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Biomedical subjects

F Locatelli

Publications and source records attributed to F Locatelli.

At least 55 records · Page 3Linked to original sources
PubMed2003

Impact of marrow unrelated donor search duration on outcome of children with acute lymphoblastic leukemia in second remission.

We analyzed the outcome of 167 consecutive children with second CR acute lymphoblastic leukemia (ALL), for whom an unrelated donor (UD) search was activated between 1989 and 1998 at a median time of 2 months after relapse. A suitable donor was identified for 70 patients at 1 year and 6.5 months before and after 1995 from search activation, respectively; a further leukemia relapse occurred during the search in 94 children at a median of 4 months after search activation, 36 of whom underwent UD (14) or other types of transplant (22), beyond second CR, while 58 died of progressive disease. Of 73 patients not experiencing a second relapse, 64 underwent UD (46) or other types of transplant (18), while nine proceeded with chemotherapy, and only four of them survived. The 3-year disease-free survival (DFS) from second CR for the 167 patients is 15.1%, whereas 3-year DFS after transplant for the 60 UD and 40 alternative donor transplanted children is 31.6 and 25.4%, respectively. In conclusion, a further relapse is the main factor adversely affecting outcome of children with second CR ALL. Thus, for these patients, the search should be activated early after relapse and either a UD or an alternative transplant should be performed as early as possible.

Adolescent↗
PubMed2003

Incidence and treatment of hemorrhagic cystitis in children given hematopoietic stem cell transplantation: a survey from the Italian association of pediatric hematology oncology-bone marrow transplantation group.

The purpose of this multicenter study was to assess the incidence and the treatment of hemorrhagic cystitis (HC) in 1218 pediatric patients, with a mean age of 10.8 years, who underwent hematopoietic stem cell transplantation (HSCT). In all, 44 patients (3.6%) developed HC a median 23 days after HSCT. The incidence of HC was higher in allogeneic than in autologous HSCT recipients (P=0.0001). Of the 44 patients, 37 (84%) recovered from HC in a median 30 days (range 3-100); the other seven children died while still suffering from HC. Hyperbaric oxygen therapy (HOT) achieved significantly better results than prostaglandin therapy (P=0.02) in the treatment of grade II-III HC. By multivariate analysis, age <96 months and allogeneic HSCT were significantly associated with the occurrence of HC: P=0.008 and 0.013, respectively. After a median follow-up of 5.75 years, the 5-year survival of patients who did or did not develop HC was: 43 vs 52%, P=0.03, respectively. This study indicates that age and type of HSCT are factors predisposing to HC in children given HSCT and demonstrates the promising role of HOT in a conservative approach to HC treatment.

Adolescent↗
PubMed2003

Neuronal differentiation of murine bone marrow Thy-1- and Sca-1-positive cells.

Recent evidence suggests that cells from bone marrow can acquire neuroectodermal phenotypes in cell culture or after transplantation in animal models and in the human brain. However, isolation of the bone marrow cell subpopulation with neuronal differentiation potential remains a challenge. To isolate and expand neural progenitors from whole murine bone marrow, bone marrow was obtained from hind limb bone of C57BL6 mice and plated in culture with neuronal medium with basic fibroblast growth factor and epidermal growth factor. After 5-7 days in culture, cellular spheres similar to brain neurospheres appeared either floating or attached to culture dishes. These spheres were collected, dissociated, and expanded. The bone marrow-derived spheres were positive for nestin as assessed by immunocytochemistry and by reverse transcriptase polymerase chain reaction. Thy-1- and Sca-1-positive bone marrow cells selected by magnetic cell sorting resulted in a higher yield of nestin-positive spheres. After exposure to neuronal differentiative medium retinoic acid with and without Sonic hedgehog, cells positive for neuronal markers tubulin III (TuJ-1) and neurofilament (NF) were detected. The mRNA profile of these cells included the expression of TuJ-1, neuronal-specific enolase (NSE), and NF-light chain. To evaluate the in vivo behavior of these cells, spheres derived from bone marrow-derived cells of transgenic green fluorescent protein (GFP) mice were transplanted into newborn mouse brain. Two months later, the mouse neural cortex contained a minor proportion of GFP(+) cells co-expressing neuronal markers (TuJ-1, NF, MAP-2, NeuN). Although cell fusion phenomena with the host cells could not be ruled out, bone marrow-derived neurosphere transplantation could be a strategy for cellular mediated gene therapy.

Animals↗
PubMed2003

Neuronal generation from somatic stem cells: current knowledge and perspectives on the treatment of acquired and degenerative central nervous system disorders.

Stem cell transplantation through cell replacement or as vector for gene delivery is a potential strategy for the treatment of neurodegenerative diseases. Several studies have reported the transdifferentiation of different somatic stem cells into neurons in vitro or after transplantation into animal models. This observation has pointed out the perspective of using an ethical and accessible cell source to "replace" damaged neurons or provide support to brain tissue. However, recent findings such as the cell fusion phenomenon have raised some doubts about the real existence of somatic stem cell plasticity. In this review, we will discuss current evidence and controversial issues about the neuroneogenesis from various sources of somatic cells focusing on the techniques of isolation, expansion in vitro as well as the inductive factors that lead to transdifferentiation in order to identify the factors peculiar to this process. The morphological, immunochemical, and physiological criteria to correctly judge whether the neuronal transdifferentation occurred are critically presented. We will also discuss the transplantation experiments that were done in view of a possible clinical therapeutic application. Animal models of stroke, spinal cord and brain trauma have improved with Mesenchymal Stem Cells or Bone Marrow transplantation. This improvement does not seem to depend on the replacement of the lost neurons but may be due to increased expression levels of neurotrophic factors, thus suggesting a beneficial effect of somatic cells regardless of transdifferentiation. Critical understanding of available data on the mechanisms governing the cell fate reprogramming is a necessary achievement toward an effective cell therapy.

Animals↗
PubMed2002

Neuroectodermal and microglial differentiation of bone marrow cells in the mouse spinal cord and sensory ganglia.

There is now evidence that bone marrow (BM) can generate cells expressing neuronal antigens in adult mouse brain. In the present study, we examined the spinal cord and dorsal root ganglia (DRG) of adult mice 3 months after BM cell transplantation from transgenic donor mice expressing the enhanced green fluorescent protein (GFP). To determine whether GFP(+) cells acquire neuroectodermal phenotypes, we tested, by immunocytochemistry followed by confocal analysis, the coexpression of the astrocytic marker glial fibrillary acidic protein (GFAP) and the neuronal markers NeuN, neurofilament (NF), and class III beta-tubulin (TuJ1). Rare GFP(+) cells coexpressing TuJ1, NF, and NeuN were found both in spinal cord and in sensory ganglia. These cells have small dimensions and short cytoplasmic processes, probably reflecting an immature phenotype. Double GFP and GFAP positivity was found only in spinal cord. To determine whether cell fusion with endogenous cells occurred, we investigated the nuclear content of cells coexpressing GFP and neuronal or astrocytic markers, demonstrating that these cells have only one nucleus and a DNA ploidy that it is not different from that of surrounding neurons and astrocytes. Large numbers of GFP(+) cells are also positively stained for F4/80, a microglial-recognizing antibody, and present a characteristic microglial-like morphology both in spinal cord and, with a higher frequency, in sensory ganglia. These data support a potential role for BM-derived stem cells in spinal cord neuroneogenesis. They also confirm that the microglial compartment within the CNS and in DRG undergoes a relatively fast turnover, with the contribution of hematopoietic stem cells. Both these findings might prove useful for the development of treatments for spinal cord neurodegenerative and acquired disorders.

Animals↗
PubMed2002

A subpopulation of murine bone marrow cells fully differentiates along the myogenic pathway and participates in muscle repair in the mdx dystrophic mouse.

Bone marrow (BM) transplantation in mice suggests the existence of pluripotent cells able to differentiate into skeletal muscle tissue, although sustained myofiber reconstitution has not yet been achieved. We investigated the myogenic potential of mouse BM cells and evaluated whether a BM fraction enriched for cells expressing skeletal muscle markers would ameliorate muscle repair, when compared to whole BM, into the dystrophic mdx mouse. We demonstrate that cells expressing striated-muscle-specific proteins are already present in the BM independently from experimentally forced myogenic conversion. We observed the presence of both markers of early myogenic program such as Pax3, Myf5, MyoD, desmin, and late myogenesis such as myosin heavy chain and alpha-sarcomeric actin. These myogenic cells are more represented in the early nonadherent BM fraction, which generates clones able to fully differentiate into myotubes. Transplantation in mdx mice by intravenous injection of whole BM and a tenfold BM myogenic enriched fraction resulted in BM reconstitution and limited dystrophin restoration. Taken together, these data show that a fraction of BM cells have a definite potential for differentiation along the skeletal muscle pathway and can be recruited by muscle repair mechanisms. They also indicate that factors limiting the degree of muscle recruitment and the host stem cell competition should be assessed in order to evaluate the usefulness of BM-derived myogenic cells into the context of cell-mediated gene therapy of inherited muscle diseases.

Animals↗
PubMed2002

Modulated generation of neuronal cells from bone marrow by expansion and mobilization of circulating stem cells with in vivo cytokine treatment.

The aim of the present study is to determine whether the expansion and mobilization of circulating bone marrow (BM) stem cells by in vivo treatment with granulocyte-colony stimulating factor (G-CSF) and stem cell factor (SCF) increase the amount of BM-derived neuronal cells in mouse brain. The presence of BM-derived cells in the brain was traced by transplanting into lethally irradiated adults and newborns adult BM from transgenic mice that ubiquitously expressed enhanced green fluorescent protein (GFP). GFP+ and Y-chromosome+ donor-derived cells were present in several brain areas of all treated mice (cortical and subcortical areas, cerebellum, olfactory bulb). The presence of GFP+ cells expressing nuclear neural specific antigen (NeuN), neurofilament, and beta-III tubulin in cortical forebrain and olfactory bulb (OB) was higher in G-CSF-SCF treated groups (P < 0.05, analysis of variance, Fisher post hoc). We observed that overall the amount of double positive cells was higher in animals treated at birth than in adults and in OB than in forebrain areas (P < 0.05). Temporal cortical areas of cytokine-treated adult animals revealed a mean threefold increase in the number of GFP+ cells expressing the nuclear neural specific antigen (211 +/- 86 GFP+NeuN+/mm(3) in G-CSF + SCF treated mice and 66 +/- 33 GFP+NeuN+/mm(3) in control animals). GFP+ cells coexpressing neuronal markers contain only one nucleus and have a DNA index (a measure of DNA ploidy) identical to that of surrounding neurons, thus excluding donor cell fusion with endogenous cells as a relevant phenomenon under these experimental conditions. Our results indicate that G-CSF and SCF administration modulates the availability of GFP+ cells in the brain and enhances their capacity to acquire neuronal characteristics. Cytokine stimulation of autologous stem cells might be seen as a new strategy for neuronal repair in neurodegenerative diseases.

Age Factors↗
PubMed2002

Transplant-related toxicity and mortality: an AIEOP prospective study in 636 pediatric patients transplanted for acute leukemia.

Hematopoietic stem cell transplantation can cure high-risk acute leukemia (AL), but the occurrence of non-leukemic death is still high. The AIEOP conducted a prospective study in order to assess incidence and relationships of early toxicity and transplant-related mortality (TRM) in a pediatric population. Between 1990 and 1997 toxicities reported in eight organs (central nervous system, heart, lungs, liver, gut, kidneys, bladder, mucosa) were classified into three grades (mild, moderate, severe) and prospectively registered for 636 consecutive children who underwent autologous (216) or allogeneic (420) transplantation, either from an HLA compatible related (294), or alternative (126) donor in 13 AIEOP transplant centers. Overall, 47% of the patients are alive in CR (3-year EFS: 45.2%, s.e.: 2.1), 19% died in CR at a median of 60 days (90-day TRM: 14.3%, s.e.: 1.4), 34% relapsed. Toxicity of any organ, but mucosa and gut, was positively correlated with early death; moderate and severe toxicity to heart, lungs, liver and kidneys significantly increased early TRM, with estimated relative risks of 9.1, 5.5, 2.7 and 2.8, respectively, as compared to absent or mild toxicity. Patients with grade III-IV aGVHD experienced more than double (56% vs. 19%) TRM than patients with grade 0-II aGVHD. A higher cumulative toxicity score, estimating the impact of toxicity on TRM, was significantly associated with transplantation from an alternative donor. Quantitative assessment allowed us to describe the extent to which 'grade' of toxicity and 'type' of involved organs were related to mortality and pre-transplant characteristics and yielded a prognostic score potentially useful to compare different conditioning regimens and predict probability of early death.

Adolescent↗
PubMed2002

Successful treatment of Griscelli syndrome with unrelated donor allogeneic hematopoietic stem cell transplantation.

Griscelli syndrome (GS) is a rare autosomal recessive disorder, characterized by pigmentary dilution of the skin and hair and in most patients by abnormal regulation of the immune system, which results in a syndrome of macrophage hyperactivation, known as hemophagocytic lymophohistiocytosis (HLH). Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment available for genetically induced HLH. Few cases of successful HSCT from a compatible donor have been reported in children with GS. We describe the first patient with GS cured with an allograft from a compatible unrelated bone marrow donor. We used a novel preparative regimen consisting of busulfan, thiotepa and fludarabine. The demonstrated curative effect of HSCT from an unrelated donor in a patient with genetically determined HLH also supports the use of a systematic diagnostic approach in these patients, in order to identify those with a worse prognosis and needing an urgent allograft in a timely manner.

Bone Marrow Transplantation↗
PubMed2002

Improvement over time in outcome for children with acute lymphoblastic leukemia in second remission given hematopoietic stem cell transplantation from unrelated donors.

Aims of this study were to verify whether reduction in transplant-related mortality (TRM) of children with acute lymphoblastic leukemia (ALL) in second complete remission (CR) given allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated volunteers has occurred over time and to investigate the role of other variables on the probabilities of relapse, TRM and event-free survival (EFS). We compared results obtained in 26 children given HSCT before January 1998 with those of 37 patients transplanted beyond that date. In all donor-recipient pairs, histocompatibility was determined by serology for HLA-A and -B antigens and by high-resolution DNA typing for DRB1 antigen. High-resolution molecular typing of HLA class I antigens was employed in 20 of the 37 children transplanted more recently. Probability of both acute and chronic GVHD was comparable in the two groups of patients. In multivariate analysis, children transplanted before January 1998, those with T-lineage ALL and those experiencing grade II-IV acute GVHD had a higher relative risk of TRM at 6 months after transplantation. Relapse rate was unfavorably affected by a time interval between diagnosis and relapse <30 months. The 2-year probability of EFS for children transplanted before and after 1 January 1998 was 27% (10-44) and 58% (42-75), respectively (P = 0.02), this difference remaining significant in multivariate analysis. EFS of unrelated donor HSCT in children with ALL in second CR has improved in the last few years, mainly due to a decreased TRM. This information is of value for counseling of patients with relapsed ALL.

Adolescent↗
PubMed2002

A rationale for an individualized administration frequency of epoetin beta: a pharmacological perspective.

Several studies have compared the efficacy of once-weekly subcutaneous (s.c.) epoetin treatment with two or three times weekly treatment in renal anaemia. Epoetin administration frequency has attracted a high level of attention in recent years, and numerous small-scale studies have shown comparable efficacy and tolerability of once-weekly vs more frequent administration. The results of two large-scale, randomized, controlled trials of once-weekly administration of epoetin beta became available recently. One of these studies, by Locatelli et al., was the first to be designed specifically to demonstrate therapeutic equivalence between once-weekly and three times weekly epoetin beta treatment, using rigorous statistical methods. This was a large, multicentre, randomized, parallel group, 24-week study in 173 chronic renal failure patients. Treatment regimens were considered equivalent if: (i) the 90% confidence interval (CI) of the difference between treatment groups was within +/-2% for the time-adjusted area under the haematocrit (Hct) curve (AUC); and (ii) for mean weekly epoetin beta dose, the 90% CI of the ratio of the groups was between 0.8 and 1.25. As recommended by current guidelines for statistical analysis of clinical trial data, multiple analysis populations were examined in order to demonstrate robustness of the results with regard to the population chosen for analysis. Findings from the primary analysis, the per-protocol population, were confirmed by both the intent-to-treat analysis and an exploratory analysis that examined the influence of five patients who received dose increases above the mean. In all three analyses, the 90% CIs were within the pre-specified equivalence ranges for both the difference between treatment groups for Hct AUC and the ratio of mean weekly epoetin beta dose. In conclusion, once-weekly and three times weekly s.c. epoetin beta treatment regimens are statistically equivalent in terms of maintaining stable Hct levels and dose requirements in haemodialysis patients. The agreement of the three analysis populations provides a convincing demonstration of the robustness of the results. These results confirm that a once-weekly epoetin beta regimen is an effective option for management of renal anaemia that may improve patient convenience and compliance.

Drug Administration Schedule↗
PubMed2002

Unrelated bone marrow transplantation in thalassemia. The experience of the Italian Bone Marrow Transplant Group (GITMO).

BACKGROUND AND OBJECTIVES: Allogeneic bone marrow transplantation (BMT) is a widely accepted therapeutic approach in homozygous beta-thalassemia. However, the majority of patients do not have a genotypically identical donor within the family. This prompted us to conduct a pilot study to investigate the feasibility of matched unrelated bone marrow transplantation in thalassemia. The major drawback was the high risk of immunologic and transplant-related complications, mainly graft-versus-host disease (GvHD) and graft failure. DESIGN AND METHODS: Our aim was to reduce this risk through careful selection of donor/recipient pairs. HLA haplotypes that show a high linkage disequilibrium among their class I, class II and class III alleles are considered extended or ancestral haplotypes. RESULTS: These haplotypes are conserved and can be shared by apparently unrelated individuals. Our study shows that matching for these haplotypes significantly improves the outcome of unrelated bone marrow transplantation in thalassemia. In fact, results were comparable to those obtained in transplants using HLA-identifical family donors. INTERPRETATION AND CONCLUSIONS: Better results were obtained in patients with lesser iron overload and when the donor shared an identity for the DPB1 alleles.

Adolescent↗
PubMed2001

Ex vivo priming for long-term maintenance of antileukemia human cytotoxic T cells suggests a general procedure for adoptive immunotherapy.

Adoptive cellular immunotherapy has proven to be a successful approach in preventing and curing cytomegalovirus infection and Epstein-Barr virus-associated lymphomas after bone marrow transplantation. Translation of this approach for preventing leukemia relapse after bone marrow transplantation might require ex vivo priming and long-term maintenance of leukemia blast-specific T cells. To accomplish this goal, procedures were optimized for the in vitro priming of naive CD8 using dendritic cells activated by CD40 ligation, interleukin-12 (IL-12), and IL-7. Using T lymphocytes and dendritic cells obtained from HLA-matched allogeneic bone marrow transplantation donors and leukemia blasts as a source of tumor antigens, anti-acute myeloid leukemia cytotoxic T lymphocytes (CTLs) were induced. In these experiments, it was found that though it is possible to induce CTLs using immature dendritic cells, IL-12, and IL-7, obtaining long-term CTLs requires the presence of CD4 T cells in the priming phase. Using this approach, long-term antileukemia CTL lines could be generated from 4 of 4 bone marrow donors. Because this procedure does not require definition of the target antigen and because it selects responding cells from a virgin T-cell repertoire, its general application is suggested in adoptive immunotherapy and in the definition of tumor rejection antigens.

Bone Marrow Transplantation↗
PubMed2001

Second allogeneic bone marrow transplantation in acute leukemia: results of a survey by the European Cooperative Group for Blood and Marrow Transplantation.

PURPOSE: Leukemic relapse is the most frequent cause of treatment failure after allogeneic hematopoietic stem-cell transplantation (HSCT). To identify prognostic factors affecting the outcome of second HSCT, we performed a retrospective study on patients with acute leukemia (AL) undergoing second HSCT who reported to the Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation registry. PATIENTS AND METHODS: One hundred seventy patients who received second HSCTs for AL experienced relapse after first HSCTs were performed from 1978 to 1997. Status at second HSCT, time between first and second HSCT, conditioning regimen, source of stem cells, treatment-related mortality (TRM), acute graft-versus-host disease (aGVHD), leukemia-free survival (LFS), overall survival (OS), and relapse were considered. RESULTS: Engraftment occurred in 97% of patients. Forty-two patients were alive at last follow-up, with a 5-year OS rate of 26%. The 5-year probability for TRM, LFS, and relapse was 46%, 25%, and 59%, respectively. Grade > or = 2 aGVHD occurred in 59% of patients, and chronic GVHD occurred in 32%. In multivariate analysis, diagnosis, interval to relapse after first HSCT > 292 days, aGVHD at first HSCT, complete remission status at second HSCT, use of total-body irradiation at second HSCT, acute GVHD at second HSCT, and use of bone marrow as source of stem cells at second HSCT were associated with better outcome. CONCLUSION: Second HSCT represents an effective therapeutic option for AL patients relapsed after allogeneic HSCT, with a 3-year LFS rate of 52% for the subset of patients who experienced relapse more than 292 days after receiving the first HSCT and who were in remission before receiving the second HSCT.

Adolescent↗