Efficacy and safety of withholding antimicrobial therapy in children with cancer, fever, and neutropenia, with a demonstrated viral respiratory infection: a randomized clinical trial.

OBJECTIVES: To validate the efficacy and safety of withholding antimicrobial therapy in a new cohort of children with cancer and febrile neutropenia (FN) having a demonstrated viral respiratory tract infection. METHODS: Prospective, multicenter, noninferiority, randomized study, approved by the ethical committee, in children presenting with FN at seven hospitals in Chile, evaluated at admission for diagnosis of bacterial and viral pathogens. Children who were positive for a respiratory virus, negative for a bacterial pathogen, and had a favourable evolution after 48-72 hours of antimicrobial therapy were randomized to either maintain or withhold antimicrobial therapy. The primary endpoint was the percentage of episodes with an uneventful resolution, whereas the secondary endpoints were days of fever, days of hospitalization, requirement of antimicrobial treatment readministration, sepsis, paediatric intensive care unit admission, and death. RESULTS: A total of 301 of 939 children with FN episodes recruited between March 2021 and December 2023 had a respiratory virus as a unique identified microorganism, of which 139 had a favourable evolution at 48-72 hours and were randomized, 70 to maintain and 69 to withdraw antimicrobial therapy. The median days of antimicrobial therapy was 5 (IQR 3-6) versus 3 (IQR 3-6) days (p < 0.001), with similar frequency of uneventful resolution 66/70 (94%) and 66/69 (96%); relative risk, 1.01; (95% CI, 0.93 to 1.09), absolute risk difference 0.01; (95% CI, -0.05 to 0.08) and similar number of days of fever and days of hospitalization. No cases of sepsis, paediatric intensive care unit admission, or death were reported. DISCUSSION: We validated the strategy of withdrawal antimicrobial therapy in children with FN and viral respiratory tract infection based on clinical and microbiological/molecular diagnostic criteria. This will enable advances in antimicrobial stewardship strategies with a possible future impact on antimicrobial resistance.

International Society of Paediatric Oncology (SIOP) Global Mapping Programme: Latin American Society of Pediatric Oncology (SLAOP) country-level report.

BACKGROUND: Latin American countries are improving childhood cancer care, showing strong commitment to implement the Global Initiative for Childhood Cancer, but there are scant publications of the situation at a continental level. METHODS: As part of the International Society of Paediatric Oncology Global Mapping project, delegates of each country participating in the Latin American Society of Pediatric Oncology (SLAOP) and chairs of national pediatric oncology societies and cooperative groups were invited to provide information regarding availability of national pediatric cancer control programs (NPCCP), pediatric oncology laws, pediatric oncology tumor registries, and training programs and support to diagnosis and treatment. RESULTS: Nineteen of the 20 countries participating in SLAOP responded. National delegates reported nine countries with NPCCP and four of them were launched in the past 5 years. National pediatric tumor registries are available in eight countries, and three provided published survival results. Fellowship programs for training pediatric oncologists are available in 12 countries. National delegates reported that eight countries provide support to most essential diagnosis and treatments and 11 provide partial or minimal support that is supplemented by civil society organizations. Seven countries have a pediatric oncology law. There are three international cooperative groups and four national societies for pediatric oncology. CONCLUSION: Despite many challenges, there were dramatic advances in survivorship, access to treatment, and availability of NPCCP in Latin America. Countries with highest social development scores in general provide more complete support and are more likely to have NPCCP, training programs, and reported survival results.

Access to Methotrexate Monitoring in Latin America: A Multicountry Survey of Supportive Care Capacity.

High-dose methotrexate (HDMTX) is used to treat a broad spectrum of cancers. Methotrexate (MTX) monitoring and adequate supportive care are critical for safe drug administration; however, MTX level timing is not always possible in low- and middle-income countries. The aim of this study was to evaluate HDMTX supportive care capacity and MTX monitoring practices in Latin America (LATAM) to identify gaps and opportunities for improvement. A multicenter survey was conducted among LATAM pediatric oncologists. Twenty healthcare providers from 20 institutions answered the online questionnaire. HDMTX was used to treat acute lymphoblastic leukemia (ALL; 100%), non-Hodgkin lymphoma (84.2%), diffuse large B-cell lymphoma (47.4%), osteosarcoma (78.9%), and medulloblastoma (31.6%). Delays in starting HDMTX infusion were related to bed shortages (47.4%) and MTX shortages (21.1%). MTX monitoring was performed at an in-hospital laboratory in 52%, at an external/nearby laboratory in 31.6%, and was not available in 10.5%. Median interval between sampling and obtaining MTX levels was ≤ 2 h in 45% and ≥ 6 h in 30%, related to laboratory location. Sites without access to MTX monitoring reduced the MTX dose for patients with high-risk ALL or did not include MTX in the treatment of patients with osteosarcoma. Respondents reported that implementation of point-of-care testing of MTX levels is feasible. In LATAM, highly variable supportive care capacity may affect the safe administration of MTX doses. Improving accessibility of MTX monitoring and the speed of obtaining results should be prioritized to allow delivery of full doses of MTX required by the current protocols.

Impact of COVID-19 in pediatric oncology care in Latin America during the first year of the pandemic.

BACKGROUND: The ongoing coronavirus 2019 disease (COVID-19) pandemic strained medical systems worldwide. We report on the impact on pediatric oncology care in Latin American (LATAM) during its first year. METHOD: Four cross-sectional surveys were electronically distributed among pediatric onco-hematologists in April/June/October 2020, and April/2021 through the Latin American Society of Pediatric Oncology (SLAOP) email list and St Jude Global regional partners. RESULTS: Four hundred fifty-three pediatric onco-hematologists from 20 countries responded to the first survey, with subsequent surveys response rates above 85%. More than 95% of participants reported that treatment continued without interruption for new and active ongoing patients, though with disruptions in treatment availability. During the first three surveys, respondents reported suspensions of outpatient procedures (54.2%), a decrease in oncologic surgeries (43.6%), radiotherapy (28.4%), stem cell transplants (SCT) (69.3%), and surveillance consultations (81.2%). Logistic regression analysis showed that at the beginning of the first wave, participants from countries with healthcare expenditure below 7% were more likely to report a decrease in outpatient procedures (odds ratio [OR]: 1.84, 95% CI: 1.19-2.8), surgeries (OR: 3, 95% CI: 1.9-4.6) and radiotherapy (OR: 6, 95% CI: 3.5-10.4). Suspension of surveillance consultations was higher in countries with COVID-19 case fatality rates above 2% (OR: 3, 95% CI: 1.4-6.2) and SCT suspensions in countries with COVID-19 incidence rate above 100 cases per 100,000 (OR: 3.48, 95% CI: 1.6-7.45). Paradoxically, at the beginning of the second wave with COVID-19 cases rising exponentially, most participants reported improvements in cancer services availability. CONCLUSION: Our data show the medium-term collateral effects of the pandemic on pediatric oncology care in LATAM, which might help delineate oncology care delivery amid current and future challenges posed by the pandemic.

Mapping Pediatric Oncology Clinical Trial Collaborative Groups on the Global Stage.

PURPOSE: The global pediatric oncology clinical research landscape, particularly in Central and South America, Africa, and Asia, which bear the highest burden of global childhood cancer cases, is less characterized in the literature. Review of how existing pediatric cancer clinical trial groups internationally have been formed and how their research goals have been pursued is critical for building global collaborative research and data-sharing efforts, in line with the WHO Global Initiative for Childhood Cancer. METHODS: A narrative literature review of collaborative groups performing pediatric cancer clinical research in each continent was conducted. An inventory of research groups was assembled and reviewed by current pediatric cancer regional and continental leaders. Each group was narratively described with identification of common structural and research themes among consortia. RESULTS: There is wide variability in the structure, history, and goals of pediatric cancer clinical trial collaborative groups internationally. Several continental regions have longstanding endogenously-formed clinical trial groups that have developed and published numerous adapted treatment regimens to improve outcomes, whereas other regions have consortia focused on developing foundational database registry infrastructure supported by large multinational organizations or twinning relationships. CONCLUSION: There cannot be a one-size-fits-all approach to increasing collaboration between international pediatric cancer clinical trial groups, as this requires a nuanced understanding of local stakeholders and resources necessary to form partnerships. Needs assessments, performed either by local consortia or in conjunction with international partners, have generated productive clinical trial infrastructure. To achieve the goals of the Global Initiative for Childhood Cancer, global partnerships must be sufficiently granular to account for the distinct needs of each collaborating group and should incorporate grassroots approaches, robust twinning relationships, and implementation science.

Cytokine and chemokine profiles in episodes of persistent high-risk febrile neutropenia in children with cancer.

BACKGROUND: In children with cancer and persistent high-risk febrile neutropenia (HRFN), cytokines/chemokines profiles can guide the differentiation of febrile neutropenia (FN) due to infections and episodes of unknown origin (FN-UO). METHODS: A prospective, multicenter study in Santiago, Chile included patients ≤ 18 years with cancer and HRFN. Clinical and microbiological studies were performed according to validated protocols. Serum levels of 38 cytokines/chemokines were determined on day 4 of persistent HRFN. We performed comparisons between i) HRFN episodes with a detected etiological agent (FN-DEA) and FN-UO, and ii) bacterial versus viral infections. ROC curves were used to assess the discriminatory power of the analytes. RESULTS: 110 HRFN episodes were enrolled (median age 8 years, 53% female). Eighty-four patients were FN-DEA: 44 bacterial, 32 viral, and 8 fungal infections. Twenty-six cases were categorized as FN-UO. Both groups presented similar clinical and laboratory characteristics. Nineteen out of 38 analytes had higher concentrations in the FN-DEA versus FN-UO group. G-CSF, IL-6, and Flt-3L showed the highest discriminatory power to detect infection (AUC 0.763, 0.741, 0.701). Serum levels of G-CSF differentiated bacterial infections and IP-10 viral agents. A combination of G-CSF, IL-6, Flt-3L, and IP-10 showed an AUC of 0.839, 75% sensitivity, and 81% specificity. CONCLUSION: A specific immune response is present on day four of persistent HRFN in children with cancer. We propose a combined measure of serum concentrations of G-CSF, IL-6, IP-10, and Flt-3L, in order to predict the presence of an infectious agent as compared to an episode of FN with unknown origin.

Caracterización clínica y microbiológica de episodios de bacteriemia por Streptococcus grupo viridans en niños con cáncer y neutropenia febril de alto riesgo / Clinical characteristics and microbiological profile of viridans group streptococci bacteremia in children with cancer and high-risk febrile neutropenia

Resumen Introducción: Streptococcus grupo viridans (SGV) ha adquirido relevancia como microorganismo causante de neutropenia febril, asociándose a morbilidad significativa. Objetivo: Caracterizar episodios de bacteriemia causados por SGV en niños con cáncer que desarrollaron neutropenia febril de alto riesgo (NFAR) desde abril de 2004 a junio de 2018 en seis hospitales pediátricos de Santiago, Chile. Pacientes y Métodos: Análisis retrospectivo de bases de datos de cuatro proyectos FONDECYT sucesivos, prospectivos y multicéntricos, registrando características clínicas y de laboratorio de los pacientes, además de patrón de resistencia antimicrobiana de las cepas aisladas. Resultados: Se registraron 95 episodios de bacteriemia asociada a SGV en 91 niños con NFAR. Destacan: leucemia mieloide aguda como enfermedad de base, neutropenia profunda, hospitalización prolongada (15 días), uso extendido de antimicrobianos (14 días), uso de citarabina en esquemas de quimioterapia (86% episodios). Las manifestaciones clínicas más frecuentes fueron respiratoria y gastrointestinal, asociándose en 26% a síndrome de shock por Streptococcus grupo viridans. Hubo elevada resistencia a β lactámicos, sin cepas no susceptibles a vancomicina. Discusión: SGV es un patógeno relevante en niños con cáncer, fiebre y neutropenia en nuestro medio, asociado a casos de sepsis. La resistencia a β lactámicos es un aspecto que requiere vigilancia epidemiológica estricta en esta población.

Abstract Background: Viridans group streptococci (VGS) has acquired relevance as a microorganism causing febrile neutropenia, associated with significant morbidity. Aim: To characterize episodes of bacteremia caused by VGS in children with cancer who developed high-risk febrile neutropenia (HRFN) during the period from April 2004 to June 2018 in six pediatric hospitals of Santiago, Chile. Method: Database analysis of 4 successive, prospective and multicentric studies recording clinical and laboratory characteristics of patients, as well as antimicrobial susceptibility pattern of isolated strains. Results: 95 episodes of VGS bacteremia in 91 children with HRFN were analyzed. It emphasizes acute myeloid leukemia as cancer type, deep neutropenia, prolonged hospitalization (15 days), with extended use of antimicrobials (14 days) and use of cytarabine in chemotherapy schemes (86% episodes). The most frequent clinical manifestations were respiratory and gastrointestinal, associating up to 26% viridans group shock syndrome. There was high resistance to β lactams. As expected, there were not non-susceptible strains to vancomycin. Discussion: VGS is a relevant microorganism in children with cancer, fever and neutropenia, with a high percentage of sepsis. Resistance to β lactams is an issue that requires strict epidemiological surveillance in this population.

Impact of a structured educational programme for caregivers of children with cancer on parental knowledge of the disease and paediatric clinical outcomes during the first year of treatment.

OBJECTIVE: To assess the impact of a structured educational programme for caregivers of children with cancer on their level of knowledge about the disease and patient's clinical outcome. METHODS: This prospective, non-randomised, experimental study included caregivers of recently diagnosed children at two hospitals in Chile. Caregivers whose children were treated at the first centre were the structured education programme group (EPG), while the second hospital provided the standard care (SCG). We evaluated caregivers' level of knowledge on days 1, 10 and 90 as well as the children's clinical outcomes over 1 year of treatment. RESULTS: A total of 102 caregivers were enrolled between 2014 and 2015. Only the EPG showed a significant increase in knowledge between days 1 and 90. The rate of central venous catheter infections was significantly lower in the EPG versus SCG (7% versus 26%; p = .01). The risk ratio was 0.35 (95% CI = 0.13-0.94), and a log-rank test showed a statistically significant difference between the two groups (p = .018). There were also fewer Emergency Department visits in the EPG for fever episodes. CONCLUSION: Providing a structured education to caregivers increased their level of knowledge and improved the clinical outcome of their children during the first year of treatment.

Usefulness of serum galactomannan in initiating and modifying antifungal therapy in children with cancer and persistent high-risk febrile neutropenia.

BACKGROUND: Invasive fungal disease is a major cause of morbidity and mortality in children with cancer and high-risk febrile neutropenia (HRFN). Repeated serum galactomannan (sGM) measurements have been described as an effective tool to guide therapy in adults under suspicion of invasive aspergillosis. However, the utility of this approach has not been reported in paediatric population. OBJECTIVES: To evaluate the usefulness of sGM measurements in initiating and modifying antifungal therapy (AFT) in children with cancer and persistent HRFN. PATIENTS/METHODS: Nested case-control study in children with cancer and persistent HRFN episodes, between July 2013 and January 2019. Patients were classified as cases and controls depending on if they received AFT or not, respectively. Through odds ratio analysis, we assessed the role of sGM positivity in the AFT initiation decision. Then, we analysed the group of patients that initiated AFT, and compared those who had AFT modifications and those who did not, analysing different sGM kinetics thresholds. RESULTS: A total of 191 episodes from children with persistent HRFN were enrolled, of which 107 received AFT and 84 did not. The median age was 7 years (IQR 4-12), 52% were male and 89% had a haematologic malignancy as underlying disease. Positive sGM was not associated with AFT initiation (OR 0.99, 95% CI 0.43-2.33, P = .99). A difference threshold in sGM Δ ≥ 0.3 sGM was significantly associated with AFT modification (OR 5.07, 95% CI 1.02- 25.70, P = .04). CONCLUSIONS: Our results suggest the utility of serial sGM sampling during AFT in children with persistent HRFN.

[Clinical characteristics and microbiological profile of viridans group streptococci bacteremia in children with cancer and high-risk febrile neutropenia]. / Caracterización clínica y microbiológica de episodios de bacteriemia por Streptococcus grupo viridans en niños con cáncer y neutropenia febril de alto riesgo.

BACKGROUND: Viridans group streptococci (VGS) has acquired relevance as a microorganism causing febrile neutropenia, associated with significant morbidity. AIM: To characterize episodes of bacteremia caused by VGS in children with cancer who developed high-risk febrile neutropenia (HRFN) during the period from April 2004 to June 2018 in six pediatric hospitals of Santiago, Chile. METHOD: Database analysis of 4 successive, prospective and multicentric studies recording clinical and laboratory characteristics of patients, as well as antimicrobial susceptibility pattern of isolated strains. RESULTS: 95 episodes of VGS bacteremia in 91 children with HRFN were analyzed. It emphasizes acute myeloid leukemia as cancer type, deep neutropenia, prolonged hospitalization (15 days), with extended use of antimicrobials (14 days) and use of cytarabine in chemotherapy schemes (86% episodes). The most frequent clinical manifestations were respiratory and gastrointestinal, associating up to 26% viridans group shock syndrome. There was high resistance to ß lactams. As expected, there were not non-susceptible strains to vancomycin. DISCUSSION: VGS is a relevant microorganism in children with cancer, fever and neutropenia, with a high percentage of sepsis. Resistance to ß lactams is an issue that requires strict epidemiological surveillance in this population.

The cancer-related transcription factor RUNX2 modulates expression and secretion of the matricellular protein osteopontin in osteosarcoma cells to promote adhesion to endothelial pulmonary cells and lung metastasis.

Osteosarcomas are bone tumors that frequently metastasize to the lung. Aberrant expression of the transcription factor, runt-related transcription factor 2 (RUNX2), is a key pathological feature in osteosarcoma and associated with loss of p53 and miR-34 expression. Elevated RUNX2 may transcriptionally activate genes mediating tumor progression and metastasis, including the RUNX2 target gene osteopontin (OPN/SPP1). This gene encodes a secreted matricellular protein produced by osteoblasts to regulate bone matrix remodeling and tissue calcification. Here we investigated whether and how the RUNX2/OPN axis regulates lung metastasis of osteosarcoma. Importantly, RUNX2 depletion attenuates lung metastasis of osteosarcoma cells in vivo. Using next-generation RNA-sequencing, protein-based assays, as well as the loss- and gain-of-function approaches in selected osteosarcoma cell lines, we show that osteopontin messenger RNA levels closely correlate with RUNX2 expression and that RUNX2 controls the levels of secreted osteopontin. Elevated osteopontin levels promote heterotypic cell-cell adhesion of osteosarcoma cells to human pulmonary microvascular endothelial cells, but not in the presence of neutralizing antibodies. Collectively, these findings indicate that the RUNX2/OPN axis regulates the ability of osteosarcoma cells to attach to pulmonary endothelial cells as a key step in metastasis of osteosarcoma cells to the lung.

Health-Related Quality of Life and Survival Outcomes of Pediatric Patients With Nonmetastatic Osteosarcoma Treated in Countries With Different Resources.

PURPOSE: Health-related quality of life (HRQOL) improves throughout treatment of patients with nonmetastatic osteosarcoma. We compared HRQOL for patients in the United States and Chile treated on an international trial (OS99) with polychemotherapy and surgery, and we assessed the relationships among HRQOL measures, event-free survival (EFS), and overall survival (OS). MATERIALS AND METHODS: Patients with newly diagnosed, localized osteosarcoma and their parents completed three HRQOL instruments (PedsQL v.4, PedsQL Cancer v.3, and Symptom Distress Scale [SDS]). Data were collected at four time points throughout therapy. Repeated measures models were used to investigate the effect of treatment site on instrument scores. The log-rank test examined the impact of treatment site on survival outcomes, and Cox proportional hazards regression models evaluated baseline HRQOL measures as predictors of EFS and OS. RESULTS: Of 71 eligible patients, 66 (93%) participated in the HRQOL studies in the United States (n = 44) and Chile (n = 22). The median age was 13.4 years (range, 5 to 23 years). Clinical characteristics were similar between treatment sites. US patients reported better scores for physical ( P = .030), emotional ( P = .027), and school functioning ( P < .001). Chilean patients reported poorer scores for worry ( P < .001) and nausea ( P = .007). Patient and parent nausea scores were similar between patients treated in the United States and Chile by the end of therapy. Differences in symptom distress were not observed between the countries. Neither HRQOL measures nor treatment site were associated with EFS or OS. CONCLUSION: Although significant differences in HRQOL were observed between countries, outcomes were similar, and HRQOL measures were not associated with prognosis.

Efficacy of pre-emptive versus empirical antifungal therapy in children with cancer and high-risk febrile neutropenia: a randomized clinical trial.

Objectives: To compare the efficacy of pre-emptive versus empirical antifungal therapy in children with cancer, fever and neutropenia. Methods: This was a prospective, multicentre, randomized clinical trial. Children presenting with persistent high-risk febrile neutropenia at five hospitals in Santiago, Chile, were randomized to empirical or pre-emptive antifungal therapy. The pre-emptive group received antifungal therapy only if the persistent high-risk febrile neutropenia was accompanied by clinical, laboratory, imaging or microbiological pre-defined criteria. The primary endpoint was overall mortality at day 30 of follow-up. Secondary endpoints included invasive fungal disease (IFD)-related mortality, number of days of fever, days of hospitalization and use of antifungal drugs, percentage of children developing IFD, requiring modification of initial treatment strategy and need for ICU. The trial was registered with Registro Brasileiro de Ensaios Clínicos (ReBEC) under trial number RBR-3m9d74. Results: A total of 149 children were randomized, 73 to empirical therapy and 76 to pre-emptive therapy. Thirty-two out of 76 (42%) children in the pre-emptive group received antifungal therapy. The median duration of antifungal therapy was 11 days in the empirical arm and 6 days in the pre-emptive arm (P < 0.001), with similar overall mortality (8% in the empirical arm and 5% in the pre-emptive arm, P = 0.47). IFD-related mortality was the same in both groups (3%, P = 0.97), as were the percentage of children with IFD (12%, P = 0.92) and the number of days of fever (9, P = 0.76). The number of days of hospitalization was 19 in the empirical arm and 17 in the pre-emptive arm (P = 0.15) and the need for ICU was 25% in the empirical arm and 20% in the pre-emptive arm (P = 0.47). Conclusions: Pre-emptive antifungal therapy was as effective as empirical antifungal therapy in children with cancer, fever and neutropenia, significantly reducing the use of antifungal drugs.

[Microorganisms isolated from blood cultures in children with cancer and high-risk febrile neutropenia from five hospitals in Santiago, Chile, 2012-2015]. / Microorganismos aislados de hemocultivos en niños con cáncer y neutropenia febril de alto riesgo en cinco hospitales de Santiago, Chile, período 2012-2015.

BACKGROUND: Microorganisms isolated from blood cultures (BC) in patients with febrile neutropenia (NF) vary over time, requiring systematic monitoring to guide appropriate empirical therapy. AIM: To identify microorganisms isolated from BC and their antimicrobial resistance profile in children with cancer and high risk NF. METHOD: Prospective, multicenter study. The analysis included episodes of high-risk FN with positive BC in children under 18 years of age treated in five hospitals in Santiago, Chile, 2012-2015. RESULTS: A total of 206 microorganisms were analyzed in 185 episodes of high-risk FN. The main isolates were Gram negative bacilli (46.6%) and Gram positive cocci (45.1%) and the most frequent microorganisms were Escherichia coli (22.8%), coagulase negative Staphylococcus (18.0%) and Klebsiella spp. (16.5%). Escherichia coli and Klebsiella spp showed 4.2% and 67.6% resistance to third generation cephalosporins (cefotaxime/ceftriaxone), 10.6% and 40.6% resistance to fluoroquinolones (ciprofloxacin) and 2.1% and 26.5% to amikacin, respectively. Coagulase negative Staphylococcus and Staphylococcus aureus had 86.4% and 22.2% resistance to oxacillin, Streptococcus viridans group had 71% resistance to penicillin. DISCUSSION: This study updates the etiology and resistance profile of microorganisms isolated in BC from children with cancer and high risk FN, an essential tool for the adequate management of these patients.

Microorganismos aislados de hemocultivos en niños con cáncer y neutropenia febril de alto riesgo en cinco hospitales de Santiago, Chile, período 2012-2015 / Microorganisms isolated from blood cultures in children with cancer and high-risk febrile neutropenia from five hospitals in Santiago, Chile, 2012-2015

Resumen Antecedentes: Los microorganismos aislados de hemocultivos (HC) en pacientes con neutropenia febril (NF) varían en el tiempo, siendo necesaria su vigilancia para orientar una terapia empírica adecuada. Objetivo: Identificar microorganismos aislados de HC y su perfil de resistencia (R) a antimicrobianos en niños con cáncer y NF de alto riesgo. Método: Estudio prospectivo, multicéntrico de episodios de NF de alto riesgo en pacientes bajo 18 años de edad, de cinco hospitales en Santiago de Chile, 2012-2015. Análisis de HC positivos. Resultados: Se analizaron 206 microorganismos en 185 episodios de NF de alto riesgo con HC positivos. Los aislados principales fueron bacilos gramnegativos (BGN) (46,6%) y cocáceas grampositivas (CGP) (45,1%) y los microorganismos más frecuentes Escherichia coli (22,8%), Staphylococcus coagulasa negativa (18,0%) y Klebsiella spp (16,5%). En resistencia (R) a antimicrobianos destaca: E. coli y Klebsiella spp 4,2 y 67,6% R a cefalosporinas de tercera generación (cefotaxima/ceftriaxona) respectivamente, 10,6 y 40,6% R a ciprofloxacina y 2,1 y 26,5% a amikacina, respectivamente. S. coagulasa negativa y S. aureus 86,4% y 22,2% R a oxacilina, Streptococcus grupo viridans 71% R a penicilina. Discusión: Este estudio actualiza la etiología y el perfil de R de microorganismos aislados en HC de niños con cáncer y NF de alto riesgo, herramienta esencial para el adecuado manejo de estos pacientes.

Background: Microorganisms isolated from blood cultures (BC) in patients with febrile neutropenia (NF) vary over time, requiring systematic monitoring to guide appropriate empirical therapy. Aim: To identify microorganisms isolated from BC and their antimicrobial resistance profile in children with cancer and high risk NF. Method: Prospective, multicenter study. The analysis included episodes of high-risk FN with positive BC in children under 18 years of age treated in five hospitals in Santiago, Chile, 2012-2015. Results: A total of 206 microorganisms were analyzed in 185 episodes of high-risk FN. The main isolates were Gram negative bacilli (46.6%) and Gram positive cocci (45.1%) and the most frequent microorganisms were Escherichia coli (22.8%), coagulase negative Staphylococcus (18.0%) and Klebsiella spp. (16.5%). Escherichia coli and Klebsiella spp showed 4.2% and 67.6% resistance to third generation cephalosporins (cefotaxime/ceftriaxone), 10.6% and 40.6% resistance to fluoroquinolones (ciprofloxacin) and 2.1% and 26.5% to amikacin, respectively. Coagulase negative Staphylococcus and Staphylococcus aureus had 86.4% and 22.2% resistance to oxacillin, Streptococcus viridans group had 71% resistance to penicillin. Discussion: This study updates the etiology and resistance profile of microorganisms isolated in BC from children with cancer and high risk FN, an essential tool for the adequate management of these patients.

Highlights from the 1st Latin American meeting on metronomic chemotherapy and drug repositioning in oncology, 27-28 May, 2016, Rosario, Argentina.

Following previous metronomic meetings in Marseille (2011), Milano (2014), and Mumbai (2016), the first Latin American metronomic meeting was held in the School of Medical Sciences, National University of Rosario, Rosario, Argentina on 27 and 28 of May, 2016. For the first time, clinicians and researchers with experience in the field of metronomics, coming from different countries in Latin America, had the opportunity of presenting and discussing their work. The talks were organised in three main sessions related to experience in the pre-clinical, and clinical (paediatric and adult) areas. The different presentations demonstrated that the fields of metronomic chemotherapy and repurposing drugs in oncology, known as metronomics, constitute a branch of cancer therapy in permanent evolution, which have strong groups working in Latin America, both in the preclinical and the clinical settings including large, adequately designed randomised studies. It was shown that metronomics offers treatments, which, whether they are combined or not with the standard therapeutic approaches, are not only effective but also minimally toxic, with the consequent improvement of the patient's quality of life, and inexpensive, a feature very important in low resource clinical settings. The potential use of metronomic chemotherapy was proposed as a cost/effective treatment in low-/middle-income countries, for adjuvant therapy in selected tumours. The fundamental role of the governmental agencies and non-governmental alliances, as the Metronomic Global Health Initiative, in supporting this research with public interest was underlined.

Respiratory Viral Infections and Coinfections in Children With Cancer, Fever and Neutropenia: Clinical Outcome of Infections Caused by Different Respiratory Viruses.

BACKGROUND: Respiratory viral infections in episodes of fever and neutropenia (FN) in children with cancer are not well characterized. We compared the clinical outcome of infections caused by different respiratory viruses (RVs) and by RV coinfection in this population. METHODS: Children with cancer and FN at 3 hospitals in Chile were prospectively evaluated by clinical examination, blood cultures and detection of 17 RVs using multiplex polymerase chain reaction (nasopharyngeal samples). Clinical characterization and outcome variables were determined and compared by the type of RV detected. RESULTS: A total of 1044 episodes of FN in 525 children were included. At least 1 RV was detected in 46%. In 350 of 1044 (34%) episodes, we detected only RVs, of which 284 (81%) were classified as a single-RV infection and 66 (19%) as a viral coinfection. Respiratory symptoms were present at admission in 65% of the episodes with any detected RV. Median age was 6 years (interquartile range, 3-10), and 51% were women. The most common RVs detected were rhinovirus, respiratory syncytial virus, parainfluenza, influenza, adenovirus and human metapneumovirus. Episodes caused by different types of RVs had no differences in the clinical outcome (days of hospitalization, days of fever, O2 requirement, admission to the intensive care unit and death) and when comparing single and viral coinfection. CONCLUSIONS: To our knowledge, this is the largest report comparing clinical outcome in FN episodes caused by different RVs in children with cancer. A positive polymerase chain reaction for RV at admission was significantly associated with the presence of respiratory symptoms. Our data showed a favorable outcome in all episodes with RV detection, including single and viral coinfections.

[Successful treatment of a persistent rhino-cerebral mucormycosis in a pediatric patient with a debut of acute lymphoblastic leukemia]. / Tratamiento exitoso de una mucormicosis rinocerebral persistente en un paciente pediátrico durante el debut de una leucemia aguda.

The fungi of the order Mucorales cause mucormycosis, which usually presents as an invasive fungal disease with rapid angioinvasion in immunocompromised patients. Rhinocerebral is the most common presentation. The lipid formulations of amphotericin B are used as primary treatment in invasive mucormycosis; the combined use of posaconazole could allow a reduction in the dose of amphotericin B improving tolerance and adherence to treatment. Caspofungin and amphotericin B association has been shown to be synergistic in vitro and effective in murine models. We present the case of a preschool patient that during the debut of acute lymphoblastic leukemia developed a rhinocerebral mucormycosis successfully responding to antifungal treatment with the combination of liposomal amphotericin and caspofungin.

[Seroconversion in response to a reinforced primary hepatitis B vaccination in children with cancer]. / Seroconversión frente a primovacunación reforzada contra hepatitis B en niños con cáncer.

INTRODUCTION: Immune response against vaccine antigens may be impaired in children with cancer. The aim of this study was to evaluate the seroconversion response against hepatitis B vaccination (HBV) at the time of chemotherapy onset and/or remission in children with cancer. PATIENTS AND METHOD: Prospective, two-centre, controlled, non-randomised study conducted on children recently diagnosed with cancer, paired with healthy subjects. Cases received HBV at time 0, 1 and 6 months with DNA recombinant HBV at a dose of 20 and 40 µg if < or > than 10 years of age, respectively, at the time of diagnosis for solids tumours and after the remission in case of haematological tumours. Controls received the same schedule, but at of 10 and 20 µg doses, respectively. HBs antibodies were measured in serum samples obtained at 2, 8 and 12 months post-vaccination. Protective titres were defined as > 10 mIU/ml at 8th month of follow up. RESULTS: A total of 78 children with cancer and 25 healthy controls were analysed at month 8th of follow up. Seroconversion rates in the cancer group reached 26.9%, with no differences by age, gender or type of tumour (P = .13, .29, and .44, respectively). Control group seroconversion was 100% at the 8th month, with P < .0001 compared with the cancer group. At month 12 of follow up, just 31.9% of children with cancer achieved anti-HBs antibodies > 10 mIU/ml. CONCLUSIONS: Vaccination against hepatitis B with three doses of DNA recombinant vaccine at an increased concentration, administrated at the time of onset of chemotherapy and/or remission provided an insufficient immune response in a majority of children with cancer. More immunogenic vaccines should be evaluated in this special population, such as a third generation, with more immunogenic adjuvants, enhanced schedules at 0, 1, 2, 6 month, evaluation of antibody titres at month 8 and 12h to evaluate the need for further booster doses.

Tratamiento exitoso de una mucormicosis rinocerebral persistente en un paciente pediátrico durante el debut de una leucemia aguda / Successful treatment of a persistent rhino-cerebral mucormycosis in a pediatric patient with a debut of acute lymphoblastic leukemia

The fungi of the order Mucorales cause mucormycosis, which usually presents as an invasive fungal disease with rapid angioinvasion in immunocompromised patients. Rhinocerebral is the most common presentation. The lipid formulations of amphotericin B are used as primary treatment in invasive mucormycosis; the combined use of posaconazole could allow a reduction in the dose of amphotericin B improving tolerance and adherence to treatment. Caspofungin and amphotericin B association has been shown to be synergistic in vitro and effective in murine models. We present the case of a preschool patient that during the debut of acute lymphoblastic leukemia developed a rhinocerebral mucormycosis successfully responding to antifungal treatment with the combination of liposomal amphotericin and caspofungin.

Los hongos del orden Mucorales causan la mucormicosis, que se presenta habitualmente como una enfermedad fúngica invasora con rápida angioinvasión en pacientes inmunocomprometidos. La presentación rino-cerebral es la más frecuente. Las formulaciones lipídicas de anfotericina B se usan como tratamiento primario en las mucormicosis invasoras; el uso combinado de posaconazol podría permitir reducir la dosis de anfotericina B generando una mejor tolerancia y adherencia al tratamiento. La asociación de caspofungina con anfotericina ha demostrado acción sinérgica in vitro y eficacia en modelos murinos. Se presenta el caso de una niña preescolar que durante el debut de una leucemia linfoblástica aguda evolucionó con una mucormicosis rino-cerebral persistente, que respondió en forma exitosa al tratamiento antifúngico combinado de anfotericina liposomal y caspofungina.