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H G Prentice

Publications and source records attributed to H G Prentice.

At least 199 records · Page 11Linked to original sources
PubMed1989

New developments in post-induction therapy for acute myeloblastic leukaemia.

80-90% of patients with acute myeloblastic leukaemia under the age of 60 can presently expect to achieve a complete remission with modern chemotherapy. A minimum of two courses of consolidation treatment beyond CR is advised to achieve a state of "minimal residual disease". In an attempt at cure patients should receive either an allogeneic BMT (less than 50 years of age) or autologous BMT (less than 60 years of age) and we currently recommend the additional use of IL2 after ABMT. Beyond 60 autologous BMT is presently not considered justified until the safety of this intensive/experimental approach is clarified. We do advocate intensive induction (needing less support than less intensive treatment) followed by consolidation therapy. Further studies into the applications of cytokines will clarify whether the large numbers of older patients could also safely benefit from these approaches.

Adult↗
PubMed1988

In vitro analysis of the interactions of recombinant IL-2 with regenerating lymphoid and myeloid cells after allogeneic marrow transplantation.

Although administration of rIL-2 post-T depleted allogeneic bone marrow transplantation (TD-BMT) offers the prospect of augmenting immune reconstitution and thereby reducing the risks of infection and relapse, it has been unclear what direct or indirect effects this agent would have on the regenerating myeloid system. We find that addition of 200 IU or rIL-2 to patient lymphocytes obtained within 6 wk of TD-BMT results in a substantial (2 to 3 log) increase in INF-gamma secretion and the production of TNF. Cytokines present in supernatants obtained from IL-2-stimulated patient lymphocytes have two contrasting effects on myeloid cells from normal donors and from marrow recipients. They prime granulocytes for enhanced oxidative metabolism as measured by ability to generate chemiluminescence in response to FMLP, whereas IL-2 added directly to neutrophils has no effect. However, these IL-2-induced cytokines also act to inhibit myeloid progenitor growth and reduce granulocyte macrophage (GM) colony formation by a mean of 53%. Preincubation of supernatants with anti-IFN-gamma antibody partially abrogates both enhancement of granulocyte chemiluminescence and suppression of marrow CFU-GM. Addition of IL-2 directly to recipient marrow also produces inhibition, leading to a 25% reduction of GM-colony growth. This effect is not due to direct interaction between myeloid progenitor cells and IL-2, because it is completely abrogated by removal of CD8 and Leu-7+ lymphocytes from the marrow. Although the suppressive effects on marrow growth in vitro are of particular concern after BMT, the potential of IL-2 to promote granulocyte function, immune reconstitution, and anti-leukemic activity after TD-BMT justify further consideration of IL-2 therapy in this setting.

Adolescent↗
PubMed1988

Seroepidemiologic studies on the acquisition of antibodies to cytomegalovirus, herpes simplex virus, and human immunodeficiency virus among general hospital patients and those attending a clinic for sexually transmitted diseases.

A total of 731 sera were collected from general hospital patients, divided into five distinct subgroups, and tested for the presence of immunoglobulin (IgG) to cytomegalovirus (CMV) and herpes simplex virus (HSV). The results indicate a high level of association between the two viruses, although HSV was found to be more prevalent in the earlier years of life, whereas CMV was acquired constantly throughout life. An increase in age was also accompanied by significantly higher antibody levels to both viruses. Individuals with antibody to HSV were significantly more likely to have antibodies to CMV, suggesting that these viruses are transmitted by similar routes (?saliva). In addition, 430 sera from 94 homosexual and 336 heterosexual males attending a clinic for sexually transmitted diseases were tested for antibody to CMV, HSV, and human immunodeficiency virus (HIV). Homosexual males were more likely to have antibody to CMV and HIV than were heterosexuals, but no difference was seen for HSV antibodies. The levels of CMV-specific IgG were significantly raised in homosexuals, compared with heterosexuals, but again no difference was seen for HSV antibodies as in the general hospital patients, however, individuals with HSV antibodies were significantly more likely to possess antibodies to CMV. However, the additional association of CMV antibodies with a homosexual lifestyle suggests that an alternative route for acquisition of this virus exists (?semen). As raised levels of CMV antibodies, but not HSV antibodies, were found among homosexuals, this suggests that frequent CMV reinfections, rather than merely reactivation of latent herpes viruses, may be occurring.

Antibodies, Viral↗
PubMed1988

Is the measurement of virus-specific antibody in the lungs of transplant recipients with cytomegalovirus pneumonitis of diagnostic or prognostic value?

We have investigated 12 transplant recipients (nine bone marrow transplants, three renal) with 15 episodes of pneumonitis caused by cytomegalovirus (CMV) and ten patients (eight bone marrow transplant recipients, two renal transplant recipients) with 12 episodes of interstitial pneumonitis in whom no CMV was detected, to determine whether levels of CMV-specific IgG in the lung are diagnostic of infection. We have also assessed whether a vigorous specific local antibody response is important for survival. CMV-specific IgG and herpes simplex (HSV)-specific IgG were measured in bronchoalveolar lavage (BAL) fluid and serum using albumin to correct for simple diffusion from serum into the lung. We have found evidence for local production or facilitated transport of CMV-specific IgG in ten patients with CMV pneumonitis but also in six patients with pneumonitis where no CMV was detected. Similar results were found for HSV-specific IgG although only one patient had a demonstrable HSV infection. There was a tendency for those patients producing large amounts of immunoglobulin in the lung to survive compared with those who died, but there were wide variations between patients in each group. The local humoral immune response in transplant patients with pneumonitis was not specific to the infecting agent and is most probably the result of polyclonal B cell activation or facilitated transport of IgG from serum to lung secretions. Measurement of CMV-specific IgG response in the lung should not, therefore, be used for diagnostic or prognostic purposes.

Adolescent↗
PubMed1988

A randomized trial of empirical antibiotic therapy with one of four beta-lactam antibiotics in combination with netilmicin in febrile neutropenic patients.

Over a two year period 174 evaluable episodes of fever in neutropenic patients were treated in a randomized study comparing four beta-lactam antibiotics, each given in combination with netilmicin. Exclusions included episodes due to viral or fungal infection, and trial violations. Most patients were receiving treatment for leukaemia, including 18% undergoing bone marrow transplantation. The overall response rate (EORTC criteria) was 66%, ranging from 56% for cefoperazone to 76% for mezlocillin. Microbial documentation was obtained in 31% of episodes; Gram-positive isolates were most frequent but Pseudomonas aeruginosa was found in 18 patients. In patients with microbiologically documented infection 70% improved, overall--from 40% with cefoperazone to 80% with piperacillin (P less than 0.05). Nephrotoxicity was seen in 6.7% and was associated with severe documented sepsis. Hypokalaemia was seen in 29% and was most marked in patients receiving ticarcillin. Rashes occurred in 6.6% overall, with no difference between the groups. Ototoxicity, shown by serial audiograms, was seen in 4.7% of patients. No evidence of vestibular dysfunction was seen in 62 patients studied. Of thirteen deaths due to the primary infection, seven were caused by Ps. aeruginosa and five by fungi.

Agranulocytosis↗
PubMed1988

Differential recovery of phenotypically and functionally distinct circulating antigen-presenting cells after allogeneic marrow transplantation.

Low-density cells (LDC) prepared from peripheral blood by fractionation over hypertonic metrizamide contain 95% of cells with veiled morphology, almost all of which are HLA-DR-positive and have characteristics of antigen-presenting cells. In normal individuals the monoclonal antibodies RFD1 and RFD2 divide these cells into three phenotypically distinct populations, D1+D2-, D1-D2+ and D1-D2-. The RFD1-positive population is nonphagocytic. We have investigated the recovery of LDC in peripheral blood after (T cell-depleted) marrow transplantation, to assess whether defects in antigen-presenting cell (APC) subpopulations could contribute to the prolonged immune-paresis of marrow graft recipients. We find that APC of donor origin and with apparently normal morphology, phenotype, and function appear within 6 weeks of BMT. By three months the donor-derived nonphagocytic RFD1-positive subset has disappeared, although phagocytic RFD2-positive cells remain. The disappearance of the RFD1-positive subset is associated with a loss of antigen presentation by patients' LDC of the soluble protein antigen tetanus toxoid, though the capacity to present alloantigen and stimulate in a mixed lymphocyte reaction is retained. Donor-derived RFD1-positive cells and soluble antigen-presenting capacity do not reappear for one year or more. This biphasic recovery of RFD1-positive cells contrasted with the continued production of RFD2-positive APC, implies that the phenotypic and functional distinction between APC subpopulations in peripheral blood also reflects a separate ontogeny. Since these marrow graft recipients retain the phagocytic (RFD2-positive) APC but lose the nonphagocytic (RFD1-positive) APC subset, there is now an opportunity to explore the role of each subset in antigen processing and presentation.

Adolescent↗
PubMed1988

Relapse after allogeneic bone marrow transplantation for acute leukaemia: a survey by the E.B.M.T. of 117 cases.

A multi-centre retrospective analysis on 117 patients relapsing after bone marrow transplantation (BMT) for acute leukaemia was carried out by the Leukaemia Working Party of the European Group for Bone Marrow Transplantation (E.B.M.T.). Forty-one patients had acute myeloid leukaemia (AML) and 76 had acute lymphoblastic leukaemia (ALL). Relapse occurred between 3 and 30 months after BMT and where investigated the leukaemia was found to have relapsed in recipient cells. In 10 cases the relapse was associated with new cytogenetic abnormalities. 74 patients received further treatment for leukaemia. Of these 21 out of 50 with ALL and 11 out of 24 with AML achieved a complete remission and had a median survival of 12 months compared with a median survival of 4 months for untreated patients or patients not achieving complete remission (P less than 0.001). Factors predictive for successful remission induction were a long interval between bone marrow transplant and relapse in ALL patients; and isolated extramedullary relapse. Presenting blast count, karyotype and remission status and number at the time of BMT were not predictive. Donor bone marrow was shown to be responsible for haemopoietic recovery occurring in the 21 out of 31 patients tested who achieved remission using donor karyotype or red blood cell antigens as markers. Nine patients received a second bone marrow transplant but only one became a long-term survivor. The results show that chemotherapy can usually prolong survival in selected patients with acute leukaemia relapsing after BMT but further BMT has a poor outlook.

Adolescent↗
PubMed1988

Antithrombin III in the diagnosis of infection in febrile neutropenic patients.

Antithrombin III levels in plasma were measured in 29 febrile neutropenic patients (31 episodes). They were lowest on day 2 in 62.5% of febrile patients and then increased or were normal in 81.3%. Low levels were present on day 2 in only 28.6% of patients with gram-negative infections, as compared with 33% of patients with doubtful infections.

Agranulocytosis↗
PubMed1988

Apparent pulmonary mycetoma following invasive aspergillosis in neutropenic patients.

After the death from massive haemoptysis of two neutropenic patients who had developed apparent pulmonary mycetomas, two subsequent patients underwent successful resection of similar lesions. Histological examination of these lesions confirmed that these so called mycetomas were masses of devitalized lung tissue infiltrated with fungus. The term mycotic lung sequestrum is therefore proposed to distinguish this condition from a fungus ball arising in a previously formed cavity. A review of 34 similar cases reported previously showed that haemoptysis occurred in about half of the cases and was fatal in just over half of these. Medical treatment appears to have little impact on survival and early consideration of surgical intervention is important.

Adolescent↗
PubMed1988

Allogeneic bone marrow transplantation. Recent developments and the potential expansion of the donor pool.

Graft versus host disease is a preventable complication of allogenic bone marrow transplantation. A complex biological manoeuvre has enabled us to achieve this. Unfortunately T-cell depletion of the donor marrow shifts the delicate immunological balance in favour of the recipient immune system. The consequence has been an increased risk of graft rejection and leukaemia relapse. It is necessary to shift this balance back in favour of the donor (derived) immune system. This can be achieved by increasing the immunosuppressive power of the 'conditioning' chemoradiotherapy. Toxicity considerations limit our scope although single fraction fast dose rate radiotherapy appears to diminish the risks inherent with T-cell depletion. Logically an approach with greater promise will be to use specific immunological means of eliminating the recipient T lymphocytes in vivo. Early experience with a monoclonal anti-lymphoid antibody in vivo in an HLA matched unrelated donor programme suggests that this approach has great promise whilst lacking toxicity. We hypothesise that a shift in immunological superiority to the donor derived immune system will not only allow T-cell depletion whilst minimising the risk of graft rejection, but also enhance the anti-leukaemic properties of the graft. Of further interest will be the potential for application of lymphokines (e.g. IL2) without increasing the risk of lethal graft versus host disease.

Bone Marrow Transplantation↗
PubMed1988

Haemolytic uraemic syndrome after bone marrow transplantation: an adverse effect of total body irradiation?

Eight cases of haemolytic uraemic syndrome occurring after bone marrow transplantation are presented and the other 15 reported cases are reviewed. Two patients were recipients of autologous marrow whereas all cases previously reported occurred after allogeneic transplantation. Six patients had not received cyclosporin and two had no evidence of cytomegalovirus infection. The roles of cyclosporin, cytomegalovirus infection, graft-versus-host disease, total body irradiation (TBI) and chemotherapeutic drugs as aetiological agents are discussed. It is postulated that TBI, perhaps potentiated by cyclophosphamide, is likely to be the most important factor but that other agents may act additively with TBI and influence the time course and severity of the disease.

Adolescent↗
PubMed1988

Humoral immune responses within the lung of bone marrow transplant recipients studied by bronchoalveolar lavage.

We investigated 20 bone marrow transplant recipients with pneumonitis using bronchoalveolar lavage (BAL) to assess the humoral immune response in the lung. We measured the levels of total IgG, IgM and IgA in bronchoalveolar lavage fluid and serum, and albumin measurements were used to correct for simple diffusion of immunoglobulins from serum into the lung. We found evidence for the local production of immunoglobulins G, M and A in 15 patients. This was independent of the cause of the pneumonitis. We also found that, although seven patients who recovered from their pulmonary problem had evidence of considerable local production of immunoglobulin, eight patients who died were also producing immunoglobulins in the lung. Death due to pneumonitis in BMT recipients cannot, therefore, be ascribed to a failure of the local humoral immune response.

Adolescent↗
PubMed1988

Correlation of immunophenotype with rearrangement of T cell antigen receptor beta and gamma genes in acute lymphoblastic leukemia of adults.

The structure of immunoglobulin heavy chain (IgH) and T cell antigen receptor (TCR) beta and gamma chain genes was studied in 38 cases of adult and two cases of childhood acute lymphoblastic leukemia (ALL). Seven cases of T-ALL all showed clonally rearranged TCR beta and gamma genes; only one of these also contained rearranged IgH genes. All precursor B cell ALLs and one case of unusual B cell ALL/lymphoma had clonally rearranged IgH genes, but a high proportion (22 of 32, 69%) of precursor B cell ALLs also had rearrangement of TCR beta and/or gamma genes. TCR beta gene rearrangement was less common in more mature precursor B cell ALL, expressing cytoplasmic IgM (pre-B-ALL) (0 of 5) than in other precursor B cell ALL cases (15 of 27). In the precursor B cell ALLs overall, 10 (32%) had rearrangement of both beta and gamma genes, while 7 (22%) had rearrangement of TCR gamma genes only. A further 5 (16%), all expressing one or more unusual immunophenotype markers, had TCR beta gene rearrangement without detectable gamma gene rearrangement. These observations, together with certain characteristics of constant-joining region usage of both TCR genes (a preference for rearrangement into the C beta 2 and C gamma 1 genes), distinguishes these "inappropriate" rearrangements from those found in T-ALL and suggests that they have arisen through a differentiation arrest which is not part of a normal T cell developmental program.

Acute Disease↗
PubMed1987

B cell development and regulation after T cell-depleted marrow transplantation.

Antibody secreting B lymphocytes from immunized donors can be adoptively transferred after T cell-depleted marrow transplantation to produce protective levels of antibody in the recipient. We have investigated whether these transferred lymphocytes remain subject to continued clonal selection and subsequently became memory B cells even in the initial absence of T cells. Twenty-eight donor/recipient pairs were randomized pretransplant to be immunized or not with tetanus toxoid (TT). The recipients were then vaccinated with TT at 3, 6, and 12 mo posttransplant, and the anti-TT antibody response (IgG and IgM) was measured. Only when both donor and recipient were immunized pretransplant could the recipient respond to antigen challenge within the first year posttransplant. Examination of the spectrotype pattern of the recipient anti-TT antibody shows that selection of B cell clones continues, so that T cell depletion does not prevent the appearance of oligoclonal antibody responses. However, because the spectrotype pattern of the recipient did not match the donors, B cell regulatory mechanisms in donor and recipient are nonidentical. These data contrast with observations made in recipients of non-T cell-depleted marrow and serve to illustrate the role of T lymphocytes in the induction and regulation of secondary antibody responses in man. The results also suggest that optimal humoral responses to any antigen after T cell depletion can only occur when both donor and recipient are immunized pretransplant, a prediction borne out by studies on the influence of donor cytomegalovirus status on the severity of cytomegalovirus infection in the recipient.

B-Lymphocytes↗
PubMed1987

Immune donors can protect marrow-transplant recipients from severe cytomegalovirus infections.

To study the importance of transferred immunity against cytomegalovirus (CMV) in allogeneic, HLA-matched, T-cell-depleted bone-marrow transplantation, the incidence, severity, and outcome of CMV infections were studied in 40 CMV-seropositive recipients in relation to the donors' immunity against CMV. There was no significant difference in the incidence of CMV infections between recipients of seropositive (n = 27) and seronegative (n = 13) marrow. However, the incidence of CMV pneumonitis (8/13 compared with 4/27; p less than 0.001) and the mortality attributable to CMV infection (6/13 compared with 1/27, p less than 0.01) were significantly greater in the group with seronegative donors than in those with seropositive donors. Multivariate regression analysis showed that recipients of seronegative marrow had a fifteen-fold greater risk of CMV pneumonitis and a fifty-fold increase in risk of a fatal CMV infection than recipients of seropositive marrow. Thus, after T-cell depletion CMV-seropositive marrow protects seropositive recipients against severe CMV infections; whenever possible, therefore, such recipients should be given marrow from seropositive donors. Ultimately, active immunisation of CMV-seronegative donors might help to protect seropositive recipients of T-cell-depleted marrow transplants against severe CMV infections.

Adult↗