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ABSTRACT The COVID‐19 pandemic underscored the critical need to strengthen healthcare systems and optimize resource allocation planning during times of disruption and crisis. This retrospective, single‐center, cross‐sectional study included 33,158 admissions for patients ≤ 17 years old admitted to the Children's Hospital (CH) between January 1, 2017, and December 31, 2021. Data was abstracted using Vizient Clinical Data Base and the internal data warehouse. A Poisson regression model was implemented to compare admission diagnosis patterns during the pre‐ and intra‐pandemic phases. CH SARS‐CoV‐2 prevalence rate was 0.1% in 2020 and 0.5% in 2021. There was a decrease in overall admissions to the CH ( p < 0.01) and PICU ( p < 0.01) at the onset of the pandemic. There were significant and variable differences in admission patterns for certain infectious and seizure‐related diagnoses. The CH experienced an increase in certain specific mental health diagnoses. Seasonality was noted for viral bronchiolitis during the pre‐pandemic phase, but was disrupted during the intra‐pandemic phase. The COVID‐19 pandemic had a significant impact on the number and pattern of admissions, despite low prevalence of SARS‐CoV‐2 in our hospital. These changes may be secondary to COVID‐19 community mitigation strategies. Results can inform anticipated patterns during future pandemics.

Objective This survey study assessed trainee attitudes and perceptions of the longitudinal public speaking curriculum at Mayo Clinic Pediatric and Adolescent Residency Program. Methods This 3-part survey of Mayo Clinic pediatric residents was conducted from 2013 to 2017 and utilized yes/no questions, Likert scales, and open-ended questions. Code book content analysis was used to analyze open-ended questions. Results A total of 121 participants (96.8%, n = 121/125) completed the survey. Most respondents (93.3%, n = 111/119) either agreed or strongly agreed that the public speaking requirement enabled them to be more effective in delivering information to large groups. Most respondents (89.2%, n = 107/120) agreed or strongly agreed that they incorporated feedback from previous public speaking feedback sessions into subsequent presentations. The 2 activities that respondents found most useful for preparing later presentations were setting goals for future presentations in a feedback session and discussing performance in a feedback session. Conclusions There was a perceived effectiveness of a longitudinal public speaking curriculum among pediatric residents at our program. Multidimensional feedback seems to be a critical aspect of a public speaking curriculum in graduate medical education.

PURPOSE Human epidermal growth factor receptor 2 (HER2), a transmembrane receptor with kinase activity involved in cell signaling through the RAS pathway, is expressed in osteosarcoma (OST). Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate with a HER2-targeting monoclonal antibody, trastuzumab, linked to a topoisomerase I inhibitor. We report results of a phase II study of T-DXd in adolescents and young adults with HER2-positive relapsed, unresectable OST (ClinicalTrials.gov identifier: NCT04616560 ). METHODS Patients age 12-39 years with relapsed, unresectable OST were eligible for centrally evaluated HER2 expression screening by immunohistochemistry. Patients with >10% of OST cells with cytoplasmic or membranous HER2 expression of any intensity were eligible to receive T-DXd at 5.4 mg/kg intravenously once every 3 weeks for up to 2 years. The study used a 9 + 15 Simon's optimal two-stage design with a primary end point of event-free survival at 24 weeks. RESULTS Fifty patients were screened for HER2, and 41 met the inclusion criteria of 10% of OST cells having membranous or cytoplasmic HER2 expression. Nine eligible patients, two younger than 18 years, were enrolled and received T-DXd. With a single patient having more than 24 weeks of stable disease (SD) of the nine planned in the first stage, this study did not meet criteria to progress to stage II. The estimated SD rate at 24 weeks is 11.1%. The median (range) number of cycles of therapy was 2 (2-12). Grade 3 and 4 possibly related adverse events occurred in three of nine patients and included nausea, vomiting, tumor hemorrhage, cytopenias (n = 3), wound infection, and hypertension. CONCLUSION T-DXd did not demonstrate sufficient activity to expand enrollment to the planned second stage in patients with OST. No new safety signals were observed.

Background : The COVID-19 pandemic profoundly impacted healthcare, emphasizing the need to strengthen future pandemic responses and optimize resource allocation planning and deployment during times of disruption and crisis. Methods : This retrospective, single-center, cross-sectional study included participants ≤17 years-old admitted to the Children’s Hospital (CH) between 01/01/2017 and 12/31/2021. Clinical data was abstracted using Vizient ® Clinical Data Base and the internal data warehouse. Using the International Classification of Disease, 10 th Revision, Clinical Modification (ICD-10-CM) admit diagnosis, frequency and pattern of total admissions during the pre-pandemic phase (2017 Q1-2019 Q4) and intra-pandemic phase (2020 Q1-2021 Q4) were compared. Results : The study included 33,158 admissions. CH SARS-CoV-2 prevalence rate was 0.1% in 2020 and 0.5% in 2021. There was a decrease in overall admissions to the CH (p <0.01) and PICU (p <0.01) at the start of the pandemic. There were significant and variable differences in admission patterns for certain infectious, mental health, and seizure related diagnoses. Seasonality was noted for viral bronchiolitis during the pre-pandemic phase but was disrupted during the intra-pandemic phase with significantly lower admission rates for viral bronchiolitis in 2020 Q4 (p <0.05) and 2021 Q1 (p <0.01), followed by a significant early increase in viral bronchiolitis admissions in 2021 Q3 (p <0.01). Conclusion : The COVID-19 pandemic significantly impacted the number and pattern of admissions despite low SARS-CoV-2 prevalence in our hospital. These changes may be secondary to COVID-19 mitigation strategies implemented in the community. Results can inform anticipated patterns during future pandemics.

TPS2695 Background: The SMARCB1/A4 gene products are core subunits of the SWItch/Sucrose Non Fermentable (SWI/SNF) chromatin remodeling complex. Tumors with defects in SWI/SNF are histologically distinct aggressive cancers occurring in children and young adults. SMARCB1/A4 deficient tumors, particularly malignant rhabdoid tumor (MRT), atypical teratoid rhabdoid tumor (ATRT), poorly differentiated chordoma (PDC), epithelioid sarcoma (ES), and renal medullary carcinoma (RMC), have immune cell infiltrates and programmed death ligand 1 (PD-L1) expression. Responses to immune checkpoint inhibition (CI) have been observed in SMARCB1/A4 deficient tumors; however, responses are not durable. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a novel inhibitory receptor expressed on multiple immune cells. TIGIT inhibits T and NK cells by binding to its ligand poliovirus receptor (PVR) and Nectin2 on both tumor and antigen-presenting cells. Utilizing RNAseq data, SMARCB1/A4 deficient tumors demonstrate high expression of PVR and Nectin2. Tiragolumab is an antibody to the TIGIT receptor. The combination of tiragolumab and atezolizumab has shown promising activity in early phase studies, and phase 3 studies are ongoing in multiple adult indications. Thus, there is rationale that the addition of tiragolumab to CI may also enhance response rates in patients with SMARCB1/A4 deficient tumors. Methods: This is a phase 1/2 trial of tiragolumab monotherapy (300 mg if ≤ 15 kg; 420 mg if > 15 kg to ≤ 40 kg; 600 mg if > 40 kg or ≥ 18 years) and in combination with atezolizumab (15 mg/kg [max 1200 mg]) if < 18 yrs or 1200 mg if ≥ 18 years) administered IV on Day 1 of 21-day cycles in patients > 12 months of age with SMARCB1/A4 deficient tumors. Part A evaluating the safety of tiragolumab monotherapy in patients < 18 years based on cycle 1 dose limiting toxicities is complete. Part B estimates the antitumor activity of tiragolumab in combination with atezolizumab in 6 histology-specific cohorts (RMC, MRT, ATRT, PDC, ES, and other SMARCB1/A4 deficient tumors) and is now open to all eligible age groups. Each cohort is conducted using a 6+4 Simon’s two stage design. Enrollment for each cohort is as follows: Part A 6/6, Part B RMC 1/6, MRT 1/6, ATRT 4/6, PDC 2/6, ES 3/6, other 6/6. Radiographic imaging central response assessment for the first stage of the “other” cohort is ongoing. Cycle 1 toxicities of the combination therapy are monitored in Part B patients < 12 yrs using a Bayesian Optimal INterval (BOIN) design with a target toxicity of 17%. Secondary objectives are to characterize the pharmacokinetics/anti-drug antibody development and to estimate progression free survival, overall survival, and duration of response. Enrollment is open at all Pediatric Early Phase Clinical Trial Network sites. Data cutoff: Jan 10, 2025. Clinical trial information: NCT05286801 .

PURPOSE The TRK inhibitor larotrectinib is US Food and Drug Administration approved for NTRK fusion–positive solid tumors that lack a satisfactory alternative or have progressed after treatment but has not been systematically studied as a frontline therapy with a defined duration of treatment. ADVL1823 evaluated larotrectinib in patients with newly diagnosed NTRK fusion–positive solid tumors with response-adapted duration of therapy and local control. METHODS Patients received larotrectinib twice daily in 28-day cycles for a predefined duration of treatment, ranging from 6 to 26 cycles depending on response to therapy and surgical resectability. The primary end point was the objective response rate (ORR) within six cycles in patients with infantile fibrosarcoma (IFS); patients with other histologic diagnoses were analyzed in a separate cohort. Secondary objectives included event-free survival (EFS) and overall survival (OS). RESULTS Thirty-three patients were enrolled: 18 with IFS and 15 with other solid tumors. The ORR within six cycles was 94% (17/18; 95% adjusted CI, 72.7 to 98.6) among children with IFS and 60% (9/15; 95% CI, 32.3 to 83.7) among children with other solid tumors. Six percent (2/33; 95% CI, 0.7 to 22.2) patients developed progressive disease while on therapy. Two-year EFS and OS among these groups were 82.2% (95% CI, 54.3 to 93.9) and 93.8% (95% CI, 63.2 to 99.1) for IFS and 80% (95% CI, 50.0 to 93.1) and 93.3% (95% CI, 61.3 to 99.0) for other solid tumors, respectively. Patients undergoing surgical resection of their tumor had prolonged EFS, with only 1 of 16 such patients experiencing disease progression. Four of 33 patients had dose-limiting toxicities. CONCLUSION Larotrectinib is highly active in patients with newly diagnosed NTRK fusion–positive solid tumors. Larotrectinib should be a frontline option for patients with IFS and other NTRK fusion–positive solid tumors. Local control with surgical resection remains important in the treatment of patients with IFS.

TPS10066 Background: The SMARCB1/A4 gene products are core subunits of the SWItch/Sucrose Non-fermentable (SWI/SNF) chromatin remodeling complex. Tumors with defects in SWI/SNF are histologically distinct aggressive cancers occurring in children and young adults. SMARCB1/A4 deficient tumors, particularly rhabdoid tumors, poorly differentiated chordoma, epithelioid sarcoma, and medullary renal cell carcinoma, have immune cell infiltrates and programmed death ligand 1 (PD-L1) expression. Response to immune checkpoint inhibition (CI) has been observed in SMARCB1/A4 deficient tumors; however, responses are not durable. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a novel inhibitory receptor expressed on multiple immune cells. TIGIT inhibits T and NK cells by binding to its ligand poliovirus receptor (PVR) and Nectin2 on tumor cells and antigen-presenting cells. Utilizing RNAseq data, SMARCB1/A4 deficient tumors demonstrate high expression of PVR and Nectin2. Tiragolumab is an antibody to the TIGIT receptor. In patients with non-small cell lung cancer, tiragolumab with atezolizumab increased survival compared to atezolizumab alone. Thus, data suggest that SMARCB1/A4 deficient tumors are susceptible to CI; however, monotherapy is unlikely to achieve durable responses; the addition of tiragolumab may enhance response rates. Methods: This is a phase 1/2 trial of tiragolumab monotherapy and in combination with atezolizumab in patients ≥ 12 months of age with SMARCB1/A4 deficient tumors administered IV on Day 1 of 21-day cycles. Part A will evaluate the safety of tiragolumab monotherapy (300 mg if ≤ 15 kg; 420 mg if >15 to ≤ 40 kg; 600 mg if > 40 kg or ≥ 18 yrs) based on cycle 1 DLTs in up to 6 evaluable patients <18 yrs of age. Part B will estimate the antitumor activity of tiragolumab in combination with atezolizumab (15 mg/kg [max 1200 mg]) if < 18 yrs or 1200 mg if ≥ 18 yrs) in 6 histology-specific cohorts (renal medullary carcinoma, malignant rhabdoid tumor, atypical teratoid rhabdoid tumor, poorly differentiated carcinoma, epithelioid sarcoma, and other) Each cohort will be conducted using a 6+4 Simon’s two stage design. Up to 13 patients may enroll in each cohort allowing for inevaluable patients (maximum n=78). Enrollment of patients ≥ 18 yrs on Part B may occur concurrently with enrollment of patients < 18 yrs on Part A. If the pediatric dose of tiragolumab is deemed safe, patients <18 yrs old may be enrolled on Part B. Cycle 1 toxicities of the combination therapy will be monitored in Part B using a Bayesian Optimal Interval Design in patients < 12 yrs of age. The secondary objectives are to characterize pharmacokinetics/anti-drug antibody and estimating progression free survival, overall survival, and duration of response. Enrollment is open for all Pediatric Early Phase Clinical Trial Network sites. Clinical trial information: NCT05286801 .

10008 Background: NTRK1/2/3 gene fusions (TRK fusions) occur in a range of pediatric cancers and are the canonical molecular alterations in IFS. Larotrectinib is a highly selective TRK inhibitor that is FDA-approved for TRK fusion solid tumors in patients with no satisfactory alternative treatments or whose cancer has progressed following initial treatment. ADVL1823 (NCT03834961) evaluated larotrectinib in children with newly diagnosed TRK fusion positive solid tumors in two histology-based cohorts. Cohort A enrolled patients with IFS and is the focus of this analysis. Methods: Newly diagnosed patients ≤30 years old with unresectable or metastatic IFS and a locally identified NTRK gene fusion were eligible for Cohort A utilizing a Simon 2-stage design. Patients received larotrectinib at a dose of 100 mg/m2/dose BID (max of 100 mg/dose) continuously in 28-day cycles until disease progression, unacceptable toxicity, the tumor becoming surgically resectable following a minimum of 6 cycles of therapy, or completion of 12 cycles (for those with CR) or 26 cycles (for those with PR) of therapy. The primary endpoint was the centrally confirmed objective response rate within 6 cycles according to RECIST 1.1; response assessment occurred every 2 cycles for the first 6 cycles. The data cutoff was December 31, 2022. Results: Between October 2019 and May 2022, 18 patients with IFS were enrolled from 14 centers. The median age was 2 months (range <1 month to 4.6 years). NTRK fusions included presumed/confirmed ETV6: NTRK3, n=15, NTRK3 (partner unconfirmed), TMP3: NTRK1 and DCTN1: NTRK1, n=1 each, and were identified by FISH (n=8), NGS (n=7), and PCR (n=3). 17 of 18 patients (94%) demonstrated confirmed objective responses (16 PR and 1 CR,) resulting in closure to enrollment after meeting the pre-specified efficacy threshold. The only patient without confirmed response demonstrated 79% tumor reduction after cycle 2, but no confirmatory scan was obtained within the first 6 cycles. No patient discontinued therapy within the first 6 cycles due to disease progression or toxicity. Four (22%) patients had dose limiting toxicities: 2 neutropenia (both CTCAE V5 grade (G)4) and 1 each G3 AST increase and G3 weight loss. All patients resumed therapy following a dose reduction. Treatment-related grade ≥ 3 toxicities occurred in 7 patients, most commonly neutropenia (n=5, 3 G3, 2 G4). Conclusions: Larotrectinib is highly active and well tolerated in newly diagnosed patients with IFS. Enrollment of this very rare molecularly defined patient population was feasible within the COG. Ongoing follow-up will evaluate durability of response after treatment discontinuation at protocol specified response-adapted timepoints with or without surgical resection of tumor. Clinical trial information: NCT03834961 .

OBJECTIVE The pediatric sepsis literature lacks studies examining the inpatient setting, yet sepsis remains a leading cause of death in children’s hospitals. More information is needed about sepsis arising in patients already hospitalized to improve morbidity and mortality outcomes. This study describes the clinical characteristics, process measures, and outcomes of inpatient sepsis cases compared with emergency department (ED) sepsis cases within the Improving Pediatric Sepsis Outcomes data registry from 46 hospitals that care for children. METHODS This retrospective cohort study included Improving Pediatric Sepsis Outcomes sepsis cases from January 2017 to December 2019 with onset in inpatient or ED. We used descriptive statistics to compare inpatient and ED sepsis metrics and describe inpatient sepsis outcomes. RESULTS The cohort included 26 855 cases; 8.4% were inpatient and 91.6% were ED. Inpatient cases had higher sepsis-attributable mortality (2.0% vs 1.4%, P = .025), longer length of stay after sepsis recognition (9 vs 5 days, P &lt;.001), more intensive care admissions (57.6% vs 54.1%, P = .002), and greater average vasopressor use (18.0% vs 13.6%, P &lt;.001) compared with ED. In the inpatient cohort, &gt;40% of cases had a time from arrival to recognition within 12 hours. In 21% of cases, this time was &gt;96 hours. Improved adherence to sepsis treatment bundles over time was associated with improved 30-day sepsis-attributable mortality for inpatients with sepsis. CONCLUSIONS Inpatient sepsis cases had longer lengths of stay, more need for intensive care, and higher vasopressor use. Sepsis-attributable mortality was significantly higher in inpatient cases compared with ED cases and improved with improved sepsis bundle adherence.