Citations

7530 Background: B-cell maturation antigen (BCMA)-directed CAR-T therapy is a highly effective treatment with potential for long-term remission of RRMM with improved outcomes vs daratumumab-based regimens. CAR-T suitability may be limited by delays/manufacturing failure and changes in pt condition, financial situation, or access to specialized treatment centers. We characterized pts with RRMM who underwent leukapheresis to prepare for CAR-T and pt treatment waiting time, to understand the delays incurred prior to CAR-T infusion. Methods: A real-world study in the US using the PharMetrics Plus claims database (July 2020–September 2024) was performed. Eligible pts were aged ≥18 years with RRMM, had their first leukapheresis claim (index date) during the index period (March 2021–August 2024), were continuously enrolled in medical/pharmacy benefits for ≥180 days prior to and ≥30 days after index date, and were not clinical trial participants. Pt characteristics, rate of CAR-T receipt, and time to CAR-T receipt were assessed during the variable follow-up. Results: Overall, 337 pts who received leukapheresis were identified. Median (interquartile range) age was 62 (55–67) years, and 59.1% of pts were male. Mean National Cancer Institute (NCI) comorbidity index was 0.52. Most pts received care in the Midwest (31.8%) or Northeast (24.6%) regions. Most pts (95.9%) received leukapheresis in an outpatient setting. Median available follow-up time was 255 days (mean 337 days). During follow-up, 183 pts (54.3%) did not receive CAR-T after leukapheresis. Among pts who had ≥12 months of follow-up (n=143), the proportion of pts who did not receive CAR-T was similar at 53.1% (n=76). Among pts who received CAR-T during the follow-up (n=154; 45.7%), the median waiting time was 54.0 days (mean 56.7 days). The cohort of pts who did not receive CAR-T had a higher proportion of females (48.6%/31.8%), were more likely to have Medicaid (29.5%/7.8%), had higher NCI comorbidity index (scores 0.55/0.47), and most commonly received care in the Northeast (35.5%/11.7%) while pts who received CAR-T most commonly received care in the Midwest (23.0%/42.2%). The most common first classes of multiple myeloma medications after leukapheresis but prior to CAR-T infusion in pts who did/did not receive CAR-T were an alkylating agent (65.6%/36.1%), proteasome inhibitor (40.3%/30.6%), steroid (38.3%/39.3%), immunomodulatory drug (22.7%/27.3%), anti-CD38 (20.8%/20.8%), and stem cell transplant (0%/17.5%). Conclusions: Over half of pts receiving leukapheresis did not receive CAR-T infusion, highlighting a persistent gap between eligibility and treatment delivery. These data emphasize an urgent need for broadly accessible BCMA-targeted therapies that provide deep and durable responses.

BACKGROUND: Hemorrhagic risk in dural arteriovenous fistulas (dAVFs) is largely determined by venous anatomy, but the contribution of systemic cardiovascular factors and their medical therapy remains poorly defined. This study examined associations between cardiovascular risk factors and antithrombotic use and hemorrhagic presentation, angiographic obliteration, and early functional outcomes after treatment. METHODS: We analyzed 1350 adults with intracranial dAVFs from the international Consortium for Dural Arteriovenous Fistula Outcomes Research registry, which retrospectively accrued cases across 14 centers in 4 countries between 1990 and 2017. Demographics, cardiovascular comorbidities, antithrombotic use, angioarchitectural features, treatment strategies, and follow-up outcomes were collected from prospectively maintained databases. Primary end points were hemorrhagic presentation, angiographic obliteration, and 90-day functional status after treatment. Univariable and multivariable logistic regressions were performed with model-specific adjustments. RESULTS: Hemorrhage occurred in 375 patients (27.8%) and was most strongly associated with high-grade dAVF classification and male sex; antithrombotic therapy was associated with lower odds of hemorrhagic presentation. Other cardiovascular risk factors showed no independent relationship with bleeding. Angiographic obliteration was achieved in 621 of 845 patients (73.5%). Hemorrhagic onset, high dAVF grade, and surgical treatment were independently associated with angiographic obliteration, whereas smoking and embolization demonstrated only nonsignificant trends after adjustment. At 90 days, 934 patients (88.9%) were functionally independent. Baseline modified Rankin Scale score was the strongest factor associated with 90-day functional outcome, while neither cardiovascular comorbidities nor treatment modality independently influenced functional status. CONCLUSIONS: In this large multicenter dAVF cohort, hemorrhagic presentation was most strongly associated with venous angioarchitecture. Male sex and antithrombotic therapy were also independently associated with hemorrhagic presentation. Angiographic obliteration was common, particularly among surgically treated lesions, and 90-day functional outcome was most strongly associated with baseline functional status.

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive yet immunogenic subtype of breast cancer (BC) and the only one with FDA-approved immune checkpoint inhibitor (ICI) - pembrolizumab. Currently, PD-L1 (22C3) is the companion biomarker for predicting pembrolizumab benefit, but its utility is limited by spatial/temporal heterogeneity, assay variability, and modest correlation with treatment response. Chemokines such as CXCL9, CXCL10, and CCL5 recruit CD8+ T cells into the tumor microenvironment and have been associated with improved response to ICI, but their predictive value alongside PD-L1 remains unclear. Here, we examined the relationship between these chemokines, PD-L1, and pembrolizumab efficacy in TNBC. Methods: We analyzed 3662 TNBC tumors profiled by NGS (592, NextSeq; WES/WTS, NovaSeq; Caris Life Sciences). Immune cells were estimated using WTS deconvolution (Quantiseq). PD-L1 positivity was defined as >10% CPS (PharmDx 22C3). CXCL9/CXCL10/CCL5-high (H) and -low (L) TNBC were classified by RNA expression above or below 50th percentile. Real-world median overall survival (mOS) was derived from insurance claims and calculated from start of pembrolizumab to last contact using Kaplan-Meier. Statistical significance was assessed by chi-square and Mann-Whitney U with multiple comparison adjustments (q<0.05). Results: TNBC expressed higher levels of CXCL9, CXCL10, and CCL5 (N = 3662, median TPM: 5.3, 14.8, and 15.1) compared to HER2+ (N = 1344; 4.8, 10.1, 10.6) and HR+HER2- BC (N = 6097; 2.7, 6.6, 9.4), all q<0.05. Moderate correlations were observed between PD-L1 CPS and each chemokine (r = 0.41, p<.01). PD-L1-positive tumors had better mOS (24.3 months (m) vs 18.6 m, HR 0.75, 95% CI 0.6-0.92, p=0.007) compared to PD-L1-negative TNBC post-pembrolizumab. Among PD-L1-negative tumors, those with CXCL9-H had better mOS (26.9 m vs 15.8 m for CXCL9-L, HR 0.61, 95% CI 0.45-0.82, p=0.001) post-pembrolizumab. Among PD-L1-positive tumors, CXCL10-H and CCL5-H was associated with improved mOS (CXCL10-H: 25.7 m vs. 20.7 m for CXC10-L, p = 0.03; CCL5-H: 26.7 vs. 18.5 m for CCL5-L, p = 0.03) post-pembrolizumab. PD-L1 negative CXCL9-H, PD-L1 positive CXCL10-H and PD-L1 positive CCL5-H groups showed higher infiltration of CD8+ T cell, B cells, M1/M2 macrophages, Tregs. They also exhibited higher T cell inflamed score, IFNy score and MAPK activation score vs. CXCL9-L, CXCL10-L and CCL5-L groups (Table). Conclusions: In TNBC, a chemokine signature comprising CXCL9, CXCL10 and CCL5 refines PD-L1 based prediction of pembrolizumab benefit. Specifically, high CXCL10 or CCL5 expression in PD-L1-positive tumors, and high CXCL9 expression in PD-L1-negative tumors, were associated with improved survival post pembrolizumab and immune-rich microenvironment. These findings support the use of chemokine profiling to complement PD-L1 and enhance patient selection for ICI therapy in TNBC. Citation Format: S. Gandhi, S. Deshmukh, S. Wu, J. Xiu, G. Sledge Jr., D. Trapani, J. Leone, S. Chumsri, M. Lustberg, C. Hong, S. Yao, K. Takabe, M. Ernstoff, M. Opyrchal, P. Chalasani, C. Paulos, G. Lesinski, A. Madabhushi, S. Badve, K. Kalinsky, P. Kalinski. Chemokine signatures improve PD-L1-based prediction of pembrolizumab response in triple-negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-08-14.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) for brain arteriovenous malformations (AVMs) can cause radiation-induced changes (RIC), but its interactions with AVM embolization are not well established. The aim of this study was to assess the effect of previous embolization on RIC in SRS-treated AVM patients. METHODS: Data of AVM patients treated with single-session SRS from 1987 to 2018 were retrieved from the International Radiosurgery Research Foundation. Univariable and stepwise backward logistic regression models were used to identify RIC predictors. Patients were stratified into those who received pre-SRS embolization (E + SRS) vs those who did not (SRS-only). Radiologic RIC (rRIC) was the primary end point. Secondary outcomes included symptomatic RIC (sRIC) and permanent symptomatic RIC (pRIC). RESULTS: Among 1187 AVM patients, the mean age was 36.4 years (SD 16.8), with 50.4% female patients. AVMs had a mean untreated AVM volume of 5.2 cm 3 . A total of 130 patients (11%) underwent neoadjuvant embolization (E + SRS). The overall rRIC and sRIC rates were 32.8% and 12.1%, respectively, with time to rRIC and sRIC being significantly longer in the E + SRS vs SRS-only cohorts (103.6 ± 339.4 vs 11.3 ± 12.5 and 60.4 ± 262.9 vs 9.5 ± 9.0 months, respectively). Seizures at presentation and ≥3-cm untreated AVM volume significantly correlated with a higher likelihood of rRIC (adjusted odds ratio [aOR] 2.32 [1.25-4.30] and aOR 2.77 [1.24-6.16], respectively). Age and pre-SRS embolization were associated with a significantly lower risk of rRIC (aOR 0.97 [0.96-0.99] and aOR 0.32 [0.13-0.74], respectively). The E + SRS cohort had significantly reduced odds of rRIC (aOR = 0.37 [0.15-0.89]) and pRIC (aOR = 0.04 [0.00-0.30]) after adjusting for significant covariates. CONCLUSION: Seizures at presentation and larger untreated AVM volume were independently associated with an increased risk of rRIC, whereas older age and pre-SRS embolization were protective. Notably, patients who underwent embolization before SRS had lower odds of rRIC and pRIC, with delayed onset of complications compared with SRS-only.

1107 Background: Chronic stress-mediated β2-adrenergic receptor (β2-AR) signaling promotes tumor growth via immunosuppression in the tumor microenvironment (TME) in preclinical models. Blockade of β2-AR has shown higher survival benefit in patients with TNBC in observational studies compared to other breast cancer (BC) subtypes. However, the molecular and immunological features associated with ADRB2 (gene for β2-AR) gene expression in TNBC are unknown, prompting this investigation. Methods: 3,038 TNBC samples were analyzed via NGS (592-gene panel, NextSeq; WES/WTS, NovaSeq; Caris Life Sciences, Phoenix, AZ). Immune cell fractions were calculated by deconvolution of WTS: Quantiseq. TNBC ADRB2 -high(H) and ADRB2 -low(L) RNA expression were classified as above or below the 50 th percentile, respectively. Real-world overall survival (OS) was obtained from insurance claims and calculated from tissue collection to last contact using Kaplan-Meier estimates. Statistical significance was assessed using chi-square and Mann-Whitney U tests with multiple comparison adjustments (q < 0.05). Results: ADRB2 gene expression was lowest in TNBC (median (TPM: 1.6) compared to N = 453 HR-HER2+ (1.9), N = 629 HR+HER2+ (2.0) and N = 4,918 HR+HER2- (2.2) BC (all q < 0.05). African American or Black patients (N = 670) had lower expression of ADRB2 compared to European American or White (N = 1,412) TNBC patients (1.3 vs 1.7, q < 0.05). ADRB2 -H TNBC had higher mutation frequency of PIK3CA (21% vs 15.4%), CDH1 (7% vs 3.5%), NF1 (8% vs 4%), AKT1 (3.5% vs 2.1%), but lower frequency of TP53 (81.6% vs 87.5%), NOTCH1 (2.5% vs 4.5%) and NOTCH3 (4.4% vs 11.7%) compared to ADRB2 -L, all q < 0.05. ADRB2 -H had greater PD-L1 (22C3) positivity (39.1% vs 30.2%, q < 0.05), higher % of B cells (4.5 vs 3.4), M1 Mφ (3.4 vs 2.8), M2 Mφ (3.9 vs 2.2), Tregs (2.2 vs 1.3), NK cells (3.1 vs 2.6), DC (3.1 vs 2.9), CD8 + T cells (0.9 vs 0.2), all q < 0.05. ADRB2 -H TNBC had higher T-cell inflamed score (95 vs -80), IFN γ score (-0.23 vs -0.37), MAPK activation score (-0.46 vs -1.7), all q < 0.05; and higher expression of immune checkpoint genes ( CD274, PDCD1, PDCD1LG2, CTLA4, LAG3, HAVCR2, FOXP3, IDO1, TNFSF14, TIGIT, BTLA, CEACAM1, CD47, CD274 ; fold change: 1.6-3.7, all q < 0.05). ADRB2 -H tumors had higher expression of genes related to inflammatory response, IFNγ response, IL6-JAK-STAT3 signaling (normalized enrichment score (NES): 1.9 – 2.1), while ADRB2 -L had enrichment of MYC targets V1, MYC targets V2, E2F targets and G2M checkpoint (NES: 2.5 – 4.2), all FDR < 0.01. ADRB2 -H TNBC had better OS (mOS: 23.6 vs 18.6 months; HR 0.81, 95% CI 0.73-0.89, p < 0.0001) compared to ADRB2 -L. Conclusions: High ADRB2 expression in TNBC is associated with better survival and an immune enriched TME, elevated immune checkpoints and other targetable vulnerabilities. Future studies are needed to investigate ADRB2 as a potential stress biomarker and therapeutic target.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) with neoadjuvant embolization is a treatment strategy for brain arteriovenous malformations (AVMs), especially for those with large nidal volume or concomitant aneurysms. The aim of this study was to assess the effects of pre-SRS embolization in AVMs with an associated intracranial aneurysm (IA). METHODS: The International Radiosurgery Research Foundation AVM database from 1987 to 2018 was retrospectively reviewed. SRS-treated AVMs with IAs were included. Patients were categorized into those treated with upfront embolization (E + SRS) vs stand-alone SRS (SRS). Primary end point was a favorable outcome (AVM obliteration + no permanent radiation-induced changes or post-SRS hemorrhage). Secondary outcomes included AVM obliteration, mortality, follow-up modified Rankin Scale, post-SRS hemorrhage, and radiation-induced changes. RESULTS: Forty four AVM patients with associated IAs were included, of which 23 (52.3%) underwent pre-SRS embolization and 21 (47.7%) SRS only. Significant differences between the E + SRS vs SRS groups were found for AVM maximum diameter (1.5 ± 0.5 vs 1.1 ± 0.4 cm 3 , P = .019) and SRS treatment volume (9.3 ± 8.3 vs 4.3 ± 3.3 cm 3 , P = .025). A favorable outcome was achieved in 45.4% of patients in the E + SRS group and 38.1% in the SRS group ( P = .625). Obliteration rates were comparable (56.5% for E + SRS vs 47.6% for SRS, P = .555), whereas a higher mortality rate was found in the SRS group (19.1% vs 0%, P = .048). After adjusting for AVM maximum diameter, SRS treatment volume, and maximum radiation dose, the likelihood of achieving favorable outcome and AVM obliteration did not differ between groups ( P = .475 and P = .820, respectively). CONCLUSION: The likelihood of a favorable outcome and AVM obliteration after SRS with neoadjuvant embolization in AVMs with concomitant IA seems to be comparable with stand-alone SRS, even after adjusting for AVM volume and SRS maximum dose. However, the increased mortality among the stand-alone SRS group and relatively low risk of embolization-related complications suggest that these patients may benefit from a combined treatment approach.

Background: Cranial dural arteriovenous fistulas with cortical venous drainage are rare lesions that can present with hemorrhage. A high rate of rebleeding in the early period following hemorrhage has been reported, but published long-term rates are much lower. No study has examined how risk of rebleeding changes over time. Our objective was to quantify the relative incidence of rebleeding in the early and later periods following hemorrhage. Methods: Patients with dural arteriovenous fistula and cortical venous drainage presenting with hemorrhage were identified from the multinational CONDOR (Consortium for Dural Fistula Outcomes Research) database. Natural history follow-up was defined as time from hemorrhage to first treatment, rebleed, or last follow-up. Rebleeding in the first 2 weeks and first year were compared using incidence rate ratio and difference. Results: Of 1077 patients, 250 met the inclusion criteria and had 95 cumulative person-years natural history follow-up. The overall annualized rebleed rate was 7.3% (95% CI, 3.2–14.5). The incidence rate of rebleeding in the first 2 weeks was 0.0011 per person-day; an early rebleed risk of 1.6% in the first 14 days (95% CI, 0.3–5.1). For the remainder of the first year, the incidence rate was 0.00015 per person-day; a rebleed rate of 5.3% (CI, 1.7–12.4) over 1 year. The incidence rate ratio was 7.3 (95% CI, 1.4–37.7; P , 0.026). Conclusions: The risk of rebleeding of a dural arteriovenous fistula with cortical venous drainage presenting with hemorrhage is increased in the first 2 weeks justifying early treatment. However, the magnitude of this increase may be considerably lower than previously thought. Treatment within 5 days was associated with a low rate of rebleeding and appears an appropriate timeframe.

Abstract Background Posttraumatic lymphedema develops more frequently than expected and reports on its management are scarce in the literature. We aimed to report the clinical outcomes of a case series of posttraumatic lymphedema patients treated with different vascularized lymph node transfers (VLNTs). Patients and Methods Five patients with secondary posttraumatic lower limb lymphedema treated with VLNT were included in this report. The groin-VLNT (n = 1), supraclavicular-VLNT (n = 2), and gastroepiploic-VLNT (n = 2) were implemented. The average flap area was 69.8 cm2. Patients underwent postoperative complex decompressive therapy for an average of 10.0 months. Results The average mean circumference reduction rate was 24.4% (range, 10.2–37.6%). Postsurgical reduction in the number of infection episodes per year was observed in all patients. The mean follow-up was 34.2 months. Conclusions VLNT is a promising surgical treatment for posttraumatic lymphedema patients. In our report, VLNT has demonstrated to reduce the volume and number of infections per year in posttraumatic lymphedema.

ABSTRACT Background Critically ill patients with severe acute kidney injury (AKI) requiring kidney replacement therapy (KRT) have a grim prognosis. Recently, multiple studies focused on the impact of KRT initiation time [i.e., accelerated versus watchful waiting KRT initiation (WWS-KRT)] on patient outcomes. We aim to review the results of all related clinical trials. Methods In this systematic review, we searched all relevant randomized clinical trials from January 2000 to April 2021. We assessed the impacts of accelerated versus WWS-KRT on KRT dependence, KRT-free days, mortality and adverse events, including hypotension, infection, arrhythmia and bleeding. We rated the certainty of evidence according to Cochrane methods and the GRADE approach. Results A total of 4932 critically ill patients with AKI from 10 randomized clinical trials were included in this analysis. The overall 28-day mortality rate was 38.5%. The 28-day KRT-dependence rate was 13.0%. The overall incident of KRT in the accelerated group was 97.4% and 62.8% in the WWS-KRT group. KRT in the accelerated group started 36.7 h earlier than the WWS-KRT group. The two groups had similar risks of 28-day [pooled log odds ratio (OR) 1.001, P = 0.982] and 90-day (OR 0.999, P = 0.991) mortality rates. The accelerated group had a significantly higher risk of 90-day KRT dependence (OR 1.589, P = 0.007), hypotension (OR 1.687, P &lt; 0.001) and infection (OR 1.38, P = 0.04) compared with the WWS-KRT group. Conclusions This meta-analysis revealed that accelerated KRT leads to a higher probability of 90-day KRT dependence and dialysis-related complications without any impact on mortality rate when compared with WWS-KRT. Therefore, we suggest the WWS-KRT strategy for critically ill patients.