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Biomedical subjects

R P Gale

Publications and source records attributed to R P Gale.

At least 19 recordsLinked to original sources
PubMed1992

Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy.

About 30% of adults with acute lymphoblastic leukemia (ALL) and 20% to 40% of children and adults with acute myelogenous leukemia (AML) never achieve remission, even with intensive chemotherapy. Most die of resistant leukemia, often within 6 months or less. In this study of 126 patients with resistant ALL or AML, allogeneic bone marrow transplants from HLA-identical siblings produced remissions in 113 of 115 (98%) evaluable patients. The 3-year probability of leukemia-free survival was 21% (95% confidence interval, 15% to 29%). Leukemia-free survival was similar in ALL (23%, 12% to 40%) and AML (21%, 14% to 31%). Only 3 of 27 patients at risk relapsed more than 2 years posttransplant.

Adolescent↗
PubMed1992

Changing trends in allogeneic bone marrow transplantation for leukemia in the 1980s.

OBJECTIVE: To identify changes in practice and outcome of bone marrow transplants for leukemia in the 1980s. DESIGN: Comparison of key explanatory and outcome variables in five 2-year cohorts, from 1980 through 1981 to 1988 through 1989, using a large database of detailed clinical information. PATIENTS: Recipients (7788) of bone marrow transplants for acute lymphoblastic, acute myelogenous, or chronic myelogenous leukemia reported to the International Bone Marrow Transplant Registry, Milwaukee, Wis, by 185 transplant teams worldwide. RESULTS: Linear increases occurred during the periods 1980 through 1981 to 1988 through 1989 as follows with 95% confidence intervals: (1) transplants for chronic myelogenous leukemia from 14% +/- 2% to 35% +/- 2%; (2) transplants from unrelated donors from 1% +/- 1% to 7% +/- 1%; (3) preparative regimens without radiation from 3% +/- 1% to 30% +/- 2%; and (4) use of methotrexate plus cyclosporine to prevent graft-vs-host disease from 2% +/- 1% to 55% +/- 2%. Among recipients of human lymphocyte antigen-identical sibling bone marrow, the 2-year probability of treatment-related mortality decreased by 6% to 22%. The probability of relapse decreased from 46% +/- 6% to 38% +/- 6% in intermediate leukemia but did not change appreciably in early or advanced leukemia. Probabilities of leukemia-free survival improved from 51% +/- 4% to 57% +/- 3% in early leukemia, from 28% +/- 4% to 36% +/- 5% in intermediate leukemia, and from 12% +/- 4% to 18% +/- 5% in advanced leukemia. A separate analysis of a homogenous population of patients indicated that improvements in outcome in the 1980s were due to improvements in transplant practice rather than improved patient selection. CONCLUSIONS: Modest increases in leukemia-free survival rates occurred after human lymphocyte antigen-identical sibling bone marrow transplants in the 1980s. Improvements were due primarily to reductions in treatment-related mortality with little or no change in relapse risk. More effective antileukemia strategies and continued reductions in treatment-related toxic effects are needed.

Adult↗
PubMed1992

Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia.

Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) has a poor prognosis when treated with conventional chemotherapy. We analyzed the outcome of 67 HLA-identical sibling bone marrow transplants (BMTs) for Ph1-positive ALL reported to the International Bone Marrow Transplant Registry (IBMTR). Twenty-one of 67 (31%) transplant recipients survived in continuous complete remission more than 2 years after transplant. Two-year actuarial probabilities (95% confidence interval) of leukemia-free survival were 38% (23% to 55%) for 33 patients transplanted in first remission, 41% (23% to 61%) for 22 patients transplanted after relapse, and 25% (9% to 53%) for 12 patients failing to achieve remission with conventional chemotherapy. These data indicate that transplants are effective treatment for Ph1-positive ALL.

Adolescent↗
PubMed1992

Should HLA-identical sibling bone marrow transplants for leukemia be restricted to large centers?

There is substantial evidence that the volume of medical procedures in a hospital has an inverse relationship with mortality. We analyzed data for 1313 recipients of HLA-identical sibling bone marrow transplants for early leukemia (acute leukemia in first remission or chronic myelogenous leukemia in first chronic phase) to determine whether transplant outcome differed in small and large centers. Transplants were performed in 86 bone marrow transplant centers active between the years 1983 and 1988, which participated in the International Bone Marrow Transplant Registry. Twenty-one (24%) centers performed five or fewer allogeneic transplants per year during the study period; five (6%) performed more than 40 per year. After adjustment for differences in patient and disease characteristics, the relative risks of treatment-related mortality (1.53, P less than .01) and treatment failure (1.38, P less than .04) were higher among patients who received transplants at centers doing five or fewer transplants per year than among those at larger centers. Among patients receiving transplants in centers performing more than five transplants a year, there was no statistically significant correlation between number of transplants and outcome.

Adult↗
PubMed1992

Bone marrow transplantation for severe aplastic anemia: influence of conditioning and graft-versus-host disease prophylaxis regimens on outcome.

Data for 595 patients with severe aplastic anemia receiving HLA-identical sibling bone marrow transplants were analyzed to determine the effect of pretransplant conditioning and graft-versus-host disease (GVHD) prophylaxis on outcome. Transplants were performed between 1980 and 1987 and reported to the International Bone Marrow Transplant Registry. Three conditioning regimens (cyclophosphamide alone, cyclophosphamide plus limited field radiation, and cyclophosphamide plus total body radiation) were studied; none was associated with superior long-term survival. Three GVHD prophylaxis regimens (methotrexate, cyclosporine, and methotrexate plus cyclosporine) were studied. Recipients of cyclosporine with or without methotrexate had a significantly higher probability of 5-year survival (69%, 95% confidence interval 63% to 74%) than patients receiving methotrexate only (56%, 49% to 62%, P less than .003). Higher survival with cyclosporine resulted from decreased risks of interstitial pneumonia (P less than .0002) and chronic GVHD (P less than .005). Additional risk factors adversely associated with survival included infection pretransplant (P less than .004), use of parous or transfused female donors (P less than .005), older patient age (P less than .005), and 20 or more pretransplant transfusions (P less than .006). These data may prove useful in planning randomized clinical trials and in identifying patients at high-risk of treatment failure.

Adolescent↗
PubMed1992

Multiple myeloma and chronic lymphocytic leukemia: parallels and contrasts.

Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) are closely related B-cell cancers. Parallel and divergent features of these diseases are reviewed. In MM, expression of multiple hemopoietic lineage-associated antigens on the malignant cells and the substantial likelihood of progression to acute myelogenous leukemia suggest transformation of a pluripotent stem cell. In CLL, transformation more likely involves a committed B-cell progenitor. Another difference is that clonal evolution with associated cytogenetic progression is common in MM but not CLL. Other data, including studies of proto-oncogenes and tumor suppressor genes, suggest that MM results both from increased proliferation and accumulation of tumor cells, whereas tumor cell accumulation is the predominant feature of CLL. These differences may be reflected in the seemingly greater role of cytokine abnormalities in MM progression. For example, osteoclast-activating properties of some cytokines account for bone involvement in MM but not in CLL. MM and CLL share common features such as stage-dependent anemia and immune deficiency. Both diseases respond to alkylating agents but vary markedly in their sensitivity to fludarabine (CLL greater than MM) and glucocorticoids (MM greater than CLL). Differences between these diseases in progression-free interval and survival may reflect different definitions of premalignant and malignant phases rather than biologic differences. Detailed comparisons between MM and CLL may provide additional insights into these and related B-cell cancers.

Humans↗
PubMed1992

Therapy of acute myelogenous leukemia.

Treatment of acute myelogenous leukemia (AML) is divided into remission induction and post-remission therapy. Remission induction is usually with cytarabine and an anthracycline. Daunorubicin is commonly used but recent data suggest idarubicin or mitoxantrone are equally effective, possibly better. High-dose cytarabine has also been used for remission induction but is not proven superior. Post-remission treatment is typically with two or more courses of drugs similar to those used for remission induction. Other studies use non-cross resistant drugs and/or high-dose cytarabine. Although some data favor use of high-dose cytarabine, no approach is clearly superior. There is considerable controversy whether persons in first remission and with an HLA-identical sibling should receive a bone marrow transplant immediately or after relapse. Although transplant results appear superior, especially in persons less than 20 years of age, the most effective strategy may be reserving transplants for persons failing chemotherapy. This strategy also applies to persons receiving autologous transplants or transplants from alternative donors, like HLA-matched related or unrelated persons.

Antineoplastic Agents↗
PubMed1992

Ethanol increases tumor progression in rats: possible involvement of natural killer cells.

The effects of acute and chronic ethanol administration on tumor progression and metastasis were studied in rat models of leukemia and breast cancer, respectively. Acute administration of 1.5-3.5 g of ethanol/kg body weight significantly reduced survival of rats injected with CRNK-16 leukemia cells in a dose-related manner. Acute administration of 2.5-3.5 g of ethanol/kg body weight, one hour before tumor inoculation, or chronic consumption of liquid diet containing ethanol for two weeks before and three weeks after tumor inoculation, significantly increased the number of lung metastases of MADB106 mammary adenocarcinoma. The ethanol-induced increase in the number of metastases was not correlated with plasma levels of corticosterone and was not altered by the opiate antagonist naltrexone. Incubation of spleen cells in vitro in the presence of ethanol, at concentrations comparable to those measured in the blood of ethanol-treated rats, significantly suppressed natural killer (NK) cell activity against MADB106 cells in a standard chromium-release assay and decreased the binding of effector to MADB106 tumor cells. However, neither acute nor chronic ethanol administration in vivo altered splenic NK activity against this tumor in the same in vitro assay, in which the ethanol would have been washed away. These results suggest that, in the presence of ethanol, tumor progression is facilitated. The possibility that this facilitation is related to ethanol-induced impairment of the normal tumoricidal interaction between NK and tumor cells is discussed.

Adenocarcinoma↗
PubMed1992

A critical reappraisal of gastrointestinal complications of allogeneic bone marrow transplantation.

Gastrointestinal toxicity is a common early complication of allogeneic bone marrow transplants. Etiologies include mucosal damage from pretransplant conditioning, opportunistic infection, and graft-versus-host disease. Because the clinical, laboratory, radiographic, and histological findings of acute graft-versus-host disease are nonspecific, accurate diagnosis is difficult or impossible. We review the differential diagnosis of gastrointestinal complications of bone marrow transplants and implications for therapy.

Bone Marrow Transplantation↗
PubMed1992

Autotransplants in advanced non-Hodgkin lymphoma: are they effective?

Recent data suggest that intensive therapy followed by a bone marrow autotransplant is effective in advanced intermediate and high-grade non-Hodgkin lymphoma (predominantly large-cell lymphoma). Twelve studies of autotransplants were analyzed to determine outcome. Results compared to data from 29 chemotherapy studies. Complete remission was reported in 53% of autotransplant recipients versus 17% of persons receiving chemotherapy. Two-year disease-free survival was 16 and 2%, respectively. It is uncertain whether these differences indicate superiority of autotransplants or reflect selection biases. Also unknown is whether similar results might not be obtained with similarly intensive treatment without an autotransplant.

Adolescent↗
PubMed1992

Fetal liver transplants.

Transplants of hematopoietic stem cells derived from fetal liver during the second trimester of pregnancy can restore hematopoiesis in animals and humans with bone marrow failure. These cells also have a reduced likelihood of causing graft-versus-host disease. Because fetal liver derived hematopoietic stem cells are relatively pure and considerable proliferative potential, they may be reasonable targets for studies of gene modification. Other possible uses of fetal liver derived stem cells are also considered as are results of fetal liver transplants in animals and humans. These data are compared to alternative sources of hematopoietic stem cells including bone marrow and umbilical cord and adult blood.

Animals↗
PubMed1992

Blood stem cell transplants come of age.

In this report we review meeting highlights. Clearly there has been substantial progress in the laboratory and clinic with regard to blood stem cells. Having proven that these transplants work, it is now time to investigate biologic features in greater detail. Also needed are randomized trials evaluating several of the issues we raise such as whether the better results of blood cell autotransplants are due to more effective treatment or subject selection and whether in vitro removal of tumor cells is necessary or effective.

Blood Cells↗
PubMed1992

Expression of the normal p53 gene induces differentiation of K562 cells.

The multistep nature of human cancers is well illustrated by chronic myelogenous leukemia (CML), a clonal hematologic malignancy with two distinct phases: chronic and acute. Transition between these phases is characterized by unregulated growth and loss of differentiation of myeloid cells and their progenitors. We recently reported that loss of normal p53 expression correlates with transition from the chronic to acute phase in at least 25% of cases of CML. However, the precise relationship between this loss and biologic features of acute-phase CML is uncertain. To study this question, we artificially expressed normal p53 in K562, an erythroid acute-phase CML cell line lacking normal p53 expression. Biological effects were assessed by determining several growth parameters and by measuring synthesis of hemoglobin, a feature of mature erythroid cells. K562 cells expressing normal p53 had an increased proportion of cells in G1 versus S + G2, a longer doubling time and a lower growth saturation density than control K562 cells or K562 cells with antisense p53. Cells with normal p53 also expressed up to 50-fold more hemoglobin than controls. These data are consistent with the notion that loss of p53 expression may be responsible for many of the features of acute-phase CML cells. The data also demonstrate direct involvement of p53 in differentiation processes.

Cell Cycle↗
PubMed1992

Cancer after bone marrow transplantation. IBMTR and EBMT/EULEP Study Group on Late Effects.

Cancer may be serious late effect of marrow transplantation. Radiation, chemotherapy, immunosuppression and the original disease for which transplantation was performed may predispose to the development of cancer. 116 of 9732 patients reported to the IBMTR (International Bone Marrow Transplant Registry) have developed a new malignancy. Late effects were evaluated by the EBMT-EULEP (European Bone Marrow Transplant-European Late Effect Project) Late Effect Study Group in 147 patients surviving 6 years and 79 patients surviving more than 10 years. New malignancies developed in 11 of these patients. Lymphomas and leukemia comprised 73 cases reported to the IBMTR and one case reported to the EBMT-EULEP study. Tumors of the skin, oropharynx, vulva vagina and cervix prevailed in 41 patients with solid tumors. The distribution of malignancies is similar to that observed in organ transplant patients not given radiation or chemotherapy and suggests immunosuppression as a major contributory factor. In dogs the incidence of malignancies was studied after either chemotherapy or total body radiation in various regimens and marrow transplantation. Both chemotherapy and radiation shortened tumor-free survival in comparison to untreated dogs. Higher doses, larger fractions and shorter treatment schedules enhanced earlier tumor development. Soft tissue sarcomas and thyroid carcinoma were most frequent in treated, mammary carcinoma in untreated dogs. In treated dogs deaths from cancer were observed starting at the age of 5 years as compared to untreated dogs at the age of 9 years. The data from animal experiments indicate that the incidence of solid tumors in marrow transplant patients may still rise in the coming decades.

Animals↗
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↗