Search

• The study cohort comprised children with leukemia who underwent partially CD3+-depleted peripheral stem cell transplantation (PSCT). • Three-year overall survival was 61.8% (95% confidence interval [CI], 50.2% to 71.4%) and event-free survival was 52.0% (95% CI, 40.3% to 62.4%). • Age ≥15 years and second complete remission were associated with worse outcomes. • The incidence of severe chronic graft-versus-host disease was lower in CD3+-depleted PSCTthan in T cell-replete PSCT. Most children who may benefit from stem cell transplantation lack a matched related donor. Alternative donor transplantations with an unrelated donor (URD) or a partially matched related donor (PMRD) carry an increased risk of graft-versus-host-disease (GVHD) and mortality compared with matched related donor transplantations. We hypothesized that a strategy of partial CD3+/CD19+ depletion for URD or PMRD peripheral stem cell transplantation (PSCT) would attenuate the risks of GVHD and mortality. We enrolled 84 pediatric patients with hematologic malignancies at the Children's Hospital of Philadelphia and the Children's Hospital of Wisconsin between April 2005 and February 2015. Two patients (2.4%) experienced primary graft failure. Relapse occurred in 23 patients (27.4%; cumulative incidence 26.3%), and 17 patients (20.2%) experienced nonrelapse mortality (NRM). Grade III-IV acute GVHD was observed in 18 patients (21.4%), and chronic GVHD was observed and graded as limited in 24 patients (35.3%) and extensive in 8 (11.7%). Three-year overall survival (OS) was 61.8% (95% confidence interval [CI], 50.2% to 71.4%) and event-free survival (EFS) was 52.0% (95% CI, 40.3% to 62.4%). Age ≥15 years was associated with decreased OS (P =.05) and EFS (P =.05). Relapse was more common in children in second complete remission (P =.03). Partially CD3+-depleted alternative donor PSCT NRM, OS, and EFS compare favorably with previously published studies of T cell-replete PSCT. Historically, T cell-replete PSCT has been associated with a higher incidence of extensive chronic GVHD compared with limited chronic GVHD, which may explain the comparatively low relapse and NRM rates in our study cohort despite similar overall rates of chronic GVHD. Partial T cell depletion may expand donor options for children with malignant transplantation indications lacking a matched related donor by mitigating, but not eliminating, chronic GVHD. [ABSTRACT FROM AUTHOR]

Jiang-Tang-San-Huang (JTSH) pill, a traditional Chinese medicine (TCM) prescription, has long been applied to clinically treat type 2 diabetes mellitus (T2DM), while the underlying antidiabetic mechanism remains unclarified. Currently, it is believed that the interaction between intestinal microbiota and bile acids (BAs) metabolism mediates host metabolism and promotes T2DM. To elucidate the underlying mechanisms of JTSH for treating T2DM with animal models. In this study, male SD rats received high-fat diet (HFD) and streptozotocin (STZ) injection to induce T2DM and were treated with different dosages (0.27, 0.54 and 1.08 g/kg) of JTSH pill for 4 weeks; metformin was given as a positive control. Alterations of gut microbiota and BA profiles in the distal ileum were assessed by 16S ribosomal RNA gene sequencing and ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), respectively. Additionally, we conducted quantitative Real Time-PCR and western blotting to determine the mRNA and protein expression levels of intestinal farnesoid X receptor (FXR), fibroblast growth factor 15 (FGF15), Takeda G-protein-coupled receptor 5 (TGR5) and glucagon-like peptide 1 (GLP-1) as well as hepatic cytochrome P450, family 7, subfamily a, poly-peptide 1 (CYP7A1) and cytochrome P450, family 8, subfamily b, poly-peptide 1 (CYP8B1), which are involved in BAs metabolism and enterohepatic circulation. Here, the results revealed that JTSH treatment significantly ameliorated hyperglycaemia, insulin resistance (IR), hyperlipidaemia, and pathological changes in the pancreas, liver, kidney and intestine and reduced the serum levels of pro-inflammatory cytokines in T2DM model rats. 16S rRNA sequencing and UPLC-MS/MS showed that JTSH treatment could modulate gut microbiota dysbiosis by preferentially increasing bacteria (e.g., Bacteroides, Lactobacillus, Bifidobacterium) with bile-salt hydrolase (BSH) activity, which might in turn lead to the accumulation of ileal unconjugated BAs (e.g., CDCA, DCA) and further upregulate the intestinal FXR/FGF15 and TGR5/GLP-1 signaling pathways. The study demonstrated that JTSH treatment could alleviate T2DM by modulating the interaction between gut microbiota and BAs metabolism. These findings suggest that JTSH pill may serve as a promising oral therapeutic agent for T2DM. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Impaired immunologic recovery (IR) after hematopoietic stem cell transplantation (HSCT) is associated with increased risk for infections and relapse. Stem cell source and graft manipulation influence the kinetics of IR. Partial T cell depletion of peripheral blood stem cell (PBSC) grafts is a novel alternative method of graft manipulation for children. We compared IR in children undergoing HSCT for hematologic malignancies receiving either T cell–depleted (TCD)-PBSCs (n = 55) or umbilical cord blood (UCB) (n = 21) over a 7-year period at a single institution. PBSC grafts underwent ex vivo negative selection for CD3+ cells using the CliniMACS system with partial T cell add-back. Recovery of CD4+ T cells was significantly delayed in TCD-PBSC recipients compared with UCB recipients, owing to impaired CD4+/CD45RA+ (naïve) T cell lymphopoiesis. Recovery of total CD3+ cells and CD3+/CD8+ cells was similar in the 2 groups. The TCD-PBSC recipients had a marked deficit in CD19+ and, to a lesser extent, IgA/IgM, owing to the need for B cell depletion of these grafts to attenuate the risk of lymphoproliferative disease after TCD HSCT. There were no significant between-group differences in response to mitogen stimulation, time to independence from intravenous immunoglobulin supplementation, or incidence of viral reactivation. Transplantation outcomes of relapse, transplantation-related mortality, event-free survival, and overall survival were similar in the 2 groups. Efforts to enhance IR after partial TCD-PBSC transplantation, such as selective αβ T cell depletion, hold promise for further improvement of this transplantation approach. [Copyright &y& Elsevier]

Context: Parents of seriously ill children hold personal beliefs about what they should do to be good parents. How these beliefs change over time is unknown.Objectives: The objectives of this study were to describe the pattern of Good-Parent Beliefs over time, and determine whether parents' hopeful patterns of thinking, affect, and perceived child's health are associated with changes in beliefs at 12 and 24 months.Methods: Our longitudinal sample included 124 parents of 100 children hospitalized with serious illness. We used latent transition models to classify parents into groups with similar Good-Parent Beliefs during the baseline and follow-up periods and modeled the change in good-parent beliefs over time as a function of covariates using generalized linear mixed models.Results: Two parent belief profiles emerged from the latent transition model: Loved ("Making sure my child feels loved," n = 61 at baseline) and Informed ("Making informed decisions," n = 63 at baseline). At 12 months, 21 parents (20.4%) had moved into the Loved group and no parents transitioned to the Informed group. By 24 months, eight parents transitioned to the Loved group and four to the Informed group (13.04%). Transition into the Loved group was associated with parents' baseline degree of hopeful thinking and positive perceptions of child's health at baseline.Conclusion: Some parents change their parenting priorities over time. Hopeful patterns of thinking and perception of child health appear to predict change. Clinicians should regularly reevaluate Good-Parent Beliefs over time to promote priority-congruent dialogue. [ABSTRACT FROM AUTHOR]

BK virus (BKV) infection is associated with hemorrhagic cystitis (HC) in hematopoietic stem cell transplantation (HSCT) recipients and nephropathy after kidney transplantation. We assessed the association between BKV and kidney and bladder complications in children developing HC by retrospectively reviewing 221 consecutive pediatric allogeneic HSCT recipients at the Children's Hospital of Philadelphia from 2005 to 2011. We included all patients with BKV PCR testing performed for clinical indication from day 0 until 1 year post-HSCT (N = 68). We assessed the association of any BKV infection (urine and/or blood) or peak BK viremia ≥ 10,000 copies/mL (high viremia) with severe HC (defined as grade IV—bladder catheterization or surgical intervention); the need for dialysis; serum creatinine–estimated glomerular filtration rate at the time of BKV testing, day 100, and day 365; and death. Children with high viremia more likely developed severe HC compared with those with peak viremia < 10,000 copies/mL (21% versus 2%; P = .02). BKV infection of the blood or urine was not associated with the need for dialysis, change in estimated glomerular filtration rate, or mortality. BKV infection is common after pediatric allogeneic HSCT, and plasma testing in those with HC may predict patients who will develop severe bladder injury. [Copyright &y& Elsevier]

• Matched sibling donor transplants have a survival and cost advantage over unrelated donor transplants. • Matched unrelated donor and unrelated cord blood transplants have similar survival outcomes. • Among unrelated donor transplants, matched unrelated donor transplants have a cost advantage. Allogeneic hematopoietic stem cell transplantation (alloHCT) may be associated with significant morbidity and mortality, resulting in increased healthcare utilization (HCU). To date, no multicenter comparative cost analyses have specifically evaluated alloHCT in children with acute leukemia. In this retrospective cohort study, we examined the relationship between survival and HCU while investigating the hypothesis that matched sibling donor (MSD) alloHCT has significantly lower inpatient HCU with unrelated donor (URD) alloHCT, and that among URDs, umbilical cord blood (UCB) alloHCT will have higher initial utilization but lower long-term utilization. Clinical and transplantation outcomes data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were merged with inpatient cost data from the Pediatric Health Information System (PHIS) database using a probabilistic merge methodology. The merged dataset comprised US patients age 1 to 21 years who underwent alloHCT for acute leukemia between 2004 and 2011 with comprehensive CIBMTR data at a PHIS hospital. AlloHCT was analyzed by donor type, with specific analysis of utilization and costs using PHIS claims data. The primary outcomes of overall survival (OS), leukemia-free survival (LFS), and inpatient costs were evaluated using Kaplan-Meier curves and Cox and Poisson models. A total of 632 patients were identified in both the CIBMTR and PHIS data. The 5-year LFS was 60% for MSD alloHCT, 47% for well-matched matched unrelated donor bone marrow (MUD) alloHCT, 48% for mismatched unrelated donor alloHCT, and 45% for UCB alloHCT (P =.09). Total adjusted costs were significantly lower for MSD alloHCT versus MUD alloHCT by day 100 (adjusted cost ratio [ACR],.73; 95% confidence interval [CI],.62 to.86; P <.001), and higher for UCB alloHCT versus MUD alloHCT (ACR, 1.27; 95% CI, 1.11 to 1.45; P <.001). By 2 years, total adjusted costs remained significantly lower for MSD alloHCT compared with MUD alloHCT (ACR,.67; 95% CI,.56 to.81; P <.001) and higher for UCB alloHCT compared with MUD alloHCT (ACR, 1.25; 95% CI, 1.02 to 1.52; P =.0280). Our data show that UCB and MUD alloHCT provide similar survival outcomes; however, MUD alloHCT has a significant advantage in cost by day 100 and 2 years. More research is needed to determine whether the cost difference among URD alloHCT approaches remains significant with a larger sample size and/or beyond 2 years post-alloHCT. [ABSTRACT FROM AUTHOR]

Graft versus host disease (GVHD) causes significant morbidity and mortality after allogeneic stem cell transplant (SCT). Little is known about genetic determinants of GVHD risk, including human leukocyte antigen (HLA) genotypes outside of HLA-mismatch. HLA-DQ2 and DQ8 genotypes are associated with celiac disease (CD) and are present in ≥90% of patients with CD. Both GVHD and CD are systemic inflammatory conditions that may have T cell-mediated enteropathy. We hypothesized HLA-DQ alleles associated with CD risk would confer increased risks of acute (a) and chronic (c) GVHD in pediatric SCT recipients. We performed a retrospective cohort study of children aged 0-21 years undergoing first allogeneic SCT at the Children's Hospital of Philadelphia from 10/1/12 — 7/1/16. Patients with primary graft failure or missing HLA-DQ genotypes were excluded. We grouped patients by low, moderate or high CD risk (Clin Gastroenterol Hepatol 2009, 7:966). Primary outcomes were 1) 100-day aGVHD incidence; 2) day 100 — 1-year cGVHD incidence; and 3) time to GVHD with relapse, death, secondary graft failure, second SCT, or donor lymphocyte infusion as competing risks. Logistic regressions were used to calculate odds ratios (OR) and 95% confidence intervals (CI). Sub-distribution hazard models were used to estimate crude and adjusted sub-distribution hazard ratios (sHR) in time-to-event analyses. Multivariate models were adjusted for race-ethnicity, malignant/nonmalignant SCT indication, donor/mismatch, and graft source. We identified 167 patients (mean age 9.2 ±6.2 years). Proportions by CD risk were: low-risk n=108 (64.7%), moderate n=33 (19.8%), and high n=26 (15.6%). Day 100 incidence of ≥grade 2 aGVHD was 14.4% (8.4% had ≥grade 3). cGVHD 1-year incidence was 42.7% (14% had extensive). CD risk was protective against GVHD but did not reach statistical significance (Table 1). Risk of clinically significant GVHD (≥grade 2 or any chronic) was reduced in children with CD risk in the adjusted time-to-event model (moderate: sHR 0.42, 95% CI 0.18 — 0.95, p=0.037; high: sHR 0.31, 95% CI 0.12 – 0.8, p=0.016; Figure 1A). The protective effect of high CD risk was more pronounced for severe GVHD (≥grade 3 or chronic extensive) but did not reach statistical significance (adjusted sHR 0.14, 95%CI 0.02-1.09, P = 0.061; Figure 1B). In contrast to our hypothesis, CD risk by HLA-DQ is protective against GVHD in a dose-responsive manner. Reports of HLA-DQ2 and DQ8 protecting against other non-CD autoimmune diseases (rheumatoid arthritis and inflammatory bowel disease) support our observations. These results require confirmation and evaluation in a larger patient sample to define this novel GVHD risk modifier more robustly. [ABSTRACT FROM AUTHOR]

Patients (pts) receiving CTL019 (tisagenlecleucel) for B-ALL with high tumor burden (HTB) are at high risk for developing severe CRS. Tocilizumab, an IL-6 receptor antibody, is a vital component of severe CRS management; however, its role in preventing severe CRS is not known. We sought to determine the effectiveness of preemptive tocilizumab (PT) administration in decreasing the rate of grade (gr) 4 CRS in HTB pts. We conducted a pilot trial of risk-adapted PT after CTL019 (NCT02906371). HTB pts, defined as ≥40% bone marrow (BM) blasts immediately before infusion, received a single dose of PT for high persistent fever (2 temperatures ≥38.5C in 24hr). The primary endpoint was frequency of gr4 CRS (Penn scale), with an observed rate of ≤5/15 predefined as clinically meaningful. Secondary endpoints included complete remission (CR) rate and ICU length of stay (LOS). A comparator cohort with HTB who received standard CRS management (stdCRS) was identified from the initial CTL019 trial (NCT01626495). Characteristics of the PT (n=15) and stdCRS (n=26) HTB cohorts are shown in Table 1. All pts developed gr≥2 CRS; median time to fever was longer in the PT cohort [PT, 3d (IQR 2-9); stdCRS, 2d (IQR 1-7), p=0.03]. Gr4 CRS was observed in 4/15 (27%) pts in the PT cohort vs. 13/26 (50%) in the prior stdCRS cohort [RR 0.53 (95% CI, 0.21-1.34), p=0.18]. In the stdCRS cohort, gr4 CRS was associated with earlier onset of fever (p=0.04). In patients with earlier CRS onset (fever by day +4), gr4 CRS was observed in 4/9 (44%) vs. 13/21 (62%) in the PT and stdCRS cohorts [RR 0.72 (95% CI, 0.32-1.60), p=0.42]. Except for a trend toward fewer vasoactive days in the PT cohort, ICU LOS and resource utilization were not significantly different (Table 2). The CR rate at day 28 was similar in the PT and stdCRS cohorts (87% vs. 85%, p=1.00). Risk-adapted PT administration reduced gr4 CRS, meeting the predefined study endpoint, without impacting the CR rate. A secondary comparison to a prior trial showed a clinically meaningful decrease in the rate of gr4 CRS from 50% to 27%; however, the analysis was not powered to detect a statistically significant difference. Ongoing analyses will evaluate CAR T cell expansion, duration of remission, and additional safety endpoints, including rates of neurotoxicity. [ABSTRACT FROM AUTHOR]

Acute lung injury is a fatal condition characterized by excessive inflammation responses. Salidroside, the active constituent of Rhodiola rosea , possesses properties including anti-oxidation, anti-aging, anti-inflammatory, anti-hypoxia, and anti-cancer activities. In the present study, Salidroside attenuated acute lung injury via inhibition of inflammatory cytokine production. Rats pre-treated with Salidroside showed attenuated lipopolysaccharide (LPS)-induced pathological damage and suppressed tumor necrosis factor-alpha (TNFα) and interleukin 6 (IL-6) secretion in the lung. Furthermore, flow cytometry showed that Salidroside reduced the production of TNFα and IL-6 in NR8383 alveolar macrophages. These findings suggest that Salidroside may attenuate LPS-induced acute lung injury. • Sal attenuates LPS-induced pathological damage and decreases the W/D lung ratio. • Sal suppresses TNFα, IL-6, and GM-CSF secretion in the ALI model. • Sal inhibits TNFα, IL-6, and GM-CSF transcription in lung tissues in the ALI model. • Sal reduces TNFα and IL-6 production induced by LPS in NR8383 cells. [ABSTRACT FROM AUTHOR]

CART19-related toxicities may require treatment inpatient or in the ICU. We sought to describe inpatient/ICU resource utilization within 30 days of CART19 infusion and evaluate trends in resource utilization from 2012-2019. We identified patients (pts) with ALL treated with CART19 on a clinical trial (NCT01626495, NCT02906371, and NCT02374333) or with the commercial product, tisagenlecleucel, at Children's Hospital of Philadelphia. Demographic, pharmacy, and inpatient data were extracted from the EHR from day of infusion (d0) to d+30 using a semi-automated EPIC data query tool. The Virtual Pediatric Systems database was queried for resource utilization data and PRISM 3 and PIM 2 severity of illness scores. Log-binomial and linear regression were used to estimate the association of patient characteristics with inpatient/ICU admission and inpatient/ICU length of stay (LOS). Similar models were used to estimate trends over time. The analyses included 213 pts. Median age was 12y (range 1-29y); 60% were male. Prior to CART19, 42% had an alloHCT. Pre-infusion, 19% had high tumor burden (HTB), defined as bone marrow blasts ≥40%. From 2012-2019, the proportion of pts with prior alloHCT or HTB decreased (Table 1). CART19 was infused in the outpatient setting in 198 (93%) pts. From d0 to d+30, 149 (70%) had ≥1 inpatient admission, starting at a median of d+2 (IQR +1 to +6). Among admitted pts, median cumulative inpatient LOS was 7d (IQR 4-13). From 2012-2019, there were linear trends toward decreases in proportion of pts admitted (p <.001) and in inpatient LOS (p <.001, Figure 1). These decreases persisted after adjustment for HTB (p =0.03 and p <.001). ICU admission was required for 49 (23%) pts, starting at a median of day +5 (IQR +4 to +7). ICU admission was more frequent for pts with HTB [HTB, 68% (95% CI, 52-81) vs. low burden, 11% (95% CI, 7-17), p <.001]. Among ICU pts, resources utilized included tocilizumab (n=36, 75%), vasoactives (n=36, 75%), invasive mechanical ventilation (n=18, 8%), and dialysis (n=4, 8%). In the 30d follow-up period, median ICU LOS was 7d (IQR 3-12), but 6 (13%) pts remained in the ICU after d+30. Median duration of vasoactive, mechanical ventilation, and dialysis use was 5d, 7d and 2d, respectively. Predicted median risk of mortality was 6% (IQR 5-7) by PIM 2 and 11% (IQR 7-27) by PRISM 3 scores. However, observed 30d mortality was 1% (n=2) across the cohort, or 4% among ICU pts. From 2012-2019, there was a decrease in ICU admissions (p <.01), but no significant change in ICU LOS (Figure 1). Other than HTB, baseline characteristics were not associated with inpatient/ICU admission or LOS. In a cohort of 213 pediatric pts, over 90% were safely infused with CART19 in the outpatient setting. Though 70% required at least one admission, the proportion of pts admitted to the hospital or ICU and cumulative inpatient LOS decreased over the past 7 years. [ABSTRACT FROM AUTHOR]

Background CD19-targeted chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable clinical efficacy in treating relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). However, there are potential treatment-related toxicities, which may be severe. Acute kidney injury (AKI) has been reported after CD19 CAR T cells, but not systematically evaluated. We sought to describe AKI incidence, severity, outcome, and risk factors in the first 30 days after CTL019, a CD19 CAR T cell therapy, for ALL in pediatric patients. Methods We studied patients treated with CTL019 through two clinical trials (NCT01626495 and NCT02906371) at Children's Hospital of Philadelphia between April 2012 and April 2018. Demographic, laboratory and pharmacy data were automatically extracted from the electronic medical record using an EPIC data query tool. The primary outcome was AKI within 30 days after CTL019 infusion. AKI was defined using the Kidney Disease: Improving Global Outcomes criteria. Stage 1 (serum creatinine (SCr) >= 1.5 times the baseline) was classified as mild AKI. Stage 2 or 3 (SCr >=2 times the baseline) were classified as severe AKI. Renal recovery was defined as improvement in SCr to within 1.5 times the baseline by day +30. Log-binomial regression was used to estimate risk ratios for the association of cytokine release syndrome (CRS) and other patient characteristics with the development of AKI. Results A total of 125 patients and 3231 creatinine values were analyzed. Median patient age was 11.2 (range: 1.4-29.1) years at CTL019 infusion; 57.6% were male, 72% were Caucasian, and 82.4% were non-Hispanic. AKI developed in 26 patients (21.0%; 95% CI, 14.5 to 28.9), severe AKI developed in 15 patients (12%; 95% CI 7.3 to 19.1), and 3 patients (2.4%; 95% CI 0.7 to 7.3) required renal-replacement therapy. Among patients who developed AKI, 22 (88%: 95% CI 66.7 to 96.4) recovered renal function by day +30. Patients with Grade 3/4 CRS had a 4.9 times greater risk of developing AKI (95% CI, 2.4 to 9.9; p<.001) and a 10.3 times greater risk of developing severe AKI (95% CI 3.1 to 34.3; p<.001) than patients with no or Grade 1/2 CRS (Figure 1). The median time to CRS start, AKI onset, and maximum SCr level was 2, 7 and 9 days after infusion, respectively. History of hematopoietic cell transplant prior to CTL019 was not significantly associated with AKI, nor were age, sex, race, and ethnicity. Conclusion In the first 30 days after CTL019 infusion, 21% of patients developed AKI, but most recovered renal function by day +30. AKI was strongly associated with Grades 3 and 4 CRS and developed at a median of 5 days after the start of CRS. Additional analyses will compare the trajectories of CRS biomarkers and tumor lysis labs with the trajectory of AKI in order to better elucidate mechanisms of renal injury and identify opportunities for intervention. [ABSTRACT FROM AUTHOR]