Citations

Objective: To systematically review studies evaluating systemic medical therapies for sporadic vestibular schwannoma (VS) and perform meta-analyses to assess associations with tumor control. Study design: Systematic review and meta-analysis. Setting: Not applicable. Patients: Sporadic VS patients. Interventions: Systemic medical therapies. Main outcome measures: Tumor growth. Results: Nine retrospective studies met criteria: 5 on nonsteroidal anti-inflammatory drugs (NSAIDs), 3 on metformin, and 1 on losartan (all level 3 evidence). A meta-analysis of ORs from 5 studies demonstrated no significant association between aspirin use and tumor growth (pooled OR: 0.77; 95% CI: 0.48-1.23; I²: 76%). Conversely, a meta-analysis of ORs from 3 studies on metformin showed significantly lower odds of tumor growth (pooled OR: 0.46; 95% CI: 0.30-0.72; I²: 0%). The study on losartan did not identify a statistically significant association of losartan with tumor growth. Less than half of the studies reported HRs to appropriately reflect the inherently time-dependent nature of tumor growth. Conclusions: Evidence for systemic therapies in sporadic VS remains preliminary. Our meta-analysis of ORs demonstrates that NSAID use is not significantly associated with tumor growth, metformin users had lower odds of tumor growth, and evidence for losartan remains limited; however, all available studies provide only level 3 evidence. At present, there is insufficient data to recommend routine use of aspirin, metformin, or losartan with the intent of mitigating VS tumor growth during wait-and-scan management. High-quality prospective studies with appropriate time-to-event methodology to assess tumor growth are required to establish the clinical utility of systemic therapies in the management of patients with sporadic VS.

Hawai‘i and other island communities around the globe are experiencing high exposures to micro- and nanoplastics (MNPs). Widespread use of various types of plastics and the action of wave physics coupled with abundant silica creates a constant production of MNPs. The community health effects of exposure to MNPs are not yet fully understood. The aquatic vertebrate model zebrafish, Danio rerio , was utilized to evaluate the developmental and behavioral effects of nanoplastic (NP) exposure as well as visual confirmation of plastic accumulation after embryonic and larval exposure. Eye and yolk size, heart rate, angle of development, and early larval locomotion behavior were quantified after early NP exposure lasting 3 or 5 days. In this work, a digital laboratory environment is used as the context for research trainees spanning high school to graduate and medical school in Hawai‘i to explore health outcomes of developmental NP exposures. Presence of MNPs in the early developmental environment led to changes in growth and behavior of exposed fish. Data analysis showed significant effects of exposures on changes in the rate of development and yolk consumption on day 2 and reduced body length and increased locomotion on day 6. Nanoplastic exposure also affected overall body length, but this effect was not significant. These data support the potential dangers of MNP exposure and demonstrate their persistent detrimental effects on development and behavior in young zebrafish. Accordingly, our work contributes toward shifting focus toward understanding longer impacts on health, growth, and behaviors and potentially the reduction of harm in developing vertebrates.

Abstract Background Recently, a posterior pathway for fluid drainage from the retina to the meningeal lymphatics in the optic nerve (ON) sheath was identified in rodents using intravitreal imaging tracers directly injected into the ocular-globe. Fluid and solute clearance along this pathway may be associated with many diseases. However, intravitreal tracers are rarely used in clinical imaging. As intravenous Gadolinium-based-contrast-agent (GBCA) can enter the globe via the blood-ocular-barriers, it may provide an alternative approach to image this pathway. Purpose To establish a clinically feasible intravenous GBCA-based MRI approach for tracking fluid and solute transport along the posterior lymphatic pathway in the ocular glymphatic system. Materials&Methods This prospective study was conducted from March 2021 to September 2022 in healthy participants. Dynamic-susceptibility-contrast-in-the-CSF (cDSC) MRI was performed before, immediately and 4 hours after intravenous-GBCA administration to track GBCA distribution in aqueous humor (AH) and cerebrospinal fluid (CSF) in regions-of-interest (ROIs) in the globe (anterior-cavity, vitreous-body), in the intraorbital and extraorbital ON, and in the intracranial CSF space proximal to the ON (chiasmatic-cistern, interpeduncular-cistern). Kruskal–Wallis tests with post-hoc Dunn’s tests were used for group comparisons. Results Sixteen healthy participants (mean age±SD: 51±21 years, 5 men) were recruited. Intravenous-GBCA enhancement was observed in all ROIs immediately after injection. At 4-hour-post-GBCA, the vitreous body showed a trend of smaller enhancement area (55±11% versus 49±11%, P =.14) and lower GBCA-concentration (0.044±0.014 versus 0.028±0.010 mmol/L, P =.07) compared to immediate-post-GBCA. The intraorbital ON showed more widespread enhancement (39±5% versus 59±6%, P =.01) and significantly higher GBCA-concentration (0.023±0.009 versus 0.059±0.015 mmol/L, P <.001) at 4-hour-post-GBCA. Conclusion Dynamic fluid and solute transportation along the posterior lymphatic pathway in the ocular glymphatic system in healthy participants was measured by tracking intravenous-GBCAs entering the globe via the blood-ocular-barriers using cDSC-MRI. Summary Statement Dynamic fluid and solute transportation along the posterior lymphatic pathway in the ocular glymphatic system in healthy participants was measured by tracking intravenous-Gadolinium-based-contrast-agents entering ocular-globe via blood-ocular-barriers using dynamic-susceptibility-contrast-in-the-CSF (cDSC)-MRI. Key Results In this prospective study of sixteen participants, Gadolinium-based-contrast-agent (GBCA)-induced signal changes were detected in the aqueous-humor and cerebrospinal fluid immediately following intravenous administration using dynamic-susceptibility-contrast-in-the-CSF (cDSC)-MRI. At 4-hour-post-GBCA, the vitreous-body showed a trend of smaller enhancement area (55±11% versus 49±11%, P =.14) and lower GBCA-concentration (0.044±0.014 versus 0.028±0.010 mmol/L, P =.07) compared to immediate-post-GBCA. The intraorbital-optic-nerve showed more widespread enhancement (39±5% versus 59±6%, P =.01) and higher GBCA-concentration (0.023±0.009 versus 0.059±0.015 mmol/L, P <.001) at 4-hour-post-GBCA.

Background. Donor-derived cell-free DNA (dd-cfDNA) has emerged as a promising noninvasive biomarker for detecting allograft rejection in solid organ transplantation. However, its diagnostic utility in pancreas transplantation, including in multiorgan recipients, remains underexplored. Methods. We conducted a retrospective analysis of 42 pancreas transplant recipients (38 simultaneous pancreas-kidney, 4 pancreas transplant alone) who underwent for-cause organ biopsy and dd-cfDNA testing between April 2020 and December 2024. dd-cfDNA was measured using the Prospera assay, with a threshold of ≥1% considered high risk and <1% low-risk. Biopsy results were correlated with dd-cfDNA to assess test performance. Results. A total of 50 dd-cfDNA tests and 45 organ biopsies were analyzed. Among simultaneous pancreas-kidney recipients, dd-cfDNA demonstrated a sensitivity of 86.7%, specificity of 52.2%, positive predictive value (PPV) of 54.2%, and negative predictive value (NPV) of 85.7% for rejection. In pancreas transplant alone recipients, all high-risk dd-cfDNA results corresponded to biopsy-proven rejection, yielding 100% sensitivity, specificity, PPV, and NPV. When combining both cohorts, dd-cfDNA testing achieved an overall sensitivity of 88.2%, specificity of 57.7%, PPV of 57.7%, and NPV of 88.2%. Additionally, dd-cfDNA kinetics suggested its potential utility as a surveillance tool posttreatment, potentially reducing the need for closure biopsies. Conclusions. dd-cfDNA is a valuable noninvasive adjunct for monitoring of rejection in pancreas transplant recipients. Further prospective studies are needed to validate these findings and define the optimal role of dd-cfDNA in posttransplant care.

Abstract Background Spinal cord injury (SCI) induces complex secondary pathophysiological cascades, including microvascular disruption, glial activation, and chronic neuroinflammation. These vascular changes are dynamic and spatially heterogeneous across acute, subacute, and chronic phases. However, limitations in in vivo imaging resolution have impeded precise, longitudinal evaluation of spinal microcirculation. Objective To quantify post-SCI alterations in spinal cord vessel density, flow speed, and morphology over time using ultrasound localization microscopy (ULM), and to correlate these changes with chronic astrocytic reactivity assessed by GFAP expression. Methods Eleven Sprague-Dawley rats underwent T9–T11 laminectomy; nine received a standardized 200 kdyn contusion using the Infinite Horizons Impactor and were assigned to acute (24h), subacute (7d), and chronic (21d) groups (n = 3/group), while two served as uninjured controls. ULM was performed using a Vevo 3100 high-frequency ultrasound system with a 40 MHz transducer following intravenous Definity® microbubble injection. Vessel density (VD) and flow speed (FS) were quantified at the lesion epicenter and adjacent rostral/caudal regions. Arterial and venous compartments were distinguished by flow direction. Histological sections were stained for glial fibrillary acidic protein (GFAP), and %Area was quantified across phases. One-way ANOVA and Tukey’s test evaluated between-group differences; Pearson correlation identified phase-specific relationships between vascular metrics and chronic GFAP expression. Results ULM provided super-resolved imaging of spinal microvasculature at 5–10 µm resolution. Venous VD significantly declined from 0.92 ± 0.18 (acute) to 0.42 ± 0.23 (subacute) and 0.11 ± 0.07 (chronic, p < 0.001), particularly in dorsal regions. Arterial VD remained stable across timepoints (p > 0.05), while FS demonstrated transient reductions in both arterial and venous systems during the subacute phase. Chronic venous FS partially recovered by Day 21. GFAP-positive area increased significantly in the chronic group (3.3 ± 0.87%) compared to acute (1.52 ± 0.42%) and subacute (1.40 ± 0.05%) (p < 0.05), indicating delayed astrocyte reactivity. Correlation analysis revealed significant inverse associations between chronic GFAP %Area and early ventral venous density (r = − 1.0, p < 0.05), as well as positive correlations with chronic ventral arterial FS (r = 1.0, p < 0.01), suggesting early microvascular deficits may predict long-term gliosis. Conclusion This study demonstrates the feasibility and power of ULM to quantify dynamic microvascular remodeling in SCI with unprecedented resolution. Venous rarefaction precedes chronic astrocytosis, while arterial flow speed partially recovers over time. These findings highlight key spatiotemporal biomarkers of injury progression and support the use of ULM as a noninvasive platform for monitoring SCI pathophysiology and guiding therapeutic timing.

Abstract Introduction Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide dual receptor agonists (GLP-1/GIP RAs) have transformed the management of obesity and type 2 diabetes, both of which are prevalent in women of reproductive age and are closely linked to fertility concerns and adverse pregnancy outcomes [1,2]. Beyond their metabolic effects, emerging evidence suggests GLP-1 RAs and GLP-1/GIP RAs can positively influence ovulatory function, menstrual regularity, and conception, particularly in women with obesity or polycystic ovary syndrome (PCOS). However, the reproductive implications of GLP-1 RA and GLP-1/GIP RA use remain poorly understood [3]. This study seeks to address this critical gap by investigating self-reported changes in sexual activity, menstruation, and fertility among reproductive-aged women using GLP-1 RAs and GLP-1/GIP RAs within an institution. 1. Kong L, Nilsson IAK, Gissler M, Lavebratt C. Associations of Maternal Diabetes and Body Mass Index With Offspring Birth Weight and Prematurity. JAMA Pediatr. Apr 1 2019;173(4):371-378. doi:10.1001/jamapediatrics.2018.5541 2. Drummond RF, Seif KE, Reece EA. Glucagon-like peptide-1 receptor agonist use in pregnancy: a review. Am J Obstet Gynecol. Jan 2025;232(1):17-25. doi:10.1016/j.ajog.2024.08.024 3. Cesta CE, Rotem R, Bateman BT, et al. Safety of GLP-1 Receptor Agonists and Other Second-Line Antidiabetics in Early Pregnancy. JAMA Intern Med. Feb 1 2024;184(2):144-152. doi:10.1001/jamainternmed.2023.6663 Objective The primary objectives of this study are: 1) to explore how GLP-1 RAs and GLP-1/GIP RAs may influence reproductive health, specifically sexual activity, menstrual regularity, fertility and conception; 2) to understand the prevalence and patterns of contraceptive use and failure and clinician counseling among women taking GLP-1 RAs and GLP-1/GIP RAs during their reproductive years; and 3) to assess whether reproductive outcomes differ by specific GLP-1 RA and GLP-1/GIP RAs. Methods This descriptive, cross-sectional survey study will be conducted across multiple sites of a major academic institution. Eligible participants include women aged 18-55 who are currently prescribed a GLP-1 RA or GLP-1/GIP RAs, identify as female, report heterosexual relationships, are English-speaking, and are patient portal users. Exclusion criteria include postmenopausal women, non-English speakers, and those unable to complete the survey independently. Participants will receive an electronic questionnaire through the patient’s portal. The survey will collect demographic information, reproductive health history, menstrual patterns, sexual activity, and contraceptive use. QR code included with link to the survey. Responses will be de-identified and stored for analysis. Descriptive statistics and correlation tests will be used to evaluate associations between GLP-1 RA and GLP-1/GIP RA use and reproductive outcomes. Results Data collection and analysis are ongoing. Preliminary results will describe participant demographics, frequency of self-reported changes in menstruation, fertility, and sexual activity, as well as patterns of contraceptive use and potential failure using GLP-1 RAs and GLP-1/GIP RAs. Conclusions This study will provide insight into the reproductive health experiences of women taking GLP-1 RAs and GLP-1/GIP RAs. By identifying self-reported menstrual, fertility, and sexual health changes, findings may inform future clinical counseling, contraceptive recommendations, reproductive safety guidance, and interdisciplinary research on broader physiological effects of GLP-1 RAs and GLP-1/GIP RAs. Ultimately, this work aims to bridge the current gap between metabolic therapy and women’s health reproductive health outcomes. Disclosure No.

Abstract The B-cell maturation antigen (BCMA)–targeting bispecific T-cell engager pavurutamab (AMG 701) directs the cytotoxic T-cell response toward multiple myeloma (MM) cells. This phase 1/1b, open-label, dose-exploration and dose-expansion study evaluated the safety, tolerability, and efficacy of pavurutamab monotherapy in patients with triple-class relapsed/refractory MM (RRMM). Pavurutamab (5-18 000 μg) was administered IV weekly with step-up dosing in week 1. Overall, 172 patients received at least 1 dose of pavurutamab; 73 received the recommended phase 2 dose (RP2D; 18 000 μg), with 2 different step-up dosing regimens in phase 1b. Twelve patients had dose-limiting toxicities, which included cytokine release syndrome (CRS) and increased transaminases; none of which occurred at the RP2D. The most frequently reported treatment-emergent adverse events included CRS (74.4%), anemia (61.0%), neutropenia (47.1%), and hypophosphatemia (45.3%). Grade ≥3 infections were noted in 60 patients (34.9%). The overall response rate (ORR) was 46.5% among all patients and 65.8% (very good partial response [VGPR] or better, 60.3%) among 73 patients treated at the RP2D. At median follow-up of 17.2 months, median duration of response (DOR) was 36.6 months (95% confidence interval [CI], 22.3 to not estimable). Median progression-free survival (PFS) for all patients was 5.5 months (95% CI, 2.8-10.1) and 16.8 months (95% CI, 5.0 to not estimable) with the RP2D. Pavurutamab exposure generally increased in a dose-proportional manner, with high soluble BCMA levels correlating with lower exposure level. The acceptable safety profile, pharmacokinetics, and preliminary efficacy of pavurutamab supports anti-BCMA T-cell engager therapy in heavily pretreated patients with RRMM. This trial was registered at www.clinicaltrials.gov as NCT03287908.