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PURPOSE Infections pose a significant risk during therapy for childhood cancer. However, little is known about the risk of infection in long-term survivors of childhood cancer. METHODS We performed a retrospective observational study of children and adolescents born in Washington State diagnosed with cancer before age 20 years and who survived at least 5 years after diagnosis. Survivors were categorized as having a hematologic or nonhematologic malignancy and were matched to individuals without cancer in the state birth records by birth year and sex with a comparator:survivor ratio of 10:1. The primary outcome was incidence of any infection associated with a hospitalization using diagnostic codes from state hospital discharge records. Incidence was reported as a rate (IR) per 1,000 person-years. Multivariate Poisson regression was used to calculate incidence rate ratios (IRR) for cancer survivors versus comparators. RESULTS On the basis of 382 infection events among 3,152 survivors and 771 events among 31,519 comparators, the IR of all hospitalized infections starting 5 years after cancer diagnosis was 12.6 (95% CI, 11.4 to 13.9) and 2.4 (95% CI, 2.3 to 2.6), respectively, with an IRR 5.1 (95% CI, 4.5 to 5.8). The survivor IR during the 5- to 10-year (18.1, 95% CI, 15.9 to 20.5) and > 10-year postcancer diagnosis (8.3, 95% CI, 7.0 to 9.7) periods remained greater than comparison group IRs for the same time periods (2.3, 95% CI, 2.1 to 2.6 and 2.5, 95% CI, 2.3 to 2.8, respectively). When potentially vaccine-preventable infections were evaluated, survivors had a greater risk of infection relative to comparators (IRR, 13.1; 95% CI, 7.2 to 23.9). CONCLUSION Infectious complications continue to affect survivors of childhood cancer many years after initial diagnosis. Future studies are needed to better understand immune reconstitution to determine specific factors that may mitigate this risk.

PURPOSE Cancer survivors develop cancer and treatment-related morbidities at younger than normal ages and are at risk for early mortality, suggestive of an aging phenotype. The Cumulative Illness Rating Scale for Geriatrics (CIRS-G) is specifically designed to describe the accumulation of comorbidities over time with estimates of severity such as total score (TS) which is a sum of possible conditions weighted by severity. These severity scores can then be used to predict future mortality. METHODS CIRS-G scores were calculated in cancer survivors and their siblings from Childhood Cancer Survivor Study cohort members from two time points 19 years apart and members of the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004. CIRS-G metrics were analyzed using Cox proportional hazards regression to determine subsequent mortality risk. RESULTS In total, 14,355 survivors with a median age of 24 (IQR, 18-30) years and 4,022 siblings with a median age of 26 (IQR, 19-33) years provided baseline data; 6,138 survivors and 1,801 siblings provided follow-up data. Cancer survivors had higher median baseline TS than siblings at baseline (5.75 v 3.44) and follow-up (7.76 v 4.79), all P < .01. The mean increase in TS from baseline to follow-up was significantly steeper in cancer survivors (2.89 males and 3.18 females) vs. siblings (1.79 males and 1.69 females) and NHANES population (2.0 males and 1.94 females), all P < .01. Every point increase in baseline TS increased hazard for death by 9% (95% CI, 8 to 10) among survivors. CONCLUSION Application of a geriatric rating scale to characterize disease supports the hypothesis that morbidity accumulation is accelerated in young adult survivors of childhood cancer when compared with siblings and the general population.

Reducing avoidable antimicrobial exposure to pediatric patients with cancer is achievable and necessary to promote optimal short- and long-term outcomes. Multiple evidence-based practices are already well established but should be more consistently implemented. Important opportunities exist to further improve the evidence to guide selective antimicrobial use in pediatric oncology.

OBJECTIVE Adverse event (AE) reporting is crucial for determining safety of trials. Adverse events are captured manually by clinical research associates (CRAs) and research nurses (RNs), and prior studies show underreporting. It is necessary to understand AE reporting training, processes, and institution-level differences to improve AE capture. METHODS A 26-item questionnaire regarding AE reporting training, identification, tracking, and challenges was distributed to all Children's Oncology Group (COG) CRAs and RNs from February 15 to March 11, 2019, regardless of if they report AEs based on limitations of COG rosters. Results were tabulated. Institutions were grouped by self-reported full-time equivalents and compared using χ2 tests. RESULTS Of 1315 CRAs and 2703 RNs surveyed, 509 (12.7%) responded. Of those, 369 (64.9%) representing 71.8% of COG institutions report AEs. Only data from respondents who report AEs were collected and analyzed. There was a range in AE training; COG training modules were most common (79.7%). There was wide variability in AE ascertainment; only 51.2% use standardized approaches at their site. There was no standard AE tracking method; larger sites more commonly use spreadsheets (P = 0.002) and smaller sites more commonly use paper (P = 0.028). The greatest AE reporting challenges were differences between protocols (70%) and between AE definitions and documentation (53%). Half of the respondents endorsed 6 of 13 proposed tools for improving reporting including online AE reporting modules (75.3%), tip sheets for interpreting Common Terminology Criteria for Adverse Events definitions (67.5%), and standardized AE tracking forms (66.9%). Only half of the respondents reported that all colleagues at their site followed the same AE reporting practices, and there was no dominant AE tracking approach across the respondents. DISCUSSION There is wide variability in AE reporting training and practices. Numerous challenges exist, including differences between trials, challenges in interpreting AE definitions, and engaging clinicians. CONCLUSIONS Respondents are eager for additional central resources. These results provide a roadmap for areas of potential improvement.

Invasive fungal disease (IFD) is a major source of morbidity and mortality for hematopoietic cell transplant (HCT) recipients. Non-invasive biomarkers, such as the beta-D-glucan assay, may improve the diagnosis of IFD. The objective was to define the utility of surveillance testing using Fungitell® beta-D-glucan (BDG) assay in children receiving antifungal prophylaxis in the immediate post-HCT period.Weekly surveillance blood testing with the Fungitell® BDG assay was performed during the early post-HCT period in the context of a randomized trial of children, adolescents, and young adults undergoing allogeneic HCT allocated to triazole or caspofungin prophylaxis. Positivity was defined at the manufacturer cutoff of 80 pg/ml. IFD was adjudicated using blinded central reviewers. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the Fungitell® BDG assay for the outcome of proven or probable IFD.A total of 51 patients (out of 290 patients in the parent trial) contributed blood specimens. In total, 278 specimens were evaluated. Specificity was 80.8% (95% confidence interval [CI]: 75.6%-85.3%), and NPV was over 99% (95% CI: 86.8%-99.9%). However, there were no true positive results, resulting in sensitivity of 0% (95% CI: 0.0%-84.2%) and PPV of 0% (95% CI: 0.0%-6.7%).Fungitell® BDG screening is of limited utility in diagnosing IFD in the post-HCT period, mainly due to high false-positive rates. Fungitell® BDG surveillance testing should not be performed in children during the early post-HCT period while receiving antifungal prophylaxis as the pretest probability for IFD is low.

Fever and infection are an important complication of childhood cancer therapy. Most research and guideline development has focussed on febrile neutropenia, with a paucity directed at non-neutropenic fever (NNF). We describe the clinical presentation, management and outcomes of NNF in children with cancer, and externally validate the Esbenshade Vanderbilt (EsVan) clinical decision rules (CDR) to predict bacteraemia.Using a prospective database, retrospective data were collected on consecutive NNF episodes (fever ≥38.0°C and absolute neutrophil count1.0 cells/mmThere were 203 NNF episodes occurring in 125 patients. Severe sepsis was uncommon (n = 2, 1%) and bacteraemia occurred in 10 (4.9%, 95% confidence interval [CI]: 2.7%-8.8%) episodes. A confirmed or presumed bacterial infection requiring antibiotics occurred in 31 (15%) patients. Total 202 (99%) episodes received at least one dose of intravenous broad-spectrum antibiotic and 141 (70%) episodes were admitted to hospital. Six (3%) episodes required intensive care unit (ICU)-level care and there were no infection-related deaths. The EsVan 1 rule had an AUC-ROC of 0.67, 80% were identified as low risk, and sensitivity and specificity were 50% and 81.5%, respectively, for a risk threshold of 10%.Serious infection and adverse outcome are uncommon in children with NNF. Many children did not have a bacterial cause of infection identified, but were still treated with broad-spectrum antibiotics and admitted to hospital. National clinical practice guidelines should be developed for this important cohort to enable risk stratification and optimise antibiotic management. Further research is required to determine appropriateness of EsVan CDR in our cohort.

Infections cause significant treatment-related morbidity during pediatric acute lymphoblastic leukemia/lymphoma (ALL/LLy) therapy. Fevers during periods without severe neutropenia are common, but etiologies are not well-described. This study sought to describe the bloodstream infection (BSI) and non-BSI risk in children undergoing therapy for ALL/LLy.Demographic and clinical data were abstracted for febrile episodes without severe neutropenia at two children's hospitals. Treatment courses were stratified by intensity. Multivariate logistic regression evaluated characteristics associated with infection.There were 1591 febrile episodes experienced by 524 patients. Of these, 536 (34%) episodes had ≥1 infection; BSI occurred in 30 (1.9%) episodes. No BSIs occurred in episodes with a recent procedural sedation or cytarabine exposure. Presence of hypotension, chills/rigors, higher temperature, and infant phenotype were independently associated with BSI (p .05). Of the 572 non-BSIs, the most common was upper respiratory infection (URI) (n = 381, 67%). Compared to episodes without infection, URI symptoms, higher temperature, absolute neutrophil count 500-999/μl, and evaluation during a low-intensity treatment course were more likely to be associated with a non-BSI (p .05) and inpatient status was less likely to be associated with a non-BSI (p .05).The BSI rate in pediatric patients with ALL/LLy and fever without severe neutropenia is low, but one-third of the time, patients have a non-BSI. Future research should test if the need for empiric antibiotics can be tailored based on the associations identified in this study.

Background Children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) are at high risk for invasive fungal disease (IFD). Methods This multicenter, randomized, open-label trial planned to enroll 560 children and adolescents (3 months to Results A planned futility analysis demonstrated a low rate of IFD in the comparator triazole arm, so the trial was closed early. A total of 290 eligible patients, with a median age of 9.5 years (range 0.3–20.7), were randomized to caspofungin (n = 144) or a triazole (n = 146; fluconazole, n = 100; voriconazole, n = 46). The day 42 cumulative incidence of proven or probable IFD was 1.4% (95% confidence interval [CI], 0.3%–5.4%) in the caspofungin group vs 1.4% (95% CI, 0.4%–5.5%) in the triazole group (P = .99, log-rank test). When stratified by specific triazole, there was no significant difference in proven or probable IFD at day 42 between caspofungin vs fluconazole (1.0%, 95% CI, 0.1%–6.9%, P = .78) or caspofungin vs voriconazole (2.3%, 95% CI, 0.3%–15.1%, P = .69). Conclusions In pediatric HCT patients, prophylaxis with caspofungin did not significantly reduce the cumulative incidence of early proven or probable IFD compared with triazoles. Future efforts to decrease IFD-related morbidity and mortality should focus on later periods of risk. Trial Registration NCT01503515.

PURPOSE Management of febrile pediatric patients with cancer with an absolute neutrophil count of 500/µL or greater is unclear. The Esbenshade Vanderbilt (EsVan) risk prediction models have been shown to predict bloodstream infection (BSI) likelihood in this population, and this study sought to prospectively validate and implement these models in clinical practice. METHODS Data were prospectively collected on febrile pediatric patients with cancer with a central venous catheter from April 2015 to August 2019 at a single site, at which the models (EsVan: 2015 to 2017; EsVan2: October 2017 to 2019) were initially developed and subsequently implemented for clinical management in well-appearing nonseverely neutropenic individuals. It was recommended that patients with low BSI risk (< 10%) be discharged home without antibiotics, those with intermediate BSI risk (10%-39.9%) be administered an antibiotic before discharge, and those with high BSI risk (> 40%) be admitted on broad-spectrum antibiotics. Seven-day outcomes were then collected and EsVan models were prospectively validated and C-statistics estimated. RESULTS In 937 febrile, nonsevere neutropenia episodes, frequencies of low-, intermediate-, and high-risk episodes were 88.9%, 8.6%, and 2.3% respectively. BSI incidence was 4.2% (39 of 937). Within risk groups, low-risk BSI incidence was 1.9% (16 of 834) with BSI incidence of 13.6% and 54.5% for intermediate- and high-risk episodes, respectively. Empirical intravenous antibiotics were administered in 21.1% of low-risk episodes at presentation and at 7 days postpresentation, 72.3% of episodes never required intravenous antibiotics. There were no deaths or clinical decompensations attributable to antibiotic delay. For BSI detection, EsVan and EsVan2 models applied to the new cohort achieved C-statistics of 0.802 and 0.824, respectively. CONCLUSION Prospective, real-time clinical utilization of the EsVan models accurately predicts BSI risk and safely reduces unnecessary antibiotic use in febrile, nonseverely neutropenic pediatric patients with cancer.

BACKGROUND Neurofibromatosis type 1 (NF-1) is a neurocutaneous autosomal dominant disorder that predisposes patients to develop intracranial low-grade gliomas (LGGs). Most LGGs in patients with NF-1 involve the optic pathway but can arise anywhere throughout the central nervous system. NF-1–related disseminated pediatric LGG (dPLGG) in the absence of a dominant optic pathway glioma has not been described. OBSERVATIONS The authors discussed a case of a 10-year-old boy who presented with consideration for biopsy with nonoptic pathway PLGG with craniospinal dPLGG in the setting of NF-1. The patient’s primary lesion, located in the right medulla, was initially treated with surveillance before induction chemotherapy with carboplatin and vincristine was initiated. However, surveillance imaging demonstrated significant increase in size and enhancement, and subsequent craniospinal imaging demonstrated extensive nodular dissemination in the cervicothoracic spine. A biopsy and molecular testing were subsequently performed to further evaluate the tumor, and the patient was diagnosed with dPLGG with CDKN2A deletion. LESSONS Thorough craniospinal magnetic resonance imaging evaluation and biopsy in nonoptic pathway–dominant brain lesions in NF-1 are warranted in patients with atypical clinical and radiological findings in whom standard chemotherapeutic therapy fails.

Background Patients receiving chemotherapy for acute myeloid leukemia (AML) are at high risk for invasive fungal disease (IFD). Diagnosis of IFD is challenging, leading to interest in fungal biomarkers. The objective was to define the utility of surveillance testing with Platelia Aspergillus galactomannan (GM) enzyme immunoassay (EIA) and Fungitell β-d-glucan (BDG) assay in children with AML receiving antifungal prophylaxis. Methods Twice-weekly surveillance blood testing with GM EIA and BDG assay was performed during periods of neutropenia in the context of a randomized trial of children, adolescents, and young adults with AML allocated to fluconazole or caspofungin prophylaxis. Proven or probable IFD was adjudicated using blinded central reviewers. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for Platelia and Fungitell assays alone and in combination for the outcomes of proven and probable invasive aspergillosis (IA) or invasive candidiasis (IC). Results Among 471 patients enrolled, 425 participants (209 fluconazole and 216 caspofungin) contributed ≥1 blood specimen. In total, 6103 specimens were evaluated, with a median of 15 specimens per patient (range 1–43). The NPV was >99% for GM EIA and BDG assay alone and in combination. However, there were no true positive results, resulting in sensitivity and PPV for each assay of 0%. Conclusions The GM EIA and the BDG assay alone or in combination were not successful at detecting IA or IC during periods of neutropenia in children, adolescents, and young adults with AML receiving antifungal prophylaxis. Utilization of these assays for surveillance in this clinical setting should be discouraged.

The aim of this study was to examine the feasibility of cognitive assessment from pre-surgery through two-year follow-up in a sample of pediatric brain tumor (BT) patients. We sought to investigate cognitive function over the course of diagnosis and treatment, and as a function of presenting problems, tumor location, treatment type, and tumor severity. Using a prospective, longitudinal design, standardized IQ measures were administered to pediatric BT patients (ages 6-16) prior to surgery (n=25), 6 months post-diagnosis (n=24), and 24 months post-diagnosis (n=23). Group differences emerged based on tumor severity and treatment type at multiple time points, including prior to surgical intervention; children with high grade tumors performed more poorly than children with low grade tumors, and children receiving surgery plus adjuvant therapy performed more poorly than children who received surgery only. When considered together, an analysis of covariance demonstrated that tumor grade significantly accounted for variability in cognitive functioning, while treatment type did not. Although there is overlap clinically between tumor severity and treatment received, results suggest that tumor severity is an important factor contributing to variability in cognitive functioning and should also be considered when monitoring risk for cognitive deficits in children diagnosed with BT.

This review focuses on diet and exercise interventions that have been conducted in pediatric cancer and pediatric stem cell transplant patients. It examines the different reasons for conducting lifestyle interventions with attention to the different outcome measurements and feasibility of these measures with an argument toward a need for standardization to move the field forward.

Monitoring serum immunoglobulin G (IgG) levels in pediatric oncology patients and treating subtherapeutic levels with intravenous immunoglobulin (IVIG) may prevent infections; however, evidence is limited. This retrospective study assessed pediatric acute lymphoblastic leukemia patients diagnosed 2006 to 2011 to evaluate if monitoring/supplementing IgG would reduce febrile illnesses during maintenance chemotherapy. A subject was categorized as "ever IgG monitored" if they had ≥1 IgG levels checked and their risk days were stratified into not IgG monitored days and IgG monitored days. IgG monitored days were further stratified into IgG monitored with IVIG supplementation, monitored with no IVIG supplementation (IgG level >500 mg/dL) and monitored with no IVIG supplementation days (IgG level

While the COVID-19 pandemic triggered numerous clinical practice changes and resulted in severe consequences either directly or indirectly for select pediatric patients, important lessons were learned, and there are silver linings for immunocompromised children evident among the chaos. At a minimum, the pandemic raised global awareness of infection risk, viral transmissibility, and the immune system. Handwashing, comprehensive disinfection practices of shared surfaces, and mask wearing are more normalized. School shutdowns during the COVID-19 pandemic not only kept children from exposure to SARS-CoV-2 but also decreased the incidence of pneumonia, otitis media, streptococcal pharyngitis, urinary tract infections, croup, gastrointestinal infections, and asthma.104 Strategies to mitigate SARS-CoV-2 infection including ventilation upgrades and cohorting methods are likely to help attenuate infectious exposures as students return to the classroom. In addition, the broad acceptance of virtual learning and incorporation of virtual learners in a hybrid classroom are practices expected to be of value to immunodeficient patients. Beyond schooling, the creative transition of other activities, for example, dance, karate, and enrichment opportunities, for example, art classes and streaming concerts, has allowed immunocompromised children to participate with their peers. As risk of SARS-CoV-2 transmission lessens, immunocompetent children will return to school and other in-person activities; the expanded services offered during the pandemic need to be continued for children with weakened immune systems. From a health care perspective, the massive uptake of telemedicine provided an alternative strategy for patients with compromised immune systems to maintain access to care with increased convenience and decreased cost. Given that immunocompromised patients are likely to benefit from continued telehealth options after the pandemic, it is imperative that action be taken to preserve the expansion of compensated telehealth options, while also appreciating that in-person visits are vital for some patients to diagnose new or progressive disease. In addition, strategies to mitigate barriers for telehealth uptake to improve equity of access as well as parental/patient preferences for care received in-person versus virtually must be explored. Although global efforts have accelerated our understanding and care of SARS-CoV-2 patients, our knowledge of clinical outcomes and treatment in immunocompromised patients is limited, particularly in inborn errors of immunity and pediatric HIV. Challenges remaining for pediatricians include sustained, global collaboration to consolidate knowledge in these rare patient groups, continued adaptation of knowledge gained from immunocompetent patients to immunocompromised cohorts, and further study on the safety and efficacy of current and developing vaccines. Persistent advocacy for rare diseases is even more critical as the clinical, scientific, and philanthropic communities remain focused on COVID-19 care and research. Finally, a comment that immunocompromised parents hear is, “I finally understand what it is like to live like you. I am afraid to get an infection. I cannot just go anywhere I want to go anymore”. Although the COVID-19 pandemic has been difficult for everyone on a personal and professional level, the anxiety of infection and social isolation will persist for immunocompromised families even as the risk of SARS-CoV-2 transmission subsides. It is imperative that we leverage knowledge gained from this pandemic to improve the health and quality of life of immunocompromised children so that they may live without fear.

Research shows promise for cognitive interventions for children diagnosed with brain tumors. Interventions have been delivered approximately 5 years postdiagnosis on average, yet recent evidence shows cognitive deficits may appear near diagnosis. The present study assessed the feasibility and initial effects of working memory training in children with brain tumors delivered soon after diagnosis and followed 2 years postdiagnosis. Children completed baseline assessments 10 months postdiagnosis and were randomized to complete adaptive or nonadaptive (i.e., control) Cogmed Working Memory Training. Children were administered the WISC-IV Working Memory Index (WMI) and NIH Toolbox Cognitive Battery (NTCB), and parents completed attentional and executive function measures at four time points. On average, participants completed half of prescribed Cogmed sessions. Retention for the three follow-up assessments proved difficult. For both Cogmed groups, WMI and NTCB scores significantly improved immediately postintervention compared to baseline scores. Significant differences were not maintained at the remaining follow-ups. There was preliminary evidence for improved executive function at the final follow-up on parent-reported measures. Working memory training closer to diagnosis proved difficult, though results suggest evidence of cognitive improvement. Future studies should continue to examine potentially efficacious interventions for children with brain tumors and optimal delivery windows to maximize impact.

One goal of precision medicine is to identify mutations within individual tumors to design targeted treatment approaches. This report details the use of genomic testing to select a targeted therapy regimen of erlotinib and rapamycin for a pediatric anaplastic oligodendroglioma refractory to standard treatment, achieving a 33-month sustained response. Immunohistochemical analysis of total and phosphorylated protein isoforms showed abnormal signaling consistent with detected mutations, while revealing heterogeneity in per-cell activation of signaling pathways in multiple subpopulations of tumor cells throughout the course of disease. This case highlights molecular features that may be relevant to designing future targeted treatments.

Context Pituitary blastoma is a rare, dysontogenetic hypophyseal tumor of infancy first described in 2008, strongly suggestive of DICER1 syndrome. Objective This work aims to describe genetic alterations, clinical courses, outcomes, and complications in all known pituitary blastoma cases. Design and Setting A multi-institutional case series is presented from tertiary pediatric oncology centers. Patients Patients included children with pituitary blastoma. Interventions Genetic testing, surgery, oncologic therapy, endocrine support are reported. Outcome Measures Outcome measures included survival, long-term morbidities, and germline and tumor DICER1 genotypes. Results Seventeen pituitary blastoma cases were studied (10 girls and 7 boys); median age at diagnosis was 11 months (range, 2-24 months). Cushing syndrome was the most frequent presentation (n = 10). Cushingoid stigmata were absent in 7 children (2 with increased adrenocorticotropin [ACTH]; 5 with normal/unmeasured ACTH). Ophthalmoplegia and increased intracranial pressure were also observed. Surgical procedures included gross/near-total resection (n = 7), subtotal resection (n = 9), and biopsy (n = 1). Six children received adjuvant therapy. At a median follow-up of 6.7 years, 9 patients were alive; 8 patients died of the following causes: early medical/surgical complications (n = 3), sepsis (n = 1), catheter-related complication (n = 1), aneurysmal bleeding (n = 1), second brain tumor (n = 1), and progression (n = 1). Surgery was the only intervention for 5 of 9 survivors. Extent of resection, but neither Ki67 labeling index nor adjuvant therapy, was significantly associated with survival. Chronic complications included neuroendocrine (n = 8), visual (n = 4), and neurodevelopmental (n = 3) deficits. Sixteen pituitary blastomas were attributed to DICER1 abnormalities. Conclusions Pituitary blastoma is a locally destructive tumor associated with high mortality. Surgical resection alone provides long-term disease control for some patients. Quality survival is possible with long-term neuroendocrine management.

Background Cisplatin-induced hearing loss (CIHL) is a common and debilitating toxicity for childhood cancer survivors. Understanding provider perspectives is crucial to developing otoprotection studies that are both informative and feasible. Two international trials (ACCL0431 and SIOPEL6) investigated the drug sodium thiosulfate (STS) as an otoprotectant, but definitive interpretation of the findings of these trials has been challenging. Adoption of STS has therefore been uneven, and provider perspectives on its role are unknown. Procedure The Children's Oncology Group (COG) Cancer Control and Supportive Care Neurotoxicity Subcommittee therefore conducted a survey of providers at COG institutions to determine perspectives on pediatric otoprotection practices and research surrounding three major themes: (1) prevalence of routine use of STS with cisplatin-based regimens, (2) application of audiometry to cisplatin therapy, and (3) preferred modalities for otoprotection research. Results Survey respondents (45%, 44/98 surveyed institutions) were of diverse institutional sizes, practice settings, and geographical locations primarily in the United States and Canada. Overall, respondents considered CIHL an important toxicity and indicated strong enthusiasm for future studies (98%, 40/41). Results indicated that while STS was the current or planned standard of care in a minority of responding institutions (36%, 16/44), most sites were receptive to its inclusion in appropriate study designs. Application of audiometry for ototoxicity monitoring varied widely across sites. For otoprotection research, systemic agents were preferred (68%, 28/41) as compared with intratympanic approaches. Conclusion These results suggest that pediatric otoprotection trials remain of interest to providers; the emphasis of these trials should remain on systemic and not intratympanic therapy.

BACKGROUND: A successful academic interview has been reported as the most important factor contributing to ranking of candidates for residency. However, little published guidance exists to help a prospective oncologist or researcher give such an interview. The International Society of Paediatric Oncology (SIOP) Young Investigator (YI) Network and Children's Oncology Group (COG) YI group thus cosponsored a survey of senior investigators seeking their advice. METHODS: An electronic survey covering aspects of the academic interview of both trainees and faculty were sent to all current/past mentors serving in the COG YI mentorship program and those registered as mentors in the SIOP YI mentorship program. The responses were quantitatively and qualitatively analyzed. RESULTS: The response rate was 43.7% (118/270) from 25 countries. Majority of United States (US) interviewers (86.8%) conducted interviews individually, while 74% of non-US interviewers conducted panel interviews or both types equally (P < .001). Majority of interviewers (83.4%) at least occasionally contacted colleagues for off the record opinions on candidates, and 40.9% conducted an internet or social media search. Enthusiasm for the job (97.2%) and being a team player (95.3%) were the qualities most rated as at least moderately important, while a priority for work-life balance (45.4%) and having interests/hobbies outside of medicine (29.2%) were considered less important. Interviewers provided interview questions, tips for candidates, and key pitfalls to avoid. DISCUSSION: Candidates should prepare for their academic interviews in advance, be enthusiastic and honest when giving responses. Detailed guidance for those applying at different career stages and in different countries are provided.

BACKGROUND Pediatric oncology patients are at an increased risk of invasive bacterial infection due to immunosuppression. The risk of such infection in the absence of severe neutropenia (absolute neutrophil count ≥ 500/μL) is not well established and a validated prediction model for blood stream infection (BSI) risk offers clinical usefulness. METHODS A 6-site retrospective external validation was conducted using a previously published risk prediction model for BSI in febrile pediatric oncology patients without severe neutropenia: the Esbenshade/Vanderbilt (EsVan) model. A reduced model (EsVan2) excluding 2 less clinically reliable variables also was created using the initial EsVan model derivative cohort, and was validated using all 5 external validation cohorts. One data set was used only in sensitivity analyses due to missing some variables. RESULTS From the 5 primary data sets, there were a total of 1197 febrile episodes and 76 episodes of bacteremia. The overall C statistic for predicting bacteremia was 0.695, with a calibration slope of 0.50 for the original model and a calibration slope of 1.0 when recalibration was applied to the model. The model performed better in predicting high-risk bacteremia (gram-negative or Staphylococcus aureus infection) versus BSI alone, with a C statistic of 0.801 and a calibration slope of 0.65. The EsVan2 model outperformed the EsVan model across data sets with a C statistic of 0.733 for predicting BSI and a C statistic of 0.841 for high-risk BSI. CONCLUSIONS The results of this external validation demonstrated that the EsVan and EsVan2 models are able to predict BSI across multiple performance sites and, once validated and implemented prospectively, could assist in decision making in clinical practice. Cancer 2017. © 2017 American Cancer Society.

Background: Despite advances in cure rates for pediatric acute lymphoblastic leukemia (ALL), infections remain a significant cause of treatment-related morbidity and mortality. Patients with a central venous catheter (CVC) who develop fever while severely neutropenic (absolute neutrophil count (ANC) < 500) are known to be at high risk for serious infections such as blood stream infections (BSIs). However, on Children's Oncology Group (COG) ALL protocols, the majority of a patient's therapy course is in the maintenance phase, during which patients are typically not severely neutropenic. While the BSI rate in all pediatric oncology patients presenting with non-neutropenic fever has been reported to be around 5 to 10% (Allaway et al Pediatr Blood Cancer 2019), minimal data are available regarding BSI and other infections in pediatric ALL patients with non-neutropenic fever. Objective: The objective of this study was to describe the infectious outcomes of children with ALL who developed non-neutropenic fever. Methods: A single institution retrospective chart review collected data on all non-neutropenic pediatric ALL patients (age 0-25 years) with a CVC who were evaluated for fever (temperature ≥ 38ºC) and had a blood culture drawn at the time of presentation from April 2019 through June 2020. Febrile events occurring within 7 days of a prior febrile episode, during administration of empiric or treatment antibiotics, and in patients within 30 days after stem cell transplant (SCT) were excluded. The primary outcome was documented infection from the day of fever evaluation including BSI, positive respiratory viral panel (RVP) result, or other clinically identified infection. The following demographic and clinical variables were abstracted to evaluate risk factors for infection: age, sex, race, ethnicity, CVC type, maximum presenting temperature, ANC, exposure to chemotherapy agents known to be associated with fever (cytarabine or anti-thymocyte globulin), patient location at presentation, history of SCT, sedation event within the prior 24 hours, and COG ALL protocol risk stratification. Institutional review board approval was obtained. Descriptive and inferential statistics, including chi-square or Fisher's exact test as appropriate, were calculated. Analyses were performed using SAS Enterprise Guide v7.1. Results: Data were collected on 299 non-neutropenic febrile episodes experienced by 150 patients. Eighty-eight (29.4%) episodes (61 patients) had at least one identified infection. Thirteen (14.8%) infections were a BSI; the overall BSI rate was 4.3%. Seven BSIs were gram-positive organisms and the remainder were gram-negative organisms. The other infections included 57 (64.8%) respiratory viral infections, 15 (17.0%) pneumonias, 6 (6.8%) ear, nose and throat infections, 3 (3.4%) gastrointestinal infections, and 5 (5.7%) other infections. There was more than one identified infection in 11 episodes (12.5% of infectious episodes) with respiratory viral infection and pneumonia as the most common co-infections (n=6). Presenting temperature ≥ 39ºC was associated with having an identifiable infection (p=0.003). Documented infections occurred less frequently in patients with an exposure to a drug associated with fever (p=0.004), who were inpatient at presentation (p=0.042), or who had a sedation in the prior 24 hours (p=0.003). Conclusion: In this single institution cohort of children with ALL, 29.4% of non-neutropenic febrile episodes were due to a documented infection. The BSI rate of 4.3% is similar to other published reports of pediatric oncology patients with a CVC who developed non-neutropenic fever. Not surprisingly, the most common type of infection was respiratory viral infection. Notably, infections occurred more frequently in patients with a presenting temperature ≥ 39ºC while having had a sedation event within the past 24 hours or having received a chemotherapy agent associated with development of fever were less likely to be associated with an infection. These results provide data that may be useful in determining need for empiric antimicrobial therapy in pediatric ALL patients with non-neutropenic fever based on height of fever and recent treatment exposures. Further evaluation of these initial results in larger, multi-institutional studies are ongoing in order to guide future approaches to treatment of children with ALL who develop non-neutropenic fever. Disclosures No relevant conflicts of interest to declare.

Background To the authors' knowledge, information regarding whether daily bathing with chlorhexidine gluconate (CHG) reduces central line–associated bloodstream infection (CLABSI) in pediatric oncology patients and those undergoing hematopoietic stem cell transplantation (HCT) is limited. Methods In the current multicenter, randomized, double‐blind, placebo‐controlled trial, patients aged ≥2 months and, In this randomized clinical trial of 177 children with cancer or those undergoing hematopoietic stem cell transplantation, chlorhexidine gluconate (CHG) bathing does not appear to reduce central line–associated bloodstream infection, total positive blood cultures, or the acquisition of resistant organisms. The results do not support the routine use of CHG bathing in this population.

OBJECTIVELittle is understood about the role that health disparities play in the treatment and management of brain tumors in children. The purpose of this study was to determine if health disparities impact the timing of initial and follow-up care of patients, as well as overall survival.METHODSThe authors conducted a retrospective study of pediatric patients (< 18 years of age) previously diagnosed with, and initially treated for, a primary CNS tumor between 2005 and 2012 at Monroe Carell Jr. Children’s Hospital at Vanderbilt. Primary outcomes included time from symptom presentation to initial neurosurgery consultation and percentage of missed follow-up visits for ancillary or core services (defined as no-show visits). Core services were defined as healthcare interactions directly involved with CNS tumor management, whereas ancillary services were appointments that might be related to overall care of the patient but not directly focused on treatment of the tumor. Statistical analysis included Pearson’s chi-square test, nonparametric univariable tests, and multivariable linear regression. Statistical significance was set a priori at p < 0.05.RESULTSThe analysis included 198 patients. The median time from symptom onset to initial presentation was 30.0 days. A mean of 7.45% of all core visits were missed. When comparing African American and Caucasian patients, there was no significant difference in age at diagnosis, timing of initial symptoms, or tumor grade. African American patients missed significantly more core visits than Caucasian patients (p = 0.007); this became even more significant when controlling for other factors in the multivariable analysis (p < 0.001). African American patients were more likely to have public insurance, while Caucasian patients were more likely to have private insurance (p = 0.025). When evaluating survival, no health disparities were identified.CONCLUSIONSNo significant health disparities were identified when evaluating the timing of presentation and survival. A racial disparity was noted when evaluating missed follow-up visits. Future work should focus on identifying reasons for differences and whether social determinants of health affect other aspects of treatment.

BACKGROUND Identification and development of young investigators (YI) is critical to the long-term success of research organizations. In 2004, the Children's Oncology Group (COG) created a mentorship program to foster the career development of YIs (faculty

There is mounting evidence that combination of antibiotic therapy with vancomycin and piperacillin/tazobactam (pip/tazo) is associated with acute kidney injury (AKI). To determine whether vancomycin plus pip/tazo is associated with higher rates of AKI compared to vancomycin plus cefepime among pediatric hematology/oncology (heme/onc) patients, we examined 121 heme/onc patients receiving at least two consecutive days of therapy with vancomycin and either pip/tazo or cefepime. Rate of AKI was higher in the pip/tazo than the cefepime group (4/27 [14.8%] vs 2/94 [2.1%], P = 0.022).

6565 Background: Patients (pts) with cancer are at increased risk of SARS-CoV-2 infection and severe COVID-19 disease. Longitudinal follow-up is needed to characterize the severity, sequelae and outcomes in pts with cancer who develop COVID-19. Methods: NCCAPS is a prospective, longitudinal study (NCT04387656) aiming to accrue 2,000 pts with cancer undergoing active treatment or prior stem cell transplant for hematologic or solid tumor malignancy. Adult patients are eligible to enroll within 14 days of their first positive SARS-CoV-2 test; pediatric patients may also enroll retrospectively. Clinical data, patient-reported outcomes, blood specimens, and imaging are collected for up to 2 years. This abstract provides initial baseline and 2-month follow-up data. Results: As of Jan 22, 2021, 585 pts (552 adults and 33 pediatric pts) had complete baseline data and of these pts, 215 adults had 2 months of complete follow-up data. 23.4% of adults and 42.4% of pediatric pts were of non-White race and/or Hispanic/Latinx ethnicity. The most common cancer diagnoses were breast (19.6%), lung (9.9%) and multiple myeloma (8.9%) in adults and acute leukemia (AML/ALL; 63.6%) in children. The most recent treatment was chemotherapy in 38.2%, immunotherapy in 9.6%, and radiation in 5.4%. Median time from positive SARS-CoV-2 test to study enrollment was 10.5 days in adults and 18 days in pediatric pts. Preliminary analysis of plasma cytokines will be presented. At enrollment, 84.6% of adults had COVID-19 symptoms. 55.9% reported symptoms 2 weeks after their positive SARS-CoV-2 test; this fell to 39.0% at 1 month and 28.8% at 2 months (see Table). Of the 215 adults with complete data at 2 months, sequelae included pulmonary (n=22, 10%), cardiovascular (n=12, 6%) thromboembolic (n=9, 4%), bleeding (n=9, 4%) and gastrointestinal (n=11, 5%). 144 (67%) reported at least one cancer treatment disruption in the first 2 months, most commonly delayed therapy (n=98; 46%).Of the 348 adults with baseline data and SARS-CoV-2 test date prior to Nov 23, 2020, 6.3% had died (median time from SARS-CoV-2 test to death: 27 days), and 22.1% reported at least one hospitalization for COVID-19. No deaths were reported in the pediatric population. Conclusion: Cancer pts with COVID-19 report ongoing symptoms after acute infection and a substantial number develop sequelae. Cancer treatment disruptions are common in the initial months following SARS-CoV-2 infection. Longer follow-up will inform whether these treatment disruptions are associated with adverse outcomes. Clinical trial information: NCT04387656. [Table: see text]

INTRODUCTION Because treatment and clinical management decisions for children with NF1-OPG remain challenging, we sought to establish evidence-based guidelines. We prospectively enrolled children with newly-diagnosed NF1-OPGs, and gathered standardized clinical neuro-oncology and ophthalmology assessments. METHODS Only children with NF1 and newly diagnosed OPGs, confirmed by central review, were eligible. Indications for obtaining the initial MRI, as well as factors associated with the decision to treat with chemotherapy or observe without treatment, were obtained. Quantitative visual acuity (VA), other ophthalmic features, and imaging were captured at standard time points. Goal enrollment is 250 subjects. RESULTS One-hundred thirty-three children (52% female) from 20 institutions met inclusion criteria, and were included in this preliminary analysis. Eighty-six percent of subjects were able to perform quantitative VA testing at enrollment. The most common reasons for the diagnostic MRI included screening related to NF1 diagnosis (36.8%), ophthalmologic concerns (29.3%), and non-ophthalmologic concerns (24.8%), such as headache. To date, twenty subjects have initiated treatment with chemotherapy, twelve (9%) at the time of the initial OPG diagnosis. Median age at OPG diagnosis was 3.1 years. Age and sex distribution were similar in subjects immediately entering the observation and treatment arms (median age 3.0 versus 3.5 years, respectively). CONCLUSION Most children with NF1-OPGs are observed at time of their initial OPG diagnosis, rather than treated. Importantly, a large proportion of children are able to complete quantitative VA testing at enrollment. Once enrollment is complete, these data will help to establish evidence-based guidelines for clinical management of NF1-OPGs.

Clostridium difficile infection (CDI) is common in pediatric oncology patients and is often associated with recurrences and complications. We hypothesized that higher intensity of chemotherapy would be associated with these outcomes. We conducted a retrospective cohort study including all cases of primary CDI in children with malignancy in our institution for over 7 years. Intensity of chemotherapy was measured by the Intensity of Treatment Rating Scale, third edition, ranging from level 1 (minimal) to 4 (highest). Outcomes included recurrence within both 56 and 180 days, CDI-associated complications, and primary treatment failure (PTF). Risk of recurrence was compared using Cox proportional hazards regression. Among 192 patients with CDI and malignancy, 122 met inclusion criteria. CDI recurred in 27% (31/115) of patients followed for 56 days and 46% (48/104) of patients followed for 180 days. Fourteen patients (11.4%) had a CDI-associated complication, including 4 intensive care unit admissions and 3 surgical procedures, but no deaths. Ten patients (8.2%) had PTF. Although PTF and severe complications were infrequent, recurrence was common in our cohort. None of these outcomes were associated with level of treatment intensity. More research is required to assess oncologic and nononcologic risk factors for CDI recurrence, PTF, and severe CDI-associated complications.

Purpose The aim of this work was to develop a clinical practice guideline for the prevention and treatment of Clostridium difficile infection (CDI) in children and adolescents with cancer and pediatric hematopoietic stem-cell transplantation (HSCT) patients. Methods An international multidisciplinary panel of experts in pediatric oncology and infectious diseases with patient advocate representation was convened. We performed systematic reviews of randomized controlled trials for the prevention or treatment of CDI in any population and considered the directness of the evidence to children with cancer and pediatric HSCT patients. We used the Grading of Recommendations Assessment, Development, and Evaluation approach to generate recommendations. Results The panel made strong recommendations to administer either oral metronidazole or oral vancomycin for the initial treatment of nonsevere CDI and oral vancomycin for the initial treatment of severe CDI. Fidaxomicin may be considered in the setting of recurrent CDI. The panel suggested that probiotics not be routinely used for the prevention of CDI, and that monoclonal antibodies and probiotics not be routinely used for the treatment of CDI. A strong recommendation to not use fecal microbiota transplantation was made in this population. We identified key knowledge gaps and suggested directions for future research. Conclusion We present a guideline for the prevention and treatment of CDI in children and adolescents with cancer and pediatric HSCT patients. Future research should include randomized controlled trials that involve children with cancer and pediatric HSCT patients to improve the management of CDI in this population.

A 10 year old presented in 2014 with left sided weakness and numbness and was found to have a large infiltrating mass involving the right perisylvian frontal and temporal cortex and causing mass effect. It was biopsied and shown to be an anaplastic oligodendroglioma (WHO Grade III) with no LOH 1p19q. The patient underwent 60 Gy cranial radiation with temozolomide and the MRI following radiation showed the mass had progressed with increased enhancement. The patient was then started on maintenance temozolomide, bevacizumab, and irinotecan but 7 months later further progressed. The patient was switched to procarbazine, lomustine and vincristine (PCV) but after 4 months showed further progression. Patient was wheel chair bound and was made do not resuscitate. Foundation One testing was sent and revealed mutations in EGFR, a receptor tyrosine kinase, and FBXW7, a member of the SCF complex predicted to sensitize cells to rapamycin. As a consequence, the patient was started on erlotinib, an EGFR inhibitor, and rapamycin, a mTOR inhibitor. The patient showed immediate response and tumor regression and continues to remain on these medications with sustained response for 2.5 years. Immunofluorescent analyses of fixed tumor specimens indicates that EGFR-positive cells in the pre-treatment tumor frequently also exhibit high levels of p-S6, an indicator of mTOR activity, suggesting that a majority of cells within this tumor may be targeted by both inhibitors simultaneously, rather than two independent populations being present. This regimen has potential to be an effective regimen in those with similar mutations.

Among brain tumors, the BRAF V600E mutation is frequently associated with pleomorphic xanthoastrocytomas (PXAs) and gangliogliomas (GGs). This oncogenic mutation is also detected in ~5 % of other pediatric low-grade gliomas (LGGs) including pilocytic astrocytomas (PAs) and diffuse astrocytomas. In the current multi-institutional study of 56 non-PXA/non-GG diencephalic pediatric LGGs, the BRAF V600 mutation rate is 36 %. V600-mutant tumors demonstrate a predilection for infants and young children (

Background Childhood cancer survivors are at risk for treatment-related adverse health outcomes, known as late effects. Through matched and longitudinal cohorts, we assessed the impact of survivorship care on patient and parent knowledge of treatment history and associated health risks. Procedure Childhood cancer survivors were recruited from a single-institution survivorship clinic and matched with survivors receiving routine follow-up care (controls) on diagnosis, age, and time off therapy. One hundred seventy-four participants completed telephone interviews assessing knowledge of diagnosis, treatment history, and risk of late effects. Additionally, 48 new survivorship patients were followed longitudinally with serial interviews for 18 months. Results In the case-control study, survivorship participants were more likely than controls to correctly report their diagnosis (98% vs. 90%, P = 0.039) and indicate a previous discussion of risk of late effects (99% vs. 62%, P

ContextNeuroblastoma (NB) is the most common extracranial tumor of childhood. Although most cases have a distinctive histology, a subset of primitive cases require immunohistochemical studies to distinguish them from other small round blue cell tumors of childhood. Immunohistochemistry is also used to detect small amounts of tumor metastatic to the bone marrow and in posttreatment samples with obscuring fibrosis, calcification, or inflammation. The transcription factor PHOX2B is essential for the differentiation and survival of sympathetic neurons and chromaffin cells, and therefore is highly specific for the peripheral autonomic nervous system.ObjectiveTo determine the diagnostic utility of PHOX2B immunohistochemistry as a marker of primary, treated, and metastatic NB.DesignNeuroblastoma tissue microarrays were stained with PHOX2B, CD57, and synaptophysin. Arrays containing rhabdomyosarcoma, Ewing sarcoma, and Wilms tumor were stained with PHOX2B, and negative bone marrow samples were stained with PHOX2B and CD57.ResultsPHOX2B and CD57 were similar to synaptophysin in their ability to detect NB. PHOX2B and CD57 similarly showed robust staining in posttreatment NB and NB metastatic to the bone marrow. In contrast to the cytoplasmic staining pattern seen with synaptophysin and CD57, clear and strong nuclear PHOX2B permitted identification of individual tumor cells. PHOX2B staining was absent in all cases of rhabdomyosarcoma, Ewing sarcoma, and Wilms tumor, and in the negative bone marrow.ConclusionsPHOX2B and CD57 are useful markers of NB. PHOX2B is specific for NB in its differential diagnosis with other small round cell tumors, and its nuclear staining may be helpful for accurate bone marrow tumor quantification.

Background Mentorship of junior faculty is an integral component of career development. The Children's Oncology Group (COG) Young Investigator (YI) Committee designed a mentorship program in 2004 whose purpose was to pair YIs (faculty ≤10 years of first academic appointment) with a senior mentor to assist with career development and involvement in COG research activities. This study reports on the committee's ability to achieve these goals. Procedure An online survey was sent to YIs who were registered with the program from 2004 to2015, assessing three major domains: (1) overall experience with the mentor pairing, (2) satisfaction with the program, and (3) academic accomplishments of the mentees. Results The response rate was 64% (110/171). Overall, YIs rated the success of their mentorship pairing as 7.2 out of 10 (median) (25th, 75th quartile 3.6, 9.6). The direct effects of the mentorship program included 70% YIs reporting a positive effect on their career, 40% reporting any grant or manuscript resulting from the pairing, 47% forming a new research collaboration, and 43% receiving appointment to a COG committee. Respondents reported success in COG with 38% authoring a manuscript on behalf of COG and 65% reporting a leadership position including seven current or past COG discipline chairs and 20 study chairs. Finally, 74% of respondents said they would consider serving as mentors in the program in the future. Conclusion The COG YI mentorship program has been well received by the majority of the participants and has helped to identify and train many current leaders in COG.

Background Pediatric oncology patients are at increased risk for blood stream infections (BSI). Risk in the absence of severe neutropenia (absolute neutrophil count [ANC] ≥500/µl) is not well defined. Procedure In a retrospective cohort of febrile (temperature ≥38.0° for >1 hr or ≥38.3°) pediatric oncology patients with ANC ≥500/µl, a diagnostic prediction model for BSI was constructed using logistic regression modeling and the following candidate predictors: age, ANC, absolute monocyte count, body temperature, inpatient/outpatient presentation, sex, central venous catheter type, hypotension, chills, cancer diagnosis, stem cell transplant, upper respiratory symptoms, and exposure to cytarabine, anti-thymocyte globulin, or anti-GD2 antibody. The model was internally validated with bootstrapping methods. Results Among 932 febrile episodes in 463 patients, we identified 91 cases of BSI. Independently significant predictors for BSI were higher body temperature (Odds ratio [OR] 2.36 P

Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5' arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 "hits" occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis.

Importance Children, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds. Objective To compare the efficacy of caspofungin vs fluconazole prophylaxis against proven or probable invasive fungal disease and invasive aspergillosis during neutropenia following acute myeloid leukemia chemotherapy. Design, Setting, and Participants This multicenter, randomized, open-label, clinical trial enrolled patients aged 3 months to 30 years with newly diagnosed de novo, relapsed, or secondary acute myeloid leukemia being treated at 115 US and Canadian institutions (April 2011-November 2016; last follow-up June 30, 2018). Interventions Participants were randomly assigned during the first chemotherapy cycle to prophylaxis with caspofungin (n = 257) or fluconazole (n = 260). Prophylaxis was administered during the neutropenic period following each chemotherapy cycle. Main Outcomes and Measures The primary outcome was proven or probable invasive fungal disease as adjudicated by blinded central review. Secondary outcomes were invasive aspergillosis, empirical antifungal therapy, and overall survival. Results The second interim efficacy analysis and an unplanned futility analysis based on 394 patients appeared to have suggested futility, so the study was closed to accrual. Among the 517 participants who were randomized (median age, 9 years [range, 0-26 years]; 44% female), 508 (98%) completed the trial. The 23 proven or probable invasive fungal disease events (6 caspofungin vs 17 fluconazole) included 14 molds, 7 yeasts, and 2 fungi not further categorized. The 5-month cumulative incidence of proven or probable invasive fungal disease was 3.1% (95% CI, 1.3%-7.0%) in the caspofungin group vs 7.2% (95% CI, 4.4%-11.8%) in the fluconazole group (overallP = .03 by log-rank test) and for cumulative incidence of proven or probable invasive aspergillosis was 0.5% (95% CI, 0.1%-3.5%) with caspofungin vs 3.1% (95% CI, 1.4%-6.9%) with fluconazole (overallP = .046 by log-rank test). No statistically significant differences in empirical antifungal therapy (71.9% caspofungin vs 69.5% fluconazole, overallP = .78 by log-rank test) or 2-year overall survival (68.8% caspofungin vs 70.8% fluconazole, overallP = .66 by log-rank test) were observed. The most common toxicities were hypokalemia (22 caspofungin vs 13 fluconazole), respiratory failure (6 caspofungin vs 9 fluconazole), and elevated alanine transaminase (4 caspofungin vs 8 fluconazole). Conclusions and Relevance Among children, adolescents, and young adults with acute myeloid leukemia, prophylaxis with caspofungin compared with fluconazole resulted in significantly lower incidence of invasive fungal disease. The findings suggest that caspofungin may be considered for prophylaxis against invasive fungal disease, although study interpretation is limited by early termination due to an unplanned interim analysis that appeared to have suggested futility. Trial Registration ClinicalTrials.gov Identifier:NCT01307579

Children with acute lymphoblastic leukemia (ALL) are at increased risk of obesity and deconditioning from cancer therapy. This pilot study assessed feasibility/initial efficacy of an exercise intervention for patients with ALL undergoing maintenance therapy.Participants were aged 5 to 10 years, receiving maintenance therapy, in first remission. A 6-month home-based intervention, with written and video instruction, was supervised with weekly calls from an exercise coach. Pre- and poststudy testing addressed strength, flexibility, fitness, and motor function.Seventeen patients enrolled (participation 63%). Twelve (71%) finished the intervention, completing 81.7 ± 7.2% of prescribed sessions. Improvements of 5% or more occurred in 67% for knee and 75% for grip strength, 58% for hamstring/low-back and 83% for ankle flexibility, 75% for the 6-Minute Walk Test, and 33% for performance on the Bruininks-Oseretsky Test of Motor Proficiency Version 2.This pilot study demonstrated that exercise intervention during ALL therapy is feasible and has promise for efficacy.

Background Corticosteroids increase risk for decreased bone mineral density, which can be worsened by vitamin D insufficiency (VDI) or deficiency (VDD). Procedure In the Vanderbilt cancer survivorship clinic, we obtained screening total 25-hydroxy vitamin D levels (VDL) in 171 cancer survivors 85th percentile (Odds ratio [OR] = 5.4; P

Background.Healthcare-associated transmission of respiratory viruses is a concerning patient safety issue.Design.Surveillance for influenza virus among a cohort of healthcare workers (HCWs) was conducted in a tertiary care children's hospital from November 2009 through April 2010 using biweekly nasal swab specimen collection. If a subject reported respiratory symptoms, an additional specimen was collected. Specimens from ill HCWs and a randomly selected sample from asymptomatic subjects were tested for additional respiratory viruses by multiplex polymerase chain reaction (PCR).Results.A total of 1,404 nasal swab specimens were collected from 170 enrolled subjects. Influenza circulated at very low levels during the surveillance period, and 74.2% of subjects received influenza vaccination. Influenza virus was not detected in any specimen. Multiplex respiratory virus PCR analysis of all 119 specimens from symptomatic subjects and 200 specimens from asymptomatic subjects yielded a total of 42 positive specimens, including 7 (16.7%) in asymptomatic subjects. Viral shedding was associated with report of any symptom (odds ratio [OR], 13.06 [95% confidence interval, 5.45–31.28]; P< .0001) and younger age (OR, 0.96 [95% confidence interval, 0.92–0.99]; P = .023) when controlled for sex and occupation of physician or nurse. After the surveillance period, 46% of subjects reported working while ill with an influenza-like illness during the previous influenza season.Conclusions.In this cohort, HCWs working while ill was common, as was viral shedding among those with symptoms. Asymptomatic viral shedding was infrequent but did occur. HCWs should refrain from patient care duties while ill, and staffing contingencies should accommodate them.

Background Pediatric acute lymphoblastic leukemia (ALL) survivors are at increased risk for the metabolic syndrome (MS). To establish the trajectory of development during active treatment, we followed patients longitudinally over the first year of maintenance therapy. Procedure In a prospective cohort of 34 pediatric ALL patients, followed over the first 12 months of ALL maintenance, we evaluated changes in body mass index (BMI), blood pressure, fasting insulin and glucose, lipids, Homeostatic Metabolic Assessment (HOMA), leptin, and adiponectin. Results Over the study time period, the median BMI z-score increased from 0.29 to 0.66 (P = 0.001), median fasting insulin levels increased from 2.9 to 3.1 µU/ml (P = 0.023), and the proportion of patients with insulin resistance by HOMA (>3.15) increased from 3% to 24% (P = 0.016). Median leptin increased from 2.5 to 3.5 ng/ml (P = 0.001), with levels correlated with BMI z-score. Median adiponectin level decreased from 18.0 to 14.0 µg/ml (P = 0.009), with levels inversely correlated to BMI z-score. No change in median total cholesterol and LDL levels was observed. Median triglycerides decreased (P

Background Children with high-risk medulloblastoma historically have had a poor prognosis. The Children's Oncology Group completed a Phase II study using oral etoposide given with radiotherapy followed by intensive chemotherapy. Procedure Patients enrolled in the study had high-risk disease defined as ≥1.5 cm2 of residual disease postsurgery or definite evidence of central nervous metastasis. All patients underwent surgery followed by radiotherapy. During radiation, the patients received oral etoposide (21 days on, 7 off) at an initial dose of 50 mg/m2 per day (treatment 1), which was reduced to 35 mg/m2 per day (treatment 2) due to toxicity. After radiotherapy, the patients received chemotherapy with three cycles of cisplatin and oral etoposide, followed by eight courses of cyclophosphamide and vincristine. Results Between November 1998 and October 2002, 53 patients were accrued; 15 received treatment 1 and 38 treatment 2. Forty-seven patients (89%) were eligible. Response to radiation was excellent, with 19 (40.4%) showing complete response, 24 (51.1%) partial response, and four (8.5%) no recorded response. The overall 2- and 5-year progression-free survival (PFS) was 76.6 ± 6% and 70.2 ± 7%, respectively. The 2- and 5-year overall survival (OS) was 80.9 ± 6% and 76.6 ± 6%, respectively. Clinical response postradiation and PFS/OS were not significantly different between the treatment groups. There was a trend toward a difference in 5-year PFS between those without and with metastatic disease (P = 0.072). Conclusions Oral etoposide was tolerable at 35 mg/m2 (21 days on and 7 days off) when given during full-dose irradiation in patients with high-risk medulloblastoma with encouraging survival data.

Background 25-hydroxyvitamin D insufficiency is common in healthy children and adolescents. There have been limited studies of the 25-hydroxyvitamin D status of survivors of pediatric and adolescent acute lymphoblastic leukemia (ALL). Procedure In a cohort of 78 ALL survivors (52 chemotherapy-treated and 26 HCT-treated), we determined the prevalence of, and host, treatment and environmental risk factors for 25-hydroxyvitamin D insufficiency and deficiency. Results There were no differences in serum 25-hydroxyvitamin D levels between ALL survivors treated with conventional chemotherapy and those treated with HCT (median 26.0 vs 25.5 ng/ml). Fifty-three percent of pediatric ALL survivors were 25-hydroxyvitamin D insufficient (15–29 ng/dl), and 12% were deficient (

Background Obesity and hypertension are reported among survivors of pediatric acute lymphoblastic leukemia (ALL). However, little is known about the trajectory of body mass index (BMI) and blood pressure over the course of ALL therapy. Procedure In a retrospective cohort of 183 pediatric ALL patients diagnosed from 2000 to 2008, prevalence, severity, and risk factors for obesity and hypertension were assessed during treatment. Results At diagnosis, 36% of patients were overweight and 19% were obese. Median BMI increased during induction therapy with a return to baseline soon after, but increased again over the first 22 months of maintenance therapy. At the end of therapy, 49% were overweight and 21% were obese. Increased BMI z-score at diagnosis was associated with increased z-score during maintenance (P

Background Febrile neutropenia (F&N) is common among pediatric oncology patients. However, there is a lack of clarity regarding parameters whereby such patients have demonstrated adequate bone marrow recovery for hospital discharge and empiric antibiotic discontinuation. Procedure A retrospective review was performed for 350 episodes of F&N occurring at a single institution between 2007 and 2012 in pediatric oncology patients who were afebrile for 24 hr and had no bacterial source identified. Seven-day postdischarge outcomes were assessed and compared based on absolute neutrophil count (ANC) at discharge in order to identify an optimal threshold. Results Overall, 7-day readmission rates were low (17/350, 4.6%), with patients discharged with post-nadir ANC of 100–199/μl (2/51, 3.9%), 200–499/μl (5/125, 4.0%), and ≥500/μl (8/160, 5.0%), all having similar rates. Patients with a discharge ANC 100/μl is a safe threshold value for empiric antibiotic discontinuation and discharge home.