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Based on serial lung function measurements performed in 142 children (68 males; 74 females) with cystic fibrosis (CF), prospectively evaluated over an age range of 6 to 20 years, we attempted to determine whether the lung clearance index (LCI) as a measure of ventilation inhomogeneities could be a discriminating factor of disease progression. Annual follow-up lung function measurements featuring FRC determined by whole-body plethysmography and multibreath nitrogen washouts, effective specific airway resistance, flow-volume curves, LCI, and gas exchange characteristics were analyzed by linear mixed-model analysis and Kaplan-Meier statistics. The earliest occurring and strongest factor of progression was the LCI, followed by maximal expiratory flow (MEF(50)) and FRC determined by plethysmography (p < 0.0001). Associations between onset of chronic Pseudomonas aeruginosa infection and CF transmembrane conductance regulator (CFTR) genotype with FEV(1) (p = 0.027) and FVC (p = 0.007) were identified. The study shows that the LCI predicts earlier in life and represented much better functional progression than FEV(1). Moreover, there is no single functional predictor of progression in CF, but aside from risk factors, such as onset of chronic P. aeruginosa infection and genotype, pulmonary hyperinflation, airway obstruction, and ventilation inhomogeneities are important pathophysiologic processes that should be evaluated concomitantly as determinants of lung progression in CF. [ABSTRACT FROM AUTHOR]

Introduction: In highly emetogenic chemotherapy, the recommended dose of the serotonin-receptor antagonist ondansetron (5 mg/m(2) q8h) may be insufficient to prevent chemotherapy-induced nausea and vomiting. In adults, ondansetron-loading doses (OLD) of 32 mg are safe. We aimed to evaluate in children the safety of an OLD of 16 mg/m(2) (top, 24 mg) i.v., followed by two doses of 5 mg/m(2) q8h.Materials and Methods: This retrospective single-center study included all pediatric oncology patients having received > or =1 OLD between 2002 and 2005. Adverse events (AE) definitely, probably, or possibly related to OLD were studied, excluding AE not or unlikely related to the OLD. Associations between potential predictors and at least moderate AE were analyzed by mixed logistic regression.Results: Of 167 patients treated with chemotherapy, 37 (22%) received 543 OLD. The most common AE were hypotension, fatigue, injection site reaction, headache, hot flashes/flushes, and dizziness. At least mild AE were described in 139 OLD (26%), at least moderate AE in 23 (4.2%), and severe AE in 5 (0.9%; exact 95% confidence interval [CI], 0.4-2.1). Life-threatening or lethal AE were not observed (0.0%; 0.0-0.6). At least moderate AE were significantly more frequent in female patients (odds ratio [OR] 3.5; 95% CI 1.4-8.8; p = 0.010), after erroneously given second OLD (17.0; 1.9-154; p = 0.012) and higher 24 h cumulative surface corrected dose (1.26 per mg/m(2); 1.06-1.51; p = 0.009). OLD given to infants below 2 years were not associated with more frequent AE.Conclusions: Ondansetron-loading doses of 16 mg/m(2) (top, 24 mg) i.v. seem to be safe in infants, children, and adolescents. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy (RT) has become an important treatment modality in pediatric oncology, but its delivery to young children with cancer is challenging and general anesthesia is often needed.Methods: To evaluate whether a psychoeducational intervention might reduce the need for anesthesia, 223 consecutive pediatric cancer patients receiving 4141 RT fractions during 244 RT courses between February 1989 and January 2006 were studied. Whereas in 154 RT courses corresponding with 2580 RT fractions patients received no psychoeducational intervention (group A), 90 RT courses respectively 1561 RT fractions were accomplished by using psychoeducational intervention (group B). This tailored psychoeducational intervention in group B included a play program and interactive support by a trained nurse according to age to get familiar with staff, equipment and procedure of radiotherapy.Results: Group A did not differ significantly from group B in age at RT, gender, diagnosis, localization of RT and positioning during RT. Whereas 33 (21.4%) patients in group A got anesthesia, only 8 (8.9%) patients in group B needed anesthesia. The median age of cooperating patients without anesthesia decreased from 3.2 to 2.7 years. In both uni- and multivariate analyses the psychoeducational intervention significantly and independently reduced the need for anesthesia.Conclusion: We conclude that a specifically tailored psychoeducational intervention is able to reduce the need for anesthesia in children undergoing RT for cancer. This results in lower costs and increased cooperation during RT. [ABSTRACT FROM AUTHOR]

Background: Food restrictions during periods of neutropenia have been widely used in oncology settings to prevent infections. As there is a lack of clearly demonstrated effectiveness, this strategy is being increasingly questioned., Methods: A multi-national panel of 23 individuals was convened to develop a clinical practice guideline (CPG) on the use of food restrictions to prevent infections in paediatric patients with cancer and haematopoietic cell transplantation (HCT) recipients. It included representation from persons with lived experience and physicians, dieticians, nurses, pharmacists and guideline methodologists working in paediatric oncology/HCT or infectious diseases. Panel members (female n = 15; 65%) were from North America (12, 52%), Europe (8, 35%), South America (2, 9%) and Australia (1, 4%). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to formulate the CPG recommendations based on a systematic review of randomised controlled trials (RCTs). MEDLINE, MEDLINE in-Process and Embase databases were searched from January 1, 1980, to May 7, 2024, with a broad strategy which combined subject headings and text words relating to neutropenia, infection and diet., Findings: The systematic review, which provided the evidence base for the CPG recommendations, identified 4312 unique citations, of which 52 were retrieved for full-text evaluation. Eight RCTs met the eligibility criteria and informed panel deliberations. Although there was clinical heterogeneity in the food restrictions evaluated, data were consistent in suggesting that food restrictions lack clinically significant benefit in preventing infections. The panel made two conditional recommendations against the use of food restrictions in a) paediatric patients with cancer receiving chemotherapy and b) in the setting of allogeneic and autologous HCT. The panel developed a good practice statement to emphasise the importance of health care organisations and families adhering to local food safety practices., Interpretation: This CPG provides the first evidence-based recommendations on use of food restrictions to prevent infections in children and adolescents undergoing chemotherapy and paediatric haematopoietic cell transplant recipients., Funding: This CPG was funded and developed through the POGO Guidelines Program., Competing Interests: FC has: 1) received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer, Knight, Sandoz; 2) received support for attending meetings and/or travel from Pfizer and Mundipharma; 3) participated on a Data Safety Monitoring Board or Advisory Board for Pfizer and Sandoz. JW’s institution has received grants from Merck, Pfizer and National Institutes of Health for his work as a co-investigator and participant in industry sponsored research and JW's institution holds a patent for use of metagenomic sequencing to predict infection. JW has also been a speaker for Cook Children's Hospital and American Association of Pediatrics. No other authors declared a conflict of interest., (© 2025 The Authors.)

Background : Empirical antibacterial therapy for febrile neutropenia reduces mortality due to Gram-negative blood stream infections (BSIs). Pediatric guidelines recommend monotherapy with an antipseudomonal beta-lactam or a carbapenem and to add a second anti-Gram-negative agent in selected situations. We evaluated the changes in the proportions of resistance of beta-lactam monotherapies vs. their combination with amikacin, and the possible impact on ICU admission or death. Results : 797 BSIs due to Gram-negative bacteria in 685 patients were included. Combination therapies with amikacin had a lower percentage of isolates resistant to one or to both drugs compared with the respective monotherapy. The highest OR for ICU admission was observed when both drugs of the combination of meropenem-amikacin were resistant. Mortality was significantly associated with relapse or the progression of the underlying malignancy, and resistance to both drugs of the combinations of cefepime-amikacin or meropenem-amikacin. Methods : This study was based on data collected for a large multinational study, in which the susceptibility of Gram-negative bloodstream isolates was categorized following either EUCAST or CLSI according to local laboratory standards. An escalation antibiogram was generated for each selected drug. For resistant bacteria, the conditional susceptibility probability on resistance was calculated. Conclusions : In pediatric cancer patients with Gram-negative BSIs, the proportion of the resistant organism correlates with ICU admission or death, which may be reduced by combination therapy. In patients with suspected or confirmed Gram-negative BSIs that are not-improving or deteriorating under monotherapy, escalation to meropenem may represent the best option. Amikacin should be preferred when combination therapy is considered with ciprofloxacin as an alternative in the case of impaired renal function.

Our objective was to update a clinical practice guideline for the prevention and treatment of Clostridioides difficile infection (CDI) in pediatric patients with cancer and hematopoietic cell transplantation recipients. We reconvened an international multi-disciplinary panel. A systematic review of randomized controlled trials (RCTs) for the prevention or treatment of CDI in any population was updated and identified 31 new RCTs. Strong recommendations were made to use either oral metronidazole or oral vancomycin for non-severe CDI treatment, and to use either oral vancomycin or oral fidaxomicin for severe CDI. A strong recommendation that fecal microbiota transplantation should not be routinely used to treat CDI was also made. The panel made two new good practice statements to follow infection control practices including isolation in patients experiencing CDI, and to minimize systemic antibacterial administration where feasible, especially in patients who have experienced CDI., Competing Interests: BTF has served on a data safety monitoring board for Astellas and BTF's institution has received grant support from Allovir and Pfizer as well as CDC, FDA and NIH for research performed. CD has received support from Abramson Cancer Center K12 and a CIHR Fellowship Award. TL's institution has received an unrestricted research grant by Gilead Sciences and TL has received payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from: Astra Zeneca, EUSA Pharma, Gilead Sciences, MSD/Merck and Pfizer. TL has received support for attending meetings and/or travel from EUSA Pharma and has served on a data safety monitoring board or advisory board for: EUSA Pharma, Gilead Sciences, Merck/MSD, Mundipharma, Pfizer and Pharming. TL has had a leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid at: Working Party Infection German Society of Pediatric Oncology and Hematology and Working Party Infection German Society of Pediatric Infectious Diseases. LS is supported by the Canada Research Chair in Pediatric Oncology Supportive Care. No other authors declared a conflict of interest., (© 2024 The Author(s).)

Purpose: Pediatric patients with cancer often develop chemotherapy-induced fever in neutropenia (FN), requiring emergency broad-spectrum antibiotics. Continuous temperature monitoring can lead to earlier FN detection and therapy with improved outcomes. We aimed to compare the feasibility of continuous core temperature monitoring with timely data availability between two wearable devices (WDs) in pediatric oncology patients undergoing chemotherapy., Methods: In this prospective observational two-center study, 20 patients (median age: 8 years) undergoing chemotherapy simultaneously wore two WDs (CORE®, Everion®) for 14 days. The predefined goal was core temperature recorded in sufficient quality and available within ≤ 30 min during ≥ 18/24 h for ≥ 7/14 days in more than 15 patients., Results: More patients reached the goal with CORE® (n = 13) versus Everion® (n = 3) (difference, 50% p < 0.001). After correcting for the transmission bottleneck caused by two WDs transmitting via one gateway, these numbers increased (n = 15 versus n = 14; difference, 5%; p = 0.69). CORE® measurements corresponded better to ear temperatures (n = 528; mean bias, - 0.07 °C; mean absolute difference, 0.35 °C) than Everion® measurements (n = 532; - 1.06 °C; 1.10 °C). Acceptance rates for the WDs were 95% for CORE® and 89% for Everion®., Conclusion: The CORE® fulfilled the predefined feasibility criterion (15 of 20 patients) after correction for transmission bottleneck, and the Everion® nearly fulfilled it. Continuous core temperature recording of good quality and with timely data availability was feasible from preschool to adolescent patients undergoing chemotherapy for cancer. These results encourage the design of randomized controlled trials on continuously monitored core temperature in pediatric patients., Clinicaltrials: gov (NCT04914702) on June 7, 2021., (© 2024. The Author(s).)

Background: Fever in neutropenia (FN) remains a serious complication of childhood cancer therapy. Clinical decision rules (CDRs) are recommended to help distinguish between children at high and low risk of severe infection. The aim of this analysis was to develop new CDRs for three different outcomes and to externally validate published CDRs., Procedure: Children undergoing chemotherapy for cancer were observed in a prospective multicenter study. CDRs predicting low from high risk infection regarding three outcomes (bacteremia, serious medical complications (SMC), safety relevant events (SRE)) were developed from multivariable regression models. Their predictive performance was assessed by internal cross-validation. Published CDRs suitable for validation were identified by literature search. Parameters of predictive performance were compared to assess reproducibility., Results: In 158 patients recruited between April 2016 and August 2018, 360 FN episodes were recorded, including 56 (16%) with bacteremia, 30 (8%) with SMC and 72 (20%) with SRE. The CDRs for bacteremia and SRE used four characteristics (type of malignancy, severely reduced general condition, leucocyte count <0.3 G/L, bone marrow involvement), the CDR for SMC two characteristics (severely reduced general condition and platelet count <50 G/L). Eleven published CDRs were analyzed. Six CDRs showed reproducibility, but only one in both sensitivity and specificity., Conclusions: This analysis developed CDRs predicting bacteremia, SMC or SRE at presentation with FN. In addition, it identified six published CDRs that show some reproducibility. Validation of CDRs is fundamental to find the best balance between sensitivity and specificity, and will help to further improve management of FN., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Santschi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: To update a clinical practice guideline (CPG) for the empiric management of fever and neutropenia (FN) in pediatric patients with cancer and hematopoietic cell transplantation recipients., Methods: The International Pediatric Fever and Neutropenia Guideline Panel reconvened to conduct the second update of this CPG. We updated the previous systematic review to identify new randomized controlled trials (RCTs) evaluating any strategy for the management of FN in pediatric patients. Using the Grading of Recommendations Assessment, Development and Evaluation framework, evidence quality was classified as high, moderate, low, or very low. The panel updated recommendations related to initial management, ongoing management, and empiric antifungal therapy. Changes from the 2017 CPG were articulated, and good practice statements were considered., Results: We identified 10 new RCTs in addition to the 69 RCTs identified in previous FN CPGs to inform the 2023 FN CPG. Changes from the 2017 CPG included two conditional recommendations regarding (1) discontinuation of empiric antibacterial therapy in clinically well and afebrile patients with low-risk FN if blood cultures remain negative at 48 hours despite no evidence of marrow recovery and (2) pre-emptive antifungal therapy for invasive fungal disease in high-risk patients not receiving antimold prophylaxis. The panel created a good practice statement to initiate FN CPG-consistent empiric antibacterial therapy as soon as possible in clinically unstable febrile patients., Conclusion: The updated FN CPG incorporates important modifications on the basis of recently published trials. Future work should focus on addressing knowledge gaps, improving CPG implementation, and measuring the impact of CPG-consistent care.

Fever in neutropenia (FN) remains an unavoidable, potentially lethal complication of chemotherapy. Timely administration of empirical broad-spectrum intravenous antibiotics has become standard of care. But the impact of time to antibiotics (TTA), the lag period between recognition of fever or arrival at the hospital to start of antibiotics, remains unclear. Here we aimed to analyze the association between TTA and safety relevant events (SRE) in data from a prospective multicenter study. We analyzed the association between time from recognition of fever to start of antibiotics (TTA) and SRE (death, admission to intensive care unit, severe sepsis and bacteremia) with three-level mixed logistic regression. We adjusted for possible triage bias using a propensity score and stratified the analysis by severity of disease at presentation with FN. We analyzed 266 FN episodes, including 53 (20%) with SRE, reported in 140 of 269 patients recruited from April 2016 to August 2018. TTA (median, 120 min; interquartile range, 49-180 min) was not associated with SRE, with a trend for less SREs in episodes with longer TTA. Analyses applying the propensity score suggested a relevant triage bias. Only in patients with severe disease at presentation there was a trend for an association of longer TTA with more SRE. In conclusion, TTA was unrelated to poor clinical outcome in pediatric patients with FN presenting without severe disease. We saw strong evidence for triage bias which could only be partially adjusted., (© 2022. The Author(s).)

Purpose: Benzene is a known carcinogen for adult leukemia. Exposure to benzene through parental occupation and the use of household products has been associated with childhood leukemia (CL). Ambient benzene has also been associated with CL and central nervous system (CNS) tumors. We aimed to investigate whether the higher ambient levels of benzene in proximity of petrol stations are associated with a greater risk of childhood cancers, leukemia, and CNS tumors., Methods: We identified children diagnosed with cancer at age 0-15 years during 1985-2015 from the Swiss Childhood Cancer Registry and selected 10 age and sex-matched controls per case from national censuses. We calculated the distance from children's home to the nearest petrol station using precise geocodes. We estimated odds ratios using conditional logistic regression adjusting for ambient levels of NO 2 , distance to highways, level of urbanization, and presence of a cantonal cancer registry. In addition, we ran a meta-analysis pooling current results for CL with those of previous studies., Results: We identified 6129 cases, of which 1880 were leukemias and 1290 CNS tumors. 24 cases lived within 50 m from a petrol station. The adjusted odds ratio of a cancer diagnosis for children thus exposed compared to unexposed children (> 500 m) was 1.29 (0.84-1.98) for all cancers combined, 1.08 (0.46-2.51) for leukemia, and 1.30 (0.51-3.35) for CNS tumors. During 2000-2015, when exposure assessment was more precise, the adjusted odds ratio for any cancer diagnosis was 1.77 (1.05-2.98). The summary relative risk estimate for CL in the meta-analysis including four studies was 2.01 (1.25-3.22)., Conclusions: Our study provides weak support for an increased risk of childhood cancers among children living close to petrol stations. A meta-analysis including our study suggests an increased risk for CL., (© 2021. The Author(s).)

Pediatric patients with cancer are at high risk for severe infections. Changes in vital signs, triggered by infections, may be detected earlier by continuous recording with a wearable device than with discrete measurements. This prospective, observational single-center feasibility study consecutively recruited pediatric patients undergoing chemotherapy for cancer. The WD Everion® was used for 14 days in each of the 20 patients on study to continuously record vital signs. Nine different vital signs and health indicators derived from them, plus six quality scores. This resulted in 274 study days (6576 hours) with 85'854 measuring points, which are a total of 772'686 measurements of vital signs and health indicators, plus 515'124 quality scores. Additionally, non-WD data like side effects, acceptability of the WD and effort for investigators were collected. In this manuscript, we present the methods of acquisition and explanations to the complete data set, which have been made publically available on open access and which can be used to study feasibility of continuous multi-parameter recording of vital signs by a WD., (© 2022. The Author(s).)

Background: Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity., Methods: Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m 2 vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m 2 etoposide taken intravenously on days 1-5; 60 mg/m 2 prednisone taken orally on days 1-15; and 40 mg/m 2 doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m 2 cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m 2 vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m 2 prednisone taken orally on days 1 to 15; and 100 mg/m 2 procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m 2 dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy analyses are reported per protocol and safety in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (trial number NCT00433459) and EUDRACT (trial number 2006-000995-33), and is closed to recruitment., Findings: Between Jan 31, 2007, and Jan 30, 2013, 2102 patients were recruited. 737 (35%) of the 2102 recruited patients were in treatment group 1 (early-stage disease) and were not included in our analysis. 1365 (65%) of the 2102 patients were in treatment group 2 (intermediate-stage disease; n=455) and treatment group 3 (advanced-stage disease; n=910). Of these 1365, 1287 (94%) patients (435 [34%] of 1287 in treatment group 2 and 852 [66%] of 1287 in treatment group 3) were included in the titration trial per-protocol analysis. 937 (69%) of 1365 patients were randomly assigned to COPP (n=471) or COPDAC (n=466) in the embedded trial. Median follow-up was 66·5 months (IQR 62·7-71·7). Of 1287 patients in the per-protocol group, 514 (40%) had an adequate response to treatment and were not treated with radiotherapy (215 [49%] of 435 in treatment group 2 and 299 [35%] of 852 in treatment group 3). 773 (60%) of 1287 patients with inadequate response were scheduled for radiotherapy (220 [51%] of 435 in the treatment group 2 and 553 [65%] of 852 in treatment group 3. In patients who responded adequately, event-free survival rates at 5 years were 90·1% (95% CI 87·5-92·7). event-free survival rates at 5 years in 892 patients who were randomly assigned to treatment and analysed per protocol were 89·9% (95% CI 87·1-92·8) for COPP (n=444) versus 86·1% (82·9-89·4) for COPDAC (n=448). The COPDAC minus COPP difference in event-free survival at 5 years was -3·7% (-8·0 to 0·6). The most common grade 3-4 adverse events (intention-to-treat population) were decreased haemoglobin (205 [15%] of 1365 patients during OEPA vs 37 [7%] of 528 treated with COPP vs 20 [2%] of 819 treated with COPDAC), decreased white blood cells (815 [60%] vs 231 [44%] vs 84 [10%]), and decreased neutrophils (1160 [85%] vs 223 [42%] vs 174 [21%]). One patient in treatment group 2 died of sepsis after the first cycle of OEPA; no other treatment-related deaths occurred., Interpretation: Our results show that radiotherapy can be omitted in patients who adequately respond to treatment, when consolidated with COPP or COPDAC. COPDAC might be less effective, but is substantially less gonadotoxic than COPP. A high proportion of patients could therefore be spared radiotherapy, eventually reducing the late effects of treatment. With more refined criteria for response assessment, the number of patients who receive radiotherapy will be further decreased., Funding: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder Gießen, Kinderkrebsstiftung Mainz, Tour der Hoffnung, Menschen für Kinder, Programme Hospitalier de Recherche Clinique, and Cancer Research UK., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: Combining intranasal fentanyl (IN FENT) with inhaled nitrous oxide (N 2 O) seems to have good properties for pediatric procedural sedation and analgesia (PSA). This study aims to assess the side effect rate of the combined use of IN FENT and N 2 O., Methods: We performed a retrospective, single-center study. Patients treated in either the pediatric emergency department (PED) or the pediatric surgery outpatient clinic (PSOC) were included, if they received PSA with IN FENT and nitrous oxide with 50% oxygen (N 2 O 50%)., Results: Three hundred seventy-five patients were included over a period of 4 years. Median age was 9.4 years (range, 3.1 to 15.9) and 39% of patients were female. Overall side effect rate was 30% (114 patients). Most frequent was dizziness (n = 63, 17%; 95% CI, 13-21), followed by nausea (n = 23, 6%; 95% CI, 4-9) and emesis (n = 14, 4%; 95% CI, 2-6), with 35 patients having either nausea and/or emesis (9%; 95% CI, 7-13). No serious side effects were recorded (0%; 95% CI, 0-0.1). Of 298 patients with information regarding satisfaction, 280 patients would like the same sedation for a similar procedure in the future (94%; 95% CI, 90-96). We found no relation between previously described risk factors and emesis and/or nausea., Conclusions: N 2 O 50% combined with IN FENT can be recommended as an effective and safe treatment in the PED and the PSOC. While the side effect rate, primarily dizziness, nausea and emesis was substantial, antiemetic prophylaxis is not indicated owing to the overall low incidence of nausea and emesis., Competing Interests: Disclosures. The authors report no conflict of interest. Supported by a grant from the Stiftung Batzebaer of the University Children's Hospital, Bern, Switzerland, and the Notfallzentrum fuer Kinder und Jugendliche, University Hospital, Bern, Switzerland., (Copyright. Pediatric Pharmacy Association. All rights reserved. For permissions, email: membership@pediatricpharmacy.org 2022.)

Purpose: There are limited data on SARS-CoV-2 (COVID-19) infection in children with cancer or after haematopoietic stem cell transplant (HSCT). We describe the severity and outcomes of SARS-COV-2 in these patients and identify factors associated with severe disease., Methods: This was a multinational, observational study of children (aged <19 years) with cancer or HSCT and SARS-CoV-2 confirmed by polymerase chain reaction. COVID-19 was classified as asymptomatic, mild, moderate, severe or critical (≥1 organ support). Exact polytomous regression was used to determine the relationship between clinical variables and disease severity., Results: One hundred and thirty-one patients with COVID-19 across 10 countries were identified (median age 8 years). Seventy-eight (60%) had leukaemia/lymphoma, 48 (37%) had solid tumour and five had primary immunodeficiency and HSCT. Fever (71%), cough (47%) and coryza (29%) were the most frequent symptoms. The median duration of detectable virus was 16 days (range, 1-79 days). Forty-nine patients (37%) were hospitalised for COVID-19 symptoms, and 15 (11%) required intensive care unit-level care. Chemotherapy was delayed/modified in 35% of patients. COVID-19 was asymptomatic in 32% of patients, mild in 47%, moderate in 8%, severe in 4% and critical in 9%. In 124 patients (95%), a full recovery was documented, and four (3%) died due to COVID-19. Any comorbidity (odds ratio, 2.94; 95% confidence interval [CI], 1.81-5.21), any coinfection (1.74; 95% CI 1.03-3.03) and severe baseline neutropenia (1.82; 95% CI 1.13-3.09) were independently and significantly associated with increasing disease severity., Conclusion: Although most children with cancer had asymptomatic/mild disease, 13% had severe COVID-19 and 3% died. Comorbidity, coinfection and neutropenia may increase the risk of severe disease. Our data may help management decisions in this vulnerable population., Competing Interests: Conflict of interest statement A.H.G. has research support from Gilead Sciences, Merck Sharp and Dohme and Pfizer; is a consultant for Amplyx, Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp and Dohme and Pfizer; and served at the speakers' bureau of Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp and Dohme and Pfizer. A.A. is a consultant for Jazz Pharmaceuticals, Amgen, Novartis, Gilead Sciences and MSD/Merck and served at the speakers' bureau of Jazz Pharmaceuticals, Amgen and Novartis. T.L. has an unrestricted research support from Gilead Sciences; is a consultant for Gilead Sciences, Merck Sharp and Dohme, Pfizer, Astellas and Roche; and serves at the speakers' bureau of Gilead Sciences, Merck Sharp and Dohme, Astellas, Pfizer and GlaxoSmithKline. All the other authors do not have to declare a conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Fever in neutropenia (FN) remains a frequent complication in pediatric patients undergoing chemotherapy for cancer. Preventive strategies, like primary antibiotic prophylaxis, need to be evidence-based., Procedure: Data on pediatric patients with any malignancy from the prospective multicenter SPOG 2015 FN Definition Study (NCT02324231) were analyzed. A score predicting the risk to develop FN with safety-relevant events (SRE; bacteremia, severe sepsis, intensive care unit admission, death) was developed using multivariate mixed Poisson regression. Its predictive performance was assessed by internal cross-validation and compared with the performance of published rules., Results: In 238 patients, 318 FN episodes were recorded, including 53 (17%) with bacteremia and 68 (21%) with SRE. The risk-prediction score used three variables: chemotherapy intensity, defined according to the expected duration of severe neutropenia, time since diagnosis, and type of malignancy. Its cross-validated performance, assessed by the time needed to cover (TNC) one event, exceeded the performance of published rules. A clinically useful score threshold of ≥11 resulted in 2.3% time at risk and 4.1 months TNC. Using external information on efficacy and timing of intermittent antibiotic prophylaxis, 4.3 months of prophylaxis were needed to prevent one FN with bacteremia, and 5.2 months to prevent one FN with SRE, using a threshold of ≥11., Conclusions: This score, based on three routinely accessible characteristics, accurately identifies pediatric patients at risk to develop FN with SRE during chemotherapy. The score can help to design clinical decision rules on targeted primary antibiotic prophylaxis and corresponding efficacy studies., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Our purpose was to compare conventional meta-analysis and network meta-analysis to evaluate the efficacy of different prophylactic systemic antibiotic classes in patients undergoing chemotherapy or haematopoietic stem cell transplant (HSCT). We included randomised trials if patients had cancer or were HSCT recipients and the intervention was systemic antibacterial prophylaxis. Three types of control groups were used: (1) placebo, no antibiotic and non-absorbable antibiotic separately; (2) placebo and no antibiotic combined; and (3) all three combined. These gave different network geometries. Strategies synthesised were fluoroquinolone, trimethoprim-sulfamethoxazole, cephalosporin and parenteral glycopeptide versus control groups. In total 113 trials met the eligibility criteria. Where treatment effects could be estimated with both conventional and network meta-analysis, values were generally similar. However, where events were sparse, network meta-analysis could be more precise. For example, trimethoprim-sulfamethoxazole versus placebo for infection-related mortality showed a relative risk ratio (RR) of 0.55, 95% CI (0.21 to 1.44) with conventional, and RR 0.43, 95% credible region (0.20 to 0.82) with network meta-analysis. Cephalosporin versus fluoroquinolone was comparable only indirectly using the network approach and yielded RR 0.59, 95% credible region (0.28 to 1.20) to reduce bacteraemia. Incoherence (difference between direct and indirect estimates raising concerns about network meta-analysis validity) was observed with network geometry where control groups were separated, but not where control groups were combined. In this situation, conventional and network meta-analysis yielded similar results in general. Network meta-analysis results could be more precise when events were rare. Some analysis could only be performed with the network approach. These results identify scenarios in which network meta-analysis may be advantageous., Competing Interests: Competing interests: BF’s institution receives research funding from Pfizer and Merck, and he serves on a Data Safety Monitoring Board for Astellas. TL has received research grants from Gilead Sciences, is a consultant to Astellas, Basilea, Gilead Sciences and Merck/MSD, and served at the speaker's bureau of Astellas, Gilead Sciences, Merck/MSD and Pfizer., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Exposure to high doses of ionizing radiation is known to cause cancer. Exposure during childhood is associated with a greater excess relative risk for leukemia and tumors of the central nervous system (CNS) than exposure in later life. Cancer risks associated with low-dose exposure (<100 mSv) are uncertain. We previously investigated the association between the incidence of childhood cancer and levels of exposure to external background radiation from terrestrial gamma and cosmic rays in Switzerland using data from a nationwide census-based cohort study. Here, we provide an update of that study using an extended follow-up period and an improved exposure model., Methods: We included all children 0-15 years of age registered in the Swiss national censuses 1990, 2000, and 2010-2015. We identified incident cancer cases during 1990-2016 using probabilistic record linkage with the Swiss Childhood Cancer Registry. Exposure to terrestrial and cosmic radiation at children's place of residence was estimated using geographic exposure models based on aerial spectrometric gamma-ray measurements. We estimated and included the contribution from 137 Cs deposition after the Chernobyl accident. We created a nested case-control sample and fitted conditional logistic regression models adjusting for sex, year of birth, neighborhood socioeconomic position, and modelled outdoor NO 2 concentration. We also estimated the population attributable fraction for childhood cancer due to external background radiation., Results: We included 3,401,113 children and identified 3,137 incident cases of cancer, including 951 leukemia, 495 lymphoma, and 701 CNS tumor cases. Median follow-up in the cohort was 6.0 years (interquartile range: 4.3-10.1) and median cumulative exposure since birth was 8.2 mSv (range: 0-31.2). Hazard ratios per 1 mSv increase in cumulative dose of external background radiation were 1.04 (95% CI: 1.01-1.06) for all cancers combined, 1.06 (1.01-1.10) for leukemia, 1.03 (0.98-1.08) for lymphoma, and 1.06 (1.01-1.11) for CNS tumors. Adjustment for potential confounders had little effect on the results. Based on these results, the estimated population attributable fraction for leukemia and CNS tumors due to external background radiation was 32% (7-49%) and 34% (5-51%), respectively., Conclusions: Our results suggest that background ionizing radiation contributes to the risk of leukemia and CNS tumors in children., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Pediatric patients with cancer are at high risk for severe infections. Infections can trigger changes of vital signs long before clinical symptoms arise. Continuous recording may detect such changes earlier than discrete measurements. We aimed to assess the feasibility of continuous recording of vital signs by a wearable device (WD) in pediatric patients undergoing chemotherapy for cancer., Methods: In this prospective, observational single-center study, pediatric patients under chemotherapy wore the Everion® WD for 14 days. The predefined patient-specific goal was heart rate recorded in good quality during ≥18/24 h per day, on ≥7 consecutive days. The predefined criterion to claim feasibility was ≥15/20 patients fulfilling this patient-specific goal., Results: Twenty patients were included (median age, 6 years; range, 2-16). Six patients aged 3-16 years fulfilled the patient-specific goal. Quality of heart rate recording was good during 3992 of 6576 (61%) hours studied and poor during 300 (5%) hours, and no data was recorded during 2284 (35%) hours. Eighteen of 20 participants indicated that this WD is acceptable to measure vital signs in children under chemotherapy., Conclusion: The predefined feasibility criterion was not fulfilled. This was mainly due to important compliance problems and independent of the WD itself. However, continuous recording of vital signs was possible across a very wide age range in pediatric patients undergoing chemotherapy for cancer. We recommend to study feasibility in the Everion® again, plus in further WDs, applying measures to enhance compliance., Trial Registration: ClinicalTrials.gov (NCT04134429) on October 22, 2019., (© 2021. The Author(s).)

Increased cell proliferation is a hallmark of acute lymphoblastic leukemia (ALL), and genetic alterations driving clonal proliferation have been identified as prognostic factors. To evaluate replicative history and its potential prognostic value, we determined telomere length (TL) in lymphoblasts, B-, and T-lymphocytes, and measured telomerase activity (TA) in leukocytes of patients with ALL. In addition, we evaluated the potential to suppress the in vitro growth of B-ALL cells by the telomerase inhibitor imetelstat. We found a significantly lower TL in lymphoblasts (4.3 kb in pediatric and 2.3 kb in adult patients with ALL) compared to B- and T-lymphocytes (8.0 kb and 8.2 kb in pediatric, and 6.4 kb and 5.5 kb in adult patients with ALL). TA in leukocytes was 3.2 TA/C for pediatric and 0.7 TA/C for adult patients. Notably, patients with high-risk pediatric ALL had a significantly higher TA of 6.6 TA/C compared to non-high-risk patients with 2.2 TA/C. The inhibition of telomerase with imetelstat ex vivo led to significant dose-dependent apoptosis of B-ALL cells. These results suggest that TL reflects clonal expansion and indicate that elevated TA correlates with high-risk pediatric ALL. In addition, telomerase inhibition induces apoptosis of B-ALL cells cultured in vitro. TL and TA might complement established markers for the identification of patients with high-risk ALL. Moreover, TA seems to be an effective therapeutic target; hence, telomerase inhibitors, such as imetelstat, may augment standard ALL treatment.

Paediatric patients with cancer and those undergoing haematopoietic cell transplantation are at high risk of bacterial infections. The 8th European Conference on Infections in Leukaemia (ECIL-8) convened a Paediatric Group to review the literature and to formulate recommendations for the use of antibiotics according to the European Society of Clinical Microbiology and Infectious Diseases grading system. The evaluation of antibacterial prophylaxis included mortality, bloodstream infection, febrile neutropenia, emergence of resistance, and adverse effects as endpoints. Initial antibacterial therapy and antibiotic de-escalation or discontinuation focused on patients with a clinically stable condition and without previous infection or colonisation by resistant bacteria, and on patients with a clinically unstable condition or with previous infection or colonisation by resistant bacteria. The final considerations and recommendations of the ECIL-8 Paediatric Group on antibacterial prophylaxis, initial therapy, and de-escalation strategies are summarised in this Policy Review., Competing Interests: Declaration of interests TL reports unrestricted research support from Gilead Sciences; is a consultant for Gilead Sciences, Merck Sharp and Dohme, Pfizer, Astellas, and Roche; and serves at the speakers' bureau of Gilead Sciences, Merck Sharp and Dohme, Astellas, Pfizer, and GlaxoSmithKline. DA reports research support from Merck Sharp and Dohme; was a consultant for Pfizer; and served at the speakers' bureau of GlaxoSmithKline. EC is a consultant for Angelini and Ferrer. CG-V reports research grants from Gilead Sciences and Merck Sharp and Dohme; research grants from the Spanish Ministerio de Sanidad, Consumo y Bienestar Social, the Instituto de Salud Carlos III in Madrid, Spain, the European Regional Development Fund, and the European Institute of Innovation and Technology; and served at the speakers' bureau of Gilead Sciences, Merck Sharp and Dohme, Novartis, Pfizer, Janssen, and Lilly. JK is a consultant for Bayer. FL served at the speakers' bureau of Gilead Sciences and Basilea. MM is a consultant for and served at the speakers' bureau of Pfizer, Gilead Sciences, Merck Sharp and Dohme, Janssen, and Biotest. MS reports research support from Gilead Sciences, Merck Sharp and Dohme, and F2G; and served on the speakers' bureau of Merck Sharp and Dohme and Gilead Sciences. JS reports support from Gilead Sciences, Merck Sharp and Dohme, Astellas, Roche, Jazz Pharmaceuticals, and Pfizer; is a consultant for Gilead Sciences, Novartis, Pfizer, Merck Sharp and Dohme; and served at the speakers' bureau of Gilead Sciences, Merck Sharp and Dohme, Fresenius, and Astellas. AW is supported by the MRC Centre for Medical Mycology at the University of Exeter (grant MR/N006364/2); reports research support from Gilead Sciences; and served at the speakers' bureau of Gilead Sciences. AHG reports research support from Gilead Sciences, Merck Sharp and Dohme, and Pfizer; is a consultant for Amplyx, Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp and Dohme, and Pfizer; and served at the speakers' bureau of Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp and Dohme, and Pfizer. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Paediatric patients with cancer and those undergoing allogeneic haematopoietic cell transplantation have an increased susceptibility to invasive fungal diseases. In addition to differences in underlying conditions and comorbidities relative to adults, invasive fungal diseases in infants, children, and adolescents are unique in terms of their epidemiology, the validity of current diagnostic methods, the pharmacology and dosing of antifungal agents, and the absence of phase 3 clinical trials to provide data to guide evidence-based interventions. To re-examine the state of knowledge and to further improve invasive fungal disease diagnosis, prevention, and management, the 8th European Conference on Infections in Leukaemia (ECIL-8) reconvened a Paediatric Group to review the literature and to formulate updated recommendations according to the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and European Confederation of Medical Mycology (ECMM) grading system, which are summarised in this Review., Competing Interests: Declaration of interests AHG reports research support from Gilead Sciences, Merck Sharp and Dohme, and Pfizer; is a consultant for Amplyx, Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp and Dohme, and Pfizer; and served at the speakers' bureau of Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp and Dohme, and Pfizer. FL served at the speakers' bureau of Gilead Sciences and Basilea. DA reports research support from Merck Sharp and Dohme; was a consultant for Pfizer; and served at the speakers' bureau of GlaxoSmithKline. EC is a consultant for Angelini Pharma and Ferrer. CG-V reports research grants from Gilead Sciences and Merck Sharp and Dohme; and served at the speakers' bureau of Gilead Sciences, Merck Sharp and Dohme, Novartis, Pfizer, Jannsen, and Lilly. JK is a consultant for Bayer. ER reports research grants from Astellas, Gilead Sciences, Merck Sharp and Dohme, and Pfizer; and is a scientific advisor and member of speakers' bureaus for Astellas, Gilead Sciences, Merck Sharp and Dohme, and Pfizer. JS reports scientific grants or serving at the speakers' bureau of Merck Sharp and Dohme, Gilead Sciences, Roche, Pfizer, and Astellas; and participated in the advisory board of Gilead Sciences, Merck Sharp and Dohme, Roche, and Pfizer. AW reports research support from Gilead Sciences; and served at the spearker's bureau of Gilead Sciences. TL reports unrestricted research support from Gilead Sciences; is a consultant for Gilead Sciences, Merck Sharp and Dohme, Pfizer, Astellas, and Roche; and serves at the speakers' bureau of Gilead Sciences, Merck Sharp and Dohme, Astellas, Pfizer, and GlaxoSmithKline. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Immunocompromised children and adolescents receiving treatment for cancer have an increased risk for potentially life-threatening infectious complications such as blood stream infections with Gram-positive and Gram-negative pathogens. Therefore, several centers for Pediatric Hematology and Oncology administer antibacterial prophylaxis to these patients to lower morbidity and mortality. Two pediatric specific guidelines on antibacterial prophylaxis were recently published. One of these guidelines was drawn up by an international group of pediatric experts of Europe, North and South America and Australia. The other guideline was prepared by an European group convened at the Eighth European Conference on Infections in Leukaemia (ECIL-8). In this review article, the working groups "Infections" of the Society of Pediatric Oncology and Hematology (GPOH) and "Fever in the neutropenic host" of the German Society for Pediatric Infectious Diseases" (DGPI) summarize the available data from randomized studies, systematic reviews and meta-analyses on antibacterial prophylaxis as well of current data on the emergence of resistance and discuss methodological aspects and the recommendations of the two guidelines., Competing Interests: TL erhielt Vortragshonorare von Astellas, Gilead Sciences, GSK, Merck/MSD und Pfizer, Honorare für Beratertätigkeiten von Astellas, Gilead Sciences, Merck/MSD und Pfizer sowie Forschungsunterstützung von Gilead Sciences. HJL erhielt Vortragshonorare und Reisekostenunterstützung von CSL Behring, Pfizer und Bayer sowie Honorare für Beratertätigkeiten von CSL Behring. AA erhielt Vortragshonorare und Reisekostenunterstützung von Jazz Pharmaceuticals und Pfizer sowie Honorare für Beratertätigkeiten von Gilead Sciences, Jazz Pharmaceuticals und Novartis. AHG erhielt Vortragshonorare von Astellas, Basilea, F2G, Gilead Scviences, Merck/MSD und Pfizer, Honorare für Beratertätigkeiten von Amplyx, Astellas, Basilea, F2G, Gilead Sciences, Merck/MSD und Pfizer sowie Forschungsunterstützung von Gilead Sciences, Merck/MSD und Pfizer. Alle anderen Autoren haben keine Interessenskonflikte., (Thieme. All rights reserved.)

Bloodstream infections (BSI) are a severe complication of antineoplastic chemotherapy or hematopoietic stem cell transplantation (HSCT), especially in the presence of antibiotic resistance (AR). A multinational, multicenter retrospective study in patients aged ≤ 18 years, treated with chemotherapy or HSCT from 2015 to 2017 was implemented to analyze AR among non-common skin commensals BSI. Risk factors associated with AR, intensive care unit (ICU) admission and mortality were analyzed by multilevel mixed effects or standard logistic regressions. A total of 1291 BSIs with 1379 strains were reported in 1031 patients. Among Gram-negatives more than 20% were resistant to ceftazidime, cefepime, piperacillin-tazobactam and ciprofloxacin while 9% was resistant to meropenem. Methicillin-resistance was observed in 17% of S. aureus and vancomycin resistance in 40% of E. faecium . Previous exposure to antibiotics, especially to carbapenems, was significantly associated with resistant Gram-negative BSI while previous colonization with methicillin-resistant S. aureus was associated with BSI due to this pathogen. Hematological malignancies, neutropenia and Gram-negatives resistant to >3 antibiotics were significantly associated with higher risk of ICU admission. Underlying disease in relapse/progression, previous exposure to antibiotics, and need of ICU admission were significantly associated with mortality. Center-level variation showed a greater impact on AR, while patient-level variation had more effect on ICU admission and mortality. Previous exposure to antibiotics or colonization by resistant pathogens can be the cause of AR BSI. Resistant Gram-negatives are significantly associated with ICU admission and mortality, with a significant role for the treating center too. The significant evidence of center-level variations on AR, ICU admission and mortality, stress the need for careful local antibiotic stewardship and infection control programs.

Background: Fever in neutropenia (FN) is a potentially life-threatening complication of chemotherapy in pediatric cancer patients. The current standard of care at most institutions is emergency hospitalization and empirical initiation of broad-spectrum antibiotic therapy., Methods: We analyzed in retrospect FN episodes with bacteremia in pediatric cancer patients in a single center cohort from 1993 to 2012. We assessed the distribution of pathogens, the in vitro antibiotic susceptibility patterns, and their trends over time., Results: From a total of 703 FN episodes reported, we assessed 134 FN episodes with bacteremia with 195 pathogens isolated in 102 patients. Gram-positive pathogens (124, 64%) were more common than Gram-negative (71, 36%). This proportion did not change over time (p = 0.26). Coagulase-negative staphylococci (64, 32%), viridans group streptococci (42, 22%), Escherichia coli (33, 17%), Klebsiella spp. (10, 5%) and Pseudomonas aeruginosa (nine, 5%) were the most common pathogens. Comparing the in vitro antibiotic susceptibility patterns, the antimicrobial activity of ceftriaxone plus amikacin (64%; 95%CI: 56%-72%), cefepime (64%; 95%CI 56%-72%), meropenem (64%; 95%CI 56%-72), and piperacillin/tazobactam (62%; 95%CI 54%-70%), respectively, did not differ significantly. The addition of vancomycin to those regimens would have increased significantly in vitro activity to 99% for ceftriaxone plus amikacin, cefepime, meropenem, and 96% for piperacillin/tazobactam (p < 0.001)., Conclusions: Over two decades, we detected a relative stable pathogen distribution and found no relevant trend in the antibiotic susceptibility patterns. Different recommended antibiotic regimens showed comparable in vitro antimicrobial activity., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Investigation of the current practice of diagnostics and treatment in pediatric cancer patients with febrile neutropenia., Methods: On behalf of the German Society for Pediatric Oncology and Hematology and the German Society for Pediatric Infectious Diseases, an Internet-based survey was conducted in 2016 concerning the management of febrile neutropenia in pediatric oncology centers (POC). This survey accompanied the release of the corresponding German guideline to document current practice before its implementation in clinical practice., Results: In total, 51 POCs participated (response rate 73%; 43 from Germany, and 4 each from Austria and Switzerland). Identified targets for antimicrobial stewardship concerned blood culture diagnostics, documentation of the time to antibiotics, the use of empirical combination therapy, drug monitoring of aminoglycosides, the time to escalation in patients with persisting fever, minimal duration of IV treatment, sequential oral treatment in patients with persisting neutropenia, indication for and choice of empirical antifungal treatment, and the local availability of a pediatric infectious diseases consultation service., Conclusion: This survey provides useful information for local antibiotic stewardship teams to improve the current practice referring to the corresponding national and international guidelines.

Background: Fever in neutropenia is the most frequent complication of chemotherapy for cancer. The temperature limit defining fever used clinically varies. A higher limit can avoid unnecessary diagnoses in patients spontaneously recovering from fever. This trial primarily aimed to determine if a limit of 39·0°C ear temperature is non-inferior to 38·5°C regarding safety., Methods: This cluster-randomised, multiple crossover, non-blinded, non-inferiority trial was done in six Swiss Paediatric Oncology Group centres (clusters) in Switzerland. Patients (aged 1 to <18 years) with any malignancy and treated with myelosuppressive chemotherapy expected to last 2 months or more were repeatedly randomly assigned (1:1), at the cluster level, to either monthly 39·0°C or 38·5°C ear temperature limits for diagnosis of fever in neutropenia. Diagnosis below the randomised limit was allowed for clinical reasons. Such a diagnosis implied emergency hospitalisation, examinations (including blood culture), as-needed antipyretics, and empirical intravenous broad-spectrum antibiotics. The primary outcome was the rate of fever in neutropenia with safety relevant events (SRE) per chemotherapy year; we also assessed efficacy in terms of rate of fever in neutropenia. The non-inferiority margin was 1·33 for safety, and for effiacy, the superiority margin was 1·00. This trial is registered at ClinicalTrials.gov, number NCT02324231., Findings: 269 patients were recruited between April 28, 2016, to Aug 27, 2018, until the trial was stopped for success after the second interim analysis. Patients were repeatedly randomly assigned, with 1210 (48%) of 2547 randomisation periods and 92 (47%) of 195 chemotherapy years randomised to 39·0°C. SREs were diagnosed in 72 (20%) of 360 fever in neutropenia episodes (zero deaths, 16 intensive care unit admissions, 22 cases of severe sepsis, and 56 cases of bacteraemia). In 92 chemotherapy years randomised to the 39·0°C fever limit, 151 episodes of fever with neutropenia were diagnosed (1·64 per year), including 22 (15%) with SRE (0·24 per year). In 103 chemotherapy years randomised to 38·5°C, 209 episodes were diagnosed (2·03 per year), including 50 (24%) with SRE (0·49 per year). The mixed Poisson regression rate ratio (RR) of fever in neutropenia with SRE in 39·0°C versus 38·5°C was 0·56 (95% upper confidence bound 0·72). The corresponding RR of fever in neutropenia was 0·83 (95% upper confidence bound 0·98)., Interpretation: In children with neutropenia and chemotherapy for cancer, 39·0°C ear temperature was safe and seemed efficacious. For Switzerland and comparable settings, 39·0°C can be recommended as new evidence-based standard fever limit except for patients with acute myeloid leukaemia or haematopoietic stem cell transplantation., Funding: Swiss Cancer League (KLS-3645-02-2015)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Bacteremia and other invasive bacterial infections are common among children with cancer receiving intensive chemotherapy and in pediatric recipients of hematopoietic stem cell transplantation (HSCT). Systemic antibacterial prophylaxis is one approach that can be used to reduce the risk of these infections. Our purpose was to develop a clinical practice guideline (CPG) for systemic antibacterial prophylaxis administration in pediatric patients with cancer and those undergoing HSCT., Methods: An international and multidisciplinary panel was convened with representation from pediatric hematology/oncology and HSCT, pediatric infectious diseases (including antibiotic stewardship), nursing, pharmacy, a patient advocate, and a CPG methodologist. The panel used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to generate recommendations based on the results of a systematic review of the literature., Results: The systematic review identified 114 eligible randomized trials of antibiotic prophylaxis. The panel made a weak recommendation for systemic antibacterial prophylaxis for children receiving intensive chemotherapy for acute myeloid leukemia and relapsed acute lymphoblastic leukemia (ALL). Weak recommendations against the routine use of systemic antibacterial prophylaxis were made for children undergoing induction chemotherapy for ALL, autologous HSCT and allogeneic HSCT. A strong recommendation against its routine use was made for children whose therapy is not expected to result in prolonged severe neutropenia. If used, prophylaxis with levofloxacin was recommended during severe neutropenia., Conclusions: We present a CPG for systemic antibacterial prophylaxis administration in pediatric cancer and HSCT patients. Future research should evaluate the long-term effectiveness and adverse effects of prophylaxis., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

In pediatric oncology, there is no evidence-based definition of the temperature limit defining fever (TLDF), which itself is essential for the definition of fever in chemotherapy-induced severe neutropenia (FN). Lowering the TLDF can increase the number of FN episodes diagnosed. This prospective, single center observational study collected data on all temperature measurements, complete blood counts (CBCs), and measures of diagnostics and therapy performed at and after FN diagnosis in pediatric oncology patients using a high standard TLDF (39 °C ear temperature). In 45 FN episodes in 20 patients, 3391 temperature measurements and 318 CBCs, plus information on antibiotics, anti-fungal therapy, antipyretics, blood cultures taken and on discharge were collected. These data can mainly be used to study the influence of virtually lowering the TLDF on diagnostic measures, treatment and length of hospitalization in pediatric FN, which in turn are directly related to costs of FN therapy, and quality of life. This approach can be expanded to include as well different definitions of neutropenia.

Purpose: Multiple interventions have been developed aiming to reduce time to antibiotics (TTA) in patients with fever and neutropenia (FN) following chemotherapy for cancer. We evaluated their effect to reduce TTA and their impact on important clinical outcomes in a systematic review., Methods: The search covered seven databases. Biases and quality of studies were assessed with the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool. Interventions could be implemented in any setting and performed by any person included in the FN management. Absolute change of TTA was the primary outcome. Registration: PROSPERO (CRD42018092948)., Results: Six thousand two hundred ninety-six titles and abstracts were screened, 177 studies were retrieved and 30 studies were included. Risk of bias was moderate to serious in 28 studies and low in two studies. All but one study reported a reduction of TTA after the intervention. Various types of interventions were implemented; they most commonly aimed at professionals. Most of the studies made more than one single intervention., Conclusion: This review may help centers to identify their specific sources of delay and barriers to change and to define what intervention may be the best to apply. This review supports the assertion that TTA can be considered a measure of quality of care, emphasizes the importance of education and training, and describes the very different interventions which have effectively reduced TTA.

Background: The aetiology of most childhood cancers is largely unknown. Spatially varying environmental factors such as traffic-related air pollution, background radiation and agricultural pesticides might contribute to the development of childhood cancer. This study is the first investigation of the spatial disease mapping of childhood cancers using exact geocodes of place of residence., Methods: We included 5947 children diagnosed with cancer in Switzerland during 1985-2015 at 0-15 years of age from the Swiss Childhood Cancer Registry. We modelled cancer risk using log-Gaussian Cox processes and indirect standardisation to adjust for age and year of diagnosis. We examined whether the spatial variation of risk can be explained by modelled ambient air concentration of NO 2 , modelled exposure to background ionising radiation, area-based socio-economic position (SEP), linguistic region, duration in years of general cancer registration in the canton or degree of urbanisation., Results: For all childhood cancers combined, the posterior median relative risk (RR), compared to the national level, varied by location from 0.83 to 1.13 (min to max). Corresponding ranges were 0.96 to 1.09 for leukaemia, 0.90 to 1.13 for lymphoma, and 0.82 to 1.23 for central nervous system (CNS) tumours. The covariates considered explained 72% of the observed spatial variation for all cancers, 81% for leukaemia, 82% for lymphoma and 64% for CNS tumours. There was weak evidence of an association of CNS tumour incidence with modelled exposure to background ionising radiation (RR per SD difference 1.17; 0.98-1.40) and with SEP (1.6; 1.00-1.13)., Conclusion: Of the investigated diagnostic groups, childhood CNS tumours showed the largest spatial variation. The selected covariates only partially explained the observed variation of CNS tumours suggesting that other environmental factors also play a role.

Purpose: Prompt antibiotic therapy is standard of care for patients with fever and neutropenia (FN) during chemotherapy for cancer. We systematically reviewed the association between time to antibiotics (TTA) and clinical outcomes., Methods: The search covered seven databases; confounding biases and study quality were assessed with the ROBINS-I tool. Safety (death, intensive care unit (ICU) admission, sepsis) and treatment adequacy (relapse of infection, persistence or recurrence of fever) were assessed as primary outcomes., Results: Of 6296 articles identified, 13 observational studies were included. Findings regarding safety were inconsistent. Three studies controlling for triage bias showed a possible association between longer TTA and impaired safety. Meta-analysis for TTA ≤ 60 min versus > 60 min was feasible on four studies, with three studies each reporting on death (OR 0.78, 95%CI 0.16-3.69) and on ICU admission (OR 1.43, 95%CI 0.57-3.60). No study reported data on treatment adequacy. Triage bias, i.e. faster treatment of patients with worse clinical condition, was identified as a relevant confounding factor., Conclusion: There seems to be an association between longer TTA and impaired safety. More knowledge about TTA effects on safety are important to optimise treatment guidelines for FN. Controlling for triage and other biases is necessary to gain further evidence., Trial Registration: Registration: PROSPERO [http://www.crd.york.ac.uk/PROSPERO/display&#95;record.php?ID=CRD42018092948].

Background:  Essential thrombocythemia is a chronic myeloproliferative neoplasm. It is extremely rare in children below 15 years of age with an estimated annual incidence of only 0.09 per million. Usually, clinical symptoms associated with essential thrombocythemia are mild or absent., Case:  Here, we present the case of a 14-year-old female patient fulminantly presenting with acute symptoms comprising visual impairment, palmar and plantar stabbing pain. Blood count revealed massive thrombocytosis of 2373 × 10 9 /L. Bone marrow morphology showed elevated numbers of mature megakaryocytes. Von Willebrand factor activity/antigen ratio was significantly reduced compatible with an acquired Von Willebrand syndrome associated with high platelet counts. Molecular analyses for driver mutations of myeloproliferative neoplasms including JAK2V617F , CALR and MPL were negative. Acute therapy comprising hyperhydration and oxygen supply complemented by acetylsalicylic acid led to amelioration of symptoms. Medication with hydroxycarbamide maintained a significant reduction of platelet counts but had to be reduced or withheld several times due to neutropenia. Repeated bleeding episodes observed in the course were clearly associated with increases in platelet counts above 1200 × 10 9 /L explained by acquired von Willebrand syndrome. Sixteen months after diagnosis, therapy was switched to pegylated interferon and platelet counts could be stabilized without significant side effects., Competing Interests: The authors have no conflict of interest to disclose., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Incidence of childhood cancer increased in most countries worldwide, but reasons are unclear. This study investigates trends of childhood cancer incidence in Switzerland from 1985 to 2014., Methods: We extracted data on all childhood cancer cases diagnosed at ages 0-14 years in Switzerland from the Swiss Childhood Cancer Registry. We included ICCC-3 main groups I-XII and calculated age-standardised, cumulative, and age-specific incidence for different diagnostic groups. We analysed trends of annual age-standardised incidence using JoinPoint regression models., Results: Over the study period from 1985 to 2014, 5104 of 5486 cancer diagnoses (93%) were microscopically verified. The proportion of children treated in paediatric cancer centres increased from 84% during 1985-1994 to 93% in 1995-2004 and 98% in 2005-2014 (p < 0.001). Using the World standard population, age-standardised incidence was 143 in 1985-1994, 154 in 1995-2004, and 162 per million in 2005-2014. Incidence increased by 0.7% (95% confidence interval (CI) 0.5; 1.0) per year for all cancers from 1985 to 2014, 0.8% (95% CI 0.2%-1.4%) for leukaemias over the same period, 3.0% (95% CI 0.2%-1.4%) for CNS tumours during 1985-2002, and 3.8% (95% CI 1.7%-6.0%) for epithelial neoplasms and melanomas over the period 1985-2014., Conclusion: Trends in incidence were driven mostly by increases among leukaemias and CNS tumours. For CNS tumours, observed trends may be explained at least partially by diagnostic changes and improved registration. For leukaemias, rising incidence may be real and due to risk factors that experience similar increases in trends., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: To determine the efficacy and safety of different prophylactic systemic antibiotics in adult and pediatric patients receiving chemotherapy or undergoing hematopoietic stem cell transplantation (HSCT)., Methods: We conducted a systematic review and performed searches of Ovid MEDLINE, MEDLINE in-process and Embase; and Cochrane Central Register of Controlled Trials. Studies were included if patients had cancer or were HSCT recipients with anticipated neutropenia, and the intervention was systemic antibacterial prophylaxis. Strategies synthesized included fluoroquinolone vs no antibiotic/nonabsorbable antibiotic; fluoroquinolone vs trimethoprim-sulfamethoxazole; trimethoprim-sulfamethoxazole vs no antibiotic; and cephalosporin vs. no antibiotic. Fluoroquinolone vs cephalosporin and levofloxacin vs ciprofloxacin were compared by network meta-analysis. Primary outcome was bacteremia., Results: Of 20 984 citations screened, 113 studies comparing prophylactic antibiotic to control were included. The following were effective in reducing bacteremia: fluoroquinolone vs no antibiotic/nonabsorbable antibiotic (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.41-0.76), trimethoprim-sulfamethoxazole vs no antibiotic (RR 0.59, 95% CI 0.41-0.85) and cephalosporin vs no antibiotic (RR 0.30, 95% CI 0.16-0.58). Fluoroquinolone was not significantly associated with increased Clostridium difficile infection (RR 0.62, 95% CI 0.31-1.24) or invasive fungal disease (RR 1.28, 95% CI 0.79-2.08) but did increase resistance to fluoroquinolone among bacteremia isolates (RR 3.35, 95% CI 1.12 to 10.03). Heterogeneity in fluoroquinolone effect on bacteremia was not explained by evaluated study, population, or methodological factors. Network meta-analysis revealed no direct comparisons for pre-specified analyses; superior regimens were not identified., Conclusions: Fluoroquinolone, trimethoprim-sulfamethoxazole, and cephalosporin prophylaxis reduced bacteremia. A clinical practice guideline to facilitate prophylactic antibiotic decision-making is required., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Fever in neutropenia (FN) is the most frequent potentially lethal complication of chemotherapy in patients with cancer. The temperature limit defining fever (TLDF) for FN is based on scarce evidence. This prospective, single center observational study recruited non-selected pediatric patients diagnosed with cancer between ≥1 and ≤17 years in 2012 and 2013. Of 40 patients potentially eligible, 39 participated. Data of 8896 temperature measurements and 1873 complete blood counts (CBCs) were recorded over 289 months (24.1 years) of chemotherapy exposure time. During this time 43 FN episodes were diagnosed. In 32 episodes, FN diagnosis was based on reaching the local (i.e. Bern, Switzerland) standard TLDF of 39.0 °C; another 11 episodes had been captured by clinical judgement (i.e. temperature < 39.0 °C). These data can be used to simulate the effects of various TLDFs on the rate of FN diagnosis. We assume merging these data with other data sets is feasible.