Platform trials are multiarm clinical studies that allow the addition of new experimental arms after the activation of the trial. Statistical issues concerning “adding new arms”, however, have not been thoroughly discussed. This work was motivated by a “two-period” pediatric osteosarcoma study, starting with two experimental arms and one control arm and later adding two more pre-planned experimental arms. The common control arm will be shared among experimental arms across the trial. In this paper, we provide a principled approach, including how to modify the critical boundaries to control the family-wise error rate as new arms are added, how to re-estimate the sample sizes and provide the optimal control-to-experimental arms allocation ratio, in terms of minimizing the total sample size to achieve a desirable marginal power level. We examined the influence of the timing of adding new arms on the design’s operating characteristics, which provides a practical guide for deciding the timing. Other various numerical evaluations have also been conducted. A method for controlling the pair-wise error rate (PWER) has also been developed. We have published an R package, PlatformDesign, on CRAN for practitioners to easily implement this platform trial approach. A detailed step-by-step tutorial is provided in Appendix A.2.

Parvovirus B19 frequently infects children and targets cells of the erythroid lineage. Although healthy children rarely suffer severe disease, children with sickle cell disease (SCD) can experience transient red cell aplasia (TRCA), hospitalization, and life-threatening anemia upon first virus exposure. Given that children with SCD can also suffer chronic inflammation and that parvovirus B19 has been associated with autoimmune disease in other patient populations, we asked if parvovirus B19 infections contributed to acute and chronic immune abnormalities in children with SCD. Nineteen hospitalized patients with SCD and parvovirus B19–induced TRCA were evaluated. Blood tests included CBC, flow cytometry, and total antibody isotype analyses. Cytokine/chemokine analyses were performed on nasal wash (NW) samples, representing a common site of viral entry. Unusually high white blood cell count (WBC) and absolute neutrophil count (ANC) values were observed in some patients. A correlation matrix with Day 0 values from the 19 patients then identified two mutually exclusive phenotype clusters. Cluster 1 included WBC, ANC, absolute reticulocyte count (ARC), absolute lymphocyte count (ALC), lactate dehydrogenase (LDH), NW cytokines/chemokines, % naïve cells among B cell and T cell populations, and parvovirus-specific IgG. This cluster was negatively associated with virus load, suggesting a signature of successful adaptive immunity and virus control. Cluster 2 included virus load, % CD38⁺CD24⁻ cells among CD19⁺ B cells (termed ‘plasmablasts’ for simplicity), % HLA-DR^low cells among CD19⁺ B cells, IgG4, and % memory phenotypes among B cell and T cell populations. Plasmablast percentages correlated negatively with parvovirus-specific IgG, possibly reflecting a non-specific trigger of cell activation. All patients were released from the hospital within 1 week after admission, and the highest WBC and ANC values were eventually reduced. Nonetheless, a concern remained that the acutely abnormal immune profiles caused by parvovirus B19 infections could exacerbate chronic inflammation in some patients. To avoid the numerous sequelae known to affect patients with SCD following hospitalizations with parvovirus B19, rapid development of a parvovirus B19 vaccine is warranted.

Background/Objectives: Children who have received hematopoietic cell transplants (HCTs) often face complex clinical courses and complications that increase their risk of functional impairments. Because of this, pediatric HCT recipients may benefit from early mobilization efforts to reduce long-term functional issues. However, early ambulation can be limited by clinical complexity and concerns about infectious transmission in HCT patients. Some patients are under contact precautions due to colonization with bacteria that produce extended-spectrum beta-lactamase (ESBL) enzymes. Our goal was to significantly increase ambulation in pediatric HCT recipients at our institution within three months of the intervention. We aimed to raise the number of ambulation events per day, the number of physical therapy (PT) visits per week, and the distance patients walked with PT per session. Methods: From January to October 2022, data on mobilization, demographics, and clinical characteristics were retrospectively collected from electronic health records. Starting in June 2022, we permitted ESBL-colonized patients to leave their rooms while wearing personal protective equipment (PPE), and we trained clinical staff about this in our QI initiative. Results: In Group 1, the ambulation rate was 1.36 times higher before the intervention than after, with an effect size of 0.3042 (p = 0.004 *). The ambulation rate in Group 2, admitted before the intervention, was 1.33 times higher than in Group 3, admitted after the intervention, with an effect size of 0.2856 (p = 0.016 *). Conclusions: The initiative did not increase ambulation among the targeted group. Patients ambulated more before the intervention, though these results lack statistical power. The lack of success of the intervention may be due to various factors, including the short monitoring period, retrospective data collection, difficulties with PPE use among young patients, and uncollected confounding variables related to clinical status.

Background/Objectives: Hematopoietic stem cell transplantation (HSCT) in pediatric and young adult (YA) patients can lead to endotheliopathy, such as thrombotic microangiopathy (TMA), sinusoidal obstruction syndrome (SOS), and diffuse alveolar hemorrhage (DAH). Natriuretic peptides have been studied as markers of endotheliopathy and critical illness. We hypothesized that an elevation in NT-proBNP was associated with the development of endotheliopathy (DAH, SOS, or TMA) in the first 100 days following HSCT in pediatric and YA patients. Methods: IRB-exempt status was obtained. This retrospective case–control study reviewed HSCT at our institution from 2016 to 2020. Cases were selected based on an endotheliopathy diagnosis in the first 100 days after HSCT. Cases were matched with controls. Baseline and near-event NT-proBNP levels were compared between cases and matched controls. The effect of NT-proBNP levels on developing endotheliopathy was estimated using conditional logistic regression. Results: Sixty-two patients were included (31 cases, 31 controls). Near-event NT-proBNP was significantly higher in cases compared to controls (median: 473 vs. 187 pg/mL, p = 0.03, Wilcoxon rank–sum test), in contrast to comparison in baseline NT-proBNP (median: 86 vs. 86 pg/mL, p = 0.51). After adjusting for covariates, an association between near-event NT-proBNP and odds of developing endotheliopathy did not achieve statistical significance. However, trends from most common transplant indications suggested an association between an elevated near-event NT-proBNP level and endotheliopathy, particularly in acute lymphoblastic leukemia (ALL) patients. Conclusions: NT-proBNP should be studied further as a biomarker for endotheliopathy in pediatric and YA patients undergoing HSCT. This may be particularly relevant for patients undergoing HSCT for ALL.

Background/Objectives: Hematopoietic stem cell transplantation (HSCT) in pediatric and young adult (YA) patients can lead to endotheliopathy, such as thrombotic microangiopathy (TMA), sinusoidal obstruction syndrome (SOS), and diffuse alveolar hemorrhage (DAH). Natriuretic peptides have been studied as markers of endotheliopathy and critical illness. We hypothesized that elevation in NT-proBNP was associated with development of endotheliopathy (DAH, SOS, or TMA) in the first 100 days following HSCT in pediatric and YA patients. Methods: IRB exempt status was obtained. This retrospective case-control study reviewed HSCT at our institution from 2016-2020. Cases were selected based on an endotheliopathy diagnosis in the first 100 days after HSCT. Cases were matched with controls. Baseline and near-event NT-proBNP levels were compared between cases and matched controls. Effect of NT-proBNP levels on developing endotheliopathy was estimated using conditional logistic regression. Results: Sixty-two patients were included (31 cases, 31 controls). Near-event NT-proBNP was significantly higher in cases compared to controls (Median: 473 vs. 187 pg/mL, p = 0.03, Wilcoxon rank-sum test), in contrast to comparison in baseline NT-proBNP (Median: 86 vs. 86 pg/mL, p = 0.51). After adjusting for co-variates, association between near-event NT-proBNP and odds of developing endotheliopathy did not achieve statistical significance. However, trends from most common transplant indications suggested an association between elevated near-event NT-proBNP level and endotheliopathy, particularly in acute lymphoblastic leukemia (ALL) patients. Conclusions: NT-proBNP should be studied further as a biomarker for endotheliopathy in pediatric and YA patients undergoing HSCT. This may be particularly relevant for patients undergoing HSCT for ALL.

Study Aim: Patients with high-risk Ewing sarcoma (ES) have dismal outcomes despite aggressive multimodal therapy. This phase II, single-institution study evaluated the response rate to two up-front cycles of irinotecan, temozolomide, and temsirolimus (ITT) and assessed the tolerability of maintenance therapy following standard treatment in high-risk ES. Methods: Eligible patients had newly diagnosed high-risk ES (age ≥14 years old, metastatic disease, or primary pelvic tumor). The therapy included two cycles of window therapy (ITT) followed by interval-compressed chemotherapy (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide) and maintenance therapy (cyclophosphamide, sorafenib, and bevacizumab). A two-stage sequential design was employed to assess a >50% WHO response (CR or PR) with 80% power. Patients who required emergent radiation were excluded from receiving window therapy. Results: Sixteen patients (median age 12.2 years; range 4.8–23.6 years) were enrolled (12 evaluable for overall response, 10 for primary tumor response). Only three achieved a PR to window therapy, leading to study closure. All evaluable patients demonstrated a decline in their primary tumor volume (mean decline: 32.5%, standard deviation: 17.6%, p-value: 0.0005) and SUV peak (mean decline: 49.9%, standard deviation: 21.1%, p-value: 0.002). Maintenance therapy was well tolerated, with only 2/13 patients discontinuing due to toxicity. Conclusions: ITT did not achieve the prespecified response rate of 50%, according to WHO criteria; however, all patients exhibited decreased volume and metabolic activity, highlighting the limitations of conventional response assessments. Maintenance therapy was feasible and well tolerated. Although limited by small sample size, heterogeneous disease presentations, and the absence of a control arm, this study supports further evaluation of ITT and a maintenance approach in larger, randomized trials for high-risk ES.