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Biomedical subjects

M Zecca

Publications and source records attributed to M Zecca.

At least 37 records · Page 2Linked to original sources
PubMed1999

Marked and sustained improvement two years after autologous stem cell transplantation in a girl with systemic sclerosis.

Autologous transplantation of hematopoietic stem cells has recently been proposed as a possible treatment for autoimmune diseases that are associated with a very severe prognosis. A 12-year-old girl who, since 4 years of age, had systemic sclerosis with progressive pulmonary involvement underwent autologous peripheral blood-derived stem cell transplantation (aPBSCT) using CD34+ selection, cyclophosphamide, and the infusion of the monoclonal antibody CAMPATH-1G. Following transplantation, in the absence of any treatment other than symptomatic therapy, the patient's exertional dyspnea and alveolitis disappeared and she experienced a marked improvement in skin score, height velocity, and general well-being that has persisted 2 years after the transplantation procedure. Autologous PBSCT associated with the infusion of the monoclonal antibody CAMPATH-1G appears to be a useful therapy for otherwise intractable forms of progressive systemic sclerosis.

Adolescent↗
PubMed1999

Resolution of immune haemolytic anaemia with allogeneic bone marrow transplantation after an unsuccessful autograft.

Autologous transplantation of lymphocyte-depleted peripheral blood stem cells (PBSC) has been proposed for treatment of patients with severe autoimmune disease. However, several patients have been reported to achieve only transient remissions. We report on a child with thalassaemia intermedia and immune-mediated haemolytic anaemia, given an autologous lymphocyte-depleted PBSC transplant, who relapsed 7 weeks after transplant. A complete remission, lasting 18 months to date, was obtained with allogeneic bone marrow transplantation (BMT) from an HLA-matched unrelated donor. This experience indicates that, in selected cases, allogeneic BMT may be the treatment of choice for life-threatening autoimmune disease. A graft-versus-autoimmunity effect may favour the eradication of the recipient autoaggressive lymphocytes.

Anemia, Hemolytic, Autoimmune↗
PubMed1999

Late pulmonary sequelae after childhood bone marrow transplantation.

BACKGROUND: Respiratory function in transplanted children is important because of the long life expectancy of bone marrow transplant recipients, particularly children. Attention is now being focused on the late sequelae of treatment on organ system function. A few papers have been published but available data are somewhat conflicting. METHODS: A cross sectional study aimed at evaluating the late effects of transplantation on lung function was performed in a group of 52 young patients who were given autologous or allogeneic bone marrow transplants during childhood for haematological malignancies. RESULTS: No patients reported chronic respiratory symptoms. The distribution of respiratory function patterns showed that only 62% of patients had respiratory function within the normal limits; 23% had a restrictive pattern and 15% had isolated transfer factor impairment. The percentage of patients with lung function abnormalities was higher in those who (1) received a bone marrow transplant after two or three complete remissions compared with those who were transplanted immediately after the first remission (54% vs 21%; p < 0.02), (2) underwent allogeneic bone marrow transplantation rather than an autologous transplantation (45% vs 26%; p = 0.06), and (3) had a pulmonary infection compared with those without (56% vs 26%; p = 0.07). CONCLUSIONS: In spite of the absence of chronic respiratory symptoms there is a high prevalence of children with late pulmonary sequelae after bone marrow transplantation. Regular testing is recommended after transplantation, in particular in subjects at higher risk of lung injuries, such as those receiving transplants after more than one remission, those receiving allogeneic transplants, and those having suffered from pulmonary infections. When lung function abnormalities become apparent, long term follow up is necessary to see whether they become clinically relevant. All patients should remain non-smokers after transplantation and should have active early and aggressive treatment for respiratory illnesses.

Adolescent↗
PubMed1999

Total-body irradiation and melphalan is a safe and effective conditioning regimen for autologous bone marrow transplantation in children with acute myeloid leukemia in first remission. The Italian Association for Pediatric Hematology and Oncology-Bone Marrow Transplantation Group.

PURPOSE: To evaluate the safety and efficacy of a preparative regimen consisting of fractionated total-body radiation (9.9 to 12 Gy) and melphalan (140 mg/m(2) in a single dose) in children with acute myeloid leukemia in first complete remission (CR) given autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Fifty-three children (30 males and 23 females; age range, 1.5 to 18 years) were enrolled onto the study. The median time from first CR to ABMT was 3.5 months (range, 1.4 to 13 months), with 45 patients (85%) undergoing transplantation within 6 months from the diagnosis. Forty-five patients received in vitro marrow purging with standard-dose mafosfamide (100 microg/mL), seven patients were treated with interleukin-2 before marrow collection, and in the remaining child, the marrow was unmanipulated. The median infused cell dose was 1.8 x 10(8)/kg (range, 0.4 to 5.8 x 10(8)/kg). RESULTS: All patients but one achieved hematopoietic engraftment, with a median time to neutrophil recovery of 24 days (range,11 to 66 days). Treatment-related toxicity was moderate and consisted mainly of mucositis. One patient died from cytomegalovirus interstitial pneumonia, and one died from pulmonary hemorrhage. Fourteen patients (26%) relapsed at a median time of 6 months after ABMT (range, 2 to 17 months), with a cumulative relapse probability of 29% (95% confidence interval, 16% to 42%). The 5-year Kaplan-Meier estimate of survival for all 53 patients was 78% (range, 65% to 90%), whereas the overall 5-year disease-free survival was 68% (range, 55% to 81%), with a median follow-up duration of 40 months (range, 7 to 130 months). CONCLUSIONS: These data suggest that, in our cohort of patients, the combination of total-body irradiation and melphalan is safe and associated with good antileukemia activity, making ABMT an appealing alternative for postremission therapy in children with acute myeloid leukemia in first CR.

Antineoplastic Agents, Alkylating↗
PubMed1999

Total body irradiation, thiotepa, and cyclophosphamide as a conditioning regimen for children with acute lymphoblastic leukemia in first or second remission undergoing bone marrow transplantation with HLA-identical siblings.

PURPOSE: Allogeneic hematopoietic stem-cell transplantation (HSCT) from HLA-identical siblings can be used to treat children with acute lymphoblastic leukemia (ALL). However, a significant proportion of patients with ALL who undergo HSCT relapse. For this reason, we prospectively evaluated a preparative regimen that included total body irradiation (TBI), thiotepa (TT), and cyclophosphamide (CY) in patients with high-risk ALL in first complete remission (CR) and in children with ALL in second CR. PATIENTS AND METHODS: Forty children (median age, 9 years; range, 1 to 18 years) with ALL in first or second CR who underwent allogeneic HSCT from HLA-identical siblings were conditioned with a combination of fractionated TBI, TT (10 mg/kg), and CY (120 mg/kg over 2 days). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine administered intravenously at a dose of 1 to 3 mg/kg/d for the first 21 days and subsequently orally at a dose of 6 mg/kg/d. RESULTS: All assessable patients were engrafted, with a median time of 11 and 24 days for neutrophil and platelet recovery, respectively. The preparative regimen was well tolerated. Only one patient died as a result of regimen-related causes. Eight patients relapsed at a median time of 8 months after transplantation (range, 3 to 9 months), and this determined a cumulative probability of relapse of 23%. Twenty-six of 40 patients (65%) are alive and in complete hematologic remission, with a median observation time of 36 months (range, 14 to 57 months), which results in a disease-free survival (DFS) at 3 years of 65%. The 13 patients who underwent transplantation in first CR had a DFS of 85%, whereas the 27 patients who underwent HSCT in second CR had a DFS of 56%. CONCLUSION: These data suggest that TT is an effective cytotoxic drug that can be safely added to the classical TBI-CY regimen. Because of its cell cycle-independent action, good CNS diffusion, and limited extramedullary toxicity, TT may contribute to increasing the percentage of children with ALL who are successfully cured with allogeneic BMT.

Adolescent↗
PubMed1999

Development of the pituitary and its abnormalities.

The embryology of the pituitary gland and its normal development is described, including the importance of Pit-1. Congenital abnormalities of the hypothalamo-pituitary region are discussed.

DNA-Binding Proteins↗
PubMed1998

Evaluation of growth hormone bioactivity using the Nb2 cell bioassay in children with growth disorders.

The Nb2 cell bioassay could be a useful tool for evaluating human growth hormone (hGH) bioactivity, but is not specific for hGH since it relies on the ability of the hormone to produce effects by cross-reacting with the lactogenic receptor on Nb2 cells. We studied the biological activity of both endogenous and exogenous hGH in short patients using the Nb2 bioassay after inhibiting the mitogenic effect of the other lactogenic hormone, that is human prolactin (hPRL), by adding a specific antibody against hPRL to each assay. The in vitro study showed a significant (p<0.0001) increase in Nb2 cell proliferation when increasing concentrations of highly purified hGH were added to the cell culture. A complete inhibition of Nb2 cell replication was observed after adding a specific antibody against hGH. The in vivo study showed a significantly (p<0.0001) lower hGH bioactivity (4.90+/-0.28 ng/ml) evaluated during stimulation tests in 9 children with total idiopathic GH deficiency, mean age 9.25+/-1.99 years, in comparison with that found in 11 short children with normal growth velocity, mean age 8.22+/-1.41 years (12.25+/-1.19 ng/ml). Likewise, serum GH levels measured by immunofluorometric assay IFMA in the same serum samples were significantly (p<0.001) lower in the 9 GH-deficient (1.97+/-0.37 ng/ml) than in the 11 short children (21.85+/-2.71 ng/ml). Moreover, we evaluated GH concentrations using both IFMA and the Nb2 cell bioassay in serum samples collected from another 11 idiopathic GH-deficient children, mean age 10.71+/-1.18 years, before and then, 6 and 24 hours following the 1 st injection of r-hGH (0.1 IU/kg sc). Serum GH values measured by both IFMA and Nb2 bioassay significantly (p<0.0001) increased 6 hours after r-hGH administration and decreased to reach basal levels after 24 hours. In conclusion, the Nb2 cell bioassay with minor modifications seems to provide a specific and sensitive assessment of hGH bioactivity.

Animals↗
PubMed1998

Immunization with Haemophilus influenzae type b conjugate vaccine in children given bone marrow transplantation: comparison with healthy age-matched controls.

Forty-seven patients (age range, 7 months-18 years) with malignant (38 cases) and nonmalignant (9 cases) disorders given an allogeneic or an autologous bone marrow transplantation (BMT) were immunized with Haemophilus influenzae type b (Hib) polysaccharide-diphtheria toxoid conjugate vaccine administered in a single dose at different time points after transplantation. Results were compared with those of 13 healthy children matched for age and sex who received the same immunization schedule. Serum and saliva samples for measurement of total IgG subclass and specific antibody levels were obtained from patients and healthy controls before and 3 weeks after vaccination. Twenty-five of the 47 patients (53%) had a specific anti-Hib IgG response, while an effective IgA and IgM response was mounted by 23 (49%) and 11 (23%) children, respectively. In the control group, 13 of 13 subjects mounted a specific IgG antibody production (P < 0.005 in comparison to the patients' response rate), while an IgA and IgM response was demonstrated in 12 (92%; P < 0.01 compared to transplanted patients) and 7 (54%; P < 0.05 in comparison to BMT recipients) children, respectively. Lapse of time from BMT to immunization was the most important factor predicting antibody response, as proved by an effective increase in prevaccination specific IgG levels in the majority of patients vaccinated after 2 years from transplant. Our data demonstrate that BMT recipients have a reduced capacity to mount an antibody response to polysaccharide antigens compared to normal controls, even when a protein-conjugated vaccine is employed. Since time after transplant is the major factor influencing the recovery of immune reactivity to polysaccharide antigens, the ontogeny of the B cell repertoire seems to follow a predetermined sequential program of development.

Adolescent↗
PubMed1998

Does the emergence and persistence of donor-derived leukaemia-reactive cytotoxic T lymphocytes protect patients given an allogeneic BMT from recurrence? Results of a preliminary study.

The frequency of CTL precursors (CTLp) directed towards recipient-derived pre-transplant leukaemic blasts (LB) was measured in the peripheral blood of nine children with acute leukaemia and given BMT from either an HLA-identical sibling or a matched unrelated donor (MUD). Patients were evaluated at various time points between 1 month and more than 2 years after transplantation. A high frequency of donor-derived LB-reactive CTLp was detectable 2-6 months after BMT in all children and persisted for at least up to 18 months in the eight patients in haematological remission, while it rapidly declined in the only patient who relapsed. Generation of LB-reactive T cell clones obtained from some of these patients demonstrates that various T lymphocyte subsets, either HLA class I-restricted/TCR-dependent or HLA-unrestricted, contribute to this phenomenon. The in vitro GVL effect here described seems to be at least partially separated from GVHR, since no correlation was observed between the emergence of LB-reactive CTLp and the development and/or severity of GVHD. Development of LB-reactive CTL in the patients was independent of the frequency of these cells in the donor. These data suggest that donor-derived CTL activity specifically directed towards leukaemic blasts may develop in patients given allogeneic BMT and contribute to the maintenance of a state of haematological remission.

Bone Marrow Transplantation↗
PubMed1998

Modulating effect of human growth hormone on tumour necrosis factor-alpha and interleukin-1beta.

We measured serum tumour necrosis factor-alpha (TNF-alpha) as well as interleukin-1betta (IL-1beta) and GH concentrations in 15 children with isolated growth hormone deficiency (GHD), age range 5.1-13.9 years, before and 4 and 24h after the first GH injection (0.1 IU/kg s.c.). No differences were found in basal concentrations of serum TNF-alpha and IL-1beta between GHD children (10.01 +/- 1.55 pg/ml and 2.14 +/- .16 ng/ml respectively) and sex- and age-matched controls (11.57 +/- 2.16 pg/ml and 3.78 +/- 1.46 ng/ml respectively). In GHD children, serum TNF-alpha and IL-1beta values had significantly increased (P < 0.002) 4h (26.75 +/- 5.57 pg/ml and 2.99 +/- 0.21 ng/ml respectively) and decreased again 24 h after GH administration. Likewise, serum GH levels had significantly increased 4 h (from 1.29 +/- 0.69 to 48.71 +/- 13.35 ng/ml, P < 0.001) and decreased to basal values 24h after GH administration. A significant correlation was found between basal serum concentrations of GH and those of both TNF-alpha (P < 0.01) and IL-1beta (P < 0.05). However, no correlation was found between serum GH concentration and either TNF-alpha or IL-1beta levels 4 and 24h after GH administration. Our data suggest that GH plays a role in modulating TNF-alpha and IL-1beta release in humans.

Adolescent↗
PubMed1998

Unrelated donor marrow transplantation for inborn errors.

From December 1989 to December 1997 40 children aged 1 year to 19 years with inborn errors other than severe combined immunodeficiencies underwent unrelated donor (UD) bone marrow transplantation (BMT) in one of 10 institutions of the Italian Bone Marrow Transplant Group participating in this program. The diseases leading to BMT included Fanconi Anemia (10), Thalassemia (8), Wiskott Aldrich syndrome (5), haemophagocytic lymphohystiocytosis (6), osteopetrosis (3), storage diseases (6), Chediak Higashi syndrome (1), Schwachman syndrome (1). Thirty-three pairs were A, B, DRB1 matched. Three pairs were one antigen mismatched and one pair was two antigens mismatched. The remaining three pairs lacked information on molecular biology. Twelve children underwent a preparative regimen including radiotherapy. The remaining 28 children were conditioned with a chemotherapy regimen which included Busulfan. GvHD disease prophylaxis included CSA and MTX alone (9) or associated with ALG (17) or in vivo Campath 1G (12). The remaining two children received CSA alone. Thirty-five children showed donor engraftment; three children with thalassemia and one with osteopetrosis failed to engraft. Five children developed secondary graft failure. Actuarial 5 year disease-free survival was 62%; grade III-IV acute GvHD developed in seven of 38 evaluable children (18%); chronic GvHD developed in seven of 27 evaluable children (26%). We confirm that Wiskott Aldrich syndrome, HLH, and osteopetrosis represent an absolute indication for UD-BMT. Prognosis of UD-BMT for FA could improve in children grafted in an early phase, but a better preparative regimen has to be identified. UD-BMT in thalassemia is acceptable only in a restricted subset of patients selected for poor compliance to therapy.

Adolescent↗
PubMed1998

Cyclosporine-A as GVHD prophylaxis in allogeneic BMT for childhood acute leukemia. AIEOP-BMT group.

We report the preliminary results of a prospective randomized study on the impact of two different dosages of Cyclosporine A (Cs-A) on probability of development of acute and chronic GVHD, transplant-related mortality (TRM), relapse rate (RR) and event-free survival (EFS). Fifty-nine pediatric patients given BMT from an HLA-identical sibling were centrally randomized to receive either Cs-A at a dosage of 1 mg/kg/die (CsA1) or at a dosage of 3 mg/kg/die (CsA3) intravenously for the first 21 days after BMT. Patients given Cs-A at a dosage of 1 mg/kg/die had a higher probability of developing acute GVHD, but a lower relapse rate, which translated into a better probability of EFS. These preliminary results to be confirmed with a longer follow-up suggest that the use of low doses of CsA is feasible even though associated with a higher incidence of GVHD, but without any increment in TRM. The reduction of immunosuppressive treatment after BMT favoured the development of a graft-versus-leukemia effect, which seems to play a relevant role in preventing leukemia recurrence and in improving the cure rate.

Bone Marrow Transplantation↗
PubMed1998

Allogeneic transplantation of peripheral blood progenitor cells in children: experience of two pediatric centers.

Between February 1995 and August 1997, 11 children (eight males, three females) aged 4-16 years (median 7 years) underwent allogeneic PBPC transplantation for treatment of hematological disorders. Seven patients with acute leukemia (n = 5 ALL, n = 1 AML) or lymphoma (n = 1) received primary allogeneic PBPC transplantation, four patients received a second allotransplantation for graft failure (n = 1 AML, n = 1 sickle cell anemia) or disease recurrence (n = 1 ALL, n = 1 MDS). Five donors were HLA-identical siblings, five were 0-1 antigen mismatched family members and one was a matched unrelated donor. Donors received G-CSF 10-12 microg/kg/day for 3-7 days, and underwent one or two leukaphereses. The median cell yield per donor expressed per kg of recipient body weight was as follows: mononucleated cells 10.8 x 10(8)/kg (range 4.7-21.2); CD34+ cells 8.6 x 10(6)/kg (range 3.2-22); CD3+ cells 3.7 x 10(8)/kg (range 2.7-7.5). All patients achieved an ANC >0.5 x 10(9)/l after a median of 12 days (11-18). An unsupported platelet count >50 x 10(9)/l was reached 15 days (13-21) after PBPC transplantation; four patients failed to reach this threshold. Acute GVHD (aGVHD) grades II to IV occurred in eight (73%) patients: seven of them experienced grade III-IV aGVHD. Seven patients evaluable for chronic GVHD (cGVHD) were scored as absent in five, limited in one and extensive in one patient. As of September 1997, six patients (55 %) were alive between 60 and 938 days post-transplant (median follow-up 274 days); four patients with malignancy were alive in CR after primary allotransplantation, two patients were alive after a second PBPC transplant. Five patients have died with the main causes of death being aGVHD (n = 3), ARDS (n = 1), relapse of the underlying disease (n = 1). In conclusion, despite the limited number of patients, these preliminary results indicate that PBPC may be considered as an alternative to bone marrow for allografting also in children.

Adolescent↗
PubMed1998

Transplantation of peripheral blood stem cells mobilized by haematopoietic growth factors in childhood.

Peripheral blood stem cells (PBSC), mobilised by means of haematopoietic growth factors (HGF) with or without chemotherapy, are being used routinely for autologous rescue after high-dose chemo-radiotherapy in paediatric patients with lymphoma and selected solid tumours because of the ease of collection and the accelerated kinetics of neutrophil and platelet engraftment as compared with bone marrow cells. Recent reports indicated that HGF-mobilised PBSC can also be employed in childhood as an alternative to bone marrow allograft when the donor is an adult or with the aim of reversing graft failure in patients who were previously given a marrow allograft. Notwithstanding this wide use of PBSC, several biological and clinical questions of crucial relevance are still unsolved. In this article, we will analyse: (1) the optimal timing for PBSC collection after cytokine-based mobilising regimens; (2) the variables affecting the yield of peripheral blood progenitors; (3) the minimum threshold and the optimal number of PBSC that should be infused for autologous and allogeneic transplant, respectively; (4) the biological mechanisms underlying mobilisation of haematopoietic stem cells into circulation; (5) the incidence of graft-versus-host disease and the biological characteristics of donor lymphocytes in patients given allogeneic transplant of PBSC; and (6) the most relevant peculiarities in the kinetics of immune recovery of patients given allogeneic transplant of PBSC, as compared to bone marrow transplant recipients.

Child↗
PubMed1997

Allogeneic bone marrow transplantation for chronic myelomonocytic leukemia in childhood: a report from the European Working Group on Myelodysplastic Syndrome in Childhood.

PURPOSE: To evaluate the role of allogeneic bone marrow transplantation (BMT) in children with chronic myelomonocytic leukemia (CMML). PATIENTS AND METHODS: Forty-three children with CMML given BMT and reported to the European Working Group on Myelodysplastic Syndrome in Childhood (EWOG-MDS) data base were evaluated. In 25 cases, the donor was a human leukocyte antigen (HLA)-identical or a one-antigen-disparate relative, in four cases a mismatched family donor, and in 14 a matched unrelated donor (MUD). Conditioning regimens consisted of total-body irradiation (TBI) and chemotherapy in 22 patients, whereas busulfan (Bu) with other cytotoxic drugs was used in the remaining patients. RESULTS: Six of 43 patients (14%), five of whom received transplants from alternative donors, failed to engraft. There was a significant difference in the incidences of chronic graft-versus-host disease (GVHD) between children transplanted from compatible/one-antigen-mismatched relatives and from alternative donors (23% and 87%, respectively; P < .005). Probabilities of transplant-related mortality for children given BMT from HLA-identical/one-antigen-disparate relatives or from MUD/ mismatched relatives were 9% and 46%, respectively. The probability of relapse for the entire group was 58%, whereas the 5-year event-free survival (EFS) rate was 31%. The EFS rate for children given BMT from an HLA-identical sibling or one-antigen-disparate relative was 38%. In this latter group, patients who received Bu had a better EFS compared with those given TBI (62% v 11%, P < .01). CONCLUSION: Children with CMML and an HLA-compatible relative should be transplanted as early as possible. Improvement of donor selection, GVHD prophylaxis, and supportive care are needed to ameliorate results of BMT from alternative donors.

Bone Marrow Transplantation↗
PubMed1996

Direct and long-range action of a wingless morphogen gradient.

Wingless (Wg), a founding member of the Wingless/Int-1 (Wnt) family of secreted proteins, acts as a short-range inducer and as a long-range organizer during Drosophila development. Here, we determine the consequences of ectopically expressing (i) a wild-type form of Wg, (ii) a membrane-tethered form of Wg, and (iii) a constitutively active form of the cytosolic protein Armadillo (Arm), which normally acts to transduce Wg, and we compare them with the effects of removing endogenous Wg or Arm activity. Our results indicate that wild-type Wg acts at long range, up-regulating the transcription of particular target genes as a function of concentration and distance from secreting cells. In contrast, tethered Wg and Arm have only short-range or autonomous effects, respectively, on the transcription of these genes. We interpret these findings as evidence that Wg can act directly and at long range as a gradient morphogen during normal development.

Animals↗