Endothelial Function in Children with Acute Lymphoblastic Leukemia (ALL) May Reflect the Clinical Outcome.

Endothelial dysfunction is a common feature of early complications of hemato-oncologic therapy. The aim of our study was to assess the profile of endothelial function at diagnosis time, then during initial treatment phase of acute lymphoblastic leukemia (ALL), and to verify the presence of its correlation with early clinical outcome (ECO). 28 ALL children and 18 healthy age-matched control ones were recruited. Study group was examined at baseline and at 33rd and 78th day of treatment. At each protocol step the endothelial function was assessed by measurement of sP-selectin (CD62-P), PAI-1(serpinE1), sE-selectin (CD62E), sICAM-1(sCD54), sVCAM-1(sCD106), and VEGF concentrations. Higher baseline sICAM-1 and sVCAM-1 levels and lower sP-selectin and VEGF were observed in children with ALL. sICAM-1, sVCAM-1, and sE-selectin levels were decreasing following the treatment with protocol I. Higher sE-selectin and lower baseline sICAM-1 levels were observed in children treated unsuccessfully. Lower PAI-1 levels were observed in children who survived. Higher baseline sE-selectin levels and lower sICAM-1 and VEGF were observed in children treated unsuccessfully. A decrease in sE-selectin and lower PAI-1 at the 78th day of therapy were associated with better ECO. High baseline VEGF and sE-selectin levels, significant increase in PAI-1, and low initial sICAM-1 levels are prognostics for poorer prognosis in the ALL children.

Elevated plasma ADMA contributes to development of endothelial dysfunction in children with acute lymphoblastic leukemia.

BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) survivors are at higher cardiovascular risk than the general population, which may result from anthracycline-related endothelial dysfunction (ED). However, a few studies indirectly show that ED may appear in ALL children before treatment begins. Hence, in this study we intended to verify the hypothesis that ED is part of the ALL phenotype. PATIENTS/METHODS: Twenty-eight ALL children and 14 healthy age-matched control children were recruited. The study group was examined at baseline, then at the 33rd and 78th day of treatment. At each step of the protocol endothelial vasodilative function was assessed by a laser Doppler flowmeter, which was followed by blood collecting for subsequent analyses. RESULTS: Compared to controls, the study group at baseline was characterized by significantly lower endothelial vasodilative responsiveness, accompanied by elevated asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) concentrations, which were correlated with lactate dehydrogenase (LDH) and aspartate transaminase (AST). Initial ALL treatment restored endothelial function, which followed changes in ADMA and LDH concentrations. DISCUSSION: This is the first demonstration that functionally assessed ED is present in ALL children at the diagnosis and results from elevated ADMA and parallel inflammatory ED.

Ethylene glycol ethers induce apoptosis and disturb glucose metabolism in the rat brain.

BACKGROUND: Ethylene glycol ethers (EGEs) are compounds widely used in industry and household products, but their potential, adverse effect on brain is poorly understood, so far. The aim of the present study was to determine whether 4-week administration of 2-buthoxyethanol (BE), 2-phenoxyethanol (PHE), and 2-ethoxyethanol (EE) induces apoptotic process in the rat hippocampus and frontal cortex, and whether their adverse effect on the brain cells can result from disturbances in the glucose metabolism. METHODS: Experiments were conducted on 40 rats, exposed to BE, PHE, EE, saline or sunflower oil for 4 weeks. Markers of apoptosis and glucose metabolism were determined in frontal cortex and hippocampus by western blot, ELISA, and fluorescent-based assays. RESULTS: BE and PHE, but not EE, increased expression of the active form of caspase-3 in the examined brain regions. BE and PHE increased caspase-9 level in the cortex and PHE also in the hippocampus. BE and PHE increased the level of pro-apoptotic proteins (Bax, Bak) and/or reduced the concentration of anti-apoptotic proteins (Bcl-2, Bcl-xL); whereas, the effect of BE was observed mainly in the cortex and that of PHE in the hippocampus. It has also been found that PHE increased brain glucose level, and both BE and PHE elevated pyruvate and lactate concentration. CONCLUSIONS: It can be concluded that chronic treatment with BE and PHE induced mitochondrial pathway of apoptosis, and disturbed glucose metabolism in the rat brain.

Oxidative Stress in Neurodegenerative Diseases.

The pathophysiologies of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD), are far from being fully explained. Oxidative stress (OS) has been proposed as one factor that plays a potential role in the pathogenesis of neurodegenerative disorders. Clinical and preclinical studies indicate that neurodegenerative diseases are characterized by higher levels of OS biomarkers and by lower levels of antioxidant defense biomarkers in the brain and peripheral tissues. In this article, we review the current knowledge regarding the involvement of OS in neurodegenerative diseases, based on clinical trials and animal studies. In addition, we analyze the effects of the drug-induced modulation of oxidative balance, and we explore pharmacotherapeutic strategies for OS reduction.

[Suspicion of anorexia nervosa as a cause of delayed diagnosis of brain tumor. A case report]. / Podejrzenie jadlowstretu psychicznego przyczyna opóznienia rozpoznania guza mózgu. Opis przypadku.

Tumors of the central nervous system (CNS) are the most common solid tumors diagnosed in children. The most frequent symptoms of brain tumors in this age group are headaches and vomiting, regardless of the location of the lesions. These symptoms are non-specific, and in each case require differential diagnosis, especially if there is no gradual improvement in the patient's condition or progression. The most common signs of anorexia nervosa are chronic vomiting, weakness of the body, pain and in extreme cases cachexia. These symptoms are similar to the clinical image of CNS tumor. Teenager, described in our case report presented the following signs for several weeks prior to the diagnosis of a brain tumor: vomiting (especially after meals), non-specific headache and epigastric pain. No significant progression in the patient's condition oriented the diagnostic process towards anorexia nervosa. Although anorexia in this age group is much more common disease, compared to a brain tumor, it is vital to ruled out/ exclude organic disorders prior to diagnosis of psychogenic disorder. At the same time the waiting for the specialist consultations (ophthalmologist, neurologist) and test results (head CT, head NMR) should not prolong the patients referral to a specialist center.

Evaluation of Renal Function in Pediatric Patients After Treatment for Wilms' Tumor.

BACKGROUND: Wilms' tumor is the most common kidney cancer in children. Treatment consists of pre- and post-operative chemotherapy, surgery and in some cases radiotherapy. The treatment of nephroblastomas is very effective. Hence, the population of adult patients cured of this cancer in their childhood is steadily growing, generating a need for long-term health assessment, including renal function, due to the specifications of the therapy and the location of the tumor. OBJECTIVES: The aim of the study was to evaluate nephrological complications after treatment for nephroblastoma. MATERIAL AND METHODS: The study group consisted of 50 children treated in the Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation at Wroclaw Medical University (Poland) from 2002 to 2012. An analysis of the patients' medical histories was carried out. The glomerular filtration rate estimated by the Schwartz formula (GFR by Schwartz), serum creatinine levels, urea and electrolyte concentrations; the results of urinalysis and blood pressure were assessed. Each of these analyses was performed at the time of diagnosis, at the end of therapy, as well as 6 months, one year and two years after its completion. RESULTS: The study showed that, in most cases, implemented therapy had no significant impact on the deterioration of renal parameters in the two-year period following treatment for Wilms' tumor. However, the group of patients treated with cyclophosphamide and carboplatin required more careful monitoring, due to a higher risk of renal function deterioration. CONCLUSIONS: The study shows that the problem of nephrotoxicity after treatment for Wilms' tumor is more frequent than indicated in other studies; however, the deterioration of kidney function in most cases is not serious. Additional attention should be paid to patients treated with cyclophosphamide and carboplatin. Assessment of the early and late effects of the treatment is a key element in improving the quality of the patients' life.

Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 1. Chemical aspects and biological sources of oxidative stress in the brain.

Oxidative stress is a dysfunctional state of living cells, caused by the disturbance of the pro-/antioxidative equilibrium. This dynamic equilibrium, constitutive for all aerobic organisms, is an inevitable necessity of maintaining the level of oxidative factors on non-destructive value to the cell. Among these factors reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the best known molecules. This review article shows the current state of knowledge on the chemical specificity, relative reactivity and main sources of ROS and RNS in biological systems. As a Part 1 to the report about the role of oxidative stress in psychiatric disorders (see Smaga et al., Pharmacological Reports, this issue), special emphasis is placed on biochemical determinants in nervous tissue, which predisposed it to oxidative damage. Oxidative stress can be identified based on the analysis of various biochemical indicators showing the status of antioxidant barrier or size of the damage. In our article, we have compiled the most commonly used biomarkers of oxidative stress described in the literature with special regard to potentially effective in the early diagnosis of neurodegenerative processes.

Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 2. Depression, anxiety, schizophrenia and autism.

The pathophysiology of psychiatric diseases, including depression, anxiety, schizophrenia and autism, is far from being fully elucidated. In recent years, a potential role of the oxidative stress has been highlighted in the pathogenesis of neuropsychiatric disorders. A body of clinical and preclinical evidence indicates that psychiatric diseases are characterized by higher levels of oxidative biomarkers and with lower levels of antioxidant defense biomarkers in the brain and peripheral tissues. In this article, we review current knowledge on the role of the oxidative stress in psychiatric diseases, based on clinical trials and animal studies, in addition, we analyze the effects of drug-induced modulation of oxidative balance and explore pharmacotherapeutic strategies for oxidative stress reduction.

Withdrawal from cocaine self-administration and yoked cocaine delivery dysregulates glutamatergic mGlu5 and NMDA receptors in the rat brain.

In human addicts and in animal models, chronic cocaine use leads to numerous alterations in glutamatergic transmission, including its receptors. The present study focused on metabotropic glutamatergic receptors type 5 (mGluR(5)) and N-methyl-D-aspartate receptor subunits (NMDAR: GluN1, GluN2A, GluN2B) proteins during cocaine self-administration and after 10-day of extinction training in rats. To discriminate the contingent from the non-contingent cocaine delivery, we employed the "yoked"-triad control procedure. Protein expression in rat prefrontal cortex, nucleus accumbens, hippocampus, and dorsal striatum was determined. We also examined the Homer1b/c protein, a member of the postsynaptic density protein family that links NMDAR to mGluR(5). Our results revealed that cocaine self-administration selectively increased GluN1 and GluN2A subunit in the rat hippocampus and dorsal striatum, respectively, while mGluR(5) protein expression was similarly increased in the dorsal striatum of both experimental groups. Withdrawal from both contingent and non-contingent cocaine delivery induced parallel increases in prefrontal cortical GluN2A protein expression, hippocampal mGluR(5), and GluN1 protein expression as well as in accumbal GluN1 subunit expression, while the mGluR(5) expression was reduced in the prefrontal cortex. Extinction training in animals with a history of cocaine self-administration resulted in an elevation of the hippocampal GluN2A/GluN2B subunits and accumbal mGluR(5), and in a 50 % decrease of mGluR(5) protein expression in the dorsal striatum. The latter reduction was associated with Homer1b/1c protein level decrease. Our results showed that both contingent and non-contingent cocaine administration produces numerous, brain region specific, alterations in the mGluR(5), NMDA, and Homer1b/1c protein expression which are dependent on the modality of cocaine administration.

Prolonged administration of antidepressant drugs leads to increased binding of [(3)H]MPEP to mGlu5 receptors.

Metabotropic glutamate 5 (mGlu5) receptors are functionally connected with NMDA receptors. The antidepressant activity of the NMDA receptor antagonist ketamine in both preclinical and clinical studies, along with the antidepressant-like activities of negative allosteric modulators (NAMs) of mGlu5, led us to investigate if prolonged administration of various antidepressant drugs or the mGlu5 NAM, MTEP, causes changes in mGlu5 receptor availability or protein expression or in expression of Homer proteins in the rat brain. Our results clearly show that prolonged treatment with antidepressants with various mechanisms of action (such as escitalopram, reboxetine, milnacipran, moclobemide and imipramine) or with MTEP led to significant increases in [(3)H]MPEP binding in homogenates of the hippocampus and/or cerebral cortex. Increases in mGlu5 expression were also observed, though they did not always parallel the increase in binding. The results indicate that adaptive up-regulation of mGlu5 receptors may be a common change induced by antidepressant drugs.

Clinical factors in relapses of Wilms' tumor--results for the Polish Pediatric Solid Tumors Study Group.

BACKGROUND: The risk factors responsible for recurrences of Wilms' tumor (nephroblastoma) are still under discussion. The aim of the study was to analyze the relationship between relapses of Wilms' tumor and the patients' clinical history. MATERIAL AND METHODS: Clinical data from children registered in the Polish Pediatric Solid Tumors Study Group were analyzed. The clinical stages (CS), pathology variants (high risk: HR, intermediate risk: INT, and low risk: LOW) and chemotherapy regimens were correlated with the outcomes. RESULTS: Recurrences developed in 34 out of 288 (11.8%) patients with Wilms' tumor treated in accordance with International Society for Pediatric Oncology 2001 (SIOP 2001) protocols. Of these 34 patients, 11 initially had CS I, seven were at CS II, four were at CS III, 11 were at CS IV and one had CS V. There were eight patients with second recurrences; of these, seven were in the INT risk group and one in the high histological risk group. There was no correlation between age (p=0.256) or gender (p=0.538) and the risk of tumor recurrence. In the study group, seven out of 10 patients with local recurrences are alive; as are 13 out of 22 patients with distant recurrences (p=0.703). Those who died due to disease progression comprised six out of 26 patients with a first recurrence (four HR, two INT), and seven out of eight with a second recurrence (one HR, six INT). CONCLUSIONS: The prognosis after relapse in initially metastatic patients did not differ from that in patients who had primarily localized disease. The pathology variants probably had more significance.

Metabotropic glutamatergic receptors and their ligands in drug addiction.

Glutamatergic excitatory transmission is implicated in physiological and pathological conditions like learning, memory, neuronal plasticity and emotions, while glutamatergic abnormalities are reported in numerous neurological and psychiatric disorders, including neurodegenerative diseases, epilepsy, stroke, traumatic brain injury, depression, anxiety, schizophrenia and pain. Also, several lines of evidence have accumulated indicating a pivotal role for glutamatergic neurotransmission in mediating addictive behaviors. Among the proteins regulating glutamatergic transmission, the metabotropic glutamate receptors (mGluR) are being developed as pharmacological targets for treating many neuropsychiatric disorders, including drug addiction. In this review we describe the molecular structure of mGluRs and their distribution, physiology and pharmacology in the central nervous system, as well as their use as targets in preclinical studies of drug addiction.

The influence of genetic RFC1, MS and MTHFR polymorphisms on the risk of acute lymphoblastic leukemia relapse in children and the adverse effects of methotrexate.

Polymorphism in genes coding drug-metabolizing enzymes may cause individual differences in the effectiveness and toxicity of many medications, including cytostatics. Although in recent years intensive treatment has positively influenced the prognosis in leukemias, many adverse effects resulting from nonspecific actions and the narrow therapeutic index of anti-cancer drugs are still observed during therapy. Determining selected gene polymorphisms may increase both the safety and the efficacy of treatment, and might help in developing individual therapies.

N-acetylcysteine possesses antidepressant-like activity through reduction of oxidative stress: behavioral and biochemical analyses in rats.

The growing body of evidence implicates the significance of oxidative stress in the pathophysiology of depression. The aim of this paper was to examine N-acetylcysteine (NAC) - a putative precursor of the most important tissue antioxidant glutathione - in an animal model of depression and in ex vivo assays to detect oxidative stress parameters. Imipramine (IMI), a classical and clinically-approved antidepressant drug was also under investigation. Male Wistar rats which underwent either bulbectomy (BULB; removal of the olfactory bulbs) or sham surgery (SHAM; olfactory bulbs were left undestroyed) were treated acutely or repeatedly with NAC (50-100mg/kg, ip) or IMI (10mg/kg, ip). Following 10-daily injections with NAC or IMI or their solvents, or 9-daily injections with a corresponding solvent plus acute NAC or acute IMI forced swimming test on day 10, and locomotor activity were performed; immediately after behavioral tests animals were decapitated. Biochemical tests (the total antioxidant capacity - TAC and the superoxide dismutase activity - SOD) were performed on homogenates in several brain structures. In behavioral studies, chronic (but not acute) administration of NAC resulted in a dose-dependent reduction in the immobility time seen only in BULB rats while chronic IMI produced a significant decrease in this parameter in both SHAM and BULB animals. On the other hand, chronic administration of NAC and IMI resulted in a significant increase in cellular antioxidant mechanisms (SOD activity) that reversed the effects of BULB in the frontal cortex, hippocampus and striatum. Our study further supports the antidepressant-like activity of NAC and links its effect as well as IMI actions with the enhancement of brain SOD activity.

The effect of the uremic toxin cyanate (CNO⁻) on anaerobic cysteine metabolism and oxidative processes in the rat liver: a protective effect of lipoate.

Chronic renal failure (CRF) patients have an increased plasma level of urea, which can be a source of cyanate. This compound can cause protein carbamoylation thereby changing biological activity of proteins. Therefore, in renal failure patients, cyanate can disturb metabolism and functioning of the liver. This work presents studies demonstrating that the treatment of rats with cyanate alone causes the following changes in the liver: (1) inhibition of rhodanese (TST), cystathionase (CST) and 3-mercaptopyruvate sulfotransferase (MPST) activities, (2) decrease in sulfane sulfur level (S*), (3) lowering of nonprotein sulfhydryl groups (NPSH) group level, and (4) enhancement of prooxidant processes (rise in reactive oxygen species (ROS) and malondialdehyde (MDA) level). This indicates that cyanate inhibits anaerobic cysteine metabolism and shows prooxidant action in the liver. Out of the above-mentioned changes, lipoate administered with cyanate jointly was able to correct MDA, ROS and NPSH levels, and TST activity. It had no significant effect on MPST and CST activities. It indicates that lipoate can prevent prooxidant cyanate action and cyanate-induced TST inhibition. These observations can be promising for CRF patients since lipoate can play a dual role in these patients as an efficient antioxidant defense and a protection against cyanate and cyanide toxicity.

[Allelic variants of TPMT and the risk of leucopenia and neutropenia in patients treated for acute leukaemia]. / Warianty alleliczne TPMT a ryzyko leukopenii i neutropenii u pacjentów leczonych z powodu ostrej bialaczki.

AIM: The objective of this study was to analyse the influence of TPMT genetic polymorphism on the occurrence of therapeutical adverse effects such as hematological disorders, leucopenia and neutropenia after thiopurines administration. MATERIAL AND METHODS: The examined group consisted of 210 patients (121 boys, 89 girls) aged between 1 and 18 (median age 7 years, average age 8 years, SD+/-5.32) treated for leukaemia (acute lymphoblastic leukaemia ALL: n=167; acute myeloblastic leukaemia AML: n=43). Analysis of treatment adverse reactions in every child was performed according to the WHO toxicity scale, during the entire length of observation period and in particular stages (6 stages). RESULTS: Analysis of changes in selected blood count parameters in the whole treatment period in the acute leukaemia group indicated that in the TPMT *2, *3A or *3C polymorphism carriers' group there is a statistically significant decrease in the white blood cell count (p=0.0025) and in the neutrophil count (p=0.019). Detailed assessment in particular treatment periods indicated that increased leukopenia in TPMT heterozygotes occurred significantly more frequently only in early re-induction period (p=0.012). CONCLUSION: Thiopurines administration is related to the increase in hemato-oncological treatment toxicity in TPMT heterozygotes.

[Influence of vitamin D on fertility and fetal development--review of literature]. / Wplyw witaminy D na plodnosc i zdrowie potomstwa--przeglad literatury.

Cholecalciferol was qualified by FDA (Food and Drug Administration) into the A category if administered in recommended doses and to the D category if the doses exceed RDA (Recommended Dietary Allowance). There are very divergent opinions among researchers concerning the optimal daily dose of vitamin D-according to some of them, the optimal dose of vitamin D should exceed 400 Ul/24h. On the other hand, there is no data to estimate the optimal dose and to formulate recommendations. It is necessary to conduct research on animal models to fully comprehend the symptoms and syndromes caused by excess or deficiency of cholecalciferol. However, the conclusions of the research done on animals should not be over-generalized. Moreover, some data concerning the influence of vitamin D administered during the pregnancy on fetal development are often ambiguous. All these facts are the reason why recommendations of vitamin D supplementation in pregnancy still remain uncertain and need thorough investigation.

[Evaluation of selected endocrine complications in patients treated with auto- and allo-haematopoietic stem cell transplantation]. / Ocena wybranych powiklan endokrynologicznych u pacjentów po autologicznym i allogenicznym przeszczepie krwiotwórczych komórek macierzystych.

AIM: The aim of this study was to evaluate the endocrine complications, in particular disorders of growth and thyroid function and glucose metabolism dysfunctions in patients treated with allo- and auto-haematopoietic stem cell transplantation (HSCT). MATERIAL AND METHODS: The investigated group consisted of: I. 16 patients after auto-HSCT (6 girls, 10 boys) aged 3-20 years (average 10,8+/-) because of acute myelogenous leukaemia (n=5), non Hodgkin lymphoma (n=3), neuroblastoma (n=3), embryonal cancer (n=2), medulloblastoma (n=1), Ewing's sarcoma/PNET (n=1), hyper eosinophilic syndrome (n=1). High dose chemiotherapy (HDC/T) included: BU/MEL (busulfan/melfalan) (n=7), BEAM (carmustine, eteposide, cytosine arabinose, melfalan) (n=3). II. 30 patients after allo-HSCT (20 girls, 10 boys) aged 3-17 years (average 9,56). Indication for HSCT was acute lymphoblastic leukaemia (n=11), acute myelogenous leukaemia (n=5), chronic myeloid leukaemia-CML (n=6), myelodysplastic syndromes (n=2), non Hodgkin lymphoma (n=1), juvenile myelomonocytic leukemia (n=1), severe aplastic anaemia (n=1), Blackfan-Diamond anaemia (n=1), severe combined immune deficiency (n=1), rhabdomyosarcoma (n=1). The patients underwent the following types of transplantation: HSCT of matched sibling donor (n=13), HSCT of matched unrelated donor (n=11) and HLA-mismatched related donor (n=6). The preparative regimens consisted of HDC/T usually BU/MEL (n=3); BU/CY/VP (busulfan, cyclophosphamide, etoposide) (6); BU/CY/ATG (anti-thymocyte globulin) (n=5), VP/ATG/TBI (total body irradiation) (n=3). 19 children received CI (cranial irradiation) prior to grafting: auto-HSCT (n=6) and allo-HSCT (n=13) and 6 patients underwent TBI. 18 children received high steroid doses at least 28 days before transplant, 4 patients in the auto-HSCT group, and in the allo-HSCT group 14 patients before and 20 after HSCT procedure. The analysis of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), hemoglobin A1c (HbA1c), prolactine (PRL), oral glucose tolerance test, growth hormone (GH test) and thyrotropin releasing hormone (TRH) test was performed in each case. RESULTS: Hypothyroidism was found in 5 patients (3 after allo-HSCT, 2 after auto-HSCT). Thyroid hormone substitution was applied. No case of hyperthyroidism was diagnosed. Growth deficit was found in 8 patients (6 girls, 2 boys) between 13 to 70 months after allo-transplantation (average 36 months). Three children from the above group received CI. Growth hormone substitution was applied in 1 girl (ALL, HLA MM REL, CI). An impaired excretion of GH after stimulation was diagnosed in 14 pts (10 after allo-HSCT, 4 after auto-HSCT). The growth process should still be observed in this subgroup. Glucose intolerance was found in 7 patients: in 4 treated with auto-HSCT and in 3 after allo-HSCT. Diabetes mellitus was diagnosed in none of them. An impaired glucose tolerance curve with increased excretion of insulin was diagnosed in 12 children. CONCLUSIONS: Early endocrinological care is necessary in patients treated both with auto-HSCT and allo-HSCT due to high risk of hormonal disorders.

[Analysis of selected undesirable effects of cytostatic drugs in treatment of the central nervous system tumours in children. Preliminary report]. / Analiza wybranych niepozadanych dzialan cytostatyków w trakcie leczenia dzieci z nowotworami osrodkowego ukladu nerwowego.

INTRODUCTION: During treatment of children with brain tumours there is a large risk of occurrence of side effects related to the narrow therapeutic range of cytostatic drugs and irradiation of the central nervous system. AIM: Determination of the patients' risk of undesirable effects and determination of intensification of myelosuppression and hepatocellular damage during treatment of central nervous system tumours, depending on the used therapeutic protocol and the time of chemotherapy. MATERIAL AND METHODS: The investigated group consisted of 17 patients (5 girls, 12 boys) aged 1.5-16 yrs, treated for primary brain tumour. The patients were treated according to different protocols. Protocol I (vincristine, etoposide, carboplatin, cyclophosphamide, ifosfamide and cisplatin) in 4 children with medulloblastoma and with PNET. Protocol II (etoposide, ifosfamide, adriamycin) in 4 children with glioblastoma multiformae, astrocytoma anaplasticum and ependymoma. Protocol III (carboplatin and vincristine) in 3 children with medulloblastoma, ependymoma and glioblastoma multiformae. Protocol IV (vincristine and carboplatin) in 4 children with astrocytoma fibrillare and astrocytoma pilocyticum. 10 patients were given radiotherapy. Frequency of occurrence and intensification of undesirable effects were valuated according to the WHO classification after each cycle of chemotherapy (average 8 cycles) during the whole treatment period (average 8 months): 1. Leucopenia (mm3): 0 grade [gr] (>4.000), 1 gr. (3.000-3.900), 2 gr. (2.000-2.900), 3 gr. (1.000-1.900), 4gr. ( 100000), 1 gr. (75-99000), 2 gr. (50-74000), 3 gr. (25-49000), 4 gr. (<25000) 3. Anaemia (g/dl): 0 gr. (N), 1 gr. (>10), 2 gr. (8-10), 3 gr. (6.5-7.9), 4 gr. (<6.5) 4. Hepatocellular damage (GPT, GOT/bilirubin): 0 gr. (N/N), 1 gr. (2.5xN/-), 2 gr. (2.6-5xN/1.5xN), 3 gr. (5.1-20xN/1.5-3xN), 4 gr. (>20xN/>3xN). RESULTS: In patients treated in accordance with the therapeutic protocols there was no appearance or exacerbation of undesirable side effects. During receiving adriamycin mild hyperbilirubinemia (R=0.53; p<0.05 bilirubin 1 degree) occurred statistically significantly more often. Correlation between usage of temodal and the activity of hepatic enzymes was noticed, meeting the requirements of 1st degree of toxicity according to WHO rates (R-0.66). Consequently, after the usage of temodal, more frequent abnormalities in liver function were shown. During treatment with cyclophosphamide, iphosphamide, etoposide, carboplatin, lomustine and vincristine, complications such as myelotoxicity and hepatotoxicity were not more frequent by statistical significance methods. CONCLUSIONS: Current results of treatment of central nervous system tumours in children showed, that patients tolerated cytostatic therapy relatively well. The observed undesirable effects were abnormal liver enzyme activity and bilirubin levels, higher after adriamycin and temodal therapy. Due to the small group of patients, these results are of preliminary significance. In future, a more in depth analysis of early and late effects of oncological treatment in children with cns tumours is needed.

[Analysis of some risk factors for abnormal growth velocity in children treated with haematopoetic stem cell transplantation]. / Analiza wybranych czynników ryzyka zahamowania tempa wzrastania u dzieci po przeszczepie komórek hematopoetycznych.

BACKGROUND: Late effects following haematopoietic stem cell transplantation occur both in children and adults. Endocrine impairment may cause abnormal growth velocity and impaired growth in children. OBJECTIVE: To assess the influence of preparative regimen-high dose chemotherapy and/or cranial irradiation as risk factors for growth impairment. MATERIAL AND METHODS: 30 children underwent haematopoetic stem cell transplantation (19 girls, 11 boys) aged 2-20 years, with autologous (N=9) or allogeneic (N=21) maneuver. 14 children received cranial irradiation prior to grafting: 18 Gy (N=10) and 24 Gy (N-4), high doses chemotherapy included Busulfan/Melphalan (N=6), Cyclophosphamide/Busulfan/ Etoposide (N=6) and total body irradiation with 12 Gy (N=2). Thyroid function was evaluated prior to and after grafting. Growth hormone secretion with standard provocative test were analyzed. Bone age was estimated. State of nutrition 12 to 5 months before and after transplantation, WLI (weight-for-length index) and BMI (body mass index) were evaluated. Abnormal growth velocity denotes decrease > or =1 SD. RESULTS: 1. Cyclophosphamide statistically significantly blunted growth velocity 4 (n=28; p=0.046; r=0.4). 2. Significant correlation (n=28; p=0.0184; r=0.45) was found between abnormal gonadal function and Busulfan. 3. Cranial irradiation prior to preparative regimen impaired growth more significantly than high dose chemotherapy (n=28; p=0.0044). 4. Evaluated WLI determined short stature after transplantation (n=26; p<0.001). CONCLUSION: Hematopoietic stem cell transplantation causes long term endocrine complications especially impaired growth.