Citations

Introduction Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase involved in immune signaling and has been implicated in tumor-intrinsic resistance to DNA-damaging therapies. Although SYK activity has been associated with poor outcomes in triple-negative breast cancer (TNBC), its role in resistance to combined radiotherapy and immune checkpoint blockade remains unclear. Methods SYK expression and clinical relevance were assessed across multiple breast cancer cohorts, including radiotherapy-treated datasets. Integrated transcriptomic analyses were used to characterize SYK-associated immune states. The functional effects of pharmacologic SYK inhibition were evaluated using in vitro assays and an immunocompetent bilateral 4T1 tumor model in female BALB/c mice treated with radiotherapy and PD-1 blockade. Treatment-associated immune remodeling was assessed by flow cytometry and transcriptomic profiling. Results Across multiple cohorts, elevated SYK expression, particularly in TNBC, was associated with inferior clinical outcomes and immune dysregulation. Pharmacologic SYK inhibition enhanced tumor responses to radiotherapy and PD-1 blockade at both irradiated and distant tumor sites. These effects were accompanied by coordinated remodeling of the tumor immune microenvironment, including suppression of neutrophil-associated signatures and reductions in immunosuppressive myeloid populations, including M2-like macrophages and myeloid-derived suppressor cells. Discussion Pharmacologic SYK inhibition enhances responses to radiotherapy and PD-1 blockade in preclinical TNBC models and is accompanied by remodeling of the immunosuppressive myeloid compartment. These findings support further investigation of SYK-targeted strategies to improve responses to combined radiotherapy and immune checkpoint blockade.

Introduction Antibody–drug conjugates (ADCs) are now widely used in breast cancer across multiple disease subtypes. With increasing clinical use, treatment-related toxicities have become an important factor in therapeutic decision-making. However, comparative safety data among ADCs are limited because direct head-to-head trials are lacking. Methods We conducted a systematic review and Bayesian network meta-analysis of randomized controlled trials evaluating ADCs in breast cancer, with the literature search updated through March 31, 2025. Treatment-related adverse events (TRAEs) and serious adverse events (SAEs) were classified according to the Common Terminology Criteria for Adverse Events. A Bayesian random-effects network meta-analysis was used to compare toxicity risks across regimens. Odds ratios (ORs) with 95% credible intervals (CrIs) were estimated, and surface under the cumulative ranking curve (SUCRA) values were used as descriptive ranking summaries interpreted alongside the corresponding comparative estimates. The protocol was registered in PROSPERO (CRD42024606194). Results Seventeen randomized trials including 8,946 patients and five ADCs—trastuzumab emtansine (T-DM1), sacituzumab govitecan (SG), trastuzumab deruxtecan (T-DXd), datopotamab deruxtecan (Dato-DXd), and ARX788—were analyzed. SG and T-DXd showed the least favorable hematologic safety profiles, with SUCRA values for anemia/neutropenia of 22.6%/17.4% and 12.0%/27.0%, respectively. T-DM1-based regimens had the highest risk of thrombocytopenia. For gastrointestinal toxicities, SG ranked worst for diarrhea (SUCRA 6.0%), whereas T-DXd was associated with higher risks of nausea (2.2%), vomiting (7.9%), and decreased appetite (8.6%). In analyses of SAEs, SG had the highest rates of anemia (11.7%) and neutropenia (8.5%), while gastrointestinal SAEs occurred more frequently with T-DXd. Conclusions This network meta-analysis highlights clinically meaningful differences in ADC safety profiles and may help guide individualized toxicity management in breast cancer.

ABSTRACT Purpose We studied histologic Ewing sarcoma (ES) tumor response at local control surgery to explore associations between histologic response and chemotherapy practice changes over time and confirm its prognostic significance in the modern era. Methods We reviewed clinical data for 126 patients with ES treated at Mayo Clinic from 1977 to 2022, analyzing the percentage necrosis as a prognostic factor across chemotherapy regimens (including modern interval‐compressed VDC‐IE). Results In the historical cohort, 5‐year event‐free survival (EFS) and overall survival (OS) for patients with ≤5% versus greater than 5% viable tumor were 76% versus 59% ( p = 0.01) and 83% versus 62% ( p = 0.01). Review of 104 specimens by two pathologists identified the percentage remaining viable tumor as more reproducible than the percentage necrosis and/or fibrosis. On multivariable analysis of patients with localized disease ( n = 87), pelvic tumors and greater than 5% viable tumor remained independent risk factors for poor survival (EFS: hazard ratio [HR] 3.1, p < 0.01; OS: HR 2.1, p = 0.048). The modern cohort consisted of 22 patients. No patients with tumor size less than 8 cm at diagnosis and 100% necrosis after surgery had events; four of seven with tumors greater than 8 cm had events despite 100% necrosis. Conclusions Our results validate the historical threshold of greater than 5% viable tumor with older chemotherapy regimens but not with modern interval‐compressed VDC‐IE. In addition, inter‐rater reliability for the percentage viable is more reproducible than the percentage necrosis. Although numbers are small, tumors less than 8 cm with no viable tumor appear to be a favorable subgroup and suggest risk stratification using a combination of tumor size and any viable tumor should be evaluated in ES.

Abstract Introduction 0.05% Chlorhexidine Gluconate (CHG) has gained popularity as an irrigant and dip for inflatable penile prosthesis (IPP) surgery. Prior in vitro data is conflicting on the impact of CHG use with hydrophilic coated devices. Objective We sought to identify possible associations between CHG use and hydrophilic IPP infection rate. Methods We conducted a retrospective cohort study of 2,933 patients undergoing IPP implantation across 14 referral centers. Data collection spanned from January 1, 2017 to March 1, 2024. Each surgeon contributed patients who underwent IPP implantation with CHG used as an irrigant and/or dip as well as an equal number of consecutive control patients without CHG use. The primary outcome was IPP explant for postoperative infection. Univariable analysis was used to compare patient demographics, and logistic regression analysis was performed to assess factors associated with infection. Results Hydrophilic devices were implanted in 2,150 patients. Median follow-up for non-CHG patients was 13 months (IQR 18) and four months (IQR 9) for CHG patients. The incidence of infection with intraoperative CHG use was significantly higher compared to those without CHG use (4.6%, 46/1,001 vs. 2.1%, 24/1,148, p&lt;0.001). On multivariable logistic regression analysis, intraoperative CHG use was associated with infection (OR 2.07, 95% CI 1.24-3.47, p=0.01). Additional variables associated with infection included immunosuppression, prior IPP infection, prior priapism, and revision surgery (p&lt;0.01, Table). On subgroup analyses, the increased infection risk of CHG was most clear when CHG was used as both irrigation and dip (OR 2.03, 95% CI 1.19-3.46, p=0.01) and when CHG was used during revision surgery (OR 3.36, 95% CI 1.15-9.82, p=0.03). Conclusions In a large multi-institutional cohort, intraoperative CHG use was associated with an elevated incidence of hydrophilic IPP infection. Providers may take these findings into consideration when performing IPP surgery with hydrophilic devices, especially during revision surgery. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Intuitive Surgical, Fidelis, Urofill, Boston Scientific, Coloplast, Cynosure, Antares Pharma, Clarus Pharmaceuticals, Acerus Pharma; Endo Pharma

TPS8124 Background: Immune checkpoint inhibitor (ICI)–based regimens are standard first-line therapy for metastatic non–small-cell lung cancer (NSCLC) without actionable driver mutations; however, most patients experience disease progression within 12 months. A subset develop oligoprogression, defined by progression at a limited number of metastatic sites with otherwise controlled disease. Oligoprogression represents a therapeutic window in which local ablative therapy could be used to prolong disease control. In the prior phase II CURB trial, SBRT was shown to significantly prolong progression-free survival (PFS) in patients with oligoprogressive NSCLC. Methods: CCTG-BR38 is an international, multicenter, open-label, randomized phase III trial conducted through the NCI National Clinical Trials Network. Adults with stage IV NSCLC receiving first-line ICI ± chemotherapy who develop ≤5 extracranial oligoprogressive lesions are randomized 1:1 to: (1) switch to second-line standard systemic therapy or (2) SBRT (30 Gy in 3 fractions) to all oligoprogressive sites followed by continuation of the same first-line systemic therapy. Randomization is stratified by type of first-line systemic therapy (ICI alone vs ICI + chemotherapy), number of oligoprogressive lesions (1–2 vs 3–5), and ECOG performance status (0-1 vs 2). Patients with treated, stable brain metastases are eligible. Primary Endpoints: Dual primary endpoints are PFS and overall survival (OS). Secondary endpoints include safety (CTCAE v5.0), patient-reported adverse events (PRO-CTCAE), quality of life (EORTC QLQ-C30/LC13), and cost-effectiveness (EQ-5D-5L; Canadian sites). Optional blood and tissue collection for exploratory biomarker analyses are planned. Statistical Considerations: A total of 320 patients (160 per arm) will be enrolled. The sample size is based on detecting a HR of 0.7 for OS (an improvement in median OS from 10 to 14.3 months) with 80% power using a 1-sided 2% level test (the overall 1-sided 2.5% type I error will be assigned 2% to OS and 0.5% to PFS). Interim analyses for futility and efficacy are planned. Current Status: The trial was centrally activated on April 3, 2025. Accrual is ongoing across Canadian and US NCTN sites. Clinical trial information: NCT06686771 .

Abstract Cholesterol has long been viewed as a structural component of cellular membranes, yet its role in DNA damage response remains poorly defined. Here, we show that ionizing radiation (IR) induces broad transcriptional upregulation of cholesterol biosynthesis, transport, and storage pathways, leading to sustained intracellular accumulation of cholesterol. BODIPY-cholesterol imaging, Filipin III staining, and quantitative subcellular fractionation confirmed selective nuclear enrichment of cholesterol following IR, coinciding with extensive chromatin remodeling. Proteomic profiling of cholesterol-interacting proteins revealed a strong enrichment of chromatin-associated factors, suggesting a previously unrecognized lipid-chromatin interface in irradiated cells. Functionally, cholesterol accumulation promoted chromatin compaction and repressive histone modification patterns, impairing DNA damage sensing and checkpoint activation despite increased underlying DNA lesions. These alterations facilitated aberrant mitotic entry, formation of cytoplasmic chromatin fragments (CCFs), and activation of cGAS-STING-NF-κB signaling. Cholesterol exposure ultimately diverted damaged cells toward a senescent fate, marked by Lamin B1 loss, p21 induction, and a robust senescence-associated secretory phenotype (SASP) enriched for IL-1 and TNF family cytokines. In vivo, dietary cholesterol exacerbated radiation-induced inflammation and weakened systemic anti-tumor immunity. Transcriptomic analyses of immunotherapy-treated patients revealed that tumors enriched for cholesterol import and senescence signatures were associated with poor response to PD-L1 blockade and worse survival. Together, these findings identify a cholesterol-chromatin-senescence axis that links metabolic remodeling to defective DNA damage signaling and immune suppression after radiation, highlighting cholesterol metabolism as a potential therapeutic vulnerability in cancer therapy. Citation Format: Yiqun Han, Yaobin Ouyang, Shouhai Zhu, Hangcheng Xu, Bin Chen, Ping Yin, Qin Zhou, Jinzhou Huang, Kuntian Luo, Zheming Wu, Huaping Xiao, Xinyi Tu, Jake A. Kloeber, Jiajun Jing, Xiaofeng Huang, Meng Xu Welliver, Zhenkun Lou, Robert Mutter. Cholesterol triggers chromatin stress to drive senescence and inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 539.

Abstract Background 0.05% Chlorhexidine gluconate (CHG) is now commonly used as an antiseptic irrigation for inflatable penile prosthesis (IPP) surgery. Limited in vitro data suggest compatibility of 0.05% CHG with antibiotic impregnated IPP devices; however, very little clinical research exists to guide use of 0.05% CHG in this population. Aim Assess the relationship of 0.05% CHG and antibiotic impregnated IPP infection in a large multi-institutional cohort. Methods We retrospectively reviewed a multi-institutional cohort of patients who underwent antibiotic impregnated IPP implantation. We identified cases using intraoperative 0.05% CHG and an equal number of consecutive control cases without 0.05% CHG use from each center for comparison. The primary outcome was IPP infection requiring explantation. Patient demographics and surgical variables were analyzed using chi-square tests and multivariable logistic regression to identify variables associated with infection. Outcomes The primary outcome was IPP infection requiring device explanation. Results Among 14 participating institutions, 761 cases using an antibiotic impregnated IPP were analyzed. Of these, 348 (45.7%) had 0.05% CHG used during the case. Median follow-up was 4 months (interquartile range 1-12) for the 0.05% CHG group and 8 months (interquartile range 2-21) for the control group. Intraoperative 0.05% CHG utilization was not associated with antibiotic impregnated IPP infection rate (1.9% vs. 2.0%, P = .9). On multivariable analysis, prior IPP infection (OR 6.32, 95% CI 1.32-30.2, P = .021) and prior priapism (OR 10.01, 95% CI 1.18-89.7, P = .039) were associated with increased infection risk. Clinical implications The use of 0.05% CHG irrigation with antibiotic impregnated IPPs was associated with similar infection rates compared to antibiotic irrigation. Strengths and limitations Limitations include the use of a historical comparator cohort which may introduce unknown confounders, practice variation between multiple sites, shorter follow-up in the 0.05% CHG cohort, and the low incidence of IPP infection which may limit statistical power despite a large sample. The major strengths include the large, multi-institutional cohort, and the use of consecutive patients to minimize selection bias. Conclusion 0.05% CHG utilization was not associated with infection rates in antibiotic impregnated IPPs.

Abstract Introduction 0.05% Chlorhexidine Gluconate (CHG) has gained popularity as an irrigant for inflatable penile prosthesis (IPP). In vitro data has explored interactions between CHG and minocycline/rifampin impregnated (M/R) IPP surfaces Objective We aimed to assess clinical infection rates between intraoperative CHG use and M/R impregnated IPPs in a large multi-institutional cohort. Methods We conducted a retrospective analysis of 1,604 patients who underwent IPP implantation across 12 referral centers. Data collection spanned from January 1, 2017 to March 1, 2024. Each surgeon contributed patients who underwent IPP implantation with the use of CHG as an irrigant and an equal number of consecutive control patients where CHG was not used. The primary outcome was explant for postoperative infection. Patient demographics were compared using chi squared testing and logistic regression analysis was performed to assess factors associated with infection. Results M/R impregnated devices accounted for 695 cases. The incidence of infection with intraoperative CHG use was 1.7% (5/289) and was not significantly different from the 2.5% (10/406) infection rate in those without CHG (p=0.429). Patients with infection had a higher prevalence of hypertension and history of priapism (Table 1). On logistic regression analysis, only a history of priapism was significantly associated with an increased odds of infection (OR 11.47, 95%CI 2.25-58.40, p=0.003). Intraoperative CHG use was not associated with postoperative infection (OR 0.69, 95%CI 0.2-2.06. p=0.514). Conclusions In a large multi-institutional cohort, there was no difference in infection rate for patients with or without intraoperative CHG use, consistent with prior in vitro findings. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Intuitive Surgical, Fidelis, Urofill, Boston Scientific, Coloplast, Cynosure, Antares Pharma, Clarus Pharmaceuticals, Acerus Pharma; Endo Pharma.