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Purpose Earlier, we showed in acute myeloid leukemia (AML) patients that the microbiota changes dramatically during anticancer treatment, coinciding with gastrointestinal mucositis: The commensal anaerobic populations reduce in favor of potential pathogens. Therefore, interventions targeting the microbiota during mucositis might be interesting but can better be tested in animals than in vulnerable mucositis patients. Here, we aimed to study the potential microbial changes during methotrexate (MTX)-induced gastrointestinal mucositis in a well-established rat model and to study whether this model can be used for future microbial intervention studies. Methods After injection with MTX or saline (day 0), rats were sacrificed between days 2 and 11. Plasma citrulline level, jejunal histology, and the number and diversity of intestinal bacteria in feces (using fluorescence in situ hybridization (FISH)) were determined. Results Mucositis was most severe on day 4 when food intake, plasma citrulline, and villus length were the lowest, compared with controls ( P <  0.0125). At the same time, MTX-treated rats showed an overall decrease (705-fold) in most bacteria (using a universal probe), compared with controls ( P <  0.125). Reduced bacterial presence was related with the presence of diarrhea and a reduced villus length (rho = 0.38, P <  0.05). At day 4, there was an absolute and relative decrease of anaerobes (13-fold and −58 %, respectively) and streptococci (296-fold and −1 %, respectively) but a relative increase of Bacteroides (+49 %), compared with controls ( P <  0.125). Conclusions In the mucositis rat model, we found substantial decreases in the number and diversity of microbiota, resembling earlier findings in humans. The model therefore seems well suited to study the effects of different microbial interventions on mucositis, prior to performing human studies.

Mucositis, also referred to as mucosal barrier injury, is one of the most debilitating side effects of radiotherapy and chemotherapy treatment. Clinically, mucositis is associated with pain, bacteremia, and malnutrition. Furthermore, mucositis is a frequent reason to postpone chemotherapy treatment, ultimately leading towards a higher mortality in cancer patients. According to the model introduced by Sonis, both inflammation and apoptosis of the mucosal barrier result in its discontinuity, thereby promoting bacterial translocation. According to this five-phase model, the intestinal microbiota plays no role in the pathophysiology of mucositis. However, research has implicated a prominent role for the commensal intestinal microbiota in the development of several inflammatory diseases like inflammatory bowel disease, pouchitis, and radiotherapy-induced diarrhea. Furthermore, chemotherapeutics have a detrimental effect on the intestinal microbial composition (strongly decreasing the numbers of anaerobic bacteria), coinciding in time with the development of chemotherapy-induced mucositis. We hypothesize that the commensal intestinal microbiota might play a pivotal role in chemotherapy-induced mucositis. In this review, we propose and discuss five pathways in the development of mucositis that are potentially influenced by the commensal intestinal microbiota: 1) the inflammatory process and oxidative stress, 2) intestinal permeability, 3) the composition of the mucus layer, 4) the resistance to harmful stimuli and epithelial repair mechanisms, and 5) the activation and release of immune effector molecules. Via these pathways, the commensal intestinal microbiota might influence all phases in the Sonis model of the pathogenesis of mucositis. Further research is needed to show the clinical relevance of restoring dysbiosis, thereby possibly decreasing the degree of intestinal mucositis.

Although dexamethasone is highly effective in the treatment of pediatric acute lymphoblastic leukemia (ALL), it can cause serious metabolic side effects. Because studies regarding the effects of dexamethasone are limited by their small scale, we prospectively studied the direct effects of treating pediatric ALL with dexamethasone administration with respect to activation of components of metabolic syndrome (MetS); in addition, we investigated whether these side effects were correlated with the level of dexamethasone. Fifty pediatric patients (3-16 years of age) with ALL were studied during a 5-day dexamethasone course during the maintenance phase of the Dutch Childhood Oncology Group ALL-10 and ALL-11 protocols. Fasting insulin, glucose, total cholesterol, HDL, LDL, and triglycerides levels were measured at baseline (before the start of dexamethasone; T1) and on the fifth day of treatment (T2). Dexamethasone trough levels were measured at T2. We found that dexamethasone treatment significantly increased the following fasting serum levels (P<0.05): HDL, LDL, total cholesterol, triglycerides, glucose, and insulin. In addition, dexamethasone increased insulin resistance (HOMA-IR>3.4) from 8% to 85% (P<0.01). Dexamethasone treatment also significantly increased the diastolic and systolic blood pressure. Lastly, dexamethasone trough levels (N = 24) were directly correlated with high glucose levels at T2, but not with other parameters. These results indicate that dexamethasone treatment acutely induces three components of the MetS. Together with the weight gain typically associated with dexamethasone treatment, these factors may contribute to the higher prevalence of MetS and cardiovascular risk among survivors of childhood leukemia who received dexamethasone treatment.

Background/Objectives: Despite significant advancements in cancer treatment outcomes, side effects, such as gastrointestinal mucositis (GIM), continue to impair patients’ quality of life. The recent literature suggests L-citrulline as a novel treatment for GIM. However, no in vitro model to study the potential for L-citrulline as a treatment for GIM is currently available, and the effect of L-citrulline on the gut microbiota remains unclear. This study aims to propose a suitable in vitro model to study the effect of L-citrulline on the gut microbiota and to determine whether it can mitigate GIM. Methods: The CaCo-2 and T84 cell lines were cultured using cell impedance assays and treated with different doses of methotrexate and melphalan to select an appropriate model for L-citrulline research. The selected model was further used to investigate the impact of L-citrulline on gut microbiota cultured using microbial culture assays containing YCFAG. Results: Neither CaCo-2 nor T84 cells treated with methotrexate were suitable models for our study due to varying responses to treatment. T84 cells treated with 100 μg/mL melphalan demonstrated a consistent response, making them a suitable model for in vitro research on treatments for GIM. The use of L-citrulline demonstrated potential protective effects, as melphalan-treated enterocytes showed less cellular damage in its presence and slightly reduced enteroaggregative E. coli growth. Conclusions: L-Citrulline supplementation reduced epithelial cell injury due to melphalan, suggesting therapeutic potential. Further testing is required to determine its efficacy in vivo and clarify the mechanisms underlying this potential benefit.

Purpose Malnutrition in childhood cancer patients has been associated with lower health-related quality of life (HRQOL). However, this association has never actually been tested. Therefore, we aimed to determine the association between nutritional status and HRQOL in children with cancer. Methods In 104 children, aged 2–18 years and diagnosed with hematological, solid, or brain malignancies, nutritional status and HRQOL were assessed at diagnosis and at 3, 6, and 12 months using the child- and parent-report versions of the PedsQL 4.0 Generic scale and the PedsQL 3.0 Cancer Module. Scores on both scales range from 0 to 100. Results Undernourished children (body mass index (BMI) or fat-free mass < −2 standard deviation score (SDS)) reported significantly lower PedsQL scores compared with well-nourished children on the domains physical functioning (−13.3), social functioning (−7.0), cancer summary scale (−5.9), and nausea (−14.7). Overnourished children (BMI or fat mass >2 SDS) reported lower scores on emotional (−8.0) and cognitive functioning (−9.2) and on the cancer summary scale (−6.6), whereas parent-report scores were lower on social functioning (−7.5). Weight loss (>0.5 SDS) was associated with lower scores on physical functioning (−13.9 child-report and −10.7 parent-report), emotional (−7.4) and social functioning (−6.0) (child-report), pain (−11.6), and nausea (−7.8) (parent-report). Parents reported worse social functioning and more pain in children with weight gain (>0.5 SDS) compared with children with stable weight status. Conclusions Undernutrition and weight loss were associated with worse physical and social functioning, whereas overnutrition and weight gain affected the emotional and social domains of HRQL. Interventions that improve nutritional status may contribute to enhanced health outcomes in children with cancer.

Purpose To develop an evidence-based decision aid for parents of children with cancer and to help guide them in the use of complementary and alternative medicine (CAM) for cancer care. Methods This study had a mixed research design. The needs of parents were investigated by survey and focus group. A systematic review and meta-analysis were performed on the effectiveness of CAM using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Clinical experts were interviewed and a decision aid on CAM treatment for pain was developed. Results Parents emphasized the importance of reliable information on CAM, focusing primarily on communication and a broad spectrum of complaints related to cancer treatment. The decision aid on CAM for pain included five modalities based on 11 randomized control trials (RCTs): hypnotherapy, mind-body techniques, massage, healing touch, and music therapy. Meta-analysis could be performed on hypnotherapy, which significantly reduced cancer-related procedural pain compared with standard care (MD, − 1.37; 95% CI, − 1.60, − 1.15; P  < 0.00001) and attention control (MD, − 1.13; 95% CI, − 1.34, − 0.94; P  < 0.00001), and massage, demonstrating no effect on pain compared with standard care (MD, − 0.77; 95% CI, − 1.82, 0.28; P  = 0.15). Research evidence and supplementary information from clinical practice and patient were incorporated in a website-based decision aid. Conclusions An evidence-based decision aid was developed to support parents of children with cancer in making decisions about CAM for pain management. Next steps will be to expand the website to include additional childhood cancer-related complaints and to evaluate its use in practice.

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.

PurposeChemotherapy can affect smell and taste function. This has never been investigated in childhood cancer patients during chemotherapy. The objective of this study was to determine whether psychophysical smell and taste tests are suitable for children with cancer. Taste and smell function, fungiform papillae density, and eating behavior were measured before (T1) and after (T2) a cycle of chemotherapy and compared with healthy controls.MethodsThirty-one childhood cancer patients treated for a hematological, solid, or brain malignancy (median age 12 years, 16 girls), and 24 healthy controls (median age: 11 years, 10 girls) participated. Smell function was measured using Sniffin’ Sticks, including a threshold, discrimination, and identification test. Taste Strips were used to determine recognition thresholds for sweet, sour, salty, and bitter taste. Papillae density was investigated by counting the fungiform papillae of the anterior tongue. Eating behavior was assessed using the Behavioral Pediatrics Feeding Assessment Scale (BPFAS).ResultsSmell and taste function could be investigated in more than 90% of the patients, while fungiform papillae density could be determined in 61% of the patients. A significant difference in smell threshold was found between patients and controls (p = 0.001), showing lower thresholds in patients. In patients, sweet taste (p < 0.001), bitter taste (p = 0.028), and total taste function (p = 0.004) were significantly different after a cycle of chemotherapy, with higher scores at T2.ConclusionThe assessment of smell, taste, and fungiform papillae density is feasible in children with cancer. Results of the current study suggest that smell and taste sensitivity increased in children with cancer.

Background Pediatric cancer diagnosis and treatment reduce Health-Related Quality of Life (HRQoL). The Pediatric Quality of Life (PedsQL) Cancer Module is the most commonly used cancer specific HRQoL instrument, but most studies included relatively small cohorts and no reference scores are available. The development of a PedsQL Cancer Module benchmark, based on a large population of pediatric cancer patients, may benefit future research by providing insight into issues children encounter during treatment or clinical trials. A benchmark would also allow for earlier identification of patients who may benefit from targeted interventions in HRQoL monitoring programs. The primary aim of this study was therefore to provide benchmark scores from a large national cohort for use in pediatric oncology care and research. Secondary aims were to compare scores between subgroups (age, sex, and diagnosis group) and to describe the prevalence of impaired HRQoL. Methods Data was collected from a national HRQoL monitoring program and extracted from medical records. HRQoL was measured with the PedsQL Cancer Module during treatment for childhood cancer, approximately 3 months after diagnosis. Comparisons were made for sex, age and diagnosis groups: hemato-oncology (HO), central nervous system-tumors (CNS), and solid tumors (ST) using the Mann-Whitney U test for the different subscales. Effect sizes were calculated. Impairment was defined on item level using descriptive statistics. Results Proxy-reports of 492 children (age 2–7 years) and self-reports of 500 children (age 8–18 years) were available. HRQoL differences between age groups, sex and diagnosis groups were small, with the exception of nausea. On the nausea subscale there was a medium effect size difference with children with ST reporting more problems than children with CNS. Impaired HRQoL was most often reported on items reflecting nausea and procedural anxiety. Conclusions Early in the cancer trajectory, there are only minor differences between subgroups based on age, sex, and diagnosis group. These results from a large national cohort can be used as benchmark data in future clinical trials, studies and clinical assessments, and offer and adapt support targeted for improving HRQoL related to treatment for childhood cancer.

PurposeThis study assessed adherence to, feasibility of, and barriers and facilitators of implementation of an app developed to monitor and follow-up with pain in children with cancer at home.MethodsChildren (8–18 years) receiving cancer treatment (all diagnoses) or their parents (of children aged 0–7 years) used the KLIK Pain Monitor app for 3 weeks. Pain was assessed twice daily using an 11-point numeric rating scale (NRS-11) (ranging from 0 to 10). Healthcare professionals (HCP’s) from the hospital’s Pediatric Pain Service were instructed to follow-up with clinically significant pain scores (≥ 4) within 120 min (scores 4–6) or 30 min (scores 7–10). Adherence, feasibility, and implementation outcomes were assessed using questionnaires, app log data, and interviews.ResultsTwenty-seven children (M age = 7.3 years, 51.8% male) and six HCP’s participated. Sixty-three percent (N = 17) of families used the app on a daily basis during three weeks, and 18.5% (N = 5) reported pain scores twice daily during that time (family adherence). Twelve out of 27 children (44.4%) reported a clinically significant pain score at least once. In 70% (14/20) of clinically significant pain scores, HCP’s followed-up with families within the set timeframe (HCP adherence). Outcomes reveal feasibility for the majority of app functions (i.e., positive evaluation by ≥ 70% families/HCP’s), and non-feasible aspects could be resolved. Identified barriers and facilitators were used to improve future implementation efforts.ConclusionUse of the KLIK Pain Monitor app seems feasible. Future research will determine its effectiveness in reducing pain in children with cancer at home.