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Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome (HS), is a life-threatening hyperinflammatory condition caused by uncontrolled proliferation of activated lymphocytes and histiocytes producing excessively proinflammatory cytokines. HLH can occur in all age groups. The most common syndromes are: prolonged fever, hepatosplenomegaly, unspecific neurological symptoms, pancytopenia, hemophagocytosis. Characteristic biochemical markers include high triglycerides, ferritin and decreased fibrinogen. There are two forms of HLH, primary (genetic) and acquired (secondary to infections, malignant and autoimmune diseases). Occurrence of both forms of HLH, acquired and genetic, is induced by infections, usually viral or by other triggering agents. Despite established diagnostic criteria many cases probably remain unrecognized. The main diagnostic difficulty is low specificity of symptoms, and in secondary form contemporary occurrence of symptoms of underlying disease. The aim of HLH treatment is to suppress hyperinflammation, what can be achieved by use of immunosuppressive/immunomodulating agents or cytostatics. Patients with genetic form of HLH require hematopoietic stem cell transplantation. Awareness of the symptoms and diagnostic criteria of HLH is important for early diagnosis and immediate application of life-saving therapy.

The objective of the thesis was the evaluation of the clinical tolerance of methotrexate (Mtx), administered in two high doses (2 g/m2 and 3 g/m2) in 218 children with acute lymphoblastic leukemia in 829 chemotherapy cycles. The assessment of the frequency and intensity of the most common adverse early effects of the therapy was keeping with the extended toxicity scale according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC). Tolerance of HD-Mtx was good, observed toxicities were not severe (most commonly of grade 1 and 2) nor prolonged. The most common early complications of the HD-Mtx therapy were: hepatic dysfunction, nausea and vomiting and infections, affecting 60%, 45-50% and 40-55% of patients, respectively. Based on the present investigations, the high risk group for severe early complications and toxicities of Mtx therapy included: patients with delayed Mtx elimination, children above 10 years of life and patients during the first HD-Mtx cycle.

Four consecutive intensive unified regimens (BFM-AML-83, PGP-AML 94, PGP-AML 98 AML-BFM 2004 Interim) for acute myelocytic leukemia (AML) have been conducted by the Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG) since 1983. The last one, introduced four years ago is still active, and only preliminary result may be presented. There were 726 children with AML diagnosed (226, 102, 247 and 151 in the I, II , III and IV periods, respectively), and 603 of them were eligible for evaluation (208, 83, 195 and 117, respectively). Complete remission rates were: 71.4%, 67.5%, 81.4% and 87% in consecutive periods, respectively. Five-year overall survival (OS) and event-free survival (EFS) rates were: 33% and 32% for PGP-AML 83 regimen, 38% and 36% for PGP-AML 94 regimen, and 53% and 46% for PGP-AML 98 regimen, respectively. For AML-BFM Interim 2004 the 3-year OS and EFS were 57% and 57%, respectively. Despite continuous improvement of the treatment results, the number of failures have remained too high, but the pattern have changed in the following way: Early deaths (from diagnosis to 15 day of treatment) decreased only in the fourth period to 3%. "Aplasia deaths" (between day 15 and 42) decreased gradually from 16% in the first period to 1.5% and 2.2% in the third and in the fourth period, respectively. Deaths in remission decreased from 10% in first and second period to 3.5% at present. Number of non responders increased between first and second period from 6% to 18%, later decreased to 8.2% at present. These trends e.g. decrease of early death and treatment related mortality reflect both the better efficacy of antileukemic treatment and the improvement of supportive care.

Central nervous system (CNS) involvement in the course of neuroblastoma (NBL) in children is relatively rare. However, it seems to become serious clinical problem in the group of patients from high risk group. They presently achieve longer time of survival caused by employment of more intensive treatment modalities. The aim of the study was clinical evaluation of the patients over 1 year of age with stage 4 NBL with CNS involvement, both at diagnosis and at relapse. From 1997 to 2007, 117 patients (age 0.2-13.5 years) started NBL treatment. In 58 children over 1 year, stage 4 of disease was diagnosed. In 4 (6.9%) cases the CNS involvement was found at diagnosis. In 5 patients (8.6%) the isolated relapse in brain was diagnosed. The clinical symptoms caused by increased intracranial pressure were observed in all patients at relapse. In the case of initial involvement no neurological symptoms were observed. All 5 children with CNS involvement as isolated relapse did not present with infiltration of skull bones, whereas at initial diagnosis the brain lesions were continuous with bone metastases. Among 5 patients with isolated relapse 4 died because of NBL progression. Among 4 children with initial CNS involvement 1 died due to haemorrhage to CNS. Probably brain involvement at initial NBL diagnosis is not an additional negative prognostic factor. Because of extremely poor prognosis in patients with CNS relapse it should be advised to consider possible implementation of preventive treatment. It is also necessary to invent new more effective treatment methods.

The aim of the paper is to present the initial results of molecular examination which was started in 2006 for children with acute myeloid leukemia. Better knowledge of biology of this disease, can result in establishing of new risk factors what allows more precise patient stratification to different therapeutic groups. Study was obtained patients until to 18 years of age treated according to AML-BFM 2004 INTERIM protocol in 14 centers of the Polish Pediatric Leukemia/Lymphoma Study Group. Mononuclear cells were collected from bone marrow on time points established according to the AML-BFM 2004 INTERIM protocol. Collected cells were isolated on Ficoll gradient, and RNA and DNA were isolated using TRIZOL reagent. To synthesize cDNA an amount of 1 mg of total RNA was used. To perform quantitative RT-PCR and RQ-PCR reactions 4 fusion gene transcripts (AML1-ETO, CBFb-MYH11, PML-RARA /subtype bcrl and bcr3/) were used according to the protocol established by Europe Against Cancer Program. An expression of WT1 gene was tested additionally. An analysis of ABL control gene was used to normalize of achieved results. Determination of duplication of FLT3 gene in DNA sample was performed with starters complementary to JM region. Genotyping was performed in 75 patients with acute myeloid leukemia so far. AML1-ETO fusion gene transcript was found in 14 patients (19%). PML-RARA (subtype bcr3) and CBFB-MYH11 gene transcripts were detected in 3 (4%) and 3 (4%) patients, respectively. Duplication of FLT3 gene was found in 4 (5.3%) cases. Between 67 tested children over expression of WT1 was present in 51 patients (76%). Analysis of MRD level in subsequent time points showed systematic decrease of number of fusion gene transcript copies and gene WT1 expression. To establish the rate of molecular marker presence in AML in children and the influence of the presence of MRD on the treatment results as well, the study has to be conducted on a larger group of patients with longer follow-up.

Until recently chemotherapy was used as adjuvant therapy after enucleation in cases with extraretinal spread of the disease (uveal extension, orbital extension, neoplastic infiltrates of the optic nerve at resection line, intracranial metastasis, generalized disease). Recent experience has proved that use of chemotherapy for intraocular retinoblastoma before local treatment (so called "chemoreduction") has allowed not only to decrease number of enucleations and indications for external beam irradiation or limit the extension of local therapy, but also increase chances for vision preservation and decrease the risk of severe complications. Seventy five children (with 106 involved eyes) aged 0.2 - 106 months with intraocular retinoblastoma diagnosed between January 1996 and June 2009 were the subject of this study. Among 106 involved eyes, in 70 (66%) the V stage according to Reese-Ellsworth classification (R-E) was established. Enucleation before chemotherapy was necessary in 9 (8.5%) cases, and in 22 more children the eye had to be removed after 1-2 courses of chemotherapy. In 68 remaining children (with 70 involved eyes) VEC (vincristine, etoposide, carboplatin) chemotherapy combined with delayed local therapy (cryotherapy, photocoagulation, brachytherapy) was employed. Out of 84 eyes treated by combined methods eye enucleation could be avoided in 47 (67%), including 18 (90%), 13 (87%) and 16 (46%) qualified to R-E group I-II, III-IV and V, respectively. First-line chemotherapy combined with the local treatment should be standard treatment for intraocular retinoblastoma groups I - IV. More effective therapy is required for R-E eye group V cases.

Approximately 60 children aged 0-18 years are diagnosed of NBL each year in Poland. About 60% of all patients suffering from NBL have a chance for durable cure. Unfortunately the prognosis for patients within the high-risk group accounting for more than 50% of all NBL patients remains poor despite the introduction of more intensive chemotherapy regimens with radical surgery procedures and megachemotherapy with subsequent stem cell transplantation. Only one third of patients in this group can be cured. To improve the treatment results of the high-risk patient group and to decrease the rate of therapy related side effects current European treatment protocols have been introduced systematically in Poland. In February 2009 information about 389 patients (age 0.1-16.5 years) diagnosed between 2001 and 2008 were obtained. Results of therapy of 319 patients who started treatment from 2001 to 2007 were analyzed. Between 104 infants and 215 children over 1 year of age, stage 4 of disease was found in 25% and 54.5%, respectively. In this period additionally to European treatment protocols, two another protocols were used. Satisfactory treatment results were obtained in 104 infants (5-year event free survival /EFS/=82.6%), irrespective of the type of treatment protocol. Over 5-year EFS for children over 1 year of age in 1, 2 and 3 stage of disease was: 100%, 86.3% and 64.5%, respectively. On the contrary, 107 patients with 4 stage of disease achieved the 5-year EFS of 27% only. Treatment results obtained in patients treated according to the European HR-NBL-1/ESIOP protocol were better than for patients treated according to other treatment protocols (5-year EFS: 31.1% and 16.4%, respectively), but difference between these groups was not significant. Between 2001 and 2007 data reporting increased to 81% from 19% noted earlier. Unfortunately, results of treatment for children over 1 year of age remain still unsatisfactory. That is why there is a need of improvement of modern, unified treatment realization as well as better data reporting. For realization of these aims adequate financial support is essential.

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