Czynniki warunkujące aktywność terapeutyczną L-asparaginazy

L-asparaginase (L-asp) is the basis of contemporary protocols used in the treatment of pediatric acute lymphoblastic leukemia and non-Hodgkin lymphomas. The key factor during L-asparaginase treatment is achieving sufficient serum activity of the drug during particular time period. There are several specified factors influencing L-asp activity. One is the preparation of the enzyme and their different pharmacokinetics. The other is L-asparaginase inactivation due to immunological response. The next factor, indirectly affecting L-asp activity, is the expression of asparagine synthetase, which is an enzyme of the opposite function to L-asparaginase.The least known process is the enzymatic degradation of L-asparaginase by lisosomal cathepsin B and asparaginyl endopeptidase

Severe vitamin B12 deficiency of unknown origin in 10-months-old girl

Niedobór witaminy B12 jest u dzieci dość rzadką przyczyną niedokrwistości makrocytarnej. W ciężkich przypadkach może prowadzić do wystąpienia zaburzeń neurologicznych i psychicznych, a także zmian troficznych błon śluzowych jamy ustnej i języka. Do najczęstszych przyczyn niedoboru witaminy B12 należą dieta uboga w tę witaminę (wegetariańska, a zwłaszcza wegańska), zaburzenia wchłaniania w żołądku i jelicie cienkim (choroba Addisona-Biermera, stan po resekcji żołądka, bezkwaśność soku żołądkowego, choroba Leśniowskiego-Crohna, celiakia, zakażenia pasożytnicze), wrodzone niedobory transkobalaminy II oraz zaburzenia metabolizmu witaminy B12. U dzieci jako przyczynę należy wziąć pod uwagę karmienie wyłącznie piersią przez matki z utajonym bądź jawnym niedoborem tej witaminy. W pracy opisano przypadek 10-miesięcznej dziewczynki z ciężkim niedoborem witaminy B12 o nieznanej etiologii, u której oprócz zaburzeń hematologicznych (pancytopenia) stwierdzono ciężkie zaburzenia neurologiczne, a także niewydolność krążenia. Wszystkie objawy całkowicie ustąpiły po wyrównaniu niedoboru witaminy. Hematologia 2011; 2, 1: 92–97Vitamin B12 is quite rare reason of macrocytic anemia in children. In severe cases it can lead to neurological and psychotic symptoms or trophic lesions of tongue and mucous membranes. The most common reasons of vitamin B12 deficiency are diet (vegetarians, and especially vegans), malabsorption (i.e. pernicious anemia, gastric resection, achlorhydria, Crohn’s disease, celiac disease, parasitic infections), congenital transcobalamin II deficiency or vitamin B12 metabolic disorders. Breast-feeding by mothers with vitamin B12 deficiency must be also considered as a reason of severe vitamin B12 deficiency in infants. We describe the case of 10-months-old child with severe vitamin B12 deficiency of unknown origin. We observed not only severe hematological problems (pancytopenia), but also neurological symptoms and heart failure. All the symptoms disappeared after compensation of vitamin B12 deficiency. Hematologia 2011; 2, 1: 92–9

The role of histone protein modifications and mutations in histone modifiers in pediatric b-cell progenitor acute lymphoblastic leukemia

While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes include MLL1, CREBBP, NSD2, and SETD2. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis

Tumor expression of survivin, p53, cyclin D1, osteopontin and fibronectin in predicting the response to neo-adjuvant chemotherapy in children with advanced malignant peripheral nerve sheath tumor

Purpose Selected cell-cycle regulators and extracellular matrix proteins were found to play roles in malignant peripheral nerve sheath tumor (MPNST) biology. We aimed to analyze whether initial tumor tissue expressions of survivin, p53, cyclin D1, osteopontin (OPN) and fibronectin (FN) correlate with the response to neo-adjuvant CHT (naCHT) in children with advanced inoperable MPNST. Methods The study included 26 children with MPNST (M/F 14/12, median age 130 months) treated in Polish centers of pediatric oncology between 1992 and 2013. Tissue expression of markers was studied immunohistochemically in the manually performed tissue microarrays and assessed semi-quantitatively as low and high, based on the rate of positive cells and staining intensity. Results Good response to naCHT was noted in 47.6%, while poor-in 52.4% of patients. The response to naCHT was influenced negatively by the presence of neurofibromatosis NF1 and high initial tumor tissue expression of OPN, survivin, p53 and cyclin D1. Patients with high tumor expression of either OPN, survivin or p53 and those with simultaneous high expression of ≥ 3 of the markers, responded significantly worse to naCHT, than patients, in whom expression of ≤ 2 markers were detected at diagnosis. Nearly, 85% of patients expressing ≥ 3 markers, responded poor to CHT; while 87.5% of children, expressing ≤ 2 markers, were good responders. Conclusion The initial tumor tissue expression of OPN, survivin, p53 and cyclin D1 may serve as markers to predict response to naCHT in pediatric advanced MPNST. Future studies in more numerous group of patients are needed to confirm these preliminary results

Clinical Study Interleukin 18 as a Marker of Chronic Nephropathy in Children after Anticancer Treatment

Novel markers of nephrotoxicity, including kidney injury molecule 1 (KIM-1), interleukin 18 (IL-18), and beta-2 microglobulin, were used in the detection of acute renal injury. The aim of the study was to establish the frequency of postchemotherapy chronic kidney dysfunction in children and to assess the efficacy of IL-18, KIM-1, and beta-2 microglobulin in the detection of chronic nephropathy. We examined eighty-five patients after chemotherapy (median age of twelve years). The median age at the point of diagnosis was 4.2 years, and the median follow-up time was 4.6 years. We performed classic laboratory tests assessing kidney function and compared the results with novel markers (KIM-1, beta-2 microglobulin, and IL-18). Features of subclinical renal injury were identified in forty-eight children (56.3% of the examined group). Nephropathy, especially tubulopathy, appeared more frequently in patients treated with ifosfamide, cisplatin, and/or carboplatin, following nephrectomy or abdominal radiotherapy ( = 0.14, = 0.11, and = 0.08, resp.). Concentrations of IL-18 and beta-2 microglobulin were comparable with classic signs of tubulopathy ( = 0.0001 and = 0.05). Concentrations of IL-18 were also significantly higher in children treated with highly nephrotoxic drugs ( = 0.0004) following nephrectomy ( = 0.0007) and abdominal radiotherapy ( = 0.01). Concentrations of beta-2 microglobulin were higher after highly toxic chemotherapy ( = 0.004) and after radiotherapy ( = 0.02). ROC curves created utilizing IL-18 data allowed us to distinguish between children with nephropathy (value 28.8 pg/mL) and tubulopathy (37.1 pg/mL). Beta-2 microglobulin and IL-18 seem to be promising markers of chronic renal injury in children after chemotherapy