Citations

Abstract Background African-American (AA) women are less likely to achieve ideal cardiovascular (CV) health compared with women of other racial/ethnic subgroups, primarily due to structural and psychosocial barriers. A potential psychosocial construct relevant to ideal CV health is the superwoman schema (SWS). Purpose We explored whether the SWS was associated with perceived stress, CV risk factors, and overall CV health among AA women. Methods This cross-sectional analysis of the FAITH! Heart Health+ Study was conducted among AA women with high cardiometabolic risk. Pearson correlation evaluated associations between SWS and CV risk factors (e.g., stress, hypertension, diabetes, etc.). The 35-item SWS questionnaire includes five domains. Stress was measured by the 8-item Global Perceived Stress Scale (GPSS). CV health was assessed using the American Heart Association Life’s Simple 7 (LS7) rubric of health behaviors/biometrics. Data acquisition spanned from February to August 2022. Results The 38 women included in the analysis (mean age 54.3 [SD 11.5] years) had a high CV risk factor burden (71.1% hypertension, 76.3% overweight/obesity, 28.9% diabetes, 39.5% hyperlipidemia). Mean GPSS level was 7.7 (SD 5.2), CV health score 6.7 (SD 1.8), and SWS score 60.3 (SD 18.0). Feeling an “obligation to help others” and “obligation to present an image of strength” had strongest correlations with GPSS score among all SWS domains (r = 0.51; p = .002 and r = 0.39; p = .02, respectively). Correlation among the SWS domains and traditional CV risk factors was not statistically significant. Conclusion Our findings suggest that an obligation to help others and to project an image of strength could be contributing to stress among AA women.

TPS5630 Background: Platinum-resistant ovarian cancer (PROC) portends a poor prognosis and, although treatments are available, response rates are low. Previous studies have demonstrated that DNA topoisomerase I (TOP1) inhibitors exhibit clinical activity in PROC. Irinotecan also has a 15-25% response rate in some studies of platinum-resistant epithelial ovarian cancer but does not have FDA approval for this indication. Additional studies in preclinical models suggest that TOP1 poisons are more active if administered at low doses on prolonged schedules. PLX038 is a long-acting prodrug of the potent TOP1 inhibitor SN-38. In PLX038, SN-38 is covalently conjugated to circulating polyethylene glycol and is slowly released at a constant rate to provide the active agent with a long half-life, a low Cmax and very high exposure – important facets for optimal safety and efficacy of this drug. Further, in preclinical studies the nanoparticle prodrug accumulates and is retained in tumors, where it slowly releases the SN-38. Methods: This single arm, phase 2 clinical trial is open at Mayo Clinic in Rochester, MN. The primary endpoint is overall response rate and secondary endpoints include progression-free survival and assessment of tolerability of PLX038. Correlative goals include i) measurement of TOP1-DNA covalent complexes in tumor biopsies and circulating tumor cells to assess successful target engagement; ii) assessment of homologous recombination status and SLFN11 expression for correlation with tumor response rate; and iii) pharmacokinetics of SN-38 and SN-38G as well as their association with GI toxicity. Assessment of gut microbiota and association with GI toxicity profile are also being investigated. Eligible patients include women with platinum resistant high grade serous ovarian, primary peritoneal, and fallopian tube cancer who have received fewer than two prior chemotherapy regimens in the platinum-resistant setting. All patients must have an ECOG performance status of 0, 1, or 2 and adequate bone marrow, renal, and hepatic function. As of January 31, 2024, 12 of planned 37 patients have enrolled. Clinical trial information: NCT05465941 .

OBJECTIVE To compare postprandial glucose excursions following a bolus with inhaled technosphere insulin (TI) or subcutaneous rapid-acting analog (RAA) insulin. RESEARCH DESIGN AND METHODS A meal challenge was completed by 122 adults with type 1 diabetes who were using multiple daily injections (MDI), a nonautomated pump, or automated insulin delivery (AID) and who were randomized to bolus with their usual RAA insulin (n = 61) or TI (n = 61). RESULTS The primary outcome, the treatment group difference in area under the curve for glucose >180 mg/dL over 2 h, was less with TI versus RAA (adjusted difference −12 mg/dL, 95% CI −22 to −2, P = 0.02). With TI, the glucose excursion was smaller (P = 0.01), peak glucose lower (P = 0.01), and time to peak glucose shorter (P = 0.006). Blood glucose <70 mg/dL occurred in one participant in each group. CONCLUSIONS Postmeal glucose excursion was smaller with TI than with RAA insulin in a cohort that included both AID and MDI users.

AbstractPediatric procedure‐related pain management is often incompletely understood, inadequately addressed, and critical in influencing a child's lifelong relationship with the larger healthcare community. We present a comprehensive review of infiltrative anesthetics, including a comparison of their mechanisms of action and relative safety and efficacy data to help guide clinical selection. We also describe the multimodal utilization of adjunct therapies—in series and in parallel—to support the optimization of pediatric periprocedural pain management, enhance the patient experience, and provide alternatives to sedation medication and general anesthesia.

e21554 Background: Pregnancy associated melanoma (PAM) occurs in 1% of female patients with melanoma and affects 1 in 2200 pregnancies. Antepartum evaluation of melanoma must incorporate both maternal and fetal factors, and currently there is lack of standardization. Our study aimed to review the incidence of antepartum melanoma at our institution and highlight patterns in management and treatment during this high-risk scenario. Methods: After IRB approval, the Mayo Clinic electronic medical record was searched with key words “melanoma” and “pregnancy”. 25 patients with melanoma during pregnancy were identified from 1987-2023. 6 patients were excluded as skin changes noted during pregnancy were not formally diagnosed as melanoma until after delivery. Abstracted data included demographic information, disease characteristics, staging (per AJCC guidelines at time of diagnosis), and clinical outcomes. Survival data were calculated. Results: 19 patients were included. Diagnosis occurred at an average maternal age of 30 years (range 24-38 years) and a mean gestational age of 20 weeks (range 6-35 weeks). All patients had a term delivery. 4 patients underwent labor induction at 37 weeks for staging/treatment. 60% of patients had a delay in imaging or treatment attributed to pregnancy, including 1 patient who was upstaged with metastatic disease based on postpartum imaging. 82% of stage I-III patients underwent wide local excision during pregnancy; however, 35% of sentinel lymph node sampling was delayed until postpartum. 3 stage II/III patients received adjuvant therapy (interferon or sargramostim) after delivery. Adjuvant immunotherapy was discussed with 2 patients in the postpartum period but ultimately not given due to the time lapse between surgery and delivery. 1 patient with stage IV disease diagnosed at a gestational age of 20 weeks was evaluated with MRI PET scan then treated with vemurafenib monotherapy during pregnancy. Workup and outcomes were reviewed by stage (Table 1). 7 of 19 patients had subsequent pregnancies, and 1 had recurrence of melanoma during a second pregnancy (stage II followed by stage IV). Due to a low number of censoring events, median progression free survival and overall survival were not reached. Conclusions: Melanoma diagnosed during pregnancy can be safely and effectively staged with sentinel lymph node surgery, MRI imaging (PET-MRI vs standard), and CT imaging with shielding without a need for early induction of labor nor a delay in cancer care. Furthermore, we report a patient with stage IV disease treated with vemurafenib during and immunotherapy after pregnancy, indicating that treating stage IV PAM with systemic therapy is a consideration. [Table: see text]

e13806 Background: Immune checkpoint inhibitor therapy-related (ICI) pneumonitis poses a significant challenge for patients with cancer. It is associated with increased clinical morbidity and mortality, often resulting in prolonged hospital stays and delays and/or discontinuation of cancer-directed treatment. Early detection and prompt treatment of ICI pneumonitis is critical to improve patient outcomes. Therefore, our institution implemented a remote patient monitoring (RPM) program leveraging in-home, electronic health record-integrated technology and virtual centralized nursing to monitor vital signs and patient symptoms in “high-risk” patients treated with immunotherapy. Methods: Patients receiving immunotherapy deemed to be “high-risk” for ICI pneumonitis seen at Mayo Clinic Rochester, Minnesota were offered enrollment in the RPM program beginning in June 2023. High-risk patients included those with pre-existing lung disease (chronic obstructive pulmonary disease, interstitial lung disease); those with a history of resolved ICI pneumonitis being rechallenged with immunotherapy; and those with grade 1 ICI pneumonitis continuing immunotherapy. Eligible patients who agreed to participate in the program were provided a kit consisting of RPM technology and electronic symptom questionnaires. The kit included an armband for continuous vital sign monitoring, a blood pressure monitor, a scale to measure weight, and a pre-connected cellular-enabled tablet for questionnaire answering. RPM data utilized real-time electronic health system integration and predetermined parameters to alert RPM nurses. Pre-specified escalation care pathways were then used to respond and escalate care, as necessary. The primary outcome of this pilot study was to assess the feasibility of implementing an RPM program in this patient population with a secondary outcome to determine the ability to detect ICI pneumonitis before significant clinical symptoms. Results: Sixteen patients were enrolled of whom 5 declined participation (2 due to inconvenience and 3 for unclear reasons) resulting in 11 patients who underwent monitoring. Five patients graduated monitoring without detection of ICI pneumonitis within a 4-month timeframe. Six patients are currently undergoing RPM. 372 alerts occurred of which 8 (2%) were escalated to physician review. These alerts included elevated heart rate in 4, shortness of breath in 3, and elevated blood pressure in 1. One patient was triaged to an emergency department and diagnosed with grade 2 ICI pneumonitis. Conclusions: We show that RPM in patients who are at high-risk for developing ICI pneumonitis can be effectively integrated into a care model and monitor pneumonitis related symptoms. Further studies are needed to prove whether RPM is beneficial in this population including other ICI toxicities.

Abstract Idiopathic pulmonary fibrosis (IPF) is an aggressive and, thus far, incurable disease characterized by aberrant fibroblast-mediated extracellular matrix deposition. Our understanding of the disease etiology is incomplete; however, there is consensus that a reduction-oxidation (redox) imbalance plays a role. In this study, we use the autofluorescent properties of two redox molecules, NAD(P)H and FAD, to quantify changes in their relative abundance in living lung tissue of mice with experimental lung fibrosis and in freshly isolated cells from mouse lungs and humans with IPF. Our results identify cell population–specific intracellular redox changes in the lungs in experimental and human fibrosis. We focus particularly on redox changes within collagen-producing cells, where we identified a bimodal distribution of NAD(P)H concentrations, establishing NAD(P)Hhigh and NAD(P)Hlow subpopulations. NAD(P)Hhigh fibroblasts exhibited elevated profibrotic gene expression and decreased collagenolytic protease activity relative to NAD(P)Hlow fibroblasts. The NAD(P)Hhigh population was present in healthy lungs but expanded with time after bleomycin injury, suggesting a potential role in fibrosis progression. We identified a similar increased abundance of NAD(P)Hhigh cells in freshly dissociated lungs of subjects with IPF relative to control subjects, as well as similar reductions in collagenolytic activity in this cell population. These data highlight the complexity of redox state changes in experimental and human pulmonary fibrosis and the need for selective approaches to restore redox imbalances in the fibrotic lung.

TPS2675 Background: Checkpoint inhibitor therapy is the standard first-line treatment for advanced/recurrent HCC, but there is a significant unmet therapeutic need for patients (pts) who progress after first-line treatment. Adoptive cellular immunotherapy may provide a novel treatment option. Glypican-3 (GPC3), a heparan sulfate proteoglycan, is overexpressed by tumor cells in HCC and virtually absent in healthy tissues, making it an ideal target for CAR-T therapy. AZD5851 is an autologous CAR-T product that expresses a CAR specific for GPC3 and a dominant negative (dn)TGFβRII as an armoring strategy. Expression of dnTGFβRII can block TGFβ signaling, protecting CAR T-cells from the immunosuppressive effects of this cytokine. Early clinical data with C-CAR031, a CAR-T product with the same GPC3-specific CAR and dnTGFβRII-armoring transgene as AZD5851, showed promising tolerability and antitumor activity in pts with HCC [1]. ATHENA (NCT06084884) is a first-in-human, single-arm, open-label, multicenter phase 1/2 study to evaluate the safety, tolerability, and antitumor activity of AZD5851 in pts with GPC3+ advanced/recurrent HCC, for whom ≥1 prior line of standard therapy failed or was not tolerable. Methods: Eligible pts are aged ≥18 years with histologically confirmed advanced/recurrent or metastatic and/or unresectable HCC, GPC3+ tumor sample as determined by immunohistochemistry, ≥1 prior line of standard systemic therapy, ≥1 measurable lesion per RECIST 1.1, Child-Pugh A, ECOG PS 0/1, and adequate organ and bone marrow function. Approximately 24 pts will be enrolled in Part A (Phase I, dose escalation) and 50 in Part B (Phase II dose expansion). Pts will undergo apheresis to collect peripheral blood mononuclear cells for AZD5851 production, after which they may receive approved bridging therapy for disease control. Upon successful generation of AZD5851 product, pts will undergo lymphodepletion before receiving a single dose of IV AZD5851. Subsequent follow-up is divided into 3 stages: Stage 1, active follow-up of all pts through 6 months post AZD5851 infusion; Stage 2, further evaluation of pts who have not progressed or started a new anticancer regimen during Stage 1; Stage 3, long-term follow-up for all pts who have received AZD5851. The primary endpoints are to assess the safety/tolerability of AZD5851 (both study parts), and to determine the recommended dose(s) of AZD5851 for expansion and phase 2 trials (Part A). Secondary endpoints include efficacy (objective response rate, best overall response, duration of response, disease control rate, durable response rate, time to response, progression-free survival, and overall survival) and pharmacokinetics. Exploratory endpoints include pharmacodynamic biomarkers and immunogenicity. Enrollment began Nov 2023. 1. Zhang et al. AACR 2023. Abstract CT097. Clinical trial information: NCT06084884 .

Abstract Background Few antiviral therapies have been studied in patients with coronavirus disease 2019 (COVID-19) and kidney impairment. Herein, the efficacy, safety, and pharmacokinetics of remdesivir, its metabolites, and sulfobutylether-β-cyclodextrin excipient were evaluated in hospitalized patients with COVID-19 and severe kidney impairment. Methods In REDPINE, a phase 3, randomized, double-blind, placebo-controlled study, participants aged ≥12 years hospitalized for COVID-19 pneumonia with acute kidney injury, chronic kidney disease, or kidney failure were randomized 2:1 to receive intravenous remdesivir (200 mg on day 1; 100 mg daily up to day 5) or placebo (enrollment from March 2021 to March 2022). The primary efficacy end point was the composite of the all-cause mortality rate or invasive mechanical ventilation rate through day 29. Safety was evaluated through day 60. Results Although enrollment concluded early, 243 participants were enrolled and treated (remdesivir, n = 163; placebo, n = 80). At baseline, 90 participants (37.0%) had acute kidney injury (remdesivir, n = 60; placebo, n = 30), 64 (26.3%) had chronic kidney disease (remdesivir, n = 44; placebo, n = 20), and 89 (36.6%) had kidney failure (remdesivir, n = 59; placebo, n = 30); and 31 (12.8%) were vaccinated against COVID-19. Composite all-cause mortality or invasive mechanical ventilation rates through day 29 were 29.4% and 32.5% in the remdesivir and placebo group, respectively (P = .61). Treatment-emergent adverse events were reported in 80.4% for remdesivir versus 77.5% for placebo, and serious adverse events in 50.3% versus 50.0%, respectively. Pharmacokinetic plasma exposure to remdesivir was not affected by kidney function. Conclusions Although the study was underpowered, no significant difference in efficacy was observed between treatment groups. REDPINE demonstrated that remdesivir is safe in patients with COVID-19 and severe kidney impairment. Clinical Trials Registration EudraCT 2020-005416-22; Clinical Trials.gov NCT04745351.