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Biomedical subjects

A Butturini

Publications and source records attributed to A Butturini.

At least 37 records · Page 2Linked to original sources
PubMed1992

Transplants in AML.

Three therapies are widely-used to treat acute myelogenous leukemia (AML): allogenic bone marrow transplants, autotransplants and chemotherapy. Which of these therapies is best is controversial. Analyzing and comparing results of these therapies is complex and controversial. Comparisons of published data are flawed by biased reporting and subject selection. Randomized trials are also reported but are limited by small numbers of subjects and the question of whether their conclusions apply to most persons with AML. Hypotheses being tested in randomized trials are often misunderstood or relevant to only a subset of persons with AML. Furthermore, in many trials a substantial proportion of subjects do not receive the intended treatment. Observational data bases are also used to compare results of different AML therapies. Although this is probably the most effective analytic approach, substantial differences in outcome-related variable between treatment groups make complex statistical adjustment necessary. Validity of these adjustments is controversial. Limitations of these diverse approaches to comparing results of different therapies of AML suggests that a precise answer to the question of how best to treat AML is unlikely to be forthcoming. This uncertainty is further confounded by the considerable subjectivity that influences how physicians choose between alternative therapies. The net result of these considerations is a consensus approach to treating AML is unlikely to develop, probably because results of diverse treatments are not very different.

Antineoplastic Agents↗
PubMed1992

What determines who develops graft-versus-host disease: the graft or the host (or both)?

Considerable experimental data suggest that most, if not all, recipients of conventional (non-T cell-depleted) HLA-identical sibling transplants are likely to develop graft-versus-host disease (GVHD). This is because all donor-recipient pairs are likely to be disparate for numerous non-HLA antigens and because these grafts contain substantial numbers of donor T cells. However, about one-third to one-half of recipients of this type of transplant have little or no GVHD. Here we review recent data in humans suggesting that others factors, like the ability of the host to modulate GVHD reactivity of immune competent cells in the graft, may explain lack of GVHD in some persons. This concept may have implications for preventing and treating GVHD in humans.

Animals↗
PubMed1992

Leukemia: stem cells, preleukemia and cure.

Several new or evolving concepts of leukemia biology and treatment are considered including: most leukèmias result from transformation of a stem cell, their phenotype reflecting the site of clonal expansion rather than transformation; most leukemias are preceded by one or more preleukemia phases; and cure may be possible by re-establishing preleukemia or forcing maturation of leukemia cells.

Cell Transformation, Neoplastic↗
PubMed1992

Controversies in therapy of acute lymphoblastic leukemia.

There are several important controversial in therapy of acute lymphoblastic leukemia including: 1. What is the best initial chemotherapy; 2. Is maintenance chemotherapy effective; 3. How is cure achieved; 4. Are assays of residual leukemia cells useful; 5. Why are some persons currently incurable; 6. What is the best treatment strategy in children; 7. What is the best treatment strategy in adults; and 8. What are new approaches to cure the incurable. Here, we consider these issues. Our conclusion is that more intensive treatment is more effective but that no specific regimen is superior. Further dose escalations are unlikely to increase cures substantially. Maintenance chemotherapy is effective; it may work by controlling the ALL clone so that normal mechanisms regulating B-cell survival operate. Cure of ALL is probably achieved by diverse mechanisms including leukemia eradication in children and leukemia control in adults. Assays of minimal residual leukemia are possible but should not yet be used to direct therapy. There are several reasons why some persons are incurable including treatment resistance and a stem cell origin of leukemia. In most children and adults, chemotherapy is the best strategy followed by allogeneic transplants in those who relapse. Autotransplants are of minimal efficacy. Finally we consider new therapy approaches including immune therapy and regulation of leukemia-related genes.

Adult↗
PubMed1992

[Hemosiderosis in thalassemia major. Quantitative study with magnetic resonance (MR)].

Hemosiderosis, which results from transfusional therapy and from increased absorption of dietary iron, is a severe complication of thalassemia major. The complication is also very difficult to manage. An accurate determination of the total amount and of the distribution of body iron stores is essential for prognostic purposes and to evaluate the efficacy of chelation therapy. Therefore, a suitable tool for the noninvasive depiction of iron overload is to be hoped for. MR imaging has been usefully employed, of late, to this purpose. Sixteen thalassemic patients have been studied to evaluate iron depositions using a 1.5 T magnet. Signal intensities from liver, pancreas, spleen, bone marrow, and heart were considered. The signals were dramatically lower than the normal values obtained in a sex- and age-matched group; the differences were due to the iron. Iron distribution appeared inhomogeneous, with the highest overload in liver and bone marrow. Since cardiomyopathy represents the first cause of death in thalassemic patients, the relationship between cardiac function and iron overload in the heart has been thoroughly investigated. Finally, the authors conclude that MR will become a widely employed method for assessing iron overload and will contribute to improve the management of thalassemia major.

Adolescent↗
PubMed1991

Maintenance chemotherapy and cure of childhood acute lymphoblastic leukaemia.

Maintenance chemotherapy with 6-mercaptopurine and methotrexate, widely believed an essential contribution to the high cure rates achieved in children with acute lymphoblastic leukaemia (ALL), is thought to work by killing the leukaemia cells that remain after intensive chemotherapy. We suggest instead that ALL commonly arises in precursor B cells normally programmed to die, and that maintenance chemotherapy does not kill these cells but controls growth of the leukaemia clone so that programmed death can occur. A similar approach may apply to other cancers in which programmed death is intrinsic to the normal counterparts of the neoplastic cells.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

BCR-ABL rearrangements in children with Philadelphia chromosome-positive chronic myelogenous leukemia.

Leukemia cells from adults with Philadelphia (Ph1)-chromosome positive chronic myelogenous leukemia (CML) have a characteristic molecular rearrangement between the BCR and ABL genes whereby major breakpoint cluster region (Mbcr) exons 2 or 3 are joined to ABL exon II. Ph1-chromosome positive CML is uncommon in children and it is unknown whether these children have similar rearrangements. We studied 17 children with Ph1-chromosome positive CML. Five were studied for Mbcr rearrangement using Southern blotting, nine for the presence of chimeric BCR-ABL mRNA using reverse transcription and polymerase chain reaction, and three for both. All eight children studied by Southern blotting had BCR rearrangement. Of 12 children in whom BCR-ABL mRNA was studied, 10 had Mbcr exon 2 joined to ABL exon II, one had Mbcr exon 3 joined to ABL II, and one had both Mbcr-ABL junctions. These data indicate a similarity to adult CML. However, mRNA processing in children may preferentially splice Mbcr exon 2 to ABL exon II. No child had BCR exon 1 joined to ABL exon II, the rearrangement typical of childhood Ph1-chromosome positive acute lymphoblastic leukemia.

Adolescent↗
PubMed1991

Therapy of advanced acute myeloblastic leukemia with cytarabine and interleukin 2.

A child with acute myelogenous leukemia who relapsed three months after an allogeneic bone marrow transplant received intermediate-dose cytarabine followed by interleukin 2 (IL-2). Complete remission was achieved after the first cycle of IL-2. Five more combined cycles of cytarabine and IL-2 were given over the next year, during which remission has persisted. IL-2 therapy affected serum tumor necrosis factor (TNF), interferon gamma (IFN gamma) and soluble IL-2 receptor (sIL-2r) levels. In vitro cytotoxicity against leukemia cell lines and recipient leukemia cells was also increased.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Relationship between clonality and transformation in acute leukemia.

In some cases of acute leukemia an initial potentially leukemogenic genetic alteration can result in clonally derived end-cells normal in appearance and numbers. We refer to this clonal expansion as preleukemia. Subsequent alterations, intrinsic or extrinsic, often referred to as transformation, result in abnormal differentiation and/or growth regulation; we refer to this as leukemia. Several issues are unresolved. Where in the hierarchy of hematopoiesis clonal expansion and transformation occur is unknown. It is quite likely that clonal expansion occurs in cells with considerable self-renewal potential--probably stem or progenitor cells. The precise site may vary in different cases and account for the diverse phenotypes of acute leukemia. How the preleukemia clone comes to dominate hematopoiesis and the fate of the residual normal stem cells and their progeny are also unknown. Likewise, there is controversy whether different models of leukemogenesis operate in different subjects. For example, are older persons or those with occupational exposure to potentially leukomogenic agents more likely to exhibit one pattern of leukomogenesis? Finally, it is unknown whether these diverse models of leukemogenesis respond differently to therapy.

Acute Disease↗
PubMed1991

Autotransplants in leukemia: current state, future progress.

Autotransplants in leukemia are controversial; their rationale and results have been questioned. Here we consider several issues central to this debate: (1) Are there convincing data to suggest that more intensive therapy increases cures? (2) Are results post-autotransplant a consequence of the transplant, or do they reflect subject-selection and time-to-treatment (time censoring) biases? (3) Does leukemia relapse after an autotransplant develop from persisting leukemia cells in the subject or the graft? (4) Do autotransplants using hematopoietic stem cells from different sources have distinct outcomes? (5) Are immune-mediated anti-leukemia mechanisms likely to prevent relapse after autotransplants? and (6) Can comparably intensive therapy be given without an autotransplant?

Bone Marrow Transplantation↗
PubMed1991

Autotransplants in acute leukaemia.

The data we review indicate that in adults with ALL in first remission intensive chemotherapy and radiation given before a transplant is more effective in eradicating leukaemia than current chemotherapy. This is not so in adults with AML in first remission where more intensive therapy does not reduce the likelihood of relapse. Furthermore, leukaemia relapse because of re-infused leukaemia cells is an important issue in autotransplants for ALL. Whether re-infusing leukaemia cells would be important in AML were more effective pretransplant therapy developed is unknown. Presently, there appears to be little sense to test in vitro approaches to remove leukaemia cells in autotransplants for AML because efficacy cannot be evaluated. (A randomized trial is an exception but would not be expected to show a difference.) Another conclusion is that attempts to induce GVHD in autotransplant recipients, such as by using cyclosporine post-transplant (Jones et al, 1989), are more likely to succeed in AML than ALL since the impact of GVHD is substantially greater (Horowitz et al, 1990). However, the GVHD-related antileukaemia effect in AML is associated with chronic GVHD whereas cyclosporine treatment of autotransplant recipients results in acute GVHD. Also, attempts to separate clinical and antileukaemia effects of GVHD were unsuccessful (Sullivan et al, 1989). Another caution is that in AML we detected an immune antileukaemia effect distinct from GVHD (termed GVL) only after HLA-identical sibling transplants. Since GVL was absent in twins it is unlikely to operate after autotransplants. In summary, there is sense in studying autotransplants in adults with acute leukaemia in first remission. However, there are currently no convincing data that autotransplants are superior to current therapy. More intensive treatment seems effective in ALL; the focus should be on increasing the antileukaemia efficacy of pretransplant therapy and on attempts to remove leukaemia cells from the graft. In AML, there is no evidence that more intensive therapy is more effective. This problem needs resolution before evaluating attempts to remove leukaemia cells from the graft. The best place to test new pretransplant regimens is in twins and recipients of HLA-identical sibling transplants without GVHD. The data and ideas we review and discuss should be useful in planning clinical trials.

Bone Marrow Transplantation↗