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In high performance integrated circuits phenomena like crosstalk, IR drops, electromigration and ground bounce are assuming increasing proportions because of the growing complexity in ultra deep submicron designs: their effects are assuming increasing impact compromising circuits functionality and not only their performances.This paper suggests a methodology to evaluate and to prevent power supply noise generation in more and more increasing dimensions circuit blocks. The power supply busses modeling is addressed to find out actual parameters to face early in the design phase noise phenomena related to power distribution. In particular using the equations reported in this paper the designer has the possibility to control the global power bus noise generation depending on the design strategy used, on the library characteristics and on the given performance constraints.The appropriateness of the developed methodology seems to be helpful if applied during the circuit design flow in conjunction with a project tool having as a target noise reduction besides delay and power optimization.

No abstract.

A high percentage of patients with acute leukaemia in established remission develop chronic liver disease: how important hepatitis-B-virus (HBV) infection is as an aetiological factor is not clear. The presence of HBV markers in liver and serum of 23 leukaemic children with liver disease was investigated at the time of a diagnostic biopsy just before treatment withdrawal. Although, at this time, none had HBV antigens or antibodies in the serum by radioimmunoassay, HBsAg was detected by direct immunofluorescence in the cytoplasm of hepatocytes in 13 children, 7 of whom also had hepatitis-B core or e antigens in hepatocyte nuclei. This pattern of both cytoplasmic and nuclear fluorescence was present in 4 of 6 patients with the histological features of chronic active hepatitis on liver biopsy. The failure of release of viral antigens into serum and the absence of an adequate immune response were probably due to the intense chemotherapy used to induce and maintain remission, since HBV markers appeared in the serum within 15 months of stopping treatment in 8 of the children in whom viral antigens had been detected in liver tissue but in none of those whose biopsy specimens were negative by immunofluorescence. These results suggest that HBV infection may be an important cause of chronic liver disease in children with leukaemia and show that during treatment serological tests may fail to detect the presence of the virus.

Juvenile chronic myelocytic leukemia (JCML) is a rare disorder of early childhood. Characteristic of JCML are the progressive appearance of high levels of fetal hemoglobin (HbF), reflecting a true reversion to a fetal type of erythropoiesis, and the presence of colony-forming cells able to grow in vitro spontaneously in the absence of growth factors. To better understand the relationship between the erythroid abnormalities and the leukemic process, we analyzed the expression pattern of specific genes related to erythroid differentiation--GATA-1, EPOR, alpha-globin, beta-globin, and gamma-globin genes--in JCML peripheral blood (PB) cells and in vitro-derived colonies. Northern blot analysis of PB cells from five JCML patients indicated levels of GATA-1 transcripts much higher than those usually found in other types of leukemic cells, and S1 nuclease protection assay detected significantly increased expression of gamma-globin mRNA. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of single granulocyte-macrophage colony-forming unit (CFU-GM) colonies, obtained in vitro in the absence of added growth factors from four JCML patients, detected GATA-1, EPOR, and globin (alpha and gamma) transcripts in most of the colonies tested, in contrast with control CFU-GM from normal bone marrow, which were positive only for GATA-1. Single JCML colonies were tested for the presence of two different transcripts; whereas alpha- and gamma-globin genes appeared mostly coexpressed, beta-globin mRNA was detected only in a minority of the gamma-globin-positive colonies, indicating that the leukemic pattern of hemoglobin synthesis is mainly fetal. In addition, the leukemic cells occurring during blast crisis of one of our patients displayed the typical features of a stem cell leukemia (CD34+, CD19-, CD2-, myeloperoxidase-). In this sorted CD34+ population, we detected the presence of a marker chromosome, der(12)t(3;12), previously identified in bone marrow cells at diagnosis and an expression pattern superimposable to that of the JCML colonies, consistently displaying a high gamma-globin:beta-globin mRNA ratio. The expression of erythroid markers within populations of leukemic cells, both in vivo and in vitro, supports the hypothesis that abnormal JCML erythroid cells may originate from the same mutated progenitor that sustains the growth of the leukemic cells.

It is well known in the literature that cancer creates educationally related barriers for all children, which may or may not contribute to clinically relevant school problems. The goal of this study was to obtain a base rate for the characteristic pattern of school functioning for children with leukemia, so that the children with the most serious difficulties might be discovered and given the different and flexible help needed. From 1988 through 1994, a questionnaire was administered annually to teachers of all leukemic children in our center. The 291 questionnaires were used to compare the school functioning of children with leukemia with that of matched controls chosen by each teacher as representative of the class as a whole, excluding special education and develop-mentally disabled students. This approach to matching was chosen as a control for socioeconomic factors as well. The study was conducted with all patients with leukemia entering the center residing in the region of Lombardy, attending school, and either in therapy or out of therapy. After initial treatment, the children with leukemia in our center as a group attended school regularly and willingly. Analyses of variance (ANOVAs) were conducted on the total scores and on scores for each of the subareas of learning socialization, and emotionality. T-tests were given to contrast individual item scores of patients with those of their matched controls. On most individual items, children with leukemia did not differ from their classmates. However, significant discrepancies between children with leukemia and their classmates appeared consistently year after year on overall total scores and on each of the three major subcomponents of the test (learning socialization, and emotionality). The groups most affected were children who were cranially irradiated and children who were under 6 years of age at diagnosis. Children who have been irradiated and children diagnosed under 6 years of age have the greatest risk for difficulties in school functioning and are candidates for greater attention and preventive efforts.

This study explores the psychosocial problems experienced by families with children aged 6 to 14 years suffering from ß-thalassemia major (N=188). The psychosocial problems and the family's adjustment to the effects of the illness were compared across a number of cultures where the disease is prevalent, namely Cyprus, Greece, and Italy. A small number of migrant children.in the United Kingdom was also included in the study. Semi-structured interviews were conducted with parents who also completed the Rutter Parental Questionnaire and the Goldberg General Health Questionnaire. Teachers were asked to complete a Children's Behaviour Questionnaire designed by Rutter. In all countries the disease seemed to have a binding effect on the family, thus mobilizing adaptive mechanisms. Father's low education level and the presence of major medical complications were predictors of poor family adjustment. Differences between and within countries may well reflect differences in health policies, existing level of socio-economic development, and in the cultural patterns in coping with a chronic illness.

Juvenile chronic myelocytic leukemia (JCML) is a rare disorder of early childhood. Characteristic of JCML are the progressive appearance of high levels of fetal hemoglobin (HbF), reflecting a true reversion to a fetal type of erythropoiesis, and the presence of colony-forming cells able to grow in vitro spontaneously in the absence of growth factors. To better understand the relationship between the erythroid abnormalities and the leukemic process, we analyzed the expression pattern of specific genes related to erythroid differentiation—GATA-1, EPOR, α-globin, β-globin, and γ-glo-bin genes—in JCML peripheral blood (PB) cells and in vitro-derived colonies. Northern blot analysis of PB cells from five JCML patients indicated levels of GATA-1 transcripts much higher than those usually found in other types of leukemic cells, and S1 nuclease protection assay detected significantly increased expression of γ-globin mRNA. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of single granulocyte-macrophage colony-forming unit (CFU-GM) colonies, obtained in vitro in the absence of added growth factors from four JCML patients, detected GATA-1, EPOR, and globin (α and γ) transcripts in most of the colonies tested, in contrast with control CFU-GM from normal bone marrow, which were positive only for GATA-1. Single JCML colonies were tested for the presence of two different transcripts; whereas α- and γ-globin genes appeared mostly coexpressed, β-globin mRNA was detected only in a minority of the γ-globin-positive colonies, indicating that the leukemic pattern of hemoglobin synthesis is mainly fetal. In addition, the leukemic cells occurring during blast crisis of one of our patients displayed the typical features of a stem cell leukemia (CD34+, CD19-, CD2-, myeloperoxidase-). In this sorted CD34+ population, we detected the presence of a marker chromosome, der(12)t(3;12), previously identified in bone marrow cells at diagnosis and an expression pattern superimposable to that of the JCML colonies, consistently displaying a high γ-globin:β-globin mRNA ratio. The expression of erythroid markers within populations of leukemic cells, both in vivo and in vitro, supports the hypothesis that abnormal JCML erythroid cells may originate from the same mutated progenitor that sustains the growth of the leukemic cells.

Antibody to the recently identified hepatitis C virus (HCV) was investigated in sera of 50 leukemic children who had chronic liver disease (CLD), observed for 1 to 12.6 years after therapy withdrawal. All patients were tested for anti-HCV at regular intervals: Ortho- enzyme-linked immunosorbent assay (ELISA) test was performed in all cases. Reactive sera were also tested by recombinant immunoblotting assay to define the specificity of the results obtained by ELISA. Twelve cases (24%) were persistently positive (group A), 11 (22%) were transiently anti-HCV+ positive (group B), and 27 (54%) were negative. Mean SGPT peak during follow-up was significantly higher in group A (P = .014, A v B and P less than .00001, A v C). SGPT normalized off- therapy in 1 of 12 cases (group A), 10 of 11 (group B), and 19 of 27 (group C) (P = .0004, A v B and P = .012, A v C). Accordingly, liver histology, available in 37 patients, showed signs of chronic hepatitis in all patients in group A while most patients in group B and C had less severe liver lesions. These results indicate that HCV plays a significant role in the etiology of chronic hepatitis in leukemic patients and that persistent anti-HCV activity correlates with a more severe CLD, which could jeopardize the final prognosis of children cured of leukemia.

During the development of functional T lymphocytes, a variety of genes involved in antigen recognition undergo somatic rearrangement. These include the alpha, beta, and gamma chain genes. Recently a fourth rearranging gene, the delta chain gene, embedded in the alpha chain locus, has been described. We have determined the structure of the beta, gamma, and delta chain genes in 15 cases of T-cell acute lymphoblastic leukemia (T-ALL) representing stage I (CD7+, CD1-, CD3-) and stage II (CD7+, CD1+, CD3-) of intrathymic T-cell development. The alpha-delta locus was rearranged in 14 of the 15 cases. In three cases the delta constant region was deleted on both chromosomes, suggesting biallelic V-J alpha rearrangement. A limited pattern of rearrangement of the delta locus was observed in the remaining 11 cases. When the alpha-delta region was rearranged, there was rearrangement of the beta and gamma TcR in all cases except two; in these cases the beta chain was in the germline configuration. These findings support the hypothesis that delta chain gene rearrangement is an early event in T- cell development, possibly contemporary to gamma gene rearrangement, and that the delta locus has a limited repertoire.

Using a two-dimensional gel electrophoresis system (sodium dodecyl sulphate/acetic acid-urea-hexadecyltrimethylammonium bromide) coupled with fluorography, we investigated the synthesis of H1 isoproteins in leukemic cells obtained from peripheral blood of eight children suffering from acute lymphoblastic leukemia (ALL) (four T-ALL, three common ALL, and one B-ALL) and in normal peripheral lymphocytes. H1 degrees was synthesized in leukemic cells but not in normal lymphocytes. Inhibition of DNA synthesis with hydroxyurea and 1-beta-D- arabinofuranosylcytosine induced an increase of relative synthesis of H1 degrees in leukemic cells but did not induce any detectable synthesis of H1 degrees in normal lymphocytes. H1 degrees synthesis was also undetectable in peripheral lymphocytes of leukemic children in complete remission after chemotherapy and in lymphocytes of a homozygotic twin of a leukemic patient. H1 degrees may be a marker of malignant transformation of lymphocytes and as such could be of use for early detection of relapse in patients with acute lymphocytic leukemia in apparent complete remission.

The chromosomal breakpoints of t(4;11) translocation of acute lymphoblastic leukemia (ALL) have been recently identified at molecular level and shown to involve the AF4 (FEL) gene on chromosome 4 and the ALL-1 (MLL, Hrx) gene on chromosome 11. The ALL-1/AF4 fusion gene is transcribed into a chimeric mRNA. Using primer sets derived from ALL-1 and AF4 cDNAs by reverse transcription-polymerase chain reaction (RT- PCR), we were able to amplify the breakpoint sites of the fusion transcript of all 15 ALL cases with karyotypic or molecular evidence of the t(4;11). DNA fragments of different size were obtained as the consequence of different breakpoints on chromosome 11 and the presence of alternative splicing of ALL-1 exon 8. The feasibility of monitoring the residual cells carrying the t(4;11) in 2 ALL patients with different clinical outcome was evaluated. Overall, the presented results provide evidence that RT-PCR can be used as a rapid method for detecting this chromosomal abnormality and following the patient's response to therapy.

Granulocytic sarcoma (GS) is a localized destructive tumor mass composed of immature cells of the granulocytic series, occurring before, concomitantly, or after the overt development of acute or chronic myelogenous leukemia. Although this tumor is known to occur in almost every site of the body, cardiac involvement is rare. We report a case of a 12-year-old female previously treated for 28 months with chemotherapy for acute promyelocytic leukemia, who presented with GS in the left mastoid 3 months after discontinuing treatment. The patient was treated with local radiotherapy only. Thirty months later she presented with heart failure, the result of a right-sided intracardiac mass, while in continuous hematological remission of the primary disease and off therapy. The cardiovascular, hematological, and postmortem findings are described and the literature is reviewed. This is the first clinicopathologic report of GS involving the heart in which the echocardiographic and pathologic findings are detailed.

Pulmonary thromboembolism (PTE) in leukemic children undergoing intensive chemotherapy should be promptly recognized so that specific therapy can be started. Our experience with the two cases reported here has led us to propose guidelines for the treatment of initial PTE in a pediatric hematology unit. Two children with leukemia developed PTE, the first during the relapse for acute lymphoblastic leukemia and the second at the onset of acute promyelocytic leukemia. In both cases, the diagnosis of PTE was based on clinical assessment of sudden acute respiratory failure with positive pulmonary perfusional scintigraphy in spite of a negative chest X-ray. The subintensive supervision consisted of instrumental monitoring with the assistance of an intensive care anesthetist. The clinical monitoring was based on the serial registration of respiratory rate, cardiac rate, SaO2and body temperature. The thrombolytic therapy, together with heparin prophylaxis, was successfully administered in the hematology ward without the need for intensive care support (i.e. mechanical ventilation). The success of the treatment was documented by the criterion of a return to the normal cardiorespiratory parameters a few hours after the start of the thrombolytic treatment. Furthermore, a chest CT scan in case 1 and an arteriography in case 2 confirmed the PTE-related hypoperfusion. On the basis of this experience, the authors point out that in the course of acute respiratory failure in leukemic children, the combination of a negative chest X-ray and a positive pulmonary perfusional scintigraphy (compared whenever possible with ventilatory scintigraphy) in the presence of a negative CT scan could be a reliable diagnostic tool for PTE. This pathology should be treated promptly and with specific therapy to avoid progression to a severe, massive PTE.

During the development of functional T lymphocytes, a variety of genes involved in antigen recognition undergo somatic rearrangement. These include the alpha, beta, and gamma chain genes. Recently a fourth rearranging gene, the delta chain gene, embedded in the alpha chain locus, has been described. We have determined the structure of the beta, gamma, and delta chain genes in 15 cases of T-cell acute lymphoblastic leukemia (T-ALL) representing stage I (CD7+, CD1 —, CD3 —) and stage II (CD7 + , CD1 +, CD3 —) of intrathymic T-cell development. The alpha-delta locus was rearranged in 14 of the 15 cases. In three cases the delta constant region was deleted on both chromo- somes, suggesting biallelic V-J alpha rearrangement. A limited pattern of rearrangement of the delta locus was observed in the remaining 11 cases. When the alpha-delta region was rearranged, there was rearrangement of the beta and gamma TcR in all cases except two; in these cases the beta chain was in the germline configuration. These findings support the hypothesis that delta chain gene rearrangement is an early event in T-cell development, possibly contemporary to gamma gene rearrangement, and that the delta locus has a limited repertoire.© 1989 by Grune & Stratton, Inc. 0006-4971/89/7308-0006$3.00/0

Using a two-dimensional gel electrophoresis system (sodium dodecyl sulphate/acetic acid-urea-hexadecyltrime-thylammonium bromide) coupled with fluorography, we investigated the synthesis of H1 isoproteins in leukemic cells obtained from peripheral blood of eight children suffering from acute lymphoblastic leukemia (ALL) (four T-ALL, three common ALL, and one B-ALL) and in normal peripheral lymphocytes. H1° was synthesized in leukemic cells but not in normal lymphocytes. Inhibition of DNA synthesis with hydroxyurea and 1-β-D-arabinofuranosylcytosine induced an increase of relative synthesis of H1° in leukemic cells but did not induce any detectable synthesis of H1° in normal lymphocytes. H1° synthesis was also undetectable in peripheral lymphocytes of leukemic children in complete remission after chemotherapy and in lymphocytes of a homozygotic twin of a leukemic patient. H1° may be a marker of malignant transformation of lymphocytes and as such could be of use for early detection of relapse in patients with acute lymphocytic leukemia in apparent complete remission.

The pattern of hepatitis C virus (HCV) serum markers and liver disease was investigated in 11 leukemic children showing anti-HCV reactivity at least once during long-term observation to define the role of HCV infection and the behavior of HCV serologic markers in this patient cohort. Antibodies to HCV by first- and second-generation enzyme-linked immunosorbent assay (ELISA) and by second-generation (four antigens) recombinant immunoblotting assay (RIBA) and HCV-RNA by nested polymerase chain reaction (PCR) were serially examined in serum. Liver disease was defined according to transaminase levels. Seven of 11 patients were found HCV-RNA positive during chemotherapy and after blood transfusion, 3 of 11 became viremic during follow-up, and 1 of 11 was always HCV-RNA negative. Seroconversion to anti-HCV positivity by second-generation ELISA occurred in all the HCV-RNA positive children either during or after chemotherapy. Alanine aminotransferase (ALT) levels were elevated in all the HCV-RNA positive patients during antileukemic treatment and normalized in seven of them after therapy withdrawal, despite persisting viremia. These results indicate that HCV- RNA testing by polymerase chain reaction is required to correctly identify HCV infection in patients with leukemia while on chemotherapy. Viremia did not correlate with ALT levels and anti-HCV patterns.

Bone marrow (BM) and peripheral blood (PB) cells from patients with juvenile chronic myelogenous leukemia (JCML) exhibit spontaneous in vitro proliferation. Several cytokines including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF alpha) have been implicated in supporting the growth of leukemic monocyte-macrophage colonies either by autocrine or paracrine pathways. In seven untreated JCML patients, we investigated the role of IL-1 in the spontaneous growth of these cells by specifically blocking IL-1 receptors. The IL-1 receptor antagonist (IL-1 Ra) was added to the clonogenic assays, and in each case significant (mean = 63%, range = 35% to 82%) inhibition of spontaneous proliferation was observed. Uncultured circulating cells from PB or BM of four out of five patients expressed IL-1 beta-specific mRNA and secreted the protein into the culture supernatants. Moreover, by means of reverse transcriptase-polymerase chain reaction (RT-PCR), we demonstrated that most of the spontaneously growing leukemic colony- forming unit cells (CFU-C) obtained from BM cells of two patients were positive for the presence of the IL-1 beta-specific mRNA. Despite the presence of a measurable amount of GM-CSF in JCML cell culture supernatants, GM-CSF-specific mRNA in CFU-C cells of four cases was not detected by RT-PCR. These data further support a central role for IL-1 beta in the pathogenesis of JCML and suggest that the use of IL-1 Ra could represent a novel therapeutic strategy against this disorder.

Nine Italian and 12 German children fulfilled the criteria of myelodysplastic syndromes (MDS), according to the French-American-British (FAB) classification. All patients belonged to the more aggressive subtypes of myelodysplastic syndromes. Four presented with refractory anemia with excess of blasts (RAEB), 16 presented with refractory anemia with excess of blasts in transformation (RAEB-T), and 1 had chronic myelomonocytic leukemia (CMML).

THE thalassaemias are a group of inherited disorders characterised by the defective production of either α(αthalassaemias) or non-α(βand δ°β° thalassaemias) globin chains of haemoglobins (Hb)1. In βthalassaemias the decreased synthesis of β-globin chains is only partially compensated by the increased production of γchains, which probably reflects2the massive hypertrophy of the erythron with selective survival of the clones of adult haemoglobin F-producing cells (F cells3,4). The situation is very different in other genetic disorders of the non-αgene cluster, known as δ°β° thalassaemias and Negro type of hereditary persistence of fetal haemoglobin (HPFH). In these two forms there is a genuine increase of γ-chain production, as shown by the high level of HbF found in heterozygotes. Although a clearcut distinction from both the clinical and haematological point of view cannot be traced between these two forms, the HPFH differs from the δ°β° thalassaemia in having a higher degree of γ-chain synthesis and a more homogeneous distribution of HbF within red cells. Recently, it has been possible to carry out gene analysis on DNA prepared from β°, δ°β° thalassaemic and HPFH patients. The β-globin gene is present in β° thalassaemias5–9, but in δ°β° thalassaemias and HPFH a major deletion, possibly involving both δand βgenes, has been demonstrated by hybridisation studies8,10–12. To characterise the molecular defect in these genetic disorders more precisely, we have hybridised DNA from homozygotes with HPFH, δ°β° thalassaemia and Hb Lepore disease (in which non-α-chains are a δβfusion product13). For this we used a pure full-size cDNAβprobe and specific 5′ end and 3′ end cDNA fragments (we designate as 5′ end cDNA the portion corresponding to the 5′ end of the mRNA; the same for the 3′ end). Our results, reported here, show that in contrast to HPFH, where a complete δand βgene deletion occurs, in δ°β° thalassaemia a 5′-end fragment of the δgene is present.

Plasma pharmacokinetics of VP16-213 were investigated after a 30–60 min infusion in 14 adult patients and six children. In adults the elimination half-life (T1/2 ß), plasma clearance (Clp) and volume of distribution (Vd) were respectively 7.05±0.67 h, 26.8±2.4 ml/min/m2, and 15.7±1.8 l/m2; in children 3.37±0.5 h, 39.34±6.6 ml/min/m2, and 9.97±3.7 l/m2. After repeated daily doses no accumulation of VP16-213 was found in plasma. The unchanged drug found in the 24 h urine after administration amounted to 20–30% of the dose.

Five paediatric patients with a myelodysplastic syndrome (MDS) (age range 4-12 years) are described. The frequency of MDS in our institution in the last 13 years is 1.12% of all leukaemic syndromes. Diagnosis and classification were made according to the recent proposals of the FAB Co-operative Group: four refractory anaemia with excess of blasts in transformation (RAEB-T) and one refractory anaemia with excess of blasts (RAEB). The haematqlogical picture at onset is presented with morphological, cytochemical, immunological and cytogenetic data. Two patients had trisomy 8 and one had monosomy 7. In three patients an evolution towards acute myeloid leukaemia was observed. Multiple drug treatment used in the chronic phase and/or during transformation in acute leukaemia did not produce complete remission. Low-dose Ara-C was employed in one case in the chronic phase without improvement. Four patients died 3-17 months after diagnosis. One is alive with persistent leukaemia 8 months after diagnosis.

The article describes a relatively rare congenital anomaly that was difficult to diagnose in a 10-year-old child with acute nonlymphoblastic leukemia. Just at diagnosis of leukemia, the patient showed a pathologic chest radiograph because of a parenchymal thickening at the right lung apex. The presence of bronchopneumonia was suspected, and broad-spectrum antibiotic therapy was started with subsequent antifungal treatment for persistent fever and concurrent chemotherapy-induced marrow aplasia, which did not favor pulmonary infiltrate recovery. Continuous culture tests, including bronchial swab, proved negative for Koch-Weeks bacillus, fungal organisms, and other pathogens. Computed tomography, however, was suggestive of Aspergillus lung involvement, and apical sepmentectomy was performed. The anatomic pathologist suggested the diagnosis of intralobar sequestration. In summary, when pulmonary pathology with an excavation is found in a leukemic child, one must consider the possibility of pulmonary sequestration complicated by an infectious disease.

Cell proliferation rate is a well-established prognostic factor in cancer, but it has not been considered to identify the risk group of childhood acute lymphoblastic leukaemia (ALL) at presentation. We carried out a study to demonstrate the prognostic importance of the rapidity of cell proliferation in patients with ALL. To measure the rapidity of cell proliferation we used the parameter relative to the area of silver-stained nucleolar organiser regions (AgNORs) as evaluated by morphometric analysis on smeared marrow blast cells. The mean AgNOR area of leukaemic marrow cells was measured in 119 children. By using a cut-off value of 3 microns2, we identified a group of 91 children with low proliferating blast activity (mean AgNOR value 2.11 microns2) and a group of 28 children with high proliferating activity (mean AgNOR value 3.29 microns2). The group of patients with a mean AgNOR value > 3 microns2 was characterised by a higher number of deaths, more frequent relapse and shorter time interval to relapse than the group of patients with mean AgNOR value < 3 microns2 (P < 0.01). Multivariate analysis performed to include T-cell immunophenotype, FAB morphology, leucocyte count and presence of mediastinal mass showed that the mean AgNOR value was the only independent predictor of unfavourable event-free survival probability (P > 0.01). Our results indicate that the rapidity of marrow blast cell proliferation is an important prognostic parameter in childhood ALL and should be routinely introduced in the group risk definition.

The therapeutic index of antineoplastic agents is generally low, therefore, errors in administration can cause severe, life-threatening toxicity. The publication of cases of overdoses may provide useful information on the causes of the mistakes, on drug-induced toxic effects, and on salvage therapy. Hi report a case of vinblastine overdose in a child affected by Langerhans' cell histiocytosis, Hand-Schüller-Christian syndrome according with the previous classification of histiocytosis X. To our knowledge this is the highest dose of vinblastine ever administered. The child was given salvage therapy with steroids and citrovorum factor. Major side effects were neurologic toxicity (seizures, coma) and marrow aplasia, which improved and gradually resolved beginning day 12.

The high level of complexity and the high degree of parallelism involved in several modern microprogrammed systems imply the design of control units having an extremely large microcode. Consequently, the necessity of limiting the size of the control store pushed research in two directions: microcode compaction, for reducing the number of words, and microcode bit minimisation, for reducing the number of control bits in a single word. In this paper, a new method for the optimisation of microword length in large microprogrammed systems is addressed. Microcode bit optimisation is formulated as a covering problem applied to a choice of maximal compatibility classes, collecting operations that can share the same bit held in the microcode. Comparisons with most of the published approaches are given using some benchmarks: results obtained show that the proposed method saves microcode bits in several cases, while in the largest examples it grants a significant reduction in computation time.

Abstract:  The aim of this study was to compare the Hickman and Groshong central venous catheters (CVCs) for incidence and severity of catheter-related complications in children. Seventy-three patients with hematological malignancies were observed, 42 with Groshong CVCs and 31 with Hickman CVCs. The number of infective episodes per 100 CVC-days was not significantly different (0.25 in the Hickman group versus 0.13 in the Groshong group;P=0.24). The most frequent type of CVC-related infection in both groups was microbiologically documented sepsis; in most cases Gram-positive bacteria were isolated. Neutropenia (P<0.001 for both CVCs) and hospital CVC management (P=0.0047 for the Hickman group, P<0.001 for the Groshong group) emerged as the major risk factors for the outbreak of infections. The rate of mechanical complication episodes per 100 CVC-days was similar in both groups (1.01 in the Hickman group versus 1.1 in the Groshong group;P=0.58). Some complications (fissures, ruptures, total lumen obstruction by clots) occurred only in the Groshong group. Our study did not demonstrate any statistically significant difference in the incidence of mechanical and infective CVC-related complications between these two types of catheter.

Early infancy (< 1 year of age), massive tumor cell burden, and extremely poor prognosis are characteristic features of a particular subset of childhood acute leukemias (AL). In these cases, chromosome aberrations at the 11q23 band are the most frequently reported cytogenetic abnormalities. We have recently cloned a genetic locus named ALL-1, in which DNA breakpoints are clustered in leukemic patients with 11q23 aberrations. Analysis of the ALL-1 genomic configuration in DNA from 15 infants with AL showed specific ALL-1 rearrangements in 12 cases (80%), including 5 with normal karyotypes. These findings indicate that a consistent genetic defect underlies this particular leukemic subset.

Eight children with previously untreated ANLL received an induction regimen consisting of daunomycin and ara-C. All patients achieved complete remission. Post-remission chemotherapy was ara-C 3 g/m2 given i.v. over 3 h, at 12-h intervals, for four doses, and L-asparaginase 6000 IU/m2 i.m. 3 h after the fourth infusion of ara-C; four cycles were given over a period of five to eight months. Two patients received additional treatment. All eight patients relapsed 2-14 months after the treatment was stopped. No benefit was demonstrated by consolidation treatment given with these modalities.

Chelation therapy for patients with transfusional hemosiderosis is guided by the degree of iron overload and ongoing transfusion requirements; liver iron concentration (LIC) is one tool for measuring current iron burden. During the clinical development of the novel oral iron chelator deferasirox, LIC was measured in subcutaneous liver biopsy samples, but also non-invasively by biomagnetic liver susceptometry (SQUID-BLS) and magnetic resonance imaging (R2-MRI: FerriScan®). These methods were compared in a substudy of a large, open-label, randomized Phase III study in 586 β-thalassemia patients with transfusional hemosiderosis; the study evaluated the efficacy and safety of long-term deferasirox and deferoxamine treatment. 48 patients (aged 17–35 yrs) gave informed consent for adding BLS and MRI assessments (baseline, 6 and 12 months) to the biopsy assessments (baseline and 12 months) of the main study. At baseline, 47 patients were assessed by BLS and biopsy, 45 by R2-MRI; at 6 months, 42 by BLS and R2-MRI; at 12 months, 41 by BLS and R2-MRI, 39 by biopsy. BLS was performed and evaluated locally at 3 centers in Hamburg, Turin and Oakland. MR images were recorded at 4 centers in Hamburg, Turin, Stanford and Los Angeles and were analyzed centrally. Data from BLS and R2-MRI remained blinded until study completion. LIC from biopsies was determined by AAS from extracted paraffin blocks in a central laboratory and used as the standardized reference method. LIC was expressed as mg/g dry weight for all methods: for BLS, a wet-to-dry weight conversion factor of 3.3 was applied, while MRI was calibrated against fresh freeze-dried liver biopsies. The relationship between BLS or R2-MRI with biopsy measurements was modeled by linear regression after log-transformation of the data. To account for the correlation between baseline and post-baseline measurements of the same patient, mixed-effects models were fitted. On average, the LIC data obtained from BLS and biopsy were related by a factor of 0.46 (95% CI: 0.32, 0.67). With R2-MRI assessment of LIC vs biopsy, the factor was 0.72 (95% CI: 0.54, 0.97). BLS and R2-MRI measurements could not be related appropriately by a factor. Overall, LIC from biopsy was generally larger than that obtained from BLS; R2-MRI measurements fell in-between biopsy and BLS. Differences are caused in part by the variability in the wet-to-dry weight ratio relating in vivo with in vitro methods. In conclusion, LIC data from 3 independent methods were correlated but not equivalent. It is therefore important that for an individual patient, a single method is consistently used under standardized conditions.

The clinical benefits of chelation therapy for treating iron overload are well established. In a large randomized Phase III study conducted in 586 iron overloaded patients with β-thalassemia to assess once daily oral therapy with deferasirox versus subcutaneous deferoxamine (DFO), we previously showed that deferasirox led to a statistically significant reduction of iron burden in patients whose baseline LIC was ≥ 7 mg Fe/g dw and that this change was similar to that observed with DFO. We have subsequently analyzed the role of transfusional iron intake in influencing individual responses. In this study, transfusion data were collected among 296 patients receiving deferasirox and 290 patients receiving DFO. If volumes (in mL RBC) were provided for the transfusions, iron intake (in mg) was calculated by multiplying the mL RBC by 1.08. If transfusion was reported as number of units, each unit was assumed to contain 185 mL RBC or 200 mg iron. For each patient, the cumulative transfusion amounts during the study were recorded, and the total iron intake was calculated as mg/kg/day using the patients’ body weight and their time on study. The average iron intake rate during the study was 0.38 mg/kg/day which corresponds to approximately 0.35 mL/kg/day. The 25–75th percentiles included 0.30 to 0.47 mg/kg/day. Among patients receiving deferasirox, 70 (23.6%), 174 (58.8%) and 52 (17.6%) had a transfusional iron intake rate of <0.3, 0.3–0.5 and >0.5 mg/kg/day, respectively. Patients in the lowest transfusional iron loading group (<0.3 mg/kg/day) had an average rate of iron intake of 0.25 mg/kg/day, whereas patients in the higher iron intake groups of 0.3–0.5 and >0.5 mg/kg/day had an average intake rate of 0.39 and 0.55 mg/kg/day, respectively. The iron intake in mg/kg/day was higher in young children compared to adolescents and adults (0.48 for <6 years, 0.43 for 6–<12 years, 0.37 for 12–<16 years, 0.35 for ≥ 16 years). Iron intake rate affected the change in LIC and serum ferritin in response to chelation therapy. In the 30 mg/kg deferasirox cohort, the greatest decreases in LIC and ferritin levels were observed in patients with the lowest iron intake (Figure). Similar results were found in the group receiving DFO. In the 10 mg/kg deferasirox cohort, the LIC decreased in 10/58 (17%) of the patients in the <0.5 mg/kg/day group but in none of the patients in the iron intake >0.5 mg/kg/day group. Effect of dose and iron intake on LIC and serum ferritin (mean ± SD) during 1 year of deferasirox treatment Effect of dose and iron intake on LIC and serum ferritin (mean ± SD) during 1 year of deferasirox treatment In conclusion, the rate of transfusional iron loading has an important effect on the outcome of chelation therapy, and dosing should be individualized based on the transfusional iron intake, the severity of iron overload and the treatment goal of maintenance or reduction of body iron.

Chelation therapy for patients with transfusional hemosiderosis is guided by the degree of iron overload and ongoing transfusion requirements; liver iron concentration (LIC) is one tool for measuring current iron burden. During the clinical development of the novel oral iron chelator deferasirox, LIC was measured in subcutaneous liver biopsy samples, but also non-invasively by biomagnetic liver susceptometry (SQUID-BLS) and magnetic resonance imaging (R2-MRI: FerriScan®). These methods were compared in a substudy of a large, open-label, randomized Phase III study in 586 β-thalassemia patients with transfusional hemosiderosis; the study evaluated the efficacy and safety of long-term deferasirox and deferoxamine treatment.

The clinical benefits of chelation therapy for treating iron overload are well established. In a large randomized Phase III study conducted in 586 iron overloaded patients with β-thalassemia to assess once daily oral therapy with deferasirox versus subcutaneous deferoxamine (DFO), we previously showed that deferasirox led to a statistically significant reduction of iron burden in patients whose baseline LIC was ≥ 7 mg Fe/g dw and that this change was similar to that observed with DFO. We have subsequently analyzed the role of transfusional iron intake in influencing individual responses. In this study, transfusion data were collected among 296 patients receiving deferasirox and 290 patients receiving DFO. If volumes (in mL RBC) were provided for the transfusions, iron intake (in mg) was calculated by multiplying the mL RBC by 1.08. If transfusion was reported as number of units, each unit was assumed to contain 185 mL RBC or 200 mg iron. For each patient, the cumulative transfusion amounts during the study were recorded, and the total iron intake was calculated as mg/kg/day using the patients' body weight and their time on study.