Strategy For Pediatric Patients Research Articles

Clinical characteristics and nomogram model for predicting the risk of recurrence of complicated urinary tract infection in pediatric patients

Complicated urinary tract infection (cUTI) has higher incidences of antibiotic resistance, recurrence, chronicity, and progression. There exist differences in the immune functions, anatomical structures and physiological functions of urinary tract system between children and adults. In addition, the immature stage of hygiene habit development and the inability to express discomfort accurately all contribute to cUTI recurrence in pediatric patients. cUTI recurrence in children can lead to serious consequences such as growth and development delay, renal scars, and progression to end-stage kidney diseases. Despite the high incidence of cUTI recurrence, no predictive model currently exists to guide targeted intervention in pediatric patients. This study aimed to establish a nomogram to predict the risk of cUTI recurrence in children, thereby facilitating targeted prevention and treatment strategies in pediatric patients. The nomogram was developed based on a retrospective cohort that included 421 pediatric patients with cUTI at West China Second University Hospital from January 2020 to August 2023. The patients were randomly divided into a training set and a validation set in a 3:1 ratio. Logistic regression analysis was used to identify risk factors and construct the nomogram for predicting the risk of cUTI recurrence, followed by validation and performance analysis. Of the 421 children with cUTI, the recurrence rate of cUTI was 68.4% (288 cases) during an average follow-up duration of 22.9 months. The nomogram comprised female gender, history of urinary tract surgery, Escherichia coli in urine culture, renal dysfunction, and vesicoureteral reflux as predictors of cUTI recurrence in pediatric patients. The model showed favorable performance with C-index values of 0.735 and 0.750 in the training dataset and the validation dataset, respectively. The decision curve analysis revealed that the nomogram might be clinically useful. The reliable nomogram would be beneficial for clinicians to identify children with high risks of cUTI recurrence for targeted intervention.

Computed tomography injection of technetium 99m macroaggregated albumin—an underutilized lung nodule localization strategy in pediatric patients

Computed tomography injection of technetium 99m macroaggregated albumin—an underutilized lung nodule localization strategy in pediatric patients

Clinical Characteristics and Whole Exome Sequencing Analysis in Serbian Cases of Clubfoot Deformity-Single Center Study.

Recognized as one of the most serious musculoskeletal deformities, occurring in 1-2 per 1000 newborns, 80% of clubfeet are idiopathic while 20% present with associated malformations. The etiopathogenesis of clubfoot is described as multifactorial, including both genetic and environmental risk factors. The aim of this study was to analyze possible genetic causes of isolated and syndromic clubfoot in Serbian children, as well as to correlate clinical and genetic characteristics that would provide insight into clubfoot etiopathogenesis and possibly contribute to global knowledge about clinical features of different genetically defined disorders. We evaluated 50 randomly selected, eligible children with clubfoot aged 3 to 16 years that were initially hospitalized and treated at University Children's Hospital between November 2006 and November 2022. The tested parameters were gender, age, dominant foot, affected foot, degree of deformity, treatment, neuromuscular disorders, positive family history, and maternal smoking. According to the presence of defined genetic mutation/s by whole exome sequencing (WES), patients were separated into two groups: positive (with genetic mutation/s) and negative (without genetic mutation/s). Seven patients were found to be positive, i.e., with genetic mutation/s. A statistically significant difference between categorical variables was found for families with a history of clubfoot, where more than half (57.14%) of patients with confirmed genetic mutation/s also had a family history of genetic mutation/s (p = 0.023). The results from this study further expand the genetic epidemiology of clubfoot. This study contributes to the establishment of genetic diagnostic strategies in pediatric patients with this condition, which can lead to more efficient genetic diagnosis.

Therapeutic effects of treat and repair strategy in pediatric patients with pulmonary arterial hypertension and simple congenital heart defects.

Surgical indications for patients with pulmonary arterial hypertension (PAH) and congenital heart defects are controversial. The treat and repair strategy has demonstrated efficacy in adult populations, but there have been no studies on pediatric patients. This study included pediatric patients with PAH and simple congenital heart defects who underwent corrective repair between 2012 and 2021. According to the preoperative treatment strategies, the patients were divided into a regular strategy group (Group 1) and a treat-and-repair strategy group (Group 2). Postoperative recovery and follow-up results were compared between the two groups. A total of 33 patients were included in this study. Group 1 consisted of 19 patients, whereas Group 2 consisted of 14 patients. The pulmonary vascular resistance index in Group 2 was higher than that in Group 1 (10.9 ± 4.1 vs. 8.2 ± 1.6 WU, p = 0.031). There were no differences in postoperative recovery between the two groups (p > 0.05). During follow-up, five patients were lost (three in Group 1 and two in Group 2). The median follow-up period was 59 months. One patient died in Group 1, and two patients died in Group 2. There was no significant difference in the survival curve (p = 0.39). At the last follow-up, another seven patients had experienced a non-low-risk condition, with a total of three non-low-risk patients in Group 1 and seven in Group 2, including one patient in each group who had a history of ICU admission. According to the ROC curve, a preoperative PVRi <8.2 WU×m2 can predict postoperative persistent low-risk state, PVRi <5.2 WU×m2 can avoid postoperative death and/or ICU administration. In pediatric patients with PAH and simple congenital heart defects, the treat and repair strategies may provide surgery opportunities, PVRi should be <8 WU×m2, and <5.2 WU×m2 is the best choice.

A survey on perioperative red blood cell transfusion trigger strategies for pediatric patients in the Nordic countries.

Transfusion of red blood cells (RBC) to rapidly increase hemoglobin levels have been associated with increased risks and worse outcomes in critically ill children. The international TAXI consensus from 2018 (pediatric critical care transfusion and anemia expertise initiative) recommended restrictive RBC transfusion strategies in pediatric patients. To elucidate physicians perioperative RBC transfusion trigger strategies for pediatric patients in the Nordic countries and to investigate what factors influence the decision to transfuse this group of patients. An electronic web-based survey designed by the TransfUsion triggers in Pediatric perioperAtive Care (TUPAC) initiative including six different clinical scenarios was sent to anesthesiologist treating pediatric patients at university hospitals in the Nordic countries on February 1, 2023 and closed May 1, 2023. The study had a response rate of 67.7% (180 responders out of 266 contacted). Median hemoglobin thresholds triggering RBC transfusions were 7.0 [IQR, 7.0-7.3] g/dL in a stable young child (1-year-old), 7.0 [IQR, 7.0-7.0] g/dL in the stable older child (5-year-old), 8.5 [IQR, 8.0-9.0] g/dL in the older child with cardiac disease, 9.0 [IQR, 8.0-10.0] g/dL the older child with traumatic brain injury, 8.0 [IQR, 7.3-9.0] g/dL in stabilized older child with septic shock and 8.0 [IQR, 7.0-9.0] g/dL in the older child with active but non-life-threatening bleeding. Apart from specific hemoglobin level, RBC transfusions were mostly triggered by high lactate level (74.2%), increasing heart rate (68.0%), prolonged capillary refill time (48.3%), and lowered blood pressure (47.8%). No statistical difference was found between the Nordic countries, work experience, or enrollment in a pediatric anesthesia fellowship program regarding RBC transfusion strategies. Anesthesiologists in the Nordic countries report restrictive perioperative RBC transfusion strategies for children that are mostly in agreement with the international TAXI recommendations. However, RBC transfusions strategies were modified to be guided by more liberal trigger levels when pediatric patients presented with severe comorbidity such as severe sepsis, septic shock, and non-life-threatening bleeding.

Radiation Therapy Technology Advances and Mitigation of Subsequent Neoplasms in Childhood Cancer Survivors

In this Pediatric Normal Tissue Effects in the Clinic (PENTEC) vision paper, challenges and opportunities in the assessment of subsequent neoplasms (SNs) from radiation therapy (RT) are presented and discussed in the context of technology advancement. The paper discusses the current knowledge of SN risks associated with historic, contemporary, and future RT technologies. Opportunities for research and SN mitigation strategies in pediatric patients with cancer are reviewed. Present experience with radiation carcinogenesis is from populations exposed during widely different scenarios. Knowledge gaps exist within clinical cohorts and follow-up; dose-response and volume effects; dose-rate and fractionation effects; radiation quality and proton/particle therapy; age considerations; susceptibility of specific tissues; and risks related to genetic predisposition. The biological mechanisms associated with local and patient-level risks are largely unknown. Future cancer care is expected to involve several available RT technologies, necessitating evidence and strategies to assess the performance of competing treatments. It is essential to maximize the utilization of existing follow-up while planning for prospective data collection, including standardized registration of individual treatment information with linkage across patient databases.

Performance of an offline systematic error correction strategy in pediatric patients receiving adjuvant conformal radiotherapy for Wilm's tumor.

Radiotherapy plays a key role as an adjuvant treatment in pediatric Wilm's tumor, improving both survival and quality of life. The success of radiotherapy depends on the precise delivery of radiation dose to the tumor while sparing radiosensitive structures in the vicinity of the tumor. Pediatric patients pose unique challenges in achieving accurate radiotherapy delivery due to their inability to understand instructions and the high radiosensitivity of their tissues. Thus, it is important to determine the optimum geometric verification strategy that will ensure accurate delivery of the prescribed target as specified in the patient's treatment plan. To evaluate the performance of an offline geometric correction strategy in ensuring accuracy and reproducibility during radiotherapy delivery in Wilm's tumor patients. The extended no-action level offline correction strategy was applied in the radiotherapy delivery of 45 Wilm's tumor patients. Gross errors from the first three fractions were used to calculate the mean errors which were then applied as offline correction factors. Mean errors among different groups were compared using a two-way analysis of variance (ANOVA) and Dunnett's pairwise comparisons. All statistical analyses and data visualization were performed using GraphPad Prism version 7 (Insight Partners, GraphPad Holdings, LLC). A total of 45 patients were included in the study. In all three orthogonal directions, the recorded gross errors were significantly lower after the application of the systematic error corrections. Random errors were significantly larger in the longitudinal direction compared to lateral (mean difference = 0.28, p = 0.036) and vertical directions (mean difference = 0.37 cm, p = 0.003). Patients' age was a significant predictor of random errors whereby the magnitude of random error decreased with increasing age. This study shows that the offline correction strategy used is effective in ensuring the accuracy of radiotherapy delivery in pediatric Wilm's tumor patients.

Is Prone Positioning Worth the Turn in Pediatrics? Unraveling the Oxygenation Mystery in Ventilated Patients with Acute Respiratory Distress Syndrome: An Observational Study Introducing a Novel SF Ratio Method for Non-Invasive Monitoring in Children

Background: Respiratory illnesses are prevalent among children, attributed to factors such as immature immune systems, anatomical variations, and increased susceptibility to infections. Acute respiratory distress syndrome (ARDS) is a significant cause of morbidity and mortality, necessitating various forms of respiratory support in pediatric intensive care units (PICUs). Prone positioning has emerged as a strategy to improve oxygenation in ARDS, but its effectiveness and correlation with non-invasive monitoring parameters remain underexplored.&#x0D; Subjects and Methods: This prospective observational study, conducted in the PICU of Dr. B.C Roy PGIPS, Kolkata, aimed to assess the impact of prone ventilation on oxygenation in children diagnosed with ARDS. The study, spanning 18 months, included 40 patients aged 3 months to 12 years requiring mechanical ventilation. Parameters such as oxygenation index (OI), oxygen saturation index (OSI), PF ratio, and SF ratio were monitored at different time points during supine and prone ventilation. Prone positioning's effectiveness was evaluated based on improvements in these parameters.&#x0D; Results: The study revealed a significant improvement in oxygenation status after four hours of prone ventilation compared to supine ventilation. Oxygenation index, OSI, SF ratio, and PF ratio showed statistically significant changes favoring prone positioning. A strong positive correlation between SF ratio and PF ratio was observed at various time points, emphasizing the potential of SF ratio as a non-invasive alternative. Responders and non-responders to prone positioning were identified based on predefined criteria, highlighting individual variability in treatment response.&#x0D; Conclusion: Prone ventilation demonstrated significant improvements in oxygenation parameters in children with ARDS. The study supports the use of non-invasive SF ratio as a reliable substitute for PF ratio, simplifying monitoring without invasive arterial sampling. This finding has implications for improving ARDS management strategies in pediatric patients, offering a less cumbersome alternative for assessing oxygenation status.

Aminoglycosides-Related Ototoxicity: Mechanisms, Risk Factors, and Prevention in Pediatric Patients.

Aminoglycosides are broad-spectrum antibiotics largely used in children, but they have potential toxic side effects, including ototoxicity. Ototoxicity from aminoglycosides is permanent and is a consequence of its action on the inner ear cells via multiple mechanisms. Both uncontrollable risk factors and controllable risk factors are involved in the pathogenesis of aminoglycoside-related ototoxicity and, because of the irreversibility of ototoxicity, an important undertaking for preventing ototoxicity includes antibiotic stewardship to limit the use of aminoglycosides. Aminoglycosides are fundamental in the treatment of numerous infectious conditions at neonatal and pediatric age. In childhood, normal auditory function ensures adequate neurocognitive and social development. Hearing damage from aminoglycosides can therefore strongly affect the normal growth of the child. This review describes the molecular mechanisms of aminoglycoside-related ototoxicity and analyzes the risk factors and the potential otoprotective strategies in pediatric patients.

Treatment strategy for acute myocarditis in pediatric patients requiring emergency intervention

BackgroundPatients with acute myocarditis present with a wide range of symptoms. Treatment strategies for pediatric patients with circulatory failure comprise extracorporeal membrane oxygenation (ECMO), emergency temporary pacing, and pharmacotherapy. However, they remain controversial. ECMO is an effective treatment but gives rise to several complications; the goal is therefore to avoid excessive treatment as much as possible. We aimed to evaluate the importance of electrocardiogram findings in differentiating severity and establish an appropriate treatment strategy in pediatric patients with acute myocarditis who required emergency interventions.MethodsThis retrospective study enrolled pediatric patients admitted to and treated in our hospital for acute myocarditis between April 1983 and December 2021. Patients were retrospectively divided into whether circulatory failure occurred (ECMO or temporary pacing was needed; emergency intervention group) or not (pharmacotherapy alone).ResultsOf the 26 pediatric patients, 11 experienced circulatory failure while 15 did not. In the circulatory failure group, six patients were treated with ECMO (ECMO group) and five patients with temporary pacing (pacing group). In the pacing group, all patients were diagnosed with complete and/or advanced atrioventricular block (CAVB and/or advanced AVB) and narrow QRS. Furthermore, these patients improved only with temporary pacing and pharmacotherapy, without requiring ECMO. Wide QRS complexes (QRS ≥ 0.12 ms) with ST-segment changes were detected on admission in five of six patients in the ECMO group and none in the pacing group (P = 0.015). Although all patients in the ECMO group experienced complications, none did in the pacing group (P < 0.008).ConclusionsRegarding emergency intervention for acute myocarditis, ECMO or temporary pacing could be determined based on electrocardiogram findings, particularly wide QRS complexes with ST-segment changes on admission. It is important to promptly introduce ECMO in patients with wide QRS complexes with ST-segment changes, however, patients with CAVB and/or advanced AVB and narrow QRS could improve without undergoing ECMO. Therefore, excessive treatment should be avoided by separating ECMO from temporary pacing based on electrocardiogram findings on admission.

Patient Blood Management after Hematopoietic Stem Cell Transplantation in a Pediatric Setting: Starting Low and Going Lower.

Despite the substantial transfusion requirements, there are few studies on the optimal transfusion strategy in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). Our study aimed to retrospectively analyze red blood cell (RBC) and platelet (PLT) transfusion practices during the first 100 days after HSCT at the pediatric hematology/oncology unit of our hospital between 2016 and 2019, due to a more restrictive approach adopted after 2016. We also evaluated the impact on patient outcomes. A total of 146 consecutive HSCT patients were analyzed. In patients without hemorrhagic complications, the Hb threshold for RBC transfusions decreased significantly from 2016 to 2017 (from 7.8 g/dL to 7.3 g/dL; p = 0.010), whereas it remained the same in 2017, 2018, and 2019 (7.3, 7.2, and 7.2 g/dL, respectively). Similarly, the PLT threshold decreased significantly from 2016 to 2017 (from 18,000 to 16,000/μL; p = 0.026) and further decreased in 2019 (15,000/μL). In patients without severe hemorrhagic complications, the number of RBC and PLT transfusions remained very low over time. No increase in 100-day and 180-day non-relapse mortality or adverse events was observed during the study period. No patient died due to hemorrhagic complications. Our preliminary observations support robust studies enrolling HSCT patients in patient blood management programs.

Reconstructive Strategies in Pediatric Patients after Oncological Chest Wall Resection: A Systematic Review.

An appropriate reconstruction strategy after surgical resection of chest wall tumors in children is important to optimize outcomes, but there is no consensus on the ideal approach. The aim of this study was to provide an up-to-date systematic review of the literature for different reconstruction strategies for chest wall defects in patients less than 18 years old. A systematic literature search of the complete available literature was performed and results were analyzed. A total of 22 articles were included in the analysis, which described a total of 130 chest wall reconstructions. All were retrospective analyses, including eight case reports. Reconstructive options were divided into primary closure (n = 21 [16.2%]), use of nonautologous materials (n = 83 [63.8%]), autologous tissue repair (n = 2 [1.5%]), or a combination of the latter two (n = 24 [18.5%]). Quality of evidence was poor, and the results mostly heterogeneous. Reconstruction of chest wall defects can be divided into four major categories, with each category including its own advantages and disadvantages. There is a need for higher quality evidence and guidelines, to be able to report uniformly on treatment outcomes and assess the appropriate reconstruction strategy.

HLA-haploidentical hematopoietic stem cells transplantation with regulatory and conventional T-cell adoptive immunotherapy in pediatric patients with very high-risk acute leukemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is still needed for many children with very high-risk acute leukemia. An HLA-haploidentical family donor is a suitable option for those without an HLA-matched donor. Here we present outcomes of a novel HLA-haploidentical HSCT (haplo-HSCT) strategy with adoptive immunotherapy with thymic-derived CD4+CD25+ FoxP3+ regulatory T cells (Tregs) and conventional T cells (Tcons) performed between January 2017 and July 2021 in 20 children with high-risk leukemia. Median age was 14.5 years (range, 4-21), 15 had acute lymphoblastic leukemia, 5 acute myeloid leukemia. The conditioning regimen included total body irradiation (TBI), thiotepa, fludarabine, cyclophosphamide. Grafts contained a megadose of CD34+ cells (mean 12.4 × 106/Kg), Tregs (2 × 106/Kg) and Tcons (0.5-1 × 106/Kg). All patients achieved primary, sustained full-donor engraftment. Only one patient relapsed (5%). The incidence of non-relapse mortality was 15% (3/20 patients). Five/20 patients developed ≥ grade 2 acute Graft versus Host Disease (aGvHD). It resolved in 4 who are alive and disease-free; 1 patient developed chronic GvHD (cGvHD). The probability of GRFS was 60 ± 0.5% (95% CI: 2.1-4.2) (Fig.6), CRFS was 79 ± 0.9% (95% CI: 3.2-4.9) as 16/20 patients are alive and leukemia-free. The median follow-up was 2.1 years (range 0.5 months-5.1 years). This innovative approach was associated with very promising outcomes of HSCT strategy in pediatric patients.

Fever and Neutropenia Management and Infectious Prevention Strategies in Children with Severe or Very Severe Aplastic Anemia: A North American Pediatric Aplastic Anemia Consortium (NAPAAC) Study

Introduction: Evidence-based clinical practice guidelines (CPGs) exist for supportive care interventions including fever and neutropenia (FN), infection prevention for children with cancer, however FN management in benign hematological conditions specifically for conditions with bone marrow failure (BMF) is not standardized. Pediatric Severe Aplastic Anemia (sAA) is an acquired BMF which develops severe and prolonged neutropenia. Data regarding FN management and infection prevention strategies in this population are lacking to inform best practices. Objective: Evaluate current practices across 53 centers participating in the North American Pediatric Aplastic Anemia Consortium (NAPAAC) regarding FN management and infection prevention strategies in pediatric patients with sAA or very severe aplastic anemia (vsAA). Method: A RedCap survey was created and electronically distributed to the 53 NAPAAC institutions. The instrument consisted of the following domains: 1. Participant demographics; 2. Institutional practices for usage of vascular catheters; FN management; Infectious Disease (ID) screening and prevention strategies, including isolation precautions, hand-hygiene and vaccination practices, and education around mitigating infection risk in pediatric patients with sAA/ vsAA. Pediatric patients were defined as individuals 0 to 18 years of age who had not received a HCT and met standard diagnostic criteria for sAA/ vsAA. Each institution was asked to submit one collective survey from June 1, 2022 through July 16, 2022. Descriptive analyses were performed. Results: In total 43 (81%) NAPAAC sites completed the survey. The participant demographics were as follows: 68% (N=29) hematologists, 30% (N=13) HCT specialists, 2% (N=1) practiced as both. Most centers diagnosed 0 to 5 new sAA/vsAA cases/ year (N=28, 65%), 3 (7%) centers diagnosed ≥11/yr. With regards to central venous catheter (CVC) utilization, 32 (74%) of centers report ≥50% of their sAA patients have a CVC placed with a majority being placed at time of anti-thymocyte globulin initiation. The preferred CVC is a peripheral intravenous central catheter (PICC, N=24, 56%) followed by an implantable CVCs (N=17, 40%). Thirteen (30%) centers had a FN CPG specific to sAA/vsAA. An additional 28 (65%) centers report using a FN CPG adapted from the management of children with malignancy. In hemodynamically stable sAA with FN, the majority of respondents prescribe empiric monotherapy with cefepime (N=36, 84%). In hemodynamically unstable FN, either vancomycin plus an anti-pseudomonal Beta-lactam (APBL) (N=30, 71%) or triple combination with vancomycin, APBL, and aminoglycoside (N=6, 14%) are prescribed. Empiric antifungals are not routinely prescribed in stable FN sAA (N=28, 70%) though 19 (48%) centers would start empiric antifungals in hemodynamically unstable sAA patients, including echinocandins (N=8, 42%), mold-active azoles (N=6, 32%), or amphotericin (N=3, 16%). Furthermore, 42% of participants reported that adequate criteria for discontinuation of FN antibiotics and discharge in clinically stable patients with sterile cultures was afebrile status for > 24 hours for both sAA and vsAA patients, regardless of ANC. Prior to the COVID-19 pandemic, centers were divided on recommendations for patients to wear a surgical mask (N=24, 43%) to outpatient clinic visits or not (N=19, 44%). 95% of institutions routinely discussed safe living and ID prevention (Table 1), though only 16 (37%) provided written education. 86% of respondents report reviewing vaccinations in all sAA /vsAA at diagnosis. Only 12 (34%) provided non-influenza, inactivated vaccines to incompletely immunized patients. Lastly, 37 (97%) of respondents provided inactivated influenza vaccine to sAA/vsAA in their clinics and 39 (93%) recommend and 27 (73%) provided COVID-19 mRNA vaccination in their clinics. 7 centers (16%) performed SARSCoV2 antibody testing to inform need for initial or booster COVID-19 vaccination. Conclusion: Most NAPAAC centers applied malignancy driven CPGs to manage FN in sAA/vsAA patients. Other infection control/prevention strategies were quite variable, including use of masks, education around topics related to infectious risk mitigation, and vaccination practices. Variation in supportive care practices in this population highlights an urgent need for quality improvement initiatives to develop evidence-based CPGs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

This Month in Anesthesiology

This Month in Anesthesiology

Abstract 5716: Using copper chelating agents to simultaneously target epigenetic mechanisms and receptor tyrosine kinase (RTK) signaling in diffuse intrinsic pontine glioma (DIPG)

Abstract DIPG is an incurable and inoperable pediatric brain cancer in the ventral pons characterized by its complex mutational profile. Epigenetic mutations to H3K27M are seen in up to 81% of patients, resulting in the global loss of the repressive H3K27 trimethylation marker, increasing chromatin accessibility and deregulating gene expression. However, these epigenetic changes are often partnered by secondary mutations, with activating mutations and copy number gains observed in a wide variety of RTK genes and their associated signaling pathways. The combination of these two mutational paradigms results in the broad alteration of cellular and metabolic mechanisms, complicating the search for effective targeted therapeutic strategies. Copper, a metal ion essential for normal cellular function is known to be highly expressed in the pons, and influence ERK and PI3K/AKT signaling. Importantly, excess copper accumulation has been implicated in the pathogenesis of multiple neurological diseases and cancers. Copper chelation therapy is a clinically approved strategy for pediatric patients with Wilson’s Disease, known to improve their neurological symptoms, and is under investigation for use in a number of cancers. Therefore, we hypothesized copper chelation may be an effective therapeutic strategy for DIPG. Cytotoxicity assays using copper chelator tetraethylenepentamine (TEPA) demonstrated millimolar efficacy and synergized with mTOR inhibitor everolimus in a panel of DIPG cell lines, with H3-K27M mutant cell lines found to be more sensitive. Western blots were used to identify copper integrated pathways, with DIPG cell lines stimulated with sub-lethal copper concentrations demonstrating increased phosphorylated expression of ERK1/2, ERK5, AKT and p70SK61. TEPA reduced the phosphorylation of these markers compared to controls. Importantly, epigenetic mechanisms were sensitive to copper, as both copper stimulation and TEPA modulated H3K27 trimethylation, and TEPA decreased pro-expression H3K27 acetylation. In further blots examining epigenetic regulators, TEPA reduced the expression of EZH2, DNMT3B and DNMT1. RNA-sequencing analysis revealed TEPA downregulated genes involved in S-adenosylmethionine production metabolism, DNA regulation, cell cycle and mTORC signaling and specifically, EZH2, DNMT3B and DNMT1 expression. In vivo investigations demonstrated TEPA’s ability to improve survival in an orthotopic xenograft model, and via xenogen luminescence imaging complete tumor regression in 25% of treated mice. This study indicates copper directly impacts epigenetic and RTK mechanisms, and that their targeting through copper chelation agents represents a potential therapeutic strategy for DIPG, both as a single agent and in combination. Citation Format: Filip Michniewicz, Federica Saletta, Tayla Watkinson, Daniele Mercatelli, Federico M. Giorgi, Jessica Bell, Maria Tsoli, David Ziegler, Orazio Vittorio. Using copper chelating agents to simultaneously target epigenetic mechanisms and receptor tyrosine kinase (RTK) signaling in diffuse intrinsic pontine glioma (DIPG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5716.

Circulating Cell-Free DNA Assessment in Biofluids from Children with Neuroblastoma Demonstrates Feasibility and Potential for Minimally Invasive Molecular Diagnostics.

Simple SummaryThe invasive nature of surgical biopsies prevents their sequential application to monitor disease. Single biopsies fail to reflect cancer dynamics, intratumor heterogeneity, and drug sensitivities that change over time. Detection and characterization of cell-free circulating tumor DNA in biofluids from patients with solid tumors may better support disease monitoring and provide advanced molecular information for clinical decision-making toward personalized medicine. Here, we investigated the cell-free DNA characteristics in blood, bone marrow, cerebrospinal fluid, and urine provided from 84 infants and children with low-, intermediate-, or high-risk neuroblastoma. We report characteristic size distribution and concentration patterns for each biofluid to provide information to support the development of successful liquid biopsy biobanking strategies. We investigate potential correlations between disease activity and cfDNA concentration and provide strong evidence that markers specific for neuroblastoma can be detected in very small blood volumes from infants.Liquid biopsy strategies in pediatric patients are challenging due to low body weight. This study investigated cfDNA size distribution and concentration in blood, bone marrow, cerebrospinal fluid, and urine from 84 patients with neuroblastoma classified as low (n = 28), intermediate (n = 6), or high risk (n = 50) to provide key data for liquid biopsy biobanking strategies. The average volume of blood and bone marrow plasma provided ranged between 1 and 2 mL. Analysis of 637 DNA electropherograms obtained by Agilent TapeStation measurement revealed five different major profiles and characteristic DNA size distribution patterns for each of the biofluids. The proportion of samples containing primarily cfDNA was, at 85.5%, the highest for blood plasma. The median cfDNA concentration amounted to 6.28 ng/mL (blood plasma), 58.2 ng/mL (bone marrow plasma), 0.08 ng/mL (cerebrospinal fluid), and 0.49 ng/mL (urine) in samples. Meta-analysis of the dataset demonstrated that multiple cfDNA-based assays employing the same biofluid sample optimally require sampling volumes of 1 mL for blood and bone marrow plasma, 2 mL for cerebrospinal fluid, and as large as possible for urine samples. A favorable response to treatment was associated with a rapid decrease in blood-based cfDNA concentration in patients with high-risk neuroblastoma. Blood-based cfDNA concentration was not sufficient as a single parameter to indicate high-risk disease recurrence. We provide proof of concept that monitoring neuroblastoma-specific markers in very small blood volumes from infants is feasible.

Pain Coping Strategies in Pediatric Patients with Acute Leukemias in the First Month of Therapy: Effects of Treatments and Implications on Procedural Analgesia

Simple SummaryChildren with leukemia have to adapt to several pain episodes related to medical procedures and to the treatment effects. This is one of the first multi-disciplinary studies involving different perspectives of pediatric hematologists, anesthetists, and psychologists. The aim of this study is to understand how specific coping strategies could be associated with the treatments’ factors and with the dosage of sedation analgesic drugs during bone marrow aspirates. Results underlined that patients’ coping with pain, such as distraction, could be influenced by treatment factors and by their age. The use of particular pain coping strategies (especially the request for social support) was associated with a lower demand for hypnotic sedative drugs during sedation for bone marrow aspirate. Contrarily, the catastrophic attitude was recognized as a negative factor that influenced a major dosage of propofol for the bone morrow sedations. Health professionals should strengthen these useful coping strategies and dampen the catastrophizing one.Children with leukemia experience difficulties adapting to medical procedures and to the chemotherapy’s adverse effects. Study’s objectives were to identify which coping strategies could be associated with the treatments’ factors and with the dosage of sedation analgesic drugs during bone marrow aspirates. A total of 125 patients (mean = 6.79 years; standard deviation = 3.40), majority with acute lymphoblastic leukemia (90.4%) and their parents received, one month after diagnosis, the Pediatric Pain Coping Inventory. Data on the severe treatment effects and on the dosage of drugs in sedation-analgesia were also collected. An ANCOVA model (R2 = 0.25) showed that, weighing the age factor (F = 3.47; df = 3; p = 0.02), the number of episodes of fever (F = 4.78; df = 1; p = 0.03), nausea (F = 4.71; df = 1; p = 0.03) and mucositis (F = 5.81; df = 1; p = 0.02) influenced the use of distraction. Cognitive self-instructions (R2 = 0.22) were influenced by the number of hospitalizations (F = 5.14; df = 1; p = 0.03) and mucositis (F = 8.48; df = 3; p = 0.004) and by child’s age (F = 3.76; df = 3; p = 0.01). Children who sought parental support more frequently (F = 9.7; df = 2; p = 0.0001) and who tended not to succumb to a catastrophic attitude (F = 13.33; df = 2; p = 0.001) during the induction treatment phase required lower drug dosages, especially propofol. The clinical application of these results could be to encourage the use of cognitive self-instructions and search for social support.

Venoarterial extra corporeal membrane oxygenation in pediatric patients and factors associated with mortality

Objective Extracorporeal membrane oxygenation (ECMO) is a life-saving strategy in pediatric patients when faced with cardiac or respiratory failure after cardiac surgery. In this article, we investigated the relationship between mortality and data, such as leukocyte, hematocrit (HCT), blood urea nitrogen (BUN), creatinine (CRE), albumin, lactate, c-reactive protein (CRP), systemic immune-inflammation index (SII), platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR), lactate- albumin ratio (LAR) which can be easily calculated from daily routine complete blood count and biochemistry tests of ECMO patients. Materials and Methods We obtained hospital records of 12 pediatric and newborn patients who needed ECMO therapy. The patients were divided into two as non-survivors (Group NS) and survivors (Group S). Factors that may affect mortality were investigated. Results Four patients (33%) were successfully weaned from ECMO and discharged. The remaining 8 patients died. 50% of the patients were male (n=6). While the median age was 28 (4-275) days in Group NS, the median age was 300 (300-960) days in Group S. Although not statistically significant (p=0.395), patients with younger age had a higher mortality rate. While the mean weight was 5.9±3.2 kg in Group NS, it was 6.9±3.2 kg in Group S. Postoperative PLR, SII in Group NS were higher compared to Group S. There was no statistically significant difference between the two groups. Bleeding rate was higher in Group NS than in Group S. There was an increase in postoperative NLR in Group NS compared to preoperative NLR. Conclusion Although postoperative PLR and SII were found to be higher in Group NS, postoperative NLR was increased compared to preoperative NLR, and bleeding complications were more common in group NS, none of these parameters reached a statistically significant level.

Magnetic resonance imaging diagnostic potential in “idiopathic” ventricular arrhythmias in children

The study aims to assess the role of magnetic resonance tomography (MRI) in identifying the substrate of “idiopathic” ventricular arrhythmias in pediatric patients.Methods. One hundred and seven children with “idiopathic” ventricular arrhythmias were enrolled. All patients underwent MRI on a high-field Magnetom Trio A Tim (Siemens) tomograph with a magnetic field induction of 3.0 T.Results. According to MRI data, dilated ventricles and/or a decreased ejection fraction were found in 55 (51%) patients. Based on structural abnormalities of the myocardium patients were divided into 2 groups: group 1 “normal”, without abnormalities, (69 (64.5%) children); group 2 - “fibrosis”, fibrotic changes were detected on late gadolinium enhancement (38 (35.5%) patients). Significant differences of indexed MR-indicators in these two groups were not found. However, in the “fibrosis” group, biventricular dysfunction occurred significantly more often than in the “normal” group, respectively (14 (37%) and 9 (13%) (p = 0.006)).Conclusion. MRI is important in assessing structural changes in pediatric patients with ventricular arrhythmias, and the combination of MRI results with clinical and electrophysiological data can significantly affect the change in management and treatment strategy in pediatric patients.