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A Pagliuca

Publications and source records attributed to A Pagliuca.

At least 55 records · Page 3Linked to original sources
PubMed1998

Adult T-cell leukemia/lymphoma in London: clinical experience of 21 cases.

Adult T-cell leukemia/lymphoma (ATLL) is uncommon in the United Kingdom and has so far been restricted to people of Afro-Caribbean extraction. Between 1981 and 1995, 21 cases presented to 2 inner London teaching hospitals where 17% of the population are of Afro-Caribbean origin. Clinical presentations were similar to those of the disease in HTLV-I-endemic areas. Major responses (CR + PR) were obtained in 10/16 assessable patients (63%) treated with combination chemotherapy. However, median survival was only 5.5 months. Disease progression and opportunistic infection were the major causes of treatment failure and death. Three patients (14%) relapsed in the central nervous system (CNS). Our cases confirm the profound immunosuppression in ATLL. The poor prognosis of acute and lymphoma types of ATLL highlight the need for new approaches to treatment such as zidovudine and alpha-interferon, incorporating prophylaxis against CNS disease and opportunistic infections.

Adult↗
PubMed1997

The clinical diversity and role of chemotherapy in lymphoproliferative disorder in liver transplant recipients.

BACKGROUND/AIMS: Post-transplant lymphoproliferative disorder is a well-documented complication with an incidence ranging from 2 to 10%, depending on the organ transplanted. Yet despite our increased understanding of the pathophysiology of this disease and the various treatments available, the mortality remains high at 60-80%. We present the clinical and histological features of ten adult liver transplant recipients with post-transplant lymphoproliferative disorder presenting over a 15-year period and review the therapeutic options. METHODS: CD20/CD45RO immunostaining was used for T/B-cell markers; polymerase chain reaction and in-situ hybridisation for Epstein-Barr virus genome detection; kappa/lambda immunostaining and gene rearrangement analysis for clonality. RESULTS: There were six females and four males (age range 24-56) with onset of post-transplant lymphoproliferative disorder-symptoms ranging from 3 to 72 months post transplant. Sites of post-transplant lymphoproliferative disorder included liver (n=4), lymph nodes (n=5), bone marrow (n=2), lungs (n=2), kidneys (n=2), brain, ovaries,: and pancreas (n=1). All lesions were classified as high-grade lymphoma, of B-cell lineage (9 tested); Epstein-Barr virus genome was detected in 7/10 cases. Three tumours were monoclonal; four were polyclonal and three undetermined. Treatment included immunosuppression reduction, antiviral therapy with acyclovir and/or chemotherapy (CHOP or VAPEC-B). Survival times for those patients not treated with chemotherapy were from 9 days to 30 months, whereas those receiving chemotherapy had remission times of 4 to 48 months. CONCLUSIONS: Longer-term remissions can be achieved in patients treated with systemic chemotherapy, although not without morbidity. Clonality assessment is important but treatment decisions should be based primarily on clinical features of progression, as polyclonal tumours can behave as aggressively as monoclonal tumours.

Adult↗
PubMed1997

Allogeneic peripheral blood stem cell transplantation for haematological malignancies--an analysis of kinetics of engraftment and GVHD risk.

We have carried out an analysis of 44 patients undergoing allogeneic PBSC transplants from fully HLA-matched related donors with particular emphasis on engraftment kinetics and the incidence and severity of GVHD. The recipients had a median age of 37 years (range 5-56 years), 16 patients had standard-risk disease and 28 had poor-risk disease. GVHD prophylaxis was with cyclosporin A and methotrexate (n = 41), cyclosporin A alone (n = 2) or cyclosporin A and methyl-prednisolone (n = 1). Stem cells were mobilised using G-CSF, collecting a median of 5.75 x 10(6) CD34+ cells/kg recipient weight (range 0.94-35 x 10(6) CD34+ cells/kg). Engraftment times to a neutrophil count > 0.5 x 10(9)/1 and platelets > 20 x 10(9)/1 were achieved at a median of day +14 (range 10-25) and day +14 (range 9-130) respectively. Patients receiving > or = 4 x 10(6) CD34+ cells/kg had significantly accelerated neutrophil and platelet engraftment and this number of CD34+ cells would appear to be a prerequisite for maximum engraftment using PBSC. Acute GVHD occurred in 25 of 43 evaluable patients although in only 12 was this clinically significant (grades II-IV). Chronic GVHD has occurred in 17 out of 36 evaluable patients, there was no significant difference between the standard- and poor-risk groups in incidence of either acute or chronic GVHD. In conclusion, these results confirm the feasibility of using PBSC for allogeneic transplantation without evidence for increased risk of either acute or chronic GVHD and provide further evidence supporting the potential of PBSC to replace bone marrow as the major source of haemopoietic cells for allogeneic transplantation.

Adolescent↗
PubMed1997

Idiopathic hyperammonaemia syndrome following allogeneic peripheral blood progenitor cell transplantation (allo-PBPCT).

An idiopathic hyperammonaemia syndrome has been reported in, and following chemotherapy for, various haematological malignancies as well as following bone marrow transplantation. It should be considered in the differential diagnosis of any neurological deterioration, and we describe a further case associated with an allogeneic peripheral blood progenitor cell transplant (allo-PBPCT).

Adult↗
PubMed1997

Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia.

Nineteen patients with high-risk myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) received fludarabine, cytarabine, granulocyte-colony stimulating factor (G-CSF), and idarubicin chemotherapy (de novo MDS/MDS-AML, nine; relapsed/refractory MDS/AML, seven; therapy-related MDS, three). Median age was 44 years and median disease duration 10 months. 16/19 (84%) patients had abnormal cytogenetics with seven (37%) harbouring abnormalities of chromosome 7. 18/19 (94.7%) patients responded to FLAG-idarubicin with 12 (63%) achieving complete remission (CR) (< 5% blasts and normal cytogenetics). 7/9 (78%) patients with de novo MDS/MDS-AML achieved CR compared to 5/10 (50%) with alternative diagnoses. Response was associated with age < 50 years, disease duration < 3 months, and cytogenetics other than abnormalities of chromosome 7. Haemopoietic regeneration was rapid in most patients and there were no toxic deaths. Nine patients received a second course of chemotherapy, three have proceeded to allogeneic bone marrow transplant and three to autologous blood stem cell/bone marrow transplantation. Follow-up is short (median 10 months). 12/19 (63%) patients remain alive and 5/12 (42%) have relapsed at a median 5 months following CR achievement. FLAG-idarubicin was well tolerated. High rates of morphological and cytogenetic remission, especially in de novo MDS, offer a window of opportunity for assessment of autologous BMT in this group of diseases where no treatment except alloBMT has led to prolongation of survival.

Acute Disease↗
PubMed1996

Acquired sideroblastic anaemia induced by a copper-chelating agent.

Acquired sideroblastic anaemia may be related to drugs and other chemicals that inhibit the activity of mitochondrial enzymes involved in haem synthesis. We report a case of secondary acquired sideroblastic anaemia following administration of triethylene tetramine dihydrochloride (trientine), a second-line copper-chelating agent used in the treatment of Wilson's disease. The anaemia improved after dose reduction of trientine. The mechanism of induction of sideroblastic anaemia in this case is unclear, but trientine does not appear to alter the function of two key mitochondrial haem enzymes, and may instead act directly on mitochondrial iron metabolism.

Adolescent↗
PubMed1996

Myelosuppressive chemotherapy to mobilize normal stem cells in chronic myeloid leukemia.

Ten patients with Ph+ chronic myeloid leukemia (CML) were treated with idarubicin, cytarabine and etoposide followed by G-CSF to harvest Ph-negative progenitor cells. Six were in first chronic phase (CP1), and four beyond CP1. Between two and six aphereses (median 3, total 36) were performed starting 9-26 days (median 14.5) after chemotherapy when the leukocyte count was 0.6-4.7 x 10(9)/l (median 1.2). 1.3-3.6 x 10(8) mononuclear cells/kg (median 2.8), 0-128.4 x 10(4) CFU-GM/kg (median 1.2; seven patients) and 0.3-25.1 x 10(6) CD34+ cells/kg (median 9.8; seven patients) were collected. Seven of 27 harvests showing metaphases were 100% Ph-negative, 11 partially Ph-negative, and nine were 100% Ph+. All three patients with 100% Ph-negative collections were in CP1 and within 4-26 months of diagnosis. Four of six CP1 patients showed significant cytogenetic response compared with none of four beyond CP1 (P = 0.036). The absolute neutrophil count remained < 0.5 x 10(9)/l for 9-44 days (median 15.5) following chemotherapy. Four patients (three Ph-negative) were autografted after 16 mg/kg busulfan (n = 2) or 200 mg/m2 melphalan (n = 2). One of the three patients receiving Ph-negative cells died of graft failure, and two are alive with 15% and 50% Ph-negative cells at 15 and 11 months on interferon-alpha. We conclude that it is possible to harvest Ph-negative cells after myelosuppressive chemotherapy in some CML patients treated early in the course of CP1. However, in view of lack of consistent response, investigation of alternative approaches is necessary.

Adolescent↗
PubMed1995

Molecular cloning of ID4, a novel dominant negative helix-loop-helix human gene on chromosome 6p21.3-p22.

Transcription factors containing a basic helix-loop-helix (bHLH) motif regulate the expression of tissue-specific genes in a number of mammalian and insect systems. DNA-binding activity of the bHLH proteins is dependent upon formation of homo- and/or heterodimers. Dominant negative HLH proteins (Id-related genes) also contain the HLH-dimerization domain but lack the DNA-binding basic domain. Consequently, Id proteins inhibit binding to DNA and transcriptional transactivation by heterodimerization with bHLH proteins. We report here the cDNA sequence of a novel human HLH gene (HGMW-approved symbol ID4) that lacks the basic domain. ID4 is differentially expressed in adult organs in four mRNA molecules, which are presumably a result of differential splicing and/or alternative usage of the polyadenylation sites. Transfection experiments indicated that enforced expression of Id-4H protein inhibits the trans-activation of the muscle creatine kinase E-box enhancer by MyoD. Finally, we localized the ID4 gene to the chromosome 6p21-p22 region.

Amino Acid Sequence↗
PubMed1995

Positional cloning of cDNAs from the human chromosome 3p21-22 region identifies a clustered organization of zinc-finger genes.

The human 3p21-22 region is frequently involved in karyotype rearrangements associated with malignancies. The high frequency of allelic loss in this region has been associated with virtually all small cell lung carcinomas and many renal carcinomas. These findings suggest that at least one tumor-suppressor gene might be located in 3p21-22. We have recently reported the isolation of a 750-kb yeast artificial chromosome (YAC) contig from 3p21-22. Here, we describe three new genes isolated from the 3p YAC contig by using a cDNA hybridization selection. Remarkably, the three new genes encode zinc-finger proteins, indicating the presence of a cluster of zinc-finger genes in human chromosome 3p21.

Adult↗
PubMed1994

Repression of transcriptional activity at a distance by the evolutionarily conserved KRAB domain present in a subfamily of zinc finger proteins.

Sub-families of related zinc finger protein genes have been defined on the basis of evolutionarily conserved structural features found outside the C2-H2 finger repeats. Such elements include the FAX domain found in a large number of Xenopus ZFPs, the evolutionarily conserved KRAB (Krüppel-associated box) and the ZiN (zinc finger N-terminal) domains. Here we describe a new evolutionarily conserved motif within zinc finger proteins which we have named the leucine rich region (LeR). Since conserved modules in regulatory proteins may specify properties relevant to their action we have determined the functional capabilities of LeR and the KRAB domains in the regulation of gene transcription by fusing relevant regions to a heterologous DNA-binding domain (GAL4 DNA-binding domain). We found that the KRAB-A domain tethered to RNA polymerase II promoters by a GAL4 DNA-binding domain actively represses transcription in a distance-independent manner. KRAB-mediated repression is dependent on the dose of the GAL4-KRAB-A fusion protein and on the presence of GAL4 binding sites on the DNA. Conversely, the LeR domain did not modulate significantly the transcription. Our results indicate that the KRAB domain present in the non-finger region of many ZFP genes quenches transcription possibly due to specific protein-protein interactions between the KRAB-A domain and components of the proximal transcriptional apparatus.

Amino Acid Sequence↗
PubMed1994

Autologous blood stem cell transplantation in hematological malignancies.

Autologous blood stem cell transplants (ABSCT) are increasingly used for the treatment of haematological malignancies. The use of hemopoietic growth factors, in conjunction with stem cell mobilization by chemotherapeutic agents, has permitted successful harvests requiring only a few leukaphereses; cells mobilized in this manner contain a relatively large number of committed precursors of all lineages, as well as early progenitor cells capable of maintaining long-term haemopoiesis. Haematological recovery after ABSCT is rapid, thereby significantly shortening the period of post-chemotherapy neutropenia and thrombocytopenia. Furthermore, blood-derived grafts may contain fewer malignant cells than the bone marrow cells. The preliminary results have been so encouraging that it is envisaged that in myeloma, Hodgkin's disease and non-Hodgkin lymphomas, ABSCT may eventually replace autologous marrow transplantation.

Blood Component Transfusion↗
PubMed1992

Primary myelodysplastic syndrome in children: the clinical experience in 33 cases.

We describe the clinicomorphological features in 33 cases of primary myelodysplastic syndrome classified according to the FAB classification which presented to a single centre over a 12 year period. Presenting features were typically related to pancytopenia although hepatosplenomegaly and granulocytic sarcomas were far more prevalent than in the adult population. Morphological assessment of the peripheral blood and the bone marrow showed seven patients had refractory anaemia (RA), 13 patients had RA with excess of blasts (RAEB), nine patients had RAEB in transformation (RAEB-t) and four patients had chronic myelomonocytic leukaemia (CMML). The overall mean survival was short (9.9 months) in all the subgroups and the leukaemic transformation rate was high. None of the patients scored 0-1 according to the Bournemouth Scoring System; four patients scored 2 whereas 29 patients scored 3 to 4. We conclude that unlike adults, the myelodysplastic syndromes in children run an aggressive clinical course, irrespective of the FAB subtype, and the pathogenesis of these diseases in paediatric practice warrants scientific scrutiny. Intensive chemotherapy such as the one used in de novo-AML lead to complete remission in some children and these early results suggest that this should be the treatment of choice in paediatric MDS.

Adolescent↗