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Biomedical subjects

R Storb

Publications and source records attributed to R Storb.

At least 577 records · Page 32Linked to original sources
PubMed1984

Secondary malignancies after marrow transplantation.

Secondary malignancies after marrow transplantation have been observed in 20 patients: 19 patients underwent marrow transplantation for the treatment of a hemopoietic malignancy and one for aplastic anemia. All but three were given total body irradiation at doses of 8.0-15.75 Gy as part of the conditioning regimen. Secondary malignancies were composed of three groups: (a) Six patients had recurrence of leukemia (three acute lymphoblastic, two acute myeloblastic, and one chronic myelocytic) in cells of donor origin 62-1074 days after grafting. (b) Eight patients developed lymphoproliferative disorders (four of immunoblastic sarcoma type, one lymphoblastic, one follicular center cell, and one Hodgkin's lymphoma and one acute lymphoblastic leukemia) 54-730 days after grafting. In four of seven patients with appropriate studies these tumors were of donor-cell origin and in three of four tested the cells contained Epstein-Barr virus genome or expressed viral antigens. (c) Six patients developed solid tumors (two glioblastoma multiforme, two adenocarcinomas, one squamous cell carcinoma, and one sarcoma) 347-1875 days after grafting. All but two patients (one with glioblastoma and one with squamous cell carcinoma) have died. These data suggest that patients undergoing marrow transplantation for a hemopoietic malignancy may be at risk of developing secondary malignancies. The etiology appears to be multifactorial, including irradiation, immunosuppression, Epstein-Barr virus infections, and other factors.

Adolescent↗
PubMed1984

Effect of hepatic dysfunction on oral cyclosporin pharmacokinetics in marrow transplant patients.

The effect of hepatic dysfunction, defined as abnormal serum bilirubin level, on oral cyclosporin (CSP) pharmacokinetics was examined in 28 marrow transplant patients who received CSP for prophylaxis of graft-v-host disease. Serum CSP concentrations were measured by radioimmunoassay. Forty-one concentration-time courses were studied, divided among patients with no (less than 1.2 mg/dL), mild (1.2 to 2.0 mg/dL), and moderate (2.0 to 5.0 mg/dL) hepatic dysfunction. CSP elimination, as determined by elimination rate constant and clearance, was delayed in patients with moderate hepatic dysfunction compared to those with no hepatic dysfunction (P less than .05). The volume of distribution, lag time for absorption, maximum serum concentration, and time at which the maximum concentration was achieved was not affected by hepatic function. These data indicate that patients with moderate hepatic dysfunction have delayed CSP or CSP metabolite elimination and may be at higher risk for developing CSP-related toxicity.

Administration, Oral↗
PubMed1984

Ineffective cellular interaction and interleukin 2 deficiency causing T cell defects in human allogeneic marrow recipients early after grafting and in those with chronic graft-versus-host disease.

Impairment in T cell proliferation in response to E. coli and in CML to unrelated alloantigens was usually observed in patients early after marrow grafting and persisted in long-term patients with chronic GVHD but not in those without chronic GVHD. We analyzed various cellular functions in the pathway of T cell activation and found that in patients with immunodeficiency, (1) their M phi usually could process and present antigens to normal T cells, (2) their T cells did not proliferate even in the presence of normal antigen-pulsed M phi, (3) IL-2 production by T cells was deficient, and (4) exogenous IL-2 restored CML activity in cells of most patients early after grafting but not in cells of most patients with chronic GVHD. Therefore, failure to induce proliferation and cytotoxicity in T cells of marrow recipients is not likely due to M phi defects but because of ineffective communication among T cell subsets, probably related to impaired IL-2 production and/or unresponsiveness to IL-2.

Bone Marrow Transplantation↗
PubMed1984

Pulmonary function of marrow transplant patients. I. Effects of marrow infusion, acute graft-versus-host disease, and interstitial pneumonitis.

The pulmonary function of patients receiving marrow transplants was studied during a two-year period. The 81 patients studied before transplantation showed a slight reduction in average lung volumes and diffusing capacity (DLCO). Studies were repeated within 48 h after marrow infusion to look for evidence of fat embolism syndrome. There was no change in the DLCO, but there was a 4% decrease in the lung volumes. Sixty-three patients (20 with aplastic anemia, 43 with hematologic malignancies) completed studies on admission and every other week during hospitalization (mean of six studies per patient). When categorized by diagnosis or conditioning regimen (including with and without total body irradiation), no differences were seen. The patients developing interstitial pneumonitis (IP) had restrictive ventilatory changes and decreases in the DLCO. The patients not developing IP remained unchanged. The patients developing IP averaged a 20% decrease in the DLCO before the clinical diagnosis of pneumonia, but a decrease in the DLCO lacked specificity for predicting occurrence of IP. Among 18 patients developing graft-versus-host disease, there was no evidence of air-flow obstruction. We conclude that patients developing IP have restrictive ventilatory changes, but in the absence of complicating IP, the marrow transplant regimen (including marrow infusion and total body irradiation) leaves pulmonary function largely unchanged.

Adolescent↗
PubMed1984

HLA and disease: relative-risk regression methods and multiple testing considerations.

This paper discusses certain statistical issues arising in an analysis to relate HLA-B antigens to the incidence of graft-versus-host disease in a clinical study. The Cox regression method is used to develop a global test of the hypothesis of no association and to produce estimated relative-risk factors corresponding to the presence of each particular allele. Multiple-testing considerations are central to any attempt to identify pairs of alleles having significantly different relative-risk factors. A number of simultaneous-testing approaches are considered including cumulative P-value plotting and a direct simulation of the null distribution of the maximum pairwise ratio.

Anemia, Aplastic↗
PubMed1983

Association between HLA-B antigens and acute graft-versus-host disease.

130 patients with severe aplastic anaemia, conditioned with high-dose cyclophosphamide, showed sustained engraftment of marrow from HLA-identical siblings. Most patients (55%) had no acute graft-versus-host disease (GVHD), 11% had transient grade I, and 34% had moderate to severe (grades II-IV) acute GVHD. The relation between the donors' (and the patients') HLA antigens and the incidence of grades I-IV acute GVHD was explored. There was no association with HLA-A antigens, but a significant correlation with HLA-B antigens. Patients with HLA-B18 had an estimated acute GVHD incidence nearly three times that of other patients, whereas the incidence in the presence of HLA-B8 or HLA-Bw35 was estimated to be about half that in the absence of these alleles.

Acute Disease↗
PubMed1983

Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings. Beneficial effect of a protective environment.

One hundred thirty patients with severe aplastic anemia were conditioned with cyclophosphamide for transplantation of marrow from HLA-identical siblings. The patients were selected for the present analysis according to the criterion of sustained marrow engraftment. Of the 130 patients, 97 are now alive between 1.4 and 11 years (median, 5) after transplantation. Twenty-nine of the thirty-three who died had either acute or chronic graft-versus-host disease (GVHD). Our analysis was directed at identifying factors predicting GVHD and survival after transplantation in patients. Our key findings were that moderately severe to severe acute GVHD had a strong adverse influence on survival; that a protective environment significantly reduced mortality, which corresponded in part to a reduction in and delayed onset of acute GVHD; that refractoriness to random-donor platelet infusions at transplantation adversely influenced survival, particularly among patients with acute GVHD; and that increasing age was associated with increased mortality.

Adult↗
PubMed1983

Canine bronchoalveolar cells: antigen-presenting macrophages are Ia-positive, lymphocytes are of non-B lineage.

Subsegmental bronchoalveolar lavages were performed in 18 healthy beagles. The average yield per lavage was 45 X 10(6) cells consisting on the average of 24% lymphocytes, 71% macrophages, and 4% granulocytes. Cells were further examined in cytofluorometric studies using monoclonal (anti-Ia, antilymphocyte, anti-T) and polyspecific (anti-Ig) antibodies. Sixty to 90% of lymphocytes were T cells as determined by the T cell antibody DT-2. No surface immunoglobulin-positive cells (B cells) could be detected. All macrophages expressed Ia antigens (p 29/34) whereas lymphocytes did not. In assays of concanavalin A-induced blastogenesis of thymocytes, alveolar macrophages functioned as accessory cells. The anti-Ia antibody 7.2 interfered with this function, indicating that Ia antigens on canine alveolar macrophages are involved in interaction with T cells resulting in T cell proliferation.

Animals↗
PubMed1983

Polymorphism of the sixth component of complement (C6) in the dog.

Isoelectric focusing was used to identify five alleles at the locus determining the production of the sixth component of complement (C6) in the dog. Four of these alleles, C6(1), C6(2), C6(4), and C6(5), were studied in family pedigrees and shown to be inherited in a codominant autosomal fashion. All alleles except for C6(4) occurred commonly in the multiple breeds tested.

Alleles↗
PubMed1983

Increased incidence of malignant tumors in dogs after total body irradiation and marrow transplantation.

One hundred fifty-three dogs were given 6.1-21.3 Gy total body irradiation at 0.02-0.2 Gy/minute delivered from two opposing cobalt sources followed by allogeneic (131 dogs) or autologous (22 dogs) marrow grafts and observed for 6-127 (median 33) months. The incidence of malignant tumors in radiation chimeras was compared to that in 242 untreated dogs observed for 6-188 (median 81) months. Thirteen malignancies were observed in 11 radiation chimeras. These tumors included two leiomyosarcomas of the mesentery, four adenocarcinomas of the breast, prostate and ovary, two mastocytomas, one hypernephroma, perianal gland carcinoma, seminoma, Brenner tumor, and an oligodendroglioma. Fifty-four malignancies were seen in 44 control dogs. These included 12 mammary carcinomas, 12 thyroid carcinomas, six lymphomas, two malignant melanomas, and a number of other solid tumors. On the basis of time-dependent Cox regression analysis, radiation chimeras had an estimated relative risk of developing a malignancy that was 5-fold higher than in control dogs (p less than 0.001). No tumor has yet been observed in a group of 15 chimeras conditioned by cyclophosphamide or dimethyl busulfan and followed for 6-97 (median 24) months. The increased risk of cancer among canine radiation chimeras suggests that high-dose total body irradiation may increase the risk of developing a malignancy and should be avoided whenever possible in the conditioning for marrow transplantation of human patients with nonmalignant diseases.

Animals↗
PubMed1983

Application of bone marrow transplantation in leukaemia and aplastic anaemia.

Marrow transplantation is effective treatment for a number of haematological diseases in patients under the age of 50 who have an HLA-identical sibling donor. It is generally successful when used early in the treatment of aplastic anaemia. It is the only treatment that offers long-term disease-free survival for patients with acute leukaemia who have relapsed at least once, with 10-30 per cent apparent cures. Although still somewhat controversial, it appears also to be the treatment of choice for patients with acute non-lymphoblastic leukaemia in first chemotherapy induced remission and for those with chronic myelogenous leukaemia in the chronic phase since approximately 50-60 per cent of these patients are surviving after marrow transplantation in complete remission, apparently cured. Marrow grafting is the only effective treatment for many patients with inherited immunological-deficiency diseases and certain genetic storage diseases. It is being explored for the therapy of patients with lymphoma, Hodgkin's disease, multiple myeloma, small-cell lung cancer, testicular cancer, ovarian cancer and genetic disorders of haematopoiesis. Cures of congenital Fanconi anaemia, Blackfan-Diamond anaemia, osteopetrosis, and paroxysmal nocturnal haemoglobinuria have been achieved by marrow grafting. Genetic disorders associated with haemolytic anaemia and cyclic neutropenia have been cured by marrow grafting in animals. Target disorders for marrow transplantation in humans are thalassaemia major and sickle cell disease, and, indeed, a first successful transplant for treatment of thalassaemia major has recently been described (Thomas et al, 1982). Marrow transplantation has been limited by the fact that many patients do not have HLA-identical siblings and very few have monozygotic twins. The Seattle team has now explored the use of less well-matched family member donors in more than 80 patients with leukaemia. These donors share one HLA haplotype genetically with the patient and are phenotypically identical at two of the three major HLA loci on the other HLA haplotype (Clift et al, 1979). Overall, the post-transplant survival appears more a reflection of the type and stage of the leukaemia than of the marrow donor. Patients with leukaemia grafted in relapse have a projected survival of 20-30 per cent and those transplanted in remission of 50 per cent. The incidence and severity of GVHD may not be significantly different from that of patients given HLA-identical sibling marrow grafts.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute Disease↗
PubMed1983

Acute renal toxicity with combined use of amphotericin B and cyclosporine after marrow transplantation.

The role of cyclosporine alone or in combination with amphotericin B in the development of renal toxicity was evaluated in 47 marrow transplant recipients. Cyclosporine alone was given to 21 patients and 10 received cyclosporine plus amphotericin B. These were compared with 16 patients who received methotrexate and amphotericin B. Serum creatinine doubled within 14-30 days in 8 of 21 patients who received only cyclosporine. Of 16 patients given amphotericin B in conjunction with methotrexate, only 3 doubled their serum creatinine within 5 days of starting amphotericin B. In contrast, of 10 patients who received amphotericin B in combination with cyclosporine, 5 doubled and 3 tripled their serum creatinine within 5 days. This increase in creatinine was significantly greater than that seen in patients receiving cyclosporine alone or methotrexate and amphotericin B combined. These results suggest that administration of cyclosporine and amphotericin B simultaneously should be undertaken with caution to avoid severe renal toxicity.

Adolescent↗
PubMed1983

Disordered salivary immunoglobulin secretion and sodium transport in human chronic graft-versus-host disease.

Whole saliva samples and lip biopsies were collected from 12 allogeneic bone marrow transplant recipients who developed extensive chronic graft-versus-host disease (GVHD) and from 10 healthy allogeneic and syngeneic recipients without GVHD. Six of ten biopsies from patients with chronic GVHD had lichenoid stomatitis or sialadenitis, or both, with sialodochitis. Seven of nine biopsies from patients free of chronic GVHD were entirely normal, and two had either mild glandular or mucosal changes. Salivary gland involvement in chronic GVHD was associated with decreased or absent levels of salivary IgA and inorganic phosphate, decreased salivary flow rates, and increased concentrations of salivary sodium, albumin, and IgG. The most striking abnormalities were found in patients with histologic evidence of sialadenitis. In contrast, marrow transplant recipients without chronic GVHD had normal salivary immunoglobulin and electrolyte levels. Secretory IgA deficiency may contribute to the frequent sinobronchial infections observed in patients with chronic GVHD.

Adolescent↗
PubMed1983

Analysis of alloreactive and cytotoxic canine lymphocytes and their precursors with murine monoclonal antibodies.

Four murine monoclonal antibodies were used in cytolytic assays to identify cell populations involved in canine T cell effector functions. Antibody DT-2, directed at T cells, and antibody DLy-6, a panlymphocyte antibody, inhibited mixed lymphocyte culture (MLC) responses and cytotoxic lymphocyte (CTL) activity only when lymphocytes were treated before culture (day 0), but they had no significant effect on these functions when cells were treated after 6 days in culture. Antibody DLy-1, reacting with canine lymphocytes and monocytes, abrogated MLC responses and CTL activity when responder cells were treated on day 0. When cells were treated after 6 days in culture, MLC responses were reduced to 47% of control, whereas CTL activity increased slightly. In contrast, the anti-Ia antibody 7.2 significantly reduced MLC responses and CTL activity of cells treated on either day 0 or day 6 of culture, suggesting that canine CTL express Ia antigens.

Animals↗
PubMed1983

Late effects on gonadal function of cyclophosphamide, total-body irradiation, and marrow transplantation.

One hundred thirty-seven patients had gonadal function evaluated 1-11 years after marrow transplantation. All 15 women less than age 26 and three of nine older than age 26 who were treated with 200 mg/kg cyclophosphamide recovered normal gonadotropin levels and menstruation. Five have had five pregnancies resulting in three live births, one spontaneous abortion, and one elective abortion. Three of 38 women who were prepared with 120 mg/kg cyclophosphamide and 920-1200 rad total-body irradiation had normal gonadotropin levels and menstruation. Two had pregnancies resulting in one spontaneous and one elective abortion. Of 31 men prepared with 200 mg/kg cyclophosphamide, 30 had normal luteinizing hormone levels, 20 had normal follicle-stimulating hormone levels, and 10 of 15 had spermatogenesis. Four have fathered five normal children. Thirty-six of 41 men prepared with 120 mg/kg cyclophosphamide and 920-1750 rad total-body irradiation had normal luteinizing hormone levels, ten had normal follicle-stimulating hormone levels, and 2 of 32 studied had spermatogenesis. One has fathered two normal children. It was concluded that cyclophosphamide does not prevent return of normal gonadal function in younger women and in most men. Total-body irradiation prevents return of normal gonadal function in the majority of patients.

Acute Disease↗
PubMed1983

Human T lymphocyte phenotypes after bone marrow transplantation. T cells expressing Ia-like antigen.

Peripheral blood Ia-positive (Ia+) T cells were enumerated in 52 patients who had received allogeneic or syngeneic bone marrow transplantation for the treatment of acute leukemia or severe aplastic anemia. Twenty-two normal people showed 3 +/- 2% of peripheral blood T cells to be Ia+. During the first 130 days posttransplant, all patient groups showed a moderate elevation in the percentage (mean: 21-26%) of Ia+ T cells, regardless of the type of transplant performed, and regardless of the presence or absence of acute graft-versus-host disease (GVHD). Although there was marked individual variation (range 5-76%), there was a trend towards a decrease in the percentage of Ia+ T cells with increasing time after transplantation. Long-term survivors still showed a small (range 3-20%, mean 10%) but significant elevation in the relative number of Ia+ T cells 1-3.4 years after transplantation, regardless of the presence or absence of chronic GVHD. It is not currently known why Ia+ T cells are found in these patients, but accelerated lymphopoiesis, subclinical infection, and excessive immune stimulation caused by microorganisms or other foreign antigens could be contributing factors.

Acute Disease↗