion of CD103⁺CD8⁺ T cells in MPE strongly correlated with intratumoral Trm abundance (R=0.86, P=0.0013). This cell population was enriched in KRAS-mutant compared to other mutant MPEs (such as EGFR-19dels). In the validation cohort, a high proportion of CD103⁺CD8⁺ T cells in MPE was associated with a significantly better objective response rate (90.9% vs. 16.7%) and longer median progression-free survival (206 vs. 70 days; HR, 0.22; 95% CI, 0.07 to 0.67; P < 0.0001). Notably, this 90.9% response rate stands in sharp contrast to the generally modest response rates (<30%) observed with ICB in unselected advanced lung cancer populations. Conclusions: CD103⁺CD8⁺ T cells in MPE constitute a tumor-specific Trm population that reflects the intratumoral immune microenvironment. This finding establishes a new, readily implementable biomarker assay from a routinely obtained liquid sample (thoracentesis). Measurement of this subset represents a clinically feasible approach that can help identify patients with advanced lung cancer most likely to benefit from immunotherapy.

Clinical feasibility of 68Ga-DOTATATE PET/CT to identify SSTR-positive soft tissue sarcoma for PRRT selection.

TPS11590 Background: Soft tissue sarcomas (STS) are biologically heterogeneous with limited effective systemic options in advanced disease. While 18F-FDG PET/CT provides metabolic assessment, it does not identify actionable receptor targets. Somatostatin receptor 2 (SSTR2) is expressed in subsets of mesenchymal tumors, and SSTR-targeted imaging with 68Ga-DOTATATE PET/CT is routinely used to select patients with neuroendocrine tumors for peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. Whether receptor-targeted PET screening can feasibly characterize SSTR expression across STS subtypes and support future PRRT trial design is unknown. This study evaluates the feasibility and yield of 68Ga-DOTATATE PET/CT as a screening strategy in STS. Methods: This is a prospective, open-label, single-center pilot study enrolling 30 adults with any-stage STS who are candidates for systemic therapy and who have undergone standard-of-care PET/CT within 30 days. Participants undergo a single 68Ga-DOTATATE digital PET/CT within 14 days of consent, acquired approximately 60 minutes post-injection with non-contrast CT for attenuation correction and anatomic localization. Quantitative metrics including SUVmax and total tumor volume are centrally derived. Optional biobanking permits pre-imaging blood collection for exploratory circulating biomarkers. Key exclusions include recent long-acting somatostatin analog use, pregnancy or lactation, acute infection, hypersensitivity to somatostatin analogs, or inability to complete imaging. The primary endpoint is screening feasibility, defined by successful scan acquisition and interpretable image quality. Secondary endpoints include lesion-level detectability, safety, and characterization of uptake patterns using modified Krenning-style criteria and quantitative PET parameters across histologic subtypes. Imaging findings may be reviewed at multidisciplinary sarcoma tumor board as part of routine clinical care, including discussion of potential PRRT eligibility, but tumor board recommendations are not study endpoints. Exploratory analyses will assess concordance between imaging findings and available tumor immunohistochemistry or circulating biomarkers. Analyses are descriptive. The planned accrual is 30 patients over approximately 24 months at a high-volume sarcoma center. Enrollment and imaging are ongoing. This study will establish the feasibility of receptor-targeted PET screening in STS and characterize the frequency and distribution of SSTR-positive disease, providing data necessary to inform the feasibility and design of subsequent 177Lu-DOTATATE interventional trials. Clinical trial information: NCT06500065 .

A prospective, single-arm, multicenter, phase IV study to evaluate the efficacy and safety of sonidegib in Chinese patients with locally advanced basal cell carcinoma.

e21555 Background: Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved for the treatment of adult patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy, by the FDA and EMA. However, the efficacy and safety profile of sonidegib in Chinese patients was unknown. Herein, we present the results from a phase IV study of sonidegib conducted among Chinese patients. Methods: The study (NCT06880848) recruited patients (pts) aged ≥18 years who had locally advanced BCC that was not amenable to radiation therapy, curative surgery, or other local therapies. All patients received 200 mg oral sonidegib once daily for up to 1 year. The primary endpoint was the independent review committee (IRC)-assessed objective response rate (ORR) based on the modified response evaluation criteria in solid tumors (mRECIST). Results: Between June 21, 2023, and July 23, 2024, 160 pts were enrolled and treated. Median age was 68 years (range, 25 – 96 years). As of data cutoff (August 26, 2025), median follow-up was 12·7 months. The IRC-assessed ORR was 58.1% (95% CI 50.1-65.9%), which was consistent across all predefined subgroups. Median duration of response (DOR) and progression-free survival (PFS) by IRC were not reached; the 12-month DOR and PFS rates were 70.8% and 67.4%, respectively. Treatment-related adverse events (TRAEs) were reported in all patients, with most graded 1-2. The most common TRAEs were elevated blood creatine kinase (60.6%), alopecia (44.4%), muscle spasms (33.8%), weight decrease (29.4%), anorexia (24.4%), dysgeusia (23.1%), aspartate aminotransferase increased (21.3%), and alanine aminotransferase increased (20.0%). The incidence of grade ≥3 TRAEs was 28.1%, with elevated blood creatine kinase as the most common (15%). Serious adverse events (SAEs) occurred in 39 patients (24.4%), of which 17 (10.6%) were treatment-related SAEs. TRAEs led to treatment discontinuation in 9 (5.6%) pts. No TRAEs led to death. Conclusions: In Chinese patients with locally advanced BCC, sonidegib demonstrated robust efficacy, consistent with previous reports in global study populations. The safety profile of sonidegib was manageable, and no new safety signals were observed. Clinical trial information: NCT06880848 .

Real-world outcomes of FOLFOX with or without bevacizumab in small bowel and ampullary adenocarcinoma: A propensity-matched analysis.

e16488 Background: Small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (ampullary AC) are rare gastrointestinal (GI) malignancies. Treatment strategies are largely extrapolated from colorectal cancer, where oxaliplatin-based regimens are the most common first-line therapy in advanced disease. Although bevacizumab is considered safe in metastatic SBA, its efficacy remains unproven, and evidence is limited to small retrospective studies. We assessed the association of adding bevacizumab to FOLFOX with survival and toxicity in a large real-world cohort. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network (January 2000-December 2025), including data from 105 healthcare organizations. Adults (≥18 years) with SBA or ampullary AC treated with FOLFOX with or without bevacizumab were identified. Cohorts were propensity score-matched on age, sex, race, comorbidities, and metastatic sites. Outcomes included overall mortality, GI perforation, bleeding, venous thromboembolism (VTE), hospital admission, and emergency department (ED) visits. Kaplan-Meier and Cox proportional hazards models were used for time-to-event analyses. Results: After matching, 818 patients were included in each cohort. In the FOLFOX + bevacizumab cohort, mean age was 66.1 ± 12.0 years and 53.8% were male; 63.7% were White, 13.8% Black, 5.6% Asian, 12.0% Unknown/Other, and 4.4% Hispanic/Latino. Over a median follow-up of 13 months, FOLFOX + bevacizumab was associated with higher overall mortality compared with FOLFOX alone (55.3% vs 45.2%; HR 1.24 [95% CI 1.1-1.4]; p = 0.002) and shorter median OS (15.1 vs 19.5 months). Rates of GI perforation (15.5% vs 16.7%; HR 0.90 [95% CI 0.71-1.15]; p = 0.39), GI bleeding (13.1% vs 13.6%; HR 0.96 [95% CI 0.73-1.25]; p = 0.74), and VTE (19.1% vs 21.4%; HR 0.88 [95% CI 0.71-1.09]; p = 0.23) were similar between groups. Hospital admissions were higher in the FOLFOX + bevacizumab cohort (2.8% vs 1.3%; HR 2.1 [95% CI 1.0-4.3]; p = 0.04). Findings were consistent at 5-year follow-up. Conclusions: In this real-world cohort, the addition of bevacizumab to FOLFOX was not associated with improved survival and was associated with higher healthcare utilization. Prospective, disease-specific studies are needed to define its role in this population. Outcomes at median 13-month follow-up after propensity matching (FOLFOX + bevacizumab vs FOLFOX). Outcome % vs % HR p Overall mortality 55.3 vs 45.2 1.24 0.002 Hospital admission 2.8 vs 1.3 2.1 0.04 ED visit 45.2 vs 42.4 1.02 0.75 GI perforation 15.5 vs 16.7 0.90 0.39 GI bleeding 13.1 vs 13.6 0.96 0.74 VTE 19.1 vs 21.4 0.88 0.23