[The adolescent with chronic disease: the oncohematologic pathology].
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Adolescent↗
Biomedical subjects
F Locatelli
Publications and source records attributed to F Locatelli.
Myelodysplastic syndromes: recent advances.
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Age Factors↗
Darbepoetin alfa. Amgen.
Amgen has launched darbepoetin alfa, synthetic recombinant novel erythropoiesis stimulating protein (NESP), for the treatment of anemia associated with renal disease. The drug was approved by the European Commission in June 2001, under the tradename Aranesp, for the treatment of anemia in chronic kidney failure including patients on and not yet on dialysis. The company launched the drug on day one of its approval in the following countries: Germany, Sweden, Denmark, Portugal, the Netherlands, the UK and Austria. Roll out of the drug in Italy, Greece and France will follow as soon as pricing and reimbursement issues are resolved [412240], [412357]. By January 2001, the product was still under review and the company anticipated approval during the first half of 2001 in both the US and Europe [396802]. Launch in the US had originally been scheduled for 2000 [387293], [396802] and Japanese launch is planned for 2004 or 2005 [405915]. In January 2001, Amgen reported that the first pivotal trial of darbepoetin alfa in treating oncology patients with anemia was successful [396526], [396802]. The company anticipated a phase III trial in US patients in 2001 for the oncology indication 13977941. In the fourth quarter of 2000, darbepoetin alfa entered phase I trials in Japan. Japanese development of darbepoetin alfa was being conducted by Kirin Brewery (under the research code KRN-321) [396653]. In January 2001, Genesis Pharma licensed the rights to distribute, market and sell darbepoetin alfa for the treatment of anemia, in Greece and Cyprus [396437]. MegaPharm Ltd signed an agreement with Amgen in February 2001, granting MegaPharm certain exclusive rights to distribute, market and sell darbepoetin alfa in Israel [398897]. In February 2000, Merrill Lynch predicted that darbepoetin alfa sales will be in excess of $1.4 billion at maturity [355817]. In October 2000, darbepoetin alfa annual sales were predicted to hit $3 billion [387293].
Anemia↗
Ethics of creating programmed stem-cell donors.
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Bone Marrow Cells↗
Cyclosporin A and short-term methotrexate versus cyclosporin A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling: results of a GITMO/EBMT randomized trial.
A randomized trial was carried out comparing cyclosporin A (CsA) and short-term methotrexate (MTX) versus CsA alone for graft versus host disease (GVHD) prophylaxis in patients with severe aplastic anemia (SAA) undergoing allogeneic bone marrow transplantation (BMT) from a compatible sibling. Seventy-one patients (median age, 19 years; range, 4-46 years) were randomized to receive either CsA and MTX or CsA alone for the first 3 weeks after BMT. Subsequently, both groups received CsA orally, with gradual drug reduction until discontinuation 8 to 12 months after BMT. Patients randomized in both arms had comparable characteristics and received the same preparative regimen (ie, cyclophosphamide 200 mg/kg over 4 days). The median time for neutrophil engraftment was 17 days (range, 11-31 days) and 12 days (range, 4-45 days) for patients in the CsA/MTX group and the CsA alone group, respectively (P =.01). No significant difference was observed in the probability of either grade 2, grade 3, or grade 4 acute GVHD or chronic GVHD developing in the 2 groups. The Kaplan-Meier estimates of 1-year transplantation-related mortality rates for patients given either CsA/MTX or CsA alone were 3% and 15%, respectively (P =.07). With a median follow-up of 48 months from BMT, the 5-year survival probability is 94% for patients in the CsA/MTX group and 78% for those in the CsA alone group (P =. 05). These data indicate that the use of CsA with MTX is associated with improved survival in patients with SAA who receive transplants from compatible siblings. (Blood. 2000;96:1690-1697)
Adolescent↗
The product of the rice myb7 unspliced mRNA dimerizes with the maize leucine zipper Opaque2 and stimulates its activity in a transient expression assay.
myb7 mRNA is present in rice in spliced and unspliced forms, splicing being enhanced by anoxia. The protein (Mybleu) encoded by the unspliced mRNA is composed of an incomplete Myb domain followed by a leucine zipper; however, it lacks canonical sequences for DNA binding, transcriptional activation, and nuclear localization. We show here that in transiently transformed tobacco protoplasts, Mybleu is able to enhance the transcriptional activity of the maize leucine zipper Opaque2 on its target b32 promoter. The Mybleu transactivation effect is strictly dependent on the presence of Opaque2 and is driven by Mybleu-Opaque2 heterodimers. Mybleu is located in the nucleus, both in rice and in transformed tobacco protoplasts. In rice, the protein is expressed in regions corresponding to undifferentiated cells of roots and coleoptiles. Therefore, myb7 mRNA encodes, depending on its splicing, two transcription factors belonging to separate classes. One of them, Mybleu, has novel structural characteristics, suggesting the existence of new mechanisms acting in the activation of transcription.
Cell Nucleus↗
Effect of nucleated marrow cell dose on relapse and survival in identical twin bone marrow transplants for leukemia.
The impact of cell dose (number of nucleated donor cells per kilogram recipient weight) on transplantation outcome is controversial and may differ for allogeneic and identical twin (syngeneic) bone marrow transplants. We studied the association between cell dose and outcome in 100 unmanipulated identical twin bone marrow transplantations for leukemia, reported to the International Bone Marrow Transplant Registry between 1985 and 1994, using Cox proportional hazards regression for multivariate analyses. Cell doses ranged from 0.3 to 7.4 x 10(8) nucleated cells/kg (median, 3.0 x 10(8)cells/kg). Median follow-up was 75 months. Five-year cumulative incidences of transplant-related mortality with high (more than 3 x 10(8) cells/kg) versus low (less than or equal to 3 x 10(8) cells/kg) cell doses were 2% (95% confidence interval [CI], 0% to 8%) versus 10% (95% CI, 4% to 20%), respectively. Five-year probabilities of leukemia-free survival were 53% (95% CI, 39% to 67%) and 37% (95% CI, 23% to 52%), respectively. In multivariate analysis, among patients surviving in remission at least 9 months after transplantation, those receiving high cell doses were at significantly lower risk for treatment failure (relapse or death) than those receiving low cell doses (RR, 0.27; 95% CI, 0.12 to 0.6; P =.001). Lower treatment failure resulted from fewer relapses in the high cell dose group (RR for relapse, 0.28; 95% CI, 1.2 to 0.66; P =.003). These findings suggest that outcomes after syngeneic bone marrow transplantation could be improved by transplanting more than 3 x 10(8) nucleated cells per kilogram. The benefit of high cell dose on relapse may represent a delayed graft-versus-leukemia effect.
Adolescent↗
Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients. European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anemia and the Gruppo Italiano Trapianti di Midolio Osseo (GITMO).
One hundred consecutive patients with severe aplastic anemia (SAA) received horse antilymphocyte globulin (ALG), cyclosporin A (CyA), 6-methylprednisolone (6Mpred), and granulocyte colony-stimulating factor (G-CSF) as first-line therapy. The median age was 16 years (range, 1-72 years) and median neutrophil count was 0.2 x 10(9)/L (range, 0-0.5 x 10(9)/L). Trilineage hematologic recovery (at a median interval of 96 days from treatment) was seen in 77 patients (48 complete, 29 partial) after 1 (n = 50) or more courses of ALG (n = 27). Of the 23 nonresponders, 11 patients died at a median interval of 83 days (range, 16-1132 days), 6 were considered treatment failures and underwent transplantation, and 6 were pancytopenic. Cytogenetic abnormalities were seen in 11% of patients, clonal hematologic disease in 8%, and relapse of marrow aplasia in 9%. The actuarial survival at 5 years was 87% (median follow-up 1424 days): 76% versus 98% for patients with neutrophil counts less than versus greater than 0.2 x 10(9)/L (P =.001) and 88% versus 87% for patients aged less than versus more than 16 years (P =.8). The actuarial probability of discontinuing CyA was 38%. Patients who did not achieve a white blood cell (WBC) count of 5 x 10(9)/L during G-CSF treatment have a low probability of responding (37%) and a high mortality rate (42%). This update confirms a high probability for SAA patients of becoming transfusion independent and of surviving after treatment with ALG, CyA, 6Mpred, and G-CSF, with a significant effect of neutrophil counts on outcome. Problems still remain, such as absent or incomplete responses, clonal evolution, relapse of the original disease, and cyclosporine dependence. Early transplantation, also from alternative donors, may be warranted in patients with poor WBC response to G-CSF. (Blood. 2000;95:1931-1934)
Adolescent↗
Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukemia given HLA-identical sibling bone marrow transplantation: results of a randomized trial.
Leukemia relapse is a major cause of treatment failure for patients with acute leukemia given allogeneic bone marrow transplantation (BMT). This study evaluated whether a reduction of the dosage of cyclosporine-A (Cs-A) used for graft versus host disease (GVHD) prophylaxis could reduce relapse rate (RR) in children with acute leukemia given BMT. Fifty-nine children who had transplantation from HLA-identical siblings were randomized to receive Cs-A intravenously at a dosage of 1 mg/kg/d (Cs-A1) or of 3 mg/kg/d (Cs-A3) until patients were able to tolerate oral intake. Subsequently, both groups received Cs-A orally at a dosage of 6 mg/kg/d, with discontinuation 5 months after BMT. The probability of developing grade II-IV acute GVHD was 57% for the Cs-A1 group versus 38% for the Cs-A3 group (P =.06); the probability of developing chronic GVHD was 30% for the Cs-A1 group and 26% for the Cs-A3 group (P = NS). Three patients died of grade IV acute GVHD: 2 were in the Cs-A1 and the third in the Cs-A3 group. The RR was 15% for the Cs-A1 group and 41% for the Cs-A3 group (P =.034); 1-year transplant-related mortality estimates were 17% and 7%, respectively (P = NS). With a median observation time of 44 months from BMT, the 5-year event-free survival for children belonging to Cs-A1 and Cs-A3 groups was 70% and 51%, respectively (P =.15). Our data demonstrate that the use of low Cs-A doses is associated with a statistically significant reduction of leukemia relapse, probably due to an increased graft versus leukemia effect. (Blood. 2000;95:1572-1579)
Acute Disease↗
Outcome of 69 allogeneic stem cell transplantations for Fanconi anemia using HLA-matched unrelated donors: a study on behalf of the European Group for Blood and Marrow Transplantation.
Allogeneic stem cell transplantation is the only treatment that can restore a normal hematopoiesis in Fanconi anemia (FA). In this retrospective multicenter study, we analyzed the results of this approach using HLA-matched unrelated bone marrow donors, and tried to identify covariates predicting the outcome of the transplant. From January 1985 to June 1998, 69 FA patients were transplanted with unrelated HLA-matched donors. Patients' characteristics before and after transplant were provided by the European group blood and marrow transplant registry and were analyzed in collaboration with the European Fanconi Anemia Registry. The 3-year probability of survival was 33%. Extensive malformations, a positive recipient cytomegalovirus serology, the use of androgens before transplant, and female donors were associated with a worse outcome. Primary graft failures were observed more frequently when female donors were used, mainly because the grafts contained lower nucleated cell doses per kilogram of recipient body weight compared with grafts coming from male donors. The probability of grade III-IV acute graft-versus-host disease (GVHD) was 34%. Elevated serum alanine/aspartate transaminases before transplantation; limb, urogenital tract, or nephrologic malformations; and non-T-cell-depleted grafts were predictors of severe acute GVHD. This study shows the dramatic impact of preexisting congenital malformations on the outcome of FA patients transplanted with HLA-matched unrelated donors. If the use of T-cell depletion has led to a dramatic reduction of acute GVHD incidence, no significant outcome improvement was observed with this approach, mainly because of an increased risk of graft failure. (Blood. 2000;95:422-429)
Adolescent↗
Method using urokinase and an antibiotic to avoid device removal in central venous catheter-related infections.
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Adolescent↗
Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT).
Congenital amegakaryocytic thrombocytopenia (CAMT) without physical anomalies is a rare disease, presenting isolated thrombocytopenia and megakaryocytopenia in infancy, which can evolve into aplastic anemia and leukemia. Recently, two heterozygous truncating mutations of the thrombopoietin (TPO) receptor MPL, coded by the c-mpl gene, were identified in a 10-year-old Japanese patient with CAMT transmitted in an autosomal recessive manner. Here, we report for the first time two different MPL amino-acid substitutions in a 2-year-old Italian boy with CAMT and compound heterozygosis for two (c-mpl point mutations. C-to-T transitions were detected on exons 5 and 12 at the 769 and 1904 cDNA nucleotide positions, respectively. The mutation in exon 5 substitutes an arginine with a cysteine (R257C) in the extracellular domain, 11 amino acids distant from the WSXWS motif conserved in the cytokine-receptor superfamily. The mutation in exon 12 substitutes a proline with a leucine (P635L) in the last amino acid of the C-terminal intracellular domain, responsible for signal transduction. As in the Japanese family, the mutations were both transmitted from the parents. TPO plasma levels were highly increased in the patient. The patient's 7-year-old brother, who was a candidate donor for allografting, turned out to be an asymptomatic heterozygous carrier of P635L and showed defective megakaryocyte colony formation from bone-marrow progenitor cells. The present study provides important confirmation that CAMT can be associated with (c-mpl) mutations.
Amino Acid Sequence↗
Tolerance and hematopoietic stem cell transplantation 50 years after Burnet's theory.
OBJECTIVE: In 1949, the original formulation of Burnet's theory on the mechanisms responsible for the capacity of the immune system to discriminate between foreign antigens (i.e., the "non-self") and the cells of its own body (i.e., the "self") was published. Since then, further refinements and reconsiderations of the basic concepts underlying the achievement of a state of tolerance toward a certain antigen have been reported. Here, we attempt to analyze critically new clinical and experimental strategies aimed at inducing alloantigen-specific unresponsiveness. DATA SOURCES: The data discussed in this review are drawn from articles and abstracts published in journals covered by the Science Citation Index and Medline. STATE OF THE ART: Induction of tolerance toward alloantigens still remains one of the most elusive goals of clinical immunology. Until now, nonspecific immunosuppressive drugs have been used to successfully perform both solid organ and hematopoietic stem cell transplantation. However, using this approach, patients given an allograft are exposed to the threat of infections, tumors, and other side effects. Moreover, in solid organ transplant recipients, permanent tolerance toward the graft's alloantigens is never achieved. Recently, considerable progress has been made in expanding our knowledge of transplant tolerance. The traditional model of central tolerance, derived from Burnet's concept, has been complemented by knowledge of mechanisms of peripheral tolerance. CONCLUSIONS: New experimental and therapeutic trials based on the blockade of costimulatory molecules, as well as on generation and infusion of either regulatory or nonimmunogenic cells, have been recently proposed for inducing alloantigen-specific tolerance.The achievements obtained in understanding the mechanisms of unresponsiveness toward non-self antigens are fundamental prerequisites for successful allogeneic transplants, and they could open a new exciting era of specific, immunosuppressive therapies.
Animals↗
Statement of current majority practices in graft-versus-host disease prophylaxis and treatment in children.
Great variations exist in the prophylaxis and treatment of GVHD in children undergoing allogeneic stem cell transplantation (SCT). The EBMT Working Party Paediatric Diseases (EBMT-WP PD) and the International BFM Study Group--Subcommittee Bone Marrow Transplantation (IBFM-SG), aimed at evaluating current local standards in the prevention and treatment of GVHD and steps which can be taken to achieve a uniform policy for the individual methods. Several conferences with their members assessed practices which are mainly applied or under investigation in children and identified where additional information is needed. For prevention of GVHD, the majority of the paediatric centres prefer CsA +/- MTX. Addition of folinic acid to MTX was considered for reduction of side-effects. During treatment of acute GVHD most centres administer prednisolone and whole blood level-adjusted CsA as medications of first choice. In cases of poor or no response to this therapy, additional immunosuppressive agents such as ATG, mycophenolate-mofetile and tacrolimus are being increasingly used. The treatment of chronic GVHD usually consists of various combinations of prednisolone and CsA. In severe cases, extracorporeal photopheresis, psoralene-UVA (PUVA) and thalidomide are administered.
Adolescent↗
Cytotoxic T lymphocyte precursor frequency as a predictor of acute graft-versus-host disease in bone marrow transplantation from HLA-identical siblings.
The measurement of precursor frequencies of donor anti-recipient cytotoxic T lymphocytes (CTL-p) has been shown to predict the incidence and the severity of acute graft-versus-host disease (aGVHD) in unrelated donor bone marrow transplantation (BMT). In HLA-identical sibling BMT, where aGVHD is most likely caused by minor histocompatibility antigen mismatches, this assay did not appear to be sensitive enough to provide similar predictive information. In this study, the CTL-p frequencies and the incidence and severity of aGVHD in 51 onco-hematological patients transplanted from HLA-identical siblings were compared. Sibling donors were selected on the basis of HLA identity using serological typing for HLA-A, B, C antigens, whereas HLA-DRB was tested by molecular analysis. Sibling identity was also confirmed by DNA heteroduplex analyses. Fifteen out of 21 (71%) patients with high precursor frequency (>1:100 x 10(3)) and 12 out of 30 (40%) with low precursor frequency (<1:100 x 10(3)) experienced clinically significant (II-IV) aGVHD. A significant correlation (P = 0.04) between CTL-p frequency and severe aGVHD was demonstrated. Moreover there was a positive trend for a high frequency response according to an increasing grade of aGVHD, which was statistically significant (P = 0.04). In our experience the CTL-p assay is a helpful predictive test for aGVHD in HLA-identical sibling BMT, indicating high risk patients possibly requiring additional prophylaxis.
Acute Disease↗
Lymphocyte subset reconstitution after HLA-identical placental blood transplantation (PBT) or PBT plus bone marrow transplantation (BMT) in three children with beta-thalassemia major.
The kinetics of circulating lymphoid cells were evaluated in three children suffering from beta-thalassemia major after HLA-identical sibling placental blood transplant (PBT) in one patient and placental blood plus bone marrow transplantation (BMT) in two patients. Recovery of the main lymphocyte subsets, as determined by phenotype analysis of circulating PBMCs, was complete within 2 months after transplant. NK (CD56+) cells were the first to appear in peripheral blood, followed by T (CD3+, CD2+, CD7+) and B (CD19+) cells. Of the T lymphocytes, the CD8+ were the first to reconstitute, but recovery of CD4+ cells was also rapid and within 6 months these T cells reached normal values. The expression of CD57 by NK or T cells was slightly delayed. The evaluation of RA and RO isoform expression of the CD45 molecule showed a prevalence of the CD45RA antigen with a ratio of 2-3:1. In the PBT only patient, T cells expressing the CD45RO antigen prevailed in the early post-transplant period. Severe or chronic GVHD was not observed. This experience demonstrates that reconstitution of lymphocyte subsets is successful in genetic hematological diseases after transplantation of HLA-identical placental blood or placental blood plus bone marrow from healthy or heterozygous siblings. Bone Marrow Transplantation (2000) 26, 743-747.
Blood Transfusion↗
Color doppler ultrasonography imaging to guide transluminal angioplasty of venous stenosis.
BACKGROUND: The objective of access surveillance is the early recognition of dysfunction in order to be able to correct the stenosis by angioplasty or surgery before access thrombosis occurs. The advent of color Doppler imaging has enabled studies of color Doppler ultrasonography (CDU) for the guidance of percutaneous transluminal angioplasty (PTA). The aim of the present study was to investigate whether color Doppler imaging alone can be safely and effectively used to diagnose vascular graft access stenoses and guide subsequent PTA. METHODS: Using the ultrasound velocity dilution method, we measured access blood flow (Qa) during the first hour of hemodialysis every month in patients with grafts as vascular access. When the decrease in Qa from the baseline value was 40% or more, CDU was performed and immediately followed by PTA in the presence of a stenosis of more than 50%. The Qa was then measured during the first dialysis after PTA and one month later. Repeated-measure analysis of variance was applied to evaluate the early and late (after one month) effect of PTA. RESULTS: Twelve PTAs were performed under CDU guidance in nine patients and led to the elimination of the stenosis or its reduction (two cases). The mean Qa was 809 +/- 263 mL/min at baseline, 468 +/- 153 before PTA, and 820 +/- 281 after PTA. The difference between the pre-PTA and post-PTA values was highly significant (P < 0.001), and the mean value after PTA was not different from baseline (P = 0.672). There were no relevant complications directly related to the procedure. CONCLUSIONS: The CDU procedure is effective for the diagnosis of vascular access stenosis and as a guide during the PTA procedure. It could improve stenosis screening by avoiding the risks of exposure to ionizing radiation and of adverse reactions to contrast media.
Aged↗
Relevance of the conductivity kinetic model in the control of sodium pool.
Changes in the body sodium pool caused by dialytic treatment have very important clinical implications, mainly in terms of intradialytic cardiovascular instability and interdialytic hyperhydration and hypertension with long-term cardiac hypertrophy and dilation. A kinetic model could be helpful in order to define the dialysate sodium concentration needed to match intradialytic hydrosodium removal with interdialytic sodium and water intake, but unfortunately, none of the sodium kinetic models are suitable for routine clinical application. Two conductivity kinetic models (one for hemodialysis and one for paired filtration dialysis) have been developed on the basis of the linear relationship between the sodium content and conductivity of every saline solution and plasma water and according to basic theory for ionic dialysance determination. These models make it possible to know at the start of each session the dialysate conductivity needed to obtain the desired final plasma water conductivity or to know the latter when the former is known. Clinical evaluations showed that conductivity kinetic models are very precise and accurate and may be used instead of sodium kinetic models. Furthermore, they are suitable for routine use because they do not require blood sampling or laboratory determinations. Clinical application of the conductivity kinetic model has shown that the reduced variability of end-dialysis plasma water conductivity obtained when using the model to identify dialysate conductivity significantly reduces cardiovascular instability, even without any changes in average sodium removal. Given that ionic dialysance can be easily, inexpensively, and repeatedly measured at each dialysis session, it seems realistic to expect that conductivity kinetic modeling will soon become a part of everyday clinical practice.
Blood Pressure↗