摘要:

PurposeAlthough it is clear that sickle cell disease is curable with bone marrow transplantation, there are few objective criteria that are helpful in the identification of suitable candidates for this aggressive and potentially life-threatening procedure. This disease is characterized by a highly variable clinical course, and there is a need to intervene with marrow transplant before the onset of disease-mediated chronic organ damage. These factors highlight the need for a clinical severity index that can prospectively identify patients who are at high risk for a turbulent clinical course and a poor prognosis.Patients and MethodsWe used the Cooperative Study of Sickle Cell Disease data base to identify features of the disease in early childhood (i.e., <2 years of age) that are associated either with significant morbidity later in childhood or early mortality. Our study population includes the 1,944 children who entered the study before 12 years of age. Univariate analysis showed that factors associated with the occurrence of cerebrovascular accident (51 patients) include hematocrit, rate of change of pocked red cell count, and polymer fraction at 40% oxygen saturation (PF40). Only low hematocrit was predictive of death in this pediatric cohort (45 disease-related deaths). Results: Our ability to identify other potential factors that correlate with these outcome measures is limited by their small numbers. Hence, it was necessary to designate a different endpoint whose relationship with various clinical and laboratory parameters could be assessed. To accomplish this, a distribution of acute events, which were defined as any episode of pain or acute chest syndrome, was calculated. Also, the age-specific “expected” event rate, defined as the mean number of events per patient-year of observation, was determined.ConclusionsThe relationship between various aspects of sickle cell disease and high positive deviance from the expected event rate will be assessed in a cohort of 519 children who entered the study prior to 7 months of age and were followed beyond their second birthday.

ISSN:0192-8562    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

B>Purpose: The rate of progression of major organ failure in sickle cell anemia is genetically controlled. It is the direct consequence of the sickle cell-evoked vasculopathy.Patients and MethodsPresence of the (βsgene cluster haplotypes and gene deletions as genetic markers indicate the expected frequency of illness and the risk of end-stage major organ failure. The risk of irreversible soft tissue organ failure is greatest in patients with a Central African Republic (CAR) chromosome, whereas morbidity is consistently lowest in patients with a Senegalese chromosome. Presence of thalassemia-2 decreases the risk of soft tissue organ failure in all haplotype combinations.ResultsOther laboratory abnormalities, when combined with haplotype and gene status, also predict the risk of clinical morbidity. The mean hemoglobin level (or red blood cell count) is lowest in patients with the most severe clinical manifestations. On the other hand, the platelet count and leukocyte count as well as the plasma fibrinogen level are elevated in the sickest patients. A threshold level of hemoglobin F at 1.2 g/dl (∼20% hemoglobin F) decreases the risk of major organ failure and is attained most frequently in those with a Senegalese chromosome. Hemorheologic findings observed during the most stable state of patients with sickle cell anemia indicate two trends: (a) the mean percentage of dense red cells is nearly twice as high in the maximal severity patients as compared with the minimal severity patients; and (b) mean red cell rigidity is greatest in the maximal severity group and least in the minimal severity group. These findings suggest that a greater percentage of dense, poorly deformable red cells are present in sickle cell patients in the genotypic category of maximal severity.ConclusionsThe combination of the (βsgene cluster haplotype and gene status correlates with both phenotypic laboratory findings (hematologic profile) and morbidity. These associations increase our ability to predict clinical severity and the future risk of major organ failure.

ISSN:0192-8562    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

PurposeTherapy of sickle cell disease with hydroxyurea is experimental.Patients and MethodsWe have begun a randomized blinded clinical trial to determine its clinical utility. The efficacy of this drug is unproved and its risks, which include mutagenesis, teratogenesis and carcinogenesis, are poorly understood. These risks are explicitly stated in our consent forms. A significant number of patients who are asked to enroll refuse to enter the study. This refusal is probably because of individual variations in perception of risk and personal inconvenience, as well as differences in perception of personal benefit. We have a few hints as to which patients are more likely to produce increased amounts of fetal hemoglobin, but our findings do not indicate which patients are most likely to show a good clinical response.ResultsOur study group decided not to treat patients under 18 years of age with hydroxyuria until clinical efficacy of the drug is proved in adults. We have criteria for selecting patients for entry into our ongoing study, but the criteria are based more on study design than on an estimate of present or future severity of the manifestations of sickle cell disease.ConclusionsFeatures of our previous study and results of the present trial may be helpful in defining indications for bone marrow transplantation in children with sickle cell disease.

ISSN:0192-8562    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

PurposeStimulating expression of the normal fetal globin genes is a preferred method of ameliorating sickle cell disease and β-thalassemia for the majority of patients in North America who do not have appropriate bone marrow donors.Patients and MethodsDue to increased survival of red blood cells that contain both hemoglobin S and hemoglobin F, as little as 4–8% fetal globin synthesis in the bone marrow can produce levels of hemoglobin F of ∼20% in the peripheral circulation. Some success has been achieved in stimulating hemoglobin F using chemotherapeutic agents (such as hydroxyurea and 5-azacytidine) and growth factors (erythropoietin) that alter erythroid growth kinetics. However, there is reluctance to treat children with chemotherapeutic agents because of possible undesirable long-term side effects.ResultsButyric acid and butyrate derivatives are generally safe compounds that stimulate the promoters of individual fetal and embryonic globin genes and thus provide a more specific therapy. An initial trial with the parent compound, given as arginine butyrate, has demonstrated rapid stimulation of fetal globin expression to levels that can ameliorate these conditions. Phase I trials of an oral butyrate derivative with a long plasma half-life have begun.ConclusionsThese agents may provide a new and specific approach for ameliorating the clinical manifestations of sickle cell disease and β-thalassemia.

ISSN:0192-8562    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The difference between research and innovative therapy is based on the goals rather than the risks or newness of the therapy. The threat to patients from research is not that an untested treatment may be hazardous. Instead, the danger is that the loyalty of their physician may be compromised by the goals of research. In the traditional conception of research, it is assumed that we know what constitutes standard therapy and how effective it is. The goal of research is to compare the effectiveness of an innovation with the standard therapy. However, when rapid progress is being made, it becomes difficult to measure improvements due to introduction of new therapies. It is difficult to determine which of many successful therapies is “best.” As a result, rapid progress makes all therapies, including both new ones and old ones, nonvalidated therapies. In such situations, scientific norms about the degree of certainty that we must have in order to judge a therapy as being efficacious are based on the values of the individuals involved, rather than on any value-free statistical or scientific calculations.There are identifiable communities (ethnic groups) that are specifically effected by certain genetic diseases, as well as communities consisting of patients who have certain nongenetic diseases. When these groups (patient advocates) and communities are politically organized, they should be consulted and allowed to participate in the process of devising strategies to evaluate new therapies.

ISSN:0192-8562    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

PurposeThis article addresses some of the psychosocial issues of bone marrow transplantation for treatment of hemoglobinopathies. The central focus is on the importance of attending to the experiences of minority patients and their families. Findings of recent studies relative to issues of bone marrow donation provide some framework for this analysis.Patients and MethodsUnanswered questions are posed by hypothetical parents to raise critical questions and to highlight the importance of truly informed consent in shared decision making.ConclusionsRecommendations for researchers and caregivers are for more personal contacts and dialogues with patients and families. There should also be involvement in grass roots activities, with attention to assessing the efficacy of bone marrow transplantation, as well as emphasizing minority representation in the process.

ISSN:0192-8562    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

PurposeIn order to assist in the management of newly diagnosed children with moderate aplastic anemia (MAA) we reviewed the clinical course and outcome of children with MAA seen at our institution over the past 12 years and compared them with children with severe aplastic anemia (SAA).Patients and MethodsMAA was defined as having a hypocellular bone marrow and cytopenia in at least two cell lines not in the severe range. Twelve children met these criteria. Twenty-eight children with SAA were seen during the same interval. Patients with MAA were treated with immunomodulation with antithymocte globulin and/or cyclosporine if they progressed to SAA.ResultsFive patients with MAA progressed to SAA at a median interval of 18 months from diagnosis. The other seven patients required no therapy or only received transfusions for ≤6 months after diagnosis. The survival of the patients with MAA was significantly better than that of patients with SAA treated with immunomodulation (p = 0.022). All patients with MAA are alive at a median follow up of 7 years and are transfusion independent; only one patient currently receives therapy. Residual hematologic abnormalities in children with MAA included thrombocy-topenia, leukopenia, and macrocytosis.ConclusionsIn this small series of children with MAA the outcome was excellent and significantly better than in patients with SAA; more than half recovered with minimal or no therapy. Patients who progressed to SAA responded well to treatment. A larger prospective study is needed to conclusively define the natural history of MAA.

ISSN:0192-8562    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

PurposeTo investigate the role of bone marrow transplantation in patients with severe sickle cell anemia (SCA).Patients and MethodsWe have designed a protocol for selecting patients with severe SCA who may benefit from bone marrow transplantation (BMT). On the basis of this protocol, a girl 3 9/12 years of age who had severe recurrent pain crises and splenic dysfunction received a BMT from her brother, who is homozygous for hemoglobin A.ResultsTransplantation resulted in prompt engraftment, followed by durable hematologic and immunologic reconstitution with donor cells. One year after BMT, the patient continued to do well. She did not experience any graft versus host disease, her growth velocity increased, and recovery of splenic function was demonstrated. Since undergoing BMT, she has not experienced any painful crises.ConclusionsBone marrow transplantation is an effective therapeutic modality that should be considered in patients with severe SCA.

ISSN:0192-8562    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

PurposeEnhanced engraftment and reduced viral complications may be achieved in bone marrow transplantation (BMT) by limiting homologous transfusions. We report on limiting donor exposures before and after BMT in a newborn with severe combined immunodeficiency (SCID) using dedicated whole blood and plateletpheresis donors as well as a sterile connecting device (SCD).Patients and MethodsA 1-day-old neonate was admitted for an allogeneic, human leukocyte antigen-disparate, T-cell-depleted BMT performed on day 43 of hospitalization. All transfused red blood cells (RBCs) and platelets were cytomegalovirus negative, and were irradiated and leukodepleted (via a Pall filter). Using the SCD, tubing above the filter was connected to the product bag, and the distal tubing was connected to a transfer pack for collection of the filtered product. Additional transfer packs were connected to the filtered product using the SCD to separate small aliquots as needed. RBC aliquots were irradiated individually before each transfusion.ResultsDuring a total of 134 days of hospitalization, only four donor exposures occurred. Eleven RBC transfusions (mean volume 46.4 ± 12.6 ml) from three donors and five plateletpheresis transfusions (mean volume 74.2 ± 7.5 ml) from one donor constituted all the patients' transfusion requirements. Evidence of engraftment was seen on day 18 post-BMT with an absolute neutrophil count sustained at 500 cells/mm3. The last transfusion was received on day 35 post-BMT.ConclusionsCurrent blood transfusion technology enables patients undergoing bone marrow transplantation to have limited donor exposures. This practice should decrease viral complications without effecting bone marrow engraftment.

ISSN:0192-8562    

出版商:OVID    

年代:1994

数据来源: OVID