Intensive chemotherapy frequently results in gut toxicity, indicated by oral and intestinal mucositis, resulting in poor treatment outcomes and increased mortality. There are no effective preventive ...strategies against gut toxicity and the role of diet is unknown.
We hypothesized that the severity of chemotherapy-induced gut toxicity in early life is diet-dependent, and that intake of bovine colostrum (BC) provides better gut protection than an artificial milk replacer (MR).
A total of 37 3-d-old pigs received for 6 d either intravenous saline control or myeloablative treatment with busulfan and cyclophosphamide, and were fed either BC or MR, resulting in the following 4 treatments (n = 8-10/group): bovine colostrum plus saline control (Ctr-BC), milk replacer plus saline control (Ctr-MR), bovine colostrum plus busulfan and cyclophosphamide chemotherapy (BUCY-BC), and milk replacer plus busulfan and cyclophosphamide chemotherapy (BUCY-MR). The gut was collected for analysis 11 d after the start of chemotherapy.
Relative to the control groups, both busulfan and cyclophosphamide chemotherapy (BUCY) groups showed signs of gut toxicity, with oral ulcers, reduced intestinal dimensions, and hematologic toxicity. Diet type did not affect mucosal structure on day 11, but BUCY-BC pigs had less vomiting than BUCY-MR pigs (1 of 10 vs. 10 of 10, P < 0.05). Markers of intestinal function were higher (up to 20-fold greater galactose absorption and 2-3-fold greater brush border enzyme activity, all P < 0.05), and tissue inflammatory cytokine concentrations and serum liver enzyme values were lower in BUCY-BC than in BUCY-MR pigs (30-50% reductions in interleukin 6 and 8, aminotransferase, and bilirubin concentrations, P < 0.05). Gut colonization was not significantly affected except that BUCY pigs had lower microbial diversity with a higher abundance of Lactobacilli.
BC may reduce gut toxicity during myeloablative chemotherapy in piglets by preserving intestinal function and reducing inflammation. Whether similar effects occur in children remains to be tested.
Chemotherapy-induced intestinal toxicity is a common adverse effect of cancer treatment. We hypothesized that a milk diet containing bovine colostrum (BC) would reduce intestinal toxicity in ...doxorubicin-treated piglets.
"Study 1" investigated intestinal parameters 9 days after a single dose of doxorubicin (1 × 75 mg/m) in piglets fed bovine milk enriched with whey protein (BM). In "study 2," responses to doxorubicin treatment were investigated in piglets receiving either 7 BC feedings per day (Only-BC, n = 13), 4 BC feedings (High-BC, n = 13), 2 BC feedings (Low-BC, n = 14), or no BC (only BM, n = 13).
Doxorubicin treatment induced clinical signs of intestinal toxicity with diarrhea and weight loss, relative to controls (P < 0.05). White blood cells, hexose absorptive function, plasma citrulline, weights of intestine, colon, and spleen were reduced, whereas gut permeability and plasma C-reactive protein levels were increased (all P < 0.05). Limited or no effects were observed for digestive enzymes, proinflammatory cytokines, or tight-junction proteins in the intestine. Increasing BC supplementation to doxorubicin-treated piglets (study 2) had no consistent effects on plasma C-reactive protein and citrulline levels, intestinal morphology, digestive enzymes, permeability, or proinflammatory cytokines. Only-BC pigs, however, had lower diarrhea severity toward the end of the experiment (P < 0.05 vs BM) and across the BC groups, intestinal toxicity was reduced (P < 0.01).
Doxorubicin-treated piglets are relevant for studying chemotherapy-induced gut toxicity. Colostrum supplementation had limited effects on doxorubicin-induced toxicity in milk-fed piglets suggesting that colostrum and a bovine milk diet enriched with whey protein provided similar protection of the developing intestine from chemotherapy-induced toxicity.
Chemotherapy-induced gastrointestinal (GI) toxicity is a common adverse effect of cancer treatment. We used preweaned piglets as models to test our hypothesis that the immunomodulatory and GI trophic ...effects of bovine colostrum would reduce the severity of GI complications associated with doxorubicin (DOX) treatment. Five-day-old pigs were administered DOX (1 × 100 mg/m(2)) or an equivalent volume of saline (SAL) and either fed formula (DOX-Form, n = 9, or SAL-Form, n = 7) or bovine colostrum (DOX-Colos, n = 9, or SAL-Colos, n = 7). Pigs were euthanized 5 days after initiation of chemotherapy to assess markers of small intestinal function and inflammation. All DOX-treated animals developed diarrhea, growth deficits, and leukopenia. However, the intestines of DOX-Colos pigs had lower intestinal permeability, longer intestinal villi with higher activities of brush border enzymes, and lower tissue IL-8 levels compared with DOX-Form (all P < 0.05). DOX-Form pigs, but not DOX-Colos pigs, had significantly higher plasma C-reactive protein, compared with SAL-Form. Plasma citrulline was not affected by DOX treatment or diet. Thus a single dose of DOX induces intestinal toxicity in preweaned pigs and may lead to a systemic inflammatory response. The toxicity is affected by type of enteral nutrition with more pronounced GI toxicity when formula is fed compared with bovine colostrum. The results indicate that bovine colostrum may be a beneficial supplementary diet for children subjected to chemotherapy and subsequent intestinal toxicity.
Information about chemotherapy-induced intestinal gene expression may provide insight into the mechanisms underlying gut toxicity and help identify biomarkers and targets for intervention.
We ...analyzed jejunal tissue from piglets subjected to two different, clinically relevant chemotherapy regimens: (1) busulfan plus cyclophosphamide (BUCY) and (2) doxorubicin (DOX).
Gene expression analysis identified 1,328 differentially expressed genes in the BUCY piglets and 594 in the DOX piglets, compared to controls. Similar changes in expression were found for 137 genes across the BUCY and DOX piglets. Selected genes of potential biological significance with a similar change in expression across the treatments were controlled by real-time polymerase chain reaction. Key innate defense molecules, including surfactant protein-D and deleted in malignant brain tumors 1, were among the upregulated genes for both treatments.
In the developing intestine, chemotherapy increases the expression of genes related to innate immune functions involved in surveillance, protection, and homeostasis of mucosal surfaces.
Allogeneic hematopoietic stem cell transplantation (HSCT) is a procedure with a high risk of treatment related mortality. The primary aim of the present study was to examine associations between ...markers of gastrointestinal toxicity, markers of systemic inflammation, and plasma levels of microRNA (miRNA) -155 and -146a during the first month after HSCT. The secondary aim was to characterize the impact of the toxic-inflammatory response on the function of circulating leukocytes during immune recovery.
Thirty HSCT patients were included. Gastrointestinal injury was monitored by toxicity scores, lactulose–mannitol test and plasma citrulline, as a measure of the enterocyte population. Nadir of citrulline and maximum of oral toxicity scores, intestinal permeability, CRP and plasma levels of IL-6 and IL-10 was seen at day +7 post-HSCT. miRNA-155 and mi-RNA-146a showed an inverse relation with significantly elevated miRNA-155 and decreased miRNA-146a levels, from day 0 to day +28 compared with pre-conditioning levels. Citrulline levels below the median at day +7 were associated with higher spontaneous production of IL-6 and TNF-α as well as higher in vitro stimulated production of IL-17A at day +21.
This study is the first to demonstrate that toxic responses to chemotherapy are accompanied by differential regulation of miRNAs with opposing effects on immune regulation. We find that a proinflammatory miRNA profile is sustained during the first three weeks after the transplantation, indicating that these miRNAs may play a role in the regulation of the inflammatory environment during immune reconstitution after HSCT.
•Gastrointestinal injury provides a pro-inflammatory milieu that may promote development of graft versus host reactions.•Low plasma citrulline levels day +7 are associated with high spontaneous cytokine production d. +21 after HSCT.•Gastrointestinal toxicity is accompanied by differential regulation of miRNAs with opposing effects on immune regulation.
Interprofessional education in childhood cancer is a multifaceted field involving multiple healthcare professionals with general and specialised knowledge and skills. Complex treatment, care and ...rehabilitation require continuous professional development and maintenance of healthcare professionals' competencies in their field of expertise. However, limited knowledge exists in comparing interprofessional and monoprofessional education. Only a few randomised studies have evaluated the effectiveness and efficiency of interprofessional education. The objective of this single-centre, investigator-initiated cluster randomised trial is to study the effect of interprofessional versus monoprofessional case-based learning on healthcare professionals' knowledge of gastrointestinal side effects and attitudes towards team collaboration.
This study will randomise healthcare professionals to participate in either the experimental interprofessional group or the control monoprofessional group of case-based learning. The topic of the case-based intervention will be gastrointestinal side effects, one of six categories identified in a three-round Scandinavian Delphi study as relevant for interprofessional education in childhood cancer. The primary outcome is the self-reported questionnaire Assessment of Interprofessional Team Collaboration Scale. Secondary outcomes are measured by the self-reported questionnaires Readiness for Interprofessional Learning Scale Questionnaire, Safety Attitudes Questionnaire, and knowledge will be evaluated using a multiple-choice quiz. Participants will receive the self-reported questionnaires about 2 weeks before and 1 month after the intervention. On the day of the intervention, participants will answer a multiple-choice quiz before and after the case-based learning. Linear mixed models will be used to compare differences between the two groups in mean scores postintervention, adjusting for preintervention scores.
This study will provide insight into the differences between interprofessional and monoprofessional case-based learning and how it affects healthcare professionals' knowledge of gastrointestinal side effects and attitudes towards team collaboration.
The intervention was registered at Clinical Trials.gov : NCT04204109 on December 102,019 and with the National Committee on Health Research Ethics: H-19087506 December 112,019 and the Danish Data Protection Agency: P-2019-637 October 152,019.
Chemotherapy-induced myeloablation prior to allogeneic hematopoietic stem cell transplantation (HSCT) may be associated with severe toxicity. The current understanding of the pathophysiology of oral ...and gastrointestinal (GI) toxicity is largely derived from studies in rodents and very little is known from humans, especially children. We hypothesized that milk-fed piglets can be used as a clinically relevant model of GI-toxicity related to a standard conditioning chemotherapy (intravenous busulfan, Bu plus cyclophosphamide, Cy) used prior to HSCT. In study 1, dose-response relationships were investigated in three-day-old pigs (Landrace × Yorkshire × Duroc, n = 6). Pigs were given one of three different dose combinations of Bu and Cy (A: 4 days Bu, 2 × 1.6 mg/kg plus 2 days Cy, 60 mg/kg; B: 4 days Bu, 2 × 0.8 mg/kg plus 2 days Cy, 30 mg/kg; C: 2 days Bu at 2 × 1.6 mg/kg plus 1 day Cy, 60 mg/kg) and bone marrow was collected on day 11. Histology of bone marrow samples showed total aplasia after treatment A. Using this treatment in study 2, Bu-Cy pigs showed lowered spleen and intestinal weights and variable clinical signs of dehydration, sepsis, and pneumonia at tissue collection. Oral mucositis was evident as ulcers in the soft palate in 4/9 Bu-Cy pigs and villus height and brush-border enzyme activities were reduced, especially in the proximal intestine. There were no consistent effects on tissue cytokine levels (IL-8, IL-6, IL-1β, TNF-α) or blood chemistry values (electrolytes, liver transaminases, bilirubin, alkaline phosphatase), except that blood iron levels were higher in Bu-Cy pigs. We conclude that a myeloablative Bu-Cy regimen to piglets results in clinical signs comparable to those seen in pediatric patients subjected to myeloablative treatment prior to HSCT. Piglets may be used as a model for investigating chemotherapy-induced toxicity and dietary and medical interventions.
Chemotherapy for cancer patients induces damaging tissue reactions along the epithelium of the gastrointestinal tract (GIT). This chemotherapy-induced mucositis (CIM) is a serious side effect of ...cytotoxic drugs, and several animal models of CIM have been developed, mainly in rodents and piglets, to help understand the progression of CIM and how to prevent it. Animal models allow highly controlled experimental conditions, detailed organ (e.g., GIT) insights, standardized, clinically relevant treatment regimens, and discovery of new biomarkers. Still, surprisingly few results from animal models have been translated into clinical CIM management and treatments. The results obtained from specific animal models can be difficult to translate to the diverse range of CIM manifestations in patients, which vary according to the antineoplastic drugs, dose, underlying (cancer) disease, and patient characteristics (e.g., age, genetics, and body constitution). Another factor that hinders the direct use of results from animals is inadequate collaboration between basic science and clinical science in relation to CIM. Here, we briefly describe CIM pathophysiology, particularly the basic knowledge that has been obtained from CIM animal models. These model studies have indicated potential new preventive and ameliorating interventions, including supplementation with natural bioactive diets (e.g., milk fractions, colostrum, and plant extracts), nutrients (e.g., polyunsaturated fatty acids, short-chain fatty acids, and glutamine), and growth factor peptides (e.g., transforming growth factor and glucagon-like peptide-2), as well as manipulations of the gut microbiota (e.g., prebiotics, probiotics, and antibiotics). Rodent CIM models allow well-controlled, in-depth studies of animals with or without tumors while pig models more easily make clinically relevant treatment regimens possible. In synergy, animal models of CIM provide the basic physiological understanding and the new ideas for treatment that are required to make competent decisions in clinical practice.
This paper presents a feasibility study assessing the acceptability, demand, implementation, and practicality of postgraduate interprofessional case-based learning in childhood cancer at Copenhagen ...University Hospital—Rigshospitalet. Healthcare professionals included nurses, doctors, social workers, physiotherapists, occupational therapists, pharmacists, pharmacologists, dieticians, nursing assistants, and professionals with a supportive function (teachers, secretaries, priests, and daycare workers). All participated in a postgraduate interprofessional case-based learning session. Feasibility was assessed using Bowen’s focus areas of acceptability, demand, implementation, and practicality. Before and after the intervention session, three measurement tools were used 2–3 weeks before participation and 3–4 weeks after participation to collect data: Assessment of Interprofessional Team Collaboration Scale, Readiness for Interprofessional Learning Scale, and Safety Attitudes Questionnaire. Representing 13 occupational groups, 49 participants completed the case-based learning sessions, indicating acceptability and practicality. The pre- and post-intervention questionnaires were completed by 79% of the participants, 88% of whom rated the professional content as good or very good. A change over time was detected on all three scales measuring mean difference post-intervention scores. The outcome measures can be used to assess the effect of the intervention. Postgraduate interprofessional case-based learning in childhood cancer is feasible in terms of acceptability, demand, implementation, and practicality. Implementation requires leadership commitment at all levels.
We measured IgA and IgG antibodies to pertussis toxin (PT) and filamentous hemagglutinin (FHA) in sera from 203 1-year-old children who had received one to three doses of a monocomponent PT toxoid ...vaccine. Ten children (5%) had IgA antibody to PT indicating recent infection; seven of these children had received three doses of vaccine. PT IgA responders did not have significantly longer coughing episodes than PT IgA non-responders. Since an IgA antibody response occurs in only ∼50% of infected children, the actual infection rate in our cohort is estimated to ∼10%. The apparent high
Bordetella pertussis
infection rate in Danish infants suggests that the monocomponent PT toxoid vaccine used in Denmark has limited efficacy against
B. pertussis
infection. A prospective immunization study comparing a multi-component vaccine with the present monocomponent PT toxoid vaccine should be undertaken.
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