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PURPOSE Thrombocytopenia is a relatively common dose-limiting toxicity during peptide receptor radionuclide therapy (PRRT) in patients with NET. Although uncommon, some patients develop persistent cytopenia and eventually therapy-related myeloid neoplasm (t-MN), which has a dismal prognosis. As the indications for PRRT are expanding, it is important to investigate factors that may predict cytopenias during/after PRRT. We prospectively evaluated the prevalence of clonal hematopoiesis (CH) and cytopenia in patients with NET undergoing PRRT. MATERIALS AND METHODS Patients with metastatic NET with plan to receive four cycles of lutetium-177 were enrolled. CH was evaluated before PRRT using a panel of 220 genes with a targeted depth of ≥1,000×. Patients were followed during PRRT and every 3 months thereafter. RESULTS Of 37 patients enrolled, the median age was 68 years and 51.4% were male. Previous treatment exposures included alkylating agents in 30%, platinum agents in 8%, and external radiation in 13%. CH was detected in 35.1% using a variant allele frequency (VAF) cutoff of ≥2% and 45.9% with a VAF of ≥1%. The most common mutations were in age-related genes ( DNMT3A, TET2). CH was not associated with anemia or neutropenia; however, it was associated with lower platelet count at baseline and more time spent in a thrombocytopenic state during/after PRRT. Five patients had bone marrow biopsies (BMBs) because of sustained hematologic dysfunction post-PRRT, and of those, diagnoses included clonal cytopenia of undetermined significance (CCUS) in three and idiopathic cytopenia of undetermined significance (ICUS) in two. CONCLUSION CH is present in 35.1% of patients with NET and is associated with thrombocytopenia risk during PRRT. Future studies with long-term follow-up will delineate whether CH might be a predictor for higher risk of t-MN after PRRT.

TPS4201 Background: Poorly differentiated, extrapulmonary NEC are rare cancers with median overall survival (OS) <1 year. Treatment is extrapolated from small cell lung cancer (SCLC) with use of P (cisplatin or carboplatin) + E. More effective treatment regimens and predictive biomarkers are needed to improve outcomes. In SCLC, induction therapy with combination of P/E + PD-L1 checkpoint inhibitor atezolizumab and maintenance atezolizumab improved OS (12.3 months vs 10.3 months; HR 0.70, 95% CI 0.54 – 0.91, P=0.007) vs P/E alone (1). No study to date has compared PD-1/PD-L1 inhibition during induction only vs during induction and maintenance therapy. In SCLC, distinct molecular subtypes can be identified by the presence of specific transcription factors (e.g., ASCL1, NEUROD1, POU2F3) or an inflamed gene signature (SCLC-I), with SCLC-I pts more likely to benefit clinically from the addition of immunotherapy (2). In this study we plan to test the benefit of adding atezolizumab to induction P/E as well as the role of adding maintenance atezolizumab after induction P/E plus atezolizumab. We also plan to correlate tumor- and blood-based subtype biomarkers with response to therapy. Methods: Eligible pts ≥18 years old have evaluable, histologically confirmed extrapulmonary NEC, Zubrod PS ≤2, and are allowed to have up to 1 cycle of P/E prior to enrollment. P (cisplatin 75 mg/m2 or carboplatin AUC 5, iv) on day 1, E 100 mg/m2 iv on days 1-3, and atezolizumab 1200 mg iv on day 1 of q21 day cycles. Pts are randomized to 1 of 3 arms: A) Induction P/E + atezolizumab -> maintenance atezolizumab B) Induction P/E + atezolizumab -> observation C) Induction P/E -> observation. The primary objective is to compare the overall survival (OS, from randomization) between arms in a fixed sequence: A vs C -> B vs C -> A vs B. Secondary objectives include comparing OS (from start of maintenance/observation), progression free survival, response rate, duration of response, and safety/tolerability across arms. Tumor and blood samples will be banked for future biomarker analyses, including immunohistochemistry of transcription factors on tissue and whole exome sequencing on tumor and circulating tumor DNA. With 189 pts (168 eligible), the study has 84% power to detect an improvement in 12-months OS from 35% to 57.5% (HR 0.53). This study was activated December 2021 with 3 pts enrolled over 1 year due to restricting enrollment of NEC of small cell histology only. The protocol was amended in January 2023 to broaden eligibility to all NEC subtypes (small cell, large cell, and undefined histology with Ki-67 ≥55%). As of January 2024, 35 patients have been enrolled. A protocol amendment is planned to remove the need for Ki-67 index for NEC of genitourinary origin to improve accrual. 1. Horn L, et al. N Engl J Med 2018. 2. Gay CM, et al. Cancer Cell 2021. Clinical trial information: NCT05058651 .

3020 Background: Radioligand therapy (RLT) use has been increasing with the approval of 177Lu-Dotatate for metastatic neuroendocrine tumors (NET) & 177Lu-PSMA-617 for metastatic castration resistant prostate cancer (mCRPC). Therapy-related myeloid neoplasms [tMN, including myelodysplastic syndrome (MDS) & acute myeloid leukemia, (AML)] have been reported after 177Lutetium (177Lu) for NET with rates of 2-20% & median time from first 177Lu to tMN of 2.8yrs [4-12]. Clonal hematopoiesis (CH) is a risk factor for tMN, with the spectrum of CH depending on selection pressures. To describe the prevalence of therapy selected CH & tMN, we performed a retrospective analysis of patients (pts) who had a bone marrow biopsy (BMB) post-177Lu. Methods: After IRB approval, we queried the electronic health record for pts with BMB post-177Lu. Pt demographics, treatment history, labs & BMB results were collected. Results: Fifty-seven pts met criteria, 41 (72%) with NET & 16 (28%) with mCRPC. . Median age at BMB was 68yrs (range, 28-85). Of the 57pts, prior treatments included: radiation (RT) in 21 (37%), temozolomide in 14 (25%), taxane in 15 (26%), & platinum agents in 10 (18%). The median number of 177Lu cycles was 4 (range, 1-11).Cytogenetics were available in 84% (n = 48) & were normal in 60% (n = 29). Of those with abnormal cytogenetics (n = 18, 38%), the most common abnormalities involved chromosome (chr) 7 (n = 12, 26%), chr 5 (n = 7, 15%), chr 20 (n = 5, 11%) and complex karyotypes in 7 (15%), with 3 (17%) of these patients having no mutations. Diagnoses were assessable in 49 (86%) pts: 15 (31%) with undefined cytopeniasand 16 (33%) with tMDS. Metastatic carcinoma was identified in 17 Fifty-one percent (n = 29), at a median of 0.5yrs (range, 0.04-2.6) after hematologic diagnosis. Conclusions: The enrichment of CH involving the DDR pathway in recipients of 177Lu underscores the impact of RLT on bone marrow progenitors.

Abstract Introduction: Historically, children undergoing cardiac catheterization have been managed with general endotracheal anesthesia (GETA). However, recent practice has favored general anesthesia with total intravenous anesthesia (TIVA). This study compares procedural outcomes in the pediatric cardiac catheterization laboratory (PCCL) for children undergoing low-risk cardiac catheterization with GETA vs. TIVA. Methods: We reviewed all patients aged 1–12 years, who underwent outpatient diagnostic or simple interventional catheterization from January 2016 – September 2023. Patients were divided into cohorts by type of anesthesia (GETA vs. TIVA). The primary outcome measure was total patient time in the PCCL (“door-to-door” time). Secondary outcomes were procedure duration (“sheath time”), length of hospital stay, and the major adverse event (MAE) rate. Results: A total of 401 patients were included. Of these patients, 226 underwent GETA and 175 underwent TIVA. There were 148 interventional procedures and 72 patients had single-ventricle physiology. There was no significant difference between the two cohorts in terms of demographic factors such as age, weight, procedure indication and physiological complexity as well as outcomes such as sheath time, hospital stay and MAE. However, the average door-to-door time of the TIVA cohort was 25 minutes shorter than the GETA cohort (p < 0.001). Conclusions: In this single center, retrospective study of anesthesia management for children undergoing low-risk cardiac catheterization, TIVA is associated with significantly shorter door-to-door time in the PCCL without an increase in procedure duration, hospital stay, or rate of complications. These findings have potential clinical significance supporting increased use of TIVA during pediatric cardiac catheterization.

Background: Our institution implemented acute-care obstetric (OB) telemedicine (TeleOB) to address rural disparities across our health system. We sought to determine whether in situ simulations with embedded TeleOB consultation increase participants’ comfort managing OB emergencies and comfort with and likelihood of using TeleOB. Methods: Rural site care teams participated in multidisciplinary in situ OB emergency simulations. Physicians in OB and neonatology at the referral center assisted via telemedicine consultation. Participants were surveyed before and after the simulations and six months later regarding their experience during the simulations. Results: Participants reported increased comfort with TeleOB activation, indications, and workflow processes, as well as increased comfort managing OB emergencies. Participants also reported significantly increased likelihood of using TeleOB in the future. Conclusions: Consistent with previous work, in situ simulation with embedded telemedicine consultations is an effective approach to facilitate telemedicine implementation and promote use by rural clinicians.

4580 Background: ICIs are used for UC in different settings. Most cases have pure urothelial carcinoma (PUC) but about a third have UC mixed with SH. We examined pts with UC treated with ICI and hypothesized that outcomes would not differ between PUC and mixed with SH. Methods: We retrospectively included pts with PUC and any SH component treated with ICI as adjuvant, 1st line [1L] upfront, maintenance avelumab [mAV], ≥2nd line [2+L] therapy; pts were divided by SH type. Pts with multiple SH were included as separate group. We excluded pts with pure non-UC histology and pts treated with neoadjuvant ICI. We calculated overall response rate (ORR), median overall, progression-free and disease-free survival [mOS, mPFS, mDFS] using KM method from ICI start. Analysis was stratified by therapy line; multivariable models were adjusted by Khaki factors for 1L/upfront, mAV and Bellmunt factors for 2+L; reference group was PUC. We used descriptive statistics for small subsets. Results: We included 1525 pts from 26 sites; n=752 1L, n=609 2+L; 76% men, 80% White, 69% smoking history, 80% lower urinary tract primary, 28% SH. Median f/u time from 1L ICI start 24 months (mo): mPFS was 3 (95%CI 2.8-3.2) mo for PUC (n=340), 3 (95%CI 2-4) mo for squamous (n=60) (HR=1, [95%CI 0.7-1.4]), 2 (95%CI 1.4-3.2) mo for micropapillary (n=36) (HR=1.3 [95% 0.9-2]) and 4 (3.5-4.5) mo for ≥2 SH (n=20) (HR=0.9 [95%CI 0.6-1.5]). Median f/u time from 2+L ICI start 26 mo: mPFS was 3 (95%CI 2.4-3.2) mo for PUC (n=264), 4 (95%CI 2-5) mo for squamous (n=33) (HR=0.8, [95%CI 0.6-1.2]), 3 (95%CI 1.6-3.7) mo for micropapillary (n=17) (HR=0.9 [95% 0.6-1.7]) and 3 (2.5-3.1) mo for ≥2 SH (n=10) (HR=1.2 [95%CI 0.6-2.2]); Table shows ORR/OS data. Data on adjuvant and mAV settings will also be presented. Conclusions: We found no significant survival difference between PUC and SH. ORR was numerically higher with sarcomatoid SH and ≥2 SH in the 1L upfront setting. Limitations: retrospective design, small sample size in a few subsets, lack of randomization and central scan/path (% SH) review, selection bias, unmeasured confounders. [Table: see text]

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.

BACKGROUND AND OBJECTIVES: Repeat stereotactic radiosurgery (SRS) for residual arteriovenous malformations (AVMs) can be considered as a salvage approach after failure of initial SRS. There are no published guidelines regarding patient selection, timing, or SRS parameters to guide clinical practice. This systematic review aimed to review outcomes and complications from the published literature to inform practice recommendations provided on behalf of the International Stereotactic Radiosurgery Society. METHODS: We performed a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive search of MEDLINE, Scopus, Web of Science, and Embase was conducted. Fourteen studies with 925 patients met the inclusion criteria. Patients were treated between 1985 and 2022. All studies were retrospective, except for one prospective cohort. RESULTS: The median patient age at repeat SRS ranged from 32 to 60 years. Four studies (630 patients) reported detailed information on Spetzler–Martin grade at the time of repeat SRS; 12.54% of patients had Spetzler–Martin grade I AVMs (79/630 patients), 46.51% had grade II (293/630), 34.92% had grade III (220/630), 5.08% had grade IV (32/630), and 0.95% had grade V (6/630). The median prescription doses varied between 15 and 25 Gy (mean, 13.06-22.8 Gy). The pooled overall obliteration rate at the last follow-up after repeat SRS was 59% (95% CI 51%-67%) with a median follow-up between 21 and 50 months. The pooled hemorrhage incidence at the last follow-up was 5% (95% CI 4%-7%), and the pooled overall radiation-induced change incidence was 12% (95% CI 7%-20%). CONCLUSION: For an incompletely obliterated AVM, repeat radiosurgery after 3 to 5 years of follow-up from the first SRS provides a reasonable benefit to the risk profile. After repeat SRS, obliteration is achieved in the majority of patients. The risk of hemorrhage or radiation-induced change appears low, and International Stereotactic Radiosurgery Society recommendations are presented.