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.

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.

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.

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.

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.

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.

Myalgic Becker Muscular Dystrophy Due to an Exon 15 Point Mutation: Case Series and Literature Review.

ABSTRACT: Dystrophinopathies result from mutations to the DMD gene. We report 5 boys in 3 families with heterogenous phenotypes due to a point mutation in the DMD gene: a hemizygous tyrosine-to-cysteine change in exon 15 (c.1724T>C) resulting in an amino acid substitution of leucine to proline at codon 575. This mutation has been reported before, with at least 3 prior patients presenting with similar clinical findings of myalgia, myoglobinuria, and occasional muscle cramping. The mutation on DMD c.1724T>C (p.Leu575Pro) is listed in the Clinvar database as a variant of unknown significance. Our report provides contributing evidence that this alteration should be classified as pathogenic.

Medical student research opportunities: a survey of osteopathic medical schools in the United States.

CONTEXT: It is important for colleges of osteopathic medicine (COMs) to provide opportunities for osteopathic medical students (OMSs) to conduct research under the guidance of professional researchers. However, COMs historically lag behind allopathic medical schools in research offerings for medical students. The literature would benefit from a synopsis of research opportunities for OMSs at COMs. OBJECTIVES: This study aims to assess the availability of research opportunities currently offered to OMSs and to identify structured research programs (SRPs) to provide data that may help COMs expand such opportunities. METHODS: Two online surveys were developed. The General Survey asked about general research opportunities, research requirements, and SRPs, which we define as optional, intramural, and mentored research programs. The follow-up SRP Survey sought to understand the history, funding, and organizational structure of SRPs. Between February and June 2021, the General and SRP Surveys were sent to all COMs in the United States. Response data were analyzed descriptively. RESULTS: Responses were received from 32 (84.2%) of 38 COMs. Nearly all COMs offered research symposia, offered third- or fourth-year research elective rotations, and provided some form of funding for OMSs to participate in research. Fourteen (43.8%) COMs had mandatory research requirements. Twenty COMs (62.5%) offered 31 SRPs, and surveys were completed for 25 (80.6%) SRPs. SRPs were founded a median (range) of 7 (1-43) years prior and accommodated 20 (4-50) OMSs annually. Among the responding SRPs, 12.0% had external funding, 96.0% required applications, 50.0% interviewed applicants prior to acceptance into the program, 72.0% required OMSs to identify their own mentors, 68.0% offered stipends to OMSs, 28.0% offered course credits, 96.0% had clinical research opportunities, and 68.0% offered research-oriented didactics. In 84.0% of SRPs, OMSs worked predominantly in the summer after OMS-I; for these SRPs, students had 4-10 weeks of dedicated time for participation in research. CONCLUSIONS: Findings from our surveys provide a synopsis of the research opportunities currently provided by COMs in the United States. Our data demonstrated wide variability of research opportunities among COMs.

Three Pediatric Siblings With CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a congenital small vessel disease of the brain due to NOTCH3 gene mutations. Although adult-onset CADASIL is well documented, more cases are being described within the pediatric population. We describe three siblings with NOTCH3 mutations with various symptomatic presentations of early-onset CADASIL and one sibling with concurrent moyamoya syndrome. METHODS: Review of electronic medical records of identified patients. RESULTS: A 19-year-old male who has experienced behavioral dysregulation, hallucinations, and memory loss along with a hyperintense signal abnormality in his temporal lobe; his 15-year-old sister who has the mildest presentation in terms of normal imaging results but experiences severe headaches, anxiety, and depression; and the youngest sibling, a 13-year-old with first reported case of a NOTCH3 mutation associated with moyamoya syndrome and a TREX1 gene mutation of uncertain clinical significance. She had multiple strokes before age five years. CONCLUSION: Our set of siblings share many similarities with other reported pediatric cases of CADASIL, all with NOTCH3 gene mutations and with early-onset symptoms that range from abnormalities in the cognitive/behavioral/psychiatric field to neurological deficits, migraines, and strokes. Gene testing and imaging studies in symptomatic children with a family history suggestive of CADASIL might aid in early diagnosis, even though there is no effective therapy. We believe that the correlation of clinical presentations and gene mutations together with increased research into the molecular mechanisms underlying CADASIL (and related arteriopathies such as moyamoya syndrome) are critical to the eventual development of targeted therapies.

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.

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.

Prevalence of elevated liver enzymes and their association with type 2 diabetes risk factors in children.

OBJECTIVES: Given their established role in hepatic function and insulin resistance for adults, early screening of type 2 diabetes mellitus (T2DM) in the pediatric population may potentially be improved by the assessment of elevated liver enzymes. METHODS: Our study enrolled 151 nondiabetic children aged 10-14 years. Patients were assessed for demographics and five risk factors for T2DM. The levels of γ-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels were determined in serum samples. The effects of demographics and risk factors on abnormal liver enzyme levels were assessed with univariate chi-square analyses and also with multivariate logistic regression analyses, which were controlled for gender. RESULTS: Frequencies for abnormal liver enzyme values were as follows: 13 (9%) for GGT, 5 (3%) for ALT, and 20 (13%) for ALP. Across analyses, two results were consistently statistically significant. Females were more likely to have abnormal ALP levels, and patients with BMI percentile ≥95% and with acanthosis nigricans were more likely to have abnormal GGT levels. CONCLUSIONS: Our study suggests GGT as potential marker for T2DM discovery in children. Subsequent long-term longitudinal studies would help to more clearly delineate GGT's association with T2DM. Additionally, future studies that elucidate the molecular contribution of GGT elevation to T2DM pathogenesis are needed.

Mentors' experiences in an osteopathic medical student research program.

CONTEXT: Medical students, especially at osteopathic medical schools, have limited research exposure. Systematic instruction in research, supervised by qualified mentors, could motivate osteopathic medical students to pursue research in their careers, thereby increasing the number of future clinician-scientists. Recruiting and retaining suitable research mentors are crucial to sustaining such programs, but this task is also particularly challenging for osteopathic medical schools. OBJECTIVES: To assess mentors' experiences in a voluntary student-mentor medical research program. METHODS: An online survey was sent to 76 university- or hospital-based participants who previously mentored 219 medical students between 2014 and 2019. The questionnaire consisted of 13 items with responses in checklist, five-point Likert scale, and categorical multiple-choice formats, assessing motivation for participation, satisfaction with the program, and interest in future participation. Data were analyzed descriptively, and responses from mentors at the university and hospital were compared using univariate logistic and ordinal regression analyses. RESULTS: Among 70 (92.1%) mentors who responded to the survey, 61 (87.1%) reported being motivated by a desire to help medical students learn research. Forty-nine (70.0%) mentors indicated that furthering their own research productivity was a motivation, and hospital-based mentors were statistically significantly more likely to endorse this source of motivation (OR=2.02; 95% CI=1.18-3.45; p=0.01). Most respondents were satisfied with the quality of the students' work (59 [84.3%]) and with the program (59 [85.5%]). However, 46 (65.7%) suggested the program could be enhanced by requiring medical students to be physically present in the clinic or laboratory for a minimum amount of time. Importantly, most (58 [84.1%]) mentors reported that they would be interested in participating in future mentored research programs. CONCLUSIONS: Mentors were motivated to participate in the voluntary research program for both altruistic and professional reasons. Since most mentors reported being satisfied with the program, it is likely they would participate in future mentored research programs. Our results suggest that mentors viewed this voluntary research program as mutually beneficial.

Prevalence and predictors of weight loss during induction therapy for childhood acute lymphoblastic leukemia.

OBJECTIVE: Children with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma often experience significant weight gain during induction therapy. However, a subgroup of patients may experience weight loss, which can impact outcomes; thus, identifying and understanding this underrecognized concern is important. Our aim was to identify the prevalence and predictors for weight loss during ALL induction therapy. METHODS: This was a single-institution retrospective study of 187 patients, ages 2 to 20 y, diagnosed with ALL or lymphoblastic lymphoma. We analyzed weight trends during induction therapy and predictors of weight loss. RESULTS: Significant weight loss (≥5%) occurred in 17% of patients. Having high-risk disease, trisomy 21, overweight/obese status at the time of diagnosis, and/or hyperglycemia were positively associated with weight loss and negatively associated with weight gain during induction therapy. CONCLUSION: Future studies should aim to better understand the etiology and importance of weight loss during induction therapy.

Impact of an opioid stewardship program on opioid exposure for pediatric appendectomy postsurgical pain.

BACKGROUND/PURPOSE: This study aimed to evaluate the impact of a Pediatric Acute Pain Guideline on postsurgical pain scores, opioid exposure, and discharge opioid prescribing habits in postappendectomy patients. METHODS: This was a retrospective single-center quality improvement project, including patients admitted for an appendectomy at a pediatric medical center between April 1 and December 31, 2018. Patients 0-17 years of age, who underwent a laparoscopic appendectomy without complications, were inpatient for at least 1 calendar day, and designated as presurgical American Society of Anesthesiologists (ASA) category 1 or 2 were included. RESULTS: Two hundred fifty-eight patients met inclusion criteria (n = 92 pre-, n = 166 post-guideline implementation). There was a decrease in the number of as needed opioid doses used (p = 0.014) and length of hospitalization (p = 0.003) post-guideline implementation compared to pre-guideline implementation. A decrease in the number of as needed doses of opioids used (p < 0.001) and in opioid exposure (p = 0.038) during hospitalization was also seen when the nonopioid pain agent was scheduled. CONCLUSIONS: The implementation of the Pediatric Acute Pain Guideline was associated with a decrease in the number of as needed opioid doses used during hospitalization, which may have contributed to a decreased length of hospitalization. Scheduling nonopioid pain medications decreased opioid exposure. LEVEL OF EVIDENCE: Treatment study level III.