Haemorrhagic cystitis: incidence and risk factors in a transplant population using hyperhydration.
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Haemorrhagic cystitis (HC) is the syndrome of haematuria and symptoms of lower urinary tract irritability in the absence of bacterial infection. We report a low incidence of HC (18.2%) in 681 haemopoietic stem cell transplant patients, using a prophylactic regimen of hyperhydration and forced diuresis. The incidence of grade 3-4 disease is 3.4%. There was a marked difference in incidence between allogeneic and autologous transplant populations, 24.2% vs. 3.5% (P<0.0005). Busulphan conditioning, acute GVHD, interstitial pneumonitis and use of methotrexate and cyclosporin immune suppression were associated with significantly increased incidence of HC in the allogeneic population. This may reflect the numerous factors that contribute to the greater immunosuppression and consequent increased risk for HC in allogeneic transplantation. (+info)
Improvement of tumor cell depletion by combining immunomagnetic positive selection of CD34-positive hematopoietic stem cells and negative selection (purging) of tumor cells.
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One possible reason for relapse after high-dose chemotherapy is retransplantation of tumor cells contaminating autologous hematopoietic stem cell transplants. Residual tumor cells can be diminished by various purging methods. We studied tumor cell depletion by sequentially combining immunomagnetic positive selection of CD34+ hematopoietic stem cells using Isolex50 or Isolex300SA and negative tumor cell depletion using MACS, MaxSep or Isolex50 systems. Using these separation systems in different selection sequences, i.e. positive followed by negative selection (+/- selection) or vice versa, four groups of double selections (Isolex50/MACS, Isolex50/MaxSep, MaxSep/Isolex50, Isolex300SA/Isolex50) were studied. Testing these double-purging procedures mean additional tumor cell depletion (deltaTCD) achieved by the second selection step ranged from 1.1+/-0.58 log (n = 5, +/- Isolex50/MACS) to 2.0+/-1.1 log (n = 7, -/+ MaxSep/Isolex50). Loss of CD34+ cells during double selection sometimes was extensive and mean yield of CD34+ cells ranged from 12.8+/-11.5% (n = 6, +/- Isolex50/MaxSep) to 43.2% (n = 2, +/- Isolex300SA/Isolex50). Calculated values for mean yield-corrected deltaTCD ranged from 0.64+/-0.3 log (n = 5, +/- Isolex50/MACS) to 1.4+/-1.3 log (n = 7, -/+ MaxSep/Isolex50). During positive selection of -/+ selection (MaxSep/Isolex50) relative tumor cell enrichment was detectable leading to an increment of mean tumor cell contamination rate. Best results for total TCD were achieved by the combination of Isolex50/MaxSep (n = 6; TCD: 4.2 log; yield CD34+: 12.8%) and Isolex300/Isolex50 (n = 2; TCD: 3.8 log; yield CD34+: 43.2%). Furthermore, we have established and tested a new simultaneous +/- selection method by using CD34-specific releasing agent PR34+ in the Isolex300i. With this method we have obtained a mean total yield-corrected TCD of 4.7 log (n = 4; range: 4.1-6.0 log) with high CD34+ cell yield (mean: 69.8%) and CD34+ cell purity (mean: 92.8%). Since this new simultaneous +/- purging procedure is safe, applicable within a closed system (GMP-like) and most effective, we recommend it for further testing in a clinical setting. (+info)
Acute quadriplegic myopathy following autologous peripheral blood stem cell transplantation for breast cancer.
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Autologous peripheral blood stem cell transplantation (APSCT) is increasingly used in the treatment of breast cancer. We report a patient who experienced septic shock, and after treatment with antibiotics, high-dose corticosteroids and mechanical ventilation due to respiratory insufficiency, developed quadriplegia. Electroneurophysiological examination, as well as a muscle biopsy, showed a typical picture of acute quadriplegic myopathy with loss of thick filament proteins. This is, to the best of our knowledge, the first reported case of this complication following APSCT. (+info)
Depletion of alloreactive T cells by a specific anti-interleukin-2 receptor p55 chain immunotoxin does not impair in vitro antileukemia and antiviral activity.
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The success of bone marrow transplantation (BMT) from HLA-disparate donors depends on the development of new strategies able, on one hand, to efficiently prevent graft-versus-host disease (GVHD) and, on the other hand, to protect leukemic patients from relapse and infections. Using an immunotoxin (IT) directed against the alpha chain (p55) of the human interleukin-2 receptor (RFT5-SMPT-dgA), we previously showed that it is possible to kill mature T cells activated against a specific HLA complex by a one-way mixed lymphocyte culture (MLC). The present study was performed to investigate whether this protocol of allodepletion affects the capacity of residual T cells to display antileukemia and antiviral activity evaluated by limiting dilution assays (LDA), measuring the frequency of cytotoxic T-lymphocyte precursors (CTLp) directed against autologous leukemic blasts (LB) and cytomegalovirus (CMV)- and Epstein-Barr virus (EBV)-infected target cells. Antileukemia activity was evaluated in peripheral blood mononuclear cells (PBMC) of 3 patients treated for acute myeloid leukemia who had developed a high frequency of LB-reactive CTLp after either autologous or allogeneic BMT. Results demonstrate that (1) depletion with RFT5-SMPT-dgA efficiently inhibited MLC; (2) fresh PBMC of patients yielded a high frequency of LB-reactive CTLp comparable to that of the mock-treated PBMC; and (3) effector cells obtained after allodepletion fully retained the capacity to lyse pretransplant LB. By contrast, the frequency of CTLp directed against patient's pretransplant BM remission cells was always undetectable. Data obtained in 4 healthy donors showed that specifically allodepleted T cells recognized and killed autologous CMV-infected fibroblasts and autologous EBV-B-lymphoblastoid cell lines. In conclusion, our data indicate that allodepletion using RFT5-SMPT-dgA efficiently removed alloreactive cells, while sparing in vitro antileukemic and antiviral cytotoxic responses. (+info)
A quantitative assessment of the healing of intramembranous and endochondral autogenous bone grafts.
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The aim of the study was to assess quantitatively the amount of new bone formed in the early stages of healing of intramembranous and endochondral autogenous bone grafts so as to gain further insight into their integration with host bone. Eighteen critical size defects were created in the parietal bone of nine New Zealand White rabbits. In the experimental group (five rabbits), each rabbit was grafted with intramembranous bone in one defect and with endochondral bone in the other. In the control group (four rabbits), one defect was left empty (passive control) and the other was grafted with rabbit skin collagen (active control). After 14 days, the rabbits were killed and the defects were prepared for histological analysis. Serial sections were made across the whole defect. Each defect was divided into five regions spaced 1500 microns apart. Two sections were randomly drawn from each region. Quantitative analysis was performed on 100 sections using an image analyser computer software system to assess the amount of new bone formed in each defect. No bone was detected across the defect in either the active or passive controls. One-hundred-and-sixty-six per cent more new bone was formed in defects grafted with intramembranous bone than those grafted with endochondral bone. This represented an extremely significant difference (P < 0.0001, unpaired t-test) between the two groups. The results show that intramembranous autogenous bone produced more bone than the endochondral bone when grafted in the skull. Clinically, it is recommended that intramembranous bone is used to replace lost membranous bone in the oral cavity, as well as in skull defects, whenever possible. (+info)
Clinical and molecular follow-up by amplification of the CDR-III IgH region in multiple myeloma patients after autologous transplantation of hematopoietic CD34+ stem cells.
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BACKGROUND AND OBJECTIVE: Autologous blood stem cell transplantation (ABSCT) using chemotherapy-induced mobilization of peripheral blood stem cells (PBSC) is being increasingly used in the treatment of multiple myeloma (MM). We report the clinical and molecular follow-up of 10 MM patients who underwent autologous stem cell transplantation with peripheral blood selected CD34+ cells, as support therapy following a myeloablative conditioning regimen. DESIGN AND METHODS: The CDR-III coding region of the IgH gene was studied by a) consensus PCR applied to 8 MM patients, or b) by direct sequencing of PCR product generated by family-specific primers in the remaining two patients (who became immunofixation analysis (IF) negative). In this case, two patient-specific primers were generated, thus obtaining a high PCR assay sensitivity and specificity (ASO PCR). RESULTS: Seven patients are alive: 4 of them have serum M protein assessable by IF, while 1 was not a secretor and 2 converted from serum IF positivity to negativity 6 and 12 months after ABSCT. Three patients died: 1 from disease progression and 2 from infective complications during clinical remission. The molecular analysis during the follow-up showed that the bone marrow samples from the two patients who obtained IF negativity were persistently PCR positive for the presence of rearranged CDR-III region. Moreover, despite the remarkable reduction of myeloma burden, a minimal level of residual myeloma cells was still detectable by molecular analysis. INTERPRETATION AND CONCLUSIONS: These results confirm that although positive selection of CD34+ cells markedly reduces the contamination of myeloma cells from apheresis products by up to 3 log, and provides a cell suspension capable of restoring normal hematopoiesis after ablative conditioning regimen, it does not abrogate myeloma cell contamination in most of the apheresis products. (+info)
The utilization of cytokines in stem cell mobilization strategies.
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High-dose myeloablative chemotherapy supported by peripheral blood progenitor cell (PBPC) transplant is rapidly replacing bone marrow transplant to treat a number of chemosensitive cancers. Numerous investigators have studied the relationship of CD34+ cell dose and engraftment kinetics in an effort to help define minimum and optimum target stem cell doses. A number of studies suggest that reinfusion of > or = 5 x 10(6) CD34+ PBPCs results in prompt and durable platelet engraftment. Mobilization of stem cells can be accomplished through use of chemotherapy alone, colony-stimulating factors, or a combination of the two. Strategies to improve PBPC yields include filgrastim in combination with chemotherapy or with other hematopoietic growth factors. In this paper, the advantages and disadvantages of these strategies will be discussed, and the results of a recently conducted, randomized, controlled phase 3 clinical trial in breast cancer patients receiving either SCF plus filgrastim or filgrastim alone for PBPC mobilization will be reviewed. (+info)
Economic considerations in the use of peripheral blood progenitor cells to support high-dose chemotherapy.
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There has been increasing interest in the development of strategies to enhance the number of CD34+ cells obtained during harvesting of peripheral blood progenitor cells (PBPC) to support high-dose chemotherapy. The strategies have included the use of chemotherapy plus cytokine for mobilization, and the development of more effective mobilizing cytokine combinations, such as stem cell factor plus filgrastim. Although there are costs associated with the implementation of these strategies, there are also predictable cost savings to be realized from the enhanced PBPC yields. Available data suggest that these cost savings include: $2000 per apheresis prevented, $6000 per back-up bone marrow harvest prevented, and at least $10200 per remobilization and apheresis stage prevented. In addition, there is emerging evidence that the administration of optimal (> or = 5 x 10(6)/kg) as opposed to acceptable but suboptimal (>1 x 10(6)/kg but <5 x 10(6)/kg) numbers of CD34+ PBPC will be associated with decreased supportive care needs and decreased costs of at least $4500-8000. These economic considerations should play a role, together with clinical data, in rational decision-making with respect to PBPC support. (+info)