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1.
Int J Cancer ; 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-39150399

RESUMEN

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.

2.
Int J Mol Sci ; 25(17)2024 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-39273528

RESUMEN

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


Asunto(s)
Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina , Factor I del Crecimiento Similar a la Insulina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Niño , Factor I del Crecimiento Similar a la Insulina/metabolismo , Femenino , Masculino , Preescolar , Adolescente , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Lactante , Estudios Prospectivos , Regulación hacia Arriba/efectos de los fármacos , Interleucina-6/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteína C-Reactiva/metabolismo , Péptidos Similares a la Insulina
3.
Int J Cancer ; 153(9): 1635-1642, 2023 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-37387257

RESUMEN

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.


Asunto(s)
Mucositis , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Niño , Mucositis/inducido químicamente , Citrulina , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Factores de Riesgo , Inflamación
4.
Eur J Haematol ; 110(6): 762-771, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36950865

RESUMEN

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.


Asunto(s)
Neutropenia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Sepsis , Humanos , Niño , Quimiotaxis , Neutrófilos , Quimiotaxis de Leucocito , Neutropenia/diagnóstico , Neutropenia/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico
5.
Pediatr Blood Cancer ; 68(1): e28793, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33155402

RESUMEN

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.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bacteriemia/diagnóstico , Biomarcadores/sangre , Citrulina/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Bacteriemia/sangre , Bacteriemia/inducido químicamente , Bacteriemia/microbiología , Bacterias/aislamiento & purificación , Niño , Preescolar , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Quimioterapia de Inducción , Lactante , Masculino , Metotrexato/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Vincristina/administración & dosificación
6.
Int J Cancer ; 147(7): 1953-1962, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32115690

RESUMEN

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.


Asunto(s)
Bacterias/clasificación , Microbioma Gastrointestinal/efectos de los fármacos , Quimioterapia de Inducción/efectos adversos , Mucositis/inducido químicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Análisis de Secuencia de ADN/métodos , Adolescente , Bacterias/genética , Bacterias/aislamiento & purificación , Estudios de Casos y Controles , Niño , Preescolar , ADN Bacteriano/genética , ADN Ribosómico/genética , Heces/microbiología , Femenino , Humanos , Lactante , Masculino , Mucositis/microbiología , Filogenia , Leucemia-Linfoma Linfoblástico de Células Precursoras/microbiología , Estudios Prospectivos , ARN Ribosómico 16S/genética , Hermanos
7.
Immunopharmacol Immunotoxicol ; 41(2): 285-291, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30892107

RESUMEN

Background: The majority of children undergoing allogenic hematopoietic stem cell transplantation (HSCT) experience severe pain due to chemotherapy-induced gastrointestinal toxicity. Inter-individual differences in pain perceived and opioid consumption remain unexplained, limiting the possibility for individualized pain control. The aim of this study was to investigate the associations between opioid consumption and markers of gastrointestinal toxicity (plasma citrulline) and systemic inflammation (plasma CRP and IL-6) in these patients. Methods: We retrospectively included 38 children undergoing HSCT in Denmark in 2010-2012. Opioids doses on days 0-21 post-HSCT were registered as intravenous morphine equivalents (MEs). CRP was measured daily on days 0-21. IL-6 was measured on day 7. Citrulline was measured before conditioning, on days 7 and 21. Results: Out of 38 children, 37 (97%) received opioids during days 0-21. CRP level and ME dose peaked on days 9-10 while citrulline level reached a nadir on day 7 indicating maximum enterocyte loss. CRP was associated with ME dose, with an estimated increase of 0.030 mg/kg (95% CI 0.024-0.035) in ME for a 50% increase in CRP level on the same day (p < .001). IL-6 was correlated with ME on day 7 (rho = 0.55, p = .002). Citrulline did not correlate with ME. Conclusions: Opioid consumption in the early post-HSCT period is associated with the degree of chemotherapy-induced systemic inflammation and not with the extent of enterocyte loss. These findings contribute to our understanding of mucositis-related pain and may be of interest for future studies on therapeutic strategies.


Asunto(s)
Enfermedades Gastrointestinales/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas , Morfina/administración & dosificación , Dolor/tratamiento farmacológico , Adolescente , Aloinjertos , Proteína C-Reactiva/metabolismo , Niño , Preescolar , Citrulina/sangre , Enterocitos/metabolismo , Enterocitos/patología , Femenino , Enfermedades Gastrointestinales/sangre , Enfermedades Gastrointestinales/genética , Enfermedades Gastrointestinales/patología , Humanos , Lactante , Inflamación/sangre , Inflamación/tratamiento farmacológico , Inflamación/etiología , Interleucina-6/sangre , Masculino , Dolor/sangre , Dolor/etiología , Dolor/patología
8.
Pediatr Blood Cancer ; 64(9)2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28423235

RESUMEN

BACKGROUND: Hepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6-thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG-asparaginase) therapy in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG-asparaginase, combined with other drugs, may trigger SOS during 6-thioguanine-free maintenance therapy. PROCEDURE: In children with ALL treated in Denmark according to the NOPHO ALL2008 protocol, we investigated the risk of SOS during methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy that included PEG-asparaginase until week 33 (randomized to two- vs. six-week intervals), as well as alternating high-dose MTX or vincristine/dexamethasone pulses every four weeks. RESULTS: Among 130 children receiving PEG-asparaginase biweekly, 29 developed SOS (≥2 criteria: hyperbilirubinemia, hepatomegaly, ascites, weight gain ≥2.5%, unexplained thrombocytopenia <75 × 109 l-1 ) at a median of 30 days (interquartile range [IQR]: 17-66) into maintenance (cumulative incidence: 27%). SOS cases fulfilling one, two, or three Ponte di Legno criteria were classified as possible (n = 2), probable (n = 8), or verified (n = 19) SOS, respectively. Twenty-six cases (90%) occurred during PEG-asparaginase treatment, including 21 (81%) within 14 days from the last chemotherapy pulse compared with the subsequent 14 days (P = 0.0025). Cytotoxic 6MP metabolites were significantly higher on PEG-asparaginase compared to after its discontinuation. Time-dependent Cox regression analysis showed increased SOS hazard ratio (HR) for erythrocyte levels of methylated 6MP metabolites (HR: 1.09 per 1,000 nmol/mmol hemoglobin increase, 95% confidence interval: 1.05-1.14). Six-week PEG-asparaginase intervals significantly reduced SOS-specific hazards (P < 0.01). CONCLUSIONS: PEG-asparaginase increases cytotoxic 6MP metabolite levels and risk of SOS, potentially interacting with other chemotherapy pulses.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Asparaginasa/administración & dosificación , Asparaginasa/efectos adversos , Niño , Preescolar , Interacciones Farmacológicas , Femenino , Humanos , Lactante , Estimación de Kaplan-Meier , Quimioterapia de Mantención , Masculino , Mercaptopurina/administración & dosificación , Mercaptopurina/efectos adversos , Mercaptopurina/metabolismo , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Modelos de Riesgos Proporcionales
9.
JPEN J Parenter Enteral Nutr ; 44(2): 337-347, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-30861163

RESUMEN

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.


Asunto(s)
Antineoplásicos , Calostro , Enfermedades Gastrointestinales , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animales , Antineoplásicos/efectos adversos , Bovinos , Niño , Método Doble Ciego , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/tratamiento farmacológico , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Embarazo
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