Background.Normally, humans are protected against infections by their anaerobic intestinal microorganisms providing colonization resistance. In immunocompromised patients, the endogenous intestinal ...gram-positive and gram-negative pathogens often cause infectious complications. Therefore, we analyzed the effect of chemotherapy treatment and antimicrobial prophylaxis on intestinal bacterial populations (microbiota) among pediatric patients with acute myeloid leukemia who are prone to intestinal mucositis and infections. Methods.During 36 chemotherapy cycles, fecal samples were collected from pediatric patients with acute myeloid leukemia. Fecal bacterial populations were analyzed by polymerase chain reaction denaturing gradient gel electrophoresis fingerprinting. Fluorescent in situ hybridization analysis with specific bacterial oligonucleotide probes was used to quantify the fecal bacteria. Results.During chemotherapy treatment, the total number of bacteria in fecal samples was 109per gram of dry weight feces, which was 100-fold lower than than in healthy control samples. Fluorescent in situ hybridization analysis showed that this decrease was the result of an up to 10,000-fold decrease in anaerobic bacteria, partly compensated for by a 100-fold increase in potentially pathogenic enterococci. Additional experiments showed that both prophylactic and therapeutic use of antibiotics could not sufficiently explain the tremendous changes in intestinal microbial composition. In vitro tests showed a direct bacteriostatic effect of chemotherapeutics. Conclusions.Patients with acute myeloid leukemia treated with chemotherapy and prophylactic antibiotics are unable to maintain colonization resistance because of a decrease in anaerobic bacteria and an increase in potentially pathogenic aerobic enterococci. We hypothesize that this disturbance in the balance between anaerobic and aerobic bacteria will further increase the risk of gram-positive aerobic infections among immunocompromised patients with cancer.
Purpose
In childhood cancer patients, malnutrition has been proposed to increase infection rates and reduce survival. We investigated whether malnutrition at diagnosis and during treatment and weight ...loss during treatment are prognostic factors for infection rates and survival, within a heterogeneous childhood cancer population.
Methods
From two previous studies, all children ≤18 years of age diagnosed with cancer between October 2004 and October 2011 were included in this study. Data regarding BMI, infections, and survival were retrieved. Patients with a BMI z-score lower than −2.0 were classified as malnourished. Weight loss more than 5 % was considered relevant.
Results
Two hundred sixty-nine childhood cancer patients were included in this study. At diagnosis, 5.2 % of all patients were malnourished. These patients showed worse survival than those who were well nourished (hazard ratio (HR) = 3.63, 95 % confidence interval (CI) = 1.52–8.70,
p
= 0.004). Malnourishment at 3 months after diagnosis (3.3 % of all patients) also showed worse survival (HR = 6.34, 95 % CI = 2.42–16.65,
p
< 0.001). Weight loss of more than 5 % in the first 3 months after diagnosis was related to increased occurrence of febrile neutropenic episodes with bacteremia in the first year after diagnosis (odds ratio (OR) = 3.05, 95 % CI = 1.27–7.30,
p =
0.012).
Conclusion
We found that malnourishment in the initial phase of therapy is associated with worse survival in childhood cancer patients. In addition, we found for the first time that weight loss during treatment is associated with increased presence of febrile neutropenic episodes with bacteremia. This underlines the importance of optimal feeding designs in childhood cancer patients.
High-dose chemotherapy causes intestinal inflammation and subsequent breakdown of the mucosal barrier, permitting translocation of enteric pathogens, clinically manifesting as fever. Antibiotics are ...mainstay for controlling these complications, however, they are increasingly recognized for their detrimental effects, including antimicrobial resistance and dysbiosis. Here, we show that mucosal barrier injury induced by the mucotoxic chemotherapeutic agent, high-dose melphalan (HDM), is characterized by hyper-active IL-1b/CXCL1/neutrophil signaling. Inhibition of this pathway with IL-1RA, anakinra, minimized the duration and intensity of mucosal barrier injury and accompanying clinical symptoms, including diarrhea, weight loss and fever in rats. 16S analysis of fecal microbiome demonstrated a more stable composition in rats receiving anakinra, with reduced pathogen expansion. In parallel, we report through Phase IIA investigation that anakinra is safe in stem cell transplant patients with multiple myeloma after HDM. Ramping-up anakinra (100-300 mg administered intravenously for 15 days) did not cause any adverse events or dose limiting toxicities, nor did it change time to neutrophil recovery. Our results reinforce that strengthening the mucosal barrier may be an effective supportive care strategy to mitigate local and systemic clinical consequences of HDM. We are now conducting a Phase IIB multicenter, placebo-controlled, double-blinded trial to assess clinical efficacy of anakinra (AFFECT-2).Trial registration: ClinicalTrials.gov identifier: NCT03233776.
Gastrointestinal mucositis is a complication of anticancer treatment, with few validated in vitro systems suitable to study the complex mechanisms of mucosal injury. Therefore, we aimed to develop ...and characterize a chemotherapeutic-induced model of mucositis using 3D intestinal organoids. Organoids derived from mouse ileum were grown for 7 days and incubated with different concentrations of the chemotherapeutic agent methotrexate (MTX). Metabolic activity, citrulline levels and cytokine/chemokine production were measured to determine the optimal dosage and incubation time. The protective effects of folinic acid on the toxicity of MTX were investigated by pre-treating organoids with (0.0005-50 µg/mL) folinic acid. The impact of microbial-derived short-chain fatty acids was evaluated by supplementation with butyrate in the organoid model. MTX caused a dose-dependent reduction in cell metabolic activity and citrulline production that was salvaged by folinic acid treatment. Overall, MTX causes significant organoid damage, which can be reversed upon removal of MTX. The protective effect of folinic acid suggest that the organoids respond in a clinical relevant manner. By using the model for intervention, it was found that prophylactic treatment with butyrate might be a valuable strategy for prophylactic mucositis prevention.
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.
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.
Purpose
This study aimed to increase our understanding of the psychosocial well-being of young adult childhood cancer survivors (YACCS) as well as the positive and negative impacts of cancer.
Methods
...YACCS (aged 18–30, diagnosed ≤ 18, time since diagnosis ≥ 5 years) cross-sectionally filled out the “Pediatric Quality of Life Inventory Young Adults” (PedsQL-YA), “Hospital Anxiety and Depression Scale” (HADS), and “Checklist Individual Strengths” (CIS-20R) to measure fatigue and survivor-specific “Impact of Cancer - Childhood Survivors” (IOC-CS), which measures the long-term impact of childhood cancer in several domains. Descriptive statistics (IOC-CS), logistic regression (HADS, CIS-20R), and ANOVA (PedsQL-YA, HADS, CIS-20R) were performed. Associations between positive and negative impacts of childhood cancer and psychosocial outcomes were examined with linear regression analyses.
Results
YACCS (
N
= 151, 61.6% female, mean age 24.1 ± 3.6, mean time since diagnosis 13.6 ± 3.8) reported lower HRQOL (− .4 ≤
d
≤ − .5,
p
≤ .001) and more anxiety (
d
= .4,
p
≤ .001), depression (
d
= .4,
p
≤ .01), and fatigue (.3 ≤
d
≤ .5,
p
≤ .001) than young adults from the general Dutch population. They were at an increased risk of experiencing (sub)clinical anxiety (OR = 1.8,
p
= .017). YACCS reported more impact on scales representing a positive rather than negative impact of CC. Various domains of impact of childhood cancer were related to psychosocial outcomes, especially “Life Challenges” (HRQOL
β
= − .18, anxiety
β
= .36, depression
β
= .29) and “Body & Health” (HRQOL
β
= .27, anxiety
β
= − .25, depression
β
= − .26, fatigue
β
= − .47).
Conclusion
YACCS are vulnerable to psychosocial difficulties, but they also experience positive long-term impacts of childhood cancer. Positive and negative impacts of childhood cancer were associated with psychosocial outcomes in YACCS. Screening of psychosocial outcomes and offering targeted interventions are necessary to optimize psychosocial long-term follow-up care for YACCS.
Invasive Aspergillus infections during the early phase of childhood acute lymphoblastic leukemia (ALL) treatment come with morbidity and mortality. The interaction with vincristine hampers first-line ...azole prophylaxis. We describe the efficacy of an alternative twice-a-week micafungin regimen for Aspergillus prophylaxis.
Newly diagnosed paediatric patients with ALL treated according to the ALL-11 protocol received micafungin twice-a-week (9 mg/kg/dose max. 300 mg) during the induction course (first 35 days of treatment) as part of routine care. A historical control cohort without Aspergillus prophylaxis was used. During the first consolidation course (day 36-79), standard itraconazole prophylaxis was used in both groups. The percentage of proven/probable Aspergillus infections during the induction/first consolidation course was compared between the cohorts. The cumulative incidence of proven/probable Aspergillus infections was estimated using a competing risk model. For safety evaluation, liver laboratory chemistry values were analysed.
A total of 169 and 643 paediatric patients with ALL were treated in the micafungin cohort (median age: 4 years range 1-17) and historical cohort (median age: 5 years range 1-17). The percentage of proven/probable Aspergillus infections was 1·2% (2/169) in the micafungin cohort versus 5·8% (37/643) in the historical cohort (p=0.013; Fisher's exact test). The differences in estimated cumulative incidence were assessed (p=0·014; Gray's test). Although significantly higher ALT/AST values were reported in the micafungin cohort, no clinically relevant side effects were observed.
Twice-a-week micafungin prophylaxis during the induction course significantly reduced the occurrence of proven/probable Aspergillus infections in the early phase of childhood ALL treatment.
Purpose
To assess the impact of maintenance therapy and the additional impact of dexamethasone treatment on cancer-related fatigue and sleep-wake rhythms in pediatric acute lymphoblastic leukemia ...(ALL) patients and to determine the association between these outcomes.
Methods
A national cohort of pediatric ALL patients (≥ 2 years) was included (± 1 year post-diagnosis). Patients receiving dexamethasone were assessed twice (assessment with and without dexamethasone). Actigraphy assessments were used to calculate sleep-wake outcomes with nonparametric methods. Cancer-related fatigue was assessed with the PedsQL Multidimensional Fatigue Scale. Sleep-wake rhythms and cancer-related fatigue were compared between patients participating in the assessment without dexamethasone and healthy children (linear regression) and between assessments with and without dexamethasone (mixed models). Using linear regression, associations between sleep-wake outcomes and cancer-related fatigue were determined during assessments with and without dexamethasone.
Results
Responses were collected for 125 patients (113 assessments with and 81 without dexamethasone). The sleep-wake rhythm was less stable (
p
= 0.03) and less robust (
p
= 0.01), with lower physical activity levels (
p
< 0.001) and higher cancer-related fatigue levels (
p
< 0.001) in ALL patients compared to healthy children. Physical activity was lower (
p
= 0.001) and cancer-related fatigue more severe (
p
≤ 0.001) during assessments with dexamethasone compared to without dexamethasone. Sleep-wake outcomes were significantly associated with cancer-related fatigue during periods without dexamethasone, but not during periods with dexamethasone.
Conclusion
Sleep-wake rhythms are disturbed, physical activity levels lower, and cancer-related fatigue levels higher during maintenance therapy. Interventions aimed to enhance sleep-wake rhythms during maintenance therapy could improve cancer-related fatigue. Families should be supported in coping with the additional burden of dexamethasone treatment to improve well-being of ALL patients.
Background
Studies about support needs of young adult childhood cancer survivors (YACCS) previously focused mainly on information needs. This study assessed support needs and associated factors ...(sociodemographic, medical, and psychosocial functioning) in Dutch YACCS.
Methods
YACCS (aged 18–30, diagnosed ≤ 18 years, time since diagnosis ≥ 5 years) cross-sectionally filled out a questionnaire regarding their need for various types of support (concrete information, personal counseling, and peer contact) in eight domains (physical consequences of childhood cancer, social-emotional consequences, relationships and sexuality, fertility, lifestyle, school and work, future perspective, insurance and mortgage), and questionnaires assessing health-related quality of life (PedsQL-YA), anxiety and depression (HADS), and fatigue (CIS-20R). Descriptive statistics were used to describe support needs. Linear regression was used to identify characteristics associated with support needs.
Results
One hundred fifty-one YACCS participated (response = 40%). Most YACCS reported a need for support in one or more domains (88.0%,
N
= 133). More than half of the participants reported a need for concrete information in the domains lifestyle, fertility, and physical consequences of childhood cancer and 25–50% in the domains insurance and mortgages, future perspective, and social-emotional consequences of childhood cancer. In the domains lifestyle and physical as well as emotional consequences of childhood cancer, 25–50% reported a need for counseling. Overall need for support was positively associated with middle (β = 0.26,
p
= 0.024) and high (β = 0.35,
p
= 0.014) compared to low educational attainment and (sub)clinical anxiety (β = 0.22,
p
= 0.017), and negatively associated with social functioning (β = − 0.37,
p
= 0.002) in multivariate analyses.
Conclusion
YACCS report the strongest need for support, for concrete information, in the domains lifestyle, fertility, and physical consequences of childhood cancer. Associated factors were mostly socioeconomic and psychosocial in nature. Psychosocial care should be an integral part of survivorship care for YACCS, with screening for psychosocial problems, information provision including associated emotional consequences and support if necessary (psycho-education) and tailored interventions, and adequate referrals to more specialized care if necessary.
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