CONTEXT:Inequitable access to quality care based on social determinants of health (SDoH) adversely impacts outcomes. Prior studies suggest that disparities extend to end-of-life (EOL) and subspecialty pediatric palliative care (SPPC) utilization, although pediatric data remain limited. OBJECTIVES:To examine relationships between SDoH, SPPC, and EOL circumstances among decedents in a quaternary children's hospital. METHODS:We conducted a retrospective cohort study of all inpatient deaths at a quaternary pediatric hospital (1.1.2018-12.31.2023). Clinical data, SDoH (race/ethnicity, interpreter involvement, insurance, and Child Opportunity Index [COI3.0]), SPPC consultation, and EOL circumstances (EOL care intensity, peri‑mortem cardiopulmonary resuscitation [CPR]) were analyzed using multivariable regression with adjusted odds ratios (aOR) and 95% confidence intervals (CI) presented. COI and race/ethnicity were modeled separately given collinearity. RESULTS:Among 679 pediatric decedents (median age 19 months [Interquartile range (IQR) 0.4-130]; 44.3% female), SPPC was involved in 334 cases (49.2%). SPPC involvement was inversely associated with age (i.e., aOR [CI] for infants vs. older children 0.39 [0.22-0.67]), general surgical diagnoses (0.49 [0.25-0.99]), international/self-pay insurance (0.18 [0.07-0.48]), and positively associated with certain subspecialties (i.e., hematology/oncology, cardiac, and chronic respiratory diagnoses aORs 9.02 [4.99-16.32], 1.65 [1.11-2.45] and 2.66 [1.67-4.24], respectively) as well as greater numbers of comorbidities. Neither COI nor race/ethnicity was associated with SPPC. For EOL circumstances, international/self-pay insurance was associated with lower EOL intensity (0.45 [0.20-1.01]), while interpreter involvement was associated with higher odds of CPR on the day of death (2.27 [1.22-4.24]), CPR as the mode of death (1.91 [0.97-3.74]), and prolonged intensive care unit stay (3.83 [1.88-7.78]). SPPC was associated with lower EOL intensity and less CPR. CONCLUSION:Clinical factors and certain social determinants, specifically insurance type and interpreter usage, were associated with SPPC involvement and EOL outcomes.

OBJECTIVE:For families navigating juvenile idiopathic arthritis (JIA) or systemic lupus erythematosus (SLE), effective communication with health care teams is vital. We examined how language preference other than English (LPOE) associates with patient-provider interactions and standardized outcome assessment. METHODS:In this retrospective cohort of patients with JIA or SLE at a tertiary care center (2016-2024), patients with LPOE were matched one-to-two to English language preference (ELP) counterparts by age, diagnosis, polyarticular course, and disease duration. We used multivariable negative binomial or logistic regression to compare rates of patient- and provider-initiated communications and adjusted for disease severity indicators and the COVID-19 pandemic period. Insurance and census tract-level Child Opportunity Index were evaluated in separate models. We secondarily compared rates of physician visual analog scale (PhVAS) completion. RESULTS:We matched 60 patients with JIA/SLE in families with LPOE to 107 counterparts with ELP. Families with LPOE initiated fewer communications in both unadjusted (incidence rate ratio [IRR] 0.45 [95% confidence interval [CI] 0.29-0.72]) and adjusted analyses (adjusted IRR [aIRR] 0.51 [95% CI 0.31-0.84]). Moreover, families with LPOE initiated 0.18-fold fewer communications during the COVID-19 pandemic (P < 0.001 for interaction). There was no significant difference in provider-initiated communication frequency by language preference. PhVAS were less often completed for families with LPOE (adjusted OR 0.58 [0.32-1.03]), but this difference was not statistically significant. CONCLUSION:Reduced communication frequency between families with LPOE with care teams may drive language-related disparities, particularly during periods of system stress. Enhanced outreach to families with barriers to health care engagement may facilitate more equitable care delivery.

Background: Shwachman Diamond syndrome (SDS) is characterized by bone marrow failure (BMF) and an increased risk of myeloid and lymphoid malignancies. Prognosis of myelodysplasia (MDS) or acute myeloid leukemia (AML) is poor, so regular surveillance is recommended to screen for early signs of clonal evolution. However, decisions regarding early transplant timing remain especially challenging due to the paucity of data regarding cumulative risks of hematologic complications with age, and reliance on published literature of outcomes utilizing outdated criteria for myeloid malignancy diagnosis. These barriers to clinical decision-making are especially difficult for rare leukemia predisposition conditions such as SDS. Objective: The goals of this study were to determine the cumulative risks with age and overall survival for: 1. myeloid malignancy, and 2. hematopoietic stem cell transplant (HSCT) for non-malignant indications. Methods: To study this rare disease, a collaborative retrospective study was developed collating data extracted from medical records and international registries for 865 patients with SBDS-associated SDS from 13 different counties and national/international registries. Third party honest broker review was conducted to identify potential overlap between patient cohorts. Severe BMF was defined as requiring transplant for BMF. For 91% of patients with MDS/AML, sufficient data were available for central review applying diagnostic criteria from the updated WHO and ICC classifications, while the local diagnosis was utilized for the remaining 9%. Competing risks were integrated into all cumulative risk analyses. Patient Characteristics: The median age at diagnosis of SDS was 2 years with a range of 0-69 years. Nine patients were diagnosed with SDS between age 40-69 years, of whom 7 initially presented with myeloid malignancy prior to SDS diagnosis. Median age at last follow up was 14.3 years with a span of 0-70 years of age. The median age at MDS and AML was 16 years (range 0-69) and 26 years (range 0.4-57), respectively. The median age at HSCT for severe BMF was 5.7 years. The median year of diagnosis for MDS/AML was 2017, with 96% diagnosed between 2000-2024. The median year of transplant unrelated to MDS/AML was 2019, with 96.3% transplanted between 2000-2024. Results: Of 865 patients, 71 developed MDS, 42 developed AML (without prior MDS), and 69 were transplanted for severe BMF. The age-associated cumulative incidence (95% CI) of myeloid malignancy (MDS or AML) was 2.0% (1.2-3.1%) at 5 years , 5.2% (3.7- 7.0%) at 10 years, 15.1% (11.8-18.9%) at 25 years, and 49.7% (40.0-58.6%) at 50 years of age. Median survival time from diagnosis of malignancy with central review was 3.2 years for MDS and 1 year for AML. No association between SBDS germline mutation and MDS/AML risk was identified. The cumulative risk of HSCT for BMF with age was 4.2% (2.9-5.7%) at 5 years, 6.0% (4.5-7.9%) at 10 years, 10.0% (7.7-12.6%) at 25 years, and 14.8% (10.2-20.2%) at 50 years of age. Additional indications for HSCT included high risk features of clonal evolution (n=24), ALL (n=1), Refractory Cytopenia of Childhood (n=1), infections (n=1), and unspecified (n=5). Seven received HSCT for del20q, i7q, or trisomy 8. Five year survival post-HSCT was 87.8% (79.6-96.8%) for severe BMF, 81.8% (67.1-99.9%) for high risk features, 47.8% (34.0-67.3%) for MDS, 28.9% (14.0-59.6%) for AML, and 85.6% (68.8-100.0%) for other indications. Overall survival was 86.2% (82.6-89.9%) by age 25 and 27.3% (16.1-46.2%) by age 50. In summary, the cumulative incidence of myeloid malignancy, severe BMF, or HSCT by age 50 years was 77.7% (95% CI: 67.3-85.1%), with death from other causes as a competing risk. Conclusion: SBDS-associated SDS carries a high cumulative risk of severe hematologic complications, with 78% of patients developing myeloid malignancy or requiring HSCT by age 50. In the context of recent advances in reduced toxicity HSCT regimens, this high lifetime risk of hematologic complications in SDS guides considerations of HSCT at younger ages when transplant outcomes are superior, and informs changes in transplant practice.

Although pediatric hematopoietic stem cell transplantation (HSCT) patients often experience sleep disruptions during hospitalization, no clinical guidelines exist for how to manage their sleep. We sought to learn how clinicians approach inpatient sleep disruptions by surveying 111 pediatric HSCT medical prescribers, nurses, and psychosocial staff from across the United States. Clinicians estimated 58% of inpatients developed sleep issues. Although they rated external factors (e.g., noise) as most impactful, clinicians were most likely to implement patient-level interventions (e.g., melatonin). Research is needed to assess the efficacy of commonly delivered treatments, as well as to develop and implement systems-level changes addressing external sleep barriers.

BACKGROUND:Numerous induction therapies have been evaluated for high-risk neuroblastoma (HRNBL). It is not known how these regimens' response rates nor toxicities compare. We aimed to describe and compare key features of HRNBL induction regimens and their associations with study-level end-induction response (EIR). METHODS:We performed a systematic review (PubMed) of prospective trials of frontline HRNBL therapy published January 1, 1995-October 31, 2024 that reported EIR. EIR was measured as partial response or better (PR+) per protocol response criteria. RESULTS:1395 unique titles were screened, yielding 95 abstracts. Of these, 29 publications evaluating 36 induction regimens met inclusion criteria, with a median of 64.5 patients (range: 7-652) per regimen. Median cycle number was 6 (range: 2-9), cycle length was 21 days (10-28), and total duration of induction was 18 weeks (11.4-36). An alkylator and a platinum agent were used in all regimens. Only six regimens (16.7%) included a novel agent. The median study level EIR rate (PR+) was 84.4% (64.3-100), with a weighted average by the number of participants of 79.4%. Study level EIR did not vary over time. Anthracycline-containing regimens had higher EIRs. Dose cisplatin intensity was negatively associated with EIR. The median toxic death rate was 0% (0-4.1). CONCLUSIONS:Over the past 30 years, induction regimens have relied heavily on conventional chemotherapy. Despite differences in agents, doses, and duration, study-level EIR rates have not improved over time. Future induction regimens incorporating novel agents will be crucial to improve EIR and reduce toxicities.

Introduction There has been a dramatic increase in the rate of venous thrombo-embolism (VTE) amongst hospitalized children in the United States. Although recent landmark pediatric trials have allowed evidence-based treatment decisions, real-world data validating the safety and efficacy of these therapeutic approaches, particularly in the management of high-risk VTE such as cerebral sinovenous thrombosis (CSVT), remain limited. The principal objective of the study is to investigate the safety and efficacy of an abbreviated course (<12 weeks) of anticoagulation using direct oral anticoagulants (DOACs) in children with infection-associated CSVT. Methods Permission for this retrospective cohort study was obtained from the Institutional Review Board. Three prospectively maintained institutional databases - neuroradiology, neurosurgery, and anticoagulation were used to identify eligible patients, defined as children (≤ 18 years of age) with infection-associated CSVT who received care at our quaternary care center between 1/1/2018 and 12/31/2024. Clinical characteristics, treatment, and radiological outcomes were abstracted from medical records. Safety (clinically relevant bleeding) and efficacy (progressive/recurrent thrombosis) were defined per criteria established by the International Society on Thrombosis and Haemostasis. Descriptive statistical analyses were conducted to summarize the data. Fisher's Exact Test was used to assess differences in the use of DOACs and abbreviated treatment courses across diagnosis years. Results Imaging data for 2991 patients was screened for inclusion. Two hundred and three patients were diagnosed with CSVT between 1/1/2018 and 12/31/2024, of which 47 (23%) patients had infection-associated CSVT. Median age (IQR) at diagnosis of infection-associated CSVT was 6.7 (3.9 – 9.8) years, and median duration of hospitalization was 14 (10-19) days. Thirty-five patients (75%) were admitted to the ICU, and 9 (19%) required mechanical ventilation. Head and neck region infections included: 28 (38%) otomastoiditis, 15 (22%) sinusitis, 4 (6%) neck infection, and 16 (23%) CNS infection. Five (11%) patients had evidence of venous infarction, and 6 (13%) had evidence of hemorrhage on initial diagnostic imaging. All patients were treated with antibiotics, and 45 (96%) received anticoagulation. Pharmaco-mechanical thrombectomy ± stent placement was performed in 4 (9%) patients, of whom two patients had recurrent thrombosis within 1 week of the procedure. Median time interval between diagnosis and starting anticoagulation was 1 (0-2) day. Forty-five (96%) patients were started on unfractionated heparin (UFH) or low molecular weight heparin, and 15 (32%) were transitioned to rivaroxaban or apixaban. Children diagnosed with infection-associated CSVT between 2022 – 2024 were more likely to receive a DOAC compared to those diagnosed between 2018 – 2021, though this was not statistically significant (41% versus 9%; p=0.07). Median duration of anticoagulation for the entire cohort was 7.8 (4.3 – 13.8) weeks. Thirty-one (74%) patients received <12 weeks of anticoagulation, and 11 (26%) received ≥ 12 weeks. Children diagnosed with infection-associated CSVT between 2022 – 2024 were not more likely to receive an abbreviated course of anticoagulation compared to those diagnosed between 2018 – 2021 (75% versus 70%; p=1). Three (6.4%) patients developed progressive thrombosis within the first week of diagnosis, while on UFH. Only one patient (3%) developed worsening hemorrhage within 24 hours of starting UFH. No patient developed recurrent/ progressive thrombosis or clinically relevant bleeding while receiving DOACs. Twenty-seven (57%) patients underwent thrombophilia testing of whom one (4%) was noted to be heterozygous for the factor V Leiden (G1691A) variant. Forty-six (98%) patients underwent follow-up imaging at our institution. Median time from diagnosis to most recent imaging was 14.1 (6.7 – 25.7) weeks. Forty-four (96%) had complete/partial thrombus resolution, and 2 (4%) had stable thrombus burden. One patient died of an underlying malignancy. Conclusion Our data suggests that an abbreviated course of anticoagulation using DOACs is safe and efficacious in the management of infection-associated CSVT in children. Additionally, thrombophilia work-up is low yield and likely not indicated in this cohort.

ABSTRACT:This study identified an increased risk of lymphoid malignancy in Shwachman-Diamond syndrome (SDS) with an observed risk 38-fold higher than expected based on population data. Increased toxicity was observed with standard therapies in patients with SDS.

OBJECTIVE:Child opportunity encompasses neighborhood resources and conditions that influence healthy childhood development. We determined whether area-level opportunity is associated with disease severity or disease control in a geographically and socioeconomically diverse multicenter cohort of patients with childhood-onset systemic lupus erythematosus (cSLE). METHODS:We linked medical records of patients with cSLE at three tertiary centers (2016-2022) to the Child Opportunity Index (COI) 2.0 (29 indicators across education, health and environment, socioeconomics). Primary outcomes included severe initial disease presentation (composite of Systemic Lupus Erythematosus Disease Activity Index [SLEDAI-2K] ≥10, intensive care, or dialysis) and acute care (inpatient/emergency) visits. Associations between nationally ranked COI levels and outcomes were estimated using mixed effects models clustered by site and adjusted for age, sex, race and ethnicity, language, and insurance status. RESULTS:Among 538 patients with cSLE, living in areas with low versus very high COI was associated with 1.93 times higher adjusted odds of severe disease presentation (95% confidence interval [CI] 1.05-3.57) and 2.03 higher adjusted incidence of acute care visits within the first year (95% CI 1.29-3.18). At the most recent follow-up, living in low versus very high COI areas was associated with higher disease activity (adjusted β 1.69 [95% CI 0.54-2.84]) and lower odds of concurrent achievement of SLEDAI-2K ≤ 4 and ≤7.5 mg/day of prednisone, adjusted for initial disease severity and disease duration (adjusted odds ratio 0.44 [95% CI 0.22-0.88]). CONCLUSION:Structural inequities in area-level child opportunity may contribute to disparities in both cSLE severity and disease control. Tailoring interventions for communities with low levels of child opportunity may improve access to pediatric subspecialty care and cSLE outcomes.

Introduction: Over 90% of children with acute lymphoblastic leukemia (ALL) will survive their cancer in the context of >2 years of multi-agent chemotherapy. This intensive treatment paradigm may lead to significant treatment-related financial toxicity for families— an outcome highly relevant to long-term child and family well-being. The magnitude and trajectories of financial toxicity are unknown in pediatric oncology, and necessary to inform optimal screening and intervention strategies for children with cancer and their families. Development of new household material hardship ([HMH], housing, food, or utility insecurity) or income loss during cancer treatment are concrete, targetable metrics of financial toxicity. We present results from Dana-Farber Cancer Institute (DFCI) ALL Consortium Trial 16-001, the first pediatric oncology clinical trial to systematically collect longitudinal HMH and household income data as an embedded correlative trial aim. Methods: DFCI 16-001 (NCT03020030) enrolled children ages 1-<22 years with de novoB- or T-cell ALL at 8 US and Canadian centers from 2017-2021. Participants <18 years were eligible to opt-in to the correlative HMH study at time of initial trial consent. Parents/guardians of participants completed surveys within 32-days of trial enrollment and longitudinally at 6-, 12-, and 24-months. Financial toxicity was the primary endpoint of interest for this secondary analysis, defined by two variables: (1) development of any new HMH domain (food, housing, or utility insecurity) at 6-24 months as compared to baseline and (2) catastrophic income loss defined as ≥25% annual household income loss at 6-24 months compared to baseline. Cumulative incidence of new HMH and catastrophic income loss in the presence of competing risks of coming off study (off-protocol therapy, death, relapse) were estimated using the Aalen-Johansen method. A subcohort analysis was conducted among participants who reported no HMH at baseline. Multivariable competing risk models evaluated the association of patient, household, and disease characteristics with risk of developing new HMH. Results: Among 422 participants (15% Hispanic and 7% non-Hispanic Black, 23% single-parent household, 40% annual household income <200% federal poverty level) with evaluable baseline survey data, 115 (27%) reported HMH at baseline. The cumulative incidence of any new HMH was 19.3% (95% CI: 15.9-23.5) at 6-months, 27.7% (95% CI: 23.8-32.4) at 12-months, and 30.0% (95% CI: 25.9-34.7) at 24-months. The cumulative incidence of catastrophic income loss was 20.3% (95% CI: 16.7-24.7) at 6-months, 28.6% (95% CI: 24.5-33.5) at 12-months, and 31.5% (95% CI: 27.2-36.5) at 24-months. Among the subcohort of 307 families with no baseline HMH, the cumulative incidences of any new HMH or catastrophic income loss at 24-months were 24.3% (95% CI: 19.9-29.6) and 27.9% (95% CI: 23.1-33.7), respectively. In multivariable modeling, children who identified as non-Hispanic Black (RR 3.5, 95% CI: 1.7-7.3), lived in a single-parent household (RR 2.1, 95% CI: 1.3-3.2), preferred a non-dominant language (i.e. non-English for US participants and non-English/French for Canadian participants, RR 2.1, 95% CI: 1.2-3.6), or had baseline household income <200% federal poverty level (RR 1.8, 95% CI: 1.1-2.9) were more likely to develop new HMH during treatment. Conclusion: Nearly a third of families of children receiving chemotherapy for ALL develop catastrophic financial toxicity during therapy including new unmet basic needs such as food insecurity, or ≥25% income loss. A majority experience this financial toxicity by 6-months into treatment, identifying a key inflection point for potential intervention. Importantly, nearly 1 in 4 families who had no HMH at the time of their child's diagnosis developed HMH during therapy. These findings stress the clinical importance of longitudinal financial screening over the course of cancer treatment, given the high prevalence of new material needs that arise and the potential to address these needs with family-centered interventions. Future work will assess the impact of early financial toxicity on clinical outcomes in this population and focus on the development of interventions to mitigate the profound financial toxicity impacting families during leukemia care.

Genetic bone marrow failure conditions are caused by mutations affecting a variety of cellular pathways including DNA repair, telomere maintenance, ribosome assembly, and transcriptional regulation. Many of these genetic bone marrow failure conditions carry an increased risk of myeloid malignancy, which is a major cause of mortality for these patients. Clonal hematopoiesis frequently develops in patients with bone marrow failure. Recent studies have elucidated maladaptive clonal pathways that drive towards malignancy, as well as adaptive clonal pathways that result in somatic rescue from the germline genetic stressor. These somatic patterns of clonal hematopoiesis are informing rational strategies for surveillance to guide timely interventions preventing progression to malignancy. The effects of somatic mutation cell of origin and cell state of the mutated clones will be discussed.

Introduction: Shwachman Diamond syndrome (SDS) is a genetic bone marrow failure syndrome associated with a predisposition to developing myeloid malignancies. Survival is exceptionally poor for patients who develop MDS or AML. Due to the rarity of this condition, the cumulative risk of myeloid malignancies with age is not well characterized, and this understanding is critical to guide effective clinical interventions that improve survival. The paucity of data regarding malignancy risk poses a major barrier to transplant decisions for patients with this leukemia predisposition syndrome. To address this unmet need, we conducted an international collaborative retrospective study with the primary objective of determining the cumulative incidence of myeloid malignancy as a function of age in patients with SDS. Methods: All patients with available reports of biallelic SBDS mutations were eligible. Data were extracted from medical records in accordance with institutional and national IRB/ethics regulations. Clinical characteristics and outcomes of patients with biallelic SBDS mutations were included for analysis from an international cohort from 7 countries, including the North American Shwachman-Diamond Syndrome Registry and the French Severe Congenital Neutropenia Registry, China, Italy, Japan, Greece, Ireland, and additional US centers (Baylor College of Medicine, Colorado Children's Hospital and Seattle Children's Hospital). The cumulative incidence of MDS and AML was estimated using cumulative incidence function (CIF) with competing risks. The survival curves were estimated using the Kaplan-Meier method and compared using the logrank test. Results: A total of 622 patients with biallelic SBDS mutations were in the study cohort. Median age at last follow up was 13.4 years (range 0-57 years) with 129 patients >age 25 years and 91 patients > age 30 years. There were 372 (59.8%) patients of male sex and 250 (40.2%) patients of female sex. MDS developed in 63 patients with a median age at diagnosis of 14.1 years (range 0-45), and AML in 42 with a median age at diagnosis of 24.2 years (range 0.5-47.3). The cumulative risk (95% confidence interval (CI)) of MDS was 2.4% (1.4-3.9) by age 5 years, 5.2% (3.5-7.4) by age 10 years, 13.4% (9.7-17.7) by age 25 years, and 32.9% (22.2-44) by age 50 years. The cumulative risk (95% CI) of AML was 0.7% (0.2-1.7) by age 5 years, 1.8% (0.9-3.3) by age 10 years, 5.1% (2.9-8.2) by age 25 years, and 28.4% (17-40.8) by age 50 years. The overall cumulative incidence (95% CI) of all myeloid malignancy was 3.2% (1.9-4.8) by age 5 years, 6.9% (4.9-9.4) by age 10 years, 16.1% (12.1-20.7) by age 25 years, and 57.2% (42.9-69.1) by age 50 years. Overall survival with age (95% CI) was 96.7% (95.3-98.2) at age 5 years, 95.8% (94.2-97.5) at age 10 years, 84.8% (80.6-89.3) at age 25 years, and 23.9% (11.8-48.6) at age 50 years. Conclusions: Previously, consideration of transplant timing was limited by the paucity of data on cumulative incidence of malignancy with age in SDS due to the rarity of this condition. This international collaboration analyzed data from the largest cohort of SDS patients to date, and found that SDS is associated with a very high lifetime risk of myeloid malignancy exceeding 50% by age 50 years. This study provides data to guide discussions of surveillance and early interventions, including hematopoietic stem cell transplant for SDS patients with evidence of impending malignant transformation prior to progression to malignancy. Development of optimal surveillance approaches for early diagnosis of clonal evolution and novel treatments are sorely needed to develop effective strategies to intercept malignancy and improve survival in patients with SDS.

Background Differential glucocorticoid exposure and related toxicity may exacerbate racial and ethnic disparities in lupus-related organ damage and mortality. Pediatric-onset systemic lupus erythematosus (pSLE) confers an even greater lifelong burden of cumulative medication exposure than adult-onset disease. Access to care and other social determinants of health may drive differential medication use. Therefore, we sought to determine how race and social determinants of health associate with cumulative glucocorticoid exposure over time in children with SLE. We hypothesized that minoritized race and living in more disadvantaged neighborhoods would be associated with greater average oral glucocorticoid exposure among children with pSLE in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. Methods This was a retrospective cohort study of children with pSLE enrolled in the CARRA Registry between March 2017-December 2021 with a baseline enrollment visit and ≥1 follow up Registry visits as well as a valid U.S. zip code. The primary exposures were self-identified race and/or ethnicity and national area deprivation index (ADI) linked to census tract. Time-averaged mean prednisone dose (mg/day) was used as the primary measure of cumulative glucocorticoid exposure, calculated using oral prednisone- equivalent milligram doses at each Registry visit. As secondary outcomes, we also evaluated occurrence of any prednisone restarts or dose increases between Registry visits during the study period and disease activity scores (SLEDAI-2K) over time. Associations between the primary exposures and time-averaged mean glucocorticoid dose were examined using univariate and multivariable linear regression models, adjusted for covariates (insurance status, age at enrollment, sex, major organ involvement, medication use at enrollment, disease duration at enrollment, and any secondary rheumatologic disease). We used logistic regression to analyze prednisone restart or dose increase. Linear mixed effects models were used to model disease activity over time with a subject-level random intercept. Results A racially diverse cohort of 540 children with pSLE self-identified as 11% Asian, 27% Black, 23% Latino/a, 5% Other race, 25% White, and 9% selected more than one race and/or ethnicity. The median age at diagnosis was 14.2 years (IQR 3.2–19.0), and 46% of participants were publicly insured. Black participants were more likely to be publicly insured, live in areas with higher social deprivation (ADI), and have renal disease (table 1). In univariate analyses, Black race and living in areas in the highest ADI quartile were significantly associated with higher time-averaged mean prednisone dose (unadjustedβ=3.24, 95% CI: [0.88, 5.60] and β=4.68, 95% CI: [2.30, 7.06], respectively). ADI remained significantly associated with time-averaged mean prednisone when adjusted for race and disease duration at enrollment (adjusted β=3.21, 95% CI: [0.68, 5.75]). However, further adjustment for either insurance status or renal involvement attenuated this estimate, and neither race nor the highest quartile of ADI were significantly associated with time-averaged mean prednisone in the fully adjusted model (table 2). Black race was also associated with higher odds of prednisone dose increases or restarts in unadjusted analysis (OR=1.8, 95% CI: [1.1, 2.9], p=0.022) and approached but did not reach statistical significance at the 0.05 level in the fully adjusted model (OR= 1.7, 95% CI: [0.99, 3.1], p=0.055). Black race was independently associated with higher adjusted disease activity compared to White race (adjusted β=0.94, 95% CI: [0.11, 1.78]). Compared to privately insured children, uninsured children also had significantly higher disease activity, albeit the number of uninsured children was small (table 3). Conclusions Insurance status and renal disease were significant predictors of greater cumulative mean prednisone dose among children with pSLE in the CARRA Registry and attenuated the associations between Black race and neighborhood-level disadvantage with prednisone dose. In contrast, Black race was independently associated with higher disease activity over time, irrespective of renal disease, neighborhood-level disadvantage, or insurance status, suggesting that there may be additional unmeasured social determinants driving this association. Furthermore, given that Black participants were much more likely to be publicly insured and live in areas of higher neighborhood disadvantage, structural confounding due to the unequal segregation of Black participants into areas of high neighborhood disadvantage must be considered. Further work to understand the complex relationships between area-level segregation and individual social determinants of health or how they mediate racial disparities is needed to identify points of intervention to improve outcomes of pSLE.

Many marrow failure conditions are associated with myeloid malignancy predisposition and a subset carry an increased risk of both myeloid and lymphoid malignancies. The increased risk of myeloid malignancy is known in Shwachman-Diamond syndrome (SDS), however, the risk of lymphoid malignancy in SDS has not been previously reported. Through the North American SDS Registry (SDSR), we identified multiple patients with SDS diagnosed with lymphoma. We report the clinical outcomes and molecular characteristics of lymphoma in SDS as well as the incidence rates of lymphoma, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) in this cohort. Patients with biallelic SBDS mutations enrolled on the SDSR were included for analysis. Age- and sex-specific incidence rates from the SEER Program (2016-2020) were multiplied by person-years of observation to obtain expected numbers of events. The crude rate per 100,000 (100,000*observed number of malignancies/person-years of follow-up) and the standardized incidence ratio (SIR) were calculated. Using validated targeted next-generations sequencing, somatic mutation and copy number variant analyses were conducted on tumor DNA extracted from lymphoma tissue samples. Four patients had a diagnosis of lymphoma: 1) 16 year-old male with primary mediastinal B-cell lymphoma 2) 24 year-old male with a kappa-restricted diffuse large B-cell lymphoma (DLBCL), later diagnosed with lambda-restricted DLBCL concurrently with AML at age 27 3) 12 year-old male with classical Hodgkin lymphoma 4) 12 year-old male with DLBCL All patients achieved complete remission (including patient 2 for each malignancy diagnosis) but experienced a number of infectious and end-organ complications with standard chemotherapy regimens. A total of 217 patients with biallelic SBDS mutations contributed 3,281 person-years to the analysis of malignancy risk. The median age in our cohort was 12.8 years (range: 0.3 - 52.8); 62.7% of the patients were male (136/217). We observed 4, 13, and 14 patients with lymphoma, MDS, and AML, respectively. The crude rates per 100,000 person-years were 120 for lymphoma, 396 for MDS, and 420 for AML. The observed risk of lymphoma in patients with SDS was 38 (95% CI:[10, 97]) times higher than expected in the general population. The observed risk of MDS and AML were 5,409 (95% CI:[2880,9250]) and 469 (95% CI:[256, 786]) times higher, respectively, than expected in the general population. Lymphoma tissue was available from patient 2 who experienced 2 instances of DLBCL, the second occurring concurrently with AML. Somatic mutation analysis conducted on tissue from the initial lymphoma diagnosis revealed an EZH2 variant (EZH2 c.1921 T>C, p.Y641H, 25% VAF) as well as two TP53 variants (TP53 c.993G>A, p.Q331Q, 16% VAF; TP53 c.524G>A, p.R175H, 15% VAF). Somatic mutation analysis conducted on tissue from the second lymphoma diagnosis demonstrated a third TP53 variant (TP53 c.838A>G, p.R280G, 73% VAF) occurring concurrently with a deletion of chromosome 17p raising concern for a biallelic TP53-mutated clone. The TP53 and EZH2 variants identified at initial diagnosis (a kappa-restricted lymphoma) were not detected in the specimen from his second diagnosis (now lambda-restricted). Copy number variant profile differed considerably between the two lymphoma specimens. Overall, these molecular profiles indicate the patient experienced a second primary TP53-mutated lymphoma rather than relapse. Our results establish that SDS is a marrow failure condition predisposing to both myeloid and lymphoid malignancies. Patients with SDS are known to develop somatic TP53 mutations, giving hematopoietic cells a selective, albeit maladaptive, advantage in the setting of ribosomal defect constraints on cell fitness. Acquisition of second mutations leading to biallelic TP53-mutated clones has been associated with progression to myeloid malignancy in SDS. However, this same mechanistic driver toward malignancy has not been previously described in lymphoid cells in SDS. We identified for the first time the presence of TP53 variants in lymphoid cells of a patient with SDS. The biological and clinical impact of the cell of origin for a somatic mutation warrants further exploration. Additionally, the role of bone marrow transplant and non-genotoxic therapies should be investigated for treatment of lymphoma in patients with genetic predisposition to myeloid malignancy.

OBJECTIVE:Health disparities may be driven by hospital-level factors. We assessed whether racial and ethnic composition of populations hospitals serve explain or modify disparities in hospital outcomes of children with systemic lupus erythematosus (SLE). METHODS:In this retrospective cohort study of patients 5 to 26 years old with SLE at 47 children's hospitals in the Pediatric Health Information System (2006-2021), race and ethnicity were assessed at the patient level and hospital level (proportion of total admissions composed of Black or Hispanic patients, respectively). Outcomes included intensive care unit (ICU) admission or adverse renal outcome (end-stage renal disease, dialysis, or transplant) during follow-up. We estimated racial and ethnic disparities, adjusted or stratified by hospital racial or ethnic composition. RESULTS:Of 8,125 patients with SLE, 2,293 (28%) required ICU admission, and 698 (9%) had an adverse renal outcome. Black and non-Hispanic White disparities in ICU admission were observed only at hospitals serving higher proportions of Black patients (odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.04-1.59 vs OR 1.07, 95% CI 0.83-1.38). Larger Black and non-Hispanic White disparities in adverse renal outcomes were observed at hospitals with higher Black racial composition (OR 2.0, 95% CI 1.4-2.8 vs OR 1.7, 95% CI 1.1-2.4). Conversely, Hispanic versus non-Hispanic disparities in renal outcomes persisted after adjustment for hospital-reported Hispanic ethnic composition but were observed only at hospitals with lower proportions of Hispanic patients. CONCLUSION:Worse Black and White disparities in SLE outcomes are observed at children's hospitals serving more Black children, whereas distinct patterns are observed for Hispanic and non-Hispanic disparities. Reporting of hospital characteristics related to populations served is needed to identify modifiable drivers of hospital-level variation.