The role of CRP, PCT, IL-6 and presepsin in early diagnosis of bacterial infectious complications in paediatric haemato-oncological patients.

Bacterial infection is the most common complication in paediatric oncological patients during cancer treatment. A suitable tool for early prediction of unfavourable course of infection is still needed. We performed a prospective longitudinal observational study to evaluate of the role of serum biomarkers (C-reactive protein, procalcitonin, interleukin-6, presepsin) in the early diagnosis of bacteraemia (gram-negative versus gram-positive) in patients with haematological malignancies. We observed 69 febrile episodes in 33 patients (17 male, 16 female; 1.5-18.9 years, mean 7.31 years, median 5 years). Within this sample, there were 22 cases of positive blood cultures, 16 cases of sepsis, 38 cases of fever with no signs or symptoms of sepsis, and two deaths from infectious complications. All markers tested had good negative predictive value (73% - 93%). CRP was characterized by good specificity for registration bacteraemia (96%, 95% CI: 85% - 99%), but other results were inconclusive. We identified comparably balanced sensitivity (64% - 81%) and specificity (61% - 88%) for interleukin-6 and procalcitonin, and we proved their quality to predict positive blood culture and clinical signs of sepsis as well. Patients with gram-negative bacteraemia had significantly elevated levels of PCT and IL-6 in comparison with a group of patients with gram-positive bacteraemia (p = 0.04 for PCT and p = 0.005 for IL-6). Presepsin was characterized by poor specificity (27%, 95% CI: 15% - 43%) and positive predictive value (24%, 95% CI: 12 - 39%) for predicting bacteraemia, and by better sensitivity (84%, 95% CI: 55% - 98%) and specificity (58%, 95% CI: 42% - 73%) for predicting clinical signs of sepsis.

[Embryonal Tumors with Multilayer Rosettes--Rare Central Nervous System Tumors in Infants]. / Embryonálne tumory s mnohovrstvovými rozetami--vzácne tumory centrálneho nervového systému v detskom veku.

INTRODUCTION: The most recent findings show a histopathological, genetic and clinical uniformity in cases of tumors called embryonal tumors with multilayer rosettes. This group is composed of medulloepithelioma, ependymoblastoma and embryonal tumor with abundant neuropil and true rosettes. Amplification of locus 19q13.42, which includes C19MC cluster containing genes for microRNA, and also LIN28A positivity are present in all three entities. Dysregulation of epigenetic modifiers is very important in pathogenesis of the disease. These tumors manifest in little children (median less than 3 years of age); overall survival is 5-10%. CASE REPORT: Almost three year-old boy diagnosed with brainstem tumor: meduloepithelioma, WHO grade IV confirmed by histological investigation. He presented with dysarthria, bulbar syndrome, central lesion of the facial nerve, quadriparesis with right-side dominancy. He received three induction cycles of chemotherapy from March to May 2014 (according to protocol COG ACNS0334). Only partial improvement of his clinical state was reached. Signs of an intracranial hypertension appeared resulting in VP shunt insertion; impairment of consciousness developed after the induction cycles and before any other treatment could be initiated. He underwent radiotherapy due to vital indication. After application of two fractions (boost in the center of the tumor), the patient became quickly comatose. Spinal cord metastasis was demarked by MRI scan (in the level of 3rd cervical vertebra). A bilateral infiltration in pulmonary parenchyma, according to a radiologist metastasis-wise, was detected by CT scan (histologisation of infiltration was not implemented). The patient died in August 2014--six months after manifestation of first symptoms. CONCLUSION: We reported our first documented case of a patient with tumor from embryonal tumors with multilayer rosettes group in Slovakia. Nowadays, there is no effective treatment of these tumors. Research of molecules targeting to epigenetic modifiers would be one of the possible promises for future therapy.

Improved outcome for children and adolescent with acute lymphoblastic leukemia in the first decade of the 21st century: A report from the Slovak Republic.

Our aim was to analyze event-free (EFS) and overall survival (OS) among children and adolescents with acute lymphoblastic leukemia (ALL) treated with International BFM Intercontinental trial (ALL IC 2002) therapy in the Slovak Republic. In total, 280 children and adolescent age 1 to 18 years were treated with ALL IC BFM 2002 based therapy from 2002 to 2012, which was divided into two periods. During 2002-2007, when patients were actively enrolled in the ALL IC-BFM 2002 trial, and during 2008-2012 when the trial was closed and patients were treated with the same therapy without randomization. Five-year EFS and OS rates were 79% (+/- 2.6%) and 86% (+/- 2.1%), respectively, similar to results obtained in the ALL-BFM 95 trial, which was the basis for ALL IC BFM 2002 therapy. The EFS (p<0.012) and OS (p<0.003) were significantly better than the prior Slovak experience in 1997-2001. Survival is improved in standard and intermediate risk groups, including those age 1 to 6 years, and older; with B-cell or T-cell immunophenotype, and is also excellent for those with good early response. The rate of death in induction, cumulative incidence of death in complete remission and of relapse decreased. However, outcome was suboptimal for patients in the high risk group. Current EFS and OS rates for children and adolescents with ALL in the Slovak Republic resembled those obtained in Western Europe as a result of clinical trial participation, and clinical experience acquired with intensive BFM type treatment.

Uncommon leukemic case of anaplastic large cell lymphoma diagnosed through a typical chromosomal abnormality t(2;5) with a null phenotype and aberrant expression of NG2 and CD13.

Anaplastic large cell lymphoma represents approximately 10-15 % of pediatric non-Hodgkin lymphomas. Leukemic presentation is very rare, and in particular, the null phenotype ALCL without typical anaplastic morphology together with aberrant expression of CD13 and/or CD11b represents a diagnostic challenge. We report a case of a 9 year-old boy with leukemic presentation of ALCL with the typical translocation t(2;5)(p23;q35); in this patient, the only positive antigens identified by immunophenotyping were CD13, NG2 HLA-DR, and CD38. To our knowledge, aberrant expression of NG2 has never been reported in ALCL cases (Tab. 1, Fig. 6, Ref. 20).

Minimal residual disease detection using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the non-MRD-based ALL IC-BFM 2002 protocol for childhood ALL: Slovak experience.

Acute lymphoblastic leukemia is the most common form of cancer in children. The 10-year event-free survival ranged from 77 to 85% after having achieved complete remission rates of 93% or higher. The main cause of treatment failure is relapse arising from outgrowth of residual leukemic cells that are refractory to therapy. An intense effort has been made to develop methods to determine the degree of minimal residual leukemia cells present in patients considered to be in morphological remission. Because of the strong correlation between minimal residual disease (MRD) levels and risk of relapse, monitoring of MRD provides unique information regarding treatment response. The MRD monitoring based on real-time quantitative PCR detection of patient-specific immunoglobulin and T-cell receptor (Ig/TCR) gene rearrangements is currently considered to be the most reliable tool for MRD-based diagnosis in ALL. Because the significance of MRD monitoring has been strongly supported by several studies and because it has been implemented in the latest protocols, there has been a significant effort to develop MRD monitoring in the Slovak Republic since 2005. Between October 2006 and December 2009, 50 children with ALL who were treated at three Slovak centers were included in the RQ PCR MRD pilot project. A total of 40 patients with BCP-ALL ( B cell precursor ALL) and 4 patients with T ALL were analyzed for Ig/TCR rearrangement. We identified 106 different rearrangements in the 44 ALL patients analyzed. Based on MRD stratification, we identified 26 patients who were stratified into the HRG ( high risk group) (n = 3; 11.5%), IRG ( intermediate risk group) (n = 14; 54%) and SRG ) standard risk group) (n = 9; 34.5%). Morphology-based risk stratification allows the identification of most HRG patients identified also by MRD-based stratification, but fails to discriminate the IRG assigned to therapy reduction. Patients in the SRG and the IRG could profit from MRD-based risk assignment

Systemic malignancies presenting as primary osteolytic lesion.

The tumor formation may be the earliest manifestation preceeding other symptoms, signs and bone marrow evidence of systemic malignancy - leukemia/lymphoma. Here we present three cases of systemic malignancy in which bone lesions were the first manifested signs of the disease. All three cases were thought to be orthopedic cases and had been treated as so without genuing improvement. We would like to draw an attention to children who present with multifocal musculoskeletal pain and the importance of whole-body scaning. We describe interesting cases of diffuse large cell lymphoma and leukemia that initially presented as primary osteolytic bone lesion and discuss the differential diagnosis, literature review of non-Hodgkin's lymphoma arising in bone as the primary site (Tab. 1, Fig. 3, Ref. 18). Full Text (Free, PDF) www.bmj.sk.

Our experience with tumor lysis syndrome treatment.

Tumor lysis syndrome (TLS) is caused by rapid tumor cell turnover resulting in a release of intracellular contents into the circulation, and subsequent numerous metabolic derangements (hyperkalemia, hypocalcemia, hyperphosphatemia, hyperuricemia). More than 90% of cases have laboratory manifestations, and only about 10% have clinical manifestations. The main complications are acute renal failure, cardiac arrhythmia and metabolic acidosis. The management of TLS consists of preventive measures in high-risk patients prior to cancer treatment as well as prompt initiation of supportive care for patients who develop acute tumor lysis syndrome during treatment. The traditional management consists of intravenous hydratation, urinary alkalinization, diuretics and control of hyperuricemia, electrolyte disturbances and dialysis if needed. The use of a new hypouricemic agent (rasburicase) in patients with TLS minimized the need for renal dialysis as well as reduced the incidence of complications seen in hyperproduction of uric acid to minimum (Tab. 4, Ref. 8). Full Text (Free, PDF) www.bmj.sk.

Bacteremia due to Pseudomonas aeruginosa: results from a 3-year national study in the Slovak Republic.

Risk factors, mortality and antimicrobial susceptibility of Pseudomonas aeruginosa bacteremias isolated from 148 patients from all University Hospitals in Slovakia were analyzed. Only 1.2% of 169 strains of P. aeruginosa were resistant to meropenem, 4.1% to piperacillin/tazobactam, 7.7% to ceftazidime as well as cefepime and 12% to amikacin. More than 30% of P. aeruginosa were resistant to ciprofloxacin. Our analysis of risk factors for antimicrobial resistance to the particular antimicrobials, indicated no difference in risk factors and outcome in cases infected with P. aeruginosa bacteremias resistant to amikacin, piperacillin/tazobactam or ceftazidime in comparison to episodes caused by P. aeruginosa due to susceptible isolates. When comparing risk factors for P. aeruginosa bacteremia in children vs. adults, cancer vs. non-cancer patients, several differences in risk factors were observed. Neither antimicrobial resistance to amikacin, ceftazidime or piperacillin/tazobactam, nor appropriateness of therapy according to two separate analyses were associated with better outcome.

Prospective study on fungemia in children with cancer: analysis of 35 cases and comparison with 130 fungemias in adults.

The aim of this prospective study on fungemia in children with cancer compared with adults with cancer appearing during the last 10 years in a pediatric hospital and in national cancer institutions was to investigate risk factors, etiology, therapy, complications and outcome. Univariate analysis showed significant differences in 35 children with cancer and fungemia in comparison with 130 cases of fungemias in adults with cancer. It was found that (1) therapy with corticosteroids (40 vs 18.5%, P<0.03), (2) breakthrough fungemia during ketoconazole prophylaxis (20 vs 7.7%, P<0.025), and (3) meningitis as a complication of fungemia (11.4 vs 0.8%, P< 0.001) occurred more frequently in the pediatric subgroup with fungemia. Candida albicans was more common as the causative agent of fungemia among adults (58.5 vs 37.1, P<0.02) than in children. However, mortality was similar in children with cancer and in adults with cancer and fungemia (31.4 vs 23.1%, NS). Comparison of risk factors revealed no differences between adults and children with cancer and fungemia except in etiology, breakthrough fungemia during prophylaxis with ketoconazole, prior therapy with corticosteroids and meningitis as a complication. The outcome was also similar in pediatric and adult cancer patients with fungal bloodstream infection.

Granular acute lymphoblastic leukemia in a 15-year-old boy.

We report a case of a boy with acute lymphoblastic leukemia expressing granular inclusions in the cytoplasm of blastic cells. Granular lymphoblasts had mostly L2 morphology but azurophilic granules were also present in part of the cells with L3 morphology. Immunophenotyping clearly indicated a lymphoid origin of the blasts and showed positivity of HLA-DR, CD10, CD19 and CD24 markers. Cytogenetic analysis brought normal karyotype 46 XY. Molecular genetic analysis showed immunoglobulin heavy chain rearrangement (IgH R/R) and T-cell receptor gamma rearrangement pattern (TCR-gamma C/R). TCR-beta and TCR-delta did not show rearrangements. The course of the disease was favourable. The patient achieved initial complete remission within 4 weeks of protocolar treatment and the remission remains until now, 5 years from the diagnosis and three years after finishing the treatment.

Is T-cell acute lymphoblastic leukemia still a high risk leukemia in children?

In a group of 21 children with T cell ALL we compared the clinical picture and laboratory finding in a subgroup of 13 patients with less mature (mCD3 negative) and a subgroup of 8 patients with mature (mCD3 positive) phenotypical type and the therapeutic response in relation to the stage of thymic differentiation of the blastic cells as well. We could not find any significant differences concerning the presence or absence of mediastinal thymic mass, organomegaly, WBC count, morphology of the blasts and their acid phosphatase and PAS reaction between cases with less mature and mature type of thymic differentiation. Concerning the therapeutic response, children with mature type of T-ALL have shown at 5 years significantly higher event free survival rate, in comparison with the group of patients with less mature type of T cells. Overall survival rate was also higher in the first group, but statistically not significant.

Is high dose methotrexate without irradiation of the brain sufficiently effective in prevention of CNS disease in children with acute lymphoblastic leukemia?

We present 5-year results of treatment in 93 children suffering from acute lymphoblastic leukemia using two therapeutic protocols containing multidrug chemotherapy including high dose methotrexate. We could ascertain different results in standard and high risk patients. In a group of 62 children with standard risk we observed improvement in complete remission rate being 98.9% after induction phase of therapy, only one patient died on septicemia. Relapse rate in this group was 21.2% and that 14.7% in the bone marrow and 6.5% in CNS and no testicular relapse at all. In the group of 31 children with high risk leukemia all patients achieved complete remission. Only one of them died on acute pancreatitis due to toxicity. Overall relapse rate in this group was 28.9% with 12.8% of medullary relapse and 16.1% of CNS relapse. The last one was significantly higher than in the previous study when brain irradiation was a part of therapeutic procedure. It seems that this treatment is effective mainly in the standard risk leukemia, however, in the high risk leukemias this procedure appears to be less effective in preventing CNS leukemia. In this group of patients irradiation of the brain need to be enclosed in the therapy.

Bacteremia and fungemia in pediatric versus adult cancer patients after chemotherapy: comparison of etiology, risk factors and outcome.

One hundred and eighteen (118) episodes of bacteremia and fungemia in children with cancer were compared to 401 episodes of bacteremia and fungemia in adults with cancer to assess differences in etiology, risk factors and outcome. A retrospective univariate analysis was performed of all episodes of bacteremia in national pediatric and adult cancer institutions appearing in 1990-1996. A total of 519 episodes of bacteremia were assessed and compared. Both cancer centers differed in prophylactic antibiotic policies. About 50% of adults but less than 5% of children received quinolone prophylaxis during neutropenia, even though the empiric antibiotic therapeutic strategy was similar. There were differences in etiology between the groups: staphylococci and Stenotrophomonas maltophilia were more frequently observed in children (P<0.01), Pseudomonas aeruginosa and Acinetobacter spp. in adults (P<0.05). Gram-positive bacteremia was surprisingly more commonly observed in adults (65.7% vs 33.3%, P<0.01). Mixed polymicrobial bacteremia occurred more commonly in adults (31.8% vs 7.6%, P<0.001) than in children. Analysis of risk factors did not observe differences in risk factors except for underlying disease (acute leukemia was more frequently observed in children -48.3% vs adults 33.7%, P<0.05 and prophylaxis: (prior prophylaxis with quinolones was more common in adults (47.5%) than in children (2.5%) P<0.0001). Overall and attributable mortality in pediatric bacteremia was significantly lower than in adults (P<0.03).

Expression of CD10, CD19 and CD34 markers in bone marrow samples of children with precursor B-cell acute lymphoblastic leukemia in clinical and hematological remission.

Long-term follow-up of the rate of CD10, CD19 and CD34 antigens expression compared with the percentage of lymphocytes and blastic cells in 196 bone marrow specimens of 91 children with early B-cell acute lymphoblastic leukemia has been performed. It was shown that during a five year period there were no significant differences concerning the percentage of CD markers and the percentage of lymphocytes and blastic cells except those in the 4th year of clinical and immunological follow-up--when increase of lymphocytes and CD19 marker percentage have been observed. Consensus, i.e. more than 20% CD markers positivity associated with more than 5% blasts (positive consensus) or less than 20% CD markers positivity combined with less than 5% blasts (negative consensus) was ascertained in 92.8% of cases. Disagreement, i.e. the rate of CD markers over 20% combined with less than 5% blasts was found in 14 (7.2%) patients. This finding present in the initial phase of the disease could be considered as a sign of not complete remission, in contrast to the finding in children who completed chemotherapy and were in long-term hematological remission, in which the increase of CD markers could be considered as a sign of increased regeneration activity of bone marrow after chemotherapy induced medullary aplasia. Anyway, the increase of CD10, CD19 and CD34 antigens in bone marrow samples over 20% should be evaluated with caution. In these cases, mainly in children with long-term hematologic remission the examination should be repeatedly performed and/or more sensitive methods for detection of minimal residual disease should be applied. In control group of 20 children without leukemia the rate of CD markers in the bone marrow was always under 20%.

Magnetic resonance imaging in children receiving quinolones: no evidence of quinolone-induced arthropathy. A multicenter survey.

Twenty-nine children with cystic fibrosis (CF) were investigated for quinolone-induced arthropathy. Magnetic resonance imaging (MRI) was performed in 14/14 children treated with ofloxacin or ciprofloxacin and in 10/15 of those never treated with quinolones. The frequency of pathologic MRI findings, concerning cartilage thickness, careful analysis of the cartilage structure, presence of edema, cartilage-bone borderline and the presence of fluid in joints did not show any difference between both groups. Thus the presence of quinolone-induced arthrotoxicity cannot be confirmed in this study.

[Long-term prognosis in children with minor glomerular abnormalities]. / Dlhodobá prognóza detí s malými abnormalitami glomerulov.

The authors evaluated the course and prognosis of the disease in 109 children with minor glomerular abnormalities manifested clinically in 45.9% as nephrotic syndrome (NS), in 33% as nephritic syndrome (GN), in 11.9% as isolated haematuria (IH) and in 9.2% as Schönlein-Henoch's purpura (PSH). In NS 78% of the children had before biopsy of the kidneys frequent relapses, 22% were resistant to cortisonoids. After biopsy all children were given cortisonoids, 94% immunosuppressive treatment with cytostatics and some of the children additional treatment. The number of resistant cases declined to 10% and the mean number of relapses from four to one in 12 months. Children under five years had more relapses (P less than 0.05) but also more complete remissions (P less than 0.001) than older children. Relapses occurred up to 10.2 years after the onset of the disease (mean = 4 years). With advancing age and duration of the disease their number declined after treatment. An adverse symptom was resistance to cortisonoids and immunosuppressive treatment, major haematuria and persisting hypertension but not immunological activity (elevated level of immune complexes, reduced C3, positive immunohistochemical finding in renal tissue). The morphological finding which at the onset was slightly beyond the range of minor abnormalities had a poorer prognosis when associated with greater clinical activity. The group developed 88% complete remissions and 6% CHRI. After 22 years the probability of survival in complete continual remission is 66%, the probability in CHRI is 10% (with morphological progression). In nephritic syndrome the children were given after biopsy prednisone in 80.6% and cytostatics in 44.4%. In PSH this treatment was given to 100% and 60% of the children, in IH to 61.5% and 7.7%. On evaluation in nephritic syndrome complete remission was recorded in 47.2%, after 0.4-10.5 years since the onset of the disease; 30.6% did not improve and in 2.8% CHRI developed. In PSH remission developed in 60% after 0.8-6.9 years, no improvement was recorded in 20%, incl. 10% where CHRI developed after a resistant course of NS. In IH 84.6% of the patients did not improve, but in none the renal function deteriorated. The course was in all instances milder than in NS, most frequently only with microscopic haematuria and/or slight proteinuria, respectively minor immunological activity. In the entire group of minor glomerular abnormalities complete remission was achieved in two-thirds of the children, in one quarter the disease did not improve, incl. 4.6% where CHRI developed, always associated with progression of morphological changes.(ABSTRACT TRUNCATED AT 400 WORDS)

[Treatment of nephrotic syndrome with cyclosporin A]. / Liecba nefrotického syndrómu cyklosporínom A.

The authors treated eight children with corticoid dependent syndrome caused by minor abnormalities of the glomeruli with Cyclosporin A. They administered Cyclosporin, 5 mg/kg/24 h., for a period of 8-16 weeks. In three patients they used Cyclosporin A alone, 5 children were given in addition 10 mg Prednisone per day. They achieved complete remission in all patients. During treatment they monitored haematological and biochemical parameters as well as Cyclosporin A levels; before treatment and after its termination they examined also immunological indicators. They did not observe any serious side effects of treatment.