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The role of different histocompatibility testing methods for selection of related and unrelated bone marrow donors.

Bone marrow transplantation has become the treatment of choice for many hematological malignancies. Approximately 30% of the patients lack an HLA-identical sibling donor, for them alternative donors have to be found. The chances of finding an unrelated donor can be estimated by consulting the Bone Marrow Donors Worldwide file and grouping the patients according to whether they have frequent or rare haplotypes. If the HLA-ABDR split antigens are taken into account, for less than 25% of the patients identical donors can be identified. In order to select the best matched donor for a patient, sensitive HLA typing techniques should be employed including DNA typing techniques, but for optimal selection of a suitable donor one should not only study genetics but also determine the immunological repertoire recognizing the histocompatibility differences between donor and recipient. Several promising cellular techniques such as the HTLp and CTLp test have recently become available and should also be used to select the best donor.

Bone Marrow Transplantation↗

Lithium and hematopoiesis: effective experimental use of lithium as an agent to improve bone marrow transplantation.

Bone marrow transplantation (BMT) has become a widely used procedure in the treatment of numerous hematological and non-hematological clinical disorders. The preparative regimen used for marrow recipients is not without risk as the immunodeficient recipient is susceptible to life-threatening infections due to the inability of the marrow to engraft properly. The monovalent cation lithium has been demonstrated to influence regenerating hematopoiesis following the use of several agents known to suppress hematopoiesis. The following report summarizes our studies which have been designed to determine the rate of hematopoietic reconstitution in lethally irradiated mice that were transplanted with bone marrow cells, harvested from either syngeneic or allogeneic donor animals, treated with lithium or phosphate buffered saline (PBS). Transplanted recipients receiving marrow cells from lithium treated donors were evaluated for their survival, peripheral blood indices and several classes of hematopoietic progenitors (granulocyte, erythroid, and megakaryocyte). Transplanted animals that received marrow cells from either syngeneic or allogeneic donors treated with lithium demonstrated greater survival, increased recovery of peripheral indices and hematopoietic progenitors compared to PBS-treated controls. These results indicate that the use of lithium to treat the donor may be an effective procedure to enhance hematopoietic recovery and engraftment in the transplanted recipient. Because of its wide-ranging effects, the use of lithium as a single agent, may be more efficacious than administering several hematopoietic growth factors in order to achieve a similar response.

Animals↗

Increased levels and activity of E2F1 transcription factor in myelodysplastic bone marrow.

The bone marrow of patients with myelodysplastic syndromes (MDS) shows excessive intramedullary apoptosis, particularly in S-phase cells. In the light of previous reports that showed a link between experimental overexpression of the E2F1 transcription factor and apoptosis in the S phase, we compared the status of E2F1 protein in bone marrow mononuclear cells of MDS patients with that of healthy donors. Nearly 67% of MDS marrow samples showed higher expression of E2F1 transcription factor than in healthy donors. The retinoblastoma gene product, Rb, is a major negative regulator of E2F1 activity; however, Rb protein levels were found to be normal in MDS marrow samples. Amplification of genomic DNA by the polymerase chain reaction (PCR) showed no E2F1 gene amplification or mutation in the Rb-binding region of E2F1 in MDS patients, nor was transcriptional up-regulation noted when E2F1 messenger RNA (mRNA) levels were estimated with real-time reverse transcriptase-PCR. Furthermore, the overexpression of E2F1 was paralleled by its increased transcriptional activity, as reflected by the increased mRNA levels for one of its target genes, dihydrofolate reductase. Importantly, in a subset of the studied MDS patients for whom a simultaneous measurement of apoptosis in S-phase cells was possible, the E2F1 protein levels showed a significant positive correlation with this phenomenon. Previously, increased E2F1 activity in human disease had been found primarily as a consequence of Rb derailment. Hence, the observation in MDS of increased E2F1 activity in the presence of normal Rb levels is novel and unique, and E2F1 activity in association with apoptosis in S-phase cells may thus have significant therapeutic implications.

Aged↗

Caregiver quality of life after autologous bone marrow transplantation.

Bone marrow transplantation (BMT) is a unique cancer therapy characterized by its novelty, intensity, and toxicity. Although families have been identified as having a critical influence on patient adaptation during the acute phase of BMT, minimal attention has been paid to their experiences during extended survivorship. This article reviews findings from a descriptive study on quality of life in primary caregivers of adult autologous bone marrow transplantation (AuBMT) survivors after acute hospitalization. Caregiver perceptions of their survival are delineated in an effort to characterize the dynamics of family recovery after BMT. Specifically, caregivers of AuBMT survivors require ongoing assistance to maintain their primary support role after BMT.

Adaptation, Psychological↗

Severe infections after bone marrow transplantation.

Bone marrow transplantation and stem cell transplantation have become standard therapies offering potential cures for a number of hematologic malignancies and immunologic disorders. Severe infection remains a life threatening complication after transplantation, contributes significantly to morbidity, and may necessitate admission to the ICU. It is estimated that between 20 and 40% of patients receiving bone marrow transplant will require ICU admission in the initial posttransplantation phase. Historically, survival rates after admission to the ICU are dismal, particularly if mechanical ventilation is required for respiratory failure. Other organ involvement worsens the prognosis still further and has led to proposals for rationing or restricting access to critical care units and supportive measures. Recent studies have reported small but significant improvements in outcome after critical illness. Whether this improvement is a result of changes in levels of supportive care or a more defined patient selection is uncertain. Moreover, risk factors identifying patients who will benefit most from intensive support are poorly defined. However, it is generally accepted that respiratory failure requiring invasive mechanical ventilation is associated with a poor prognosis in this patient group. Early involvement of intensivists in the management of critical illness in transplant recipients is likely to continue to improve survival in this group of patients.

Bone Marrow Transplantation↗

Evidence for structured variation in self-renewal capacity within long-term bone marrow cultures.

Bone marrow pluripotent stem cells (CFUs) demonstrate capacity for both proliferation and differentiation. The proliferative capacity of CFUs has been measured by serial transplantability and by the Rs, a measurement of CFU production in a single 14-day transfer. In the present study, the self-renewal capacity fo both adherent and nonadherent CFUs from long-term bone marrow cultures was measured. Culture conditions were established such that nonadherent cells were derived from the adherent cell layer. Both adherent and non-adherent cells produced spleen colonies, demonstrating that significant proliferative potential was present in both locations; however, at all times in culture, the CFUs within the adherent stromal cell layer had a significantly greater self-renewal capacity than did the nonadherent CFUs. During the initial establishment of the cultures, the self-renewal capacity of the adherent CFUs decreased as the total number of CFUs per flask increased. After 3 weeks in culture, the self-renewal potential of the adherent CFUs stabilized and was maintained. These results suggest two different mechanisms of stem cell proliferation. In order to increase the most primitive stem cell pool size, there was initial proliferation of early stem cells with a concomitant decrease in self renewal capacity. Once this pool was established, the self-renewal capacity of the adherent CFUs maintained for 13 weeks in culture suggests that CFU production and cell maintenance were achieved by clonal succession.

Animals↗

Exact relevance of bone marrow cells in the healing process after myocardial infarction: analysis with a murine model of bone marrow cell transplantation.

BACKGROUND: Cellular cardiomyoplasty has created new possibilities in cardiac regeneration. Several cell types can be used in the procedure, such as skeletal myoblasts and bone marrow cells. Recent publications have suggested that bone marrow cells may be excellent candidates due to their pluripotency, but their actual role in cardiac regeneration is unknown. OBJECTIVE: To evaluate the exact physiological role of bone marrow cells in the healing process after myocardial infarction. METHODS: A mouse bone marrow cell transplantation model was used in which transplanted cells were easily detectable by immunohistochemistry. Chimeric mice were subjected to myocardial infarction by ligation of the left descending coronary artery. After one month, the mice were sacrificed and the scars were analyzed. RESULTS: Transplanted bone marrow cells were detected in the scars and these cells seemed able to transdifferentiate into endothelial cells, but no transdifferentiation into cardiomyocytes occurred. This mechanism of regeneration was dismissed because only 2% of the vessels in the scars were positive for transplanted cells. CONCLUSIONS: Bone marrow cells might be involved in myocardial healing, but this physiological mechanism is insufficient to allow correct regeneration.

Analysis of Variance↗

In vivo effects of recombinant human stem cell factor treatment. A morphologic and immunohistochemical study of bone marrow biopsies.

Bone marrow (BM) aspirate and biopsy specimens from seven female patients with advanced or metastatic breast cancer and preserved marrow function treated on a phase I trial of recombinant methionyl human stem cell factor (r-metHuSCF; SCF) were evaluated by immunohistochemical staining before and after treatment with SCF. Doses of SCF included 10 g/kg/day in 2 patients, 25 micrograms/kg/day in 2 patients, and 50 micrograms/kg/day in 3 patients administered as subcutaneous bolus injections for 14 days. Following treatment, bone marrow cellularity increased up to 1.6-fold (P = NS), with an increased frequency of promyelocytes (P < .002), but an unchanged relative frequency of other marrow hematopoietic cells. The mean relative frequency of BM CD34+ progenitor cells increased from 0.9% to 1.8% (P < .001). The mean proportion of BM cells stained by Ki-67/MIB 1 and PCNA/PC10, monoclonal antibodies (MoAb) recognizing proliferation-associated nuclear proteins, increased from 18.6% to 35.4% (P < .003) and from 32.4% to 49.4% (P < .01), respectively. Most of the Ki-67 and PCNA positive cells were represented by promyelocytes, proerythroblasts, and myeloblasts. SCF therapy was not associated with marrow fibrosis or increases in the number of macrophages. Peripheral white blood cell counts increased 1.3- to 3.6-fold following SCF. The mean absolute neutrophil counts increased from 3.9 x 10(9)/L (range 2.6-5.3) to 7.2 x 10(9)/L (range 4.7-12.3), and reticulocyte counts increased by a mean of 1.5 fold (range 1.2-fold to 2.0-fold). No consistent difference in platelet counts was seen. These results suggest that SCF given in vivo is effective in increasing the frequency of CD34+ BM progenitor cells, and has the capacity to increase the proliferation and differentiation rate of hematopoietic precursor cells. These effects indicate that SCF may represent a cytokine capable of affecting multiple hematopoietic lineages.

Adult↗

Communication with patients and their families, who undergo bone marrow transplantation.

Bone marrow transplantation (BMT) is a widely accepted treatment for malignant and nonmalignant diseases. With advances such as autologous and allogenic stem cell transplant, umbilical cord blood transplant, and improved biomedical support therapies, the need to evaluate the impact technology on the patient and the family continues to be an important aspect of medical and nursing research. BMT has been described as a procedure associated with isolation of the patient, prolonged hospitalizations, rapid fluctuations in medical conditions, frequent and often life-threatening infections, and graft-versus-host disease (GVHD). Although some patients encounter such difficult experiences during recovery and a significant mortality rate is associated with the procedure, other patients experience rapid recovery with minimum risk of serious complications and a shortened hospital length of stay. Issues related to the caregiver availability and caregiver burden become more important in theses aggressive outpatient settings. The paper discusses the psychosocial impact of BMT on the patient as well as on the family. The psychosocial nursing care during BMT is discussed. The cultural influence is recognized and stressed. Quality-of-life dimensions and the impact of BMT as well as implications for nursing are stressed. Also, the experience of donating bone marrow to a relative will be discussed and the implications for a nursing practice will be described.

Bone Marrow Transplantation↗

Acquired immunodeficiency syndrome. Distinctive features of bone marrow biopsies.

Bone marrow biopsies from 30 patients with acquired immunodeficiency syndrome (AIDS), diagnosed according to accepted clinical criteria, were studied in order to determine if characteristic histopathologic features were present. The biopsies were compared with 20 biopsy specimens submitted from patients with fever of unknown origin or with known neoplastic disease, including four biopsies from patients with a history of narcotics addiction being treated in the methadone clinic, and with biopsies from three homosexual men who did not have AIDS. Characteristic biopsy features were recognized in 31 (86%) of 36 biopsy specimens from AIDS patients. Nineteen of 36 patients (53%) showed a distinctive pattern of hypercellularity in which hematic cells (immature granulocytic cells, megakaryocytes, eosinophils, and large lymphocytes) separated, but did not efface, fat cells; these cells were designated as "AIDS-pattern." Twelve specimens showed a less complete (probable-AIDS) bone marrow change. Reticulin fibers were increased in 28 of 36 biopsies.

Acquired Immunodeficiency Syndrome↗

Delayed complications and long-term effects after bone marrow transplantation.

Bone marrow transplantation is being used with increasing frequency and success for an expanding number of indications. At present, more than 1000 patients are surviving more than 5 years and several hundred more than 10 years after transplantation. Extended observation periods have shown that numerous complications have to be expected in these patients, particularly in those given TBI as part of the conditioning regimen. However, other factors including chemotherapy, GVHD, viral infections, host environment, and genetic factors also contribute to the problem. It has been pointed out by critics of bone marrow transplantation that success is often reported as disease-free survival, meaning survival in remission. However, there are, obviously, secondary problems that can significantly impair patients' quality of life, even though their leukemia (or lymphoma) is in unmaintained remission. Very few data on quality of life in long-term surviving patients have been reported. Several studies are currently ongoing (Forman S, Blume K, personal communication), and the results are urgently needed. It will also be of interest to compare patients given, allogeneic transplants with those given autologous marrow infusions in an attempt to determine to what extent conditioning regimens and alloreactivity contribute to long-term side effects. It will be even more important to design regimens that are less likely to induce these problems and to design therapeutic approaches to treat complications effectively.

Bone Marrow Transplantation↗

Enteral nutrition support in a child after bone marrow transplantation.

Bone marrow transplantation (BMT) has been associated with numerous negative side effects, which include prolonged anorexia. Historically, parenteral nutrition has been the method of choice for nutrition support. The possibility that enteral feedings may be a practical form of nutrition therapy for those BMT patients who have prolonged anorexia and who have adequate gastrointestinal function was investigated. RR, a 10-year-old male, was diagnosed with acute lymphocytic leukemia in March 1989. The patient received a bone marrow transplant in July 1992 from a human leukocyte antigen genotype-matched sibling. Because of the patient's prolonged anorexia, he was started on enteral feedings via a percutaneous endoscopic gastrostomy feeding tube on day +63. Over the next 300 days of enteral nutrition support the patient's nutritional status improved as demonstrated by an increased weight and height and the maintenance of normal visceral protein stores. This suggests that enteral feedings may be beneficial for those BMT patients who have prolonged anorexia and have adequate gastrointestinal function.

Anorexia↗

Sinusitis in bone marrow transplantation.

Bone marrow transplantation has become a beneficial and curative technique used in treatment of patients with different hematologic conditions. It has become widely used at our institution for hematologic malignancies and certain resistant solid tumors. However, this treatment can result in immunosuppression, with an increased chance of infection. The purpose of this study was to review the causes of infections and determine the number of patients diagnosed with sinusitis. In the retrospective study, we evaluated the cases of bone marrow transplant patients for incidence and cause of fever. Sixty-eight percent of patients had fever after transplant; of these, 59% had fever of unknown origin. Only 1% of the patients with fever were diagnosed with sinusitis. In the evaluation of fever, sinusitis was not usually suspected and therefore was not included in the differential diagnosis. With such a high percentage of fever of unknown origin in this growing patient population, appropriate pretreatment evaluation of each case to rule out sinusitis should be considered.

Bone Marrow Transplantation↗

Mesenchymal stem cells from patients with chronic myeloid leukemia do not express BCR-ABL and have absence of chimerism after allogeneic bone marrow transplant.

Bone marrow is a heterogeneous cell population which includes hematopoietic and mesenchymal progenitor cells. Dysregulated hematopoiesis occurs in chronic myelogenous leukemia (CML), being caused at least in part by abnormalities in the hematopoietic progenitors. However, the role of mesenchymal stem cells (MSCs) in CML has not been well characterized. The objectives of the present study were to observe the biological characteristics of MSCs from CML patients and to determine if MSCs originate in part from donors in CML patients after bone marrow transplantation (BMT). We analyzed MSCs from 5 untreated patients and from 3 CML patients after sex-mismatched allogeneic BMT. Flow cytometry analysis revealed the typical MSC phenotype and in vitro assays showed ability to differentiate into adipocytes and osteoblasts. Moreover, although some RT-PCR data were contradictory, combined fluorescence in situ hybridization analysis showed that MSCs from CML patients do not express the bcr-abl gene. Regarding MSCs of donor origin, although it is possible to detect Y target sequence by nested PCR, the low frequency (0.14 and 0.34%) of XY cells in 2 MSC CML patients by fluorescence in situ hybridization analysis suggests the presence of contaminant hematopoietic cells and the absence of host-derived MSCs in CML patients. Therefore, we conclude that MSCs from CML patients express the typical MSC phenotype, can differentiate into osteogenic and adipogenic lineages and do not express the bcr-abl gene. MSCs cannot be found in recipients 12 to 20 months after BMT. The influence of MSCs on the dysregulation of hematopoiesis in CML patients deserves further investigation.

Adolescent↗

Incompatibility for CD31 and human platelet antigens and acute graft-versus-host disease after bone marrow transplantation.

Bone marrow transplantation (BMT) is often complicated by acute graft-versus-host disease (aGVHD). In patients transplanted with an HLA-matched donor the occurrence of this complication is believed to be favoured by disparities at the minor histocompatibility antigens (mHA). However, few of these polymorphic molecules have been identified. We sought to determine whether donor/recipient incompatibility for HPA-1, HPA-2, HPA-3, HPA-5 or CD31 (codon 125) antigens represented a risk factor for aGVHD and genotyped these antigens in 70 bone marrow donors and their HLA-identical recipients. All patients were children who received BMT for haematological malignancies at a single institution according to well-defined therapy protocols. Statistical analysis showed that incompatibility for CD31 (codon 125) was a risk factor for grade II-IV aGVHD in the overall patient population, whereas HPA-3 incompatibility predicted aGVHD occurrence in HLA-A2 patients only. The magnitude of the aGVHD risk was directly related to the number of HPA/CD31 incompatibilities. No correlation was found between non-identity for HPA/CD31 and aGVHD. Since incompatibility but not non-identity for CD31 or HPA-3 was a risk factor for aGVHD, we suggest that allelic variants of these molecules can serve as mHA in BMT recipients from HLA-identical donors.

Adolescent↗