Recent therapeutic advances for treating medulloblastoma: focus on new molecular targets.

Medulloblastoma is the most common malignant brain tumor in children. This malignant tumor of the cerebellum commonly affects children and is believed to arise from the precursor cells of the external granule layer or neuroepithelial cells from the cerebellar ventricular zone of the developing cerebellum. The standard treatment, consisting of surgery, craniospinal radiotherapy and chemotherapy, still provides a poor overall survival for infants and young children. Furthermore, the dose of radiation that can be safely given without causing extensive neurocognitive and endocrinologic sequelae is limited. Therefore, understanding the oncogenic pathways that lead to medulloblastoma, as well as the identification of specific molecular targets with significant therapeutic implications in order to develop new strategies for therapy, is crucial to improve patient survival without substantially increasing toxicity. In this review, we discuss recent therapeutics for treating medulloblastoma, focusing on new molecular targets, as well as advances in translational studies for the treatment of this malignancy.

The effects of sample size on the outcome of ovarian tissue cryopreservation.

Cryopreservation of ovarian tissue is known to affect follicular survival. Several variables may be responsible for this. Little attention has focused on the effect of the size of the fragment to be cryopreserved. This study was conducted to assess the effect of the size of the tissue on follicular histology after freezing with 1,2-propanediol. Histological evaluations were performed of control and cryopreserved tissue. Fragments were cut 10 x 3 x 2 mm(3) (2 mm group) or 10 x 3 x 4 mm(3) (4 mm group). Percentages of normal follicles in control fragments cut into 2 and 4 mm slices were 56% and 34%, respectively. The relative risks to obtain normal follicles in the 2 mm and the 4 mm fragments after cryopreservation were 0.63 and 0.47, respectively. Freezing reduced follicle survival to a significantly greater extent in the larger tissue fragments. There is an increased risk of damage to primary and primordial follicles, when the tissue slices are cut with all dimensions larger than 2 mm.

Sodium butyrate enhances the cytotoxic effect of antineoplastic drugs in human lymphoblastic T-cells.

Sodium butyrate (NaB), a potent histone deacetylase inhibitor, induces cell cycle arrest and apoptosis in malignant cells. We investigated the effects on cellular proliferation in vitro when combining NaB with antineoplastic drugs commonly used to treat leukemias. Our results demonstrate that NaB increases the cytotoxic effects of cytarabine and etoposide, but not of bleomycin, doxorubicin, vincristine or methotrexate. These data suggest that NaB is a promising adjuvant therapeutic agent for the treatment of lymphoblastic leukemias, and provides a basis for further studies in this field.

Use of Amifostine in the Therapy of Osteosarcomain Children and Adolescents

Amifostine protects normal tissue from the cytotoxic damage induced by radiation and chemotherapy. In this study, 39 consecutive newly diagnosed children with osteosarcoma were assessed; 20 received amifostine and 19 did not. The chemotherapy regimen included an induction phase of three cycles of cisplatin (100 mg/m2), carboplatin (500 mg/m2), and doxorubicin (60 mg/m2), followed by surgery. Alternating cycles of cisplatin/ifosfamide (9 mg/m2), ifosfamide/doxorubicin, carboplatin/doxorubicin, and ifosfamide/carboplatin were administered every 3 weeks to complete 26 weeks of treatment. Amifostine was administered 15 minutes before the infusions of cisplatin and carboplatin in a total of 193 infusions. Side effects during infusions and renal, hearing, and bone marrow toxicities were evaluated and compared between the two groups. Hypotension was observed in 28 (14.5%) infusions. No patient required discontinuation of therapy. Fewer than two episodes of vomiting occurred in 130 (71%) infusions and two to five episodes occurred in 51 (28%) infusions, and no patient had grade 4 toxicity. There was no difference between the two groups regarding renal toxicity (creatinine clearance). Neutropenia and leukopenia were significantly less frequent in the amifostine group. No difference was observed in platelet and hearing toxicities. Amifostine was well tolerated in doses of 740 mg/m2 in children and adolescents, and myelotoxicity was less severe in the amifostine group. This was a pilot study for further evaluation in a larger randomized trial.

[Bone marrow transplantation and cord blood transplantation in children] / Transplante de medula óssea e transplante de sangue de cordão umbilical em pediatria.

OBJECTIVE: To review the indications, main steps and complications of bone marrow transplantation in children. SOURCES: Medline-based literature review. SUMMARY OF THE FINDINGS: We comment about the indications of autologous, allogeneic and syngeneic bone marrow transplantation, donor selections, harvest and infusion of the hematopoietic progenitor cells that will reconstitute the hematopoietic and immune systems. We describe the different conditioning regimens and the new sources of cells, such as cord blood. We also describe the most common events after the procedure, including infections, graft versus host disease, and cardiovascular, pulmonary, hepatic, genitourinary, and gastrointestinal complications. The late effects and their impact on quality of life are also discussed. CONCLUSIONS: Bone marrow transplantation does not confer an absolutely normal life span to all the patients; however, it represents the only chance of cure for children with certain neoplastic or immunological diseases. By knowing the steps of the procedure, pediatricians can be a source of information on bone marrow transplantation to the patients and their families.

Protein kinase C-mediated in vitro invasion of human glioma cells through extracellular-signal-regulated kinase and ornithine decarboxylase.

We investigated the involvement of protein kinase C (PKC) in the in vitro invasiveness of the A-172, U-87 and U-373 human glioma cell lines, as well as the role of ornithine decarboxylase (ODC) and/or extracellular-signal-regulated kinase (ERK) in the actions of PKC. Thus, cells were treated under serum-free conditions with the PKC activator phorbol 12-myristate 13-acetate (PMA), or with the PKC inhibitors bisindolylmaleimide I (GF 109203X) or calphostin C in the absence or presence of the ODC inhibitor D,L-alpha-difluoromethylornithine (DFMO), and/or the mitogen-activated protein kinase/extracellular-signal-regulated kinase inhibitor 2'-amino-3'-methoxyflavone (PD 098059). Subsequently, cells were assessed for membrane-type 1 matrix metalloproteinase (MT1-MMP) mRNA contents, 72-kD latent, and 59/62-kD activated matrix metalloproteinase 2 (MMP-2) in conditioned media, as well as invasiveness. For these purposes, we used Northern blot analysis, gelatine zymography, and an in vitro filter invasion assay, respectively. Data were related to those found with untreated cells. PKC activity was 2- to 3-fold stimulated by PMA (100 nM for 30 min), and about 2-fold inhibited by calphostin C (40 nM for 2 h) or GF 109203X (5 microM for 20 min). This was accompanied by a similar increase or decrease, respectively, in MT1-MMP mRNA expression, 59/62-kD MMP-2 activity, and in vitro invasion. Inhibition of ODC activity (about 2-fold by 24 h DFMO 5 mM), ERK activation (almost completely by 20 min PD 098059 50 microM), or both these enzymes simultaneously led to a reduction by about half in levels of MT1-MMP mRNA, 59/62-kD MMP-2 activity, and invasion in untreated as well as PMA-stimulated cells. The use of these compounds did not significantly alter the inhibitory effects of GF 109203X or calphostin C. Modulation of PKC and/or ERK activity resulted in corresponding changes in ERK and/or ODC activities, but interference with ODC affected neither ERK nor PKC. Our data suggest a regulatory role for PKC, in co-operation with ERK and ODC, in glioma cell invasion, by modulation of MT1-MMP mRNA expression and MMP-2 activation.

Vanilmandelic acid and homovanillic acid levels in patients with neural crest tumor: 24-hour urine collection versus random sample.

Neuroblastoma is the most common solid tumor in childhood and is the most frequent neural crest tumor (NCT). More than 90% of the patients excrete high levels of vanilmandelic acid (VMA) and homovanillic acid (HVA) in the urine. Original biochemical methods for measuring these two metabolites of catecholamines employed a collection of urine for 24 hours to avoid errors related to circadian cycle variations. More recently, attempts have been made to replace the 24-hour collections by random samples (RSs). This has practical advantages particularly for young children. The objective of this study is to assess whether urinary VMA related to urinary creatinine levels can be determined reliably by the method of Pisano et al. from RSs in patients with NCT. The determination of the consumption of VMA in urine stored for prolonged periods of time was also studied. We found a good correlation between the values of metabolites of catecholamines in RSs compared with 24-hour urine collections. There was consumption of VMA in urine samples after storage. We conclude that determination of VMA in RSs of urine by Pisano's method may identify NCT production of catecholamines and that the consumption of these catecholamines is an important factor to consider in the interpretation of values obtained with stored urine specimens.

Gut hormones and gastrointestinal motility in children with cystic fibrosis.

Intestinal dysmotility may be an important factor contributing to various gastrointestinal complications associated with cystic fibrosis. Motilin, enteroglucagon, neurotensin, and peptide YY may each play a role as endocrine hormones influencing gastrointestinal motor activity. Fasting children with cystic fibrosis (N = 8) and controls (N = 18) received a liquid nutrient test meal (fat 4 g/100 ml, protein 4 g/100 ml, carbohydrate 20 g/100 ml, 125 kcal/100 ml; 200 ml/m2) containing lactulose (5 g/100 ml), and the plasma concentrations of these peptides were studied. Mouth-to-cecum transit time was simultaneously studied using the breath H2 technique. Fasting levels of peptide YY and the postprandial response of all four peptides were significantly increased in those with cystic fibrosis. In repeat studies on those with cystic fibrosis after a period of altered pancreatic enzyme supplementation, no significant changes in peptide concentrations were observed. A rise in breath H2 permitting estimation of mouth-to-cecum transit time was noted in 17 control subjects (70-220 min, median 140). In contrast, a rise occurred in only two with cystic fibrosis after low-dose enzyme (70 and 180 min), and four after high-dose enzyme replacement (120-230 min, median 155). Altered gut hormone secretion may play a role in the pathophysiology of intestinal dysmotility in patients with cystic fibrosis.

Phase II study of teniposide in patients with AIDS-related Kaposi's sarcoma.

Antitumour activity of cytotoxic agents, evaluated in patients with AIDS-related Kaposi's sarcoma (KS), is about 30-80%. However, responses are mostly partial and short. Experience with etoposide is similar. Teniposide has a longer elimination half-life and superior antitumour activity compared with etoposide in some experimental models. Thus a phase II trial was done in 25 patients with AIDS-related KS. Teniposide was given by 60-min infusion at 360 mg/m2 every 3 weeks. 10 (40%) showed a partial response, median duration of 9 (6-20) weeks. The main side-effects were leukopenia, thrombocytopenia, nausea and vomiting, alopecia and mucositis.

The effect of pharmacological modification of gastric emptying and mouth-to-caecum transit time on the absorption of sugar probe marker molecules of intestinal permeability in normal man.

The present study examined the hypothesis that altered motility of the gastrointestinal tract affects absorption of probe markers of intestinal permeability. Seven healthy subjects, aged 32-44 years, received saline, 600 micrograms atropine or 10 mg metoclopramide in randomized order at weekly intervals. After 10 min they ingested a test solution containing 5 g lactulose, 5 g mannitol and 2 g 3-O-methyl glucose in 100 ml tap water. The molarity of the solution was 542 mmol l-1 and the dose administered was 80 ml m-2 body surface area. Gastric emptying was measured by ultrasound, mouth-to-caecum transit time by breath hydrogen analysis and sugar concentrations by gas-liquid chromatography. Gastric emptying half-times (min) were [mean (95% confidence intervals)] 14.9 (11:4-18.5) after saline, 22 (18.7-25.2) after atropine and 10.3 (7.0-12.6) after metoclopramide (P less than 0.002). Transit times (min) were 68.9 (52-85.2) after saline, 143 (126-159) after atropine and 38 (21.2-54.5) after metoclopramide; P less than 0.0001. Analysis of plasma levels of mannitol and 3-O-methyl glucose showed a significant within-subject effect of drug with time (P less than 0.03). Urinary excretion of mannitol in the first 5 h after ingestion of the test solution was 1256 (974-1620) mg after saline, 1560 (1210-2013) mg after atropine and 955 (740-1232) mg after metoclopramide (P less than 0.03). There were no significant differences in lactulose and 3-O-methyl glucose urinary excretion between drug treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Health education: patients' perception

Two hundred and six mothers of children under 5 years of age attending pediatric helth services in Jamaica were interviewed to determine their perceived and preferred source of health education. The seven topics of health education which were surveyed were family planning, breast feeding, infant feeding, oral rehydration solution, growth chart, prevention of accidents, and immunization. Mothers perceived nurses as their main providers of health information. However, they named doctors as their preferred source for health information in most of the topics surveyed. Assessment of mothers' knowledge of the growth chart, in those who had received specific education about this, revealed that 88 per cent had an inadequate understanding of a curve falling through the percentiles. this study highlights the importance of providing doctors and nurses with the necessary training and motivation to fulfil their role as health educators. (AU)

Clostridium difficile in an oncology unit.

In one year 21 new cases of Clostridium difficile infection occurred on a paediatric oncology unit. Eleven cases were in a two month period. This infection should be regarded as a communicable disease. Investigations to detect C difficile should be carried out in children with malignant disease who have diarrhoea.