Markers of intestinal mucositis to predict blood stream infections at the onset of fever during treatment for childhood acute leukemia.

Despite chemotherapy-induced intestinal mucositis being a main risk factor for blood stream infections (BSIs), no studies have investigated mucositis severity to predict BSI at fever onset during acute leukemia treatment. This study prospectively evaluated intestinal mucositis severity in 85 children with acute leukemia, representing 242 febrile episodes (122 with concurrent neutropenia) by measuring plasma levels of citrulline (reflecting enterocyte loss), regenerating islet-derived-protein 3α (REG3α, an intestinal antimicrobial peptide) and CCL20 (a mucosal immune regulatory chemokine) along with the general neutrophil chemo-attractants CXCL1 and CXCL8 at fever onset. BSI was documented in 14% of all febrile episodes and in 20% of the neutropenic febrile episodes. In age-, sex-, diagnosis- and neutrophil count-adjusted analyses, decreasing citrulline levels and increasing REG3α and CCL20 levels were independently associated with increased odds of BSI (OR = 1.6, 1.5 and 1.7 per halving/doubling, all p < 0.05). Additionally, higher CXCL1 and CXCL8 levels increased the odds of BSI (OR = 1.8 and 1.7 per doubling, all p < 0.0001). All three chemokines showed improved diagnostic accuracy compared to C-reactive protein and procalcitonin. These findings underline the importance of disrupted intestinal integrity as a main risk factor for BSI and suggest that objective markers for monitoring mucositis severity may help predicting BSI at fever onset.

Thirty-day surgical morbidity and risk factors in pediatric brain tumor surgery: a 10-year nationwide retrospective study.

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.

The Danish national haemoglobinopathy screening programme: Report from 16 years of screening in a low-prevalence, non-endemic region.

The Danish national haemoglobinopathy screening programme seeks to determine parental haemoglobinopathy carrier state antenatally. In this retrospective register-based study, we evaluated the 16-year trajectory of this programme, utilising the Danish Red Blood Cell Centre's laboratory database, covering approximately 77% of the Danish population. During the study period, we observed a substantial increase in annual diagnostic examinations performed, from 389 in 2007 to 3030 in 2022. Women constituted 88% of these cases, aligning with the emphasis of the screening programme. Of these, 54% of women of reproductive age (15-40 years) and 10% of women >40 years were specified as pregnant. During our study period, 61 children were born with a severe haemoglobinopathy, out of which 23 children were born from mothers not residing in Denmark during their first trimester thus not included in the screening programme. Prenatal invasive testing was performed for 60 fetuses, identifying 12 with homozygous or compound heterozygous haemoglobinopathy. The Danish haemoglobinopathy screening programme has provided screening, information and reproductive choices for numerous families. During the study period, screening for haemoglobinopathies has been steadily increasing and is expected to continue to increase. Awareness of and adherence to the screening programme is subject of further investigation and optimisation.

Epidemiological Study of Malignant Paediatric Liver Tumours in Denmark 1985-2020.

BACKGROUND: Malignant liver tumours in children are rare and national outcomes for this tumour entity are rarely published. This study mapped paediatric liver tumours in Denmark over 35 years and reported on the incidence, outcomes and long-term adverse events. METHODS: We identified all liver tumours from the Danish Childhood Cancer Registry and reviewed the case records for patient and tumour characteristics, treatment and clinical outcome. RESULTS: We included 79 patients in the analyses. Overall crude incidence was ~2.29 per 1 million children (<15 yr) per year, with 61 hepatoblastomas (HB), 9 hepatocellular carcinomas and 9 other hepatic tumours. Overall 5-year survival was 84%, 78% and 44%, respectively. Nine patients had underlying liver disease or predisposition syndrome. Seventeen children underwent liver transplantation, with two late complications, biliary stenosis and liver fibrosis. For HB, age ≥ 8 years and diagnosis prior to 2000 were significant predictors of a poorer outcome. Adverse events included reduced renal function in 10%, reduced cardiac function in 6% and impaired hearing function in 60% (19% needed hearing aids). Behavioural conditions requiring additional support in school were registered in 10 children. CONCLUSIONS: In Denmark, incidences of malignant liver tumours during the last four decades have been increasing, as reported in the literature. HB survival has improved since the year 2000 and is comparable with international results. Reduced hearing is the major treatment-related side effect and affects approximately 60% of patients.

Gastrointestinal barrier integrity and mucosal inflammation as risk factors of blood stream infections in children treated for acute lymphoblastic leukaemia.

Chemotherapy-induced mucositis increases the risk of blood stream infections (BSI) due to translocation of bacteria across the intestinal epithelium. Our study investigated if quantitative measures of intestinal mucositis severity, including plasma citrulline (a marker of functional enterocytes) and CCL20 (an intestinal immune homeostatic chemokine), could identify patients at risk of BSI. A total of 106 children with ALL undergoing induction treatment (NOPHO ALL 2008) were included and information regarding BSI episodes was collected from the patients' medical records. Twenty-seven patients (25%) developed BSI during induction. Patients with BSI had a larger decrease in citrulline after chemotherapy than patients without BSI, and nearly all BSI episodes (25/27) occurred in the group of patients exhibiting a drop in citrulline (OR = 6.4 [95% CI: 1.4-29.3], P = .008). Patients who developed BSI had higher plasma CCL20 levels on days 8, 15 and 22 than patients without BSI (all P < .05), and elevated CCL20 levels on day 8 increased the risk of subsequent BSI (OR = 1.57 [1.11-2.22] per doubling of CCL20 level, P = .01) in a multivariable logistic regression analysis. These findings suggest that children with ALL who develop BSI during chemotherapy are characterised by more severe intestinal mucositis, as measured by plasma citrulline and CCL20. These markers may be useful in early risk stratification to guide treatment decisions.

Physician-defined severe toxicities occurring during and after cancer treatment: Modified consensus definitions and clinical applicability in the evaluation of cancer treatment.

Overall survival after cancer is increasing for the majority of cancer types, but survivors can be burdened lifelong by treatment-related severe toxicities. Integration of long-term toxicities in treatment evaluation is not least important for children and young adults with cancers with high survival probability. We present modified consensus definitions of 21 previously published physician-defined Severe Toxicities (STs), each reflecting the most serious long-term treatment-related toxicities and representing an unacceptable price for cure. Applying the Severe Toxicity (ST) concept to real-world data required careful adjustments of the original consensus definitions, translating them into standardized endpoints for evaluating treatment-related outcomes to ensure that (1) the STs can be classified uniformly and prospectively across different cohorts, and (2) the ST definitions allow for valid statistical analyses. The current paper presents the resulting modified consensus definitions of the 21 STs proposed to be included in outcome reporting of cancer treatment.

Markers of neutrophil chemotaxis for identification of blood stream infections in children with acute lymphoblastic leukemia undergoing induction treatment.

BACKGROUND: Although neutropenic fever is frequently observed during chemotherapy, only a minor proportion is caused by blood stream infections (BSI). This study investigated measurements of neutrophil chemotaxis as risk markers for BSI in children with acute lymphoblastic leukemia (ALL). METHODS: The chemokines CXCL1 and CXCL8 were measured weekly in 106 children with ALL during induction treatment. Information regarding BSI episodes was collected from the patients' medical records. RESULTS: During induction treatment, 102 (96%) patients developed profound neutropenia and 27 (25%) were diagnosed with BSI, debuting on median day 12 (range: 4-29). Patients developing BSI had increased levels of CXCL1 on days 8 and 15 as well as increased CXCL8 on days 8, 15, 22, and 29 compared to patients without BSI (all p < 0.05). Patients with BSI < day 12 exhibited increased CXCL1 and CXCL8 levels as early as day 8 (81 vs. 4 pg/mL, p = 0.031 and 35 vs. 10 pg/mL, p < 0.0001, respectively), while CXCL1 and CXCL8 were increased on day 15 (215 vs. 57 pg/mL, p = 0.022 and 68 vs. 17 pg/mL, p = 0.0002) and after (all p < 0.01) in patients with BSI ≥ day 12. CONCLUSION: The markers of neutrophil chemotaxis, CXCL1, and CXCL8 may help to identify patients at increased risk of BSI during chemotherapy-induced neutropenia.

A survey on thromboprophylaxis and coagulation assessment in children and young adults with acute lymphoblastic leukaemia (ALL) in the Nordic and Baltic countries: Different practices of assessment and management.

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.

PET/CT imaging detects intestinal inflammation in a mouse model of doxorubicin-induced mucositis.

Introduction: A severe side effect of cancer chemotherapy is the development of gastrointestinal mucositis, characterised by mucosal inflammation. We investigated if 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography combined with computed tomography (2-[18F]FDG-PET/CT) could visualise gastrointestinal mucositis in mice treated with the chemotherapeutic agent doxorubicin. Methods: In this study, gastrointestinal inflammation was longitudinally evaluated by 2-[18F]FDG-PET/CT scans before and 1, 3, 6, and 10 days after treatment with doxorubicin. Doxorubicin-treated mice were compared to saline-treated littermates using the abdominal standard uptake value of 2-[18F]FDG corrected for body weight (SUVBW). Results: Abdominal SUVBW was significantly increased on day 1 (p < 0.0001), day 3 (p < 0.0001), and day 6 (p < 0.05) in the doxorubicin-treated group compared to controls. Abdominal SUVBW returned to baseline levels on day 10. In the doxorubicin group, the largest weight loss was observed on day 3 (control vs doxorubicin, mean percent of baseline weight: (98.5 ± 3.2% vs 87.9 ± 4.6%, p < 0.0001). Moreover, in the doxorubicin-treated group, villus lengths were decreased by 23-28% on days 1 and 3 in the small intestine (p < 0.05), and jejunal levels of tumour necrosis factor and interleukin-1ß were significantly increased on day 3 (p < 0.05). Discussion: Together, these findings indicate that sequential 2-[18F]FDG-PET/CT scans can objectively quantify and evaluate the development and resolution of intestinal inflammation over time in a mouse model of doxorubicin-induced mucositis.

No effect of deleted in malignant brain tumors 1 deficiency on chemotherapy induced murine intestinal mucositis.

Mucositis is a serious adverse effect of chemotherapeutic treatment. During intestinal mucositis, the mucosal barrier is compromised, increasing the risk of severe infections. Mucositis necessitates dose reduction or pauses in treatment, which affect the outcome of the treatment. Deleted in malignant brain tumors 1 (DMBT1) is a secreted scavenger protein with effects on innate immunity and epithelial regeneration. We have previously shown that jejunal DMBT1 expression is increased in piglets during chemotherapeutic treatment. We hypothesized that DMBT1 ameliorates doxorubicin-induced mucositis. Individually-caged Dmbt1+/+ (WT) and Dmbt1-/- (KO) female mouse littermates received intraperitoneal injections of either doxorubicin or saline. They were euthanized after three (D3) or seven days (D7). Weight loss was monitored every day, and serum citrulline levels were measured at termination. Intestinal tissue was analyzed for the expression of DMBT1 and proinflammatory cytokines (IL-1ß, IL-6, and TNF). Specimens from the small intestines and colon were scored for inflammation and epithelial and mucosal architecture changes. We detected no effect of DMBT1 on weight loss, serum citrulline levels, expression of proinflammatory cytokines, or histologic damage. We detected a significant increase in crypt depth in WT mice compared to that in KO mice on D3. In conclusion, DMBT1 does not affect doxorubicin-induced mucositis in mice.

Peptidoglycan Recognition Peptide 2 Aggravates Weight Loss in a Murine Model of Chemotherapy-Induced Gastrointestinal Toxicity.

Introduction: Chemotherapy-induced gastrointestinal toxicity (CIGT) is a frequent, severe and dose-limiting side effect. Few treatments have proven effective for CIGT. CIGT is characterized by activation of the nuclear factor kappa B pathway which, leads to upregulation of proinflammatory cytokines. The innate immune protein peptidoglycan recognition peptide 2 (PGLYRP2) binds to and hydrolyzes microbial peptidoglycan. Expression of PGLYRP2 is upregulated in the intestine of chemotherapy-treated piglets. In this experimental study, we investigated the role of Pglyrp2 in the development and severity of murine CIGT. Methods: Pglyrp2 wildtype and Pglyrp2 knockout mice received intraperitoneal injections of chemotherapy (Doxorubicin 20 mg/kg) to induce CIGT. Weight was monitored daily, and animals were euthanized after 2 or 7 days. Expression of proinflammatory cytokines in the jejunum was measured by quantitative real-time polymerase-chain reaction and enzyme-linked immunosorbent assay. Villus height, crypt depth, and histologic inflammation were evaluated on haematoxylin and eosin stained tissue specimens. Results: Chemotherapeutic treatment induced weight loss (p < 0.05), shortening of the small intestine (p < 0.05), elongation of villus height (p < 0.05), increased crypt depth (p < 0.05), and led to elevated mRNA levels of II1ß (p < 0.05), II6 (p < 0.05), and Tnf (p < 0.001) at day 2. Protein levels of IL1ß, IL6, and TNFα did not change after exposure to chemotherapy. Doxorubicin treated wildtype mice had a more pronounced weight loss compared to knockout mice from day 3 to day 7 (D3-D6: p < 0.05 and D7: p < 0.01). No other phenotypic differences were detected. Conclusion: Pglyrp2 aggravates chemotherapy-induced weight loss but does not induce a specific pattern of inflammation and morphological changes in the small intestine.

FIBCD1 ameliorates weight loss in chemotherapy-induced murine mucositis.

PURPOSE: Chemotherapy-induced gastrointestinal toxicity is a common adverse event during chemotherapeutic treatment. No uniformly applicable strategies exist to predict, prevent, or treat gastrointestinal toxicity. Thus, a goal of mucositis research is to identify targets for therapeutic interventions and individualized risk prediction. Fibrinogen C domain containing 1 (FIBCD1) is a transmembrane protein expressed in human intestinal epithelial cells with functions in the innate immune system. Previous observations have shown that FIBCD1 ameliorates dextran sulfate sodium (DSS)-induced intestinal inflammation in vivo. We evaluated the effect of FIBCD1 in a murine model of chemotherapy-induced gastrointestinal toxicity and inflammation. METHODS: Transgenic (Tg) mice overexpressing FIBCD1 in the intestinal epithelium (Fibcd1Tg) and wild-type (WT) littermates (C57BL/6N) were randomized to receive an intraperitoneal injection of doxorubicin 20 mg/kg or saline and were terminated 2 or 7 days after the injection. Gastrointestinal toxicity was evaluated by weight change, intestinal length, villus height/crypt depth, and histological mucositis score. Expression of inflammatory markers (IL-6, IL-1ß, and Tnfα) was measured by quantitative real-time PCR in intestinal tissue samples. RESULTS: Following doxorubicin treatment, WT mice exhibited an increased weight loss compared with Tg littermates (p < 0.001). No differences between genotypes were seen in mucositis score, intestinal length, villus height/crypt depth, or IL-6, IL-1ß, and Tnfα expression. CONCLUSION: Our findings suggest that FIBCD1 could ameliorate chemotherapy-induced gastrointestinal toxicity by reducing weight loss; however, the mechanism of this possible protective effect remains to be defined warranting additional investigations.

Citrulline as a biomarker of bacteraemia during induction treatment for childhood acute lymphoblastic leukaemia.

BACKGROUND: Systemic infections are a major cause of morbidity in children with acute lymphoblastic leukaemia (ALL). However, identification of patients at increased risk is still a challenge. Knowing that both neutropaenia and gastrointestinal toxicity are risk factors for bacteraemia, we aimed at comparing absolute neutrophil counts (ANC) and plasma citrulline levels (indicating enterocyte loss) in children with ALL with and without bacteraemia during induction treatment. PROCEDURE: We prospectively included 61 children with ALL treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 protocol. ANC and plasma C-reactive protein (CRP) were measured on treatment days 1, 8, 15, 22 and 29. Plasma citrulline was measured on days 1, 8, 15 and 29. Bacteraemia episodes during induction treatment were recorded retrospectively. RESULTS: Nineteen of sixty-one (31%) patients experienced bacteraemia occurring on median day 13 (range 5-20). Patients with bacteraemia during induction treatment had lower citrulline level on day 15 (P < .01) compared to patients without bacteraemia, indicating more severe enterocyte loss. Nevertheless, ANC was similar in the two patient groups on days 8 and 15. CRP was negatively correlated with same-day citrulline (P < .03 for all) and ANC (P < .04 for all). CONCLUSIONS: During chemotherapy-induced neutropaenia, plasma citrulline may help identify patients at increased risk of bacteraemia.

Gastrointestinal toxicity during induction treatment for childhood acute lymphoblastic leukemia: The impact of the gut microbiota.

Intestinal mucositis is a common side effect of chemotherapy leading to diarrhea, abdominal pain and increased risk of infections. The intestinal microbiota has been recognized as a key regulator of mucosal immune responses. Therefore, we hypothesized that intestinal microbial changes would be associated with enterocyte loss and systemic inflammation during induction treatment for childhood acute lymphoblastic leukemia (ALL). We prospectively included 51 children newly-diagnosed with ALL treated in Denmark in 2015-2018. Plasma C-reactive protein (CRP), plasma citrulline (marker of functional enterocytes mass) measurements and fecal samplings were performed on treatment Days 1, 8, 15, 22 and 29. Moreover, intestinal mucositis was scored by a trained nurse/physician. Fecal samples in patients and 19 healthy siblings were analyzed by 16S rRNA gene sequencing (V3-V4 region). Bacterial alpha diversity was lower in patients compared to siblings. It decreased from Day 1 to Days 8-22 and increased on Day 29. Shannon alpha diversity index was correlated with CRP on Days 15-29 (rho = -0.33-0.49; p < 0.05) and with citrulline on Days 15 and 29 (although with p values <0.06, rho = 0.32-0.34). The abundance of unclassified Enterococcus species (spp.) was correlated with CRP on Days 22-29 (rho = 0.42-0.49; p < 0.009), while the abundance of unclassified Lachnospiraceae spp. was correlated with citrulline on days 8-15 (rho = 0.48-0.62, p < 0.001). Systemic inflammation, enterocyte loss and relative abundance of unclassified Enterococcus spp. reached a peak around Day 15. In conclusion, specific changes in the microbiota were associated with the severity of enterocyte loss and systemic inflammation during chemotherapy.

Minimal residual disease monitoring cannot fully replace bone marrow morphology in assessing disease status in pediatric acute lymphoblastic leukemia.

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 Against Chemotherapy-Induced Gastrointestinal Toxicity in Children With Acute Lymphoblastic Leukemia: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: The toxic effect of chemotherapy on the gastrointestinal tract may lead to mucositis and is associated with the pathogenesis of other treatment-related complications. We hypothesized that nutrition supplementation with bovine colostrum, rich in bioactive factors, would ameliorate gastrointestinal toxicity and reduce the incidence of fever and infectious complications during induction treatment for childhood acute lymphoblastic leukemia (ALL). METHODS: Children with newly diagnosed ALL were included in a 2-center, randomized, double-blind, placebo-controlled clinical trial. Patients were randomized to receive a daily colostrum or placebo supplement during 4 weeks of induction treatment. Data on fever, bacteremia, need for antibiotics, and mucosal toxicity were prospectively collected. (Trial registration: www.clinicaltrials.gov NCT01766804). RESULTS: Sixty-two patients were included. No differences were found for the primary outcome (number of days with fever). No difference was observed for neutropenic fever, intravenous antibiotics, or incidence of bacteremia. Peak severity of oral mucositis was significantly reduced by colostrum (7/29 patients, 24% mild; 6/29, 21% moderate; 1/29, 3% severe) compared with placebo (12/31, 39% mild; 1/31, 3% moderate; 7/31, 23% severe) (P = 0.02). Among patients receiving at least 1 dose of supplement (colostrum: n = 22; placebo: n = 30), the peak weekly self-reported oral mucositis score was overall significantly less severe in the colostrum group (P = 0.009). CONCLUSION: The use of prophylactic bovine colostrum showed no effect on fever, infectious morbidity, or inflammatory responses. Nevertheless, these data may suggest protective effects on the oral mucosa during induction therapy in childhood ALL, encouraging additional studies confirming these findings.

Trophic factors in the treatment and prevention of alimentary tract mucositis.

PURPOSE OF REVIEW: Mucositis is a common adverse effect of cytotoxic anticancer treatment with serious implications for the quality of life, morbidity and mortality of cancers patients. Although, evidence supporting the use of certain treatments exists there is no gold standard for preventing or treating mucositis. Current management strategies are scarce with recommendations referring primarily to specific cytotoxic treatment regimens in certain clinical scenarios. RECENT FINDINGS: Trophic factors may contribute to preserve epithelial integrity, function, and accelerate regeneration after chemotherapeutic treatment. Accordingly, various growth factors have been evaluated in the prevention or treatment of alimentary tract mucositis. However, in spite of often showing promising results in preclinical testing currently perlifermin is the only trophic factor recommended for the prevention of mucositis. SUMMARY: More knowledge from representative preclinical models, and testing growth factor interventions across different models, may be the key to advance the field from basic science to clinical application of new growth factors. For promising new therapies, subsequent establishment of adequately powered clinical trials and uniform reporting of mucositis, are important elements to help establish new standard interventions that can be included into the continuously updated clinical recommendations for treatment of mucositis.

Animal models of chemotherapy-induced mucositis: translational relevance and challenges.

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.