Biomedical subjects
A M Mauer
Publications and source records attributed to A M Mauer.
New directions in the treatment of acute lymphoblastic leukemia in children.
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The importance of an isolated central nervous system relapse in children with acute lymphoblastic leukemia.
We assessed the influence of an initial isolated meningeal relapse on treatment outcome in 839 children with acute lymphoblastic leukemia (ALL) who were admitted to St Jude Children's Research Hospital (Memphis) from mid-1967 through mid-1979. The patients were entered in a series of five clinical trials (Total Therapy Studies V through IX), each designed to test one or more modifications of treatment for ALL. Two groups were compared: 699 children who received CNS prophylaxis (2,400-rad craniospinal irradiation or 2,400-rad cranial irradiation plus intrathecal methotrexate) v 56 who did not. Our results, obtained with a time-dependent covariate model and a matching technique, indicate a 2 to 3.5-fold increase in the risk of hematologic relapse or death among patients who experienced an isolated CNS relapse compared with similar patients (matched for leukocyte count and length of complete remission) who remained free of CNS involvement. Of the 107 children with an initial isolated CNS relapse, 89 (83%) have died or have had a subsequent relapse. There was no detectable difference in the rate of hematologic relapse or death after a CNS relapse between patients who had received preventive therapy and those who had not. We conclude that CNS prophylaxis is important both for the prevention of initial CNS leukemia and for reducing the risk of hematologic relapse or death subsequent to a CNS relapse.
Rearrangement of immunoglobulin heavy chain genes in T cell acute lymphoblastic leukemia.
We studied the arrangement of the immunoglobulin heavy chain genes by Southern blot analysis of DNA freshly obtained from marrow blast cells of 14 children with T cell acute lymphoblastic leukemia (T-ALL) using probes to the C mu and JH gene segments: At least one of the C mu-gene alleles was rearranged in three cases. In two of these, one C mu gene had the germ-line configuration and one was rearranged, whereas both alleles were rearranged in the third case. In one case, a rearranged heavy chain gene hybridized to the C mu-region probe, but not to the JH probe, indicating that the entire JH region had been deleted. These results demonstrate that immunoglobulin heavy chain gene rearrangements are not restricted to B lineage lymphoproliferative diseases in humans.
American Academy of Pediatrics Committee on Nutrition: Use of oral fluid therapy and posttreatment feeding following enteritis in children in a developed country.
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A pediatrician attends the National Institutes of Health Consensus Conference on Lowering Blood Cholesterol.
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Prophylaxis in severe granulocytopenia.
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Issues for informed consent.
Informed consent from a cytapheresis donor is the culmination of a complex decision making process during which the blood collecting agency presents sufficient information to enable the donor to make a free choice whether or not to donate. The institution bears the responsibility for providing all information relevant to the donor's decision, whether favorable or unfavorable. At no other stage of its contact with the donor can a collecting agency discharge its public trust more meaningfully. Thus, informed consent is not only the greatest altruistic expression from the unrelated volunteer donor, or the expression of deepest commitment to the family for the related donor, it is also the fullest expression of the value which the institute places on the autonomy of the donor. The foundation upon which the concept of informed consent rests has been laid by law, medicine, government, ethics, and religion. Although the procedures accompanying the informed consent process appear bureaucratic, they should be viewed as the components of a remarkable, dynamic process. The consent of a donor to undergo cytapheresis is an eloquent statement of the value he or she places on the importance of another human being's life.
Anaphylactoid reactions to Escherichia coli and Erwinia asparaginase in children with leukemia and lymphoma.
The incidence and clinical characteristics of anaphylactoid reactions to intravenous asparaginase were assessed in 196 patients given E. coli asparaginase and 49 patients given Erwinia asparaginase. All patients were given a 50 IU intravenous test dose followed in 30 min by the full dosage (10,000 IU/m2), if no reaction occurred to the test dose. Twenty-nine of 196 patients (14.8%) given E. coli asparaginase had an anaphylactoid reaction, occurring after their first through 12th doses. The probability of an anaphylactoid reaction was significantly greater in those patients not receiving concomitant prednisone-vincristine and patients with a hiatus between courses of asparaginase therapy. By logistic regression analysis, other variables such as age, sex, race, diagnosis, total number of doses and concurrent methotrexate or arabinosylcytosine did not contribute significantly to the probability of a reaction. Twenty-three of the patients who had reacted to E. coli asparaginase and 26 patients who had not reacted to E. coli asparaginase were subsequently given Erwinia asparaginase. Seven of these 49 patients (14%) had an anaphylactoid reaction. The probability of a reaction to Erwinia asparaginase was significantly related to a prior reaction to E. coli asparaginase, concomitant prednisone-vincristine therapy, total number of asparaginase doses, number of prior E. coli asparaginase doses, and diagnosis, when assessed by a logistic regression model. However, after adjusting for prior reaction to E. coli asparaginase and the total number of asparaginase doses given, the other variables did not contribute significantly to the probability of a reaction. Only 5/29 patients reacting to E. coli asparaginase and 1/7 reacting to Erwinia asparaginase had a reaction to the test dose. None of the reactions were fatal.
Acute lymphocytic leukemia: biological markers of clinical response.
Treatment for acute lymphocytic leukemia (ALL) has been successful in producing cures for some children with that disease. It has become increasingly important therefore to develop treatment regimens for curable All that are effective for disease control but carry minimal risks of late detrimental consequences. For other children current therapy is still inadequate and treatment failure occurs. For these children current altered treatment strategy must be developed that includes intensification of some treatment components, since improved methods of disease control are the primary consideration. In this paper the clinical and laboratory methods by which risk groups can be defined at diagnosis have been described. We have increasingly effective means by which the expected treatment outcome with current therapy can be defined at diagnosis. This assignment to a specific risk group is important to provide children with ALL with the most appropriate therapy for their expected clinical response. These studies of clinical utility also pose biological questions concerning the relationship to such things as white blood count, leukemic cell karyotype, and initial proliferative activity to the likelihood of drug resistance emerging. During the coming decade there will no doubt be an increasing emphasis on a biological characterization of leukemic cell populations. Answers must be developed to such questions as the mechanism for leukemic cell growth regulation. Biological information developed in this model tumor cell system in humans will likely produce information of value in understanding human cancer in general.
Clinical and cell kinetic studies of the effects of the epipodophyllotoxin VP16-213 during therapy of refractory acute nonlymphocytic leukemia.
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Determination of the significance of in vitro blast cell [3H]thymidine labelling indices obtained initially and serially during induction therapy of acute non-lymphocytic leukemia.
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Ethical complications of clinical therapeutic research on children.
Usual discussion by ethicists and physicians of the ethical implications of research on children with catastrophic disease, and the guidelines established by the Federal Government for this research, rest on applying general moral principles to problems. Whatever the merits of this approach for establishing policy, it does not adequately reflect the life situation of patients and the complexity of a single regimen which is simultaneously both therapeutic and research oriented. Also, the issues become more complex when there is disagreement among the parents about a course of treatment. It is our contention that such cases are properly resolved by considering the degree of paternalism to be exercised by the clinician-researcher.
Interaction of health-care professionals with critically ill children and their parents.
The stress imposed on the emotional equilibrium of a team of health-care professionals by the serious illness of a child can disrupt communication among the team, the child, and the parents. Such stresses may be so severe as to interfere with the ability to the adults to meet the child's needs. Although the feelings and attitudes of critically ill children and their parents are well described in the medical literature, very little has been written about the psychosocial interaction among those responsible for the patient's care. Patterns of interaction which would be most beneficial to the child are still in doubt. The purpose of this article is to review available information, as well as experience at St. Jude Children's Research Hospital, on the psychosocial interaction of the health-care team with critically ill children and their parents. An awareness of the difficulties of caring for such patients is essential in overcoming communication barriers, in reducing any interprofessional tensions that might arise during treatment, and in ensuring high-quality medical care.
Current therapy for acute lymphocytic leukemia: is it rational?
It can be concluded that the therapy for acute lymphocytic leukemia has indeed been developed in a rational manner. Within the three decades of therapy evolution, evidence has accumulated that for some children with this disease cure is now a realistic goal. Two major areas of concern remain. As an increasing number of children achieve long-term disease-free survival, late consequences of the disease and its therapy have emerged as a serious consideration in the design of new treatment programs. Of these late consequences, the impaired intellectual performance found in some children, presumably related to CNS prophylaxis, is a particularly important concern. Current and future therapy protocols must address the problem of effective control of CNS leukemia with minimal consequences for normal brain function. The major deterrent to effective disease control at this time is bone marrow relapse. In some patients, drug-resistant leukemic cells, either preexistent at the time of diagnosis or acquired by modulation during drug exposure, develop a growth advantage and cause a return of the disease manifestation. Once relapse has occurred, expectations for subsequent cure are minimal. During the past decade, several clinical and biological features of acute lymphocytic leukemia have allowed for an increasingly accurate prediction of the risk for bone marrow relapse. Future studies must focus on therapeutic strategies designed to take into account the individual patient's risk of relapse. Further biological studies must focus on mechanisms of the acquisition of drug resistance and its prevention.
Cytokinetically based induction chemotherapy and splenectomy for childhood acute nonlymphocytic leukemia.
A four-drug regimen, based on cell kinetic principles, induced complete remissions in 68 of 95 children (72%) with acute nonlymphocytic leukemia (ANLL). Patients entered remission after 2-5 weekly cycles of vincristine-daunorubicin (day 1) followed by sequential cytosine arabinoside and 6-azauridine (days 4-7). With continuation therapy of monthly vincristine-doxorubicin-cyclophosphamide, weekly cytosine arabinoside, and daily 6-mercaptopurine, the median duration of complete remission was 10 mo and the median survival time 21 mo. Portal triaditis, evident in 11 of 23 patients with liver biopsies, was associated with long remissions. A larger spleen size (greater than 5 cm) and a higher myeloblast labeling index (greater than 10%) at diagnosis were clearly related to shorter durations of remission. Splenectomy within 1 mo of remission had no statistically significant effect on the frequency of relapse or length of remission. Patients without central nervous system (CNS) leukemia at diagnosis, all treated prophylactically with intrathecal methotrexate, had a low frequency of initial CNS relapse (3/56, 5%). The 2-yr disease-free survival rate is 29% (20 of 68 patients attaining complete remission). fifteen patients have completed 2.5 yr of therapy, and each remains in continuous complete remission, off treatment, for 1+ -36+ mo. This induction chemotherapy was as effective as more intensive regimens, with the advantage of less toxicity and shorter periods of hospitalization.
Aneuploidy and percentage of S-phase cells determined by flow cytometry correlate with cell phenotype in childhood acute leukemia.
Cellular DNA content distributions of propidium-iodide-stained bone marrow blasts were determined by flow cytometry (FCM) for 225 untreated children with acute leukemia and were correlated with leukemia cell phenotype and karyotype. Aneuploidy of the primary malignant stem line was detected in 54 cases (24%): 51 hyperdiploid and 3 hypodiploid. A second stem line with approximately twice the DNA content of the primary stem line was recognized by FCM in 28 cases (23 ALL, 5 ANLL) and may be an important source of leukemia cell heterogeneity. The degree of DNA content abnormality detected by FCM was highly correlated (r = 0.98) with the number of whole chromosome gains or losses in the leukemia karyotype. Aneuploidy detectable by FCM was more frequent in acute lymphoblastic leukemia (ALL) (52 of 173, 30.1%) than in acute nonlymphoblastic leukemia (2 of 52, 3.8%) (p less than 0.001). In the ALL group, aneuploidy was significantly correlated with the cell surface expression of common ALL antigen: 46 of 127 antigen-positive cases were aneuploid compared to 6 of 46 antigen-negative cases (p less than 0.003). Only 2 of 21 cases of T-cell ALL without common ALL antigen had detectable aneuploidy, which was significantly less than in the common ALL group (p = 0.02). The median percentage of cells in S-phase was significantly greater for B-cell and erythrocyte rosette-positive T-cell ALL, than for the other phenotypic subgroups. We conclude that aneuploidy and S-phase cell percentage are correlated with the state of leukemia cell differentiation. The biologic basis for the correlation is not established, but may be linked to the process of malignant transformation.
Sounding board. Compensation and cancer research.
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