Evaluation of chemotherapy-induced nausea and vomiting in pediatric patients with high-grade glioma treated with lomustine-a case series.

PURPOSE: Although lomustine has been used as a chemotherapeutic agent for decades, no recommendation on appropriate chemotherapy-induced nausea and vomiting (CINV) prophylaxis is available. As CINV is considered one of the most bothersome side effects of chemotherapy, adequate prophylaxis is of relevance to improve quality of life during cancer treatment. The aim of this retrospective case series was to report the incidence and severity of CINV in pediatric patients with high-grade glioma treated with lomustine and to formulate recommendations for appropriate CINV prophylaxis. METHODS: Pediatric patients treated with lomustine for high-grade glioma according to the ACNS 0423 protocol were identified retrospectively. Two researchers independently reviewed and classified complaints of CINV and administered CINV prophylaxis. Treatment details, tumor localization, and response to therapy were systematically extracted from the patients' files. RESULTS: Seventeen children aged 8-18 years received a median of four cycles of lomustine. CINV complaints and administered prophylaxis were evaluable in all patients. Moderate or severe CINV was observed in 13/17 (76%) patients. Administered prophylactic CINV regimens varied from no prophylaxis to triple-agent combinations. CONCLUSION: In this case series, we identified lomustine as a highly emetogenic chemotherapeutic agent. According to the current guidelines, CINV prophylaxis with a 5-HT3 receptor antagonist in combination with dexamethasone and (fos)aprepitant is recommended.

A 20-year overview of fertility preservation in boys: new insights gained through a comprehensive international survey.

STUDY QUESTION: Twenty years after the inception of the first fertility preservation programme for pre-pubertal boys, what are the current international practices with regard to cryopreservation of immature testicular tissue? SUMMARY ANSWER: Worldwide, testicular tissue has been cryopreserved from over 3000 boys under the age of 18 years for a variety of malignant and non-malignant indications; there is variability in practices related to eligibility, clinical assessment, storage, and funding. WHAT IS KNOWN ALREADY: For male patients receiving gonadotoxic treatment prior to puberty, testicular tissue cryopreservation may provide a method of fertility preservation. While this technique remains experimental, an increasing number of centres worldwide are cryopreserving immature testicular tissue and are approaching clinical application of methods to use this stored tissue to restore fertility. As such, standards for quality assurance and clinical care in preserving immature testicular tissue should be established. STUDY DESIGN SIZE DURATION: A detailed survey was sent to 17 centres within the recently established ORCHID-NET consortium, which offer testicular tissue cryopreservation to patients under the age of 18 years. The study encompassed 60 questions and remained open from 1 July to 1 November 2022. PARTICIPANTS/MATERIALS SETTING METHODS: Of the 17 invited centres, 16 completed the survey, with representation from Europe, Australia, and the USA. Collectively, these centres have cryopreserved testicular tissue from patients under the age of 18 years. Data are presented using descriptive analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Since the establishment of the first formal fertility preservation programme for pre-pubertal males in 2002, these 16 centres have cryopreserved tissue from 3118 patients under the age of 18 years, with both malignant (60.4%) and non-malignant (39.6%) diagnoses. All centres perform unilateral biopsies, while 6/16 sometimes perform bilateral biopsies. When cryopreserving tissue, 9/16 centres preserve fragments sized ≤5 mm3 with the remainder preserving fragments sized 6-20 mm3. Dimethylsulphoxide is commonly used as a cryoprotectant, with medium supplements varying across centres. There are variations in funding source, storage duration, and follow-up practice. Research, with consent, is conducted on stored tissue in 13/16 centres. LIMITATIONS REASONS FOR CAUTION: While this is a multi-national study, it will not encompass every centre worldwide that is cryopreserving testicular tissue from males under 18 years of age. As such, it is likely that the actual number of patients is even higher than we report. Whilst the study is likely to reflect global practice overall, it will not provide a complete picture of practices in every centre. WIDER IMPLICATIONS OF THE FINDINGS: Given the research advances, it is reasonable to suggest that cryopreserved immature testicular tissue will in the future be used clinically to restore fertility. The growing number of patients undergoing this procedure necessitates collaboration between centres to better harmonize clinical and research protocols evaluating tissue function and clinical outcomes in these patients. STUDY FUNDING/COMPETING INTERESTS: K.D. is supported by a CRUK grant (C157/A25193). R.T.M. is supported by an UK Research and Innovation (UKRI) Future Leaders Fellowship (MR/S017151/1). The MRC Centre for Reproductive Health at the University of Edinburgh is supported by MRC (MR/N022556/1). C.L.M. is funded by Kika86 and ZonMW TAS 116003002. A.M.M.v.P. is supported by ZonMW TAS 116003002. E.G. was supported by the Research Program of the Research Foundation-Flanders (G.0109.18N), Kom op tegen Kanker, the Strategic Research Program (VUB_SRP89), and the Scientific Fund Willy Gepts. J.-B.S. is supported by the Swedish Childhood Cancer Foundation (TJ2020-0026). The work of NORDFERTIL is supported by the Swedish Childhood Cancer Foundation (PR2019-0123; PR2022-0115), the Swedish Research Council (2018-03094; 2021-02107), and the Birgitta and Carl-Axel Rydbeck's Research Grant for Paediatric Research (2020-00348; 2021-00073; 2022-00317; 2023-00353). C.E is supported by the Health Department of the Basque Government (Grants 2019111068 and 2022111067) and Inocente Inocente Foundation (FII22/001). M.P.R. is funded by a Medical Research Council Centre for Reproductive Health Grant No: MR/N022556/1. A.F. and N.R. received support from a French national research grant PHRC No. 2008/071/HP obtained by the French Institute of Cancer and the French Healthcare Organization. K.E.O. is funded by the University of Pittsburgh Medical Center and the US National Institutes of Health HD100197. V.B-L is supported by the French National Institute of Cancer (Grant Seq21-026). Y.J. is supported by the Royal Children's Hospital Foundation and a Medical Research Future Fund MRFAR000308. E.G., N.N., S.S., C.L.M., A.M.M.v.P., C.E., R.T.M., K.D., M.P.R. are members of COST Action CA20119 (ANDRONET) supported by COST (European Cooperation in Science and Technology). The Danish Child Cancer Foundation is also thanked for financial support (C.Y.A.). The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

The applicability of the central line-associated bloodstream infection (CLABSI) criteria for the evaluation of bacteremia episodes in pediatric oncology patients.

BACKGROUND: The aim of this study was to investigate the applicability of the central line-associated bloodstream infection (CLABSI) criteria of the Centers for Disease Control and Prevention in pediatric oncology patients. METHODS: Bacteremia episodes from 2020 to 2022 from a prospective cohort of pediatric oncology patients with a central venous catheter were included. Episodes were classified by three medical experts following the CLABSI criteria as either a CLABSI or non-CLABSI (i.e., contamination, other infection source, or mucosal barrier injury-laboratory confirmed bloodstream infection (MBI-LCBI)). Subsequently, they were asked if and why they (dis)agreed with this diagnosis following the criteria. The primary outcome was the percentage of episodes where the experts clinically disagreed with the diagnosis given following the CLABSI criteria. RESULTS: Overall, 84 bacteremia episodes in 71 patients were evaluated. Following the CLABSI criteria, 34 (40%) episodes were classified as CLABSIs and 50 (60%) as non-CLABSIs. In 11 (13%) cases the experts clinically disagreed with the diagnosis following the CLABSI criteria. The discrepancy between the CLABSI criteria and clinical diagnosis was significant; McNemar's test p < .01. Disagreement by the experts with the CLABSI criteria mostly occurred when the experts found an MBI-LCBI a more plausible cause of the bacteremia than a CLABSI due to the presence of a gram negative bacteremia (Pseudomonas aeruginosa n = 3) and/or mucositis. CONCLUSIONS: A discrepancy between the CLABSI criteria and the evaluation of the experts was observed. Adding Pseudomonas aeruginosa as an MBI pathogen and incorporating the presence of mucositis in the MBI-LCBI criteria, might increase the applicability.

Central Venous Catheter-related Bloodstream Infections Caused by Enterobacterales in Pediatric Oncology Patients: Catheter Salvage or Removal.

BACKGROUND: The aim was to determine whether salvage treatment with systemic antibiotics is a safe and effective strategy for Enterobacterales bloodstream infections (BSI) in pediatric oncology patients with a central venous catheter (CVC). METHODS: A retrospective study was performed on oncology and stem cell recipient patients with a CVC and blood culture with Enterobacterales , at the Princess Máxima Centre for Pediatric Oncology, Utrecht, the Netherlands. Analyses were performed for all BSI and for episodes meeting central line-associated bloodstream infection (CLABSI) criteria. The cumulative incidence of an event (ie, removal, intensive care admission or death) was estimated after blood culture collection for episodes primarily treated with antibiotics. The effect of prognostic factors on the hazard of the event of interest was assessed by estimating a Cox proportional hazard regression model. RESULTS: In total, 95 CVC-related Enterobacterales BSIs in 82 patients were included; 12 (13%) BSIs required immediate CVC removal and for 83 (87%) BSIs CVC salvage was attempted. The cumulative incidence of events at 60 days was 53.0% [95% confidence interval (CI): 41.7-63.1] for BSIs (n = 83), and 64.4% (95% CI: 48.3-76.7) for CLABSIs (n = 45). The events occurred after a median of 6 (Q1-Q3: 2-15) and 6 (Q1-Q3: 2-20) days for BSIs and CLABSIs, respectively. Intensive care admission after salvage treatment was required in 16% of the BSIs and CLABSIs, resulting in death in 5% and 2% of cases, respectively. No significant association between risk factors and events was found. CONCLUSIONS: The cumulative incidence of an event at 60 days after salvage treatment for Enterobacterales CLABSIs and BSIs in pediatric oncology patients is high. Immediate CVC removal appears recommendable for this patient group.

Treatment of breakthrough and prevention of refractory chemotherapy-induced nausea and vomiting in pediatric cancer patients: Clinical practice guideline update.

This clinical practice guideline update provides recommendations for treating breakthrough chemotherapy-induced nausea and vomiting (CINV) and preventing refractory CINV in pediatric patients. Two systematic reviews of randomized controlled trials in adult and pediatric patients informed the recommendations. In patients with breakthrough CINV, escalation of antiemetic agents to those recommended for chemotherapy of the next higher level of emetogenic risk is strongly recommended. A similar recommendation to escalate therapy is made to prevent refractory CINV in patients who did not experience complete breakthrough CINV control and are receiving minimally or low emetogenic chemotherapy. A strong recommendation to use antiemetic agents that controlled breakthrough CINV for the prevention of refractory CINV is also made.

CATERPILLAR-study protocol: an assessor-blinded randomised controlled trial comparing taurolidine-citrate-heparin to heparin-only lock solutions for the prevention of central line-associated bloodstream infections in paediatric oncology patients.

INTRODUCTION: The efficacy of taurolidine containing lock solutions for the prevention of central line-associated bloodstream infections (CLABSI) in paediatric oncology patients is still unknown. If the taurolidine-citrate-heparin lock appears to decrease the incidence of CLABSIs, we hope to increase the quality of life of children with cancer by subsequently reducing the central venous access device (CVAD)-removal rates, dispense of antibiotics, hospital admissions and incidence of severe sepsis resulting in intensive care unit admission. METHODS AND ANALYSIS: This assessor-blinded randomised controlled trial including 462 patients was designed to compare the taurolidine-citrate-heparin lock to the heparin-only lock for the prevention of CLABSIs in paediatric oncology patients. Patients receiving their first CVAD at the Princess Máxima Centre for Paediatric Oncology, Utrecht, the Netherlands, are eligible for inclusion. The primary outcome of this study is the incidence of first CLABSIs from CVAD insertion until the end of the study, maximum follow-up of 90 days. An intention-to-treat and a per-protocol analysis will be performed. An interim analysis will be performed after the inclusion of 50% of the patients. The results of the interim analysis and overall conduct of the trial will be discussed by a data safety monitoring board. ETHICS AND DISSEMINATION: The medical ethics committee NedMec, Utrecht, the Netherlands, has approved this research (number 20/370). Written informed consent for participation in this trial and publication of the trial data is obtained from all patients and/or their parents/guardians. The results of this trial will be published in a peer-reviewed journal and the data will be made available on reasonable request after publication of the main results manuscript. TRIAL REGISTRATION NUMBERS: NTR6688; NCT05740150.

Childhood cancer and hematological disorders negatively affect spermatogonial quantity at diagnosis: a retrospective study of a male fertility preservation cohort.

STUDY QUESTION: What is the impact of cancer or hematological disorders on germ cells in pediatric male patients? SUMMARY ANSWER: Spermatogonial quantity is reduced in testes of prepubertal boys diagnosed with cancer or severe hematological disorder compared to healthy controls and this reduction is disease and age dependent: patients with central nervous system cancer (CNS tumors) and hematological disorders, as well as boys <7 years are the most affected. WHAT IS KNOWN ALREADY: Fertility preservation in pediatric male patients is considered based on the gonadotoxicity of selected treatments. Although treatment effects on germ cells have been extensively investigated, limited data are available on the effect of the disease on the prepubertal male gonad. Of the few studies investigating the effects of cancer or hematologic disorders on testicular function and germ cell quantity in prepuberty, the results are inconsistent. However, recent studies suggested impairments before the initiation of known gonadotoxic therapy. Understanding which diseases and at what age affect the germ cell pool in pediatric patients before treatment is critical to optimize strategies and counseling for fertility preservation. STUDY DESIGN, SIZE, DURATION: This multicenter retrospective cohort study included 101 boys aged <14 years with extra-cerebral cancer (solid tumors), CNS tumors, leukemia/lymphoma (blood cancer), or non-malignant hematological disorders, who were admitted for a fertility preservation programme between 2002 and 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: In addition to clinical data, we analyzed measurements of testicular volume and performed histological staining on testicular biopsies obtained before treatment, at cryopreservation, to evaluate number of spermatogonia per tubular cross-section, tubular fertility index, and the most advanced germ cell type prior to chemo-/radiotherapy. The controls were data simulations with summary statistics from original studies reporting healthy prepubertal boys' testes characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: Prepubertal patients with childhood cancer or hematological disorders were more likely to have significantly reduced spermatogonial quantity compared to healthy controls (48.5% versus 31.0% prevalence, respectively). The prevalence of patients with reduced spermatogonial quantity was highest in the CNS tumor (56.7%) and the hematological disorder (55.6%) groups, including patients with hydroxyurea pre-treated sickle cell disease (58.3%) and patients not exposed to hydroxyurea (50%). Disease also adversely impacted spermatogonial distribution and differentiation. Irrespective of disease, we observed the highest spermatogonial quantity reduction in patients <7 years of age. LIMITATIONS, REASONS FOR CAUTION: For ethical reasons, we could not collect spermatogonial quantity data in healthy prepubertal boys as controls and thus deployed statistical simulation on data from literature. Also, our results should be interpreted considering low patient numbers per (sub)group. WIDER IMPLICATIONS OF THE FINDINGS: Cancers, especially CNS tumors, and severe hematological disorders can affect spermatogonial quantity in prepubertal boys before treatment. Consequently, these patients may have a higher risk of depleted spermatogonia following therapies, resulting in persistent infertility. Therefore, patient counseling prior to disease treatment and timing of fertility preservation should not only be based on treatment regimes, but also on diagnoses and age. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Marie Curie Initial Training Network (ITN) (EU-FP7-PEOPLE-2013-ITN) funded by European Commision grant no. 603568; ZonMW Translational Adult stem cell research (TAS) grant no. 116003002. No competing interests. TRIAL REGISTRATION NUMBER: N/A.

A simple extemporaneous oral suspension of aprepitant yields sufficient pharmacokinetic exposure in children.

INTRODUCTION: Aprepitant is used for the treatment of chemotherapy induced nausea and vomiting. A liquid formulation is needed for treatment of young children. However, the commercial (powder for) suspension was not available worldwide for a prolonged period of time and, therefore, a 10 mg/mL aprepitant oral suspension was extemporarily prepared to prevent suboptimal antiemetic treatment. The current pharmacokinetic study was developed to investigate whether this extemporaneous oral suspension offers an appropriate treatment option. METHODS: From 49 pediatric patients (0.7-17.9 years) 235 plasma concentrations were collected. Patients were either treated with our extemporaneous oral suspension (n = 26; 53%), commercially available capsules (n = 18; 37%), or the intravenous prodrug formulation of aprepitant (fosaprepitant, n = 5; 10%). Pharmacokinetic analyses were performed using nonlinear mixed effects modelling. RESULTS: A one-compartment model adequately described the pharmacokinetics of aprepitant in children. The bioavailability of the extemporaneous oral suspension was not significantly different to that of the capsules (P = 0.26). The observed bioavailability throughout the total population was 83% (95% CI 69%-97%). The absorption of the extemporaneous oral suspension was 39.4% (95%CI 19.5-57.4%) faster than that of capsules (mean absorption time of 1.78 h (95%CI 1.32-2.35), but was comparable to that of the commercial oral suspension. The median area under the curve after (fos)aprepitant was 22.2 mg/L*h (range 8.9-50.3 mg/L*h) on day 1. CONCLUSION: Our extemporaneous oral suspension is an adequate alternative for the commercially (un)available oral suspension in young children. An adequate exposure to aprepitant in children was yielded and the bioavailability of the extemporaneous suspension was comparable to capsules.

Prevention of acute and delayed chemotherapy-induced nausea and vomiting in pediatric cancer patients: A clinical practice guideline.

This clinical practice guideline provides recommendations for preventing acute and delayed phase chemotherapy-induced nausea and vomiting (CINV) in pediatric patients. The recommendations are based on two systematic reviews of randomized controlled trials evaluating interventions to prevent (1) acute phase CINV and (2) delayed phase CINV. Recommendations for acute phase and delayed phase CINV prophylaxis are made for patients receiving chemotherapy of varying emetogenicity, as well as for patients not able to receive dexamethasone or a neurokinin-1 receptor antagonist. Evidence gaps, including antiemetic safety and optimal dosing, were identified.

Overestimation of the effect of (fos)aprepitant on intravenous dexamethasone pharmacokinetics requires adaptation of the guidelines for children with chemotherapy-induced nausea and vomiting.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) are common side effects in pediatric oncology treatment. Besides 5-HT3-antagonists, both dexamethasone and aprepitant are cornerstone drugs in controlling these side effects. Based on results of adult studies, the dexamethasone dose is reduced by 50% when combined with aprepitant, because of a drug-drug interaction, even though data on the interaction in children is lacking. The current study was developed to investigate the effect of aprepitant on dexamethasone clearance (CL) in children, in order to assess if dexamethasone dose reduction for concomitant use of aprepitant is appropriate in the current antiemetic regimen. METHODS: In total, 65 children (0.6-17.9 years), receiving intravenous or oral antiemetic therapy (dexamethasone ± aprepitant) as standard of care, were included. 305 dexamethasone plasma concentrations were determined using LC-MS/MS. An integrated dexamethasone and aprepitant pharmacokinetic model was developed using non-linear mixed effects modelling in order to investigate the effect of aprepitant administration on dexamethasone CL. RESULTS: In this population, dexamethasone CL in patients with concomitant administration of aprepitant was reduced by approximately 30% of the uninhibited CL (23.3 L/h (95% confidence interval 20.4-26.0)). This result is not consistent with the results of adult studies (50% reduction). This difference was not age dependent, but might be related to the route of administration of dexamethasone. Future studies are needed to assess the difference in oral/intravenous dexamethasone. CONCLUSION: When dexamethasone is given intravenously as a component of triple therapy to prevent CINV in children, we advise to reduce the dexamethasone dose by 30% instead of 50%.

Interventions for the prevention of acute phase chemotherapy-induced nausea and vomiting in adult and pediatric patients: a systematic review and meta-analysis.

PURPOSE: To identify effective and safe interventions to prevent acute phase chemotherapy-induced nausea and vomiting (CINV) in adult and pediatric patients. METHODS: We conducted a systematic review of randomized trials evaluating interventions to prevent acute CINV. Outcomes assessed were complete chemotherapy-induced vomiting (CIV) control, complete chemotherapy-induced nausea (CIN) control, complete CINV control, and discontinuation of antiemetics due to adverse effects. RESULTS: The search identified 65,172 citations; 744 were evaluated at full-text, and 295 (25 pediatric) met eligibility criteria. In patients receiving highly emetogenic chemotherapy (HEC), complete CIV (risk ratio (RR) 1.23, 95% confidence interval (CI) 1.05-1.44) and CIN (RR 1.34, 95% CI 1.10-1.62) control improved when olanzapine was added. The addition of a neurokinin-1 receptor antagonist (NK1RA) to a corticosteroid plus a serotonin-3 receptor antagonist (5HT3RA) also improved complete CIV (RR 1.11, 95% CI 1.08-1.14) and CIN (RR 1.05, 95% CI 1.01-1.08) control. Compared to granisetron/ondansetron, palonosetron provided improved complete CIV control when the 5HT3RA was given alone or when combined with dexamethasone. In patients receiving moderately emetogenic chemotherapy (MEC), dexamethasone plus a 5HT3RA improved complete CIV control compared to a 5HT3RA alone (RR 1.29, 95% CI 1.21-1.39). Only a single meta-analysis evaluating the safety outcome was possible. CONCLUSIONS: For patients receiving HEC, various antiemetic regimens improved CIV and CIN control. For patients receiving MEC, administration of a 5HT3RA plus dexamethasone improved CIV control. Analysis of antiemetic safety was constrained by lack of data.

Central venous catheter-associated complications in pediatric patients diagnosed with Hodgkin lymphoma: implications for catheter choice.

PURPOSE: The purpose of this study was to determine the most optimal central venous catheter (CVC) for pediatric patients with Hodgkin lymphoma (HL) in terms of complications. METHODS: A retrospective study including patients diagnosed with HL from 2015 to 2021 at the Princess Máxima Center was performed. Patients were followed from CVC insertion until removal or 06-2021, whichever came first. The primary outcome was the CVC-related complication incidence rate (IR) per 1000 CVC-days. Furthermore, the incidence rate ratio (IRR) was calculated by comparing complication IRs between peripherally inserted central catheters (PICC) and totally implantable venous access ports (TIVAP). Additionally, risk factors for central venous thrombosis (CVT) were identified. RESULTS: A total of 98 patients were included. The most frequently observed complications were local irritation/infections (18%; IR 0.93), malfunctions (15%; IR 0.88), and CVC-related CVTs (10%; IR 0.52). Single lumen PICCs were associated with a higher risk of complications (49% vs. 26%; IRR 5.12, CI95% 2.76-9.50), severe complications (19% vs. 7%; IRR 11.96, CI95% 2.68-53.42), and early removal (18% vs. 7%; IRR 9.96, CI95% 2.18-45.47). A single lumen PICC was identified as a risk factor for CVC-related CVT when compared to TIVAPs (12% vs. 7%, IRR 6.98, CI95% 1.45-33.57). CONCLUSION: The insertion of a TIVAP rather than a PICC should be recommended for pediatric patients with HL, especially in the presence of CVT-related risk factors. Future trials should evaluate the efficacy and safety of direct oral anticoagulants for the primary prevention of CVT in pediatric patients with a PICC and other CVT-related risk factors.

Clostridioides difficile infection in paediatric patients with cancer and haematopoietic stem cell transplant recipients.

BACKGROUND: Epidemiology of Clostridioides difficile infection (CDI) in paediatric cancer patients is uncertain. The primary objective was to describe the prevalence of CDI outcomes among paediatric patients receiving cancer treatments. Secondary objectives were to describe clinical features of CDI, propose a definition of severe CDI and to determine risk factors for CDI clinical outcomes. METHODS: A multi-centre retrospective cohort study that included paediatric patients (1-18 years of age) receiving cancer treatments with CDI. Severe CDI definition was achieved by consensus. Univariable and multivariable regression was conducted to evaluate risk factors for CDI outcomes. RESULTS: There were 627 eligible patients who experienced 721 CDI episodes. The prevalence of clinical cure was 82.9%, recurrence was 9.6%, global cure was 75.0% and repeated new CDI episode was 12.8%. The proposed definition of severe CDI was the presence of colitis, pneumatosis intestinalis, pseudomembranous colitis, ileus or surgery for CDI, occurring in 70 (9.7%) episodes. In univariable regression, initial oral metronidazole or initial oral vancomycin were not significantly associated with failure to achieve clinical cure or CDI recurrence. In multiple regression, oral metronidazole was significantly associated with higher odds (odds ratio (OR) 1.7, 95% confidence interval (CI) 1.0-2.7) and oral vancomycin was significantly associated with lower odds (OR 0.4, 95% CI 0.2-0.8) of repeated new episodes. CONCLUSION: The prevalence of clinical cure was 82.9% and recurrence was 9.6% in pediatric patients receiving cancer treatments. Severe CDI, as per our proposed definition, occurred in 9.7% episodes. Initial oral vancomycin was significantly associated with a reduction in repeated new CDI episodes.

Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population.

Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005-2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition.

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Prophylactic antibiotics for preventing gram-positive infections associated with long-term central venous catheters in adults and children receiving treatment for cancer.

BACKGROUND: This is an updated version of a Cochrane Review last published in 2013. Long-term central venous catheters (CVCs), including tunnelled CVCs (TCVCs) and totally implanted devices or ports (TIDs), are increasingly used when treating people with cancer. Despite international guidelines on sterile insertion and appropriate CVC maintenance and use, infections remain a common complication. These infections are mainly caused by gram-positive bacteria. Antimicrobial prevention strategies aimed at these micro-organisms could potentially decrease the majority of CVC-related infections. The aim of this review was to evaluate the efficacy of prophylactic antibiotics for the prevention of gram-positive infections in people with cancer who have long-term CVCs. OBJECTIVES: To assess the effects of administering antibiotics prior to the insertion of long-term CVCs or as a flush/lock solution, or both during long-term CVC access to prevent gram-positive CVC-related infections in adults and children receiving treatment for cancer. SEARCH METHODS: The search for this updated review was conducted on 19 November 2020. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE via Ovid and Embase via Ovid. We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform portal for additional articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared either the administration of prophylactic antibiotics prior to long-term CVC insertion versus no administration of antibiotics, or the use of an antibiotic versus a non-antibiotic flush/lock solution in long-term CVCs, in adults and children receiving treatment for cancer. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two authors independently selected studies, classified them and extracted data onto a predesigned data collection form. The outcomes of interest were gram-positive catheter-related infection events and total number of CVCs and CVC days. We pooled the data using a random-effects model for meta-analyses. We used the GRADE approach to assess the certainty of the evidence.  MAIN RESULTS: For this update, we identified 310 potentially relevant studies and screened them for eligibility. We included one additional RCT with 404 participants. The original review included 11 RCTs with a total of 840 people with cancer (adults and children). In total this review included 12 RCTs with 1244 participants. Antibiotics prior to insertion of the CVC Six trials compared the use of antibiotics (vancomycin, teicoplanin, ceftazidime or cefazolin) versus no antibiotics given before the insertion of a long-term CVC. One study did not observe any CVC-related infection events in either group was not included in the quantitative analysis as it was not possible to calculate a risk ratio. Administering an antibiotic prior to insertion of the CVC may not reduce gram-positive CVC-related infections (pooled risk ratio 0.67, confidence interval (CI) 95% 0.32 to 1.43; control versus intervention group risk 10.4% versus 7.3% of the participants; 5 studies, 648 participants; moderate-certainty evidence). We sought adverse event data, but these were not described by the authors. The overall risk of bias was deemed low.   Antibiotics as a flushing or locking solution Six trials compared a combined antibiotic (vancomycin, amikacin or taurolidine) and heparin solution with a heparin-only solution for flushing or locking the long-term CVC after use. One study did not observe any CRS events and was not include this study in the quantitative analysis as it was not possible to calculate a risk ratio. Flushing and locking long-term CVCs with a combined antibiotic and heparin solution likely reduced the risk of gram-positive CVC-related infections compared to a heparin-only solution (pooled rate ratio 0.47, CI 95% 0.26 to 0.85; control versus intervention group rate ratio 0.66 versus 0.27 per 1000 CVC-days; 5 studies, 443 participants; moderate-certainty evidence). One trial reported a higher incidence of occlusions and participants in one trial reported an unpleasant taste after flushing associated with a combined antibiotic and heparin solution. The overall risk of bias was deemed low.  AUTHORS' CONCLUSIONS: Since the last version of this review, we included one additional study. There was no observed benefit of administering antibiotics before the insertion of long-term CVCs to prevent gram-positive CVC-related infections. Flushing or locking long-term CVCs with an antibiotic solution likely reduces gram-positive CVC-related infections experienced in people at risk of neutropenia through chemotherapy or disease. However, a limitation of this review is heterogeneity between the studies for both outcomes. Insufficient data were available to evaluate if the conclusions apply equally for different CVC types and for adults versus children. It must be noted that the use of an antibiotic flush/lock solution may increase microbial antibiotic resistance, therefore it should be reserved for high-risk people or if the baseline CVC-related infection rates are high. Further research is needed to identify high-risk groups most likely to benefit from these antibiotic flush/lock solutions.

Oncofertility care for newly diagnosed girls with cancer in a national pediatric oncology setting, the first full year experience from the Princess Máxima Center, the PEARL study.

BACKGROUND: Childhood cancer patients often remain uninformed regarding their potential risk of gonadal damage. In our hospital we introduced a five step standard oncofertility care plan for all newly diagnosed female patients aiming to identify, inform and triage 100% of patients and counsel 100% of patients at high risk (HR) of gonadal damage. This observational retrospective study (PEARL study) evaluated the use of this standard oncofertility care plan in the first full year in a national cohort. METHODS: The steps consist of 1)timely (preferably before start of gonadotoxic treatment) identification of all new patients, 2)triage of gonadal damage risk using a standardized gonadal damage risk stratification tool, 3)informing all patients and families, 4)counseling of a selected subset of girls, and 5) fertility preservation including ovarian tissue cryopreservation (OTC) in HR patients using amended Edinburgh criteria. A survey of the medical records of all girls newly diagnosed with cancer the first year (1-1-2019 until 31-12-2019) was conducted. RESULTS: Of 261 girls, 228 (87.4%) were timely identified and triaged. Triage resulted in 151 (66%) low(LR), 32 (14%) intermediate(IR) and 45 (20%) high risk(HR) patients. Ninety-nine families were documented to be timely informed regarding gonadal damage risk. In total, 35 girls (5 LR, 5 IR, 25 HR) were counseled by an oncofertility expert. 16/25 HR patients underwent fertility preservation (1 ovariopexy + OTC, oocyte cryopreservation (1 with and 1 without OTC) and 13 OTC). Fertility preservation did not lead to complications or delay of cancer treatment in any patient. CONCLUSION: We timely identified and triaged most girls (88%) with cancer with a high risk of gonadal damage to be counseled for fertility preservation. We aim to optimize the oncofertility care plan and the standardized gonadal damage risk stratification tool based on this experience and these may be of value to other pediatric oncology centers.

Prevention and treatment of anticipatory chemotherapy-induced nausea and vomiting in pediatric cancer patients and hematopoietic stem cell recipients: Clinical practice guideline update.

This 2021 clinical practice guideline update provides recommendations for preventing anticipatory chemotherapy-induced nausea and vomiting (CINV) in pediatric patients. Recommendations are based on systematic reviews that identified (1) if a history of acute or delayed CINV is a risk factor for anticipatory CINV, and (2) interventions for anticipatory CINV prevention and treatment. A strong recommendation to optimize acute and delayed CINV control in order to prevent anticipatory CINV is made. Conditional recommendations are made for hypnosis, systematic desensitization, relaxation techniques, and lorazepam for the secondary prevention of anticipatory CINV. No recommendation for the treatment of anticipatory CINV can be made.

Fertility preservation for female patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Female patients with childhood, adolescent, and young adult cancer are at increased risk for fertility impairment when treatment adversely affects the function of reproductive organs. Patients and their families desire biological children but substantial variations in clinical practice guidelines reduce consistent and timely implementation of effective interventions for fertility preservation across institutions. As part of the PanCareLIFE Consortium, and in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in female patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. This clinical practice guideline leverages existing evidence and international expertise to develop transparent recommendations that are easy to use to facilitate the care of female patients with childhood, adolescent, and young adult cancer who are at high risk for fertility impairment. A complete review of the existing evidence, including a quality assessment, transparent reporting of the guideline panel's decisions, and achievement of global interdisciplinary consensus, is an important result of this intensive collaboration.

Fertility preservation for male patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Male patients with childhood, adolescent, and young adult cancer are at an increased risk for infertility if their treatment adversely affects reproductive organ function. Future fertility is a primary concern of patients and their families. Variations in clinical practice are barriers to the timely implementation of interventions that preserve fertility. As part of the PanCareLIFE Consortium, in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in male patients who are diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. Recognising the need for global consensus, this clinical practice guideline used existing evidence and international expertise to rigorously develop transparent recommendations that are easy to use to facilitate the care of male patients with childhood, adolescent, and young adult cancer who are at high risk of fertility impairment and to enhance their quality of life.