Clinical Outcomes In Pediatric Patients Research Articles

Genome-Wide Association Study Identifies Variants Associated with Clinical Outcomes in Pediatric Patients with Newly Diagnosed Acute Myeloid Leukemia

Genetic aberrations in leukemic blasts are associated with clinical outcomes in patients with AML. However, the role of inherited genetic variants with regards to variation in AML treatment outcome remains obscure. To that end, we conducted a genome wide association study (GWAS) on 400 newly diagnosed pediatric AML patients to identify single nucleotide polymorphism (SNPs) that may be associated with minimal residual disease (MRD1) after induction 1 chemotherapy, event-free survival (EFS) and overall survival (OS). In this study, we utilized whole-genome genotyping with Illumina's Omni2.5Exome-8 BeadChip array to investigate SNPs for association with clinical outcome in 2 pediatric AML cohorts: the multi-site AML02 [NCT00136084, n=167] and AML08 [NCT00703820, n=233] trials. Post GWAS quality control, 1,365,439 unphased SNP genotypes were selected for imputation using TOPMed Imputation Server. Following imputation and additional quality control filtering, 6,741,200 SNPs evaluated for association with clinical outcomes (MRD1, EFS and OS). To improve statistical rigor, two GWAS approaches were utilized: i) A one-stage GWAS with both clinical trial cohorts combined (n=400) and ii) A two-stage GWAS where we utilized a two-step iterative resampling procedure (PMID: 26377241) by splitting the cohort at a 70:30 ratio into discovery and replication cohorts, balanced by clinical trial, treatment arm and initial risk group at diagnosis (100 randomizations performed). For each of the 100 iterations of the two-stage GWAS, we used the discovery cohort to perform a genome-wide analysis, followed by a replication screen. SNPs replicated in at least 20 of 100 rounds of discovery-replication were prioritized. A comparison of the two approaches showed all significant SNPs in the two-stage GWAS were also captured in the one-stage GWAS. For EFS, a Bonferroni-adjusted genome-wide significant association was observed for a SNP in CSMD1 and this SNP was replicated in 83 out of 100 discovery-replication rounds for two-stage GWAS. For CSMD1 SNP, presence of variant A allele has significantly reduced EFS (HR=3.29, 95% CI (2.177-4.975), P=1.61x10-8, Figure 1A). CSMD1 is a membrane-bound complement inhibitor that has been shown to act as a putative tumor suppressor gene in other malignancies (PMIDs:27764775, 35623420). Another significant marker worth mentioning was an intronic SNP in CDKN2B-AS1 that associated with poor outcome [EFS: HR=2.37, 95% CI (1.700-3.317), P=4.40x10-7] and [OS: HR=2.87, 95% CI (1.954-4.225), P=8.06x10-8, Figure 1B]. This marker is in high linkage disequilibrium with 26 other SNPs within the CDKN2B and CDKN2B-AS1 cluster. The product of this gene is an RNA molecule that interacts with polycomb repressive complex-1 (PRC1) and -2 (PRC2) involved in silencing other genes within this cluster through epigenetic mechanisms (PMID: 20716771). CDKN2B-AS1 has been reported to play a role in tumorigenesis and chemoresistance in pediatric T-cell acute lymphoblastic leukemia and with the risk of chronic lymphocytic leukemia (PMIDs: 32976214/23770605). Though limited by numbers, this is one of the largest GWAS conducted in pediatric AML to identify SNPs associated with clinical outcomes. Our top results show that genetic variation in several genes of biological relevance may impact MRD1, EFS and OS. Future studies are aimed at looking at SNP/gene and association with gene expression collected from leukemic cells at time of diagnosis to establish AML-specific eQTLs and functional validation of the most promising candidates. Additionally, future analyses will include other subgroups such as cytogenetic risk group and validation of these findings in larger cohort of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Low-dose proton radiotherapy for pediatric choroidal hemangioma

<h3>Objectives</h3> Background: Management of pediatric choroidal hemangioma complicated by large exudative retinal detachment can be challenging, with few treatment options available. Limited data have been published on the outcomes following the use of low-dose proton radiotherapy (PRT) for the management of exudative diffuse and circumscribed choroidal hemangioma in pediatric populations. <h3>Purpose</h3> To describe the clinical outcomes of pediatric patients with exudative diffuse and circumscribed choroidal hemangiomas treated with low-dose PRT. <h3>Methods</h3> Retrospective single-center chart review of all pediatric patients treated with PRT between 1999 and 2018 for either exudative diffuse or circumscribed choroidal hemangioma. Data on patient characteristics, tumor characteristics, treatment parameters, and post-PRT clinical outcomes were recorded. Adverse events were classified according to the Common Terminology Criteria for Adverse Events (Version 5.0). <h3>Results</h3> Eleven patients were identified. Ten patients had diffuse choroidal hemangioma (DCH). Nine patients had a diagnosis of Sturge-Weber Syndrome. Nine patients were treated with a radiation regimen of 20 Gy (relative biologic effectiveness [RBE]) in 10 fractions. Two patients were treated with 15 Gy (RBE) in 4 fractions. Best-correct visual acuity improved in 8 patients (73%) and remained stable in the remaining 3 patients (27%). In patients with imaging follow-up (10 patients), subretinal fluid resolved in 9 of 10 patients (90%) and tumor thickness decreased in 10 of 10 patients (100%). Intraocular pressure (IOP) largely remained stable across patients, with a pre- and post-PRT median of 18 mmHg amongst patients with both pre- and post-PRT IOP measurements available. Grade I adverse events were observed in 8 of 11 (72.7%) patients. No grade ≥2 events were reported during the follow-up period. <h3>Conclusion</h3> This is the largest study exploring outcomes of PRT in DCH. Our findings suggest that low-dose PRT is effective in the management of exudative choroidal hemangioma in pediatric patients with an acceptable side effect profile.

Clinical outcomes of pediatric patients receiving multimodality treatment of second central nervous system relapse of neuroblastoma.

In high-risk neuroblastoma, multimodality therapy including craniospinal irradiation (CSI) is effective for central nervous system (CNS) relapse. Management of post-CSI CNS relapse is not clearly defined. Pediatric patients with neuroblastoma treated with CSI between 2000 and 2019 were identified. Treatment of initial CNS disease (e.g., CSI, intraventricular compartmental radioimmunotherapy [cRIT] with 131 I-monoclonal antibodies targeting GD2 or B7H3) and management of post-CSI CNS relapse ("second CNS relapse") were characterized. Cox proportional hazards models to evaluate factors associated with third CNS relapse and overall survival (OS) were used. Of 128 patients (65% male, median age 4years), 19 (15%) received CSI with protons and 115 (90%) had a boost. Most (103, 81%) received cRIT, associated with improved OS (hazard ratio [HR] 0.3, 95% confidence interval [CI]: 0.1-0.5, p<.001). Forty (31%) developed a second CNS relapse, associated with worse OS (1-year OS 32.5%, 95% CI: 19-47; HR 3.8; 95% CI: 2.4-6.0, p<.001), and more likely if the leptomeninges were initially involved (HR 2.5, 95% CI: 1.3-4.9, p=.006). Median time to second CNS relapse was 6.8months and 51% occurred outside the CSI boost field. Twenty-five (63%) patients underwent reirradiation, most peri-operatively (18, 45%) with focal hypofractionation. Eight (20%) patients with second CNS relapse received cRIT, associated with improved OS (HR 0.1; 95% CI: 0.1-0.4, p<.001). CNS relapse after CSI for neuroblastoma portends a poor prognosis. Surgery with hypofractionated radiotherapy was the most common treatment. Acknowledging the potential for selection bias, receipt of cRIT both at first and second CNS relapse was associated with improved survival. This finding necessitates further investigation.

Abdominal tumors in children: A comprehensive study on the diagnosis, management, and clinical outcome of pediatric patients with lymphoma in Kashmir

Background: Although primary abdominal tumors are rare but their diagnosis, high-cost treatment and psychological instability among both patients and parents are challenging. There are several types of abdominal tumors in pediatric age group which include neuroblastoma, Wilm’s tumor, hepatoblastoma, lymphomas, soft-tissue sarcomas, and germ cell tumors. Aims and Objectives: The present study was objectively conducted to identify Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) tumors among all patients presented with abdominal tumors. In addition to this, histopatological profile, clinical profile and disease prognosis among such patients has also been analyzed. Materials and Methods: A total of 64 pediatric patients presented with primary abdominal tumors were included in the study but only 20 patients with lymphoma were identified. The study was conducted at the Department of Pediatric Division, SMHS Hospital Srinagar with effect from 2005 to 2008. Results: The Majority of NHL patients were found to have Stage II and Stage IV. Moreover, all the four cases of Hodkins lymphoma had Stage IV. Out of the 20 patients with lymphoma six died, of them five had NHL and one patient had HL, thus placing the overall survival rate as 70%. Conclusion: The present study demonstrated that both NHL and HL tumors may develop to advanced stage and even patient may die if the timely diagnosis and proper management is not there. We recommend collective team work of medicos from various departments for the precise diagnosis and optimal management of such patients.

MicroRNA profiling of paediatric AML with FLT-ITD or MLL-rearrangements: Expression signatures and invitro modulation of miR-221-3p and miR-222-3p with BRD4/HATs inhibitors.

Novel therapeutic strategies are needed for paediatric patients affected by Acute Myeloid Leukaemia (AML), particularly for those at high-risk for relapse. MicroRNAs (miRs) have been extensively studied as biomarkers in cancer and haematological disorders, and their expression has been correlated to the presence of recurrent molecular abnormalities, expression of oncogenes, as well as to prognosis/clinical outcome. In the present study, expression signatures of different miRs related both to presence of myeloid/lymphoid or mixed-lineage leukaemia 1 and Fms like tyrosine kinase 3 internal tandem duplications rearrangements and to the clinical outcome of paediatric patients with AML were identified. Notably, miR-221-3p and miR-222-3p resulted as a possible relapse-risk related miR. Thus, miR-221-3p and miR-222-3p expression modulation was investigated by using a Bromodomain‑containing protein 4 (BRD4) inhibitor (JQ1) and a natural compound that acts as histone acetyl transferase inhibitor (curcumin), alone or in association, in order to decrease acetylation of histone tails and potentiate the effect of BRD4 inhibition. JQ1 modulates miR-221-3p and miR-222-3p expression in AML with a synergic effect when associated with curcumin. Moreover, changes were observed in the expression of CDKN1B, a known target of miR-221-3p and miR-222-3p, increase in apoptosis and downregulation of miR-221-3p and miR-222-3p expression in CD34+ AML primary cells. Altogether, these findings suggested that several miRs expression signatures at diagnosis may be used for risk stratification and as relapse prediction biomarkers in paediatric AML outlining that epigenetic drugs, could represent a novel therapeutic strategy for high-risk paediatric patients with AML. For these epigenetic drugs, additional research for enhancing activity, bioavailability and safety is needed.

Comparison of laboratory parameters, clinical symptoms and clinical outcomes of COVID-19 and influenza in pediatric patients: A systematic review and meta-analysis.

BACKGROUNDNew and more severe clinical manifestations associated with the coronavirus disease 2019 (COVID-19) are emerging constantly in the pediatric age group. Patients in this age group are also primary carriers of the influenza virus and are at a higher risk of developing severe infection. However, studies comparing influenza and COVID-19 to show which condition causes a more severe form of disease amongst the pediatric age group are scarce. AIMTo compare the laboratory results, clinical symptoms and clinical outcomes in pediatric patients with COVID-19 and influenza.METHODSA systematic and comprehensive search was carried out in databases and search engines, including EMBASE, Cochrane, MEDLINE, ScienceDirect and Google Scholar from 1964 until January 2022. A meta-analysis was carried out using a random-effects model and pooled odds ratio (OR) or standardized mean difference (SMD) and 95%CI.RESULTSA total of 16 studies satisfied the inclusion criteria. Pediatric COVID-19 patients had a significantly reduced risk of cough (pooled OR = 0.16; 95%CI: 0.09 to 0.27), fever (pooled OR = 0.23; 95%CI: 0.12 to 0.43), and dyspnea (pooled OR = 0.54; 95%CI: 0.33 to 0.88) compared to influenza patients. Furthermore, total hemoglobin levels (pooled SMD = 1.22; 95%CI: 0.29 to 2.14) in COVID-19 patients were significantly higher as compared to pediatric influenza patients. There was no significant difference in symptoms such as sore throat, white blood cell count, platelets, neutrophil and lymphocytes levels, and outcomes like mortality, intensive care unit admission, mechanical ventilation or length of hospital stay.CONCLUSIONCOVID-19 is associated with a significantly lower rate of clinical symptoms and abnormal laboratory indexes compared to influenza in the pediatric age group. However, further longitudinal studies of the outcomes between influenza and COVID-19 pediatric patients are needed.

Association between chest radiographic findings and clinical outcomes in pediatric patients with bronchiolitis at King Abdulaziz University Hospital

Association between chest radiographic findings and clinical outcomes in pediatric patients with bronchiolitis at King Abdulaziz University Hospital

Pediatric spinal cord injury with radiographic abnormality: the Beijing experience

BACKGROUND CONTEXTSpinal cord injury (SCI) without radiographic abnormality (SCIWORA) is a syndrome that usually occurs in children primarily because of the unique biomechanics of the pediatric spine. We recently found that the histopathological and behavioral effects of SCI with radiographic abnormality (SCIWRA) and SCIWORA are very different from each other in animal models. Although numerous studies were conducted to understand the epidemiological and clinical characteristics of the overall pediatric SCI population and the pediatric SCIWORA population, the characteristics of the pediatric SCIWRA population and their differences from those of the SCIWORA population are poorly understood. PURPOSETo describe the epidemiology and clinical outcomes of pediatric patients with SCIWRA and their differences from those with SCIWORA. STUDY DESIGN/SETTINGRetrospective study. PATIENT SAMPLEA total of 47 pediatric SCIWRA patients. OUTCOME MEASURESEpidemiological characteristics, injury severities, functional deficits, and management and recovery outcomes. METHODSReview of all cases with SCIWRA at Beijing Children's Hospital between July 2007 and December 2019 and comparison between the present data and our previous SCIWORA data. RESULTSOf the 187 pediatric SCI patients, 47 had SCIWRA (age: 7.06 ± 3.75 years, male-to-female ratio: 3:2). Main causes of SCIWRA were fall (38%) and traffic accidents (38%). Lesions were often located at multiple levels (62%). Incubation period was 3 ± 18 hours. According to the American Spinal Injury Association impairment scale (AIS), many SCIWRA patients had incomplete impairment (AIS B, 9%; AIS C, 9%; AIS D, 32%). Specifically, many of them had abnormal upper and lower limb muscle powers (55% and 60%), upper and lower limb muscle tones (34% and 49%), sensation (38%), and knee, ankle, and abdominal reflexes (47%, 34%, and 36%). 72% of SCIWRA patients were treated with methylprednisolone, dexamethasone, or both. 81% of them showed neurological improvement before discharge. There was no association between corticosteroid therapy and neurological improvement. Moreover, functional outcomes of their upper and lower limb muscle powers were significantly associated with functional outcomes of their upper and lower limb muscle tones (p < 0.01), respectively. In comparison to the SCIWRA population, the SCIWORA population had a higher ratio of younger and female patients of sports-related thoracic injuries with long incubation period leading to lower-body deficits and complete impairment (p<0.05 or p<0.01). Despite all the differences, their neurological improvement was similar (p>0.05). CONCLUSIONSDemographic differences exist in the SCIWRA population. Corticosteroids do not appear to be effective in the different types of pediatric SCI. Limb muscle tone may be used to evaluate the functional status of limb muscle power. The epidemiological and clinical characteristics of SCIWRA and SCIWORA are very different from each other. It is important to formulate tailor-made prevention, evaluation, and management strategies for the pediatric population to optimize the SCI outcomes.

Time to antibiotics is unrelated to outcome in pediatric patients with fever in neutropenia presenting without severe disease during chemotherapy for cancer

Fever in neutropenia (FN) remains an unavoidable, potentially lethal complication of chemotherapy. Timely administration of empirical broad-spectrum intravenous antibiotics has become standard of care. But the impact of time to antibiotics (TTA), the lag period between recognition of fever or arrival at the hospital to start of antibiotics, remains unclear. Here we aimed to analyze the association between TTA and safety relevant events (SRE) in data from a prospective multicenter study. We analyzed the association between time from recognition of fever to start of antibiotics (TTA) and SRE (death, admission to intensive care unit, severe sepsis and bacteremia) with three-level mixed logistic regression. We adjusted for possible triage bias using a propensity score and stratified the analysis by severity of disease at presentation with FN. We analyzed 266 FN episodes, including 53 (20%) with SRE, reported in 140 of 269 patients recruited from April 2016 to August 2018. TTA (median, 120 min; interquartile range, 49–180 min) was not associated with SRE, with a trend for less SREs in episodes with longer TTA. Analyses applying the propensity score suggested a relevant triage bias. Only in patients with severe disease at presentation there was a trend for an association of longer TTA with more SRE. In conclusion, TTA was unrelated to poor clinical outcome in pediatric patients with FN presenting without severe disease. We saw strong evidence for triage bias which could only be partially adjusted.

Individualised prophylaxis based on personalised target trough FVIII level optimised clinical outcomes in paediatric patients with severe haemophilia A.

As standard care of severe haemophilia A (SHA), prophylaxis should be individualised. This study aimed to investigate the effectiveness of this new-proposed individualised prophylaxis protocol. Boys with SHA were enrolled and followed a PK-guided, trough-level escalating protocol of prophylaxis after a six-month observational period. In the next 2 years, clinical assessments including joint bleeds, ultrasound (US) scores and Haemophilia Joint Health Score (HJHS) in both sides of ankles, knees and elbows were conducted every 6 months as a scoring system, which determined whether the trough level's escalation. Adjustment of dosing regimen was based on WAPPS-Hemo. Fifty-eight SHA boys were finally analysed. Their age and bodyweight were 5.3(2.8,6.9) years and 21.5(16,25) kg. During the study, 47 escalations were conducted. At study exit, the patient number and proportion of different trough level groups were:<1IU/dl, 17.2% (10/58); 1-3IU/dl, 53.5% (31/58); 3-5IU/dl, 15.5% (9/58);>5IU/dl, 13.8% (8/58). Significantly reduced annualised bleeding rate [4(0,8) to 0(0,2), p<.0001] and annualised joint bleeding rate [2(0,4) to 0(0,.25), p<.0001] was observed at study exit as well as the continuous trend of increased zero bleeding proportion (ZBP) (27.6%-69.0%) and zero joint bleeding proportion (46.5%-81.3%). Besides, 85% (6/7) of the target joints vanished. Statistical improvements of US scores (p=.04) and HJHS (p=.02) were also reported at study exit. Our results showed the effectiveness of our protocol based on individualised target trough level and emphasise the importance of personalised prophylaxis.

P362: MINIMAL-LOSS-CYTOMETRY FOR EVALUATION OF CEREBROSPINAL FLUID IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA. SINGLE CENTER STUDY.

Background: Central nervous system (CNS) involvement at diagnosis of acute lymphoblastic leukemia (ALL) represents a risk factor for CNS relapse. Currently, examination of the cerebrospinal fluid (CSF) is performed and evaluated quantitatively using a counting chamber and qualitatively using cytomorphological analysis of cytospin. Recently, flow cytometry (FC) evaluation of CSF was shown to provide more reliable results and to predict relapse risk (de Haas et al., 2021, Thastrup et al., 2020). Independently of these studies, we applied a lyse-no wash technique aiming at minimizing cell loss during preparation and at improved cell concentration estimate. Aims: Our aim was to compare our findings with morphological criteria and published data and correlate them with clinical outcome in pediatric patients with ALL. Methods: We included pediatric patients with newly diagnosed ALL (04/2014 – 01/2022), whose CSF examination was performed in CLIP laboratory (n=208). Patients were classified as B cell precursor ALL (BCP ALL; 85%) and T ALL (15%) and treated according to following protocols: AIEOP-BFM ALL 2009 (n=118), AIEOP-BFM ALL 2017 (n=71), EsPhALL(n=8), Interfant06 (n=5), off-protocol (n=6). During follow up, 14 patients relapsed (5 CNS incl. combined, 9 non-CNS). CSF (drawn into tube with no fixative agent and processed within 2 hours) was concentrated by centrifugation and incubated with combination of antibodies (CD20/CD10/CD45/CD34/CD19/CD3/Syto41 in BCP ALL and CD4/CD99/CD5/CD3/CD7/CD16 + 56/CD8/CD45/Syto41 in T ALL). Residual erythrocytes were lysed with NH4Cl solution, followed by immediate acquisition on BD FACS Lyric or BD LSRII cytometers. Blasts were quantified to initial CSF volume. Cluster of 20 events was required to assign samples as FC positive (FC+). In parallel, CNS status was concluded according to morphological criteria, being classified as CNS1 (no blasts), CNS2a/b (≤5 WBC/μL with blasts), CNS2c/CNS3 (≥5 WBC/μL with blasts) according to treatment protocol guidelines. Continuous variables were compared with the Mann–Whitney test, survival data were analyzed using Mantel-Cox test. P values<0.05 were considered as significant. Results: Using FC, we identified atypical blasts in 50 out of the 208 analyzed samples (24%). Median of analyzed CSF volume was 367µL (range 143-1033µL), which enabled median sensitivity 0.054 events/µL (range 0.02-0.14ev/µL). Mean blast concentration was 0.47ev/µL (range 0-25ev/µL) in all samples and 2 ev/µL (range 0.01-25ev/µL, median 0.53ev/µL) in FC+ samples. We observed significantly higher blast concentration in patients with T ALL, in patients with CNS2 and CNS3 and those who subsequently relapsed. Patients with FC+ had significantly lower relapse-free survival than FC- patients (55% vs 94%), which provided better separation than CNS status (68% vs.85% for CNS2/3 vs. CNS1, respectively). Image:Summary/Conclusion: Using fresh CSF sample with lyse-no wash protocol enabled us to detect approximately 10x higher blast count (0.24ev/µL in FC+CNS1 and 1.25ev/µL in FC+CNS2/3) than was recently published (0.015ev/µL in FC+CNS1 and 0.073ev/µL in FC+CNS2/3 in Thastrup et al., 2020), and thus it better correlates to cytomorphological data. Interestingly, the proportion of FC+ patients in our cohort is comparable to (24% vs 25%), showing that although in our method we lose fewer cells, we identify the same proportion of FC+ patients. The presented study shows a higher impact of FC positivity on relapse risk than described previously. The disadvantage of our method is a need for a fresh sample, which is investigated locally. Supported by UNCE/MED/015, NU20J-07-00028.

Association of Right Ventricular–to–Left Ventricular Diameter Ratio at End-Systole With Outcomes in Children Who Underwent Repair of Tetralogy of Fallot

RATIONALE: Tetralogy of Fallot (TOF) is a right-sided dominant cardiac lesion with a stenotic right ventricular (RV) outflow tract and hypertrophied RV, which could result in septal shift and RV dilation. This study evaluated the RV/left ventricular (LV) diameter ratio at end-systole in association with clinical outcomes in children who underwent repair of TOF. The main aim of this study was to determine the association of RV/LV diameter ratio at end-systole with the outcomes of TOF repair. The specific objectives were to determine whether the preoperative (demographic and echocardiographic data) parameters were associated with the clinical outcomes of TOF repair and to determine whether the intraoperative (cardiopulmonary bypass time and aortic cross-clamp time) parameters were associated with the clinical outcomes of TOF repair. METHODOLOGY: This prospective cohort single-center study enrolled 112 TOF patients aged 1 to 18 years admitted for surgical repair. The RV/LV ratio was measured using echocardiography preoperatively, indexed to patient’s weight and body surface area, and associated with its postoperative cardiac complications using logistic regression analysis. RESULTS: Cumulative incidence of cardiopulmonary complications was at 28.7% (32 of 112). Reperfusion lung injury had the most cases (11.6%), followed by low cardiac output syndrome (9.8%) and postpericardiotomy syndrome (5.4%). Both RV and LV diameters, indexed to patient’s weight and body surface area, (P = 0.0051, P &lt; 0.001), RV/LV ratio (P &lt; 0.001), and LV end diastolic size with z scores (P &lt; 0.001), showed statistically significant results. Increase in RV/LV ratio is associated with adverse postoperative clinical outcomes in pediatric patients who underwent repair of TOF (P &lt; 0.001). Significant preoperative parameter showed that stunting is associated with complications postoperatively (P = 0.017), whereas for the intraoperative parameters, prolonged cardiopulmonary bypass time and aortic cross-clamp time were also associated with postoperative complications. CONCLUSION: The increased value of RV/LV end-systolic diameter ratio at 1.63 (±0.256), which incorporates both pathologic septal shift and RV dilation, is associated with higher incidence of postoperative cardiac complications among patients with tetralogy of Fallot.

Extended time window mechanical thrombectomy for pediatric acute ischemic stroke.

Endovascular thrombectomy (EVT) for the treatment of acute ischemic stroke (AIS) remains an off-label procedure seldom utilized in the pediatric population; this holds especially true for patients presenting outside the standard 6-hour time window. In this review we describe the published literature regarding usage of the extended time window EVT in pediatric stroke. We searched PubMed for all pediatric AIS cases and case series that included patients treated with extended time window EVT. We found data from 38 cases found in 27 publications (15 case reports and 12 case series). The median age was 10 years; 60.5% males. The median NIHSS before EVT was 13 with a median time-to-treatment of 11 hours. The posterior circulation was involved in 50.0%. Stent retrievers were used in 68.5%, and aspiration in 13.2%. Angiographic outcome TICI ≥2B was achieved in 84.2%, whereas TICI˂2B was reported in 10.6%. A favorable clinical outcome (NIHSS score ≤4, modified Rankin score ≤1, or Pediatric Stroke Outcome measure score ≤1) occurred in 84.2%. Eight cases that did not report the clinical outcome employing a standardized scale described mild to absent neurological residual deficits. This study found data that supports that extended window EVT produces high recanalization rates and good clinical outcomes in pediatric patients with AIS. Nevertheless, the source materials are indirect and contain substantial inconsistencies with an increased risk of bias that amount to low evidence strength.

Therapeutic Drug Monitoring of Conditioning Agents in Pediatric Allogeneic Stem Cell Transplantation; Where do We Stand?

Allogeneic hematopoietic stem cell transplantation (HSCT) is an established curative treatment that has significantly improved clinical outcome of pediatric patients with malignant and non-malignant disorders. This is partly because of the use of safer and more effective combinations of chemo- and serotherapy prior to HSCT. Still, complications due to the toxicity of these conditioning regimens remains a major cause of transplant-related mortality (TRM). One of the most difficult challenges to further improve HSCT outcome is reducing toxicity while maintaining efficacy. The use of personalized dosing of the various components of the conditioning regimen by means of therapeutic drug monitoring (TDM) has been the topic of interest in the last decade. TDM could play an important role, especially in children who tend to show greater pharmacokinetic variability. However, TDM should only be performed when it has clear added value to improve clinical outcome or reduce toxicity. In this review, we provide an overview of the available evidence for the relationship between pharmacokinetic parameters and clinical outcome or toxicities of the most commonly used conditioning agents in pediatric HSCT.

Using Aggregate Vasoactive-Inotrope Scores to Predict Clinical Outcomes in Pediatric Sepsis.

ObjectivesThe heterogeneity of sepsis makes it difficult to predict outcomes using existing severity of illness tools. The vasoactive-inotrope score (VIS) is a quantitative measure of the amount of vasoactive support required by patients. We sought to determine if a higher aggregate VIS over the first 96 h of vasoactive medication initiation is associated with increased resource utilization and worsened clinical outcomes in pediatric patients with severe sepsis.DesignRetrospective cohort study.SettingSingle-center at Children's Wisconsin in Milwaukee, WI.PatientsOne hundred ninety-nine pediatric patients, age less than 18 years old, diagnosed with severe sepsis, receiving vasoactive medications between January 2017 and July 2019.InterventionsRetrospective data obtained from the electronic medical record, calculating VIS at 2 h intervals from 0–12 h and at 4 h intervals from 12–96 h from Time 0.MeasurementsAggregate VIS derived from the hourly VIS area under the curve (AUC) calculation based on the trapezoidal rule. Data were analyzed using Pearson's correlations, Mann-Whitney test, Wilcoxon signed rank test, and classification, and regression tree (CART) analyses.Main ResultsHigher aggregate VIS is associated with longer hospital LOS (p < 0.0001), PICU LOS (p < 0.0001), MV days (p = 0.018), increased in-hospital mortality (p < 0.0001), in-hospital cardiac arrest (p = 0.006), need for ECMO (p < 0.0001), and need for CRRT (p < 0.0001). CART analyses found that aggregate VIS >20 is an independent predictor for in-hospital mortality (p < 0.0001) and aggregate VIS >16 for ECMO use (p < 0.0001).ConclusionsThere is a statistically significant association between aggregate VIS and many clinical outcomes, allowing clinicians to utilize aggregate VIS as a physiologic indicator to more accurately predict disease severity/trajectory in pediatric sepsis.

398 - Reduction in Neutrophil Extracellular Traps May Contribute to the Effect of Abatacept on Clinical Outcomes in Pediatric Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplant

398 - Reduction in Neutrophil Extracellular Traps May Contribute to the Effect of Abatacept on Clinical Outcomes in Pediatric Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplant

Prognostic Relevance of Structural Maintenance of Chromosomes 4 Overexpression in Pediatric Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Abnormal expression of structural maintenance of chromosomes (SMC) 4 has been observed in multiple tumors and plays a vital role in cancer development. However, the association between SMC4 expression and clinical characteristics in Chinese childhood patients with ALL is unknown. Thus, this study aimed to investigate the relationship between SMC4 expression and clinical features and prognosis in these patients. Real-time quantitative polymerase chain reaction (PCR) was performed to detect the expression of SMC4 in Chinese pediatric ALL patients and in patients achieving complete remission (CR). Then, the relationships between SMC4 expression and clinical features, such as gender, age, white blood cell (WBC) count, French-American-British (FAB) classification, immunophenotype, fusion gene, prednisone response, and minimal residual disease (MRD) were determined. Furthermore, survival and prognostic factor analyses were carried out to examine the prognostic value of SMC4 expression. The expression level of SMC4 was significantly higher in bone morrow cells of newly diagnosed pediatric ALL patients than in those of healthy controls (p = 0.006), especially in B-cell precursor ALL (BCP ALL). Moreover, SMC4 expression was correlated with different clinical parameters. Furthermore, a decrease of SMC4 expression was detected in BCP ALL patients achieving CR. The high SMC4 expression group had both worse event-free survival rate and poorer overall survival rate. However, multivariate analysis showed that SMC4 expression was not an independently predictive factor of BCP ALL outcome. These results revealed that SMC4 expression in BM was associated with various clinical outcomes in pediatric patients with ALL, although it was not an independent outcome factor.

AKAP9 Upregulation Predicts Unfavorable Prognosis in Pediatric Acute Myeloid Leukemia and Promotes Stemness Properties via the Wnt/β-Catenin Pathway

BackgroundPRKA kinase anchor protein 9 (AKAP9) is a scaffold protein involved in various cellular processes, including cell adhesion, proliferation, differentiation, and apoptosis. Although the oncogenic role of AKAP9 in solid tumors is well elucidated, the functions and mechanisms of AKAP9 in acute myeloid leukemia (AML) are still not understood.MethodsWe used the gene expression omnibus (GEO) database (GSE2191) to determine the mRNA expression of AKAP9 in the bone marrow of pediatric AML and healthy patients. We further used the therapeutically available research to generate effective treatments (TARGET) database to elucidate the relationship between AKAP9 expression and clinical outcomes in pediatric patients with AML. In addition, cell proliferation, cell cycle, apoptosis, RT-PCR, and Western blotting assays were applied to reveal the functions of AKAP9 and the underlying mechanisms of AKAP9 silencing in THP1 and HL60 cell lines.ResultsAKAP9 is overexpressed in the bone marrow of pediatric AML patients as compared with that of healthy patients. High expression of AKAP9 was found to be a predictor of poor overall survival (OS) and event-free survival (EFS). Using univariate and multivariate survival analyses, we found that high AKAP9 expression is an independent predictor of a worse OS and EFS. Functionally, AKAP9 silencing significantly inhibited AML cell proliferation, and cell cycle progression and promoted apoptosis. Moreover, AKAP9 silencing significantly downregulated the expression of stemness markers and β-catenin.ConclusionAKAP9 upregulation is a predictor of unfavorable prognosis, promotes stemness, and activates the Wnt/β-catenin pathway in AML patients. AKAP9 may act as a prognostic biomarker of AML in pediatric patients and a future therapeutic target.

The effect of Pseudomonas aeruginosa eradication regimens on chronic colonization and clinical outcomes in pediatric patients with cystic fibrosis.

Chronic Pseudomonas aeruginosa colonization (Pa-CC) affects cystic fibrosis (CF) progression, including pulmonary exacerbations and pulmonary function tests. There are few studies of the effects of eradication protocols on colonization time. Here, we aimed to evaluate the effect of eradication regimens on chronic colonization and assess the impact of Pa-CC on body mass index, lung functions, and pulmonary exacerbations. A retrospective review was conducted of medical records, over a period of 11 years, of children aged under 18 years with CF who had Pa-CC in our tertiary care pediatric hospital. Pseudomonas aeruginosa was detected in 215 of our patients with CF during the study period. Forty-four patients with Pa-CC were recruited for the study. The eradication treatment for the initial acquisition of P. aeruginosa was inhaled antibiotics in 27 (61.4%) patients; the remainder were given intravenous antibiotics. It was observed that eradication treatment with either IV or inhaled antibiotics did not affect the time between the P. aeruginosa and the time of Pa-CC(P = 0.791). There was a non-significant decrease in the body mass index z-score from the Pa-IA to the last visit(P = 0.27), a significant decline in forced expiratory volume in 1 s (FEV1%) (P = 0.01) over time, and the annual number of exacerbations after colonization was significantly higher than before colonization (P = 0.03). There was no difference between eradication regimens in delaying the age at Pa-CC. Pseudomonas aeruginosa colonization in patients with CF was also associated with poorer lung functions, lower body mass index, and more pulmonary exacerbation regardless of mucoid type. Consequently, to slow the progression of lung disease, we must prevent Pa-CC, which we can achieve with early eradication. Despite conventional eradication protocols, future studies need to evaluate those who fail to clear P. aeruginosa.

Clinical Evaluation of a Novel Laser-Ablated Titanium Implant System for Bone Anchored Hearing Systems in a Pediatric Population and the Relationship of Resonance Frequency Analysis With Implant Survival.

Objective:To evaluate the clinical outcomes of pediatric patients implanted a novel 4.5 mm wide laser ablated titanium bone anchored implant system and to evaluate the implant stability over the first 12-month period.Study Design:A prospective, single-subject, repeated measure, cohort study. Participants served as their own controls.Setting:Community and tertiary referral hospital pediatric assessment center.Patients:A total of 115 consecutive pediatric patients aged 4 to 15 years were implanted with 176 laser ablated titanium bone anchored implants from January 2016 to January 2019.Main Outcome Measure:Clinical outcomes, implant failure rates, and post implantation implant stability quotient (ISQ) scores were studied over the first 12-month period. Data were analyzed for statistical significance through mixed effect modeling, with the significance level p = 0.01.Results:A median 12-month survival of 96.6% was observed. Six implants (3.5%) were lost in total, one of these (0.6%) was lost due to trauma. Adverse skin reactions (Holgers grade 2–4) were observed in 4.4% of all postoperative visits, occurring in 22 individuals (19.1%). Neither the ISQ high (ISQH) nor ISQ low (ISQL) values increased significantly between the stage 1 and 2 surgeries. In contrast, the ISQ results, irrespective of abutment size, demonstrated an increasing trend from 49.1 to 57 over the 12 months review period. A statistically significant change was only demonstrated from the 3 months follow up onwards.Conclusion:The use of 4.5 mm wide laser-ablated titanium bone anchored hearing implants resulted in superior survival rates and excellent clinical outcomes compared with previous implant systems.