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PubMed2002

Bone marrow transplantation for nonmalignant diseases.

Bone marrow transplantation (BMT) has emerged as a major therapeutic option for a number of nonmalignant disorders affecting the bone marrow and leading to clinical manifestations most likely affecting distant organs. Disorders such as autoimmune diseases, metabolic disorders, hemoglobinopathies, immunodeficiencies, and others have been the target of high-dose therapy and autologous or allogeneic bone marrow, stem cell, or cord blood transplantation. Successful results have been reported in a large number of these disorders. In most instances the goal of transplantation is to provide sufficient degree of marrow engraftment to allow long-term amelioration of disease phenotype. For many of these disorders, early diagnosis is crucial in achieving the desired results as transplantation becomes difficult when significant end-organ damage sets in. Major unsolved problems, including toxicity of conditioning regimens, graft-versus-host disease, and donor availability, need to be addressed. We attempt to provide a comprehensive review of BMT and discuss unique features of this modality for treatment of nonmalignant disorders.

Bone Marrow Transplantation↗
PubMed2003

Roles of bone marrow cells in glomerular diseases.

Bone marrow transplantation (BMT) has been used as a tool to investigate various roles of bone marrow cells in glomerular diseases. BMT from IgA nephropathy-prone mice caused glomerular IgA deposition associated with increased circulating macromolecular IgA in normal recipients. Conversely, glomerular mesangial lesions of IgA nephropathy-prone mice were markedly diminished by BMT from normal donors, and the circulating levels of macromolecular IgA were also decreased in the recipients. These data suggest that IgA nephropathy may be a stem-cell disease. BMT clearly decreased the glomerular injuries in glomerular diseases other than murine IgA nephropathy. Theoretically, one mechanism underlying the therapeutic effect of BMT is the replacement of the recipient's destructive immune cells with the donor's bone marrow cells. Interestingly, when BMT was performed by using bone marrow cells of green fluorescent protein (GFP) transgenic mice to investigate the differentiation of bone marrow stem cells in recipients, it was revealed that bone marrow-derived cells differentiated into glomerular cells in mice receiving BMT. This result suggests an alternative mechanism, in that bone marrow cells not only replace harmful immune cells but that they also replenish injured glomerular cells in BMT recipients, which results in the repair of glomerular lesions after BMT. In addition, the glomerular remodeling could participate in maintaining glomerular homeostasis. If the mechanisms of glomerular remodeling are investigated, this could offer a new therapeutic strategy for the repair of glomerular injuries.

Animals↗
PubMed1999

Long-term follow-up following bone marrow transplantation for Hunter disease.

Bone marrow transplantation (BMT) was performed in 10 patients with Hunter disease (mucopolysaccharidosis type II, iduronate-2-sulphatase deficiency). The donor was an HLA-identical sibling in 2 cases, an HLA-nonidentical relative in 6 cases, a volunteer unrelated donor in 1 case, and details were not available in 1 case. Only three patients have survived for more than 7 years post BMT; however, this high mortality probably resulted from poor donor selection. In two, there has been a steady progression of physical disability and mental handicap. One patient has maintained normal intellectual development, with only mild physical disability. It is possible that BMT may be useful in selected patients with MPS II.

Adolescent↗
PubMed1996

Bone marrow transplantation in immunodeficiency diseases.

Bone marrow transplantation (BMT) has become the treatment of choice in an increasing number of primary immunodeficiency disorders. In many of these otherwise lethal genetic diseases, BMT can completely reverse the immunological abnormality and patients may be permanently cured. In this review, current approaches in the application of this treatment and results obtained in various entities of primary immunodeficiencies are presented. A significant prognostic factor for the outcome is the clinical condition of the patient at the time of BMT, and prompt recognition of these rare disorders remains an important prognostic factor for BMT.

Bone Marrow Transplantation↗
PubMed1988

Histiocytic diseases of bone marrow.

The disease most likely to be associated with large numbers of bone marrow storage histiocytes is Gaucher's disease. In our community of western Pennsylvania, eastern Ohio, and West Virginia, we have encountered 30 patients with Gaucher's disease during the past 25 years. During the same 25 years, a group of about 20 other patients have been examined for storage cells caused by diseases other than Gaucher's disease. These other conditions are associated with smaller numbers of storage cells, and these patients require a more extensive examination that should include serum or tissue lipid analyses, enzymology, and electron microscopy to assist in the diagnosis.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Bone marrow examination in Hodgkin's disease.

Bone marrow aspiration and biopsy was performed as part of routine staging in 425 patients with primary Hodgkin's disease. Only seven patients were found to have bone marrow disease by biopsy and only four by aspiration. All these patients had B symptoms and stage III or IV before bone marrow examination. Bone marrow infiltration did not influence treatment decision and there was no association between bone marrow findings and outcome of the disease.

Adult↗
PubMed2004

Bone marrow biopsy in Hodgkin's disease.

Bone marrow biopsies of 58 untreated patients with Hodgkin's disease were evaluated. Marrow involvement was seen in 36.2 % cases. Positive marrow biopsies were seen mainly in patients with clinical stages III and IV. Bone marrow involvement was most common in patients with less than 15 years of age and in males. HD patients with mixed cellularity had highest incidence of marrow involvement while none of the patients with lymphocytic predominance showed BM involvement. Focal infiltration was found to be more common. Bone marrow aspiration smears were negative in majority of cases with positive marrow biopsies. Thus BM trephine biopsy is a simple tool for assessment of disease spread.

Biopsy, Needle↗
PubMed2001

Imaging of metabolic bone disease and marrow disorders in children.

There are a wide variety of metabolic and infiltrative diseases that involve the bones. Conventional radiography is the primary imaging examination for the initial evaluation of most of these disorders. MR imaging, however, provides detailed information about the bone marrow and is gaining an increasingly important role in the management of disorders of bone marrow infiltration.

Adolescent↗
PubMed1976

Bone marrow manifestations of Hodgkin's disease.

Bone marrow trephine biopsies were performed on 107 previously untreated patients with Hodgkin's disease (HD). Fifteen patients (14%) exhibited bone marrow involvement. These consisted of two of three patients (67%) with lymphocyte depletion, six of 27 patients (22%) with mixed cellularity, five of 64 patients (8%) with nodular sclerosis, and two who were unclassified. Twelve patients manifested a diffuse pattern of involvement; three, a focal pattern. In eight patients more than 70% of the marrow biopsy was replaced by Hodgkin's tissue, in one patient 50% of the marrow biopsy was replaced, and in six patients less than 30% of the marrow biopsy was replaced. Typical Reed-Sternberg (RS) cells were found in the trephine biopsies in 13 of the 15 patients and mononuclear RS variants in two. Bone marrow involvement was the only evidence of stage IV disease in 10 of the 15 patients. In addition to the 15 patients with initial involvement with HD, 11 patients without marrow involvement exhibited granulomas (six) and benign lymphocytic aggregates (five) in their trephine sections. Hematological parameters were studied in all pretreatment patients. Only in the nodular sclerosis group were these parameters useful in differentiating patients with and without Hodgkin's involvement of the marrow. Seventeen additional patients who had been previously treated at the time HD was demonstrated in their bone marrow were also studied. Large areas of necrosis were frequently seen in previously treated patients and one patient demonstrated cryptococcosis in the bone marrow.

Adolescent↗
PubMed1994

Early bone marrow transplantation in Hodgkin's disease.

Bone marrow transplantation can be curative for patients with advanced Hodgkin's disease. Results are better when patients are transplanted after only one chemotherapy regimen at a time of minimal disease. Clinical trials are beginning testing bone marrow transplantation as part of the initial treatment for patients with widely disseminated, poor prognosis Hodgkin's disease.

Actuarial Analysis↗
PubMed2002

Bone marrow transplantation: a new strategy for intractable diseases.

Bone marrow transplantation is becoming a powerful strategy for the treatment of hematologic disorders (leukemia, aplastic anemia, etc.), congenital immunodeficiencies, metabolic disorders and also autoimmune diseases. Using various animal models for autoimmune diseases, we have previously found that allogeneic (not autologous) bone marrow transplantation can be used to treat autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, immune thrombocytic purpura, insulin-dependent diabetes mellitus, chronic glomerulonephritis and certain types of non-insulin-dependent diabetes mellitus. In contrast, we have found that the transplantation of T-cell-depleted bone marrow cells or partially purified hemopoietic stem cells from autoimmune-prone mice to normal mice leads to the induction of autoimmune diseases in the recipients. These findings have recently been confirmed even in humans; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and Crohn's disease were resolved after allogeneic bone marrow transplantation. However, there have recently been reports on the rapid recurrence or persistence of autoimmune diseases after autologous bone marrow transplantation. Conversely, the adoptive transfer of autoimmune diseases such as myasthenia gravis, insulin-dependent diabetes mellitus and Graves' disease by allogeneic bone marrow transplantation from donors to recipients has been reported. Owing to these findings, we have proposed that autoimmune diseases are "stem cell disorders." We have thus succeeded in treating autoimmune diseases in various autoimmune-prone mice, except MRL/lpr mice, by conventional bone marrow transplantation. The MRL/lpr mouse itself is radiosensitive (<8.5 Gy), while the abnormal hemopoietic stem cells of the MRL/lpr mouse are radioresistant (>8.5 Gy); conventional bone marrow transplantation (8.5 Gy plus bone marrow transplantation) has a transient effect on autoimmune diseases, which recur three months after the bone marrow transplantation. However, bone marrow transplantation plus bone grafts (to recruit donor stromal cells) completely prevents the recurrence of autoimmune diseases in MRL/lpr mice. Donor-derived stromal cells (including mesenchymal stem cells) thus seem to play a crucial role in successful allogeneic bone marrow transplantation, since there is a major histocompatibility complex restriction between hemopoietic stem cells and stromal cells. We have, however, found that the combination of bone marrow transplantation plus bone grafts has no effect on the treatment of autoimmune diseases in MRL/lpr mice, since MRL/lpr mice become more radiosensitive after the onset of lupus nephritis due to the development of uremic enterocolitis. To reduce the cytotoxic effect of radiation on the intestine, we carried out fractionated irradiation and devised a new strategy. We injected allogeneic whole bone marrow cells (including a small number [<3%] of T cells, hemopoietic stem cells and stromal cells) from donors directly into the intra-bone marrow of recipients so that donor-derived hemopoietic cells including stromal cells could effectively accumulate in the bone marrow. All the MRL/lpr mice survived more than one year (>60 weeks after birth) without the recurrence of autoimmune diseases, and immunological functions were completely restored even when the radiation dose was reduced to 5 Gy x 2. These findings suggest that intra-bone marrow injection-bone marrow transplantation can be used to treat intractable autoimmune diseases under reduced radiation doses without using any immunosuppressants.Intra-bone marrow injection-bone marrow transplantation seems to be the best strategy for allogeneic bone marrow transplantation: 1) no graft-versus-host disease develops even if T cells are not depleted from the bone marrow; 2) no graft failure occurs even if the dose of radiation as the conditioning for bone marrow transplantation is reduced to 5 Gy x 2; 3) hemopoietic recovery is rapid; and 4) T-cell functions are completely restored even in donor-recipient combinations across the major histocompatibility complex barriers. Using cynomolgus monkeys, we have recently established a new method (the "perfusion method") for collecting bone marrow cells from the long bones (femur, humerus, etc.) without peripheral blood contamination. This method has various advantages: 1) no graft-versus-host disease develops even in cynomolgus monkeys, since the percentage of T cells in the bone marrow cells collected is less than 3%; 2) a large number of bone marrow cells can be collected quickly and safely; and 3) the bone marrow cells collected contain stromal cells including mesenchymal stem cells. We therefore believe that this method (intra-bone marrow injection-bone marrow transplantation in conjunction with the perfusion method) will become a powerful new strategy for not only allogeneic bone marrow transplantation but also organ transplantation in conjunction with bone marrow transplantation. Furthermore, this method could become a valuable strategy in regeneration therapy for injured organs and tissues (myocardial infarction, cerebral infarction, Alzheimer's disease, etc.), since it can efficiently reconstitute the recipient with both donor-derived hemopoietic stem cells and mesenchymal stem cells.

Animals↗
PubMed1997

Preclinical investigations that subserve efforts to employ bone marrow transplantation for rheumatoid or autoimmune diseases.

Bone marrow transplantation (BMT) results in the replacement of host immunohematopoiesis with that of the donor. This procedure may be appropriate for patients with severe combined immunodeficiency disease, Wiskott-Aldrich syndrome, and after lethal myeloablation for treatment of leukemia. Preclinical studies in experimental mice with autoimmune disorders indicate that BMT may successfully prevent the development or induce remission of disease. In some experimental models both marrow and stroma must be transplanted for a successful outcome. Allogeneic, rather than syngeneic, transplants are required for successful outcome in these genetically based spontaneous models of autoimmune disease. However, remissions of relapsing forms of demyelinating autoimmune (acquired) central nervous system diseases can be achieved with both syngeneic and allogeneic marrow transplantation. These preclinical studies form part of the rationale for considering BMT as treatment for severe autoimmune diseases.

Animals↗
PubMed1998

Bone marrow transplantation in congenital immunodeficiency diseases.

Bone Marrow transplantation (BMT) is the treatment of choice in a large number of primary immunodeficiencies, for which this treatment is potentially curative. BMT needs to be considered as soon as possible after diagnosis because these disorders usually run an unpredictable course and may be rapidly fatal. Beside conventional HLA-matched donor BMT, there is growing and increasingly favourable experience with alternative, in particular HLA-haploidentical donors. In this review, current results of BMT are presented.

Bone Marrow Transplantation↗
PubMed1989

Hodgkin's disease with bone marrow involvement.

Bone marrow involvement was seen in 11 percent of patients with Hodgkin's Disease which was determined from pre-treatment biopsy specimens using established histopathologic criteria. Analysis of 32 evaluable patients with marrow involvement showed male preponderance with a peak in fourth decade of life. Twenty four cases (75%) had B-symptoms and 15 (46%) presented within six months of onset of symptoms. On categorizing for clinical staging, 21 (65%) belonged to stage III and IV. Hepatomegaly (greater than or equal to 2 cms) was present in seven cases (21%) and splenomegaly in 13 cases (40%). Mixed cellularity and lymphocytic depletion histopathologic subtypes showed the highest frequency of involvement (21 cases; 65%). Out of 28 cases ESR was raised in 27 cases (96%). Eighteen cases (56%) showed elevated serum alkaline phosphatase levels. Serum copper levels were determined in 14 cases, out of which 12 (85%) showed elevated levels. These parameters along with anemia (hemoglobin of 12 g/dl or less) in 26 cases (81%), correlated well with the disease activity. Only four cases had leukopenia at presentation pointing to no hindrance for aggressive chemotherapy. All cases received minimum of six courses of standard combination chemotherapy with or without local radiotherapy. Sixteen cases (50%) relapsed subsequently and were managed accordingly. A five year follow-up revealed a minimal 31 percent overall survival, and 18 percent of patients were disease free and well since the time of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Actuarial Analysis↗
PubMed2003

Increased angiogenesis in the bone marrow of HIV-positive patients with myelodysplasia.

AIM: Little is known about the significance of angiogenesis in the bone marrow of HIV-positive patients with myelodysplastic features (MDF). However, this process has been associated with the pathogenesis of primary myelodysplastic syndromes (MDS). The aim of the study was to investigate angiogenesis in the bone marrow of HIV-positive patients. METHODS: Bone marrow biopsies from 28 HIV-positive patients were immunostained for factor VIII and the microvessel density (MVD) was quantitatively evaluated and compared with that of 32 biopsies from patients with primary MDS and to 18 control bone marrows from patients with no evidence of bone marrow disease. RESULTS: Bone marrow MVD in HIV-positive patients was similar to that of MDS. However, both groups revealed significantly higher MVD counts compared to those of control bone marrows (MDF vs controls P=0.022, MDS vs controls P=0.001). CONCLUSIONS: Bone marrow from HIV-positive patients with MDF reveals similar microvessel counts compared to those with primary MDS, although both differ significantly from that of control bone marrow. Elucidation of the mechanisms underlying bone marrow angiogenesis in HIV-positive patients, may provide further insights into the pathobiology of AIDS and might be of value for the development of new therapeutic strategies for this disease.

Adult↗
PubMed2004

Camptothecin analogs (irinotecan or topotecan) plus high-dose cyclophosphamide as preparative regimens for antibody-based immunotherapy in resistant neuroblastoma.

PURPOSE: We used high-dose cyclophosphamide plus topotecan/vincristine (CTV) or irinotecan (C/I) in patients with resistant neuroblastoma. The aim was to use a regimen with little risk to major organs to (a) achieve or consolidate remission in heavily treated patients and to (b) induce an immunological state conducive to passive immunotherapy with the murine 3F8 antibody. EXPERIMENTAL DESIGN: CTV and C/I included cyclophosphamide 140 mg/kg ( approximately 4200 mg/m(2)). With CTV, topotecan 2 mg/m(2) was infused i.v. (30 min) on days 1-4 (total, 8 mg/m(2)), and vincristine 0.067 mg/kg was injected on day 1. With C/I, irinotecan, 50 mg/m(2) was infused i.v. (1 h) on days 1-5 (total, 250 mg/m(2)). Mesna and granulocyte colony-stimulating factor were used. RESULTS: Twenty-nine patients received 38 courses of CTV, and 26 patients received 38 courses of C/I. All patients had previously received topotecan, a hemopoietic stem-cell transplant, and/or high-dose cyclophosphamide. CTV and C/I caused myelosuppression of comparably prolonged duration as follows: absolute neutrophil counts <500/ micro l lasted 5-12 days in patients who had not previously received transplant and 7-21 days in patients who were post-transplant. Other significant toxicities included typhlitis (two CTV-treated patients, one C/I-treated patient) and hemorrhagic cystitis (one C/I-treated patient). Major responses were seen in 4 (15%) of 26 CTV and 4 (17%) of 24 C/I-treated patients with assessable disease. Bone marrow disease resolved in 5 (28%) of 18 CTV-treated patients and in 4 (27%) of 15 C/I-treated patients. 3F8 after CTV or C/I was not blocked by neutralizing antibodies, consistent with the desired immunosuppressive effect of high-dose cyclophosphamide. CONCLUSIONS: CTV and C/I require transfusional and antibiotic support but otherwise entail tolerable morbidity. They have modest antineuroblastoma activity in heavily treated patients and are good preparative regimens for passive immunotherapy with monoclonal antibodies.

Adolescent↗
PubMed2004

Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation.

Hepatic venoocclusive disease (HVOD) in bone marrow transplantation (BMT) is attributed to toxicity of cytoreductive agents, especially busulfan and cyclophosphamide, in the conditioning therapy. Busulfan, as well as the metabolites of cyclophosphamide, are conjugated with glutathione (GSH), catalyzed by enzymes of the glutathione S-transferase (GST) family. To assess the impact of polymorphisms of the GST genes, GSTM1 and GSTT1, on the risk of HVOD, we evaluated 114 consecutive patients with beta-thalassemia major undergoing BMT. There was a significantly increased incidence of HVOD in patients with the GSTM1-null genotype compared with those with the GSTM1-positive genotype (46.5% vs 18.3%; P =.001). Pharmacokinetic analysis in these patients showed that the clearance of busulfan was higher and first-dose steady-state concentration was lower among those with HVOD (0.403 +/- 0.06 vs 0.33 +/- 0.071 L/h/kg, Student t test P value =.000 01; and 508 +/- 125 vs 656 +/- 255 ng/mL, t test P value =.001, respectively). We conclude that the GSTM1-null genotype predisposes to HVOD, and the sinusoidal endothelial cells and hepatocyte damage may be mediated by metabolites of busulfan through depletion of the cellular GSH pool.

Adolescent↗