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Biomedical subjects

H G Prentice

Publications and source records attributed to H G Prentice.

At least 163 records · Page 9Linked to original sources
PubMed1991

Granisetron, a selective 5-HT3 receptor antagonist, for the prevention of radiation induced emesis during total body irradiation.

The antiemetic efficacy of granisetron was tested in an open trial in patients undergoing highly emetogenic treatment by single fraction total body irradiation. Thirty-two consecutive patients were entered. Results were both patient- and observer-rated. Following a single intravenous dose of granisetron 18 patients (56.3%) experienced total protection and a further 13 (40.6%) had major antiemetic protection with four of these patients experiencing nausea only. One patient experienced an anaphylactic reaction on infusion of monoclonal antibody-treated donor marrow 5 h after administration of the trial drug and vomited on multiple occasions. The reaction was associated with hypotension. A further patient experienced transient hypotension secondary to septicaemia 8 h after receiving granisetron. Three patients required a second dose. Headache was the most frequent side-effect occurring in three patients, but in to of these patients the test drug was not thought to be implicated. In conclusion granisetron is a highly effective agent in controlling radiation induced emesis with a favourable toxicity profile.

Adolescent↗
PubMed1991

Failure of purged autologous bone marrow transplantation in high risk acute lymphoblastic leukaemia in first complete remission.

Patients in first remission of acute lymphoblastic leukaemia (ALL) considered to be at high risk of relapse were offered autologous bone marrow transplantation (ABMT) using purged marrow as a therapeutic alternative to cranial irradiation and maintenance chemotherapy. Twenty-seven bone marrows taken in remission, were purged using monoclonal antibodies (anti CD7 for T lineage and anti CD10 and/or anti CD19 for B lineage leukaemias) plus rabbit complement. Retrospective analysis of 19 purged marrows by immunophenotyping or immunoglobulin gene rearrangement studies demonstrated no evidence of disease. Engraftment was seen in 26 of the patients. No correlation was found between the numbers of infused nucleated cells or colony forming units-granulocyte-macrophage (CFU-GM) and subsequent engraftment kinetics. The actuarial disease-free survival (DFS) is 32% at 7 years (median follow-up 3.4 years). There were two transplant related deaths (actuarial risk 8%); the main cause of treatment failure has been disease recurrence with an overall actuarial risk of 67%; 76% for T-ALL (five of nine), 62% for common ALL (five of 10), two of five pre B and none of three patients with B-ALL. In these 27 high risk patients in vitro purging of remission marrow as part of ABMT appears not to improve patient outcome, although confirmation of this would require a randomized trial.

Adolescent↗
PubMed1990

Immunity against Pseudomonas aeruginosa adoptively transferred to bone marrow transplant recipients.

Infection is a common problem for bone marrow transplant (BMT) recipients during the period of neutropenia that immediately follows the procedure. Gram-negative infections present a particular hazard in these immunocompromised hosts. To augment host defenses against one such pathogen, Pseudomonas aeruginosa, we immunized bone marrow transplant donors and/or recipients with a polyvalent O-polysaccharide-toxin A conjugate vaccine. When either donor or recipient alone was vaccinated before transplant, no increase in specific antibody titers to any of the vaccine components was observed in the recipient. However, when both donor and recipient were vaccinated before transplant, increases in antibody titers to all polysaccharide components occurred to levels shown to be protective in animal models of gram-negative sepsis. Specific antibodies were primarily of the IgG1 and IgG2 subclass even though IgG2 subclass deficiency is common after BMT. The requirement for both donor and recipient immunization reflects the need for primed donor B lymphocytes in the marrow inoculum to be transferred into an antigen-containing environment so that maximum B-cell proliferation and antibody secretion can occur. Adoptive transfer of antibody responses to Pseudomonas aeruginosa and other common bacterial pathogens has the potential to reduce infection-related morbidity and mortality after allogeneic bone marrow transplantation.

Adolescent↗
PubMed1990

Gamma-interferon and tumor necrosis factor production after bone marrow transplantation is augmented by exposure to marrow fibroblasts infected with cytomegalovirus.

After bone marrow transplantation (BMT), mortality from viral infections such as cytomegalovirus (CMV) remains high. Gamma-Interferon (gamma IFN) and tumor necrosis factor (TNF) are produced constitutively after BMT and have anti-viral properties. To study the effects of these cytokines on CMV interaction with host cells, we have used patient marrow fibroblasts since marrow stroma is a target for CMV infection correlating with myelosuppression in vivo. Both gamma IFN and TNF are constitutively produced by recipient CD3+ and CD16+ lymphocytes, but not by their marrow fibroblasts. Secretion by peripheral blood mononuclear cells is increased if they are cultured with host fibroblasts infected with CMV in vitro and the levels of gamma IFN and TNF produced are within the range that protects fresh fibroblasts from CMV infection. Constitutive secretion of cytokines by lymphocytes declines by 8 weeks after BMT, a time when the risk of CMV disease increases sharply. The in vitro phenomenon that we have described needs to be evaluated in correlative studies on individual BMT recipients to determine whether such a cytokine-mediated defense mechanism against CMV may operate in vivo.

Antigens, CD↗
PubMed1990

Requirements for the adoptive transfer of antibody responses to a priming antigen in man.

Antibody responses to recall vaccines can be adoptively transferred after marrow transplantation in man. Transfer of responses to priming Ag has not been successful, although this would broaden the range of organisms to which recipients could be protected. To investigate the importance of T cells and Ag in such transfer we primed marrow donors with keyhole limpet hemocyanin (KLH) 1 or 3 wk before marrow harvesting. B cells secreting IgM and IgG anti-KLH antibody were present in donor marrow at both 1 and 3 wk after immunization. After T cell depletion, donor marrow was infused into chemo-irradiated recipients, half of whom were immunized pretransplant with KLH. We found no evidence for the transfer of the IgM component of the response. Clonal expansion of the transferred IgG antibody-secreting cells with a corresponding rise in recipient serum IgG antibody levels was seen only when donors were primed 3 wk before marrow harvest and when the recipients were also immunized. IEF and immunoblotting demonstrated that successful transfer coincided with maturation of the IgG primary response from a polyclonal to an oligoclonal pattern and confirmed that donor oligoclonal bands appeared in the recipient serum. We conclude that the immunization protocols required for the transfer of antibody responses to priming Ag reflect the initial dependence of unprimed B cells on T cell help and on prolonged Ag stimulation. Ag-stimulated primary B cells in T cell-depleted marrow respond only to the noncognate growth and differentiation signals available in the chemo-irradiated recipient after an initial period of clonal selection and expansion in the donor which is both T cell and Ag dependent. Even after this initial selection, continued expansion of antibody-secreting clones in recipients retains an absolute dependence on Ag stimulation. Immunization techniques to protect transplant recipients against organisms such as Pseudomonas and CMV may need to be modified accordingly.

Antibody Formation↗
PubMed1990

Origin of marrow stromal cells and haemopoietic chimaerism following bone marrow transplantation determined by in situ hybridisation.

The origin and cell lineage of stromal cells in the bone marrow is uncertain. Whether a common stem cell exists for both haemopoietic and stromal cells or whether these cell lines arise from distinct stem cells is unknown. Using in situ hybridisation for detection of the Y chromosome, we have examined histological sections of bone marrow from seven patients who received marrow transplants from HLA-matched donors of the opposite sex. Stromal cells (adipocytes, fibroblasts, endothelial cells, osteoblasts and osteocytes) were identified in these recipients as being of host origin. This result is consistent with the concept of a distinct origin and separate cell lineage for cells of the haemopoietic and stromal systems. It also shows that engraftment of marrow stromal cell precursors does not occur and that host stromal cells survive conditioning regimens for marrow transplantation. With the exception of one case, with a markedly hypocellular marrow, mixed chimaerism was seen in haemopoietic cells, indicating that this is not a rare event after marrow transplantation.

Adolescent↗
PubMed1990

Unrelated donor marrow transplantation between 1977 and 1987 at four centers in the United Kingdom.

Retrospectively we analyzed the histocompatibility data and clinical results of bone marrow transplantation in 51 patients who received marrow from unrelated donors (UD) from 1977 to 1987 at one of four UK BMT centers. We compared the results with those obtained in 51 transplants carried out at the same centers using HLA-identical (ID) sibling donors. Of the UD/recipient pairs 32 (63%) were serologically identical for HLA A, B, and DR antigens, and 37% showed varying degrees of mismatch. UD-BMT primary diagnoses were: severe aplastic anemia or Fanconi's anemia (n = 17), acute leukemia (n = 11), chronic myeloid leukemia (n = 21), and other conditions (n = 2). T cell depletion of the graft was associated with a significant improvement in survival in both UD and ID-BMT. Graft failure was more common in recipients of UD than of ID transplants (13 [25%] vs. 5 [10%] P = 0.05) but there was no significant difference in the frequency of acute or chronic graft-versus-host disease. Actuarial survival was superior for recipients of ID transplants (UD vs. ID: 49% vs. 78%, respectively, at 3 months; 32% vs. 63% at one year). Reduced survival for recipients of UD-BMT was confirmed in case control regression analysis (relative risk 3.0, P = 0.01). Nevertheless in patients whose only alternative is a partially mismatched family donor we think that UD-BMT is justified.

Bone Marrow Transplantation↗
PubMed1990

Malignant plasma cells are sensitive to LAK cell lysis: pre-clinical and clinical studies of interleukin 2 in the treatment of multiple myeloma.

To assess the role of the cytokine interleukin 2 (IL2) in the treatment of patients with multiple myeloma, we examined the sensitivity of plasma cell lines and malignant plasma cells from multiple myeloma (MM) patients to cell and cytokine-mediated killing induced by IL2. Unstimulated peripheral blood mononuclear cells (PBM) from normal donors produced little killing (mean lysis 1.0 +/- 1.0%, effector:target (ET) ratio 50:1), but cytotoxicity was modestly increased when PBM were incubated with IL2 prior to assay (8.0 +/- 2.9%). Unstimulated PBM from patients with MM also failed to kill autologous malignant plasma cells (mean 0.6 +/- 0.6%), but after exposure to IL2 they induced substantial lysis of autologous malignant cells (mean 55.3 +/- 22.1%). In addition, tumour necrosis factor (TNF) and interferon-gamma (IFN-gamma), two cytokines released from mononuclear cells in response to IL2, also reduced the survival and thymidine uptake of malignant plasma cells in culture. To determine whether these potentially beneficial immunomodulatory effects could be reproduced by in vivo administration of IL2, we have administered seven courses of IL2 to four patients with MM after autologous bone marrow transplant (ABMT). No serious adverse effects were noted. Increases in natural killer (NK) and lymphokine-activated killer (LAK) activity of PBM occurred during IL2 infusion, although cells capable of killing autologous MM cells did not circulate. However, IL2 infusions also induced substantial increases in the production of the cytokines TNF and IFN-gamma from peripheral blood lymphocytes. These results suggest that the in vivo administration of IL2 in MM deserves further evaluation, particularly for its potential to control minimal residual disease.

Adult↗
PubMed1990

Pneumonitis in bone marrow transplant recipients results from a local immune response.

Eighteen recipients of allogeneic T cell-depleted bone marrow who developed 22 episodes of interstitial pneumonitis were investigated by bronchoalveolar lavage for the cause of pneumonitis. The cells obtained were examined using a panel of monoclonal antibodies with immunocytochemical techniques to identify lymphocyte subsets and the presence of surface molecules indicative of lymphocyte activation. The majority of patients had an excess of lymphocytes in lavage and most of these cells were positively stained with the McAb recognizing the CD8 antigen (suppressor/cytotoxic type T cells). Although the proportions of CD4+ (helper type) T cells were below normal, the absolute numbers were within normal limits, thus the CD4:CD8 ratio was consistently 1:1 or less. A large proportion of the CD8+ cells displayed HLA-DR molecules (RFDR1+), interleukin-2 (IL-2) receptors (CD25+) and high concentration of CD7 antigen (RFT2+). Further analysis revealed that most CD8+ cells were CD5+ (RFT1+) yet a large proportion (20-40%) were CD5-. A majority of CD8+ cells was also CD38+ (RFT10+) and Leu7+. No clear correlation between the emergence of a raised proportion of activated CD8+ cells and diagnosed cytomegalovirus infection was found. These results demonstrate, however, that cells with the phenotype of the resident T cells of the bronchial epithelium (CD8+CD5-) emerge to the air spaces and express activation markers. This raises the intriguing paradox of an aggressive local immune response occurring in an otherwise immunosuppressed group of patients.

Adolescent↗
PubMed1990

A role of herpes virus serology for the development of acute graft-versus-host disease. Leukaemia Working Party of the European Group for Bone Marrow Transplantation.

Pretransplant herpes virus serology and acute graft-versus-host disease (GVHD) were studied in 379 leukaemic bone marrow transplant (BMT) recipients and their HLA-identical sibling donors. In logistic multivariate regression analysis pretransplant seropositivity to three or more different herpes viruses among the recipients was the only significant factor associated with grade II-IV acute GVHD (p = 0.03). If this factor was excluded, older donor age (p less than 0.001), absence of T cell depletion (p less than 0.001), pharmacological immunosuppression by monotherapy of methotrexate or cyclosporin versus a combination therapy of both (p = 0.002), and seropositivity to three or more herpes viruses among the donors (p = 0.03) prior to BMT, were also significantly associated with acute GVHD. The data indicate that latent herpes viruses in the host may act as minor histocompatibility antigens or by other means to trigger acute GVHD.

Adolescent↗
PubMed1990

Trisomy 8 in acute lymphoblastic leukemia (ALL): a case report and update of the literature.

A case of acute lymphoblastic leukemia (ALL) cytogenetically characterized by trisomy 8 as a sole aberration is described. The patient, one of 116 adults with ALL investigated cytogenetically, was a 36-year-old male with leukocyte count 12.3 x 10(9)/liter with 90% blasts of FAB type L1 and common ALL immunological phenotype. Remission was achieved with the current U.K. treatment trial. The patient recovered from an autologous bone marrow transplant (BMT) in first remission but relapsed 15 months later. BMT, in second remission, from an unrelated donor, was rejected. Autologous reinfusion failed and he died 26 months after diagnosis. Molecular investigation of immunoglobulin gene rearrangement identified the same B cell clone at diagnosis and in relapse. The clinical and cytogenetic findings of six published cases of ALL with trisomy 8 have been reviewed with updates supplied by the authors. These reveal an heterogeneous group of patients ranging in age from 9 months to 39 years with no apparent association with a particular immunophenotype. Four patients were alive after 10-108 months follow-up. Two patients died, in relapse, 7 and 17 months after diagnosis. Thus trisomy 8 occurs in ALL with an incidence of 1-2%. The prognostic significance of this remains to be determined.

Adult↗
PubMed1990

Allogeneic bone marrow transplantation for leukemia in Europe: regional differences. Report from the Leukemia Working party of the European Group for Bone Marrow Transplantation.

The results of 1904 allogeneic HLA identical sibling donor bone marrow transplants performed in 52 European centers between 1979 and 1986 and reported to the EBMT leukemia registry were analysed by geographical location of the transplant. Patients were grouped into six regions: United Kingdom, Nordic Group, Benelux, France, Central Europe and Southern Europe. There were significant differences between these regions with respect to patient population and outcome. The relative proportion of the three major disease categories, stage and subtype of the diseases, graft-versus-host disease prevention methods, donor recipient sex combinations, age of the patient, year of the transplant and the time intervals from diagnosis to transplant, from diagnosis to first complete remission for acute leukemia and the time from first complete remission to the transplant varied from region to region. The analysis of outcome parameters showed a significant difference in relapse incidence from region to region. This influence of region was confirmed in a multivariate analysis and was independent of the other factors known to affect outcome. Leukemia-free survival and transplant-related mortality were not different. The reasons for these differences could not be explained by the data in the registry. We conclude that regional factors must be considered when bone marrow transplant data are compared and we postulate that pretransplant factors probably affect outcome more than was previously realized.

Adolescent↗