Abstract Prolonged neutrophil recovery during acute lymphoblastic leukemia (ALL) treatment increases infection risk and delays chemotherapy. Emerging evidence implicates the 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 samplings were monitored until day 29 during ALL induction treatment. Fecal sequencing by 16S rRNA revealed an overall significant reduction in bacterial diversity and Enterococcus overgrowth throughout the induction treatment. Prolonged neutropenia (ANC < 0.5x109 cells/L at day 36) and elevated chemokines levels were associated with 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 unrelated to microbiota changes. Overall, this study reveals that diminished abundance of specific intestinal commensals and Enterococcus overgrowth are associated with delayed neutrophil reconstitution and increased chemokine signaling. These findings enhance our understanding of the mechanisms behind the huge variability in neutrophil reconstitution post-chemotherapy, emphasizing the need for gut microbiota-sparing strategies to minimize the impact of gut dysbiosis on immune recovery.
Patients undergoing treatment for acute lymphoblastic leukaemia (ALL) are at risk of coagulopathy, especially thromboembolism. We conducted a survey on practices in the assessment and management of coagulopathy during the new ALLTogether protocol in 29 (17 paediatric, 12 adult) Nordic and Baltic cancer centres. While 92% of adult centres used thromboprophylaxis with low-molecular-weight heparin, no paediatric centre did. Almost all providers performed baseline coagulation studies, but only 59% continued the assessment. Fibrinogen replacement was conducted in 59%, and antithrombin replacement in 28% of the centres. The survey highlights the need for guidelines in the management of coagulopathy during ALL therapy.
Abstract Background Surfactant protein D (SP‐D) is a host defense molecule of the innate immune system that enhances pathogen clearance and modulates inflammatory responses. We hypothesized that circulating SP‐D levels are associated with chemotherapy‐induced mucositis and infectious morbidity in children with acute lymphoblastic leukemia (ALL). Procedure In a prospective study, 43 children receiving treatment for ALL were monitored for mucosal toxicity from diagnosis through the induction phase of treatment. Serial blood draws were taken to determine the levels of SP‐D, interleukin‐6 (IL‐6), C‐reactive protein, and white blood cells. Data on fever, antibiotics, and bacteremia were collected. Baseline levels of circulating SP‐D were compared with healthy controls. Results Baseline values of circulating SP‐D were similar to levels in healthy controls (median: 829 ng/ml vs. 657 ng/ml, respectively, P > 0.05). After initiation of chemotherapy, a significant reduction in SP‐D levels was observed at all time points: 704 ng/ml at day 8, 413 ng/ml at day 15, 395 ng/ml at day 22, and 520 ng/ml at day 29 (all, P < 0.05). No significant associations between SP‐D values, the occurrence of mucosal toxicity, or infectious morbidity were observed. However, loss of circulating SP‐D from days 8 to 15 was associated with more systemic inflammation, and lower SP‐D values at day 15 were associated with elevated intestinal mucositis scores ( P < 0.05). Conclusions The current study supports the hypothesis that the detrimental effect of chemotherapy on patients’ immune functions includes decreased circulating levels of innate mucosal molecules such as SP‐D, potentially aggravating mucosal and systemic inflammatory responses.
Abstract Background Hereditary anemias are a group of genetic diseases prevalent worldwide and pose a significant health burden on patients and societies. The clinical phenotype of hereditary anemias varies from compensated hemolysis to life-threatening anemia. They can be roughly categorized into three broad categories: hemoglobinopathies, membranopathies, and enzymopathies. Traditional therapeutic approaches like blood transfusions, iron chelation, and splenectomy are witnessing a paradigm shift with the advent of targeted treatments. However, access to these treatments remains limited due to lacking or imprecise diagnoses. The primary objective of the study is to establish accurate diagnoses for patients with hereditary anemias, enabling optimal management. As a secondary objective, the study aims to enhance our diagnostic capabilities. Results The DAHEAN study is a nationwide cohort study that collects advanced phenotypic and genotypic data from patients suspected of having hereditary anemias from all pediatric and hematological departments in Denmark. The study deliberates monthly by a multidisciplinary anemia board involving experts from across Denmark. So far, fifty-seven patients have been thoroughly evaluated, and several have been given diagnoses not before seen in Denmark. Conclusions The DAHEAN study and infrastructure harness recent advancements in diagnostic tools to offer precise diagnoses and improved management strategies for patients with hereditary anemias.
Minimal residual disease (MRD) monitoring has a strong prognostic value in childhood lymphoblastic leukemia (ALL) and is currently utilized in all major pediatric ALL protocols. MRD monitoring is done by multiparameter flow cytometry, IG/TCR quantitative PCR or reverse transcriptase quantitative PCR of leukemic fusion transcripts providing a reliable measurement of treatment response. However, occasionally bone marrow (BM) aspirates may not yield representative material or be misinterpreted due to treatment‐induced changes in MRD marker profile, undetected subclones at diagnosis, contamination with peripheral blood or cell adhesion and stroma cell interactions posing a risk for underestimating MRD levels and misclassifying resistant disease that may be detected by traditional BM morphology methods, immunohistochemistry, karyotyping and FISH. We present four cases with high MRD levels where MRD monitoring failed to provide the correct stratification information. Through these cases, we discuss the continued need to consider all available information including BM smears, touch imprints and trephine biopsy preparations not only at diagnosis but throughout remission monitoring in pediatric ALL.
Bovine colostrum, the first milk that cows produce after parturition, contains high levels of growth factors and immunomodulatory components. Some healthy and diseased individuals may gain health benefits by consuming bovine colostrum as a food supplement. This review provides a systematic, critical evaluation of the current state of knowledge in this area. Fifty-one eligible studies were identified from the following databases: Medline, Embase, Global Health, the Cochrane Library, and the Cumulative Index to Nursing and Allied Health Literature. Studies were heterogeneous with regard to populations, outcomes, and methodological quality, as judged by the Jadad assessment tool. Many studies used surrogate markers to study the effects of bovine colostrum. Studies suggesting clinical benefits of colostrum supplementation were generally of poor methodological quality, and results could not be confirmed by other investigators. Bovine colostrum may provide gastrointestinal and immunological benefits, but further studies are required before recommendations can be made for clinical application. Animal models may help researchers to better understand the mechanisms of bovine colostrum supplementation, the dosage regimens required to obtain clinical benefits, and the optimal methods for testing these effects in humans.
ABSTRACT Background Neuroendocrine tumors (NETs), although rare, are considered one of the most common gastrointestinal and bronchopulmonary pediatric neoplasms. We aimed to determine the incidence, tumor characteristics, management, and outcome of NETs and explore the role of genetic predisposition, focusing on low and intermediate grade tumors. Methods Using the Danish National Pathology Registry, we conducted a nationwide retrospective study including all Danish children aged ≤18 years diagnosed with a pathology‐proven NET between 1995 and 2020. Results We identified 220 patients, with a 1.89:1 female to male ratio. The yearly incidence was 6.84 per 1 million children, with no significant change in incidence throughout the observation period. NETs were located in the appendix (93.2%), the pulmonary system (4.5%), and pancreas (2.3%). One recurrence was noted in the pancreas in a genetically predisposed patient with multiple neuroendocrine neoplasia type 1 (MEN1), resulting in an overall recurrence rate of 0.5% (0% in appendiceal NETs; 0% in bronchopulmonary NETs; 20.0% in pancreatic NETs). No NET‐related mortality was registered. Four patients had a known predisposing genetic condition, one appendiceal NET associated with neurofibromatosis type 1, and three pancreatic NETs associated with MEN1. Postsurgical surveillance regimes, choice of tumor markers, and imaging modality varied throughout the study period. Conclusions We confirmed a stable incidence of pediatric NETs during the study period. The overall recurrence rate was 0.5% and no NET‐related mortality was observed. Known genetic predisposition was present in 1.8% of patients. Future guidelines should consider the apparent indolent nature and excellent prognosis of these tumors.
OBJECTIVE Pediatric neuro-oncological surgery is often associated with significant risk; however, comprehensive data on surgical morbidity remain limited. The purpose of this study was therefore to provide national population-based data on both the incidence and characteristics of poor postoperative outcomes following pediatric intracranial neuro-oncological surgery. Additionally, the authors aimed to evaluate key risk factors for poor postoperative outcomes including overall morbidity, significant morbidity, and the most frequent types of morbidity. METHODS The authors conducted a registry-based, nationwide, retrospective study including all children receiving surgical treatment for a CNS tumor over a 10-year period. Patients were identified using the Danish Childhood Cancer Registry, and 30-day morbidity was assessed through manual review of electronic health records. Significant morbidity was defined as complications in need of treatment under general anesthesia, ICU admission, or persistent neurological deficits at 30 days following surgery or death. Risk factors including sex, age, tumor location, tumor malignancy grade, and preoperative hydrocephalus were investigated using multivariate logistic regression analysis. RESULTS A total of 349 children undergoing 473 tumor procedures were included, with an overall morbidity rate of 66.0% and a significant morbidity rate of 34.2%. The most frequent complications included neurological deficits (41.4%) and CSF-related morbidity consisting of CSF leaks, pseudomeningoceles, and postoperative hydrocephalus. Highly significant associations between infratentorial tumor location and both significant morbidity (OR 1.26, 95% CI 1.11–1.43; p < 0.001) and neurological deficits (OR 1.38, 95% CI 1.21–1.57; p < 0.001) were identified. In addition, younger age was revealed as a major risk factor of both postoperative CSF leakage and CSF-related morbidity in general. CONCLUSIONS In this large, population-based cohort, the authors show that postoperative morbidity is frequent, occurring in about two-thirds of all patients, largely driven by neurological deficits and CSF-related complications. In addition, infratentorial tumor location and younger age emerged as key risk factors for poor postoperative outcomes.
