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R A Nash

Publications and source records attributed to R A Nash.

At least 19 recordsLinked to original sources

Allogeneic HSCT for autoimmune diseases: conventional conditioning regimens.

Allogeneic hematopoietic stem cell transplantation (HSCT) tests the hypothesis that the replacement of a 'diseased' autoreactive immunological and stem cell compartment with one that is not autoreactive (but potentially alloreactive) can cure severe autoimmune diseases. The primary risks of allogeneic HSCT are the morbidity and morality associated with delayed immune reconstitution and GVHD. Although the risk of complications and mortality is greater than autologous HSCT, studies of allogeneic HSCT should be conducted in selected cases because there is a greater potential for sustained remissions. This review will discuss the anticipated results from allogeneic HSCT by summarizing outcomes in aplastic anemia and chronic myelogenous leukemia as well as a brief description of Seattle's experience with allogeneic HSCT in the first two patients with systemic sclerosis.

Autoimmune Diseases↗

IL-2 does not enhance the conversion to complete donor chimerism following nonmyeloablative hematopoietic cell transplantation in dogs.

A dog model of stable mixed hematopoietic chimerism was established in which leukocyte-antigen-identical littermates receive nonmyeloablative total body irradiation before hematopoietic cell transplantation and postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. Unmodified donor lymphocyte infusion (DLI) into stable mixed chimeras failed to increase donor chimerism, while DLI from donors sensitized to recipient minor-histocompatibility antigens promptly converted all recipients to complete donor chimerism. This established a model for studying approaches to enhance the graft-versus-host (GVH)-effect, a potential surrogate for graft-versus-leukemia activity. We asked if interleukin-2 (IL-2) given after unmodified DLI could result in reliable conversion to complete donor chimerism. IL-2, 4 x 10(5) IU/kg/day, was administered to six mixed chimeric dogs for 14 days. Four dogs received unmodified DLI with IL-2. At 20-40 weeks after DLI, all dogs remained mixed chimeras. For the two recipients of IL-2 only, mixed chimerism also remained unchanged. These results show that IL-2 given with DLI after nonmyeloablative transplantation in dogs is not effective in reliably converting mixed to complete donor chimerism.

Animals↗

Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease.

BACKGROUND: In a pilot trial we evaluated the toxicity and efficacy of sirolimus (rapamycin) as second-line therapy for the treatment of acute graft-versus-host disease (GVHD) in 21 patients (1-46 years of age) after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: All patients were treated with methylprednisolone at 2 mg/kg/day, but failed to respond satisfactorily. Sirolimus was started 19-78 (median 37) days after HSCT when 10 patients had grade III and 11 had grade IV GVHD. The first four patients received a loading dose (15 mg/m2) of oral sirolimus on day 1 followed by 5 mg/m2/day for 13 days. The next 17 patients received either 5 (n=7) or 4 (n=10) mg/m2/day for 14 days without a loading dose. Eleven patients completed the 14-day sirolimus course. Five patients were treated for 9-13 days, two for 6 days, and three for 1-3 days. RESULTS: Sirolimus was discontinued early in 10 patients because of lack of improvement in GVHD (n=5), myelosuppression (n=2), seizure (n=2), and attending physician preference (n=1). The most common and significant adverse events were thrombocytopenia (n=7) and neutropenia (n=4). Other side effects included increased blood triglycerides (n=8) and cholesterol (n=3). Five patients had evidence of a hemolytic uremic syndrome concurrently with or after sirolimus treatment. Eighteen of the 21 patients received 6 or more doses of sirolimus and 12 responded, 5 with complete and 7 with partial responses. Six of the 12 responders (28% of all patients enrolled) and 1 nonresponder are currently alive at 400-907 days after HSCT, 3 with chronic GVHD. Fourteen of the 21 patients (66%) died 40-263 days after transplant. CONCLUSION: These data suggest that sirolimus has activity in the treatment of steroid-refractory acute GVHD. However, there was considerable toxicity and further dose optimization studies seem warranted.

Acute Disease↗

Immunity of patients surviving 20 to 30 years after allogeneic or syngeneic bone marrow transplantation.

The duration of immunodeficiency following marrow transplantation is not known. Questionnaires were used to study the infection rates in 72 patients surviving 20 to 30 years after marrow grafting. Furthermore, in 33 of the 72 patients and in 16 donors (siblings who originally donated the marrow) leukocyte subsets were assessed by flow cytometry. T-cell receptor excision circles (TRECs), markers of T cells generated de novo, were quantitated by real-time polymerase chain reaction. Immunoglobulin G(2) (IgG(2)) and antigen-specific IgG levels were determined by enzyme-linked immunosorbent assay. Infections diagnosed more than [corrected] 15 years after transplantation occurred rarely. The average rate was 0.07 infections per patient-year (one infection every 14 years), excluding respiratory tract infections, gastroenteritis, lip sores, and hepatitis C. The counts of circulating monocytes, natural killer cells, B cells, CD4 T cells, and CD8 T cells in the patients were not lower than in the donors. The counts of TREC(+) CD4 T cells in transplant recipients younger than age 18 years (at the time of transplantation) were not different from the counts in their donors. In contrast, the counts of TREC(+) CD4 T cells were lower in transplant recipients age 18 years or older, even in those with no history of clinical extensive chronic graft-versus-host disease, compared with their donors. The levels of total IgG(2) and specific IgG against Haemophilus influenzae and Streptococcus pneumoniae were similar in patients and donors. Overall, the immunity of patients surviving 20 to 30 years after transplantation is normal or near normal. Patients who received transplants in adulthood have a clinically insignificant deficiency of de novo-generated CD4 T cells, suggesting that in these patients the posttransplantation thymic insufficiency may not be fully reversible.

Adolescent↗

Administration of cyclosporine for 24 months compared with 6 months for prevention of chronic graft-versus-host disease: a prospective randomized clinical trial.

This study compared the incidence of clinical extensive chronic graft-versus-host disease (GVHD), transplantation-related mortality, survival, and relapse-free survival among recipients randomly assigned to receive a 24-month or a 6-month course of cyclosporine prophylaxis after transplantation of allogeneic marrow from an HLA-identical sibling or alternative donor. Patients who did not have clinical manifestations of chronic GVHD on day 80 after transplantation were eligible for the study if they previously had acute GVHD or if a skin biopsy showed histologic evidence of chronic GVHD. Clinical extensive chronic GVHD developed in 35 of the 89 patients (39%) in the 24-month group and 37 of the 73 patients (51%) in the 6-month group. The hazard of developing chronic GVHD was not significantly different in the 2 groups (hazard ratio = 0.76; 95% confidence interval, 0.48-1.21; P =.25). In addition, there were no significant differences between the 2 groups in transplantation-related mortality, survival, or disease-free survival.

Adult↗

Engraftment of DLA-haploidentical marrow with ex vivo expanded, retrovirally transduced cytotoxic T lymphocytes.

Genetically modified donor T cells with an inducible "suicide" gene have the potential to improve the safety and availability of allogeneic hematopoietic stem cell transplantation by enhancing engraftment and permitting control of graft-versus-host disease (GVHD). However, several clinical studies of gene-modified T cells have shown limited to no in vivo function of the ex vivo expanded T cells. Using the well-established dog model of allogeneic marrow transplantation, the question was asked if retrovirally transduced, donor derived, ex vivo expanded cytotoxic T lymphocytes (CTLs) that are recipient specific could enhance engraftment of dog leukocyte antigen (DLA)-haploidentical marrow following a single dose of 9.2 Gy total body irradiation and no postgrafting immunosuppression. In this setting, only 4 of 11 control recipients of DLA-haploidentical marrow without added CTLs engrafted. CTLs did not enhance engraftment of CD34(+) selected peripheral blood stem cells. However, recipient-specific CTLs enhanced engraftment of DLA-haploidentical marrow in 9 of 11 evaluable recipients (P =.049). All dogs that engrafted developed multiorgan GVHD. To facilitate in vivo tracking, 8 dogs received CTLs transduced with a retroviral vector encoding green fluorescent protein (GFP) and neomycin phosphotransferase (neo). Recipients that engrafted had sharp increases in the numbers of circulating GFP(+) CTLs on days +5 to +6 after transplantation. GFP(+) CTLs isolated from blood were capable of recipient-specific lysis. At necropsy, up to 7.1% of CD3(+) cells in tissues were GFP(+) and polymerase chain reaction in situ hybridization for neo showed infiltration of transduced CTLs in GVHD-affected organs. These results show that ex vivo expanded, transduced T cells maintained in vivo function and enhanced marrow engraftment.

Animals↗

Nonmyeloablative hematopoietic stem cell transplantation: transplantation for the 21st century.

Conventional approaches to allogeneic stem cell transplantation have used toxic high-dose conditioning therapy to achieve allogeneic engraftment and control of underlying disease. For engraftment purposes, preclinical studies and clinical observations have shown that conditioning regimens can be markedly reduced in intensity, resulting in reduced treatment toxicities. Preclinical canine studies demonstrated that the use of potent pre- and postgrafting immunosuppression allows for reduction in conditioning regimens while facilitating development of stable mixed chimerism. If attenuated conditioning regimens can be successfully translated to human stem cell transplantation, an improved safety profile will allow potentially curative treatment to a more representative patient profile not currently offered such therapy. Mixed chimerism could prove curative of disease phenotype of various nonmalignant disturbances of the hematopoietic and immune systems. For patients with hematopoietic malignancy, spontaneous conversion to full donor hematopoeisis after stem cell transplant may prove curative by virtue of graft versus host reactions directed against the malignancy, however infusion of additional donor lymphocytes may be needed to treat persistent disease.

Animals↗

Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects.

Toxicities have limited the use of allogeneic hematopoietic cell transplantation (HCT) to younger, medically fit patients. In a canine HCT model, a combination of postgrafting mycophenolate mofetil (MMF) and cyclosporine (CSP) allowed stable allogeneic engraftment after minimally toxic conditioning with low-dose (200 cGy) total-body irradiation (TBI). These findings, together with the known antitumor effects of donor leukocyte infusions (DLIs), led to the design of this trial. Forty-five patients (median age 56 years) with hematologic malignancies, HLA-identical sibling donors, and relative contraindications to conventional HCT were treated. Immunosuppression involved TBI of 200 cGy before and CSP/MMF after HCT. DLIs were given after HCT for persistent malignancy, mixed chimerism, or both. Regimen toxicities and myelosuppression were mild, allowing 53% of eligible patients to have entirely outpatient transplantations. Nonfatal graft rejection occurred in 20% of patients. Grades II to III acute graft-versus-host disease (GVHD) occurred in 47% of patients with sustained engraftment. With median follow-up of 417 days, survival was 66.7%, nonrelapse mortality 6.7%, and relapse mortality 26.7%. Fifty-three percent of patients with sustained engraftment were in complete remission, including 8 with molecular remissions. This novel allografting approach, based on the use of postgrafting immunosuppression to control graft rejection and GVHD, has dramatically reduced the acute toxicities of allografting. HCT with the induction of potent graft-versus-tumor effects can be performed in previously ineligible patients, largely in an outpatient setting. Future protocol modifications should reduce rejection and GVHD, thereby facilitating studies of allogeneic immunotherapy for a variety of malignancies. (Blood. 2001;97:3390-3400)

Adult↗

Isolation and characterization of canine hematopoietic progenitor cells.

The purpose of this study was to purify and characterize canine hematopoietic progenitor cells for surface antigen phenotype and reconstitution ability. Canine hematopoietic progenitor cells were isolated by density gradient sedimentation, lineage depletion with monoclonal antibodies, and fluorescence-activated cell sorting (FACS) for selection of cells with low-forward and right-angle scatter that were rhodamine 123 (Rh-123)(dull). Isolated cells were characterized for expression of CD34, c-kit, and Flt-3. A canine/murine xenograft model and a mixed-chimerism assay were used to examine the in vivo proliferative potential of isolated cells. The lineage-positive (Lin(+)) cells represented 80 +/- 11% (n = 22) of the input mononuclear cells. Lineage depletion resulted in a fourfold increase in colony-forming unit granulocyte/monocyte (CFU-GM), a 2.5-fold increase in burst-forming unit-erythroid (BFU-E), and a twofold increase in the number of Rh-123(dull) cells over nonlineage-depleted bone marrow mononuclear cells (BMMCs). Lineage depletion led to a 2.7-fold enrichment of CD34 cells, a 10.4-fold enrichment of c-kit cells, and a 10.8-fold enrichment of CD34/c-kit(+1) cells over total BMMCs. Nineteen percent of lineage-negative (Lin(-)) cells were positive for Flt-3. Injection of canine cells into irradiated (400 rads) NOD/SCID mice resulted in the detection of canine CD45(+) cells with BMMCs, Lin(-) cells, or Rh-123(dull) cells. Transplantation of purified Lin(-) cells in dog leukocyte antigen-matched littermates resulted in low-level engraftment for at least 10 weeks. The development of methods for purification and characterization of canine hematopoietic progenitor cells should enhance the utilization of the canine model for a variety of experimental and therapeutic purposes.

Animals↗

Purified canine CD34+Lin- marrow cells transduced with retroviral vectors give rise to long-term multi-lineage hematopoiesis.

Human CD34+ cells have been shown to retain long-term hematopoietic engrafting potential in preclinical and clinical studies. However, recent studies of human and murine CD34- stem cells suggest that these are functionally important early progenitors. Using autologous transplantation, we investigated whether canine CD34 and CD34- marrow cells could be transduced and give rise to long-term hematopoiesis. CD34+Lin- and CD34-Lin- cell populations purified by fluorescence-activated cell sorting were separately cocultivated with retroviral vectors LN (CD34+Lin-) and LNY (CD34-Lin-), which carry the neomycin (neo) gene. After myeloablative total body irradiation (920 cGy), 3 dogs received transplants of both CD34+Lin- cells and CD34-Lin- cells and 2 dogs received only CD34-Lin- cells. Untransduced autologous marrow cells were given to ensure hematopoietic recovery. Using CFU-C assays, transduction efficiencies of CD34+Lin- cells ranged from 6% to 18% with no CFU-C formation from CD34-Lin- cells. PCR-based detection of the neo gene from WBCs was used to detect transduced cells weekly after transplantation. Additional PCR studies in 3 dogs given both CD34+Lin- and CD34-Lin- cells were performed on monocytes, granulocytes, and T cells (2 dogs, one at 7.5 months and the other at 9 months) and granulocytes (1 dog at 12 months). LN was detected up to 12 months posttransplantation in WBCs and mono-myeloid and lymphoid populations from 3 dogs receiving transplants of transduced CD34+Lin- cells. LNY was not detected at any time after transplantation in 5 dogs that received transduced CD34-Lin- cells. Whereas canine CD34+Lin- marrow cells contributed to long-term multilineage hematopoiesis, progeny of CD34-Lin- progenitor cells were not detected after transplantation in these experiments.

Animals↗

Collection of hematopoietic stem cells from patients with autoimmune diseases.

We reviewed data from 24 transplant centers in Asia, Australia, Europe, and North America to determine the outcomes of stem cell collection including methods used, cell yields, effects on disease activity, and complications in patients with autoimmune diseases. Twenty-one unprimed bone marrow harvests and 174 peripheral blood stem cell mobilizations were performed on 187 patients. Disease indications were multiple sclerosis (76 patients), rheumatoid arthritis (37 patients), scleroderma (26 patients), systemic lupus erythematosus (19 patients), juvenile chronic arthritis (13 patients), idiopathic autoimmune thrombocytopenia (8 patients), Behcet's disease (3 patients), undifferentiated vasculitis (3 patients), polychondritis (1 patient) and polymyositis (1 patient). Bone marrow harvests were used in the Peoples Republic of China and preferred worldwide for children. PBSC mobilization was the preferred technique for adult stem cell collection in America, Australia, and Europe. Methods of PBSC mobilization included G-CSF (5, 10, or 16 microg/kg/day) or cyclophosphamide (2 or 4 g/m2) with either G-CSF (5 or 10 microg/kg/day) or GM-CSF (5 microg/kg/day). Bone marrow harvests were without complications and did not affect disease activity. A combination of cyclophosphamide and G-CSF was more likely to ameliorate disease activity than G-CSF alone (P < 0.001). g-csf alone was more likely to cause disease exacerbation than the combination of cyclophosphamide and g-csf (P = 0.003). Three patients died as a result of cyclophosphamide-based stem cell collection (2.6% of patients mobilized with cyclophosphamide). When corrected for patient weight and apheresis volume, progenitor cell yields tended to vary by underlying disease, prior medication history and mobilization regimen. Trends in the approaches to, and results of, progenitor cell mobilization are suggested by this survey. While cytokine-based mobilization appears less toxic, it is more likely to result in disease reactivation. Optimization with regard to cell yields and safety are likely to be disease-specific and prospective disease-specific studies of mobilization procedures appear warranted.

Adolescent↗

Assessment of myocardial hypertrophy by echocardiography in adult patients receiving tacrolimus or cyclosporine therapy for prevention of acute GVHD.

The incidence of myocardial hypertrophy was determined in a comparative study of tacrolimus-based immunosuppression with cyclosporine-based immunosuppression for prevention of acute graft-versus-host disease (GVHD) after unrelated donor bone marrow transplantation. Patients were evaluated for clinical and echocardiographic abnormalities at baseline (prior to pretreatment conditioning and the first dose of study drug) and at 5-8 weeks after transplant when stable levels of oral tacrolimus or cyclosporine had been achieved. Left ventricular geometry and performance were assessed by echocardiography which included 2-D measurements and one Doppler measurement. Derived echocardiographic measurements and left ventricular mass index (LVMI) were also determined. A cut-off of <111 g/m(2) was used for the upper limit of normal for LVMI. Forty-four patients were included in this study (21 tacrolimus and 23 cyclosporine), of which 31 were evaluable for a comparison with both baseline and post-transplant values. There was no significant difference in the changes from baseline for mean left ventricular mass (LVM) or LVM index (LVMI) between treatment groups. Also, within the tacrolimus group there were no significant changes for these variables from baseline to post-transplant evaluations. Within the cyclosporine group there were significant increases from baseline for mean LVM (P = 0.011) and LVMI (P = 0.007). The incidence of myocardial hypertrophy (change of LVMI from <111 g/m(2) baseline to >111 g/m(2) post transplant) was 20% in the tacrolimus group and 56% in the cyclosporine group (P = 0.109). Changes in the LVMI from baseline to post baseline were greater with cyclosporine than with tacrolimus therapy, and there was no evidence that tacrolimus causes myocardial hypertrophy or significant clinical changes in adult bone marrow transplant patients. The increase in LVMI after transplant in the cyclosporine group was greater than in the tacrolimus group but was not associated with any significant clinical events.

Acute Disease↗

A proposed objective way to assess results of randomized prospective clinical trials with acute graft-versus-host disease as an outcome of interest.

The assessment of graft-versus-host disease (GVHD) as an end-point in clinical trials requires subjective judgement to distinguish morbidity caused by GVHD from morbidity caused by other complications. We developed a method based on ordinal regression for longitudinal assessment of morbidity involving the skin, liver and gut, regardless of cause as an objective end-point in randomized prospective phase III treatment or prevention trials for which GVHD is an outcome of interest. This method was validated for treatment studies by showing that morbidity was more severe among patients with grade II-IV GVHD than among those who did not have GVHD. We found no differences in morbidity involving the skin, liver and gut after the diagnosis of GVHD in a group of 30 patients who received peripheral blood stem cells and a group of 37 who received marrow in a randomized phase III clinical trial. These preliminary results suggest that objective end-points could be used in randomized clinical trials for treatment of GVHD. Further studies will be needed to determine if similar methods could be used in randomized clinical trials for prevention of GVHD.

Acute Disease↗

Severe canine hereditary hemolytic anemia treated by nonmyeloablative marrow transplantation.

Severe hemolytic anemia in Basenji dogs secondary to pyruvate kinase (PK) deficiency can be corrected by marrow allografts from healthy littermates after a conventional high-dose myeloablative conditioning regimen. The nonmyeloablative conditioning regimen used here, which consisted of a sublethal dose of 200 cGy total body irradiation before and immunosuppression with mycophenolate mofetil and cyclosporine after a dog leukocyte antigen (DLA)-identical littermate allograft, has been found to be effective in establishing stable mixed donor/host hematopoietic chimerism in normal dogs. We explored the feasibility of nonmyeloablative marrow allografts for the treatment of canine PK deficiency and studied the effect of stable allogeneic mixed hematopoietic chimerism on the natural course of the disease. Five affected dogs received transplants, of which 3 dogs had advanced liver cirrhosis and myelofibrosis. Both complications were presumed to be due to iron overload. All 5 dogs showed initial engraftment. Two rejected their grafts after 6 weeks but survived with completeautologous marrow recovery and return of the disease. One died from liver failure on day 27 with 60% donor engraftment. Two dogs have shown sustained mixed donor/host chimerism for more than a year with 85% and 12% donor hematopoietic cells, respectively. Overall clinical response correlated with the degree of donor chimerism. The dog with the low degree of chimerism achieved partial resolution of hemolysis, but the disease symptoms persisted as manifested by increasing iron overload resulting in progression of marrow and liver fibrosis. The dog with the high degree of donor chimerism achieved almost complete resolution of hemolysis with a decrease of marrow iron content and resolution of marrow fibrosis. These observations suggest that mixed hematopoietic chimerism can be relatively safely established in dogs with PK deficiency even in the presence of advanced liver cirrhosis. However, although effective in correcting or delaying the development of myelofibrosis, a low degree of mixed chimerism was not sufficient to prevent continued hemolysis of red blood cells of host origin. Complete donor chimerism appears necessary to achieve a long-term cure.

Anemia, Hemolytic, Congenital↗

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↗

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↗

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↗