RESUMO
Severe intestinal mucositis (IM) increases the risk of bloodstream infections (BSI) and inflammatory toxicity during acute lymphoblastic leukaemia (ALL) induction treatment. However, the implications of IM in subsequent ALL therapy phases after achieving remission remain unknown. This study investigated the relationship between IM (measured by plasma citrulline and the chemokine CCL20) and the development of BSI and systemic inflammation (reflected by C-reactive protein, CRP) in children with ALL during high-dose methotrexate (HDMTX) treatment, an important part of ALL consolidation therapy. The study compared patients treated according to the NOPHO ALL 2008 protocol (n = 52) and the ALLTogether1 protocol (n = 42), both with identical HDMTX procedures but different scheduling. One week post-HDMTX, citrulline dropped to median levels of 14.5 and 16.9 µM for patients treated according to the NOPHO ALL 2008 and ALLTogether1 protocols, respectively (p = 0.11). In a protocol and neutrophil count-adjusted analysis, hypocitrullinaemia (<10 µmol/L) was associated with increased odds of BSI within 3 weeks from HDMTX (OR = 26.2, p = 0.0074). Patients treated according to the NOPHO ALL 2008 protocol exhibited increased mucosal- and systemic inflammation post-HDMTX compared to patients treated according to ALLTogether1, with increased CCL20 (14.6 vs. 3.7 pg/mL, p < 0.0001) and CRP levels (10.0 vs. 1.0 mg/L, p < 0.0001). Both citrulline and CCL20 correlated with CRP for these patients (rs = -0.44, p = 0.0016 and rs = 0.35, p = 0.016, respectively). These results suggest that hypocitrullinaemia following HDMTX increases the risk of BSI, confirming previous observations from more intensive treatments. Moreover, these data indicate that the patients' vulnerability to mucositis and inflammatory toxicity after chemotherapy varies with treatment protocol.
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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.
Assuntos
Hemoglobinopatias , Criança , Gravidez , Feminino , Humanos , Adolescente , Adulto Jovem , Adulto , Prevalência , Estudos Retrospectivos , Hemoglobinopatias/diagnóstico , Hemoglobinopatias/epidemiologia , Inquéritos e Questionários , Dinamarca/epidemiologiaRESUMO
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.
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Mucosite , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Criança , Mucosite/induzido quimicamente , Citrulina , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Fatores de Risco , InflamaçãoRESUMO
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.
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Neutropenia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Sepse , Humanos , Criança , Quimiotaxia , Neutrófilos , Quimiotaxia de Leucócito , Neutropenia/diagnóstico , Neutropenia/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológicoRESUMO
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.
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Transtornos da Coagulação Sanguínea , Leucemia-Linfoma Linfoblástico de Células Precursoras , Tromboembolia Venosa , Anticoagulantes/uso terapêutico , Antitrombinas/efeitos adversos , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Criança , Fibrinogênio/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Tromboembolia Venosa/induzido quimicamente , Tromboembolia Venosa/prevenção & controle , Adulto JovemRESUMO
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bacteriemia/diagnóstico , Biomarcadores/sangue , Citrulina/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Bacteriemia/sangue , Bacteriemia/induzido quimicamente , Bacteriemia/microbiologia , Bactérias/isolamento & purificação , Criança , Pré-Escolar , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Quimioterapia de Indução , Lactente , Masculino , Metotrexato/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Vincristina/administração & dosagemRESUMO
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.
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Antineoplásicos/uso terapêutico , Mucosite/induzido quimicamente , Mucosite/tratamento farmacológico , Receptores de Superfície Celular/uso terapêutico , Redução de Peso/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Genótipo , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
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.
Assuntos
Bactérias/classificação , Microbioma Gastrointestinal/efeitos dos fármacos , Quimioterapia de Indução/efeitos adversos , Mucosite/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Análise de Sequência de DNA/métodos , Adolescente , Bactérias/genética , Bactérias/isolamento & purificação , Estudos de Casos e Controles , Criança , Pré-Escolar , DNA Bacteriano/genética , DNA Ribossômico/genética , Fezes/microbiologia , Feminino , Humanos , Lactente , Masculino , Mucosite/microbiologia , Filogenia , Leucemia-Linfoma Linfoblástico de Células Precursoras/microbiologia , Estudos Prospectivos , RNA Ribossômico 16S/genética , IrmãosRESUMO
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.
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Antineoplásicos/toxicidade , Mucosa Gástrica/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosite/induzido quimicamente , Pesquisa Translacional Biomédica/métodos , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Modelos Animais de Doenças , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Mucosa Gástrica/fisiopatologia , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Mucosa Intestinal/fisiopatologia , Mucosite/metabolismo , Mucosite/patologia , Mucosite/fisiopatologia , Especificidade da EspécieAssuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide , Pseudotumor Cerebral , Humanos , Criança , Pseudotumor Cerebral/complicações , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Doença CrônicaRESUMO
The congenital dyserythropoietic anemias (CDAs) are a group of rare inherited blood disorders characterized by ineffective erythropoiesis as the principal cause of anemia. We present a child with CDA 1b-the rarest and least well-described type-due to a mutation in the C15orf41 gene. The patient presented with severe in utero and neonatal manifestations, typical peripheral limb anomalies as well as rarely reported cardiac manifestations, visual impairment, short stature, and hip dysplasia. Anemia was complicated by iron overload and pronounced extra medullary erythropoiesis leading to skull deformities. The patient responded to treatment with pegylated interferon alfa-2a.
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Anemia Diseritropoética Congênita , Hematopoese Extramedular/efeitos dos fármacos , Interferon alfa-2/administração & dosagem , Sobrecarga de Ferro , Mutação , Anemia Diseritropoética Congênita/diagnóstico por imagem , Anemia Diseritropoética Congênita/tratamento farmacológico , Anemia Diseritropoética Congênita/genética , Humanos , Recém-Nascido , Sobrecarga de Ferro/diagnóstico por imagem , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/genética , Masculino , Crânio/anormalidades , Crânio/diagnóstico por imagemRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Mucosite/diagnóstico , Pneumonia/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Proteína D Associada a Surfactante Pulmonar/sangue , Adolescente , Proteína C-Reativa/análise , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Interleucina-6/sangue , Masculino , Mucosite/sangue , Mucosite/induzido quimicamente , Mucosa/efeitos dos fármacos , Estadiamento de Neoplasias , Pneumonia/sangue , Pneumonia/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Estudos ProspectivosRESUMO
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.
Assuntos
Antibióticos Antineoplásicos , Colostro/metabolismo , Doxorrubicina , Nutrição Enteral/efeitos adversos , Fórmulas Infantis/toxicidade , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Mucosite/induzido quimicamente , Animais , Animais Recém-Nascidos , Proteína C-Reativa/metabolismo , Bovinos , Modelos Animais de Doenças , Nutrição Enteral/métodos , Feminino , Humanos , Recém-Nascido , Mediadores da Inflamação/sangue , Interleucina-8/metabolismo , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Masculino , Microvilosidades/enzimologia , Microvilosidades/patologia , Mucosite/metabolismo , Mucosite/patologia , Mucosite/fisiopatologia , Estado Nutricional , Permeabilidade , Sus scrofa , Aumento de PesoRESUMO
OBJECTIVE: 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. METHODS: "Study 1" investigated intestinal parameters 9 days after a single dose of doxorubicin (1â×â75 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, nâ=â13), 4 BC feedings (High-BC, nâ=â13), 2 BC feedings (Low-BC, nâ=â14), or no BC (only BM, nâ=â13). RESULTS: Doxorubicin treatment induced clinical signs of intestinal toxicity with diarrhea and weight loss, relative to controls (Pâ<â0.05). 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 Pâ<â0.05). 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 (Pâ<â0.05 vs BM) and across the BC groups, intestinal toxicity was reduced (Pâ<â0.01). CONCLUSIONS: 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.
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Antibióticos Antineoplásicos/toxicidade , Colostro/efeitos dos fármacos , Doxorrubicina/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/administração & dosagem , Proteína C-Reativa , Bovinos , Colostro/metabolismo , Doxorrubicina/administração & dosagem , Feminino , Mucosa Intestinal/metabolismo , Leite/metabolismo , Suínos , Aumento de PesoRESUMO
BACKGROUND: Information about chemotherapy-induced intestinal gene expression may provide insight into the mechanisms underlying gut toxicity and help identify biomarkers and targets for intervention. METHODS: We analyzed jejunal tissue from piglets subjected to two different, clinically relevant chemotherapy regimens: (1) busulfan plus cyclophosphamide (BUCY) and (2) doxorubicin (DOX). RESULTS: 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. CONCLUSION: In the developing intestine, chemotherapy increases the expression of genes related to innate immune functions involved in surveillance, protection, and homeostasis of mucosal surfaces.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Proteína D Associada a Surfactante Pulmonar/metabolismo , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/patologia , Bussulfano/farmacologia , Bussulfano/uso terapêutico , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Modelos Animais de Doenças , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Quimioterapia Combinada , Regulação da Expressão Gênica/efeitos dos fármacos , Imunidade Inata , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Mucosite/metabolismo , Mucosite/patologia , Proteína D Associada a Surfactante Pulmonar/deficiência , Proteína D Associada a Surfactante Pulmonar/genética , Reação em Cadeia da Polimerase em Tempo Real , SuínosRESUMO
Invasive aspergillosis (IA) is a potentially life-threatening complication of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). We conducted a systematic review and meta-analyses of studies on acute leukemia in children aged 0-17 years since 2000. Findings were reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We included 24 studies with 3,661 ALL patients and 1,728 AML patients. IA cumulative incidence varied (0%-10% for ALL and 0%-18% for AML) across the studies. Pooled cumulative IA incidences were estimated at 3.2% (95% CI: 1.8% - 5.8%) in ALL and 5.2% (95% CI: 3.1% - 8.6%) in AML, with corresponding case-fatality-rates of 13.3% (95% CI: 6.3% - 25.9%) and 7.8% (95% CI: 0.7% - 51.2%), respectively. Our analysis highlights the impact of IA in childhood leukemia, underscoring the need to address strategies for prevention, early detection, and treatment of IA in pediatric leukemia.
RESUMO
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.
Assuntos
Leucemia , Mucosite , Neoplasias , Humanos , Criança , Mucosite/etiologia , Mucosite/complicações , Neoplasias/complicações , Citrulina , Febre/diagnóstico , Febre/etiologiaRESUMO
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.
Assuntos
Neoplasias Encefálicas , Hidrocefalia , Neoplasias Infratentoriais , Criança , Humanos , Estudos Retrospectivos , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/complicações , Fatores de Risco , Morbidade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Hidrocefalia/epidemiologia , Hidrocefalia/cirurgia , Hidrocefalia/complicações , Neoplasias Infratentoriais/cirurgiaRESUMO
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.
Assuntos
Anemia , Humanos , Dinamarca , Estudos de Coortes , Feminino , Masculino , Anemia/diagnóstico , Garantia da Qualidade dos Cuidados de Saúde , CriançaRESUMO
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.