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Biomedical subjects

R Storb

Publications and source records attributed to R Storb.

At least 505 records · Page 28Linked to original sources
PubMed1986

Recurrence of acute leukemia more than two years after allogeneic marrow grafting.

The records of 232 patients with acute leukemia in continuous complete remission at two years after a marrow graft from genotypically or phenotypically HLA-identical family member were reviewed. With a followup time of 2-14.2 years, 17 patients have developed recurrent leukemia 2.0-6.3 years after grafting. No relapses have occurred beyond 6.3 years. Actuarial analysis shows a low but significant risk of recurrence of leukemia more than two years after grafting. These data suggest that the majority of the disease-free patients have had their original leukemic clone eliminated. It is important to study the leukemic cells in patients who suffer a relapse more than two years after grafting to determine whether the leukemia is of host or donor origin.

Acute Disease↗
PubMed1986

Adverse effect of severe marrow fibrosis on hematologic recovery after chemoradiotherapy and allogeneic bone marrow transplantation.

We reviewed the records and marrow biopsy specimens of 75 patients with leukemic, myelodysplastic, or myeloproliferative disorders to determine whether the presence of marrow fibrosis affected engraftment after allogeneic marrow transplantation. While 28 control patients without fibrosis achieved prompt engraftment, two of 32 patients (6%) with mild and five of 15 patients (33%) with severe fibrosis failed. The rate of myeloid recovery was significantly slower and the dependence on platelet and red blood cell transfusions was significantly longer in patients with severe fibrosis than in patients with no fibrosis. A finding of severe marrow fibrosis should therefore be taken into account when evaluating the risks and benefits of marrow transplantation.

Adolescent↗
PubMed1986

Marrow transplantation for severe aplastic anemia: methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graft-versus-host disease.

Forty-six patients with severe aplastic anemia (median age, 23 years) were treated with high-dose cyclophosphamide followed by infusion of marrow from an HLA-identical family member. To evaluate postgrafting prophylaxis for graft-v-host disease (GVHD), they were entered into a prospective randomized trial comparing the effect of a combination of methotrexate and cyclosporine (n = 22) to that of methotrexate alone (n = 24). Forty-four of the forty-six patients had evidence of sustained marrow engraftment. Only one patient in each of the two study groups showed graft rejection. A significant reduction in the cumulative incidence of grades II to IV acute GVHD was seen in patients given methotrexate/cyclosporine (18%) compared with those given methotrexate alone (53%) (P = .012). In three patients given methotrexate alone, grade III developed, and in six, grade IV acute GVHD developed, compared with none given methotrexate/cyclosporine. Eighteen of the 22 patients given methotrexate/cyclosporine and 15 of the 24 given methotrexate alone are alive between 5.5 and 44.5 months (median, 18 months), with actuarial survival rates at 2 years of 82% and 60%, respectively (P = .062). The incidence of fatal infections was higher in patients given methotrexate alone, whereas there are as yet no significant differences in the incidence of chronic GVHD. We conclude that methotrexate/cyclosporine treatment resulted in a significant decrease in the incidence and severity of acute GVHD in patients who received transplants for severe aplastic anemia and thus an improvement in survival.

Acute Disease↗
PubMed1986

Characterization of host cells involved in resistance to marrow grafts in dogs transplanted from unrelated DLA-nonidentical donors.

A canine model of marrow transplantation was used to further define the host cells mediating resistance to marrow engraftment. Recipient dogs were given 9.2 Gy of total body irradiation followed by marrow infusion from unrelated DLA-nonidentical donors. No postgrafting immunosuppression was given. At three and ten days posttransplantation recipient marrow and peripheral blood cells were obtained and characterized by the following in vitro studies: morphologic analysis; phenotypic analysis with monoclonal antibodies; assays for natural killer cell (NK) activity; and cocultures with donor marrow to study the effect on donor CFU-GM growth. Daily differential cell counts revealed a proliferation of peripheral blood mononuclear cells approximately eight days posttransplant. By day 10 surviving host cells were uniformly large granular lymphocytes which were phenotypically of T cell lineage, had NK activity, and were capable of suppressing donor marrow CFU-GM growth. Mononuclear cells from dogs given total body irradiation only and no marrow infusion (radiation control group), did not suppress CFU-GM growth when cocultured with marrow from unrelated DLA-mismatched dogs. These results suggest that radioresistant host cells with the morphology of large granular lymphocytes and NK activity and which proliferate in response to the infused donor marrow cells mediate resistance to DLA-nonidentical marrow grafts. It remains to be determined, however, whether in vitro functional studies reflect the mechanisms involved in vivo.

Animals↗
PubMed1986

Decreased incidence of marrow graft rejection in patients with severe aplastic anemia: changing impact of risk factors.

Patients with severe aplastic anemia were conditioned with cyclophosphamide (200 mg/kg) and given marrow grafts from HLA-identical family members. Among 233 patients transplanted, 225 survived greater than or equal to 14 days and could be evaluated for engraftment. Forty-four of the 225 rejected their graft; 33 of these died and 11 survive. One hundred eighty-one patients had sustained engraftment; of these, 46 died and 135 survived. Binary logistic regression analyses revealed five risk factors for graft rejection: year of transplant, a large number of platelet transfusions, a positive relative response in mixed leukocyte culture, a low marrow cell dose, and omission of donor buffy coat cell infusion for transfused patients. These data show that patients transplanted recently had a lower likelihood of graft rejection than did patients transplanted in earlier years. Conceivably, this was related to changes in transfusion practices, but other factors as yet unidentified are likely to be involved. The data confirm that the largest possible number of marrow cells should be transplanted. Although the difference in the incidence of graft rejection between untransfused and transfused patients was not significant, it should be noted that transfused patients were given buffy coat cells. Because the addition of buffy coat cells results in a higher incidence of chronic graft-v-host disease (GVHD), it is still desirable to transplant patients with marrow alone early in their course before they have been transfused.

Anemia, Aplastic↗
PubMed1986

Graft-versus-host disease after marrow transplantation.

In random bred species including dog and man, a marrow graft from a donor genetically identical for the major histocompatibility complex is followed by significant graft-versus-host disease (GVHD) in 30% to 50% of the recipients despite the administration of postgrafting immunosuppression. Controlled trials comparing the immunosuppressive drugs methotrexate or cyclosporine have shown no differences in long-term survival, although cyclosporine reduces the incidence of mucositis and is associated with somewhat earlier engraftment. Observations in the canine model indicating efficacy of combining a brief course of methotrexate with the cyclosporine regimen are now being confirmed in patients with early results indicating a reduction in GVHD and an improved survival. In both species failure to administer immunosuppression after grafting is associated with a high incidence of acute GVHD and an adverse effect on survival. Removal of donor T cells from the marrow inoculum reduces the incidence of acute GVHD but at the risk of a higher likelihood of subsequent graft failure and maybe even leukemic recurrence. Results of studies in canine and human chimeras agree with murine data indicating a principal role for T cells in the pathogenic mechanism of GVHD. Chimera lymphocytes (of donor origin) from dogs and patients with acute GVHD show proliferative responses to previously stored host cells, and lymphocytes cytotoxic to host target cells are seen in patients with GVHD. Observations indicate a direct, rather than an indirect, role for T cells in GVHD. "Specific" suppressor cells may be responsible for maintaining stable graft-host tolerance while "nonspecific" suppressor cells may play a role in the impaired immune defenses in patients with chronic GVHD. Chronic GVHD, which resembles systemic collagen vascular disease, occurs in approximately 40% of HLA-identical recipients, particularly following acute GVHD and is more frequent in older patients. Efforts to treat both acute and chronic GVHD with prednisone, antithymocyte globulin, cyclosporine and azathioprine are only unpredictably effective. Data in dogs pointed out the feasibility of transplants from partially matched related donors or matched unrelated donors, an approach that is now being pursued in human patients. Marrow grafts from HLA-partially matched family members resulted in a higher incidence of acute GVHD. There was no difference in acute GVHD comparing class I to class II antigen differences and long term survival was influenced by patient age and disease status rather than HLA incompatibility.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute Disease↗
PubMed1985

Morphologic and phenotypic analysis of canine natural killer cells: evidence for T-cell lineage.

Canine natural killer (NK) activity and antibody-dependent cell-mediated cytotoxicity were studied utilizing a canine thyroid adenocarcinoma cell line and a lymphoblastoid cell line (CT-45S), respectively, as cell targets. Fractionation of peripheral blood mononuclear cells by Percoll discontinuous-gradient centrifugation resulted in a six- to sevenfold enrichment in large granular lymphocytes (LGL) in parallel with a twofold increase in NK activity (%specific lysis) in low-density fractions. Further enrichment in LGL (78 +/- 6%) and NK activity (threefold increase) was obtained by lytic treatment of low-density fractions 2 and 3 with monoclonal antibody WIG4. By means of cytolytic treatment with additional monoclonal antibodies the phenotype of canine NK cells was determined as Dly-1+, Dly-6+, 1A1+, E-11+, DT-2-, WIG4-. Some NK cells were also Ia+. NK activity was relatively radioresistant with 40% specific lysis even after irradiation with 40 Gy. Among the populations examined, the highest NK activity was found in peripheral blood mononuclear cells, followed by splenic mononuclear cells and bone marrow mononuclear cells. These results indicate that canine NK cells have the morphology of LGL, are relatively radioresistant, and express cell surface antigens suggesting a T-cell lineage.

Adenocarcinoma↗
PubMed1985

Marrow transplantation from related donors other than HLA-identical siblings.

Marrow transplantation has generally been limited to patients with a sibling who is genotypically identical for HLA. In a study of the acceptable limits of HLA incompatibility, 105 consecutive patients with hematologic cancers who received marrow grafts from haploidentical donors (study group) were compared with 728 similar patients concurrently receiving grafts from HLA genotypically identical siblings (control group). The unshared haplotypes differed variably: 12 were phenotypically but not genotypically identical for HLA-A, HLA-B, and HLA-D; 63 differed at one locus (A, B, or D); 24 at two loci; and 6 at three. A higher proportion of study patients had delayed engraftment, granulocytopenia, or graft rejection. Acute graft versus host disease occurred earlier and with greater frequency in study patients. The risk of the disease did not correlate with disparity for Class I (A or B) versus Class II (D-region) loci. Thus, incompatibility for HLA has an important effect on the course after clinical marrow transplantation. In spite of these complications, there was no statistically significant difference in the survival of the study patients and control patients who received their transplants during remission.

Acute Disease↗
PubMed1985

Subsets of patients with aplastic anemia identified by flow microfluorometry.

We used flow microfluorometry to analyze peripheral-blood mononuclear cells from 50 patients with aplastic anemia, to determine whether patients who would recover after immunosuppressive therapy could be distinguished before treatment from those who would not recover. Cells were labeled with murine monoclonal antibodies that are relatively specific for B cells, T cells, T-cell subsets, and monocytes. The data suggested that the number of lymphocytes and the ratios of various subclasses of T cells were not useful in identifying patients who were likely to recover. The complete absence of monocytes was found to identify patients who would not recover, but the presence of monocytes was also sometimes associated with lack of recovery. An unexpected finding was the significant (P less than 0.0001) association between clinical recovery and the presence of a population of small cells (4 to 8 micron) that were phenotypically associated with the erythroid lineage. If this association is confirmed, flow microfluorometry may be useful in selecting the optimal treatment for individual patients with aplastic anemia.

Adolescent↗
PubMed1985

Treatment of acute graft-versus-host disease after allogeneic marrow transplantation. Randomized study comparing corticosteroids and cyclosporine.

Seventy-seven patients (age 12 to 46 years) who underwent allogeneic marrow transplantation for hematologic malignancy or aplastic anemia and who had grade II to IV acute graft-versus-host disease despite methotrexate prophylaxis were randomly assigned to receive methylprednisolone 2 mg/kg per day intravenously (n = 39) or cyclosporine (n = 38) either 12 to 15 mg/kg per day orally or 3 to 5 mg/kg per day intravenously. In both groups, clinical and histologic evidence of graft-versus-host disease was detected at medians of 16 and 25 days, respectively. Drugs were given for a minimum of 14 days unless significant deterioration occurred. If graft-versus-host disease did not improve with this therapy, treatment with a second agent was initiated. Treatment responses were scored after reviewing clinical and laboratory data collected before, during, and after the 14-day treatment period. Possible scores were as follows: -1, worse; 0, no change; + 1, improvement in one organ system (skin, liver, gut) with no deterioration in the other two; +2, complete resolution of all involved systems. The median response score among 39 methylprednisolone-treated patients was 0. Sixteen patients (41 percent) showed response to treatment, 11 with partial and five with complete response. The median response score among 38 cyclosporine-treated patients was +1. Twenty-three patients (61 percent) showed response to treatment, 15 with partial and eight with complete response (p = 0.039). Twenty patients receiving methylprednisolone and 18 receiving cyclosporine required additional therapy. The incidence of chronic graft-versus-host disease was similar in both groups. It developed in all nonresponding patients at risk who had received secondary therapy. Among responding patients (scores +1 or +2) who were not given additional treatment, chronic graft-versus-host disease developed in eight of 11 (72 percent) receiving methylprednisolone and five of ten (50 percent) receiving cyclosporine. Survival beyond 17 months was similar in the two groups (28 percent and 24 percent, respectively). These data suggest that cyclosporine is a useful agent for the treatment of acute graft-versus-host disease, comparable in its efficacy to methylprednisolone.

Acute Disease↗
PubMed1985

Marrow transplantation for leukemia following fractionated total body irradiation. A comparative trial of methotrexate and cyclosporine.

Fifty-six patients, 30-47 yr of age, with leukemia in relapse received allogeneic marrow transplants from HLA-identical siblings. All patients were treated with cyclophosphamide (120 mg/kg) and 7 daily fractions of 2.25 Gy of total body irradiation (TBI) for seven consecutive days. Nine patients (16%) are currently alive and free of disease 324-845 days from transplantation. The actuarial relapse and survival rates at 2 yr were 56% and 9.5% respectively. These data were not remarkably different from those in previous studies using 10 Gy of TBI administered as a single dose. Thirty patients were randomized to receive methotrexate (MTX) and 26 to receive cyclosporine (CSP) as postgrafting prophylaxis for acute graft-versus-host disease (GVHD). The probability of developing significant acute GVHD by day 100 post-transplant was 71% for patients in the MTX group and 45% for patients in the CSP group (p less than 0.05). The probability of relapse was 37% for patients in the MTX group and 70% for patients in the CSP group (p less than 0.05). Transplant-related deaths were more frequent in the MTX group and leukemic deaths were more frequent in the CSP group although this may have been related to an uneven distribution of high-risk patients. Long-term disease-free survival was comparable. Patients in the MTX group had more severe mucositis, more alveolar pneumonias and possibly more deaths due to complications of acute and chronic GVHD. Patients in the CSP group had a higher incidence of hypertension, neurological complications and renal dysfunction.

Adult↗
PubMed1985

DLA-D-specific suppressor cells characterized by monoclonal antibodies.

Canine lymphocytes alloantigen-primed in mixed leukocyte culture (MLC) were tested for their ability to suppress MLC reactivity. These cells were added to fresh responder cells in MLC at ratios of 1:50 and 1:20 and suppressed reactivity 90 +/- 7% (mean +/- 1 SD) and 91 +/- 3% respectively. At lower ratios no suppression was observed. Monoclonal antibody E11 (IgG3) recognized a subset of canine Thy1+ T cells, and with complement treatment was capable of depleting suppressor cells from bulk MLC (11 +/- 6% of control suppression), but DT-2 (IgG2a), another canine T-cell antibody, had no such effect (84 +/- 11%) (P = 0.028). Antibody A5 (IgG2b), reactive with all T and most non-T cells, also eliminated suppression. Positively selected E11+ bulk-MLC cells suppressed (91%) and E11- bulk-MLC cells did not (4%). At the ratios described, suppression was specific for the DLA-D phenotype of the stimulator cells. In tests with the original stimulators, suppression was 91 +/- 7%; in tests with DLA-D identical stimulators it was 92 +/- 5%; and for DLA-D nonidentical stimulators it was 38 +/- 25% (P = 0.005). Nonspecific suppression increased with increasing numbers of suppressor cells. At ratios of 1:10 and 1:5 nonspecific suppression was 72 +/- 13% and 92 +/- 8%, respectively. These studies show that under appropriate conditions, Thy1+, E11+, A5+, DT-2- alloantigen-activated canine T lymphocytes function as DLA-D-specific suppressor cells and DT-2+ cells do not.

Animals↗
PubMed1985

Marrow transplant studies in dogs with malignant lymphoma.

Ninety-five dogs with spontaneous malignant lymphoma in chemotherapy-induced remission were treated with total-body irradiation (TBI) and bone marrow transplantation. Among 38 dogs treated with 8.4 Gy delivered at 4 cGy/min, 9 (24%) became long-term disease-free survivors. Ten of the 38 (26%) died of transplant-related complications and the actuarial relapse rate was approximately 65%. Forty animals were treated with higher-dose TBI (13.5 Gy). The higher-dose TBI led to an increased incidence of transplant-related deaths (55% vs. 26%) and did not reduce the actuarial relapse rate. Eight animals were treated with 8.4 Gy at 4 cGy/min, allogeneic marrow from unrelated donors, and posttransplant immunosuppression with methotrexate and cyclosporine. Of 8 animals, 6 died within 2 weeks of transplant of infection and 2 died later of graft-versus-host disease. Finally, 9 dogs were treated with 8.4 Gy at 4 cGy/min, autologous marrow, and posttransplant methotrexate and cyclosporine. Six of these animals died within 2 weeks of transplant. These studies thus demonstrated that dogs with malignant lymphoma in remission can be cured with high-dose TBI and autologous marrow transplantation, that increasing the total dose of TBI led to increased toxicity without a decrease in the relapse rate, and that post-transplant therapy with methotrexate and cyclosporine was poorly tolerated in these animals.

Animals↗
PubMed1985

Treatment of human acute graft-versus-host disease with antithymocyte globulin and cyclosporine with or without methylprednisolone.

Forty-eight patients with hematologic malignancies treated by allogeneic marrow transplantation developed acute graft-versus-host disease (GVHD), grades II-IV, despite prophylaxis with methotrexate. They were treated with a combination of antithymocyte globulin (ATG) and cyclosporine (CsA), with or without the addition of methylprednisolone (MP). Thirty patients had received HLA-identical and 18 HLA-nonidentical transplants. Median onset of GVHD was day 13 (range 8-60) for patients with HLA-nonidentical grafts and day 18 (range 7-48) for patients given HLA-identical grafts (P = 0.01). Forty-five patients could be evaluated for response on day 7 of therapy. Among these, 13 of 27 given ATG/CSP and 6 of 18 given ATG/CSP/MP improved. Among 33 patients evaluable on day 14 of therapy 13 of 19 given ATG/CSP and 5 of 14 given ATG/CSP/MP showed improvement of GVHD. Patients given HLA-nonidentical grafts responded somewhat (although not significantly) less frequently than patients given HLA-identical grafts. Chronic GVHD developed in 16 of 18 evaluable patients given ATG/CSP and in 5 of 6 given ATG/CSP/MP. Viral, bacterial, and fungal infections were the major cause of death in both groups. Interstitial pneumonitis was more frequent among patients given ATG/CSP/MP. Survival beyond 6 months was 67% among patients treated with ATG/CSP and 25% with ATG/CSP/MP. These data indicate that a regimen of ATG/CSP is of value in the treatment of acute GVHD. The addition of MP was not beneficial and resulted in decreased survival--presumably because of excessive immunosuppression and associated complications.

Adolescent↗
PubMed1985

Recognition of target cell determinants associated with DLA-D-locus-encoded antigens by canine cytotoxic lymphocytes.

Cytotoxic lymphocytes (CTL) were generated in bulk mixed leukocyte culture (MLC) using peripheral blood mononuclear cells from homozygous dogs identical to each other for DLA-A and -B but different for DLA-D loci. These CTL were tested against 51Cr-labeled targets (Con-A-stimulated PBMC) derived from the MLC sensitizing dogs and from other dogs homozygous for various DLA-D locus alleles. Indirect cell-mediated lympholysis (CML) assays, with and without cold target blocking and pretreatment of 51Cr-labeled targets with DLA alloantisera were used to study the target cell determinants recognized by these CTL. The resultant target cell lysis and cold target blocking of specific target cell lysis indicated target determinants associated with DLA-D-locus-encoded specificities, and different from those encoded by DLA-A and -B loci. The pattern of shared target determinants among different DLA-D HTC may be explained by: (A) two separate previously unrecognized MHC associated loci, each with 2 alleles defined so far; or (B) epitopes shared among certain DLA-D alleles but not present in others. This study demonstrates that DLA-D associated determinants different from previously described DLA-D specificities may serve as CML target cell determinants when there are no apparent DLA-A and -B loci encoded antigen differences between responder and stimulator cells used to generated MLC-derived CTL.

Animals↗
PubMed1985

Incidence of hypertension after marrow transplantation among 112 patients randomized to either cyclosporine or methotrexate as graft-versus-host disease prophylaxis.

We investigated the frequency of hypertension (sustained diastolic blood pressure greater than or equal to 90 mmHg) in 112 patients given HLA-identical marrow grafts. Patients were conditioned with 2 X 60 mg/kg of cyclophosphamide and 6 X 2 Gy of total body irradiation and randomized to receive as graft-versus-host disease prophylaxis either the standard methotrexate regimen (n = 61) or cyclosporine (n = 51), starting on day -1 as 12.5 mg/kg/d orally or as 3 mg/kg/d i.v. and later converting to p.o. when oral intake was tolerated. Kaplan-Meier estimates indicate a 60% incidence of hypertension in the first 120 d in patients given cyclosporine (median time to onset: 4 d post transplant) compared to 20% in patients given methotrexate (P less than 0.0001). Multifactorial analysis using a Cox regression model showed that cyclosporine was was the most significant risk factor for developing hypertension (relative risk: 32.1, P less than 0.0001). In addition, glucocorticoids, used for treatment of GVHD, were associated with an increased risk for hypertension (relative risk 7.2, P less than 0.0001). Age, sex, underlying disease, cyclosporine trough levels, and renal function had no significant association with hypertension. Early therapy of hypertension in cyclosporine-treated patients appears to be indicated.

Adolescent↗