Neurotoxicidad subaguda por metotrexato en pacientes con enfermedad oncohematológica. Reporte de tres casos / Subacute methotrexate neurotoxicity in patients with oncohematological disease. A report of 3 cases

El metotrexato es un fármaco análogo del ácido fólico ampliamente utilizado en el tratamiento de enfermedades autoinmunes, leucemias y linfomas. Su uso puede ocasionar la aparición de múltiples efectos adversos entre los que se encuentran aquellos relacionados con la presencia de toxicidad neurológica, que puede presentarse de forma aguda, subaguda o crónica. La neurotoxicidad subaguda es aquella que ocurre típicamente entre los 2 y los 14 días posteriores a la administración y puede manifestarse con una amplia gama de síntomas neurológicos. En la mayoría de los casos, no recurre con futuras exposiciones al medicamento. Presentamos tres casos de neurotoxicidad subaguda por metotrexato con manifestaciones clínicas diferentes en pacientes oncohematológicos que se internaron entre los años 2018 y 2020. Dos de ellos presentaron recurrencia frente a la nueva administración del fármaco y todos evidenciaron lesiones en resonancia magnética nuclear.

Methotrexate is a folic acid analogue widely used in the treatment of autoimmune diseases, leukemias, and lymphomas. Methotrexate use may cause multiple adverse effects, including those related to the presence of neurological toxicity, which may be acute, subacute, or chronic. Subacute neurotoxicity typically occurs between 2 and 14 days after administration and may present as a wide range of neurological symptoms. In most cases, it does not recur with future exposures to the drug. Here we describe 3 cases of subacute methotrexate neurotoxicity with different clinical manifestations in patients with oncohematological disease who were hospitalized between 2018 and 2020. Two of them showed recurrence with a new drug administration. Lesions were observed in the magnetic resonance imaging tests of all of them.

Prognostic analysis of children with Philadelphia chromosome-like acute lymphoblastic leukemia common genes / 中华儿科杂志

Objective: To summarize the clinical data and prognosis of children with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) common genes. Methods: This was a retrospective cohort study.Clinical data of 56 children with Ph-like ALL common gene cases (Ph-like ALL positive group) treated from January 2017 to January 2022 in the First Affiliated Hospital of Zhengzhou University, Henan Children's Hospital, Henan Cancer's Hospital and Henan Provincial People's Hospital were collected, 69 children with other high-risk B cell acute lymphoblastic leukemia (B-ALL) at the same time and the same age were selected as the negative group. The clinical characteristics and prognosis of two groups were analyzed retrospectively. Comparisons between groups were performed using Mann-Whitney U test and χ2 test. Kaplan-Meier method was used for survival curve, Log-Rank test was used for univariate analysis, and the Cox regression model was used for multivariate prognosis analysis. Results: Among 56 Ph-like ALL positive patients, there were 30 males and 26 females, and 15 cases were over 10 years old. There were 69 patients in Ph-like ALL negative group. Compared with the negative group, the children in positive group were older (6.4 (4.2, 11.2) vs. 4.7 (2.8, 8.4) years), and hyperleukocytosis (≥50×109/L) was more common (25% (14/56) vs. 9% (6/69)), the differences were statistically significant (both P<0.05). In the Ph-like ALL positive group, 32 cases were positive for IK6 (1 case was co-expressed with IK6 and EBF1-PDGFRB), 24 cases were IK6-negative, of which 9 cases were CRLF2 positive (including 2 cases with P2RY8-CRLF2, 7 cases with CRLF2 high expression), 5 cases were PDGFRB rearrangement, 4 cases were ABL1 rearrangement, 4 cases were JAK2 rearrangement, 1 case was ABL2 rearrangement and 1 case was EPOR rearrangement. The follow-up time of Ph-like ALL positive group was 22 (12, 40) months, and 32 (20, 45) months for negative group. The 3-year overall survival (OS) rate of positive group was significantly lower than the negative group ((72±7) % vs. (86±5) %, χ2=4.59, P<0.05). Compared with the 24 IK6-negative patients, the 3-year event free survival (EFS) rate of 32 IK6 positive patients was higher, the difference was statistically significant ((88±9) % vs. (65±14) %, χ2=5.37, P<0.05). Multivariate Cox regression analysis showed that the bone marrow minimal residual disease (MRD) not turning negative at the end of first induction (HR=4.12, 95%CI 1.13-15.03) independent prognostic risk factor for patient with Ph-like ALL common genes. Conclusions: Children with Ph-like ALL common genes were older than other high-risk B-ALL patients at diagnosis, with high white blood cells and lower survival rate. The bone marrow MRD not turning negative at the end of first induction were independent prognostic risk factor for children with Ph-like ALL common gene.

Correlation Analysis between Cerebrospinal Fluid Status and Prognosis in Childhood with Acute Lymphoblastic Leukemia by Flow Cytometry / 中国实验血液学杂志

OBJECTIVE@#To study the cerebrospinal fluid (CSF) status and prognosis value in patients with newly diagnosed acute lymphoblastic leukemia (ALL) by flow cytometry (FCM).@*METHODS@#The clinical features of the 75 newly diagnosed ALL patients from September 2020 to December 2021 in our centre were retrospective analyzed, as well as the bone marrow (BM) and CSF minimal residual disease (MRD) data, and the CSF conventional cytology data. Central nervous system infiltration(CNSI) positive was as CSF MRD positive by FCM or leukemia cells detected by conventional cytology. The status of CSF were compared and analyzed by FCM and conventional cytology, the clinical features and the prognosis value of different CNSI status in these patients were analyzed.@*RESULTS@#Among 75 newly diagnosed ALL, 16 cases (21%) with CNSI positive (CNSI+) were detected by FCM, while only 2 positive cases (3%) were detected by conventional cytology. The CNSI+ rate detected by FCM was significantly higher than conventional cytology(P<0.05). Compared with CNSI- ALL patients, the median age of CNSI+ ALL patients was significantly younger, and the median platelet count was significantly lower, the difference was statistically significant (P<0.05). Up to follow-up time (August 31, 2022), four ALL patients were died, including 3 patients were CNSI- and 1 patient was CNSI+. Furthermore, three cases were primary disease relapse, including 1 case was CNSI+. There was no significant difference in overall survival (OS) rate and relapse-free survival (RFS) rate of the patients with different CNSI status.@*CONCLUSION@#Compared with conventional cytology, FCM is a more sensitive assay to evaluate the central nervous system status in ALL patients. After active treatment, there was no significant difference in OS and RFS between patients with different CNSI status at diagnosis.

A cohort study of vincristine-induced peripheral neuropathy in children / 中国当代儿科杂志

OBJECTIVES@#To study the characteristics of vincristine-induced peripheral neuropathy (VIPN) in children with acute lymphoblastic leukemia (ALL) and the factors influencing the development of VIPN.@*METHODS@#The children with ALL, aged 1-18 years, who were treated with CCCG-ALL2015 or CCCG-ALL2020 regimen in the Affiliated Hospital of Guizhou Medical University from January 2018 to February 2022 were enrolled as subjects. According to the influence of age on risk, the children were divided into 1-10 years group with 91 children and >10 years group with 29 children. VIPN was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (5th edition), and the incidence rate, severity, and type of VIPN were compared between different groups.@*RESULTS@#A total of 120 children were enrolled in this study, among whom 56 (46.7%) developed VIPN. The >10 years group had a significantly higher incidence rate of VIPN than the 1-10 years group (69% vs 40%, P<0.05). Among the 56 children with VIPN, 12 (21%) had grade 3 VIPN or above, and 44 (79%) had grade 2 VIPN. There were 77 cases of autonomic nerve symptoms (59.7%), 42 cases of peripheral nerve injury (32.5%), and 10 cases of cranial nerve injury (7.8%). There were no significant differences in the severity and type of VIPN between the groups with different ages, sexes, degrees of risk, or treatment regimens (P>0.05). The results of binary logistic regression analysis showed that age is the influencing factor for the occurrence of VIPN (P>0.05).@*CONCLUSIONS@#There is a relatively high incidence rate of VIPN in children with ALL, with the highest incidence rate of autonomic nervous symptoms. The incidence of VIP in children over 10 years old is relatively high.

Optimized treatment of childhood B-lineage acute lymphoblastic leukemia / 中国当代儿科杂志

Childhood acute lymphoblastic leukemia (ALL) accounts for about 75% of childhood leukemia cases, and B-lineage acute lymphoblastic leukemia (B-ALL) accounts for more than 80% of childhood ALL cases. Over the past half century, new molecular biological targets discovered by new techniques have been used in precise stratification of disease prognosis, and there has been a gradual increase in the 5-year overall survival rate of childhood ALL. With the increasing attention to long-term quality of life, the treatment of childhood B-ALL has been constantly optimized from induction therapy to the intensity of maintenance therapy, including the treatment of extramedullary leukemia without radiotherapy, which has been tried with successful results. The realization of optimized treatment also benefits from the development of new techniques associated with immunology and molecular biology and the establishment of standardized clinical cohorts and corresponding biobanks. This article summarizes the relevant research on the implementation of precise stratification and the intensity reduction and optimization treatment of B-ALL in recent years, providing reference for clinicians.

Applicability of Seven Glomerular Filtration Rate Evaluation Formulas in Dose Adjustment of High Concentration of Methotrexate Chemotherapy in Children with ALL / 中国实验血液学杂志

OBJECTIVE@#To investigate the diagnostic efficacy of seven glomerular filtration rate (GFR) evaluation formulas Schwartz2009, Schwartz1976, Counahan-Barratt, Filler, CKD-EPIscysc, Cockrofi-Gault, CKD-EPIScysC-Scr in high concentration of methotrexate (HDMTX) chemotherapy dose adjusted cut-off point (GFR ≤85 ml/min) in children with acute lymphoblastic leukemia (ALL).@*METHODS@#One hundred and twenty-four children with ALL were included in the study. GFR determined by renal dynamic imaging (sGFR) was used as the standard to evaluate the accuracy, consistency of eGFR calculated by seven formulas and sGFR, and the diagnostic efficacy of each formula when the sGFR ≤85 ml/min boundary.@*RESULTS@#All of the accuracy of eGFR estimated by Schwartz2009 were greater than 70% in the 0-3, >4 and ≤6, >6 and ≤9, >9 and ≤16 years old group and male group, and the consistency exceeded the professional threshold. When the sensitivity of the ROC curve sGFR ≤85 ml/min was 100% of CKD-EPIscysc in the 0-3, >3 and ≤4 years old group, Filler in the >3 and ≤4 years old group, and Cockrofi-Gault in the >6 and ≤9 years old group, the specificity was 73.02%, 78.95%, 78.95%, 69.32%, respectively, and the AUC under the ROC curve was the largest (P<0.05).@*CONCLUSION@#Schwartz2009 formula predicts the highest accuracy of eGFR in the 7 glomerular filtration rate. CKD-EPIscysc, Filler, and Cockrofi-Gault formulas have more guiding signi-ficance for the adjustment of HDMTX chemotherapy in pre-adolescence in children with ALL when sGFR ≤85 ml/min.

Relación entre competencia para el cuidado domiciliario y la presencia de infecciones respiratorias en niños con tratamiento oncológico en el contexto de la pandemia por COVID-19 / Relationship between competence for home care and the presence of respiratory infections in children with cancer treatment in the context of the COVID-19 pandemic / Relação entre a proficiência para dar os cuidados em casa e a presença de infecções respiratórias em crianças sob tratamento oncológico no contexto da pandemia de COVID-19

Introducción: Los cuidados domiciliarios para los niños con enfermedades neoplásicas, representan costos sociales y económicos, además de posibles riesgos de infección. Por lo que, la importancia del cuidado de los menores ante las infecciones respiratorias virales durante la infancia radica en asegurar las correctas medidas de prevención del contagio. El objetivo de este estudio fue determinar la relación existente entre la competencia para el cuidado domiciliario y la presencia de infecciones respiratorias en los niños con tratamiento oncológico. Método: Estudio de enfoque cuantitativo, diseño correlacional, de corte transversal y descriptivo. La muestra se compone de 75 díadas. La competencia del cuidado domiciliario se midió con el instrumento CUIDAR. El análisis estadístico se realizó con el programa estadístico SPSS versión 25, utilizando estadística descriptiva y estadística inferencial no paramétrica. Resultados: La prevalencia de infecciones respiratorias fue del 4% para los menores con cuidadores con un nivel alto de competencia para el cuidado domiciliario, 12% para el nivel medio y 21.3%para el nivel bajo, mostrando dependencia entre las variables de estudio(X2=14.4, gl= 2, p=0.001). Además, se determinó una asociación (r=-.439, p<.001)entre las mismas. Discusión: La competencia con un nivel alto en los cuidados domiciliarios, supone un adecuado desempeño del rol como cuidador familiar con efecto en calidad de vida de la díada cuidador familiar-persona con cáncer. Conclusiones: A mayor competencia para el cuidado, menor la prevalencia de infecciones respiratorias; existiendo una relación entre la competencia para el cuidado domiciliario y la presencia de infecciones respiratorias en los niños con tratamiento oncológico.

Introduction: Home care for children with neoplastic diseases represents social and economic costs, as well as possible risks of infection. Therefore, the importance of caring for minors in the face of viral respiratory infections during childhood lies in ensuring the correct measures to prevent contagion. The objectiveof this study was to determine the relationship between competence for home care and the presence of respiratory infections in children undergoing cancer treatment. Method: Study of quantitative approach, correlational, cross-sectional and descriptive design. The sample consists of 75 dyads. Home care competence was measured with the CARE instrument. Statistical analysis was performed with the statistical program SPSS version 25.0, using descriptive statistics and non-parametric inferential statistics. Results: The prevalence of respiratory infections was 4% for children with caregivers with a high level of home care competence, 12% for the medium level and 21.3% for the low level, showing dependence between the study variables (X2=14.4, gl= 2, p=0.001). In addition, an association (r=-.439, p<.001) was determined between them. Discussion: The competence with a high level in home care supposes an adequate performance of the role as family caregiver with effect on quality of life of the family caregiver-person with a cancer dyad. Conclusions:The higher the caregiving competence, the lower the prevalence of respiratory infections; there is a relationship between home caregiving competence and the presence of respiratory infections in children undergoing cancer treatment.

Introdução: Os cuidados domiciliares para as crianças com doenças neoplásicas representam custos sociais e econômicos, além dos possíveis riscos de infecção. Por isso, a importância de tomar conta delas no que diz respeito às infecções respiratórias virais durante sua meninice radica em segurar as medidas adequadas para prevenir o contágio. O objetivo deste estúdio foi determinar a relação entre as infecções respiratórias nas crianças sob tratamento contra o cancro e a habilitação para lhes fornecer os cuidados em casa. Método: Estúdio da abordagem quantitativa, desenho correlacional, de corte transversal e descritivo. A amostra se compõe de 75 díades. A habilitação dos cuidados em casa foi medida com o instrumento TOMAR CONTA. A análise estatística se realizou com o programa estatístico SPSS, versão 25. Foi utilizada a estatística descritiva e a estatística inferencial não paramétrica. Resultados: A prevalência de infecções respiratórias foi de 4% para as crianças que receberam os cuidados em casa com um alto nível de efetividade; 12%, quando a efetividade dos cuidados foi intermediária; e para a baixa chegou até 21,3%. Isto demonstra a correlação entre as variáveis de estudo (X2= 14,4; gl= 2; p= 0,001). Além disso, se determinou uma associação (r= -,439; p<,001) entre elas. Discussão:A aptidão adequada para fornecer os cuidados em casa aponta que o responsável pela família desempenhou bem seu papel, o que fez com que houvesse repercussões positivas na qualidade de vida da díade "cuidador familiar-pessoa com câncer". Conclusões: Quanto maior é a proficiência para dar os cuidados, menor é o impacto das infecções respiratórias. Existe uma relação entre a habilitação para os cuidados em casa e a presença de infecções respiratórias nas crianças que recebem tratamentos oncológicos

Evolução do Estado Nutricional de Crianças e Adolescentes com Leucemia Linfoide Aguda submetidos à Terapia Oncológica / Evolution of the Nutritional status of Children and Adolescents with Acute Lymphoid Leukemia undergoing Cancer Therapy / Evolución del Estado Nutricional de Niños y Adolescentes con Leucemia Linfoide Aguda en Tratamiento Oncológico

Introdução: Quando se fala em câncer infantojuvenil, a leucemia linfoide aguda (LLA) ganha destaque por causa da sua elevada prevalência nessa população. De todos os tipos de câncer que atingem esse público, crianças e adolescentes parecem ser mais suscetíveis aos efeitos adversos como a má nutrição e/ou excesso de peso ao longo do tratamento. Objetivo: Avaliar a evolução do estado nutricional de crianças e adolescentes com LLA submetidos à terapia oncológica. Método: Estudo retrospectivo, longitudinal, com pacientes portadores de LLA submetidos à terapia antineoplásica, realizado com 69 crianças e adolescentes (até 19 anos), de ambos os sexos. As medidas de peso e altura foram coletadas em oito ocasiões distintas ao longo de todo o tratamento, tendo o primeiro registro acontecido no início e o último ao término de todas as sessões do tratamento antineoplásico. Resultados: Ao diagnóstico, houve uma prevalência de pacientes classificados como eutróficos. Quando correlacionados a faixa etária e o indicador Altura/Idade para idade, foi observado que crianças menores de 10 anos apresentaram valores mais baixos se comparados com os maiores de 10 anos no decorrer do tratamento, além de uma tendência de incremento no escore Peso/Idade de forma lenta até o seu final. Conclusão: Os pacientes submetidos ao tratamento antineoplásico de LLA apresentaram uma redução na velocidade de crescimento, além de leve ganho de peso ao final da terapia, o que sugere uma interferência negativa da terapêutica empregada sobre o estado nutricional nessa população

Introduction: When it comes to childhood cancer, acute lymphoid leukemia (ALL) stands out due to its high prevalence in this population. Of all types of cancer affecting this population, children and adolescents seem to be more susceptible to adverse effects such as malnutrition and/or overweight during treatment. Objective: To evaluate the evolution of the nutritional status of children and adolescents with acute ALL undergoing cancer therapy. Method: Retrospective, longitudinal study with patients with ALL undergoing antineoplastic therapy carried out with 69 children and adolescents (up to 19 years old) of both sexes. Weight and height measurements were collected on eight different occasions throughout the treatment, the first at the beginning of the treatment and the last at the end of all the sessions of antineoplastic treatment. Results: At diagnosis, there was prevalence of patients classified as eutrophic. When the age group and the indicator of Height/Age for age were correlated, it was observed that children under 10 years old had lower values when compared to those older than 10 years during the treatment, in addition to a rising trend of the Weight/Age score slowly until its end. Conclusion: Patients undergoing antineoplastic treatment for ALL presented a reduction in the velocity of growth, in addition to a slight weight gain at the end of the therapy, which suggests a negative interference on the nutritional status of this population

Introducción: En lo que respecta al cáncer infantil, se destaca la leucemia linfoide aguda (LLA) por su alta prevalencia en esta población. De todos los tipos de cáncer que afectan a este público, los niños y adolescentes parecen ser más susceptibles a efectos adversos como desnutrición y/o sobrepeso durante el tratamiento. Objetivo: Evaluar la evolución del estado nutricional de niños y adolescentes con LLA en tratamiento oncológico. Método: Estudio longitudinal retrospectivo con pacientes con LLA sometidos a tratamiento antineoplásico. Realizado con 69 niños y adolescentes (hasta 19 años), de ambos sexos. Las medidas de peso y talla se recogieron en ocho ocasiones diferentes a lo largo del tratamiento, donde el primer registro tuvo lugar al inicio del tratamiento y el último al final de todas las sesiones de tratamiento antineoplásico. Resultados: Al diagnóstico, hubo una prevalencia de pacientes clasificados como eutróficos. Cuando el grupo de edad y el indicador Altura/Edad se correlacionaron, se observó que los niños menores de 10 años presentaron valores menores en comparación con los mayores de 10 años durante el tratamiento, además de una tendencia a aumentar el Peso/Edad puntúe lentamente hasta el final. Conclusión: Los pacientes sometidos a tratamiento antineoplásico de LLA mostraron una reducción en la velocidad de crecimiento, además de un ligero aumento de peso al final de la terapia, lo que sugiere una interferencia negativa de la terapia utilizada sobre el estado nutricional de esta población

Clinical analysis of 3 cases of mucormycosis in children with acute lymphoblastic leukemia and literature review / 中华儿科杂志

Objective: To investigate the clinical features, diagnosis,treatment and prognosis of children with acute lymphoblastic leukemia complicated with mucormycosis, and to improve the understanding of the disease. Methods: The clinical data of 3 children with acute lymphoblastic leukemia (ALL) complicated with mucormycosis treated at the First Affiliated Hospital of Zhengzhou University between October 2020 and January 2021 were analyzed retrospectively. Literature search and review covered the China national knowledge infrastructure, Wanfang database and Pubmed using the keywords of "acute lymphoblastic leukemia" and "mucormycosis" up to June 2021. Results: Case 1, a 12-year-old boy, was diagnosed with ALL, developed fever and chest pain during induction therapy. The Metagenomic next-generation sequencing (mNGS) testing of alveolar perfusion fluid suggested infection with Rhizopus oryzae. Amphotericin B combined with posaconazole was applied and amphotericin B was removed after improvement. Bone destruction was indicated by CT. Amphotericin B was applied again. Case 2, a 4-year-old boy, with a history of pallor and tetter, was diagnosed with ALL. He developed cough and fever during induction therapy. mNGS of blood suggested infection with Rhizomucor pusillus. Amphotericin B combined with voriconazole was applied, but the situation was not significantly improved. The disseminated infection occurred. Amphotericin B combined with posaconazole was applied and vacuum sealing drainage was performed. Case 3, a 2-year-old girl, was diagnosed with ALL, developed fever and cough during induction therapy. Rhizomucor pusillus was indicated by mNGS. Amphotericin B combined with posaconazole was used, and posaconazole was stopped after improvement. Follow-up until June 2021, the condition of the 3 children improved. There was no recurrent Mucor infection, and the primary hematopathy was in complete remission. According to the literature, 7 reports were found in Chinese journals, while 17 reports were found in English literature, 25 cases have been reported. Among a total of 28 children, 11 cases rhino-orbito-cerebral mucormycosis, four pulmonary mucormycosis, 2 cutaneous mucormycosis, 2 gastrointestinal mucormycosis and 9 disseminated mucormycosis. There were 17 cases developed infection during induction chemotherapy, 8 cases during maintenance therapy, 3 cases after hematopoietic stem cell transplantation. Voriconazole was used in 15 cases; 19 cases were treated with combined surgery, 7 cases were treated with drugs only, 2 cases were untreated; 21 cases showed improvement after treatment. Death occurred in seven cases. Conclusions: ALL complicated with mucormycosis often occurs in the stage of induction therapy. The clinical features lacked specificity, mNGS can help find the pathogen and provide evidence for diagnosis. Surgical treatment also could be combined when necessary, which is helpful to improve the prognosis.

Prognostic Value of Average Daily Platelet Increase in Childhood B-cell Acute Lymphoblastic Leukemia Patients / 中国实验血液学杂志

OBJECTIVE@#To evaluate the prognosis value of average daily platelet amount increase in children with B-cell acute lymphoblastic leukemia(B-ALL) treated by CCCG-ALL-2015 regimen.@*METHODS@#106 children with primary B-ALL were retrospective analyzed, standardized MRD test protocol was used to detect the MRD level (19 d and 46 d) after chemotherapy. The platelet count was measured by Sysmex XE-2100. Kaplan-Meier survival curve statistics was used to analyze the event free survival(EFS) rate of the children.@*RESULTS@#The trend of negative correlation existed between PPC and TPR (rs=-0.519, P=0.021). The 3-year EFS rate of the patients in Ap>5.4×109/L group was 95.7%, which was significantly higher than those in Ap≤5.4×109/L group(79.5%) (χ2=5.236, P=0.035); multivariate analysis showed that Ap≤5.4×109/L was the independent prognostic factor affecting survival of the patients (RR=3.978; 95%CI: 1.336-11.523, P=0.041). With both MRD and Ap≤5.4×109/L as candidate variables, Ap≤5.4×109/L lost its independent prognostic value (RR=1.225; 95%CI: 0.892-13.696, P=0.089), the correlation between d 19/d 46 MRD levels and Ap>5.4×109/L (χ2=4.318, P=0.038) could explain the phenomenon.@*CONCLUSION@#Ap can reflect the effect of B-ALL chemotherapy and can be used to monitor the curative effect and prognosis of B-ALL children.

Single Center Clinical Analysis of Bloodstream Infection Pathogens in Children with Acute Leukemia / 中国实验血液学杂志

OBJECTIVE@#To investigate the clinical features, distribution of pathogenic bacteria, and drug resistance of bloodstream infection in children with acute leukemia.@*METHODS@#Clinical data of 93 blood culture-positive children with acute leukemia from January 2015 to December 2019 in Department of Pediatrics, The Second Hospital of Anhui Medical University were analyzed retrospectively.@*RESULTS@#In these 93 cases, 78 cases were in the period of neutrophil deficiency. There were 54 Gram-negative bacteria (G-) (58.1%) found through blood culture, and the top 4 strains were Escherichia coli (15.1%), Klebsiella pneumoniae (13.9%), Pseudomonas aeruginosa (6.5%), and Enterobacter cloacae (6.5%). There were 39 Gram-positive bacteria (G+) (41.9%) detected, and the top 4 strains were Staphylococcus epidermidis (10.8%), Streptococcus pneumoniae (6.5%), Staphylococcus hemolyticus (5.4%), and Staphylococcus human (5.4%). Among 74 strains of pathogenic bacteria from acute lymphoblastic leukemia (ALL) children, there were 29 strains of G+ bacteria (39.2%) and 45 strains of G- bacteria (60.8%). While in 19 strains from acute myeloblastic leukemia (AML) patients, G- bacteria accounted for 47.4% and G+ bacteria accounted for 52.6%. In 15 ALL children without neutropenia, G+ bacteria made up the majority of the strains (66.7%). In the 93 strains of pathogenic bacteria, 13 (13.9%) strains were multidrug-resistant. Among them, extended-spectrum β-lactamases accounted for 42.9%, carbapenemase-resistant enzyme Klebsiella pneumoniae 15.4%, and carbapenemase-resistant enzyme Enterobacter cloacae strains 33.3%, which were detected from G- bacteria. While, 13.3% of methicillin-resistant coagulase-negative Staphylococci accounted for 13.3% detected from G+ bacteria, but linezolid, vancomycin, teicoplanin Staphylococcus and Enterococcus resistant were not found. The average procalcitonin (PCT) value of G- bacteria infection was (11.02±20.282) ng/ml, while in G+ infection it was (1.81±4.911) ng/ml, the difference was statistically significant (P<0.05). The mean value of C-reactive protein (CRP) in G- infection was (76.33±69.946) mg/L, and that in G+ infection was (38.34±57.951) mg/L. The prognosis of active treatment was good, and only one case died of septic shock complicated with disseminated intravascular coagulation (DIC) and gastrointestinal bleeding caused by carbapenemase-resistant enzyme enterobacteriaceae.@*CONCLUSION@#G- is the major bacteria in acute leukemia children with bloodstream infection, but the distribution of ALL and AML strains is different. G- bacteria dominates in ALL, while G+ bacteria and G- bacteria are equally distributed in AML. Non-agranulocytosis accompanied by bloodstream infections is dominant by G+ bacteria. The mean value of PCT and CRP are significantly higher in G- bacteria infection than in G+ bacteria.

Changes of intestinal flora in children with acute lymphoblastic leukemia before and after chemotherapy / 中国当代儿科杂志

OBJECTIVES@#To examine the changes of intestinal flora in children newly diagnosed with acute lymphoblastic leukemia (ALL) and the influence of chemotherapy on intestinal flora.@*METHODS@#Fecal samples were collected from 40 children newly diagnosed with ALL before chemotherapy and at 2 weeks, 1 month, and 2 months after chemotherapy. Ten healthy children served as the control group. 16S rDNA sequencing and analysis were performed to compare the differences in intestinal flora between the ALL and control groups and children with ALL before and after chemotherapy.@*RESULTS@#The ALL group had a significant reduction in the abundance of intestinal flora at 1 and 2 months after chemotherapy, with a significant reduction compared with the control group (P<0.05). Compared with the control group, the ALL group had a significant reduction in the diversity of intestinal flora before and after chemotherapy (P<0.05). At the phylum level, compared with the control group, the ALL group had a significant reduction in the relative abundance of Actinobacteria at 2 weeks, 1 month, and 2 months after chemotherapy (P<0.05) and a significant increase in the relative abundance of Proteobacteria at 1 and 2 months after chemotherapy (P<0.05). At the genus level, compared with the control group, the ALL group had a significant reduction in the relative abundance of Bifidobacterium at 2 weeks, 1 month, and 2 months after chemotherapy (P<0.05); the relative abundance of Klebsiella in the ALL group was significantly higher than that in the control group at 1 and 2 months after chemotherapy and showed a significant increase at 1 month after chemotherapy (P<0.05); the relative abundance of Faecalibacterium in the ALL group was significantly lower than that in the control group before and after chemotherapy and showed a significant reduction at 2 weeks and 1 month after chemotherapy (P<0.05). The relative abundance of Enterococcus increased significantly at 1 and 2 months after chemotherapy in the ALL group (P<0.05), and was significantly higher than that in the control group (P<0.05).@*CONCLUSIONS@#The diversity of intestinal flora in children with ALL is significantly lower than that in healthy children. Chemotherapy significantly reduces the abundance of intestinal flora and can reduce the abundance of some probiotic bacteria (Bifidobacterium and Faecalibacterium) and increase the abundance of pathogenic bacteria (Klebsiella and Enterococcus) in children with ALL.

Distribution and drug resistance profiles of pathogens causing bloodstream infection after chemotherapy in children with acute lymphoblastic leukemia / 中国当代儿科杂志

OBJECTIVES@#To study the changes in the distribution and drug resistance profiles of pathogens causing bloodstream infection after chemotherapy in children with acute lymphoblastic leukemia.@*METHODS@#The medical data were collected from the children with acute lymphoblastic leukemia who were admitted to the First Affiliated Hospital of Zhengzhou University between January 2015 and December 2020 and developed bloodstream infection after chemotherapy. The samples were divided into the first three years group and the next three years group according to the time of testing to investigate the differences in the distribution and drug resistance profiles of pathogens as time.@*RESULTS@#A total of 235 strains of pathogens were isolated, among which there were 159 Gram-negative strains (67.7%; mainly Escherichia coli and Klebsiella pneumoniae), 61 Gram-positive strains (26.0%; mainly Staphylococcus epidermidis), and 15 strains of fungi (6.4%; mainly Candida albicans). There were no significant differences between the first three years group and the next three years group in the detection rate of Gram-negative bacteria (68.8% vs 66.9%, P>0.05) or Gram-positive bacteria (29.2% vs 23.7%, P>0.05). Compared with the first three years group, the next three years group had significant increases in the detection rate of Streptococcus mitis (5.8% vs 0.0%, P<0.05) and fungi (9.4% vs 2.1%, P<0.05). There was no significant difference in the drug resistance rate of Gram-negative or Gram-positive bacteria between the two groups (P>0.05).@*CONCLUSIONS@#Enterobacteriaceae bacteria are the main pathogens of bloodstream infection after chemotherapy in children with acute lymphoblastic leukemia, while the detection rates of Streptococcus mitis and fungi tend to increase as time, which needs to be taken seriously in clinical practice.

Preclinical characterization and comparison between CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecific antibodies against B-cell acute lymphoblastic leukemia: targeted immunotherapy for acute lymphoblastic leukemia / 医学前沿

The CD19-targeting bispecific T-cell engager blinatumomab has shown remarkable efficacy in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. However, several studies showed that blinatumomab has a short plasma half-life due to its low molecular weight, and thus its clinical use is limited. Furthermore, multiple trials have shown that approximately 30% of blinatumomab-relapsed cases are characterized by CD19 negative leukemic cells. Here, we design and characterize two novel antibodies, A-319 and A-2019. Blinatumomab and A-319 are CD3/CD19 bispecific antibodies with different molecular sizes and structures, and A-2019 is a novel CD3/CD19/CD20 trispecific antibody with an additional anti-CD20 function. Our in vitro, ex vivo, and in vivo experiments demonstrated that A-319 and A-2019 are potent antitumor agents and capable of recruiting CD3 positive T cells, enhancing T-cell function, mediating B-cell depletion, and eventually inhibiting tumor growth in Raji xenograft models. The two molecules are complementary in terms of efficacy and specificity profile. The activity of A-319 demonstrated superior to that of A-2019, whereas A-2019 has an additional capability to target CD20 in cells missing CD19, suggesting its potential function against CD19 weak or negative CD20 positive leukemic cells.

Quimioterapia intensiva asociada a imatinib en leucemia linfoblástica aguda del adulto, Philadelphia positivo. Experiencia en un hospital público / Intensive chemotherapy with tyrosine kinase inhibitors in philadelphia-positive acute lymphoblastic leukemia

Background: Before the advent of tyrosine kinase inhibitors (TKIs), patients with Philadelphia-positive Acute Lymphoblastic Leukemia (Ph+ALL) had a poor prognosis. The association of TKIs to intensive chemotherapy (CT) improved outcome. Aim: To evaluate results of an intensive CT protocol including TKI in a public hospital in Santiago, Chile. Material and Methods: All patients with Ph+ALL diagnosed between January 2010 and February 2019, and who met inclusion criteria for intensive CT, received the Ph+ALL national protocol in association with imatinib and were included in this analysis. Results: Thirty-five patients aged 15 to 59 years received treatment. Complete response (CR) was obtained in 97%. Measurable residual disease (MRD) was negative in 61% (19/31 evaluable cases) during follow-up, and 55% (16/29) were MRD (-) before three months. Relapse was observed in 13 cases. Three patients underwent allogeneic hematopoietic stem cell transplant (HSCT), two in CR1. The overall survival (OS) and event-free survival (EFS) at three years were 52 and 34%, respectively. In patients who achieved MRD negativity before three months, no statistically significant differences in OS (64 and 42% respectively, p = 0.15) or EFS (35 and 32% respectively, p = 0.37) were observed. Conclusions: The prognosis of Ph+ALL improved with the association of imatinib to intensive CT. MRD-negative status before three months in this series was not significantly associated with better outcomes. Our series suggests that the Ph+ALL national protocol associated to TKI is a therapeutic alternative with high CR and aceptable MRD (-) rates.

Encefalopatía subaguda reversible por metotrexato: notificación de un caso pediátrico / Methotrexate-induced stroke-like syndrome: A pediatric case report

Las leucemias son las neoplasias malignas más frecuentes en la infancia; la leucemia linfoblástica aguda (LLA) es la más frecuente. Desde principios de los 80, la adición de metotrexato intratecal a los esquemas de quimioterapia ha sido beneficiosa para prevenir la recidiva en el sistema nervioso central y evitar el uso de radioterapia. Su mecanismo de acción es la inhibición de la enzima dihidrofolato reductasa, por lo que posee múltiples efectos adversos (neurotoxicidad aguda, subaguda o crónica) después de la infusión intratecal o de dosis altas por vía intravenosa.Se presenta un paciente de 11 años con diagnóstico de LLA de línea T (LLA-T), que presenta hemiparesia faciobraquial y afasia de expresión de instauración aguda 8 días después de la administración intratecal de metotrexato. Luego de excluir otras patologías más frecuentes de origen vascular y la evolución típica del cuadro, con resolución espontánea ad integrum de los síntomas, se arribó al diagnóstico de encefalopatía subaguda reversible por metotrexato.

Leukemias are the most frequent malignant neoplasms in childhood; acute lymphoblastic leukemia (ALL) is the most frequent. The addition of intrathecal methotrexate to chemotherapy regimens has been beneficial in preventing relapse to the central nervous system and avoiding the use of radiation therapy. Due to its mechanism of action, by inhibiting the enzyme dihydrofolate reductase, when it is used systemically, it has multiple expected adverse effects such as mucositis, myelosuppression and it has also been observed after intrathecal administration or high intravenous doses, acute, subacute neurotoxicity where stroke like syndrome is found. We present an 11-year-old patient diagnosed with T-ALL, who manifested after 8 days of intrathecal administration of methotrexate, faciobrachial hemiparesis and acute onset expression aphasia. The diagnosis of subacute encephalopathy reversible by methotrexate was reached by excluding other more frequent pathologies and the typical evolution, with spontaneously ad integrum resolution of the symptoms

Seed oil of Brucea javanica induces apoptosis through the PI3K/Akt signaling pathway in acute lymphocytic leukemia Jurkat cells / 中国天然药物

Brucea javanica oil emulsion (BJOE) has been used to treat tumor in China for more than 40 years. However, its components and effectiveness in the treatment of acute lymphocytic leukemia (ALL) and its mechanism of anti-cancer activity remain unknown. In the current study, high-performance liquid chromatography-evaporative light scattering detector (HPLC-ELSD) was used to analyze the components of BJOE. Then, the anti-leukemia effects of BJOE were examined both in vitro and in vivo using ALL Jurkat cells and the p388 mouse leukemia transplant model, respectively. The primary ALL leukemia cells were also used to confirm the anti-leukemia effects of BJOE. The apoptotic-related results indicated that BJOE induced apoptosis in Jurkat cells and were suggestive of intrinsic apoptotic induction. Moreover, BJOE inhibited Akt (protein kinase B) activation and upregulated its downstream targets p53 and FoxO1 (forkhead box gene, group O-1) to initiate apoptosis. The activation of GSK3β was also involved. Our findings demonstrate that BJOE has anti-leukemia effects on ALL cells and can induce apoptosis in Jurkat cells through the phosphoinositide3-kinase (PI3K) /Akt signaling pathway.

Clinical features and prognosis of children with acute leukemias of ambiguous lineage under different diagnostic criteria / 中国当代儿科杂志

OBJECTIVES@#To study the clinical features and prognosis of children with acute leukemias of ambiguous lineage (ALAL) under different diagnostic criteria.@*METHODS@#A retrospective analysis was performed on the medical data of 39 children with ALAL who were diagnosed and treated from December 2015 to December 2019. Among the 39 children, 34 received treatment. According to the diagnostic criteria for ALAL by World Health Organization and European Group for the Immunological Characterization of Leukemias, the 39 children were divided into two groups: ALAL group (@*RESULTS@#The 34 children receiving treatment had a 3-year event-free survival (EFS) rate of 75%±9% and an overall survival rate of 88%±6%. The children treated with acute myeloid leukemia (AML) protocol had a 3-year EFS rate of 33%±27%, those treated with acute lymphoblastic leukemia (ALL) protocol had a 3-year EFS rate of 78%±10%, and those who had no remission after induction with AML protocol and then received ALL protocol had a 3-year EFS rate of 100%±0% (@*CONCLUSIONS@#ALL protocol has a better clinical effect than AML protocol in children with ALAL, and positive MRD after induction therapy suggests poor prognosis. Hyperleukocytosis and adverse genetic changes are not observed in children with myeloid expression, and such children tend to have a good prognosis, suggesting that we should be cautious to take it as ALAL in diagnosis and treatment.

Efficacy of Posaconazole for Primary Prophylaxis in the Induction Therapy of Childhood Acute Lymphoblastic Leukemia / 中国实验血液学杂志

OBJECTIVE@#To explore the effect of posaconazole in the primary prevention of invasive fungal disease (IFD) in the induction therapy of childhood acute lymphoblastic leukemia (ALL).@*METHODS@#From August 2018 to November 2020, 144 pediatric patients with ALL treated in Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University were selected, 88 cases received fluconazole as IFD prophylaxis (fluconazole prophylaxis group), 56 cases received posaconazole as IFD prophylaxis (posaconazole prophylaxis group). The incidence of IFD and treatment-related adverse reactions between the two groups were compared, and the safety of posaconazole was evaluated.@*RESULTS@#The incidence of IFD in the fluconazole prophylaxis group was 20.4% (18/88), and in the posaconazole prophylaxis group was 7.1% (4/56). The incidence of IFD between the two groups was statistically significant different(P=0.030). There was no serious adverse reactions in the two groups. The incidence of mild adverse reactions in the posaconazole prophylaxis group (23.2%) was lower than that in the fluconazole prophylaxis group(39.8%), and the difference was statistically significant (P=0.039). There were 12 cases died in the fluconazole prophylaxis group and 4 in the posaconazole prophylaxis group, while no significant difference in the overall survival rate between the two groups (P=0.281).@*CONCLUSION@#The effect of posaconazole in the primary prophylaxis of IFD is better and incidence of adverse reactions is lower than fluconazole. Posaconazole can be tolerated, and expected to become the first-line primary prophylaxis drug for IFD during the induction remission therapy of childhood ALL.

Analysis on Death Cases in Children with Acute Lymphoblastic Leukemia Treated with the CCLG-ALL 2008 Protocol / 中国实验血液学杂志

OBJECTIVE@#To retrospective analyze the reason of death in children with acute lymphoblastic leukemia (ALL) treated with CCLG-ALL 2008 protocol, and the experience was summarized in order to reduce the mortality.@*METHODS@#916 children diagnosed as ALL and accepted CCLG-ALL 2008 protocol from April 2008 to April 2015 in our hospital were enrolled, the dead cases in them were analyzed retrospectively.@*RESULTS@#169 children died, including 111 (65.7%) males and 58 (34.3%) females. Recurrence was the main reason of death. 150 (88.7%) children died due to recurrence, among them, 86 (57.3%) cases gave up directly. The second reason of death was infection. The main clinical sites of infection were concentrated in respiratory system and digestive system. Bacterial infection was most common (Gram-negative was common).@*CONCLUSION@#Enough finance and improving family compliance can decrease the mortality in children with ALL. Early rational use of antibiotics can reduce infection-related mortality in children with ALL.