Quantitative expression evaluation of PRAME gene in osteosarcoma.

BACKGROUND: In a previous study, our group observed that 68% of the osteosarcoma (OS) samples presented PRAME (Preferentially Expressed Antigen in Melanoma) gene expression. In this work, we propose to investigate quantitatively gene expression of PRAME in distinct patients groups. METHODS AND RESULTS: 61 osteosarcoma samples, from 3 distinct patients groups were selected for this study: (1) Patients younger than 10 years old at diagnosis, (2) Patients that had poor evolution of disease and (3) Patients that were in remission of disease and had treatment with no intercurrences) PRAME gene expression levels were obtained using quantitative Real-Time Polymerase Chain Reaction method (qRT-PCR). Clinical parameters were collected from patient's medical charts. Results demonstrated an increase in PRAME gene expression in all samples, with high variation in expression levels, when considering all samples and when analyzed in each group. In addition, no statistical difference was found when considering clinical data collected or patients groups. CONCLUSION: PRAME gene expression quantitative investigation did not bring any complementary information beyond of what had already been observed in other qualitative investigations published by our group, there is no relation between PRAME gene expression levels and disease evolution. However, the findings in this work contribute for validation PRAME gene expression as a good biomarker to OS, which, in the future, may allow identification circulating tumor cell or molecules to contribute with early diagnostic of metastasis, a genuine problem in OS that determinate flattening in survival curves.

Pharmacogenetics of the Primary and Metastatic Osteosarcoma: Gene Expression Profile Associated with Outcome.

Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. In recent decades, OS treatment has reached a plateau and drug resistance is still a major challenge. Therefore, the present study aimed to analyze the expression of the genes related to pharmacogenetics in OS. The expression of 32 target genes in 80 paired specimens (pre-chemotherapeutic primary tumor, post-chemotherapeutic primary tumor and pulmonary metastasis) obtained from 33 patients diagnosed with OS were analyzed by the real-time PCR methodology. As the calibrators (control), five normal bone specimens were used. The present study identified associations between the OS outcome and the expression of the genes TOP2A, DHFR, MTHFR, BCL2L1, CASP3, FASLG, GSTM3, SOD1, ABCC1, ABCC2, ABCC3, ABCC5, ABCC6, ABCC10, ABCC11, ABCG2, RALBP1, SLC19A1, SLC22A1, ERCC1 and MSH2. In addition, the expression of the ABCC10, GGH, GSTM3 and SLC22A1 genes were associated with the disease event, and the metastasis specimens showed a high expression profile of ABCC1, ABCC3 and ABCC4 genes and a low expression of SLC22A1 and ABCC10 genes, which is possibly an important factor for resistance in OS metastasis. Therefore, our findings may, in the future, contribute to clinical management as prognostic factors as well as possible therapeutic targets.

Candida spp bloodstream infections in a Latin American Pediatric Oncology Reference Center: Epidemiology and associated factors.

BACKGROUND: Invasive fungal disease is a significant cause of morbidity and mortality in immunosuppressed children. The recognition of patients at risk for candidaemia is paramount to a better prognosis. OBJECTIVES: To characterize Candida spp bloodstream infections (BSI) in a reference centre for paediatric oncology and to describe the most prevalent risk factors associated with candida infections. PATIENTS/METHODS: This is a retrospective cohort study carried out with paediatric patients followed up with at the Institute of Pediatric Oncology, Brazil, who presented positive blood culture for Candida spp from January 2004 to December 2016. RESULTS: Ninety episodes of candidaemia were analysed; patients had a median age of 4.5 years, and 57.8% were males, with a diagnosis of solid tumours in 54.5% of cases. The most common Candida species were C albicans (35.6%), C parapsilosis (30.0%) and C tropicalis (16.7%). C tropicalis BSI was associated with neutropenia and skin lesions. Therapy was successful in 67.1% of the episodes. Older age and thrombocytopenia were associated with therapeutic failure. Death within 30 days occurred in 24.4% of patients; predictive factors were older age and admission to an ICU C parapsilosis candidaemia was a protective factor for death when compared to C albicans. CONCLUSION: The main species isolated were C albicans, C parapsilosis and C tropicalis. C tropicalis BSI was associated with neutropenia and skin lesions. The death rate was significant, and a worse prognosis was associated with older age, thrombocytopenia and admission to an ICU C parapsilosis infection proved to be a protective factor against mortality.

MAPK7 variants related to prognosis and chemotherapy response in osteosarcoma.

Osteosarcoma (OS) is a class of cancer originating from the bone, affecting mainly children and young adults. Our previous study showed that MAPK7 gene overexpression was significantly associated with tumor progression, poor treatment response, and worse overall survival, suggesting that MAPK7 could play an important role in OS tumorigenesis. We have investigated if MAPK7 overexpression was a result of any genomic changes in OS tumor specimens. We identified five SNPs (Single Nucleotide Polymorphism) previously described in databases, dbSNP and COSMIC, and identified two single nucleotide substitution not yet described. We found, in prechemotherapy specimens, a significant association of MAPK7 rs2233072G allele variant with metastasis at diagnosis and relapse (0.0909 and 0.0455, respectively). In post-chemotherapy, rs1054206GG specimen's genotype was associated with osteoblastic histological type (P= 0.0249) and presented decreased MAPK7 gene expression when compared with pre-chemotherapy specimens of same patients (P = 0.0095). Interestingly, it was observed some SNPs genotype exchange after chemotherapy. Our data indicated that MAPK7 gene expression associated with genotype exchange after chemotherapy, and these SNPs associated with important clinical parameters might be a valuable indicator for predicting in OS.

A pharmacokinetic model for voriconazole in a highly diversified population of children and adolescents with cancer.

BACKGROUND: The wide pharmacokinetic variability of voriconazole leads to uncertainty regarding adequate exposure. OBJECTIVES: To create a pharmacokinetic model that could help to explain the variability. METHODS: Retrospective review of paediatric patients with cancer. Models were built using Pmetrics. RESULTS: We analysed 158 trough measurements in 55 patients; in 41.8%, the serum levels were between 1 and 6 mg/L on initial measurement. After the measurements, dosage adjustments were made in 42 (76.3%) patients, and the percentage of adequate levels rose to 54.5%. Fourteen deaths (25.4%) were attributed to invasive fungal diseases. The mean serum levels were higher in deceased patients (mean ± SD: 3.1 ± 3.2 mg/L vs 2.5 ± 3.6 mg/L in survivors; P = 0.018), but the median doses per kg were higher in survivors. Drug exposure was also higher in deceased patients (mean ± SD of AUC: 19.2 ± 8.1 vs 9.5 ± 19.1 in survivors; P = 0.005). No correlation was found between serum concentrations <1 mg/L and death attributable to fungal disease. Bioavailability was estimated in 50%. The maximum velocity of clearance was reduced in deceased patients. CONCLUSIONS: Extremely ill patients can be poor metabolizers of voriconazole. Therapeutic monitoring promotes only a limited improvement in drug management.

Results of a randomized, prospective clinical trial evaluating metronomic chemotherapy in nonmetastatic patients with high-grade, operable osteosarcomas of the extremities: A report from the Latin American Group of Osteosarcoma Treatment.

BACKGROUND: Metronomic chemotherapy (MC) consists of the administration of a low dose of chemotherapy on a daily or weekly basis without a long break to achieve an antitumoral effect through an antiangiogenic effect or stimulation of the immune system. The potential effect of MC with continuous oral cyclophosphamide and methotrexate in patients with high-grade operable osteosarcomas (OSTs) of the extremities was investigated. METHODS: Patients with high-grade OSTs who were 30 years old or younger were eligible for registration at diagnosis. Eligibility for randomization included 1) nonmetastatic disease and 2) complete resection of the primary tumor. The study design included a backbone of 10 weeks of preoperative therapy with methotrexate, adriamycin, and platinum (MAP). After surgery, patients were randomized between 2 arms to complete 31 weeks of MAP or receive 73 weeks of MC after MAP. The primary endpoint was event-free survival (EFS) from randomization. RESULTS: There were 422 nonmetastatic patients registered (May 2006 to July 2013) from 27 sites in 3 countries (Brazil, Argentina and Uruguay), and 296 were randomized to MAP plus MC (n = 139) or MAP alone (n = 157). At 5 years, the EFS cumulative proportions surviving in the MAP-MC group and the MAP-alone group were 61% (standard error [SE], 0.5%) and 64% (SE, 0.5%), respectively, and they were not statistically different (Wilcoxon [Gehan] statistic = 0.724; P =.395). The multivariate analysis showed that necrosis grades 1 and 2, tumor size, and amputation were associated with shorter EFS. CONCLUSIONS: According to the current follow-up, EFS with MAP plus MC is not statistically superior to EFS with MAP alone in patients with high-grade, resectable OSTs of the extremities. Cancer 2017;123:1003-10. © 2016 American Cancer Society.

MAPK pathways regulation by DUSP1 in the development of osteosarcoma: Potential markers and therapeutic targets.

Osteosarcoma (OS) is the most frequent primary bone tumor that affect children and adolescents. This tumor is highly aggressive with high risk of metastasis and the implementation of new drugs has not been successful. The search for biomarkers or new therapeutic targets is urgently needed and can help in advances of OS treatment. MAPKs are major signaling transduction molecules that play an important role in regulating a variety of cellular responses. DUSP1 is a phosphatase that dephosphorylates the MAPKs. Both MAPKs and DUSPs have been implicated as major modulators of critical signaling pathways that are dysregulated in various diseases. In a previous study, we found an increase in MAPK7 gene expression contributed for worst overall survival and treatment response. We analyzed gene expression of MAPK pathways that participate in MAPK7 regulation, and DUSP1 gene using paired 28 pre/post-chemotherapy and 12 metastasis OS samples. To understand the DUSP1 role in the pathogenesis of OS, we assessed the function of DUSP1 in four OS cell lines through a series of cellular assays combined with gene silencing technique. Our findings showed increased MAP2K6, MAP4K3, and DUSP1 gene expression in post-chemotherapy OS samples presenting poor prognosis. We also found that the suppression of DUSP1 gene expression resulted in decreased proliferation, migration, and invasion in OS cells. These results suggest that members of MAPK family may be possible prognostic markers in OS and DUSP1 has a relevant role in the OS pathogenesis and can be an attractive therapeutic target in new strategies of OS treatment.

Cytokine Kinetics in Febrile Neutropenic Children: Insights on the Usefulness as Sepsis Biomarkers, Influence of Filgrastim, and Behavior of the IL-23/IL-17 Pathway.

BACKGROUND: The study aimed to describe the kinetics of various cytokines from day 1 to day 14 of the onset of fever in neutropenic children and to evaluate their performances as discriminators of sepsis in the first 24 hours of fever, the possible influence of filgrastim, and the functioning of the IL-23/IL-17 axis. METHODS: IL-1ß, TNF-α, IL-10, IL-12/23p40, IL-21, IL-6, IL-8, IL-17, G-CSF, and GM-CSF were measured in plasma on days 1, 2, 3, 5, and 14 from the onset of fever in 35 patients. RESULTS: Thirteen patients (37.1%) developed sepsis. In mixed models, IL-6, IL-8, IL-10, and G-CSF showed higher estimated means in septic patients (P < 0.005), and IL-12/23p40 and IL-17 in nonseptic patients (P < 0.05). On day 1, IL-6, IL-8, and IL-10 appeared upregulated in patients who received filgrastim. Only IL-6, IL-8, IL-10, and procalcitonin were useful as discriminators of sepsis. Associating the markers with each other or to a risk assessment model improved performance. CONCLUSIONS: Cytokines kinetics showed proinflammatory and anti-inflammatory responses similar to what is described in nonneutropenic patients. IL-8, IL-6, IL-10, and procalcitonin are useful as early biomarkers of sepsis. Filgrastim upregulates expression of these markers, and we observed deficiency in the IL-23-IL-17 axis accompanying sepsis.

MAPK7 gene controls proliferation, migration and cell invasion in osteosarcoma.

Osteosarcomas (OS) are the most common malignant bone tumors, and the identification of useful tumor biomarkers and target proteins is required to predict the clinical outcome of patients and therapeutic response as well as to develop novel therapeutic strategies. In our previous study, MAPK7 has been identified as a candidate oncogene, and a promising prognostic marker for OS. Sequential activation of protein kinases within the mitogen-activated protein kinase (MAPK) cascades is a common mechanism of signal transduction in many cellular processes. In this study, we investigated the behavior of MAPK7 gene in OS cell lines. Technical viability, proliferation, migration, invasion, and apoptosis were used to evaluate the function of the MAPK7 gene. We evaluated the behavior of the OS cells with MAPK7 gene silenced, not silenced, and exposed to the main chemotherapy drugs used in OS treatment. We found that silenced MAPK7 gene is effective at suppressing cell proliferation, inhibiting cell migration, and invasion. Furthermore, MAPK7 is an important activator of transcription factors and is the main expression modulator of other key genes in the MAPK pathway. In summary, our study suggests that MAPK7 might be a promising therapeutic target for OS. © 2015 Wiley Periodicals, Inc.

Clinical relevance of molecular identification of microorganisms and detection of antimicrobial resistance genes in bloodstream infections of paediatric cancer patients.

BACKGROUND: Bloodstream infections (BSIs) are the major cause of mortality in cancer patients. Molecular techniques are used for rapid diagnosis of BSI, allowing early therapy and improving survival. We aimed to establish whether real-time quantitative polymerase chain reaction (qPCR) could improve early diagnosis and therapy in paediatric cancer patients, and describe the predominant pathogens of BSI and their antimicrobial susceptibility. METHODS: Blood samples were processed by the BACTEC system and microbial identification and susceptibility tests were performed by the Phoenix system. All samples were screened by multiplex 16 s rDNA qPCR. Seventeen species were evaluated using sex-specific TaqMan probes and resistance genes blaSHV, blaTEM, blaCTX, blaKPC, blaIMP, blaSPM, blaVIM, vanA, vanB and mecA were screened by SYBR Green reactions. Therapeutic efficacy was evaluated at the time of positive blood culture and at final phenotypic identification and antimicrobial susceptibility results. RESULTS: We analyzed 69 episodes of BSI from 64 patients. Gram-positive bacteria were identified in 61 % of the samples, Gram-negative bacteria in 32 % and fungi in 7 %. There was 78.2 % of agreement between the phenotypic and molecular methods in final species identification. The mecA gene was detected in 81.4 % of Staphylococcus spp., and 91.6 % were concordant with the phenotypic method. Detection of vanA gene was 100 % concordant. The concordance for Gram-negative susceptibilities was 71.4 % for Enterobacteriaceae and 50 % for Pseudomonas aeruginosa. Therapy was more frequently inadequate in patients who died, and the molecular test was concordant with the phenotypic susceptibility test in 50 %. CONCLUSIONS: qPCR has potential indication for early identification of pathogens and antimicrobial resistance genes from BSI in paediatric cancer patients and may improve antimicrobial therapy.

Single agent vinorelbine in pediatric patients with progressive optic pathway glioma.

The management of progressive unresectable low-grade glioma remains controversial. Treatment options have included radiotherapy, and more recently chemotherapy, usually following an initial period of observation. Within this context, we evaluated vinorelbine, a semi-synthetic vinca alkaloid that has shown evidence of activity against glioma. From July 2007 an institutional protocol with vinorelbine (30 mg/m(2) days 0, 8, 22) for a total of 18 cycles, has been conducted at IOP/GRAACC/UNIFESP for children with optic pathway glioma (OPG). The main objectives were clinical and radiological response, as well as toxicity profile. Twenty-three patients with progressive OPG with a mean age of 69 months (4-179) were enrolled. Three patients had a diagnosis of neurofibromatosis type 1. Twenty-two patients were assessable for response with an overall objective response rate of 63 %, with eight patients showing stable disease. The most important toxicity was hematologic (grade III/IV neutropenia) observed in four patients. Gastrointestinal toxicity (grade I/II vomiting) was observed in seven patients and only 1 patient showed grade I peripheral neuropathy. The median progression-free survival (PFS) was 33 months (6.9-69) with a 3 and 5 year PFS of 64 ± 19 and 37 ± 20 %, respectively, for an overall 3 and 5 year-survival of 95 ± 10 %. This study suggests that vinorelbine may be an interesting option for pediatric low-grade gliomas, showing low toxicity profile and providing a good quality of life for patients with such chronic disease.

Osteosarcoma in patients younger than 12 years old without metastases have similar prognosis as adolescent and young adults.

BACKGROUND: Childhood cancer is relatively rare and tends to present specific age distribution, as a prognostic factor for some of these diseases. Information on how young age affects prognosis, response to chemotherapy, and local control options in children versus AYA with osteosarcoma (OST) is minimal. METHODS: In order to identify the main differences in clinical pathologic features, surgical approaches and survival rates of primary high grade OST of the extremity between children (n = 156; <12 years old) and AYA (n = 397; 12-30 years old), the institutional database with 553 patients treated by BOTG studies over 15 years were reviewed. RESULTS: There were no differences in metastases at diagnosis, tumor size, and grade of necrosis between the two age groups. The rate of amputation was 30% higher in the children group (P = 0.018). The rate of limb salvage surgery using reconstruction with allograft or autograft was 70% higher in the children group (P = 0.018) while endoprosthesis rate was 40% higher in the AYA group (P = 0.018). The log rank test revealed that survival is similar between the two age groups for non-metastatic patients (P = 0.424 for OS and P = 0.393 for EFS). Metastatic patients of both ages group had higher risk of dying compared to non-metastatic (HR 3.283 95% CI 2.581-4.177; P < 0.001). Children with metastases at diagnosis had less OS time (P = 0.049) and EFS time (P = 0.032) than adolescents. CONCLUSION: Non-metastatic OST in preadolescent patients does not appear to be significantly different from those seen in AYA patients, but has local control challenges. Children presenting with metastases should be considered an ultra-high-risk group.

The water supply system as a potential source of fungal infection in paediatric haematopoietic stem cell units.

BACKGROUND: We conducted a prospective study to investigate the presence of microfungal contamination in the water supply system of the Oncology Paediatric Institute, São Paulo-Brazil after the occurrence of one invasive Fusarium solani infection in a patient after Haematopoietic Stem Cell Transplantation (HSCT). During a twelve-month period, we investigated the water supply system of the HSCT unit by monitoring a total of fourteen different collection sites. METHODS: One litre of water was collected in each location, filtered through a 0.45 µm membrane and cultured on SDA to detect the presence of filamentous fungi. Physicochemical analyses of samples were performed to evaluate the temperature, turbidity, pH, and the concentration of free residual chlorine. RESULTS: Over the 12 months of the study, 164 samples were collected from the water supply system of the HSCT unit, and 139 of the samples tested positive for filamentous fungi (84.8%), generating a total of 2,362 colonies. Cladosporium spp., Penicillium spp., Purpureocillium spp. and Aspergillus spp. were ranked as the most commonly found genera of mould in the collected samples. Of note, Fusarium solani complex isolates were obtained from 14 out of the 106 samples that were collected from tap water (mean of 20 CFU/L). There was a positive correlation between the total number of fungal CFU obtained in all cultures and both water turbidity and temperature parameters. Our findings emphasise the need for the establishment of strict measures to limit the exposure of high-risk patients to waterborne fungal propagules. CONCLUSIONS: We were able to isolate a wide variety of filamentous fungi from the water of the HSCT unit where several immunocompromised patients are assisted.

Insights on PRAME and osteosarcoma by means of gene expression profiling.

BACKGROUND: Osteosarcoma (OS) is the most frequent bone tumor in children and adolescents. Tumor antigens are encoded by genes that are expressed in many types of solid tumors but are silent in normal tissues, with the exception of placenta and male germ-line cells. It has been proposed that antigen tumors are potential tumor markers. OBJECTIVES: The premise of this study is that the identification of novel OS-associated transcripts will lead to a better understanding of the events involved in OS pathogenesis and biology. METHODS: We analyzed the expression of a panel of seven tumor antigens in OS samples to identify possible tumor markers. After selecting the tumor antigen expressed in most samples of the panel, gene expression profiling was used to identify osteosarcoma-associated molecular alterations. A microarray was employed because of its ability to accurately produce comprehensive expression profiles. RESULTS: PRAME was identified as the tumor antigen expressed in most OS samples; it was detected in 68% of the cases. Microarray results showed differences in expression for genes functioning in cell signaling and adhesion as well as extracellular matrix-related genes, implying that such tumors could indeed differ in regard to distinct patterns of tumorigenesis. CONCLUSIONS: The hypothesis inferred in this study was gathered mostly from available data concerning other kinds of tumors. There is circumstantial evidence that PRAME expression might be related to distinct patterns of tumorigenesis. Further investigation is needed to validate the differential expression of genes belonging to tumorigenesis-related pathways in PRAME-positive and PRAME-negative tumors.

ALVEOLAR RECRUITMENT MANEUVERS FOR CHILDREN WITH CANCER AND ACUTE RESPIRATORY DISTRESS SYNDROME: A FEASIBILITY STUDY.

OBJECTIVE: Acute respiratory distress syndrome (ARDS) can be a devastating condition in children with cancer and alveolar recruitment maneuvers (ARMs) can theoretically improve oxygenation and survival. The study aimed to assess the feasibility of ARMs in critically ill children with cancer and ARDS. METHODS: We retrospectively analyzed 31 maneuvers in a series of 12 patients (median age of 8.9 years) with solid tumors (n=4), lymphomas (n=2), acute lymphoblastic leukemia (n=2), and acute myeloid leukemia (n=4). Patients received positive end-expiratory pressure from 25 up to 40 cmH20, with a delta pressure of 15 cmH2O for 60 seconds. We assessed blood gases pre- and post-maneuvers, as well as ventilation parameters, vital signs, hemoglobin, clinical signs of pulmonary bleeding, and radiological signs of barotrauma. Pre- and post-values were compared by the Wilcoxon test. RESULTS: Median platelet count was 53,200/mm3. Post-maneuvers, mean arterial pressure decreased more than 20% in two patients, and four needed an increase in vasoactive drugs. Hemoglobin levels remained stable 24 hours after ARMs, and signs of pneumothorax, pneumomediastinum, or subcutaneous emphysema were absent. Fraction of inspired oxygen decreased significantly after ARMs (FiO2; p=0.003). Oxygen partial pressure (PaO2)/FiO2 ratio increased significantly (p=0.0002), and the oxygenation index was reduced (p=0.01), but all these improvements were transient. Recruited patients' 28-day mortality was 58%. CONCLUSIONS: ARMs, although feasible in the context of thrombocytopenia, lead only to transient improvements, and can cause significant hemodynamic instability.

Low mRNA expression of the apoptosis-related genes CASP3, CASP8, and FAS is associated with low induction treatment response in childhood acute lymphoblastic leukemia (ALL).

BACKGROUND: Defects in apoptosis signaling have been considered to be responsible for treatment failure in many types of cancer, although with controversial results. The objective of the present study was to assess the expression profile of key apoptosis-related genes in terms of clinical and biological variables and of the survival of children with acute lymphoblastic leukemia (ALL). PROCEDURE: The levels of mRNA expression of the apoptosis-related genes CASP3, CASP8, CASP9, FAS, and BCL2 were analyzed by quantitative real-time PCR in consecutive samples from 139 consecutive children with ALL at diagnosis treated by the Brazilian protocol (GBTLI-ALL 99). Gene expression levels and clinical and biological features were compared by the Mann-Whitney test. Event-free survival (EFS) was calculated by Kaplan-Meier plots and log-rank test. RESULTS: A significant correlation was detected between CASP3, CASP8, CASP9, and FAS expression levels (P < 0.01) in ALL samples. Higher levels of BCL2 were significantly associated with white blood cell (WBC) count <50,000/mm(3) at diagnosis (P = 0.01) and low risk group classification (P = 0.008). Lower expression levels of CASP3, CASP8 and FAS gene were associated with a poor response at day 7 according the GBTLI-ALL 99 protocol (P = 0.03, P = 0.02 and P = 0.008, respectively). There was a relationship between FAS gene expression lower than the 75th percentile and lower 5-year EFS (P = 0.02). CONCLUSION: These findings suggest an association between lower expression levels of the pro-apoptotic genes and a poor response to induction therapy at day 7 and prognosis in childhood ALL.

Leukemia, non-Hodgkin's lymphoma, and Wilms tumor in childhood: the role of birth weight.

There is emerging evidence that higher birth weight is associated with increased risk of cancer, in particular childhood leukemia. The purpose of this paper is to study whether this correlation is also significant with other childhood cancer. For this, we conducted a case-control study including 410 childhood cancer patients and 1,575 matched controls to investigate birth weight as a risk factor for leukemia, Wilms tumor, and non-Hodgkin's lymphoma. The estimated risk for all cancers has been found to be statistically and significantly higher in birth weight of more than 4,000 g (odds ratio, 2.50 and 95% confidence intervals (CI), 1.72-3.63). For leukemia, the estimated risk was 1.86 (95% CI, 1.04-3.30), for non-Hodgkin lymphoma, 1.99 (95% CI, 1.08-3.69), and being more remarkable for Wilms tumor, 4.76 (95% CI, 2.73-8.28). Moreover, moderate increased risk of both leukemia and non-Hodgkin lymphoma was also associated with birth weight between 3,000 and 3,999 g. High birth weight was associated with all cancers also when adjusted by gestational age, length at birth, and gender (odds ratio, 6.10 and 95% CI, 1.15-32.57). No associations were found for maternal alcohol consumption during pregnancy, maternal smoking, or smoking by other people at home or presence of obstetric variables (e.g., gestational diabetes, preeclampsia, and abruptio placentae). The present study supports the hypothesis that high birth weight is an independent risk factor for childhood Wilms tumor, leukemia, and non-Hodgkin lymphoma. Further studies should explore biological reasons to explain this relationship and, ultimately, to expand our knowledge about prenatal influences on the occurrence of this disease.

Invasive pneumococcal disease in children with cancer: Incidence density, risk factors and isolated serotypes.

BACKGROUND: Pediatric oncology patients (POP) have a high risk of infections due to impaired immunity. Invasive pneumococcal disease (IPD) is an important cause of severe infection in these patients and it is associated with high mortality. This study aimed to evaluate the incidence and risk factors associated with IPD at a Pediatric Oncology Center in Brazil. METHODS: This was a retrospective case-control study. All IPD cases in children with cancer from 2005 through 2016 were reviewed. Each case of IPD was matched with two controls from a cohort of patients matched for year of IPD, age and disease in order to assess risk factors. The incidence density was calculated as the number of IPD per 100,000 patients-year. RESULTS: A total of 51 episodes of IPD in 49 patients was identified. All pneumococci were isolated from blood cultures. The median age was five years and 67% were male; mortality rate was 7.8%. The IPD incidence density rate in POP was 311.21 per 100,000 patients-year, significantly higher than the rate in the general pediatric population. Severe neutropenia was the only risk factor associated with IPD, after multivariate conditional logistic regression analysis. CONCLUSION: Although pneumococcal disease decreased after the introduction of 10-valent pneumococcal vaccine in the Brazilian national immunization schedule in 2010, there was no decrease in the IPD incidence rate in our cohort. A higher coverage rate of pneumococcal vaccination in children in the general population might be necessary to reduce the incidence rate in this high-risk population.

New therapeutic target for pediatric anaplastic ependymoma control: study of anti-tumor activity by a Kunitz-type molecule, Amblyomin-X.

EPNs comprise a heterogeneous group of neuroepithelial tumors, accounting for about 10% of all intracranial tumors in children and up to 30% of brain tumors in those younger than 3 years. Actually, the pattern therapy for low-grade EPNs includes complete surgical resection followed by radiation therapy. Total surgical excision is often not possible due to tumor location. The aim of this study was to evaluate, for the first time, the anti-tumor activity of Amblyomin-X in 4 primary cultures derived from pediatric anaplastic posterior fossa EPN, Group A (anaplastic, WHO grade III) and one primary culture of a high grade neuroepithelial tumor with MN1 alteration, which was initially misdiagnosed as EPN: i) by in vitro assays: comparisons of temozolomide and cisplatin; ii) by intracranial xenograft model. Amblyomin-X was able to induce cell death in EPN cells in a more significant percentage compared to cisplatin. The cytotoxic effects of Amblyomin-X were not detected on hFSCs used as control, as opposed to cisplatin-treatment, which promoted a substantial effect in the hAFSCs viability. TEM analysis showed ultrastructural alterations related to the process of cell death: mitochondrial degeneration, autophagosomes and aggregate-like structures. MRI and histopathological analyzes demonstrated significant tumor mass regression. Our results suggest that Amblyomin-X has a selective effect on tumor cells by inducing apoptotic cell death and may be a therapeutic option for Group AEPNs.

Risk factors for death in children and adolescents with cancer and sepsis/septic shock.

OBJECTIVE: To assess risk factors for mortality in children and adolescents with cancer and sepsis/septic shock, admitted to intensive care unit. PATIENTS AND METHODS: Retrospective study of a cohort of cancer and sepsis/septic shock patients (n=155) admitted to Oncological Pediatric Intensive Care Unit, between October 1998 and October 2001, with assessment of 12 potential risk factors for mortality by univariate analysis, followed by multivariable analysis. RESULTS: Forty-seven out of 155 patients died (30.3%). In the present sample, after multivariable analysis, 3/12 variables proved to be statistically significant: respiratory infection [hazard ratio (HR)=2.3 and 95% confidence interval (CI)=1.3-4.2], duration of granulocytopenia (HR=2.4 and 95% CI=1.2-4.9), and number of organ dysfunction (HR=7.4 and 95% CI=2.6-21.3). CONCLUSIONS: Our data suggest that mortality in Oncological Pediatric Intensive Care Unit is high and the main factors involved in prognosis are number of dysfunctional organs, respiratory infections, and duration of granulocytopenia; the mortality rises 7.4 times for each dysfunctional organ. We believe that prospective and multicenter studies are necessary to better characterize risk factors that are specific for cancer patients to produce a particular score to predict severity of complications and mortality of children with cancer.