Implementation of a light therapy team to administer photobiomodulation therapy: A standardized protocol to prevent and treat oral mucositis in the pediatric hematopoietic stem cell transplant population.

BACKGROUND: Oral mucositis (OM) is a painful and common complication of hematopoietic stem cell transplant (HSCT). The Children's Oncology Group recently published guidelines recommending photobiomodulation (PBM) for preventing and treating OM in pediatric HSCT patients. However, this is a rarely used intervention in pediatric hospitals. PROCEDURE: Patients undergoing allogeneic HSCT, or autologous HSCT for a neuroblastoma diagnosis, had PBM administered from the first day of conditioning to transplant Day +20. We successfully developed a standardized treatment protocol and workflow to ensure consistent and uniform delivery of PBM. In addition, clinical patient data were compared before and after PBM implementation. RESULTS: The administration of PBM at our center was feasible, but required dedicated staff. A registered nurse (RN) was determined to be the best fit to deliver PBM. Sixty-two patients received PBM from October 2022 to September 2023; patients from 2021 before PBM implementation were used for comparison. Patients receiving PBM were more likely (p = .03) to engage in teeth brushing (56/62 = 90%) compared to baseline (61/81 = 75%). Mean days of OM decreased from 11.3 to 9 days; patients who received PBM were less likely (p < .001) to be discharged on total parental nutrition (TPN) (11/62 = 18%) compared to baseline (50/82 = 61%). OM-related supportive care costs (TPN and patient-controlled anesthesia [PCA]) were lower (p = .02) for those who received PBM (median cost = $31,229.87 vs. $37,370.66). CONCLUSION: PBM, as the standard of care in the pediatric HSCT population, is safe, feasible, and well-tolerated. At our center, a dedicated RN was critical to providing standardized treatment and ensuring sustainability.

Addressing a Pre-Clinical Pipeline Gap: Development of the Pediatric Acute Myeloid Leukemia Patient-Derived Xenograft Program at Texas Children's Hospital at Baylor College of Medicine.

The survival rate of pediatric acute myeloid leukemia (pAML) is currently around 60%. While survival has slowly increased over the past few decades, the development of novel agents likely to further improve survival for this heterogeneous patient population has been limited by gaps in the pAML pre-clinical pipeline. One of the major hurdles in evaluating new agents for pAML is the lack of pAML patient-derived xenograft (PDX) models. Unlike solid tumors and other types of leukemias, AML is notoriously hard to establish in mouse models, likely due in part to the need for specific human microenvironment elements. Our laboratory at TCH/BCM addressed this gap by establishing a systematic PDX workflow, leveraging advanced immunodeficient hosts and capitalizing on our high volume of pAML patients and close coordination between labs and clinical sections. Patients treated at TCH are offered the chance to participate in specimen banking protocols that allow blood and bone marrow collection as well as the collection of relevant clinical data. All patients who consent and have samples available are trialed for PDX development. In addition, samples from the Children's Oncology Group (COG) are also trialed for PDX generation. Serially transplanting PDX models are validated using short tandem repeat (STR) and characterized using both targeted DNA/RNA next generation sequencing and RNAseq. As of March 2023, this systematic approach has resulted in 26 serially transplanting models. Models have been shared with requesting labs to facilitate external pAML pre-clinical studies. Available PDX models can be located through the BCM PDX Portal. We expect our growing PDX resource to make a significant contribution to expediting the testing of promising novel therapeutics for pAML.

Tibial Spine Fractures in the Child and Adolescent Athlete: A Systematic Review and Meta-analysis.

BACKGROUND: Tibial spine fractures (TSFs) are uncommon injuries that may result in substantial morbidity in children. A variety of open and arthroscopic techniques are used to treat these fractures, but no single standardized operative method has been identified. PURPOSE: To systematically review the literature on pediatric TSFs to determine the current treatment approaches, outcomes, and complications. STUDY DESIGN: Meta-analysis; Level of evidence, 4. METHODS: A systematic review of the literature was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) guidelines using PubMed, Embase, and Cochrane databases. Studies evaluating treatment and outcomes of patients <18 years old were included. Patient demographic characteristics, fracture characteristics, treatments, and outcomes were abstracted. Descriptive statistics were used to summarize categorical and quantitative variables, and a meta-analytic technique was used to compare observational studies with sufficient data. RESULTS: A total of 47 studies were included, totaling 1922 TSFs in patients (66.4% male) with a mean age of 12 years (range, 3-18 years). The operative approach was open reduction and internal fixation in 291 cases and arthroscopic reduction and internal fixation in 1236 cases; screw fixation was used in 411 cases and suture fixation, in 586 cases. A total of 13 nonunions were reported, occurring most frequently in Meyers and McKeever type III fractures (n = 6) and in fractures that were treated nonoperatively (n = 10). Arthrofibrosis rates were reported in 33 studies (n = 1700), and arthrofibrosis was present in 190 patients (11.2%). Range of motion loss occurred significantly more frequently in patients with type III and IV fractures (P < .001), and secondary anterior cruciate ligament (ACL) injury occurred most frequently in patients with type I and II fractures (P = .008). No statistically significant differences were found with regard to rates of nonunion, arthrofibrosis, range of motion loss, laxity, or secondary ACL injury between fixation methods (screw vs suture). CONCLUSION: Despite variation in TSF treatment, good overall outcomes have been reported with low complication rates in both open and arthroscopic treatment and with both screw and suture fixation. Arthrofibrosis remains a concern after surgical treatment for TSF, but no significant difference in incidence was found between the analysis groups. Larger studies are necessary to compare outcomes and form a consensus on how to treat and manage patients with TSFs.

Postoperative Strength Differences at Short-Term Follow-up Vary Based on Autograft Harvest Site After Adolescent Transphyseal Anterior Cruciate Ligament Reconstruction.

PURPOSE: To compare the clinical and patient-reported outcomes of adolescent patients who underwent anterior cruciate ligament reconstruction (ACLR) with quadriceps tendon (QT) versus hamstring tendon (HT) autograft. METHODS: This was a retrospective cohort study of adolescent patients aged 18 years or younger treated at a single tertiary care children's hospital who underwent primary transphyseal ACLR using QT or HT between January 2018 and December 2019. All patients had minimum 6-month follow-up. Outcomes included isokinetic strength testing, postoperative Patient-Reported Outcomes Measurement Information System and International Knee Documentation Committee scores, and complications; these were compared between the QT and HT cohorts. RESULTS: A total of 84 patients (44 HT and 40 QT patients) were included. The QT cohort had a higher proportion of male patients (62.5% vs 34.1%, P = .01). At 3 months, HT patients had a lower hamstring-quadriceps (H/Q) strength ratio (60.7 ± 11.0 vs 79.5 ± 18.6, P < .01) and lower Limb Symmetry Index in flexion (85.6 ± 16.1 vs 95.5 ± 15.7, P = .01) whereas QT patients had a lower Limb Symmetry Index in extension (67.3 ± 9.5 vs 77.4 ± 10.7, P < .01). The H/Q ratio at 6 months was lower in HT patients (59.4 ± 11.5 vs 66.2 ± 7.5, P < .01). Patient-Reported Outcomes Measurement Information System and International Knee Documentation Committee scores were not different at 3 months or latest follow-up. QT patients had more wound issues (20.0% vs 2.3%, P = .01). Patients receiving HT autograft had more ipsilateral knee injuries (18.2% vs 2.5%, P = .03), but there was no difference in graft failure for ACLR using HT versus QT (9.1% vs 2.5%, P = .36). CONCLUSIONS: There were no differences in patient-reported outcome measures between patients receiving QT autografts and those receiving HT autografts. Patients with QT grafts had more postoperative wound issues but a lower rate of ipsilateral knee complications (graft failure or meniscal tear). Differences in quadriceps and hamstring strength postoperatively compared with the contralateral limb were observed for adolescent ACLR patients receiving QT and HT autografts, respectively. This contributed to higher H/Q ratios seen at 3 and 6 months postoperatively for patients receiving QT autografts. LEVEL OF EVIDENCE: Level III, retrospective comparative therapeutic study.

Achilles Tendon Injuries in the Pediatric Population.

BACKGROUND: Achilles tendon injuries are common in adults, and there is extensive literature describing the injury characteristics and treatment of these adult injuries. However, Achilles injuries are rare in the pediatric population and as a result, there is limited research reported on this age group. We therefore sought to characterize the injury presentation, treatment and outcomes for pediatric patients with partial and complete Achilles injuries. METHODS: A retrospective chart review was conducted of patients aged 0-18 treated for Achilles tendon injuries at 2 geographically distinct tertiary institutions between 2008 and 2021. Data collected included demographics, injury characteristics, and treatment course. Injury types were separated into 2 cohorts: traumatic Achilles injuries and ruptures due to muscular contraction. Traumatic injuries were further delineated into 2 injury mechanisms: open injuries related to penetrating trauma and closed injuries related to blunt trauma. Standard descriptive analyses were utilized to summarize findings. RESULTS: Thirty-nine patients (43.6% female, median age 15 years) were identified, 29 (74.4%) of whom had complete tears. Twenty-five patients (64.1%) presented with traumatic injuries; among these, 48.0% (n=12/25) were ≤12 years. All patients ≤12 years sustained a traumatic injury. The most common traumatic mechanism was an open laceration due to penetrating trauma (68.0%), followed by closed ruptures associated with blunt trauma (32.0%). Fourteen patients (35.9%) presented with closed ruptures due to muscular contraction. Four patients (10.2%) had a prior history of clubfoot treated with Achilles tenotomy. Thirty-five patients (89.7%) were surgically treated with an open repair. The median immobilization period across all patients was 11 weeks (interquartile range: 10-12), starting most commonly with a posterior splint (46.2%) and concluding with a CAM boot (94.9%). Of patients with full follow-up data (n=22/39), all resumed normal activities, with a median clearance time of 6 months (interquartile range: 5-7.9). CONCLUSIONS: We found that older adolescents (≥14 y) were more likely to rupture their Achilles tendon through a forceful muscular contraction, whereas younger patients (≤12 y) were more likely to injure their Achilles via a traumatic mechanism. Most patients were treated operatively and returned to sports at a median time of 6 months. A further prospective study is warranted to better characterize treatment protocols and patient outcomes in this population. LEVEL OF EVIDENCE: Level-IV.

Venetoclax for Acute Myeloid Leukemia in Pediatric Patients: A Texas Medical Center Experience.

The BCL-2 inhibitor venetoclax improves survival for adult patients with acute myeloid leukemia (AML) in combination with lower-intensity therapies, but its benefit in pediatric patients with AML remains unclear. We retrospectively reviewed two Texas Medical Center institutions' experience with venetoclax in 43 pediatric patients with AML; median age 17 years (range, 0.6-21). This population was highly refractory; 44% of patients (n = 19) had ≥3 prior lines of therapy, 37% (n = 16) had received a prior bone marrow transplant, and 81% (n = 35) had unfavorable genetics KMT2A (n = 17), WT1 (n = 13), FLT3-ITD (n = 10), monosomy 7 (n = 5), TP53 (n = 3), Inv(3) (n = 3), IDH1/2 (n = 2), monosomy 5 (n = 1), NUP98 (n = 1) and ASXL1 (n = 1). The majority (86%) received venetoclax with a hypomethylating agent. Grade 3 or 4 adverse events included febrile neutropenia in 37% (n = 16), non-febrile neutropenia in 12% (n = 5), anemia in 14% (n = 6), and thrombocytopenia in 14% (n = 6). Of 40 patients evaluable for response, 10 patients (25%) achieved complete response (CR), 6 patients (15%) achieved CR with incomplete blood count recovery (CRi), and 2 patients (5%) had a partial response, (CR/CRi composite = 40%; ORR = 45%). Eleven (25%) patients received a hematopoietic stem cell transplant following venetoclax combination therapy, and six remain alive (median follow-up time 33.6 months). Median event-free survival and overall survival duration was 3.7 months and 8.7 months, respectively. Our findings suggest that in pediatric patients with AML, venetoclax is well-tolerated, with a safety profile similar to that in adults. More studies are needed to establish an optimal venetoclax-based regimen for the pediatric population.

Repurposing Atovaquone as a Therapeutic against Acute Myeloid Leukemia (AML): Combination with Conventional Chemotherapy Is Feasible and Well Tolerated.

Survival of pediatric AML remains poor despite maximized myelosuppressive therapy. The pneumocystis jiroveci pneumonia (PJP)-treating medication atovaquone (AQ) suppresses oxidative phosphorylation (OXPHOS) and reduces AML burden in patient-derived xenograft (PDX) mouse models, making it an ideal concomitant AML therapy. Poor palatability and limited product formulations have historically limited routine use of AQ in pediatric AML patients. Patients with de novo AML were enrolled at two hospitals. Daily AQ at established PJP dosing was combined with standard AML therapy, based on the Medical Research Council backbone. AQ compliance, adverse events (AEs), ease of administration score (scale: 1 (very difficult)-5 (very easy)) and blood/marrow pharmacokinetics (PK) were collected during Induction 1. Correlative studies assessed AQ-induced apoptosis and effects on OXPHOS. PDX models were treated with AQ. A total of 26 patients enrolled (ages 7.2 months-19.7 years, median 12 years); 24 were evaluable. A total of 14 (58%) and 19 (79%) evaluable patients achieved plasma concentrations above the known anti-leukemia concentration (>10 µM) by day 11 and at the end of Induction, respectively. Seven (29%) patients achieved adequate concentrations for PJP prophylaxis (>40 µM). Mean ease of administration score was 3.8. Correlative studies with AQ in patient samples demonstrated robust apoptosis, OXPHOS suppression, and prolonged survival in PDX models. Combining AQ with chemotherapy for AML appears feasible and safe in pediatric patients during Induction 1 and shows single-agent anti-leukemic effects in PDX models. AQ appears to be an ideal concomitant AML therapeutic but may require intra-patient dose adjustment to achieve concentrations sufficient for PJP prophylaxis.

IL-10 and TNFα are associated with decreased survival in low-risk pediatric acute myeloid leukemia; a children's oncology group report.

Pediatric acute myeloid leukemia (AML) is a devastating disease with a high risk of relapse. Current risk classification designates patients as high or low risk (LR) based on molecular features and therapy response. However, 30% of LR patients still suffer relapse, indicating a need for improvement in risk stratification. Cytokine levels, such as IL-6 and IL-10, have been shown to be prognostic in adult AML but have not been well studied in children. Previously, we reported elevated IL-6 levels in pediatric AML bone marrow to be associated with inferior prognosis. Here, we expanded our investigation to assess cytokine levels in diagnostic peripheral blood plasma (PBP) of pediatric AML patients and determined correlation with outcome. Diagnostic PBP was obtained from 80 patients with LR AML enrolled on the Children's Oncology Group AAML1031 study and normal PBP from 11 controls. Cytokine levels were measured and correlation with clinical outcome was assessed. IL-6, TNFα, MIP-3a, and IL-1ß were significantly higher in AML patients versus controls when corrected by the Bonferroni method. Furthermore, elevated TNFα and IL-10 were significantly associated with inferior outcomes. Our data demonstrate that in diagnostic PBP of LR pediatric AML patients, certain cytokine levels are elevated as compared to healthy controls and that elevated TNFα and IL-10 are associated with inferior outcomes, supporting the idea that an abnormal inflammatory state may predict poor outcomes. Studies are needed to determine the mechanisms by which these cytokines impact survival, and to further evaluate their use as prognostic biomarkers in pediatric AML.

Chlorhexidine gluconate (CHG) foam improves adherence, satisfaction, and maintains central line associated infection rates compared to CHG wipes in pediatric hematology-oncology and bone marrow transplant patients.

CHG-based hygiene methods are often a component of daily hygiene bundles to prevent central line-associated blood stream infections (CLABSIs) in pediatric hematology-oncology patients; however, adherence with 2% CHG wipes was inconsistent within our institution, risking infection for immunocompromised patients. A new 4% CHG foam method offers an alternative and is applied while bathing, as opposed to wipes used 1 h after bathing. An initial cohort of 24 high-risk oncology and bone marrow transplant (BMT) patients agreed to use 4% CHG foam in place of wipes, and then answered surveys to describe their experiences. Ninety-two percent preferred foam over wipes and were more likely to use the foam moving forward. CHG foam was then made available as an option to all patients in need of central line care upon admission to the hospital. Hygiene bundles in the electronic medical record were reviewed to measure baseline adherence rates. Random audits by nursing administration prospectively assessed CHG adherence. CLABSI data were collected prospectively with routine quality metric reports. Results were analyzed using run charts and u-charts, respectively. Hematology-Oncology unit adherence rates remained at a higher rate of adherence, and BMT unit adherence rates increased from an average of 55%-81.6% (p < 0.001). Primary CLABSIs remained rare events (average <1/1000 CVL days). On cost analysis, utilizing CHG foam results in an annual savings estimate of $40,000 for a 24-bed unit. In conclusion, 4% CHG foam provides a cost-effective and patient-preferred option for daily hygiene that maintains CLABSI preventative efforts.

A Novel Oncodental Collaborative Team: Integrating Expertise for Central Line-Associated Bloodstream Infection Prevention in Pediatric Oncology Patients.

PURPOSE: Pediatric oncology and bone marrow transplant patients are at high risk of infection, and limitations to dental expertise among medical providers render patients vulnerable to central line-associated bloodstream infections from oral pathogens. Traditionally, oral health maintenance relied on patients and bedside nurses; however, routine methods are often suboptimal to prevent central line-associated bloodstream infection in high-risk patients. Limited overlap of medical and dental expertise, and limited dental resources in typical oncology units, prevent optimal oral care for children with cancer, requiring novel solutions to better integrate specialties. METHODS: Here, we outline the creation of a novel Pediatric oncodental team to address oral-systemic infection prevention strategies for high-risk patients. RESULTS: Our oncology and dental teams created a systematic approach for increasing oral surveillance and treatment in select high-risk patients. Supervised pediatric dental residents participated in scheduled oncology rounds, and a permanent oral health educator with a background in dental hygiene was also hired as a dedicated dental professional within our oncology department. CONCLUSION: Our pediatric oncodental team aims to sustain optimal oral complication prevention strategies to reduce the risk of infection, provide education on the significance of the oral-systemic link in cancer care, and improve access and continuity of care.

Ex Vivo Drug Sensitivity Correlates with Clinical Response and Supports Personalized Therapy in Pediatric AML.

Acute myeloid leukemia (AML) is a heterogeneous disease that accounts for ~20% of all childhood leukemias, and more than 40% of children with AML relapse within three years of diagnosis. Although recent efforts have focused on developing a precise medicine-based approach towards treating AML in adults, there remains a critical gap in therapies designed specifically for children. Here, we present ex vivo drug sensitivity profiles for children with de novo AML using an automated flow cytometry platform. Fresh diagnostic blood or bone marrow aspirate samples were screened for sensitivity in response to 78 dose conditions by measuring the reduction in leukemic blasts relative to the control. In pediatric patients treated with conventional chemotherapy, comprising cytarabine, daunorubicin and etoposide (ADE), ex vivo drug sensitivity results correlated with minimal residual disease (r = 0.63) and one year relapse-free survival (r = 0.70; AUROC = 0.94). In the de novo ADE analysis cohort of 13 patients, AML cells showed greater sensitivity to bortezomib/panobinostat compared with ADE, and comparable sensitivity between venetoclax/azacitidine and ADE ex vivo. Two patients showed a differential response between ADE and bortezomib/panobinostat, thus supporting the incorporation of ex vivo drug sensitivity testing in clinical trials to further evaluate the predictive utility of this platform in children with AML.

Validation of atovaquone plasma levels by liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring in pediatric patients.

Background: Atovaquone has traditionally been used as an antiparasitic and antifungal agent, but recent studies have shown its potential as an anticancer agent. The high variability in atovaquone bioavailability highlights the need for therapeutic drug monitoring, especially in pediatric patients. The goal of our study was to develop and validate the performance of an assay to quantify atovaquone plasma concentrations collected from pediatric cancer patients using LC-MS/MS. Methods: Atovaquone was extracted from a 10 µL volume of K2-EDTA human plasma using a solution consisting of ACN: EtOH: DMF (8:1:1 v:v:v), separated using reverse-phase chromatography, and detected using a SCIEX 5500 QTrap MS system. LC-MS/MS assay performance was evaluated for precision, accuracy, carryover, sensitivity, specificity, linearity, and interferences. Results: Atovaquone and its deuterated internal standard were analyzed using a gradient chromatographic method that had an overall cycle-time of 7.4 min per injection, and retention times of 4.3 min. Atovaquone was measured over a dynamic concentration range of 0.63 - 80 µM with a deviation within ≤ ± 5.1 % of the target value. Intra- and inter-assay precision were ≤ 2.7 % and ≤ 8.4 %, respectively. Dilutional, carryover, and interference studies were also within acceptable limits. Conclusions: Our studies have shown that our LC-MS/MS-based method is both reliable and robust for the quantification of plasma atovaquone concentrations and can be used to determine the effective dose of atovaquone for pediatric patients treated for AML.

Real-world experience in treating pediatric relapsed/refractory or therapy-related myeloid malignancies with decitabine, vorinostat, and FLAG therapy based on a phase 1 study run by the TACL consortium.

Current therapies for relapsed/refractory (R/R) pediatric myeloid neoplasms are inadequately effective. Real-world data (RWD) can improve care by augmenting traditional studies and include individuals not eligible for clinical trials. The Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium recently completed T2016-003, a phase 1 study of decitabine, vorinostat, fludarabine, cytarabine, and granulocyte colony-stimulating factor (G-CSF) in R/R acute myeloid leukemia (AML), which added epigenetic drugs to a cytotoxic backbone. We report results of RWD from six centers that treated 28 pediatric patients (26 with AML, two with other myeloid neoplasms) identically to the TACL study but who were not enrolled. This allowed unique analyses and the ability to compare data with the 35 TACL study patients. The overall response rate (ORR) (complete response [CR] plus CR with incomplete count recovery) among 26 RWD evaluable patients was 65%. The ORR of 13 patients with relapsed AML with epigenetic alterations was 69% (T2016-003 + RWD: 68%, n = 25), of eight patients with refractory AML was 38% (T2016-003 + RWD: 41%, n = 17) and of five patients with therapy-related AML (t-AML) was 80% (T2016-003 + RWD: 75%, n = 8). The mean number of Grade 3/4 toxicities experienced by the T2016-003-eligible RWD population (n = 22) (one per patient-cycle) was not meaningfully different than those (n = 6) who would have been TACL study-ineligible secondary to comorbidities (two per patient-cycle). Overall, this therapy was well tolerated and effective in pediatric patients with R/R myeloid neoplasms, particularly those with epigenetic alterations, t-AML, and refractory disease.

Near-Haploid B-Cell Acute Lymphoblastic Leukemia in a Patient with Rubinstein-Taybi Syndrome.

Rubinstein-Taybi syndrome (RSTS) is a rare disorder characterized by developmental delay, short stature, dysmorphic facies and skeletal abnormalities. RSTS has been linked to a variety of malignant and benign tumors, but the frequency and characteristics of RSTS-related neoplasms remain unclear. We describe a unique case of near haploid B-cell lymphoblastic leukemia (B-ALL) in a 6-year-old girl with RSTS who harbors a likely pathogenic variant in CREBBP. Somatic CREBBP variants are enriched in some subsets of ALL; however, germline variants have not been previously described in childhood leukemia and may represent an underrecognized predisposition to malignancy. Our patient's disease responded poorly to conventional chemotherapy and relapsed following a complete remission achieved with CD19 CAR T cell therapy. We propose that the constitutional CREBBP variant may have played a significant role in the leukemia's resistance to chemotherapy and this patient's poor response to therapy.

Levofloxacin prophylaxis for pediatric leukemia patients: Longitudinal follow-up for impact on health care-associated infections.

BACKGROUND: Bloodstream infections (BSIs) cause morbidity and mortality in pediatric patients with leukemia. Antibiotic prophylaxis during periods of chemotherapy-induced neutropenia may reduce the incidence of BSIs. PROCEDURE: A levofloxacin prophylaxis guideline was implemented for pediatric patients with acute myeloid leukemia and relapsed acute lymphoblastic leukemia. We conducted a retrospective cohort study over 4 years (2 years pre and 2 years post implementation) of the practice guideline to assess the impact on central line-associated bloodstream infections (CLABSI) and BSI events. Secondary outcomes included incidence of Clostridioides difficile-associated diarrhea, bacteremia due to multidrug-resistant organisms (MDRO), and bacteremia due to levofloxacin nonsusceptible organisms. STATA was used for data analysis. RESULTS: Sixty-three and 72 patients met inclusion criteria for the pre- and postimplementation cohorts, respectively. Demographics were similar between the groups. We observed 60 BSI events in the pre-group versus 49 events in the post-group (p = .1). Bacteremia due to Gram-negative rods (risk ratio [RR] 0.37 [0.21, 0.66], p < .001) and National Healthcare Safety Network (NHSN) CLABSIs (RR 0.62 [0.44, 0.89], p = .01) were significantly reduced in the postimplementation group. The incidences of C. difficile-associated diarrhea and MDRO bacteremia were similar between groups. However, we observed an increase in the incidence of BSI due to Gram-negative rods that were nonsusceptible to levofloxacin (RR 3.38 [0.72, 6.65], p < .001). CONCLUSION: Following implementation of a levofloxacin prophylaxis guideline, we observed a significant decrease in BSIs due to Gram-negative rods and NHSN CLABSIs. Vigilant monitoring of outcomes post guideline implementation is critical to track emergence of resistant organisms.

Defining the transcriptional control of pediatric AML highlights RARA as a superenhancer-regulated druggable dependency.

Somatic mutations are rare in pediatric acute myeloid leukemia (pAML), indicating that alternate strategies are needed to identify targetable dependencies. We performed the first enhancer mapping of pAML in 22 patient samples. Generally, pAML samples were distinct from adult AML samples, and MLL (KMT2A)-rearranged samples were also distinct from non-KMT2A-rearranged samples. Focusing specifically on superenhancers (SEs), we identified SEs associated with many known leukemia regulators. The retinoic acid receptor alpha (RARA) gene was differentially regulated in our cohort, and a RARA-associated SE was detected in 64% of the study cohort across all cytogenetic and molecular subtypes tested. RARA SE+ pAML cell lines and samples exhibited high RARA messenger RNA levels. These samples were specifically sensitive to the synthetic RARA agonist tamibarotene in vitro, with slowed proliferation, apoptosis induction, differentiation, and upregulated retinoid target gene expression, compared with RARA SE- samples. Tamibarotene prolonged survival and suppressed the leukemia burden of an RARA SE+ pAML patient-derived xenograft mouse model compared with a RARA SE- patient-derived xenograft. Our work shows that examining chromatin regulation can identify new, druggable dependencies in pAML and provides a rationale for a pediatric tamibarotene trial in children with RARA-high AML.

Introduction to the Special Issue on Pediatric Acute Myeloid Leukemia: Current Management and Future Directions.

This Special Issue brings together an original research report, a fascinating case report, and three timely reviews on a variety of topics related to pediatric leukemia [...].