Identification of HLA-DRB1(*)1114 by oligonucleotide typing and DNA sequencing.
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Alleles↗
Biomedical subjects
N Bunin
Publications and source records attributed to N Bunin.
Bone marrow transplantation for children with acute myelogenous leukemia.
This article reviews bone marrow transplantation (BMT) in acute myelogenous leukemia (AML) of children from adoption of allogeneic BMT for children in first complete remission to the present where autologous BMT, marrow purging, and alternative donors are the major issues. Match related BMT in first remission achieved long-term disease free survival in well over half the young patients. However, as only 25-30% of patients have a matched sibling donor, other options for BMT has been explored, including autologous BMT and unrelated donor BMT. There are many issues that require further study regarding autologous transplant, including the efficacy and benefits of marrow purging. Unrelated donor transplants offer encouraging results in suitable patients, but bring with them the increased risk of complications. BMT is also successful in some children in second remission or who have refractory disease. A recent development in the transplant of children with AML is the use of nonradiation-containing conditioning regimens to avoid potential long-term sequelae of total body irradiation. Nonradiation regimens appear to be as efficacious as radiation-containing regimens for these children. The superiority of BMT over chemotherapy has recently been challenged, as improved supportive care and extremely intensive therapy have resulted in approximately 75% of children achieving a remission and 30-40% of patients surviving. Recent studies have focused upon answering the question regarding the role of BMT in children in first remission. Strategies to improve the outcome of BMT and comparison sequelae of BMT to those on high dose chemotherapy are issues that need to be addressed.
Bone Marrow Transplantation↗
Bone marrow transplantation for high risk neuroblastoma at the Children's Hospital of Philadelphia: an update.
A bone marrow transplant (BMT) protocol including surgical excision, local and total body irradiation, and high dose multiagent chemotherapy based on melphalan and bone marrow rescue has been in effect for children with high risk or relapsed neuroblastoma at the Children's Hospital of Philadelphia since 1979. The initial results were reported in 1984 [August et al.: J Clin Oncol 2:609-616, 1984]. This report updates the initial results and those that followed changes in the original conditioning regimen. Forty-two patients were treated between may 1979 and November 1987, and included 27 whose disease had relapsed and 15 who received BMT as part of primary treatment. Allogeneic marrow was given to 12 and autologous marrow to 30; in 7 of these 30, the marrow was purged with monoclonal antibodies and magnetic beads. The 4-year actuarial survival rate is 29%. Ten patients died of early treatment-related complications, 18 died of progressive disease, and 2 died of late complications (1 AIDS and 1 acute myelogenous leukemia). Censoring the two late complications the actuarial 4-year relapse-free survival rate becomes 32%. The longest interval after BMT to relapse was 20 months. There was no significant difference in the survival for patients transplanted following relapse or in first remission. The better survival for patients rescued with autologous marrow (30%) is not statistically significantly different from the result with allogeneic marrow (17%).
Adult↗
Increasing incidence of adenovirus disease in bone marrow transplant recipients.
Adenovirus infections in 201 bone marrow transplant (BMT) recipients over 4 years were retrospectively reviewed. Forty-two patients (20.9%) had positive adenovirus cultures after BMT. There was a higher incidence of adenovirus infections in pediatric patients than in adults (31.3% vs. 13.6%, P = .003). In addition, the time of onset of adenovirus infection after transplant was earlier in pediatric patients (mean, < 30 days) than in adults (> 90 days). Adenovirus type 35 was the most common serotype identified. One-third of adenovirus-positive patients had definite or probable adenovirus disease. Moderate to severe acute graft-versus-host disease and isolation of adenovirus from two or more sites were significant risk factors for adenovirus disease. This report documents a higher incidence of both adenovirus infection and disease than do previous studies. Adenovirus may emerge as a more frequent pathogen as more high-risk BMT transplants are done.
Adenovirus Infections, Human↗
DNA-based HLA typing of nonhematopoietic tissue used to select the marrow transplant donor for successful treatment of transfusion-associated graft-versus-host disease.
Transfusion-associated graft-versus-host disease (TAGVHD) is a rare and usually fatal complication of blood transfusion which can arise when immunocompetent lymphocytes from the donor of a cellular blood product are transfused into a severely immunocompromised recipient. We describe the case of an 8-month-old male with a severe combined immunodeficiency syndrome who developed TAGVHD after receiving an unirradiated transfusion. Serologic HLA typing of the parents, the patient, and the blood donor demonstrated the foreign origin of circulating lymphocytes, confirming the diagnosis of TAGVHD. The manifestations of TAGVHD did not respond to medical immunosuppressive therapy, and bone marrow transplantation was planned to treat the underlying immunodeficiency as well as the TAGVHD. By using DNA-based class I and class II HLA typing, the child's HLA type was determined from nonhematopoietic tissues. This information proved critical in selecting the bone marrow donor. The child received immunosuppression, myeloablation, and a T-depleted, maternal bone marrow graft mismatched at one HLA class II allele. Trilineage hematopoietic engraftment occurred within 3 weeks, and the child remains clinically stable with no evidence of TAGVHD more than 2 years after the transplant. This case illustrates that TAGVHD can be successfully treated by allogeneic bone marrow transplantation and that DNA-based HLA typing can play a unique role in the diagnosis and management of TAGVHD.
Bone Marrow Transplantation↗
T-cell-depleted maternal bone marrow transplantation for siblings with X-linked severe combined immunodeficiency.
Prenatal diagnosis of X-linked severe combined immunodeficiency in a male fetus made possible elective neonatal bone marrow transplantation before onset of symptoms. Bone marrow transplantation was performed by using T-cell-depleted maternal marrow that had been cryopreserved 2 years earlier, at the time that his older affected brother underwent transplantation. The second patient had less morbidity and more rapid reconstitution of his immune function.
Alleles↗
Central role of tumour necrosis factor, GM-CSF, and interleukin 1 in the pathogenesis of juvenile chronic myelogenous leukaemia.
In previous studies on patients with juvenile chronic myelogenous leukaemia (JCML), we found excessive proliferation of malignant monocyte-macrophage elements in the absence of exogenous growth factor, and impaired growth of normal haematopoietic progenitors. In the current study, six newly-diagnosed JCML patients were investigated to characterize the disease further. In co-cultures, JCML cell culture supernatant as well as patient plasma obtained at diagnosis produced a striking reduction in numbers of control marrow BFU-E, CFU-GM, CFU-Meg and CFU-GEMM colonies. Monoclonal anti-tumour necrosis factor alpha neutralizing antibodies (anti-TNF-alpha Ab) abolished these inhibitory properties. In sharp contrast, JCML supernatants exerted a marked growth-promoting effect on autologous JCML cells cultured in clonogenic assays. Anti-TNF-alpha Ab and anti-granulocyte-macrophage colony-stimulating factor neutralizing antibodies (anti-GM-CSF Ab) both reversed the stimulating effect. Recombinant GM-CSF and recombinant TNF alpha produced a profound increase in JCML colonies when tested individually and anti-GM-CSF Ab reversed the TNF-alpha effect. Expression studies of TNF-alpha and TNF-alpha receptor genes of cultured JCML cells demonstrated mRNAs for both. Further, TNF-alpha activity was assayed in a wide variety of cell culture supernatants and in normal and patients' plasma, and only the JCML specimens showed increased TNF-alpha values. Recombinant interleukin-1 alpha (IL-1 alpha) also stimulated JCML colony growth, but polyclonal anti-IL-1 neutralizing antibodies did not suppress JCML colony numbers nor did it reverse the effects of TNF-alpha or GM-CSF. The evidence indicated that the JCML monokine which inhibits normal haematopoiesis is TNF-alpha and that the endogenously-produced TNF-alpha and GM-CSF from JCML cells play an important role in the pathogenesis of the disease by acting as autocrine growth factors. IL-1 alpha also stimulates JCML cell proliferation as an accessory factor and augments the effect of GM-CSF, TNF-alpha or both.
Base Sequence↗
Chromosome 7 abnormalities in children with Down syndrome and preleukemia.
Three children, two boys and one girl, with Down syndrome (DS) who presented with preleukemia and loss of all or part of chromosome 7 were studied. Initial presentation, with cytopenias and less than 25% blasts in the bone marrow, was between 13 and 30 months of age. Progression to acute nonlymphocytic leukemia occurred 1-8 months after initial presentation. The morphologic type was megakaryoblastic in two, and undifferentiated in one. Two children achieved remission with intensive therapy, and one continues in remission off therapy; the other child died in remission of accidental causes. The third child died of respiratory distress and leukemia after no intervention was chosen. These cases represent the first examples of chromosome 7 abnormalities associated with DS and leukemia, and suggest differences from the "monosomy 7" syndrome seen in children without DS.
Child, Preschool↗
Successful allogeneic transplantation of T-cell-depleted bone marrow from closely HLA-matched unrelated donors.
We describe a four-year experience with bone marrow transplantation involving closely HLA-matched unrelated donors and 55 consecutive patients with hematologic disease who were seven months to 48.6 years old (median, 18 years). An intensive pretransplantation conditioning regimen and graft-versus-host disease (GVHD) prophylaxis with CD3-directed T-cell depletion and cyclosporine were employed. Durable engraftment was achieved in 50 of 53 patients who could be evaluated (94 percent; 95 percent confidence interval, 83 to 98 percent). Acute GVHD of Grade II to IV developed in 46 percent of the patients (confidence interval, 27 to 66 percent). The incidence and severity of acute GVHD were increased in recipients of HLA-mismatched marrow as compared with recipients of phenotypically matched marrow (incidence of 53 percent [confidence interval, 37 to 68 percent] vs. 17 percent [confidence interval, 5 to 45 percent]; P less than 0.05). Extensive chronic GVHD and deaths not due to relapse also tended to be more frequent when HLA-mismatched marrow was used, but not significantly so. With a median follow-up of more than 19 months (range, greater than 9 to greater than 39), the actuarial disease-free survival of transplant recipients with leukemia and a relatively good prognosis (acute leukemia in first remission and chronic myelogenous leukemia in chronic phase) was 48 percent (confidence interval, 24 to 73 percent), and that of recipients with more aggressive leukemia was 32 percent (confidence interval, 18 to 51 percent); the actuarial survival of recipients with non-neoplastic disease was 63 percent (confidence interval, 31 to 86 percent). We conclude that marrow transplantation with closely HLA-matched unrelated donors can be effective treatment for neoplastic and non-neoplastic diseases. Although transplants from phenotypically HLA-matched unrelated donors appear to be most effective, transplants with limited HLA disparity can also be successful in some patients.
Adolescent↗
Oral fluconazole for treatment of disseminated fungal infection.
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Administration, Oral↗
Immunoblastic peripheral T-cell lymphoma confined to bone marrow in an infant presenting with aspergillosis.
A 16-month-old female infant presenting with pancytopenia and fever was found to have pulmonary aspergillosis and large-cell immunoblastic non-Hodgkin's lymphoma of peripheral post-thymic origin isolated to bone marrow. Extensive noninvasive evaluations failed to demonstrate the disease in other extramedullary sites. The malignant cells were large and polymorphous; lacked terminal transferase; expressed surface CD-2, CD-3, CD-8, and HLA-DR antigens, and showed rearrangements of the T-cell-receptor beta-chain gene. To our knowledge, this type of lymphoma in an infant has not been reported before. Furthermore, aspergillosis is a rare presenting feature in patients with lymphoproliferative disease. In our case, it may reflect an underlying immune deficiency associated with the transformation and proliferation of a suppressor T cell.
Aspergillosis↗
Provocative pattern of rearrangements of the genes for the gamma and beta chains of the T-cell receptor in human leukemias.
To examine the distribution of rearrangements of the gamma- and beta-chain T-cell receptor (TCR) genes in T- and non-T acute lymphoblastic leukemias (ALLs), and potentially to determine which genes rearrange first in ontogeny, we analyzed high molecular weight DNA from 102 patients with acute leukemia. Rearranged gamma- and beta-chain genes were found in all T-cell ALLs (22/22) examined. Overall, 27% (18/66) of B-lineage ALLs had beta-chain gene rearrangements, and 41% (24/58) had gamma-chain gene rearrangements, but the distribution of rearranged genes varied according to the stage of B-cell differentiation. The gamma-chain genes were rearranged in 11% (1/9) of the B-lineage patients negative for the common acute lymphoblastic leukemia antigen (cALLA) and 50% (23/46) of cALLA+ ALL patients, while the beta-chain genes were not rearranged in any of the 7 cALLA- ALL patients examined but were rearranged in 32% (18/56) of the cALLA+ patients. Neither TCR gene was found to be rearranged in acute nonlymphoid leukemia patients (0/12) or in patients with B-cell (surface immunoglobulin-positive) leukemia (0/3). Of the 44 cALLA+ patients in which a direct comparison of gamma- and beta-chain gene rearrangements could be made, 34% had both genes rearranged, 16% had only gamma-chain gene rearrangements, and the remaining 50% had both genes in the germ-line configuration. beta-Chain rearrangements have not been found in the absence of gamma-chain rearrangements, thus supporting a proposed hierarchy of TCR gene rearrangements. A provocative finding was that only a small percentage (11%) of the patients with cALLA- B precursor cell ALLs had rearranged TCR genes, while 50% of the cALLA+ leukemia patients had at least gamma-chain rearrangement, raising a question as to whether indeed cALLA- cells are precursors to cALLA+ cells. Interestingly, 18% (2/11) of the cytoplasmic immunoglobulin (cIg)-positive cALLA+ (pre-B) ALLs involved TCR gene rearrangements, compared to 60% (21/35) of the cIg-negative cases, suggesting the possibility that the majority of functional B cells are derived from the cALLA+ pool that contains immunoglobulin but not TCR gene rearrangements.
Adolescent↗
Ocular relapse in the anterior chamber in childhood acute lymphoblastic leukemia.
We reviewed 11 cases of ocular relapse in the anterior chamber in children with acute lymphoblastic leukemia (ALL), representing 0.5% of all primary relapses seen at this center. Nine patients had hypopyon, and two had iris involvement only. Concomitant testicular relapse was present in two children and hematologic relapse in one. Ocular relapse occurred at 12 to 74 months (median, 36 months) from the data of initial diagnosis. Children who relapsed after therapy was discontinued did so within 1 year of completing therapy. Topical steroids and systemic chemotherapy were administered to all patients with ocular relapse; four also received radiation to the involved eye (600 to 1,050 cGy). Four children, each with a prolonged initial complete remission, remain free of disease for 15+, 32+, 34+, and 145+ months following anterior chamber relapse; three had received radiation therapy. Five patients died of recurrent leukemia, and two of infection while in remission. Aggressive retreatment appears warranted in cases of anterior chamber relapse of ALL, as some of these children may attain prolonged new remissions.
Adolescent↗
Pancreatitis following cisplatin: a case report.
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Child↗
Immune reconstitution after autologous purged bone marrow transplantation in children.
PURPOSE: Immune reconstitution was studied in 30 children who had received purged autologous bone marrow transplantation for neuroblastoma or acute myeloid leukemia (AML). METHODS: Patients with neuroblastoma received high-dose chemotherapy and total body irradiation, and patients with AML received chemotherapy alone. Marrows were purged ex vivo with either antineuroblastoma monoclonal antibodies (neuroblastoma) or 4-hydroperoxycyclophosphamide (AML). Lymphocyte subsets, mitogen stimulation studies, and immunoglobulin levels were studied every 4 months. RESULTS: There were no significant differences between the two groups of patients in lymphocyte number or subsets over time. In both groups, CD2+ and CD4+ cells were below normal in 33% of patients at 12 months. CD4+/CD8+ ratios were below normal for up to 8 months after transplantation and natural killer cells were elevated for up to 2 years in most patients. Median IgG and IgA levels were below the age mean even at 2 years after transplantation, although patients with AML had significantly higher IgG levels at 12 months compared with those with neuroblastoma. Lymphocyte proliferative responses to mitogens were markedly reduced at 4 months but returned to normal at 8 months. Despite the delay in immune reconstitution, there were no life-threatening infections. CONCLUSIONS: There appeared to be little difference in the overall kinetics of immune reconstitution between the children with neuroblastoma, who received total body irradiation and high-dose chemotherapy, and those with AML, who received high-dose chemotherapy alone as their pretransplant preparative regimen.
Acute Disease↗
Growth in children after bone marrow transplantation for acute myelogenous leukemia as compared to acute lymphocytic leukemia.
Previous studies of growth in children following bone marrow transplantation for leukemia have demonstrated poor growth with little ability to "catch-up" two to four years after transplantation. Because of small patient numbers, these studies did not distinguish patients with differing types of leukemia. 12 children with acute myelogenous leukemia who survived over 3 years after transplantation were compared with 12 who survived transplantation for acute lymphoblastic leukemia. The initial height standard deviation scores were similar in both groups prior to transplantation. The height standard deviation scores in the acute lymphoblastic leukemia group decreased for each of the 5 years after transplantation while the height score for the acute myelogenous leukemia group after 5 years was not statistically different from pre-transplantation. The growth of the children with myelogenous leukemia was better possibly because these children were older, had received less cranial irradiation at the time of transplantation, and had a lower incidence of severe chronic graft-versus-host disease.
Adolescent↗
Intraocular Ki-1 lymphoma in a 2-year-old boy.
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Antineoplastic Combined Chemotherapy Protocols↗
Alternative donor bone marrow transplantation for children with juvenile myelomonocytic leukemia.
The purpose of this study was to evaluate the outcome of children with juvenile myelomonocytic leukemia (JMML) treated with alternative donor bone marrow transplantation (BMT). Twelve consecutive patients with JMML confirmed by in vitro clonogenic assays underwent alternative donor BMT. Ten patients received pretransplant chemotherapy for one to seven cycles (cytosine arabinoside regimens). Eight underwent splenectomy before the transplant. Donors were unrelated for nine patients and partially matched related for three. Conditioning included total body irradiation for all but one patient. Graft-versus-host disease (GVHD) prophylaxis included in vitro partial T-lymphocyte depletion for five patients with cyclosporine arabinoside, and cyclosporine arabinoside and methotrexate for seven. Acute GVHD developed in all patients, and chronic GVHD developed in 7 of 11 evaluable patients. Relapses occurred in two patients, and two died of transplant-related causes. Eight patients remain in remission with a median follow-up of 31 months after the BMT. The event-free survival rate for this series is 64% (95% confidence interval, 27%-85%). The roles of pretransplant chemotherapy and splenectomy for leukemic reduction to prevent relapse, and the use of conditioning regimens with total body irradiation require study in a larger series of patients. GVHD may be beneficial in preventing relapses, which has been the major cause of treatment failure for these patients.
Adolescent↗