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Biomedical subjects

R A Nash

Publications and source records attributed to R A Nash.

At least 37 records · Page 2Linked to original sources
PubMed2001

Secondary failure of platelet recovery after hematopoietic stem cell transplantation.

After primary recovery of platelet counts after transplantation, there can be a late persistent decline called secondary failure of platelet recovery (SFPR), which may occur although the counts of other cell lineages remain within the normal range. SFPR was defined as a decline of platelet counts below 20,000/microL for 7 consecutive days or requiring transfusion support after achieving sustained platelet counts > or = 50,000/microL without transfusions for 7 consecutive days after hematopoietic stem cell transplantation (HSCT). The study population consisted of 2871 consecutive patients receiving transplants from January 1990 to March 1997. After primary recovery of platelet counts, SFPR not due to relapse of the underlying disease was observed in 285 of 1401 (20%) patients undergoing allogeneic transplantation and 36 (8%) of 444 patients undergoing autologous transplantation, with a median time of onset after transplantation at day 63 (range, day 21-156) and day 44 (range, day 24-89), respectively. Concomitant neutropenia was seen in 57 (20%) of 285 patients undergoing allogeneic HSCT and 7 (19%) of 36 patients undergoing autologous HSCT with SFPR. By multivariable analysis, the following were factors significantly associated with SFPR after allogeneic HSCT: a transplant from an unrelated donor; a graft-versus-host disease (GVHD) prophylaxis other than methotrexate and cyclosporine; development of grade 2 through 4 acute GVHD; impaired renal or liver function; conditioning with the combination of busulfan, cyclophosphamide, and total body irradiation; stem cell dose; and infections. Cytomegalovirus infection after engraftment and source of stem cells were the only significant risk factors after autologous HSCT. The hazard rate of death was significantly higher in patients who experienced SFPR (hazard ratio = 2.6 for allogeneic HSCT; hazard ratio = 2.2 for autologous HSCT). SFPR was associated with serious complications and poor outcome after transplantation. The identification of the characteristics and risk factors for SFPR could improve patient counseling and management and lead to the design of effective treatment strategies.

Adolescent↗
PubMed2001

Evaluation of a tapered-sleeve transcortical pin to reduce stress at the bone-pin interface in metacarpal bones obtained from horses.

OBJECTIVE: To evaluate stiffness and bone-pin interface stress for a transcortical tapered-sleeve pin (TSP) that incorporates bilateral tapered sleeves over a transcortical pin. SAMPLE POPULATION: 14 third metacarpal bones (MCIII) collected from adult horses of various breeds. PROCEDURE: Each MCIII was cut in half to provide 2 test specimens. Pins (conventional and TSP) of 3 diameters (6.35, 7.94, and 9.50 mm) were inserted in specimens (3 specimens for each diameter and each type of pin). The test fixture simulated a typical sidebar-span skeletal fixation device for horses. Single cycle load-deflection tests were performed. Cyclic fatigue tests of TSP were performed to evaluate fatigue characteristics and stress conditions at the bone-pin interface. Maximum stress and strain were calculated, and results were compared with existing data on fatigue characteristics of bone. RESULTS: Significant increases in stiffness (load-deflection) and higher loads at yield point were detected for the TSP (stiffness for conventional 9.50mm pins, 4,500 N/mm; stiffness for TSP, 19,988 N/mm). Results of cyclic tests revealed a close correlation with existing data on fatigue characteristics. CONCLUSIONS AND CLINICAL RELEVANCE: The TSP described here is stiffer than conventional transcortical pins, and stress across the bone-pin interface is more evenly distributed. Use of this TSP should minimize major problems encountered during external fixation associated with the transcortical pin and bone-pin interface (ie, bone necrosis, infection of the pin track, pin loosening, and bone failure).

Animals↗
PubMed2001

Nonmyeloablative hematopoietic cell transplantation. Replacing high-dose cytotoxic therapy by the graft-versus-tumor effect.

Conventional allografting produces considerable regimen-related toxicities that generally limit this treatment to patients younger than 55 years and in otherwise good medical condition. T cell-mediated graft-versus-tumor (GVT) effects are known to play an important role in the elimination of malignant disease after allotransplants. A minimally myelosuppressive regimen that relies on immunosuppression for allogeneic engraftment was developed to reduce toxicities while optimizing GVT effects. Pre-transplant total-body irradiation (200 cGy) followed by post-transplant immunosuppression with cyclosporine (CSP) and mycophenolate mofetil (MMF) permitted human leukocyte antigen (HLA)-matched sibling donor hematopoietic cell engraftment in 82% of patients (n = 55) without prior high-dose therapy. The addition of fludarabine (90 mg/m2) facilitated engraftment in all 28 subsequent patients. Overall, fatal progression of underlying disease occurred in 20% of patients after transplant. Non-relapse mortality occurred in 11% of patients. Toxicities were low. Grade 2-4 acute graft-versus-host disease (GVHD) associated with primary engraftment developed in 47% of patients, and was readily controlled in all but two patients. Donor lymphocyte infusions (DLI) were not very effective at converting a low degree of mixed donor/host chimerism to full donor chimerism; however, the addition of fludarabine reduced the need for DLI. With a median follow-up of 244 days, 68% of patients were alive, with 42% of patients in complete remission, including molecular remissions. Remissions occurred gradually over periods of weeks to a year. If long-term efficacy is demonstrated, such a strategy would expand treatment options for patients who would otherwise be excluded from conventional allografting.

Adult↗
PubMed2000

Polyclonal hematopoiesis with variable telomere shortening in human long-term allogeneic marrow graft recipients.

Donor-derived hematopoiesis was assessed in 17 patients who received allogeneic marrow grafts from HLA-matched siblings between 1971 and 1980. Complete blood counts were normal or near normal in all patients except one. Chimerism analyses, using either dual-color XY-chromosome fluorescence in situ hybridization (FISH) or analysis of variable number tandem repeat loci, indicated that 15 out of 16 patients had greater than 97% donor-derived hematopoiesis, whereas 1 patient had indeterminate chimerism. All 12 recipients of grafts from female donors exhibited polyclonal hematopoiesis by X-linked clonal analysis with the use of molecular probes. Of the 17 recipients, 9 exhibited a less than 1.0-kilobase shortening of granulocyte telomere length compared with their respective donors, according to terminal restriction fragment analysis or flow-FISH with a fluorescein-labeled peptide nucleic acid probe. These data suggest that under standard transplantation conditions, the stem cell proliferative potential is not compromised during hematopoietic reconstitution. (Blood. 2000;96:3991-3994)

Adolescent↗
PubMed2000

Thalidomide for treatment of patients with chronic graft-versus-host disease.

In a randomized, placebo-controlled, double-blind trial, thalidomide or placebo together with glucocorticoids and either cyclosporine or tacrolimus was administered as initial therapy for clinical extensive chronic graft-versus-host disease (cGVHD). All patients had thrombocytopenia or cGVHD that evolved directly from acute GVHD as an indicator of a poor prognosis. The study drug (thalidomide or placebo) was administered initially at a dose of 200 mg orally per day, followed by a gradual increase to 800 mg/d if side effects were tolerable. Treatment with the study drug was discontinued before resolution of cGVHD in 23 (92%) of the 25 patients who received thalidomide and in 17 (65%) of the 26 patients who received placebo (P =.02). Neutropenia and neurologic symptoms were the most frequent reasons for early discontinuation of treatment with thalidomide. The duration of treatment with thalidomide was too short to assess its efficacy in controlling cGVHD. (Blood. 2000;96:3995-3996)

Actuarial Analysis↗
PubMed2000

Ex vivo expansion of canine dendritic cells from CD34+ bone marrow progenitor cells.

BACKGROUND: The aims of this study were to ex vivo expand canine dendritic cells and determine their phenotype and functional characteristics. METHODS: CD34+-selected cells and CD34+-depleted canine bone marrow (BM) cells were cultured in Iscove's modified medium for 14 days. Cytokines added to the cultures included human granylocyte/macrophage colony-stimulating factor 5 ng/ml, hFlt3 ligand 200 ng/ml, and human tumor necrosis factor-alpha 10 ng/ml. Cultured cells and purified subpopulations were assessed for cell surface antigen expression, morphology, and function by flow cytometric analysis, electron microscopy, and an allogeneic mixed lymphocyte reaction at day 14. RESULTS: Two main cell populations were identified, DR++(bright)/CD14- and DR+(dim)/CD14+. Ex vivo expanded CD34+-selected cells showed increased allostimulatory activity compared to both cultured CD34+-depleted cells and mononuclear cells. In contrast, ex vivo expansion from CD34+-depleted cells was unsuccessful. After sorting cells from the ex vivo expanded CD34+-selected bone marrow to enrich for DR++/CD14- cells, a 42-fold increase (median) of allostimulatory activity was observed as compared with sorted DR+/CD14+ cells (P=0.02). CONCLUSIONS: Cells with dentric cell-like phenotypes and functions can be cultured from canine CD34+-selected bone marrow cells. Future studies will address the roles of these cells in engraftment, graft versus host reactions and graft-host tolerance in a canine hematogoietic stem cell transplantaton model.

Animals↗
PubMed2000

Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors.

After the transplantation of unmodified marrow from human leukocyte antigen-matched unrelated donors receiving cyclosporine (CSP) and methotrexate (MTX), the incidence of acute graft-versus-host disease (GVHD) is greater than 75%. Tacrolimus is a macrolide compound that, in previous preclinical and clinical studies, was effective in combination with MTX for the prevention of acute GVHD. Between March 1995 and September 1996, 180 patients were randomized in a phase 3, open-label, multicenter study to determine whether tacrolimus combined with a short course of MTX (n = 90), more than CSP and a short course of MTX (n = 90), would reduce the incidence of acute GVHD after marrow transplantation from unrelated donors. There was a significant trend toward decreased severity of acute GVHD across all grades (P =.005). Based on the Kaplan-Meier estimate, the probability of grade II-IV acute GVHD in the tacrolimus group (56%) was significantly lower than in the CSP group (74%; P =.0002). Use of glucocorticoids for the management of GVHD was significantly lower with tacrolimus than with CSP (65% vs 81%, respectively; P =. 019). The number of patients requiring dialysis in the first 100 days was similar (tacrolimus, 9; CSP, 8). Overall and relapse-free survival rates for the tacrolimus and CSP arms at 2 years was 54% versus 50% (P =.46) and 47% versus 42% (P =.58), respectively. The combination of tacrolimus and MTX after unrelated donor marrow transplantation significantly decreased the risk for acute GVHD than did the combination of CSP and MTX, with no significant increase in toxicity, infections, or leukemia relapse.

Acute Disease↗
PubMed2000

Adoptive immunotherapy in canine mixed chimeras after nonmyeloablative hematopoietic cell transplantation.

Development of nontoxic and nonmyeloablative regimens for allogeneic hematopoietic stem-cell transplantation will decrease transplantation-related mortality caused by regimen-related toxic effects. In pursuit of this goal, a dog model of stable mixed hematopoietic chimerism was established in which leukocyte-antigen-identical litter mates are given sublethal total-body irradiation (2 Gy) before stem-cell transplantation and immunosuppression with mycophenolate mofetil and cyclosporine afterward. In the current study, we examined whether donor lymphocyte infusion (DLI) could be used as adoptive immunotherapy to convert mixed to complete donor chimerism. First, 8 mixed chimeras were given unmodified DLI between day 36 and day 414 after stem-cell transplantation. After a 10- to 47-week follow-up period, there were no significant changes in the percentage of donor engraftment. Next, we immunized the donor to the minor histocompatibility antigens (mHA) of the recipient by means of repeated skin grafting. Lymphocytes from the mHA-sensitized donor were infused between day 201 and day 651 after transplantation. All 8 recipients of mHA-sensitized DLI had conversion to greater than 98% donor chimerism within 2 to 12 weeks of the infusion. Complications from mHA-sensitized DLI included graft-versus-host disease in 2 dogs and marrow aplasia in 1. These results showed that the low-dose transplant regimen establishes immune tolerance, and mHA-sensitized DLI is required to break tolerance, thereby converting mixed to complete donor chimerism. We propose that mixed chimerism established after nonmyeloablative allogeneic stem-cell transplantation provides a platform for adoptive immunotherapy that has clinical potential in the treatment of patients with malignant diseases.

Animals↗
PubMed2000

Cytotoxic T lymphocyte antigen 4-immunoglobulin fusion protein combined with methotrexate/cyclosporine as graft-versus-host disease prevention in a canine dog leukocyte antigen-nonidentical marrow transplant model.

BACKGROUND: We studied whether blocking of the T cell costimulatory signal from B7-->CD28 by cytotoxic T lymphocyte antigen 4-immunoglobulin fusion protein would, either by itself or when added to methotrexate/cyclosporine, result in improved graft-versus-host disease prevention after dog leukocyte antigen nonidentical canine hematopoietic stem cell transplantation after 920 cGy total body irradiation. RESULTS AND CONCLUSIONS: Survivals of cytotoxic T lymphocyte antigen 4-immunoglobulin fusion protein-treated dogs were only slightly prolonged over controls. It appeared that the addition of cytotoxic T lymphocyte antigen 4-immunoglobulin fusion protein failed to induce graft-host tolerance in this model beyond that achieved with methotrexate/cyclosporine alone.

Abatacept↗
PubMed2000

Changing from cyclosporine to tacrolimus as salvage therapy for chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) is the principal cause of transplantation-related morbidity and nonrelapse mortality late after allogeneic hematopoietic stem cell transplantation. The safety and potential efficacy of tacrolimus for the salvage treatment of chronic GVHD was evaluated in a single-arm, open-label phase 2 study. A total of 39 evaluable patients with chronic GVHD who failed previous immunosuppressive therapy with cyclosporine and prednisone were treated with tacrolimus starting at a median of 20 months (range, 3-68 months) after transplantation. At 3 years after the start of treatment, 5 patients (13%) had discontinued tacrolimus and were in complete remission, and 3 were considered clinically stable but not able to discontinue tacrolimus. A total of 31 patients (79%) experienced treatment failure; 22 (56%) who failed therapy had a change in immunosuppressive regimen because of progression (n = 18) or toxicity (n = 4). Nine patients (23%) died during continued treatment with tacrolimus. Two patients were lost to follow-up, at 11 and 19 months. The median duration of treatment with tacrolimus was 9 months (range, 1-29 months). Infections (144 episodes) were the most frequent adverse event. Nephrotoxicity occurred in 16 patients (41%); tacrolimus was discontinued in only 2 patients because of progressive deterioration in renal function. The Kaplan-Meier estimate of survival was 64% (95% confidence interval, 49%-79%) at 3 years posttransplantation. Seven patients had discontinued all immunosuppression at last contact, leading to an estimated 29% probability of stopping all immunosuppression by 3 years posttransplantation. Four patients died after relapse of malignancy. The response rate is consistent with previous reports of salvage treatment for chronic GVHD, indicating that a small group of patients failing cyclosporine may respond or stabilize with tacrolimus.

Adolescent↗
PubMed2000

A phase I trial of recombinant human thrombopoietin in patients with delayed platelet recovery after hematopoietic stem cell transplantation.

Delayed platelet recovery is a significant complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT). A multicenter, phase I dose-escalation study of recombinant human thrombopoietin (rhTPO) was conducted to assess its safety and to obtain preliminary data on its efficacy in patients with persistent severe thrombocytopenia (<20,000/microL) >35 days after HSCT. Thirty-eight patients, 37 of whom were evaluable, were enrolled in the study from April 1996 through January 1997. rhTPO was administered at doses of 0.6, 1.2, and 2.4 microg/kg as a single dose (group A) or in multiple doses every 3 days for a total of 5 doses (group B). No significant adverse effects were observed. Ten patients had recovery of platelet counts during the 28-day study period; 3 of these 10 had an increase in marrow megakaryocyte content 7 days after completing treatment with rhTPO. When all baseline marrows were compared with samples after rhTPO treatment, there was no difference in marrow megakaryocyte content (P = 0.49). This study design could not answer the question of whether the recoveries of platelet counts observed in some patients were spontaneous or influenced by rhTPO treatment; nonetheless, the authors found no correlation between the dose of rhTPO and the recovery of platelet counts. Increases in serum TPO levels were dose-dependent and remained significantly elevated for up to 72 hours after treatment. To evaluate response, further studies of treatment strategies with rhTPO in patients with delayed platelet recovery are required.

Adolescent↗
PubMed2000

Prospects of stem cell transplantation in autoimmune diseases.

Severe autoimmune diseases are not cured by current conventional treatments. Preclinical studies of treatments requiring stem cell transplantation have shown sustained remissions in some models of autoimmune diseases. Both autologous stem cell transplantation after high-dose immunoablative therapy and allogeneic stem cell transplantation have a profound effect on the recipient's immunological system. Pilot clinical studies of autologous stem cell transplantation are being conducted. Sustained remissions will require the induction of tolerance to autoantigens during recovery. In a group of patients highly selected to minimize transplant-related mortality, allogeneic stem cell transplantation should be tested to determine if elimination of the autoreactive immunological system will achieve sustained remissions. These are promising therapies which will require long-term follow-up of patients to evaluate efficacy.

Autoimmune Diseases↗
PubMed2000

Clinical outcome after conversion to FK 506 (tacrolimus) therapy for acute graft-versus-host disease resistant to cyclosporine or for cyclosporine-associated toxicities.

This retrospective study describes the outcome in 53 patients who had immunosuppressive treatment changed from cyclosporine (CSP) to tacrolimus for resistant acute GVHD (n = 23), hemolytic uremic syndrome (HUS) (n = 13) or CSP-associated neurotoxicity (n = 17). Tacrolimus was administered at doses of 0.03 mg/kg/day intravenously or 0.12 mg/kg/day orally in divided doses, as tolerated. Median time of conversion to tacrolimus after transplant was day 47. Nineteen patients had treatment changed to tacrolimus for resistant acute GVHD grades III or IV, with the median day of conversion being day 49 after transplant. Two of 20 evaluable patients had a complete resolution of GVHD after changing treatment to tacrolimus, with 18 showing no improvement. Eleven evaluable patients had therapy changed to tacrolimus for CSP-associated neurotoxicity at a median of 36 days after transplant. Eight patients had resolution of neurotoxicity and three had partial improvement. Eleven evaluable patients had therapy changed to tacrolimus for HUS at a median of 46 days after transplant. One patient had complete resolution of HUS and 10 showed no response. Side-effects related to tacrolimus included renal toxicity (34%), neurotoxicity (15%) and HUS (9%). Nine (17%) patients remain alive, including six patients who had therapy changed to tacrolimus for CSP-associated neurotoxicity. While often successful for dealing with neurotoxicity, only a rare patient improved after therapy was changed from CSP to tacrolimus for HUS or resistant acute GVHD.

Acute Disease↗
PubMed1999

Stable mixed hematopoietic chimerism in dogs given donor antigen, CTLA4Ig, and 100 cGy total body irradiation before and pharmacologic immunosuppression after marrow transplant.

Stable mixed chimerism can be established in dogs given a sublethal dose of 200 cGy total body irradiation (TBI) before and immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP) for 28 and 35 days, respectively, after dog leukocyte antigen-identical marrow transplantation. Most likely, the role of pretransplant TBI was to provide host immunosuppression, since stable mixed chimerism was also achieved in MMF/CSP-treated dogs when 450 cGy irradiation, targeted to cervical, thoracic, and upper abdominal lymph nodes, was substituted for TBI. When TBI was reduced from 200 to 100 cGy, all grafts were rejected within 3 to 12 weeks. Here, we asked whether stable engraftment after 100 cGy TBI could be accomplished by first reducing the intensity of host immune responsiveness with help of the fusion peptide CTLA4Ig, which blocks T-cell costimulation through the B7-CD28 signal pathway. Accordingly, recipient T cells were activated with intravenous (IV) injections of 10(6) donor peripheral blood mononuclear cells (PBMC)/kg per day on days -7 to -1 before 100 cGy TBI, with concurrent administration of CTLA4Ig 4 mg/kg/d IV. All 7 dogs so treated showed initial mixed chimerism. Two rejected their allografts after 8 and 20 weeks, respectively, and survived with autologous marrow recovery; 1 mixed chimera was unevaluable because of death at 3 weeks from intussusception; and 4 showed persisting mixed chimerism, including unirradiated marrow and lymph node spaces, for now more than 46 to 70 weeks after transplant. Data support the hypothesis that stable marrow allografts can be established by combining nonmyeloablative pretransplant host immunosuppression with posttransplant host and donor cell immunosuppression using MMF/CSP.

Abatacept↗
PubMed1999

CD34+ selected bone marrow grafts are radioprotective and establish mixed chimerism in dogs given high dose total body irradiation.

BACKGROUND: Canine stem cell transplantation models have provided important preclinical information for human clinical studies. The recent cloning of cDNA for canine CD34 and the production of monoclonal antibodies that recognize canine CD34 have been the basis for the development of techniques for the large-scale enrichment of canine hematopoietic progenitor cells. In this study, we evaluated the in vivo functional properties of canine bone marrow CD34+ cells after a myeloablative conditioning regimen. METHODS: After 920 cGy total body irradiation, three dogs received infusion of autologous CD34+ selected cells from the marrow, three dogs CD34+ depleted autologous marrow cells, and two dogs received CD34+ autologous marrow cells that were immunomagnetically selected and then further purified by cell sorting. In addition, four dogs received allogeneic marrow enriched for CD34+ cells from dog leukocyte antigen-identical littermates to investigate long-term repopulating function of CD34+ cells. Chimerism studies were performed using polymerase chain reaction to detect highly polymorphic microsatellite markers. RESULTS: In three recipients of autologous marrow enriched for CD34+ cells to between 29% and 70% (1.6 x 10(6) to 3.4x10(6) CD34+ cells/kg), prompt and full hematopoietic recovery occurred, whereas in three dogs that received marrow depleted of CD34+ cells (1 x 10(7) cells/kg), no hematopoietic recovery was achieved. In two dogs that received highly purified CD34+ cells (purity: 98% and 96%, 0.79x10(6) to 0.547x 10(6) CD34+ cells/kg), delayed but full hematopoietic recovery was seen. Three of four allograft recipients of 1.75x10(6) to 6.8x10(6) CD34+ cells/kg engrafted and showed full hematopoietic recovery, whereas one dog rejected the graft. The three long-term survivors showed stable mixed hematopoietic chimerism with predominantly donor hematopoiesis. CONCLUSION: Transplantation of canine CD34+ cells after lethal total body irradiation provides radioprotection and gives rise to long-term hematopoietic reconstitution. Stable donor/host mixed chimerism was observed in allograft recipients most likely as a result of T-cell depletion of the grafts. Our findings suggest a future role for canine preclinical transplant studies involving in vitro manipulation of hematopoietic pro.

Animals↗
PubMed1999

Stable mixed hematopoietic chimerism in dog leukocyte antigen-identical littermate dogs given lymph node irradiation before and pharmacologic immunosuppression after marrow transplantation.

Stable mixed donor/host hematopoietic chimerism can be accomplished in dog leukocyte antigen (DLA)-identical littermate dogs given sublethal (200 cGy) total-body irradiation (TBI) before and immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP) after transplant (Blood 89:3048, 1997). Studies were based on the hypothesis that drugs that prevent graft-versus-host disease (GVHD) after transplant also suppress host-versus-graft (HVG) reactions and thereby enhance engraftment. Here, we asked whether pretransplant TBI provided marrow space for the graft to home or caused host immunosuppression. To address the questions, recipients were given pretransplant irradiation to cervical, thoracic, and abdominal lymph nodes (except pelvis), DLA-identical littermate marrow grafts, and MMF/CSP posttransplant. Six dogs that received 450 cGy irradiation showed initial engraftment. Two rejected their grafts after 8 and 18 weeks, 1 died with GVHD and engraftment, and 3 are alive as mixed chimeras after 57 to 97 weeks. Four dogs given 200 cGy irradiation also showed initial engraftment, but rejected their grafts after 10 to 18 weeks. Mixed chimerism was present in nonirradiated marrow and lymph node spaces and involved granulocytes, T cells, and monocytes. While other explanations are possible, results seem consistent with the hypothesis that pretransplant radiation provides host immunosuppression, and grafts can create their own marrow space. These data set the stage for the development of novel transplant regimens that substitute immunosuppressive for cytotoxic agents.

Animals↗