Klaus Müller

Objectives: Pediatric acute myeloid leukemia (AML) chemotherapy regimens are frequently burdened by fever episodes, systemic inflammation and bloodstream infections (BSI). Mucosal barrier injury may contribute to these complications, but its role in childhood AML remains uninvestigated. This study assessed mucosal barrier injury using plasma citrulline and examined associations with inflammation, fever, and BSI. Methods: Twenty children (1–16 years) with AML were prospectively studied during two induction courses (NOPHO‐DBH AML 2012 protocol). Plasma citrulline was measured weekly from days 1–29 of each course. Results: All patients exhibited marked reductions in citrulline during both inductions, reaching nadir on day 15 and recovering by day 29. C‐reactive protein (CRP) levels > 50 mg/L occurred in 19/20 patients, and 10/20 developed BSI. Fever occurred in all patients during induction I and in 16/19 during induction II. Severe mucosal damage (citrulline AUC) correlated with higher CRP and more febrile days, particularly in induction II ( r _s = −0.72, p = 0.0011; r _s = −0.47, p = 0.06). Patients with BSI showed lower citrulline on days 22 and 29 following induction II (11.1 vs. 16.2 μM, p = 0.024) and (10.1 vs. 17.3 μM, p = 0.012). Conclusions: Pediatric AML treatment causes significant mucosal barrier injury, which is associated with inflammatory and infectious complications and may represent a target for supportive interventions.

Background: Survivors of hematopoietic stem cell transplantation (HSCT) during childhood face significant late effects. This study aimed to map the dietary micronutrient intake of long-term survivors of pediatric HSCT and explore its associations with transplant outcomes, body composition, and physical capacity. Methods: We included 85 long-term survivors of HSCT (median age 30 years) The median time since HSCT was 19.9 years, reflecting a long-term survivor population. Dietary intake was assessed using a 3-day food record. Body composition was measured by DXA, and physical capacity was evaluated through cardiorespiratory fitness and physical performance tests. Results: We observed an inadequate intake of several vitamins and minerals including vitamins A, C, D, E, selenium, and potassium, with a median intake below recommendations. While dietary intake of vitamin D was reduced in patients with chronic graft versus host disease (cGvHD), the occurrence of cGvHD was not associated with overall micronutrient intake. Twelve percent of the participants had reduced skeletal muscle mass and 16% displayed a low bone mass density during DXA scans. These conditions were not related to the micronutrient intake. Likewise, reduced cardiorespiratory fitness and physical performance were unrelated to micronutrient intake. Total energy intake was found to significantly influence micronutrient intake (p = 0.001), explaining 66% of the variation. Conclusions: Long-term survivors of pediatric HSCT demonstrated inadequate intake of multiple micronutrients. These findings suggest that inclusion of comprehensive micronutrient assessment and nutritional guidance should be considered for inclusion in follow-up care protocols.

Delayed neutrophil recovery during acute lymphoblastic leukemia (ALL) treatment increases the risk of infection and causes delay in chemotherapy. Emerging evidence implicates gut microbiota in neutrophil reconstitution after chemotherapy. We explored the interplay between the gut microbiota and neutrophil dynamics, including neutrophil chemoattractants, in 51 children with newly diagnosed ALL. Daily absolute neutrophil count (ANC), weekly plasma chemokines (CXCL1 and CXCL8), granulocyte colony-stimulating factor (G-CSF), and fecal samples were monitored until day 29 during ALL induction treatment. Fecal sequencing using 16S ribosomal RNA revealed an overall significant reduction in bacterial diversity and Enterococcus overgrowth throughout the induction treatment. Prolonged neutropenia (ANC <0.5 × 109 cells per L at day 36) and elevated chemokine levels were associated with a decreased abundance of genera from the Ruminococcaceae and Lachnospiraceae families, decreased Veillonella genus, and Enterococcus overgrowth from diagnosis and throughout induction treatment. G-CSF was upregulated in response to neutropenia but was unrelated to microbiota changes. Overall, this study revealed that a diminished abundance of specific intestinal commensals and Enterococcus overgrowth is associated with delayed neutrophil reconstitution and increased chemokine signaling, indicating that disruption of the microbiota may contribute to prolonged neutropenia. These findings lay the groundwork for future investigations into the mechanisms underlying these associations and their clinical implications for developing gut-sparring strategies to minimize the impact of gut dysbiosis on immune recovery.

Purpose: To improve the understanding of what influences the motivation of children and adolescents diagnosed with cancer to engage in exercise during the first six months of treatment. Materials and Methods: Qualitative design using semistructured interviews with children (6–17 years) diagnosed with cancer ( n = 12) and their parents ( n = 12). A deductive thematic analysis based on self‐determination theory was applied. Results: Three predefined themes described different aspects of motivation for exercise during treatment. Amotivation: Treatment‐related illness and fatigue causing amotivation was described as a dominant barrier. Exercise driven by negative reinforcements facilitated short‐term exercise engagement but was perceived as amotivation. Controlled Regulation: Exercise regulated by exercise professionals could facilitate and introject positive experiences with exercise (i.e., ameliorated side effects) and create confidence in physical capabilities. Autonomous Self-Regulation: An autonomy‐supportive approach using cocreation and age‐appropriate and treatment‐regulated exercise, facilitated trust, and confidentiality with exercise professionals. Conclusion: Motivation for exercise is a dynamic interplay that can be facilitated or negatively affected by treatment, parents, peers, and external regulation. Exercise interventions should use an individual and autonomy‐supportive approach, encompassing treatment‐related daily variations of physical capacity. Externally regulated motivation can facilitate exercise on a short‐term basis when children are inactive or hesitant to engage in exercise.

Introduction Cancer treatment with high-dose chemotherapy damages the mucosal barrier of the gastrointestinal (GI) tract and is associated with severe toxicity involving mucositis, severe inflammation and organ dysfunction. Currently, there is no effective prophylaxis against this. Glucagon-like peptide 1 (GLP-1), a well-known regulator of blood glucose, has been suggested in mouse studies to possess trophic effects on gut epithelial cells as well as anti-inflammatory properties. In line with this, endogenous GLP-1 levels have been shown to be inversely correlated with toxicities after haematopoietic stem cell transplantation (HSCT) and treatment with a GLP-1 receptor agonist (GLP-1RA) was shown to limit chemotherapy-induced mucositis in rodents. This present study investigates the effects of the GLP-1RA semaglutide on GI mucositis severity score in patients with lymphoma undergoing high-dose chemotherapy followed by autologous (auto) HSCT. Methods and analysis This is a randomised, double-blind, placebo-controlled, two-centre investigator-initiated clinical study. Forty adult patients with malignant lymphoma referred for auto-HSCT will be randomised in a 1:1 manner to receive either semaglutide or placebo once-weekly for 8 weeks. This includes a run-in period of 3–4 weeks with semaglutide 0.25 mg prior to high-dose chemotherapy treatment followed by a period of 4–5 weeks with semaglutide 0.5 mg including the 1 week of high-dose chemotherapy treatment. Clinical assessment of endpoint measurements and safety will be performed weekly during treatment and in a follow-up period of 10 weeks. The primary endpoint is GI mucositis severity (mean severity grade (0–II) during week 1–4 after auto-HSCT). Secondary endpoints include C-reactive protein increment, quality of life and safety. Fever, bacteraemia, antibiotic use, weight loss, morphine consumption, duration of hospitalisation, use of parenteral nutrition, change in muscle mass and clinical and laboratory evidence of organ toxicities will also be assessed. Ethics and dissemination The study complies with Danish and European Union legislation and is approved by the Danish Medicines Agency, the Danish National Medical Research Ethics Committee (EU CT #2022-502139-20-00) and the Danish Data Protection Agency. The study is monitored by the Capital Region of Denmark’s good clinical practice unit. All results, positive, negative and inconclusive, will be disseminated at national and international scientific meetings and in peer-reviewed scientific journals. Trial registration number NCT06449625

We explored the dietary intake and metabolic syndrome (MetS) in 85 survivors of pediatric stem cell transplantation (median age 30 years, median follow-up time 20 years). Overall, the distribution of fatty acid deviated from the recommendations with a higher intake of saturated fat and a lower intake of unsaturated fat but was comparable to that of the background population. The prevalence of MetS was 27%, corresponding to that of the elderly background population. We compared the intake of macronutrients between those with MetS and those without MetS and found that overall fat intake was higher in patients with MetS (36.7E% [range, 27.2–51.2E%] vs. 33,5E% (range, 23.4–45.1E%), P = 0.016). Within the subgroup of patients treated with total body irradiation (TBI), we found a higher fat intake in those with MetS (36.8E% (range, 27.2–51.2E%) versus 32.0E% (range, 24.6–42.1E%), P = 0.013). This was confirmed in a multivariate analysis adjusted for TBI, sex, and age at follow-up (OR 1.20 (1.06–1.39), P = 0.008). Our findings suggest that conditioning with the use of TBI may induce a state of hypersensitivity to the potentially harmful effects of fat in the diet and suggest that this risk of MetS after TBI treatment may be modifiable by dietary changes.

The treatment of childhood cancer is challenged by toxic side effects mainly due to chemotherapy-induced organ damage and infections, which are accompanied by severe systemic inflammation. Insulin-like growth factor I (IGF-I) is a key regulating factor in tissue repair. This study investigated associations between the circulating IGF-I levels and chemotherapy-related toxicity in pediatric acute lymphoblastic leukemia (ALL). In this prospective study, we included 114 patients (age: 1–17 years) with newly diagnosed ALL treated according to The Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2013 and 2018. The patients’ plasma levels of IGF-I, and the primary binding protein, IGFBP-3, were measured weekly during the first six weeks of treatment, including the induction therapy. The patients’ systemic inflammation was monitored by their C-reactive protein (CRP) and interleukin (IL)-6 levels and their intestinal epithelial damage by their plasma citrulline levels. IGF-I and IGFBP-3 were converted into sex-and age-adjusted standard deviation scores (SDS) using 1621 healthy children as reference. At ALL diagnosis, IGF-I levels were decreased (median (quartiles): −1.2 SDS (−1.9 to −0.5), p = 0.001), but increased significantly following the initiation of chemotherapy, peaking on day 8 (0.0 SDS (from −0.8 to 0.7), p < 0.001). This increase correlated with the levels of CRP (rho = 0.37, p < 0.001) and IL-6 (rho = 0.39, p = 0.03) on day 15, when these markers reached maximum levels. A larger IGF-I increase from day 1 to 15 correlated with a slower recovery rate of the intestinal damage marker citrulline from day 15 to 29 (rho = −0.28, p = 0.01). Likewise, IGFBP-3 was reduced at diagnosis, followed by an increase after treatment initiation, and was highly correlated with same-day IGF-I levels. This study demonstrates a chemotherapy-induced increase in IGF-I, with a response that appears to reflect the severity of tissue damage and systemic inflammation, preceding CRP and IL-6 increases. IGF-I may have potential as an early reactive biomarker for acute toxicity in patients with ALL.