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G Longton

Publications and source records attributed to G Longton.

34 records · Page 2Linked to original sources
PubMed1992

Acute graft-versus-host disease: analysis of risk factors after allogeneic marrow transplantation and prophylaxis with cyclosporine and methotrexate.

Previous studies of risk factors for acute graft-versus-host disease (GVHD) involved patients receiving predominantly single-agent prophylaxis. Therefore, a retrospective analysis was performed on 446 patients, from a single institution, who received transplants of marrow from HLA-identical siblings and the combination of cyclosporine (CSP) and methotrexate (MTX) to determine risk factors for acute GVHD associated with this more effective form of GVHD prophylaxis. The incidences of Grades II-IV and Grades III-IV (severe) acute GVHD were 35% and 16%, respectively. Increased clinical grades of acute GVHD in patients without advanced malignant disease were associated with a decreased survival. In a multivariate Cox regression analysis, risk factors associated with the onset of Grades II-IV acute GVHD were sex mismatch and donor parity (P = .001), increased dose of total body irradiation (TBI) (P = .001), and reduction to less than 80% of the scheduled dose of MTX (P = .02) or CSP (P = .02). The multivariate analysis indicated a relative risk of 1.37 for acute GVHD in a group defined as having advanced malignant disease at transplant; however, this difference failed to reach conventional levels of statistical significance (P = .07). Reduction of MTX and CSP occurred in up to 36% and 44% of patients, respectively, primarily because of renal or hepatic dysfunction. The periods of increased risk for the onset of acute GVHD were up to 1 week after a reduction of MTX and 2 weeks after a reduction in CSP. When only patients who developed Grades II-IV acute GVHD were considered, the more severe acute GVHD of Grades III-IV was associated with increased patient age of 40 years or greater (P = .05) and dose reductions of CSP (P = .008). Serologic status of patient and donor for cytomegalovirus (CMV), HLA antigens in the A and B loci, and isolation in a laminar air flow room during marrow transplantation, all previously identified as risk factors for acute GVHD, were not confirmed as risk factors in this study population. The toxicity of MTX and CSP and the development of acute GVHD from inadequate immunosuppression because of dose reduction warrants further trials with potentially less toxic immunosuppressive agents. Risk factors for acute GVHD should be considered in clinical management and in the design of clinical trials.

Adult↗
PubMed1992

A pilot study of low-dose cyclosporin for graft-versus-host prophylaxis in marrow transplantation.

Nineteen patients with leukaemia, preleukaemia, and aplastic anaemia were treated by marrow transplantation from HLA-identical siblings. All were given postgrafting immunosuppression with a combination of methotrexate (days 1, 3, 6 and 11) and cyclosporin (days--1 to 180). In an attempt at reducing cyclosporin-associated toxicity, we explored whether the cyclosporin dose during the first 2 weeks could be decreased by 50% (from 3.0 to 1.5 mg/kg/d intravenously) without adversely affecting the incidence, onset, and severity of acute graft-versus-host disease (GVHD) and overall survival. Results from this pilot study were compared to those of a matched cohort of 38 patients given a standard dose of 3.0 mg cyclosporin/kg/d starting on day--1. The cumulative incidence of grade II and III acute GVHD in the 'low dose' cyclosporin group was 42% compared to 51% in the 'standard dose' group (P = 0.60). Three-year survival was 63% and 54% respectively (P = 0.59). Patients receiving the reduced cyclosporin dose during the first 14 d appeared to have less hepatotoxicity, and the methotrexate and cyclosporin doses administered were closer to the doses intended per protocol. We suggest that 'low dose' cyclosporin from day--1 to day 15 postgrafting might be as effective as 'standard dose' cyclosporin during that time period for the prevention of acute GVHD.

Acute Disease↗
PubMed1991

A qualifier Q for the survival function to describe the prevalence of a transient condition.

We propose an estimator of the prevalence of a transient condition among surviving patients using right censored data. The prevalence of opportunistic infection among surviving AIDS patients and the probability of being in tumour response following cancer therapy conditional on being alive are two examples of such functions. In essence these functions describe a major aspect of the quality of life for surviving patients and may be useful when viewed in conjunction with the survival curves themselves. The method is illustrated using data from a randomized trial of bone marrow transplant patients where the prevalence of chronic graft-versus-host disease is of interest. The non-parametric estimator which we have proposed is contrasted with estimators derived from Markov and semi-Markov models.

Bone Marrow Transplantation↗
PubMed1991

On estimating HLA/disease association with application to a study of aplastic anemia.

A multiplicative model is described relating HLA typing information to disease incidence. A likelihood-based method for estimating parameters in this model is proposed for use with data sets in which HLA haplotype information is available on a series of cases and their parents. This approach is extended to incorporate information from a matched control series for the purpose of estimating HLA and environmental risk factor effects simultaneously. The method is applied to data from aplastic anemia patients treated by bone marrow transplantation and the results are compared to unmatched case-control analyses using the same case series and several different control series.

Anemia, Aplastic↗
PubMed1990

Previous donor pregnancy as a risk factor for acute graft-versus-host disease in patients with aplastic anaemia treated by allogeneic marrow transplantation.

To determine if previous donor pregnancies influence the development of acute graft-versus-host disease (GVHD) we evaluated data from 136 patients with aplastic anaemia greater than 15 years of age and given marrow grafts from HLA-identical sibling donors. Of the 136 marrow donors, 30 were parous females (previous history of pregnancy), 30 were nulliparous females (no history of pregnancy or abortions), and 76 were males. The cumulative incidence of grade II-IV GVHD was 57%, 21% and 46% for patients with parous, nulliparous and male donors, respectively. A multivariate analysis of the data confirmed that the risk of grade II-IV acute GVHD was significantly increased among patients receiving marrow from parous females as compared to those from nulliparous females (relative risk = 2.5, P = 0.02). There was no statistically significant difference in the incidence of acute GVHD, however, between patients with parous donors and male donors (relative risk = 1.3, P = 0.26). Male patients given grafts from parous donors showed a higher incidence of acute GVHD (63%) than female patients (45%), though this difference was not statistically significant. The 5-year probability of survival was 47% for patients with parous donors, 68% for patients with nulliparous donors and 70% for those with male donors. We confirm that prior donor pregnancy represents an important factor in selecting marrow donors or designing clinical protocols for GVHD prophylaxis.

Acute Disease↗
PubMed1990

Cytomegalovirus infection after marrow transplantation for aplastic anemia.

Data from 137 patients who underwent allogeneic marrow transplantation for aplastic anemia and who had sufficient virologic and serologic surveillance data were reviewed for risk factors for cytomegalovirus (CMV) infection and associations between CMV infection and acute or chronic graft-versus-host disease (GVHD). Total CMV infection (i.e. excretion or seroconversion) occurred in 58% of the patients. Twelve patients (9%) developed CMV pneumonia. Among seropositive patients occurrence of acute GVHD was associated with increased risk of total CMV infection and CMV excretion, but not of seroconversion. Acute GVHD did not influence the likelihood of total CMV infection, excretion, or seroconversion in seronegative patients. Among seronegative patients marrow donor seropositivity, buffy coat infusions, and granulocyte transfusions were significant risk factors for total CMV infection and seroconversion, but not for CMV excretion. No influence of either total CMV infection or the patient's or donor's serologic status for CMV was found on the risk of developing chronic GVHD in this homogeneous group of patients who underwent allogeneic marrow transplantation for aplastic anemia.

Adolescent↗
PubMed1989

Factors predicting chronic graft-versus-host disease and survival after marrow transplantation for aplastic anemia.

The cumulative incidence of chronic graft-versus-host disease (GVHD) was 48% among 165 patients with severe aplastic anemia who had been discharged from Seattle 3 months after they were treated with marrow grafts from HLA-identical siblings. Estimated 10-year survival was 85%. Preceding acute GVHD had a dominating influence on the development of chronic GVHD. Almost all patients with grades II-IV and 67% of those with grade I acute GVHD developed chronic GVHD. Among patients without previous acute GVHD, three factors were independently correlated with an increased risk of de novo chronic GVHD: increasing patient age, the infusion of buffy coat cells in addition to the marrow, and corticosteroid therapy before transplantation. For example, patients below and above age 20 years who had neither buffy coat cell transfusions nor preceding corticosteroid therapy had an incidence of chronic GVHD of only 4-8%, while those with either buffy coat cell transfusions or corticosteroids or both had incidence rates of 33-70%. The development of chronic GVHD significantly influenced survival. Among 83 patients without chronic GVHD, only one died (on day 150 with interstitial pneumonia), compared to 23 deaths among 82 patients with chronic GVHD. For results of marrow grafting for aplastic anemia to improve, better prevention of chronic GVHD is needed.

Adolescent↗
PubMed1988

Single dose or fractionated total body irradiation and autologous marrow transplantation in dogs: effects of exposure rate, fraction size, and fractionation interval on acute and delayed toxicity.

Dogs were given single dose or fractionated total body irradiation (TBI) and autologous marrow grafts to prevent death from myelosuppression. Acute and delayed non-marrow toxicities were compared. Fifty-six dogs were given single dose TBI at 2.1 (n = 13), 5 (n = 12), 10 (n = 15), or 20 (n = 16) cGy/min. Acute radiation toxicity and mortality was related to the exposure rate; radiation doses resulting in 50% mortality at 7 days (LD 50/7) at 2.1, 5, 10 and 20 cGy/min were 1,692, 1,499, 1,261, and 1,056 cGy respectively. Fifty-three dogs were given fractionated TBI, 200 cGy three times a day with 6-hour intervals at 2.1 (n = 13), 5 (n = 9), 10 (n = 13), or 20 (n = 18) cGy/min. The LD 50/7 at the four exposure rates were 1,628, 1,470, 1,184, and 1,320 respectively. Thus, for exposure rates of 2.1, 5, and 10 cGy/min, the tolerated doses were comparable for single dose and fractionated TBI. At 20 cGy/min dose fractionation appeared to offer some advantage, although this fractionation effect in part may have been due to random variation with small numbers of dog treated. Following recovery from the immediate TBI-related toxicity, eight dogs given single dose and four dogs given fractionated TBI died, generally from infections, 8-30 days following transplantation. There was a striking difference in regards to long-term survival dependent upon the TBI regimen. Among dogs given greater than or equal to 1,000 cGy of TBI and alive 30 days after transplant only 1 of 18 given single dose TBI became a long-term survivor compared to 19 of 22 given fractionated TBI. Causes of death included pancreatic fibrosis, malnutrition, hepatic failure, and a generalized wasting syndrome. All 5 dogs given a single dose of 800 cGy (at 20 cGy/min) became long-term survivors. Fourteen dogs were given increments of 150 cGy at 7 cGy/min every 3 hours for total doses of 1,500-2,400 cGy. The LD 50/7 was approximately 1,900 cGy. All 6 dogs alive at 30 days became healthy long-term survivors. Four dogs were given increments of 600 cGy at 2.1 cGy/min every 48 hours for a total dose of 1,800 cGy. All 4 dogs became long-term survivors. In conclusion, exposure rate and total dose are the most important parameters for acute toxicity associated with TBI. The effect of dose fractionation is minimal at low exposure rates and appears to be dependent also upon increment size and fractionation interval.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Selective inhibition of the canine mixed lymphocyte response by HLA-DR and DP-reactive monoclonal antibodies.

Twenty-three of 37 anti-Ia McAb reactive with human B cells, as determined by indirect immunocytofluorescence, were shown to be reactive with canine peripheral blood mononuclear cells (PBMC). Using a panel of human B cell lines that differ in their expression of HLA-DR, -DP, and -DQ molecules, it was shown that 15 of these antibodies identify HLA-DR and DP molecules (i.e., broadly reactive), while 22 identify only HLA-DR molecules. Fourteen of the 15 broadly reactive McAb were reactive with canine PBMC while only 9 of the 22 HLA-DR-specific McAb reacted with canine PBMC, suggesting that broadly reactive anti-Ia McAb are much more likely to react with canine cells than narrowly reactive McAb. Ten of the canine reactive McAb that were shown to identify typical Ia bimolecular structures on canine cells using immune precipitation analysis were tested for blocking activity in the canine mixed lymphocyte culture (MLC). All four of the broadly reactive McAb (B1F6, J-70, 9-49, and HB10a) plus two of the six narrowly reactive McAbs (H81.98.21 and H40.164.3) blocked the canine MLC when added to culture wells on day 0, suggesting that inhibition may be related to the specificity of the anti-Ia McAb employed. Since the MLC may reflect cellular interactions occurring during graft-versus-host disease, this assay may be useful for screening functionally relevant broadly reactive McAb in experimental canine bone marrow transplantation studies. These data suggest that the dog may be a useful model to study anti-Ia immunotherapy.

Animals↗
PubMed1988

Improvement in rejection, engraftment rate and survival without increase in graft-versus-host disease by high marrow cell dose in patients transplanted for aplastic anaemia.

Two hundred and fifty-two consecutive patients with severe aplastic anaemia were conditioned by cyclophosphamide and given marrow transplants from HLA-identical siblings or parents. The results were analysed to examine the influence of marrow cell dose on graft rejection, speed of engraftment, survival and acute and chronic graft-versus-host disease (GVHD). Sixty patients received a corrected marrow cell dose below 2.2 x 10(8) nucleated cells per kg body weight, 73 patients between 2.2 and 3.2 x 10(8) cells/kg, 60 patients between 3.3 and 4.2 x 10(8) cells/kg, and 59 patients more than 4.2 x 10(8) cells/kg. The significant association between high marrow cell dose and low risk of graft rejection previously reported was confirmed. In addition, high marrow cell dose resulted in small but statistically significant reductions in time to granulocyte and platelet recoveries in patients with sustained engraftment. High marrow cell dose was also associated with a significant improvement in patient survival, a result solely due to the reduction in the incidence of graft rejection. Neither acute nor chronic GVHD were influenced by marrow cell dose. We conclude that the maximum marrow cell dose should be transplanted in patients with severe aplastic anaemia. Maximum marrow cell doses are likely to decrease the incidence of graft rejection, shorten the time to engraftment thereby decreasing the need for blood products and antibiotic support, and improve overall patient survival.

Adolescent↗
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↗
PubMed1983

Identification and functional characterization of two distinct epitopes on the human T cell surface protein Tp50.

The structural and functional domains of Tp50, the human T lymphocyte surface protein associated with the E rosette receptor, were probed with the use of two murine monoclonal antibodies. Lysostripping, immune precipitation, and competitive binding experiments demonstrated that antibodies 9.6 and 35.1 bind to Tp50 epitopes in close proximity. In functional studies, both antibodies caused a similar degree of antigenic modulation, inhibited T cell proliferative responses, and inhibited cytotoxic T lymphocyte function without affecting cells that mediate antibody-dependent cell-mediated cytotoxicity. The antibodies were strikingly different, however, in that antibody 9.6 inhibited E rosette formation and natural killer cell-mediated lysis, whereas antibody 35.1 did not. These results could not be ascribed to differences in antibody class or binding characteristics, because Scatchard analysis demonstrated that these two IgG2a antibodies have comparable avidity and that T cells bind each antibody in equivalent amounts. The differential binding of antibodies 9.6 and 35.1 to T cells from nonhuman primates further supports the interpretation that the differences between the antibodies in their effects on E rosette formation and natural killer function stem from the fact that they bind to distinct epitopes of Tp50. The implications of these findings for understanding the functions of Tp50 molecules are discussed.

Animals↗
PubMedDate not supplied

Incorporating the time dimension in receiver operating characteristic curves: a case study of prostate cancer.

Early diagnosis of disease has potential to reduce morbidity and mortality. Biomarkers may be useful for detecting disease at early stages before it becomes clinically apparent. Prostate-specific antigen (PSA) is one such marker for prostate cancer. This article is concerned with modeling receiver operating characteristic (ROC) curves associated with biomarkers at various times prior to the time at which the disease is detected clinically, by two methods. The first models the biomarkers statistically using mixed-effects regression models, and uses parameter estimates from these models to estimate the time-specific ROC curves. The second directly models the ROC curves as a function of time prior to diagnosis and may be implemented using software packages with binary regression or generalized linear model routines. The approaches are applied to data from 71 prostate cancer cases and 71 controls who participated in a lung cancer prevention trial. Two biomarkers for prostate cancer were considered: total serum PSA and the ratio of free to total PSA. Not surprisingly, both markers performed better as the interval between PSA measurement and clinical diagnosis decreased. Although the two markers performed similarly eight years prior to diagnosis, it appears that total PSA performed better than the ratio measure at times closer to diagnosis. The area under the ROC curve was consistently greater for total PSA than for the ratio four and two years prior to diagnosis and at the time of diagnosis.

Adult↗