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Abstract Introduction With the growing use of 0.05% Chlorhexidine Gluconate (CHG) as irrigation and dip for inflatable penile prosthesis (IPP) surgery, understanding the possible relationship between CHG use and non-infectious complications is imperative. Such information may guide provider decision-making during implant surgery. Objective We therefore sought to determine whether the use of 0.05% Chlorhexidine Gluconate (CHG) during inflatable penile prosthesis (IPP) surgery was associated with non-infectious wound complications. Methods We performed a multi-institutional retrospective cohort study of patients undergoing IPP surgery from January 2017 to March 2024. The primary outcome was wound complications (ex. rash, wound dehiscence, edema). Secondary outcomes included other non-infectious complications (Table 1). The primary exposure was whether patients received intraoperative CHG either as irrigation or dip. Descriptive comparisons were used to compare CHG and non-CHG cohorts. Univariable logistic regression was utilized to assess if CHG use was associated with any non-infectious complication. Multivariable logistic regression was subsequently performed to assess factors associated with certain non-infectious complications after IPP surgery – controlling for age, body mass index, race, diabetes, and hypertension as covariables. Results Across 2,933 patients, there were 1,573 non-CHG and 1,359 CHG patients. Non-infectious complications occurred in 83 (5%) non-CHG patients and in 65 (5%) CHG patients. Median follow-up was 22 months (IQR 7-59) for non-CHG patients and 8 months (IQR 3-16) for CHG patients. The incidence of wound complications was greater among CHG patients than non-CHG patients (1.0% vs. 0.1%, p<0.01). On univariable logistic regression, CHG use was associated with increased odds of wound complications (OR 7.34, 95% CI 1.65-32.71) but was not associated with any other non-infectious complication (Table 2). On multivariable logistic regression, CHG use remained associated with an increased odds of wound complications (OR 13.86, 95% CI 1.80-106.44). Conclusions Among patients experiencing non-infectious complications after IPP, CHG use during IPP surgery appears to be associated with an increased odds of wound complications. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Coloplast Corporation and Boston Scientific

Abstract Introduction: Patients (pts) with soft tissue plasmacytomas noncontiguous with bone (true extramedullary disease [EMD]) have poor outcomes with standard therapies shown by low overall response rates (ORRs), which are not durable. Talquetamab (Tal; anti-GPRC5D×CD3) and teclistamab (Tec; anti-BCMA×CD3) are first-in-class bispecific antibodies (BsAbs) approved as monotherapies for triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM). Primary analysis from the RedirecTT-1 (NCT04586426) dedicated phase 2 EMD cohort (March 2025 data cut; median follow-up [mFU] 12.6 mo) showed Tal + Tec elicited an ORR of 78.9% (assessed by independent review committee) and a 12-mo progression-free survival (PFS) of 61.0%. Here, we report updated efficacy, using investigator assessment, and safety results from the phase 2 RedirecTT-1 EMD cohort with Tal + Tec. Importantly, we report EMD location and a novel analysis of tumor burden as a prognostic indicator of ORR. Methods: Pts had TCE RRMM and true EMD defined as ≥1 nonradiated soft tissue plasmacytoma noncontiguous with bone ≥2 cm in 1 dimension (with or without paramedullary plasmacytomas). Nonsecretory/oligosecretory disease was permitted. Prior CAR-T and non-BCMA/-GPRC5D BsAb therapies were permitted. Pts received Tal 0.8 mg/kg + Tec 3.0 mg/kg Q2W, preceded by step-up doses, with a permitted switch to monthly dosing at investigator's discretion after cycle 6 or after cycle 4 with confirmed ≥VGPR. Response was assessed per IMWG; EMD response was assessed by PET-CT or MRI whole-body scans. Tumor burden was assessed by total EMD tumor volume. Results: As of July 2025, 90 pts received Tal + Tec, with a median follow-up of 16.3 mo (range 0.5–23.7). Baseline characteristics were as previously reported; 39% had nonsecretory/oligosecretory disease, 20% had prior anti-BCMA CAR-T therapy, and 9% had prior BsAb therapy (all anti-FcRH5). The median number of plasmacytomas was 2 (range 1–7); 17 (18.9%), 29 (32.2%), and 74 (82.2%) pts, respectively, had ≥1 nodal, organ, or soft tissue EMD, while 11 (12.2%) also had ≥1 additional paramedullary plasmacytoma. Of 268 EMDs across all pts, 95 (35.4%) were nodal EMD, 77 (28.7%) were organ EMD (most commonly liver), and 64 (23.9%) were soft tissue EMD; 32 (11.9%) were paramedullary. Baseline EMD tumor volume was <25 cm2in 43 (47.8%) pts, 25–50 cm2 in 21 (23.3%) pts, and >50 cm2 in 26 (28.9%) pts. Per investigator assessment, ORR (95% CI) was 77.8% (67.8–85.9); 50.0% had a ≥CR. Median duration of response (DOR) was not estimable (NE; 12-mo DOR rate, 60.1%), 12-mo PFS was 55.6%, and median overall survival (OS) was NE (12-mo OS rate 73.8%). ORR was 90.7% (77.9–97.4; ≥CR 60.5%) in pts with EMD tumor volume <25 cm2, 66.7% (43.0–85.4; ≥CR 52.4%) for 25–50 cm2, and 65.4% (44.3–82.8; ≥CR 30.8%) for >50 cm2. Common adverse events (AEs) included CRS (77.8%; no grade [gr] 3/4) and neutropenia (72.2%; gr 3/4 62.2%). Taste changes (78.9%), non-rash skin AEs (68.9%), and nail AEs (55.6%) were all gr 1/2, and rash AEs (30.0%) were mostly gr 1/2. ICANS occurred in 11 (12.2%) pts (gr 3, 1.1%; gr 4, 1.1%). Infections occurred in 72 (80.0%) pts (gr 3/4 40.0%), most commonly upper respiratory tract infection (26.7%; gr 3/4 5.6%); IVIG was highly recommended to prevent and manage hypogammaglobulinemia and infection. Ten (11.1%) pts discontinued Tal + Tec due to treatment-emergent AEs (4 pts due to infections and 6 due to gr 5 AEs). Two pts discontinued Tal only due to AEs. In total, 11 (12.2%) pts had gr 5 AEs (6 due to infections), 6 of which were deemed to be drug related by investigators. Data will be updated with an additional 4 mo of follow-up for the presentation. Conclusions: With longer follow-up in pts with TCE RRMM with true EMD regardless of baseline tumor characteristics, Tal + Tec efficacy exceeded all approved therapies, including T-cell redirecting and cellular therapies, noting limitations of cross-study comparisons. Lower total EMD tumor volume was associated with a higher ORR but low pt numbers in each group and lack of statistical testing limits robust interpretation. The safety profile of Tal + Tec was generally consistent with each monotherapy; AEs were not exacerbated with the combination. These data continue to highlight the clinical benefit of the novel combination of Tal + Tec in pts with true EMD, a population with high disease burden and significant unmet need.

Abstract Introduction: Teclistamab is the first FDA approved BCMA-directed bispecific antibody for the treatment of relapsed and refractory multiple myeloma (RRMM). With BCMA-targeting CAR-T therapies, cytokine release syndrome (CRS) is a risk factor for cardiotoxicity. Teclistamab was associated with fatal cardiovascular adverse events (CVAEs) in a recent US pharmacovigilance database analysis, but this analysis was limited by reporting bias. Therefore, the aim of our study is to conduct a multicenter study to define the real-world incidence of CVAEs in RRMM patients treated with teclistamab. Method We performed a retrospective multi-center cohort study of patients receiving teclistamab at 5 medical centers. Baseline oncologic and cardiovascular characteristics (including vital sign and echocardiographic data) were collected. Baseline cardiovascular disease (CVD) was defined as presence of coronary artery disease, congestive heart failure, severe or symptomatic valvular heart disease, or stroke at baseline. CVAE was collected and categorized based on CTCAE v5.0 by each institution. Major adverse cardiovascular event (MACE) was a composite outcome with any of the following: congestive heart failure, asymptomatic cardiomyopathy (interval LVEF drop >10% to resultant LVEF less than 50%), coronary artery disease requiring intervention, stroke or cardiovascular death. Arrhythmia was a composite outcome with any of the following: atrial tachyarrhythmia, ventricular tachyarrhythmia or bradyarrhythmia. Median follow-up was calculated through reverse Kaplan-Meier method. Multivariable Cox regression analysis was used to define the relation between MACE and survival. Cause of death was categorized as myeloma-related death or non-myeloma-related deaths (i.e. CRS, infection or cardiovascular death). Cause-specific Cox regression was performed to define relationship between MACE and cause of death. Results In a cohort of 219 patients treated with teclistamab with median follow-up of 20.1 months, 7.3% (N=16) developed MACE, 7.3% (N=16) developed arrhythmia and 12.8% (N=28) developing any MACE or arrhythmia. MACE occurred at a median of 4.5 days (IQR 2.25-15.75 days) after teclistamab step-up. The incidence of MACE was 16.4% in patients with baseline CVD versus 2.7% in those without baseline CVD (p<0.001). Patients who developed MACE had inferior ECOG performance status (PS) (PS >=2: 62.5% vs. 27.7%; p=0.008). Additionally, baseline hemoglobin level (9 vs 10g/dL; p=0.072) was numerically lower in MACE, compared to no MACE. There was no difference in age, sex, bone marrow (BM) plasma cell burden, ferritin, C-reactive protein or LDH levels between MACE vs. no MACE group. Patients who developed MACE had lower baseline diastolic blood pressure (67.7 vs 73.8mmHg; p=0.041) and numerically lower LVEF (51.4 vs 59.3%; p=0.059; baseline echocardiogram performed in 86% of all cohort). Patients who developed MACE had similar incidences of CRS (Grade >=2: 25.0 vs 16.7%; p=0.620) and immune effector cell-associated neurotoxicity (ICANS) grade 2 or higher (12.5 vs 7.5%; p=0.812). In multivariable Cox regression analysis, MACE was independently associated with inferior overall survival (HR 2.72; 95% CI 1.41-5.25; p=0.003), after adjusting for baseline CVD, age, high BM burden, extramedullary disease, and plasma cell leukemia. In cause-specific multivariable Cox regression analysis, MACE was independently associated with non-myeloma-related death (HR: 10.77 95% CI 4.39- 26.41; p<0.001) but not with myeloma-related death (1.54; 95% CI 0.64- 3.70; p=0.336). Conclusion In conclusion, in this large, real-world multicenter study, we observed that MACE occurred in over 7% of patients following teclistamab for RRMM, typically within 2 weeks of initiation. MACE was significantly associated with increased non-myeloma-related mortality. In contrast to CAR-T therapy, CRS or ICANS were not associated with MACE, whereas majority of patients who developed MACE had ECOG PS >=2 or baseline cardiovascular disease. More studies are necessary to define mechanisms and strategies to reduce these MACE and improve survival. Patients with baseline cardiovascular disease or poor performance status may benefit from cardiovascular optimization before and during teclistamab therapy.

Objective Mycophenolate mofetil (MMF) can stabilize or improve lung function in systemic sclerosis–related interstitial lung disease (SSc‐ILD). We hypothesized that combining MMF with pirfenidone (PFD) would produce a significantly more rapid and/or greater improvement in lung function. Methods A randomized (1:1), double‐blind, placebo (PLA)‐controlled phase 2 trial was conducted in SSc‐ILD in which patients received PFD or PLA (801 mg three times daily) along with MMF (1,500 mg twice daily) for 18 months. The primary outcome was change in percent predicted forced vital capacity (FVC‐%). Linear mixed‐effects models assessed treatment differences in a modified intention‐to‐treat population. Results Only fifty‐one of 150 intended subjects (34%) were randomized (MMF+PLA, n = 24; MMF+PFD, n = 27). The FVC‐% improved from baseline to 18 months by 2.24 ± 1.35 (least‐squares mean [LSM] ± SEM) in the MMF+PLA group and 2.09 ± 1.28 in the MMF+PFD group (LSM treatment difference −0.14; P = 0.93). Median time to achieve a ≥3% improvement in FVC‐% was numerically faster in the MMF+PFD versus MMF+PLA group (12.3 vs 17.8 months, respectively), but the difference was not significant ( P = 0.33). For secondary outcomes, only the change over 18 months in the Patient‐Reported Outcomes Measurement Information System 29‐item physical function score, favoring MMF+PFD, reached statistical significance ( P = 0.04). Although other related patient‐reported outcomes (PROs) numerically favored the MMF+PFD group, as did quantitative high‐resolution computed tomography measures of ILD, the differences between groups did not reach statistical significance. Early withdrawals from study medication and adverse events of special interest were numerically greater with MMF+PFD (n = 8 vs 2 and n = 20 vs 7, respectively). Conclusion In this underpowered study, there was no statistically significant treatment difference in overall change in FVC‐% between groups. MMF+PFD was not as well tolerated as MMF+PLA.

Src homology 2-domain containing protein tyrosine phosphatase 2 (SHP2), encoded by the Ptpn11 gene (Tyrosine-protein phosphatase non-receptor type 11), is a key downstream effector of PD-1/PD-L1 signaling and is likely important, in addition to immune modulation, in tumor development and vascular homeostasis. SHP2 conveys PD-1 mediated inhibitory signaling in T cells, and is emerging as a therapeutic target. Importantly, there is an association between immune checkpoint inhibitors (ICIs), immune-related adverse events (irAEs), and cardiovascular complications, underscoring the need to understand SHP2’s role in these processes. This review aims to summarize current knowledge on SHP2/PTPN11 biology, its role in immune regulation, cancer progression, and vascular homeostasis, and to discuss emerging therapeutic strategies targeting this pathway. The concept of using SHP2 inhibitors with immune checkpoint inhibitors (ICIs) is being investigated to address ICI resistance and to improve anti-tumor efficacy substantially. SHP2 is also being studied in non-cancer cell contexts, and signaling responses can differ by large magnitudes depending on the biological context and stimuli. Under normal circumstances, SHP2 promotes vascular homeostasis in endothelial cells (ECs) and myeloid cells and inhibits inflammation, and the reduction in SHP2 activity by oxidative stress, such as in atherosclerosis or diabetes, upregulates inflammation. In contrast, in response to radiation, the fibrotic response and subsequent lung injury were increased by endothelial SHP2 induction via Notch-Jag1 signaling. Vascular smooth muscle cells SHP2 act as a pro-atherogenic effector by enhancing ERK/MAPK signaling, and the upregulation of mitochondria localized SHP2 can also induce cellular senescence-associated inflammation by upregulating mitochondrial reactive oxygen species. Taken together, the two opposite signaling effects of SHP2 suggest that both the immune and vascular system responses appear to be more modulated by the redox, cell, and compartment-specific signaling of SHP2. More studies are needed for mitigating cardiovascular toxicity to patients, particularly with ICI-based treatment regimens.

Importance The introduction of immune checkpoint inhibitor (ICI) therapy has improved cancer outcomes but at the cost of adverse events, mainly related to the immune system. Cardiovascular (CV) toxic effects, and especially myocarditis, are of particular concern and are the subject of this position statement by the International Cardio-Oncology Society with representation of experts from oncology, hematology, and cardiology. Observations CV toxic effects of ICI therapies include inflammation-associated diseases, such as myocarditis, pericarditis, and vasculitis, as well as the aggravation of chronic inflammatory conditions, such as atherosclerosis with acute ischemic complications (myocardial infarction and stroke). Patients taking ICI therapies can also develop cardiac dysfunction, stress-induced cardiomyopathy (Takotsubo or apical ballooning syndrome), and heart failure without inflammatory cell infiltration of the myocardium. Atrial and ventricular arrhythmias can emerge in the setting of a systemic inflammatory milieu, myocarditis, or ischemia. Of all potential CV adverse effects, myocarditis remains of highest concern, although fatality rates have declined over time with a broadening spectrum of presentations ranging from troponin elevation of uncertain significance to smoldering, nonsevere, and severe or fulminant myocarditis. Conclusions and Relevance Concerns for myocarditis continue to dominate the spectrum of CV toxic effects in patients receiving ICI therapy. Recommendations for management vary according to severity. Multidisciplinary collaborations remain key for managing acute toxic effects and future cancer treatment decisions, including ICI rechallenge. Ischemic heart disease constitutes the main differential diagnosis in these patients, while pericarditis can be concomitantly present, and atrial and ventricular arrhythmias can also complicate the clinical picture. Several gaps in knowledge are identified and require further research.

Malignant glioma is considered invariably recalcitrant, thus necessitating development of new therapeutic approaches. Spontaneously arising canine glioma exhibits important molecular and pathological similarities to malignant pediatric glioma, making it an invaluable model for testing novel therapies. We evaluated safety and activity of RNA lipid particle aggregates (LPAs) designed to provoke cancer immunogenicity in 10 dogs with histologically confirmed glioma. Vaccine manufacturing was feasible in all subjects and generally well tolerated. Median survival time was 123 and 155 days in dogs receiving three (Group A) or four (Group B) vaccines, respectively; this was increased from historical reporting of subjects receiving palliative care. Responding animals had a robust cytokine response following infusions. In animals receiving non-specific RNA-LPAs, there was localization of messenger RNA (mRNA) payloads to the brain tumor microenvironment and a rapid shift in immunologic gene signatures consistent with a viral response. These data demonstrate the ability to induce rapid viremic response in the tumor microenvironment following a single peripherally administered mRNA vaccine. Since RNA-LPAs are amenable to repeat boosts, these formulations may overcome challenges of tumor immunosuppression and therapeutic access and are currently under evaluation in first-in-human trials ( NCT04573140 , NCT06389591 ).

Importance Primary brain and central nervous system cancer (collectively referred to as CNS cancer) comprises 2% of all human cancers and poses significant health and economic challenges in the United States. Objective To analyze CNS cancer burden in the US, stratified by time, location (state and division), sex, age group, and Sociodemographic Index (SDI). Design, Setting, and Participants This cross-sectional study involved a repeated analysis of Global Burden of Disease Study (GBD) 2021 data in 2024. Using data from 183 sources, CNS cancer metrics in the US were estimated across states and years. US CNS cancer metrics across all sexes and age groups were included in the GBD. Exposure CNS cancer diagnosis. Main Outcomes and Measures Overall and age-standardized estimates of the incidence, prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost, and years lived with disability per 100 000 population, including 95% uncertainty intervals (UIs), and time trends. Results In 2021, for all age groups and sexes across the US, there were 31 780 incident cases (95% UI, 29971.1 to 32843.9). Age-standardized incidence, DALYs, and mortality rates per 100 000 population were 6.91 (95% UI, 6.58 to 7.12), 134.38 (95% UI, 129.83 to 137.95), and 4.1 (95% UI, 3.87 to 4.22), respectively. Despite no significant change observed in the overall incidence between 1990 and 2021, DALY and mortality rates decreased by 15.77% (95% UI, −17.75% to −13.68%) and 8.41% (95% UI, −11.09% to −6.22%), respectively. Substantial geographic variability was noted. Mississippi, Alabama, Kentucky, and Kansas (West North Central and East South Central divisions) and West Virginia faced persistently high burdens over the past 30 years. Sex differences were evident; disease burden was consistently higher in males compared with females. Age-specific estimates showed a bimodal distribution: the youngest group (<5 years) showed a significant decrease in incidence rate (−34.42% to −11.56%), whereas older age groups (>70 years) experienced increasing trends. DALYs and mortality rates were negatively correlated with SDI (ρ = −0.6860 and ρ = −0.6391; P < .001). Conclusions and Relevance These findings provide valuable insights into the CNS cancer burden across the US by age, sex, location, and SDI, enabling better public health status assessments, health care policy restructuring, and resource redistribution for improved care.