Lessons Learned: Utilization of a Reference Laboratory for Targeted Sequencing of Pediatric Tumors at a Single Institution.

Our study aims to report the prevalence of potentially actionable oncogenic variants in a sample of pediatric tumors from a single institution using a reference laboratory for tumor profiling. We investigated genomic alterations and immunotherapy biomarkers such a tumor mutation burden, microsatellite instability, and programmed death-ligand 1. Patients treated in the Cook Children's Health Care System who had tumor profiling performed by Foundation Medicine between January 1, 2013, and May 1, 2019, were included. Demographic variables, results of tumor profiling, and subsequent use of targeted therapies were captured. Eighty-one patients were in our final data set; patients had diagnoses of central nervous system tumors (n=5), leukemia and lymphoma (n=4), neuroblastoma (n=32), and other solid tumors (n=40). One or more genomic alterations were identified in 68 (84%) of patients, 34 of which had potential targeted therapies available. In all, 44/51 patients tested for tumor mutation burden had low tumor burden, and the rest had intermediate burden. All 41 patients tested for microsatellite instability status were microsatellite stable. Six of 34 patients tested for programmed death-ligand 1 status were positive. Twelve patients received targeted therapy. This study highlights a subset of pediatric tumors harboring targetable genetic alterations and describes the use of a reference laboratory for tumor profiling.

Favorable Parental Perception of Proactive Nutrition Intervention in High-risk Pediatric Brain Tumor Population and Impact on Nutrition Outcomes.

Children with certain brain tumors often present with malnutrition and experience a decline in nutritional status throughout treatment. This can negatively affect outcomes. Studies have demonstrated that proactive enteral feeding can be beneficial to childhood cancer patients in helping to maintain or improve their nutritional status. To date, no classification parameters exist for pediatric brain tumor diagnoses and their corresponding nutritional risk. Our neuro-oncology team set out to develop a nutrition risk classification for pediatric brain tumors with a corresponding decision aid for nutrition intervention. We report the use of this decision aid in 15 pediatric brain tumor patients at high risk for nutritional deficits. Despite being high risk, weight loss did not exceed 5% in 93% (14/15) and 87% (13/15) of our patients from diagnosis to start of cycle 2 of chemotherapy and from diagnosis to end of therapy, respectively. Patients underweight at diagnosis (5/15) experienced improvements in nutritional status, and only 1 patient had a negative change in body mass index z-score ≥1 SD from diagnosis to end of therapy. This strategy was well-accepted by parents who reported satisfaction with the approach, their child's nutritional status throughout treatment, and the psychosocial aspects of feeding.

Characterization of Febrile Neutropenia in Pediatric Patients With Cancer Before and After Implementation of Coronavirus Disease 2019 Precautions.

Historically, febrile neutropenia (FN) has constituted a common but life-threatening emergency in pediatric oncology patients. As such, hygiene precautions have consistently been recommended for immunosuppressed patients. These precautions, however, were more strictly and widely adopted during the coronavirus disease 2019 pandemic. Universal mask mandates, emphasis on hand hygiene, and encouragement of social distancing were some of the many initiatives introduced in an effort to reduce transmission of the virus. There is little data available regarding whether the universal adoption of these precautions was associated with any changes in the incidence of hospitalizations for FN in pediatric oncology patients. A retrospective chart review was utilized to evaluate newly diagnosed patients admitted for FN in the first 14 months of the pandemic compared with the same time period during the previous year. During the pandemic, the admission rate for FN was 28.9%, compared with 29.1% prepandemic ( P = 0.97). There was no significant difference in causative organisms when comparing time periods. In addition, the presence of a state government-enforced mask mandate was associated with an increased admission rate for FN during the pandemic period.

Proactive Glucose Screening Tool Effective for Time-sensitive Identification of Hyperglycemia in Childhood Cancer Patients.

Approximately 4% to 35% of pediatric patients undergoing treatment for acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LLy) develop drug-induced hyperglycemia. Though hyperglycemia is associated with poor outcomes, no guidelines for identifying drug-induced hyperglycemia currently exist, and the time course for developing hyperglycemia remains relatively uncharacterized after induction therapy. The present study evaluated a hyperglycemia screening protocol that was implemented to identify hyperglycemia more promptly, examined predictors of hyperglycemia during ALL and LLy therapy, and described the timeline for developing hyperglycemia. A retrospective review of 154 patients diagnosed with ALL or LLy at Cook Children's Medical Center between March 2018 and April 2022 was performed. Predictors of hyperglycemia were examined with Cox regression. The hyperglycemia screening protocol was ordered for 88 (57%) patients. Fifty-four (35%) patients developed hyperglycemia. In multivariate analyses, age 10 years or older (hazard ratio = 2.50, P = 0.007) and weight loss (vs gain) during induction (hazard ratio = 3.39, P < 0.05) were associated with hyperglycemia. The present study identified a population of patients at risk of developing hyperglycemia and identifies strategies for hyperglycemia screening. In addition, the present study showed that some patients developed hyperglycemia after induction therapy, which highlights the importance of continued blood glucose monitoring in at-risk patients. Implications and suggestions for further research are discussed.

Intracranial Relapse in Pediatric Sarcoma.

Advances in local control techniques, chemotherapy regimens, and imaging modalities have led to improvements in both morbidity and mortality in pediatric sarcoma patients. However, approximately one-third of patients develop disease relapse and intracranial metastasis was considered rare. The incidence of sarcoma brain metastasis is thought to have increased and is associated with grim outcomes. This was a retrospective study of 3 deidentified patient charts illustrating the possibility of the central nervous system as a potential site for pediatric sarcoma relapse and investigate the patterns of such relapses. We note this is the first report of infantile fibrosarcoma brain metastasis and a rare report of sarcoma lymph node metastasis. In addition, each patient was treated with targeted therapies, including entrectinib, Ruxolitnib, and pazopanib. Caregivers in cases 2 and 3 reported new-onset neurological manifestations before identification of new brain metastasis, indicating a lag in detection of new intracranial relapse in asymptomatic sarcoma patients. We suggest implementing a brief review of systems screening tool focused on concerning neurological manifestations to screen for new brain metastasis.

Factors Affecting Presentation and Treatment of Pediatric/Adolescent Cancer Patients Diagnosed With SARS-CoV-2.

BACKGROUND: It is thought that the clinical course of actively treated pediatric/adolescent cancer patients diagnosed with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is more severe than experienced by the general pediatric population. We describe the clinical course, risk factors affecting presentation, and management of coronavirus disease 2019 (COVID-19) infection for these patients. METHODS: Patients at a single institution receiving cancer therapy while diagnosed with SARS-CoV-2 between January 2020 and June 2021 were retrospectively reviewed. Data collected included age at SARS-CoV-2 diagnosis, sex, ethno-race, adjusted body mass index, and active therapies. RESULTS: Twenty-nine patients met inclusion criteria, with 16 (55.2%) experiencing symptoms. Twenty-three (79.3%) patients required no institutional support; 10 (34.4%) required hospitalization, of which 80.0% required oxygen, 30.0% required intensive care, and 10.0% required intubation. Three (10.3%) patients developed MIS-C. Obesity increased odds of hospitalization (odds ratio=25.5; P =0.002) and oxygenation (odds ratio=14.88; P =0.012). CONCLUSIONS: Hospitalization and MIS-C rates were significantly higher than, whereas mortality rates and symptom presentations were consistent with, rates in the general pediatric population. Obesity was the only risk factor predictive of clinical severity. Cancer treatment modifications and pre-emptive administration of COVID-19 treatment did not modify clinical course.

Pediatric Hemophagocytic Lymphohistiocytosis: Formation of an Interdisciplinary HLH Working Group at a Single Institution.

Fever of unknown origin is a common presentation in children with an extensive differential diagnosis that encompasses multiple specialties. From a hematologic standpoint, the differential includes hyperinflammatory syndrome, such as hemophagocytic lymphohistiocytosis (HLH), among others. Due to the rarity of HLH and nonspecific symptoms at initial presentation, specialists are often consulted later in the disease progression, which complicates disease evaluation further. Cook Children's Medical Center (CCMC) has recently developed a multidisciplinary histiocytic disorder group that is often consulted on cases presenting with fever of unknown origin to increase awareness and potentially not miss new HLH cases. In this study, we examine the clinical presentation and workup of 13 patients consulted by the HLH work group at a single institution and describe the clinical course of 2 patients diagnosed with HLH. The goal of this project was to describe the formation of a disease-specific team and the development of a stepwise diagnostic approach to HLH. A review of the current diagnostic criteria for HLH may be warranted given findings of markers such as soluble IL2 receptor and ferritin as nonspecific and spanning multiple disciplines including rheumatology, infectious disease, and hematology/oncology.

Detethering of MRI-Demonstrated Tethered Cord Syndrome.

INTRODUCTION: Recognition of tethered cord syndrome (TCS) in children is important because as the child grows, the spinal cord is stretched, leading to ischemia and subsequent neurological deficits, including bowel or bladder dysfunction, back and leg pain, or lower extremity weakness. Imaging findings raising concerns for tethering include presence of a fatty and/or thickened filum or a conus medullaris located caudal to L2. OBJECTIVES: The objective of this study was to describe the symptomatic presentation of TCS in our institution, detect demographic and diagnostic predictors of signs and symptoms, assess changes in symptoms over time, and examine whether demographic and diagnostic variables affect changes in symptoms over time. METHODS: Using a retrospective chart review from patients who underwent detethering at our institution between April 1, 2015 and March 31, 2019, we report on the signs and symptoms of patients undergoing detethering surgery at presentation and examine possible demographic and diagnostic predictors of those symptoms and changes in symptoms over time. Logistic regression analyses were used to determine whether symptoms at presentation were related to demographic and diagnostic predictors and to assess a change in symptoms over time. RESULTS: A total of 273 patients underwent detethering and were analyzed. Of these, 144 (53%) were <5 years of age, 151 (55%) were male, 233 (85%) had a fatty filum, 179 (66%) had a thickened filum, and 106 (39%) had a low-lying conus. Patients <5 years of age were less likely to have urological, gastrointestinal, and neurological or orthopedic symptoms; patients with thickened fila (i.e., greater than 2 mm in diameter regardless of fat-infiltration) were less likely to have urological symptoms; and patients with low-lying coni were less likely to have gastrointestinal symptoms. Patients exhibiting symptoms at presentation had reduced rates of symptoms at the follow-up, but a reduction in rates of symptoms over time was unrelated to demographic or diagnostic variables. Surprisingly, 123 (45%) patients presented with intractable constipation. CONCLUSION: In the population studied, several presenting symptoms, particularly constipation, were commonly reported. Children <5 years old were less likely to manifest clinically evident neurological/orthopedic, urological, and gastrointestinal symptoms than the older cohorts. Patients were less likely to report symptoms at both their first and second postoperative visit compared to presentation.

Time to referral to a nephrology clinic for pediatric hypertension.

BACKGROUND: Rates of pediatric hypertension have increased, but adherence to the current diagnostic criteria for hypertension (HTN) in pediatrics is not well known. We investigated the timeline and predictors of time to referral for those referred to nephrology for elevated blood pressure (EBP). METHODS: A retrospective study was conducted on patients, aged 3-18 years, referred to a nephrology clinic for EBP over a 3-year period. Patients were excluded if they were referred previously, were referred for other conditions, or did not have ≥ 1 prior visit with EBP. Analyses were performed to determine whether sex, age, ethnicity, socioeconomic status, and obesity predicted number of prior visits with EBP and time to referral. RESULTS: There were 120 patients (64% male; 53% obese) included and 82 (68%) had ≥ 3 prior visits with EBP ≥ 95%. Medians were as follows: 15.08 years of age at referral; 5 visits with EBP and 3.45 years from first EBP ≥ 90%; 4 visits with EBP and 1.42 years from third EBP ≥ 95%. No variables significantly predicted number of prior visits with EBP or time to referral from the first EBP. Starting with the third EBP ≥ 95%, only obesity significantly predicted number of prior visits and time to referral: Obese patients had more visits (p = 0.01), and took longer to be referred (p = 0.03) than healthy patients. CONCLUSION: Patients with EBP were generally not referred to nephrology promptly, which was especially true for obese patients. Further research is needed to identify interventions to improve time to referral for EBP.

Mutation of CEP72 Gene May Predispose Patients to Hepatotoxicity.

Drug toxicities during treatment of acute lymphoblastic leukemia play a pivotal role in influencing the outcome as certain toxicities may impair treatment compliance. Polymorphisms in CEP72 have been linked to increased incidence of vincristine-induced toxicities, namely peripheral neuropathy. We hypothesize that polymorphisms in the same gene may increase a patient's risk of developing hepatotoxicity when receiving potentially hepatotoxic agents during chemotherapy. This report describes hepatotoxicity that first developed during consolidation in a patient homozygous for the CEP72 risk alleles. Bilirubin levels normalized following dose reduction of 6-mercaptopurine. The patient continues to tolerate maintenance therapy at a reduced dose of 6-mercaptopurine.

Side Streets and U-Turns: Effects of Context Switching, Direction Switching, and Factor Switching on Interitem Correlations and Misresponse Rates.

This study tested implications of the context switching perspective proposed by Hamby, Ickes, and Babcock ( 2016 ). Using trained raters to assess the amount of reframing required to interpret the meaning of the subsequent (second) item within all adjacent item pairs, we first established that this process variable could be measured reliably. Then, in the data for 18 personality measures drawn from 3 individual-difference domains, we found that the amount of reframing (i.e., context switching) needed to interpret successive items predicted both lower interitem correlations and a greater percentage of misresponders. Similarly, item pairs that were mismatched in "directional" wording also predicted both lower interitem correlations and more misresponders. Finally, item pairs representing different factors predicted lower interitem correlations. Although the effects of direction switching and factor switching were partially mediated by the amount of reframing required, they remained significant even when the mediating effect of reframing was statistically controlled. These results indicate that interpreting the meaning of test items is a task for which the level of difficulty can vary with each successive item, as a function of how the current item compares to the previous item in aspects such as its context generality or specificity, directional wording, and content domain.

Early Nutrition Intervention Attenuates Weight Gain for Pediatric Acute Lymphoblastic Leukemia Patients in Maintenance Therapy.

Obesity following treatment of pediatric acute lymphoblastic leukemia (ALL) has become a significant long-term concern. Excessive weight gain often occurs during treatment, particularly during induction and the first 6 months of maintenance therapy, and it may be potentially modifiable. This retrospective study aimed to evaluate the impact of an early, 3-visit nutrition intervention on weight gain during maintenance therapy in ALL patients. Medical records of the intervention group were compared with historical controls who were treated on the same ALL treatment protocols during an earlier time period. Anthropometrics were collected throughout intensive therapy and at every monthly visit during the first 12 months of maintenance therapy. In total, 67 patients were evaluated (33 in the intervention group and 34 in the control group). After controlling for significant predictors of body mass index (BMI) z-scores in maintenance therapy-including higher BMI at diagnosis and weight gain throughout intensive therapy-the intervention group demonstrated more controlled weight gain during maintenance therapy (P<0.0001). A 3-visit nutrition intervention was effective in attenuating weight gain trends during ALL maintenance therapy.

Evidence for Context Switching in the Effects of Average Item Length and Item-Length Variability on Internal Consistency.

This investigation examined the effects of 3 item characteristics-the average number of words per item, within-scale variability in item length, and item "direction"-on internal consistency reliability and interitem correlation. In Study 1, we examined the effects of these variables on overall scale-level reliability using 444 subscales from 9 personality scales. In Study 2, we examined interitem correlation at the paired-item level using 477 nonredundant item pairs from 14 personality scales. Lower scale reliability was associated with more average words per item, greater within-scale variability in item length, and a greater percentage of reverse-keyed items. Similarly, smaller interitem correlations were associated with a greater degree of mismatch in item length between the paired items and with a mismatch (vs. match) in the items' respective "directions." The pattern of results across both studies supports our notion that lower internal consistency results from increased context switching; that is, from the confusion that occurs when respondents must switch back and forth between the interpretive frames pertaining to short versus long items, or between items pertaining to one pole of a personality dimension and its "opposite" pole. Suggestions for maximizing the internal consistency of personality scales are proposed.

Utilization of Genomic Tumor Profiling in Pediatric Liquid Tumors: A Clinical Series.

Hematologic tumors are mostly treated with chemotherapies that have poor toxicity profiles. While molecular tumor profiling can expand therapeutic options, our understanding of potential targetable drivers comes from studies of adult liquid tumors, which does not necessarily translate to efficacious treatment in pediatric liquid tumors. There is also no consensus on when profiling should be performed and its use in guiding therapies. We describe a single institution's experience in integrating profiling for liquid tumors. Pediatric patients diagnosed with leukemia or lymphoma and who underwent tumor profiling were retrospectively reviewed. Ten (83.3%) patients had relapsed disease prior to tumor profiling. Eleven (91.7%) patients had targetable alterations identified on profiling, and three (25%) received targeted therapy based on these variants. Of the three patients that received targeted therapy, two (66.7%) were living, and one (33.3%) decreased. For a portion of our relapsing and/or treatment-refractory patients, genetic profiling was feasible and useful in tailoring therapy to obtain stable or remission states. Practitioners may hesitate to deviate from the 'standard of therapy', resulting in the underutilization of profiling results. Prospective studies should identify actionable genetic variants found more frequently in pediatric liquid tumors and explore the benefits of proactive tumor profiling prior to the first relapse.

Utility of preoperative urine cultures and cystoscopies before ureteral reimplantation in pediatrics.

BACKGROUND: Ureteral reimplantation remains the primary surgical method used for patients with vesicoureteral reflux (VUR). Cystoscopy is commonly performed first to visualize anatomy and rule out possible abnormalities. Urine cultures may also be obtained. The objective of this study is to evaluate the prudency of preoperative urine cultures and cystoscopies in pediatric patients undergoing ureteral reimplantation. METHODS: Pediatric urologists were surveyed regarding collecting urine cultures in asymptomatic patients and cystoscopies before reimplantation. A retrospective review was also conducted of patients who underwent ureteral reimplantation for VUR between March 2018 and April 2021 at Cook Children's Medical Center. RESULTS: When physicians were asked the frequency they obtain urine cultures before reimplantation on asymptomatic patients, 36% said "never" and 38% said "always." Regarding cystoscopy, 53% said "never" and 32% said "always." Inclusion criteria were met by 101 patients. Cystoscopies were performed in 46 patients and never altered the reimplantation. There were 20 preoperative, 90 intraoperative, and 61 postoperative urine cultures. Complications were associated with positive cultures of urine collected intraoperatively and postoperatively only. CONCLUSION: Cystoscopies and asymptomatic urine cultures obtained before ureteral reimplantation provide no additional benefit while increasing cost for patients' families. Further research is needed to thoroughly identify the prudency of such practices in ureteral reimplantation for VUR.

Successful use of enteral nutrition for asparaginase-induced pancreatitis in children with acute lymphoblastic leukemia and lymphoblastic lymphoma: A case series.

Asparaginase-induced acute pancreatitis (AAP) is a concerning adverse effect in the treatment of pediatric acute lymphoblastic leukemia and lymphoblastic lymphoma. Typically, treatment of AAP follows a nil per os approach with or without parenteral nutrition (PN). However, with accounts of increased risk of adverse events, such as bacterial translocation and multiorgan failure when PN is used in lieu of enteral nutrition (EN), the recent literature has advocated for a change in practice to the early use of EN for children and adults with acute pancreatitis. Despite these recommendations, a gap remains in the literature regarding whether or not early enteral feedings are currently being used in pediatric oncology patients with acute pancreatitis. In our case series, we account for the successful use of EN to manage AAP in three pediatric patients with acute lymphoblastic leukemia/lymphoblastic lymphoma. Additionally, we describe the development of an early enteral feeding protocol for pediatric oncology patients with pancreatitis. To the best of our knowledge, this is the first case series chronicling the nutritional management of AAP using EN in the pediatric oncology population. The successful use of EN we have seen in our patients supports the shift in treatment practice to the use of EN in lieu of PN for this population.