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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.

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.

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.

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 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.

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 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.

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).

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.

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 (

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.

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 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 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.

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.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.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%, P0.0001). Compared to controls, survivorship participants were 13% more sensitive reporting chemotherapeutics (95%CI 2.8-23.7%, P = 0.013) and 12% more sensitive reporting late effect risk (95%CI 7.3-16.6%, P0.0001). In the longitudinal cohort, participants were 7% more sensitive reporting chemotherapeutics (95%CI 5.4-10.8%, P 0.001) and 9% more sensitive reporting late effect risk (95%CI 5.6-23.8%, P0.001) at 3 months compared to baseline. In regression analysis, baseline knowledge correlated with subsequent interview performance, and time since survivorship visit correlated with decreased knowledge of late effects, but not diagnosis or treatment history.Survivorship care was associated with increased knowledge of diagnosis, treatment history, and risk of late effects in both cohorts. Knowledge of late effects decreases with time, suggesting the need for additional educational strategies.

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.In a retrospective cohort of febrile (temperature ≥38.0° for1 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.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 0.001), tunneled external catheter (OR 13.79 P 0.001), peripherally inserted central catheter (OR 3.95 P = 0.005), elevated ANC (OR 1.19 P = 0.024), chills (OR 2.09 P = 0.031), and hypotension (OR 3.08 P = 0.004). Acute lymphoblastic leukemia diagnosis (OR 0.34 P = 0.026), increased age (OR 0.70 P = 0.049), and drug exposure (OR 0.08 P 0.001) were associated with decreased risk for BSI. The risk prediction model had a C-index of 0.898; after bootstrapping adjustment for optimism, corrected C-index 0.885.We developed a diagnostic prediction model for BSI in febrile pediatric oncology patients without severe neutropenia. External validation is warranted before use in clinical practice. Pediatr Blood Cancer 2015;62:262-268. © 2014 Wiley Periodicals, Inc.

Corticosteroids increase risk for decreased bone mineral density, which can be worsened by vitamin D insufficiency (VDI) or deficiency (VDD).In the Vanderbilt cancer survivorship clinic, we obtained screening total 25-hydroxy vitamin D levels (VDL) in 171 cancer survivors23 years old who were treated with prolonged corticosteroids for their cancer, and compared this group to a control group of 97 healthy pediatric patients.VDD was diagnosed in 15.8% and VDI in 34.5% of cancer survivors and VDD/VDI combined was associated with body mass index (BMI)85th percentile (Odds ratio [OR] = 5.4; P 0.001), older age (OR = 2.2; P = 0.012), non-Caucasian or Hispanic race (OR = 4.5; P = 0.008) and summer versus winter season (OR = 0.12; P 0.001). In multivariable analysis, VDI/VDD prevalence did not differ from the control group (VDI/VDD (43.3%)). In the combined survivor/control group multivariable analysis, cancer diagnosis did not increase VDI/VDD risk, but significant associations persisted with elevated BMI (P 0.001), age (P = 0.004), non-Caucasian or Hispanic race (P 0.001), and seasonality (P 0.001).VDD/VDI is equally common in pediatric cancer survivors treated with corticosteroids and healthy children. The impact of VDD/VDI in cancer survivors may be greater due to risk for impaired bone health superimposed on that conferred from corticosteroid exposure. Thus, screening VDLs should be obtained in pediatric cancer survivors treated with corticosteroids, particularly in those with elevated BMI, older age, or non-Caucasian race. Prospective studies evaluating the impact of interventions to minimize VDD/VDI on long-term bone health in survivors are required.

BACKGROUND: Dapsone, used for Pneumocystis jiroveci (PCP) prophylaxis, is associated with increased risk of methemoglobinemia. Absence of cytochrome b5 reductase enzyme activity causes congenital methemoglobinemia, but its role in dapsone-associated methemoglobinemia is unknown. The authors sought to elucidate drug-related risk factors for dapsone-associated methemoglobinemia in pediatric oncology patients, including contribution of cytochrome b5 reductase enzyme activity. METHODS: Among 167 pediatric patients treated for hematologic malignancies or aplastic anemia who received dapsone for PCP prophylaxis, demographic and dapsone treatment data were retrospectively collected. Drug-related risk factors were evaluated by Cox proportional hazards, and in a cross-sectional subgroup of 40 patients, cytochrome b5 reductase enzyme activity was assessed. RESULTS: Methemoglobinemia (median methemoglobin level = 9.0% [3.5-22.4]) was documented in 32 (19.8%) patients. There was a 73% risk reduction in methemoglobinemia with dosing ≥20% below the target dose of 2 mg/kg/d (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.09-0.78; P = .016), whereas methemoglobinemia risk was increased with dosing ≥20% above the target dose (HR, 6.25; 95% CI, 2.45-15.93; P < .001). Sex, body mass index, and age were not associated with increased risk. Cytochrome b5 reductase enzyme activity did not differ by methemoglobinemia status (median 8.6 IU/g hemoglobin [Hb]; [5.5-12.1] vs 9.1 IU/g Hb; [6.7-12.7]). No patient developed PCP on dapsone. CONCLUSIONS: Methemoglobinemia occurred in almost 20% of pediatric oncology patients receiving dapsone for PCP prophylaxis. Higher dapsone dosing is associated with increased risk. A cross-sectionally acquired cytochrome b5 reductase enzyme activity level was not associated with methemoglobinemia risk. Studies are needed to define biologic correlates of methemoglobinemia and evaluate lower dapsone doses for PCP prophylaxis. Cancer 2011. © 2011 American Cancer Society.

Ehrlichiosis, a tickborne illness transmitted by tick vectors Amblyomma americanum and Ixodes scapularis, can be acquired in endemic areas. Clinical manifestations range from asymptomatic to fulminant in nature. We report three cases of ehrlichiosis in pediatric oncology patients, one of whom was a stem cell transplant recipient. Early symptoms included fever, malaise, and vague gastrointestinal symptoms. Laboratory abnormalities were initially attributed to chemotherapy toxicity. Illness was severe in all three patients and one patient died even after initiation of doxycycline. These cases emphasize the need for a high index of suspicion for tickborne illness in oncology patients, and the importance of a low threshold for starting empiric treatment before confirming the diagnosis. Pediatr Blood Cancer 2010;54:776–778. © 2010 Wiley-Liss, Inc.