Clinical Pharmacokinetics of Triazoles in Pediatric Patients

Triazoles represent an important class of antifungal drugs in the prophylaxis and treatment of invasive fungal disease in pediatric patients. Understanding the pharmacokinetics of triazoles in children is crucial to providing optimal care for this vulnerable population. While the pharmacokinetics is extensively studied in adult populations, knowledge on pharmacokinetics of triazoles in children is limited. New data are still emerging despite drugs already going off patent. This review aims to provide readers with the most current knowledge on the pharmacokinetics of the triazoles: fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole. In addition, factors that have to be taken into account to select the optimal dose are summarized and knowledge gaps are identified that require further research. We hope it will provide clinicians guidance to optimally deploy these drugs in the setting of a life-threatening disease in pediatric patients

Treatment of High Dose Methotrexate Toxicity with Glucarpidase

High Dose Methotrexate (HD-MTX) toxicity can cause renal dysfunction in patients due to a presence of risk factors such as body mass index >25 kg/m2, comedication (salicylates, NSAID`s, sulfonamides, beta-lactam antibiotics, aminoglycosides), urine pH<7, iv fluid intake <3 l/m2/24 hours, hepatic dysfunction, renal insufficiency prior to HD-MTX, diarrhea and pleural effusions. To prevent renal dysfunction and further MTX toxicity Glucarpidase can be used which degrades MTX to its metabolites. Cases: A 17 year-old and a 14 year-old boy were treated with HD-MTX, developed renal insufficiency and were treated with Glucarpidase. In both patients unexpected renal dysfunction was seen still 3-4 weeks after treatment with Glucarpidase. A theoretic concern regarding the use of Glucarpidase is that the rapid formation of MTX metabolite called DAMPA, which is almost 10-fold less soluble than MTX, may lead to further renal toxicity by precipitation in the renal tubules. If we compare our patient data with data we found in the literature there is almost no difference in renal dysfunction duration between patients who got Glucarpidase (21 days) and those with only supportive therapy (19 and 12 days). After treatment with Glucarpidase the question on how and when to restart HDMTX therapy raised. The safe option for our two patients would be first a rechallange with 50-75% HD-MTX after a full recovery of the renal function. After the first rechallange kindey function and MTX levels should be closely monitored and if no problems are observed the second rechallange should be with 100% HD-MTX. If we closely look at our data and available data from the published articles there is a concern on how effective and safe Glucarpidase is. Glucarpidase should be given only in cases if supportive therapy is not effective enough in lowering MTX plasma levels. Even then, health care professionals should use Glucarpidase cautiously because of its uncertain benefits unpredictable side effect

Animal models of mucositis: critical tools for advancing pathobiological understanding and identifying therapeutic targets

PURPOSE OF REVIEW:Mucositis remains a prevalent, yet poorly managed side effect of anticancer therapies. Mucositis affecting both the oral cavity and gastrointestinal tract predispose to infection and require extensive supportive management, contributing to the growing economic burden associated with cancer care. Animal models remain a critical aspect of mucositis research, providing novel insights into its pathogenesis and revealing therapeutic targets. The current review aims to provide a comprehensive overview of the current animal models used in mucositis research. RECENT FINDINGS:A wide variety of animal models of mucositis exist highlighting the highly heterogenous landscape of supportive oncology and the unique cytotoxic mechanisms of different anticancer agents. Golden Syrian hamsters remain the gold-standard species for investigation of oral mucositis induced by single dose and fractionated radiation as well as chemoradiation. There is no universally accepted gold-standard model for the study of gastrointestinal mucositis, with rats, mice, pigs and dogs all offering unique perspectives on its pathobiology. SUMMARY:Animal models are a critical aspect of mucositis research, providing unprecedent insight into the pathobiology of mucositis. Introduction of tumour-bearing models, cyclic dosing scheduled, concomitant agents and genetically modified animals have been integral in refining our understanding of mucositis.Hannah R. Wardill, Wim J.E. Tissing, Hannelouise Kissow and Andrea M. Stringe

The predictive performance and impact of pediatric early warning systems in hospitalized pediatric oncology patients-A systematic review

Pediatric early warning systems (PEWS) arewidely used to identify clinically deteriorating patients. Hospitalized pediatric oncology patients are particularly prone to clinical deterioration. We assessed the PEWS performance to predict early clinical deterioration and the effect of PEWS implementation on patient outcomes in pediatric oncology patients. PubMED, EMBASE, and CINAHL databases were systematically searched from inception up to March 2020. Quality assessment was performed using the Prediction model study Risk-Of-Bias Assessment Tool (PROBAST) and the Cochrane Risk-of-Bias Tool. Nine studies were included. Due to heterogeneity of study designs, outcome measures, and diversity of PEWS, it was not possible to conduct a meta-analysis. Although the studies reported high sensitivity, specificity, and area under the receiver operating characteristics curve (AUROC) of PEWS detecting inpatient deterioration, overall risk of bias of the studies was high. This review highlights limited evidence on the predictive performance of PEWS for clinical deterioration and the effect of PEWS implementation

Pre-therapy fasting slows epithelial turnover and modulates the microbiota but fails to mitigate methotrexate-induced gastrointestinal mucositis

BACKGROUND: Recent findings by Tang et al. (2020) show dietary restriction (30%, 2 weeks) prevents methotrexate-induced mortality by modulation of the microbiota, specifically the expansion of Lactobacillus. While fundamentally insightful, upscaling this schedule is a major obstacle to clinical uptake. Here, we evaluate a safe and clinically achievable schedule of pre-therapy fasting for 48 h on microbiota composition, body composition and intestinal proliferation, and assess its impact on the severity of methotrexate-induced gastrointestinal mucositis using a validated preclinical rat model. METHODS: Age- and weight-matched male Wistar rats were treated with a sublethal dose of 45 mg/kg methotrexate with or without pre-therapy fasting. The impact of acute fasting on epithelial proliferation, body composition and the microbiota was assessed using plasma citrulline, Ki67 immunohistochemistry, miniSpec and 16S rRNA sequencing. The severity of gastrointestinal mucositis was evaluated using plasma citrulline and body weight. RESULTS: Whilst pre-therapy fasting slowed epithelial proliferation and increased microbial diversity and richness, it also induced significant weight loss and was unable to attenuate the severity of mucositis in both age- and weight-matched groups. In contrast to Tang et al., we saw no expansion of Lactobacillus following acute fasting. CONCLUSIONS: Our findings suggest that the beneficial effects of acute fasting are masked by the detrimental effects on body weight and composition and lacking influence on Lactobacillus. Future studies should consider alternative fasting schedules or aim to induce comparable microbial and mucosal manipulation without compromising body composition using clinically feasible methods of dietary or microbial intervention

Effect of Antibacterial Prophylaxis on Febrile Neutropenic Episodes and Bacterial Bloodstream Infections in Dutch Pediatric Patients with Acute Myeloid Leukemia:A Two-Center Retrospective Study

Bloodstream infections (BSIs), especially those caused by Gram-negative rods (GNR) and viridans group streptococci (VGS), are common and potentially life-threatening complications of pediatric acute myeloid leukemia (AML) treatment. Limited literature is available on prophylactic regimens. We retrospectively evaluated the effect of different antibacterial prophylaxis regimens on the incidence of febrile neutropenic (FN) episodes and bacterial BSIs. Medical records of children (0–18 years) diagnosed with de novo AML and treated at two Dutch centers from May 1998 to March 2021 were studied. Data were analyzed per chemotherapy course and consecutive neutropenic period. A total of 82 patients had 316 evaluable courses: 92 were given with single-agent ciprofloxacin, 138 with penicillin plus ciprofloxacin, and 51 with teicoplanin plus ciprofloxacin. The remaining 35 courses with various other prophylaxis regimens were not statistically compared. During courses with teicoplanin plus ciprofloxacin, significantly fewer FN episodes (43% vs. 90% and 75%; p < 0.0001) and bacterial BSIs (4% vs. 63% and 33%; p < 0.0001) occurred than with single-agent ciprofloxacin and penicillin plus ciprofloxacin, respectively. GNR and VGS BSIs did not occur with teicoplanin plus ciprofloxacin and no bacterial BSI-related pediatric intensive care unit (PICU) admissions were required, whereas, with single-agent ciprofloxacin and penicillin plus ciprofloxacin, GNR BSIs occurred in 8% and 1% (p = 0.004), VGS BSIs in 24% and 14% (p = 0.0005), and BSI-related PICU admissions were required in 8% and 2% of the courses (p = 0.029), respectively. Teicoplanin plus ciprofloxacin as antibacterial prophylaxis is associated with a lower incidence of FN episodes and bacterial BSIs. This may be a good prophylactic regimen for pediatric AML patients during treatment

F-18-FDG PET/CT in the Diagnostic and Treatment Evaluation of Pediatric Posttransplant Lymphoproliferative Disorders

We aimed to evaluate the diagnostic performance of 18F-FDG PET/CT for the detection of posttransplantation lymphoproliferative disorder (PTLD) in a pediatric population and explore its feasibility during response assessment. Methods: This retrospective study included 28 pediatric transplant recipients who underwent a total of 32 18F-FDG PET/CT scans due to clinical suspicion of PTLD within an 8-y period. Pathology reports and 2 y of follow-up were used as the reference standard. Twenty-one response assessment 18F-FDG PET/CT scans were reevaluated according to the Lugano criteria. Results: The diagnosis of PTLD was established in 14 patients (49%). Sensitivity, specificity, positive predictive value, and negative predictive value of 18F-FDG PET/CT for the detection of PTLD in children with a clinical suspicion of this disease were 50% (7/14), 100% (18/18), 100% (7/7), and 72% (18/25), respectively. False-negative results occurred in patients with PTLD in the Waldeyer's ring, cervical lymph nodes, or small bowel with either nondestructive or polymorphic PTLD. Two of 5 interim 18F-FDG PET/CT scans and 3 of 9 end-of-treatment 18F-FDG PET/CT scans were false-positive. Conclusion:18F-FDG PET/CT had good specificity and positive predictive value but low to moderate sensitivity and negative predictive value for the detection of PTLD in a 28-pediatric-patient cohort with a clinical suspicion of this disease. False-negative results were confirmed in the Waldeyer's ring, cervical lymph nodes, and small bowel with either nondestructive or polymorphic PTLD subtypes. 18F-FDG PET/CT appears to have a limited role in the response assessment setting of pediatric PTLD, given the observed high proportions of false-positives both at interim and at end-of-treatment evaluations

The views of parents of children with cancer and pediatric physical therapists on a network for continuity and optimal quality of care for children with cancer: KinderOncoNet

Purpose: Children with cancer require specific therapeutic guidance. Parents prefer physical therapy close to home, while pediatric physical therapists (PPTs) working in the community may lack specific knowledge. The aim of this study is to determine the needs of parents of children with cancer and PPTs to inform the design and development of a care network, named “KinderOncoNet.” Methods: We explored the perspectives and needs of parents of children with cancer and PPTs in the community, and we investigated the added value that KinderOncoNet could offer. We used an iterative process; data collection consisted of (1) gathering information from parents of children with cancer and PPTs through a survey and (2) co-creation sessions with stakeholders. Results: In total, 98 parents and 177 PPTs participated in the survey. Parents (97%) and PPTs (93%) indicated that the care network would bring added value. All but one parent stressed the importance of a local PPT being aware of both the condition and the side and late effects of oncological treatment. Moreover, 40% of PPTs thought they do not have sufficient knowledge to provide high-quality therapy and that they would embrace opportunities for education. Through the co-creation sessions, a prototype of the care network was conceptualized. Conclusion: KinderOncoNet can contribute to the continuity and quality of physiotherapy care for children with cancer during and after the oncological treatment. Such a network would allow for sharing knowledge, developing skills, and improving accessibility and communication in the Netherlands