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Biomedical subjects

H G Prentice

Publications and source records attributed to H G Prentice.

At least 253 records · Page 14Linked to original sources
PubMed1985

Virological and serological diagnosis of cytomegalovirus infection in bone marrow allograft recipients.

To detect cytomegalovirus (CMV) infections, a total of 1,074 cultures of urine, saliva, or blood were collected weekly from 43 consecutive patients undergoing allogeneic bone marrow transplantation. Twenty-three patients were seronegative before transplant and primary infection occurred in 2 (9%). Twenty patients were initially seropositive and recurrent infections occurred in 5 (25%). Three patients in the recurrent group had proven CMV pneumonitis; viraemia was detected in two recipients, while the third had CMV isolated only from bronchial lavage fluid. The serological response of the 43 patients was defined by testing 559 serial sera for specific IgG and IgM antibodies by radioimmunoassay. Passive acquisition of IgG antibodies from blood products was found in 78% of initially seronegative recipients. One patient with primary infection responded in a pattern typical of immunocompetent individuals with long-term production of specific IgG and transient production of specific IgM antibodies. The second patient also had a typical response, but this was delayed until several weeks after the start of virus excretion. In patients with recurrent infections, specific IgM production did not correlate with episodes of virus excretion. Three of five such patients failed to mount a specific IgM response, and these were the only patients in the study to develop CMV pneumonitis. We conclude that CMV infection in bone marrow recipients can only be diagnosed by detection of virus; therefore, the ability of these patients to mount humoral immune responses should not be relied upon for diagnostic purposes.

Antibodies, Viral↗
PubMed1985

Sequential studies on the role of mitoxantrone in the treatment of acute leukemia.

Mitoxantrone (Novantrone; 1, 4-dihydroxy-5, 8-bis [[2-[(2-hydroxyethyl) amino]ethyl]amino-] 9, 10 anthracenedione dihydrochloride (NSC 301739] is a synthetic anthracenedione with intercalating properties. Activity has been shown in preclinical studies in mice bearing intraperitoneal P388 and L1210 leukaemias, ADJ-Pc6 plasmacytoma and a variety of solid tumours. In a phase I/II collaborative study fourteen consecutive patients with relapsed or primarily refractory acute leukaemia received a single infusion of mitoxantrone (20-32 mg/m2) at fourteen-day intervals. Antileukaemic activity was seen but there were no complete remissions and toxicity was minimal. Mitoxantrone was subsequently given in a five-day schedule at a dose of 10mg/m2 daily to twenty-one patients with relapsed or refractory acute leukaemia or chronic myeloid leukaemia in blast crisis (CML-BC). Four of five patients in first relapse of acute non-lymphoblastic leukaemia (ANLL) achieved a complete remission (CR). The overall response rate (CR + partial remission (PR] was 48%. In an ongoing phase III study the same (5-day) mitoxantrone treatment has been given in conjunction with a 7-day continuous infusion of cytosine arabinoside (Ara-C) in a kinetically designed schedule based upon the preclinical studies of the Mount Sinai group.

Acute Disease↗
PubMed1985

Deoxycoformycin in the treatment of leukemias and lymphomas.

A new cytotoxic drug, 2'-deoxycoformycin, has been shown to be highly active in the treatment of lymphocytic leukemias and lymphomas, particularly T cell acute lymphoblastic leukemia, in which the drug, used as a single agent, can induce CRs in patients who have failed to respond to a wide variety of other compounds. Further work is required to elucidate the cause of the renal failure that has occurred in some patients, but prescribed within the dose range of the patients reported in this paper, toxicity is acceptable in consideration of the results achieved and the prognosis of this highly malignant group of diseases.

Acute Kidney Injury↗
PubMed1985

Non-suppression of cortisol secretion by long term treatment with ketoconazole in patients with acute leukaemia.

Ketoconazole, a potent antifungal agent, inhibits adrenal steroidogenesis in normal subjects during short term treatment. Since this drug is used in the long term prophylaxis of fungal infections in patients with haematological malignancies, we have investigated whether such patients have evidence of adrenocortical suppression. Six patients on long term prophylaxis with ketoconazole were given tetracosactrin stimulation tests. All patients had high basal cortisol concentrations, which increased further after administration of 25 IU of tetracosactrin. It is concluded that leukaemic patients receiving long term ketoconazole treatment do not have adrenocortical suppression. They may, in fact, have hyperstimulated adrenocortical function due to stress and hypovolaemia.

Adult↗
PubMed1984

Rapid diagnosis of cytomegalovirus infection in immunocompromised patients by detection of early antigen fluorescent foci.

Cell-cultures of cytomegalovirus (CMV) were fixed after 24 hours' incubation and examined by a monoclonal antibody based immunofluorescence method for the detection of CMV-specific early antigens. 385 urine, saliva, or blood samples from 63 immunocompromised patients were inoculated onto cell-cultures. Comparison with the results of conventional cell-cultures in patients who remained uninfected showed that the new technique had a specificity of 100%. The sensitivity was 80%. This immunofluorescence method gave positive results 27h after inoculation of the specimens instead of the mean of 17 X 5 days with the conventional method based on detection of cytopathic effect. 3 saliva samples, from patients who had previously excreted CMV, reacted in the immunofluorescence method but CMV, reacted in the cell-cultures-perhaps because the assay identified defective, interfering particles in these samples. The monoclonal antibodies were also used successfully in another immunofluorescence system to diagnose cytomegalovirus pneumonitis in 3 patients by testing material obtained by bronchoalveolar lavage.

Antibodies, Monoclonal↗
PubMed1984

Allogeneic bone marrow transplantation in a patient with acute myeloid leukemia secondary to Hodgkin's disease.

A patient with Hodgkin's disease entered complete clinical remission by combination radiochemotherapy. He developed dyshematopoiesis 1.5 years later and an overt acute nonlymphocytic leukemia 3 years after diagnosis. A complete remission was achieved following 2 courses of intensive polychemotherapy. Four months later, while still in remission, he underwent an allogeneic bone marrow transplantation (BMT) from an HLA-identical sister. Mild chronic graft versus host disease of the skin occurred 3 months after BMT, and now the patient has been in complete remission of leukemia for over 2 years. This appears to be a unique case of prolonged remission of a leukemia secondary to an intensively treated Hodgkin's disease.

Acute Disease↗
PubMed1984

Depletion of T lymphocytes in donor marrow prevents significant graft-versus-host disease in matched allogeneic leukaemic marrow transplant recipients.

For more than 15 years preclinical studies have suggested that acute graft-versus-host disease (aGvHD) might be prevented by the removal of immunocompetent T lymphocytes from the donor marrow inoculum. To test this observation in man 14 patients were given marrows virtually (greater than 99%) depleted of identifiable donor marrow T lymphocytes by the use of a "cocktail" of specific anti-T-cell monoclonal antibodies (MBG6 and RFT8) and rabbit complement. Patients were not given immunosuppressive prophylaxis after bone-marrow transplantation. Moderate to severe (grades II-IV) GvHD was totally prevented. 2 of 13 evaluable patients showed mild (grade I) skin GvHD only. Although peripheral blood recovery was slower than that obtained with other forms of GvHD prophylaxis, no fatal infections occurred. All patients survived the early post-transplant period.

Acute Disease↗
PubMed1984

The role of monoclonal antibodies in the prevention of graft versus host disease.

We have previously reported that the elimination of T-lymphocytes (greater than 99%) from the donor bone marrow prevents significant graft versus host disease (GvHD). This has been confirmed by other centres. Many of these groups have applied monoclonal antibodies with cytolytic rabbit complement. In some of these studies mostly patients with fully matched sibling donors have been studied and no further immunosuppression has been given during the regeneration period. The experience here shows that the haemopoietic regeneration (to recover a total leucocyte count of 1.0 X 10(9)/l) has only been minimally delayed (mean 25 days) when compared to patients receiving standard methotrexate (Mtx) GvHD prophylaxis (22 days). The incidence of cytomegalovirus (CMV) infections (14%; none fatal) was lower than that in our previous 54 patients (43% CMV infections, 13% fatal). Furthermore, no fatal pneumonitis was seen. The regeneration of T-cells in our patients has shown normal values of T8-positive cells in the circulation from 45 to 50 days onwards, as opposed to the previous groups of patients whose T8-positive cells regenerated to 3-4 times higher than normal values. These observations indicate that T-cell depletion with monoclonal antibodies is an effective method for preventing GvHD, but further studies are necessary to investigate the cause(s) of a new occasional complication, the rejection of the newly established bone marrow.

Adolescent↗
PubMed1984

Mechanisms of deoxyadenosine toxicity in human lymphoid cells in vitro: relevance to the therapeutic use of inhibitors of adenosine deaminase.

Deoxyadenosine (AdR) appears to be central to the molecular events mediating immunodeficiency in children born with adenosine deaminase (ADA) deficiency but it is still uncertain whether lymphotoxicity is due to AdR directly inhibiting transmethylation reactions in which S-adenosylmethionine is the methyl group donor, or is due to phosphorylation of AdR to deoxyadenosine triphosphate (dATP) which then inhibits ribonucleotide reductase or is due to other mechanisms. Using AdR and the ADA inhibitor deoxycoformycin (dCF) and assessing cell viability, nucleoside incorporation into RNA and DNA, as well as measuring deoxyribonucleoside triphosphate (dNTP) concentrations and S-adenosylhomocysteine (SAH) hydrolase activity, we have studied various types of human lymphoid cells and demonstrated in them the relative importance of the above two mechanisms of AdR toxicity. Treatment of normal resting peripheral blood lymphocytes in culture with AdR and dCF resulted in impaired viability. Although elevated dATP levels as well as decreased SAH hydrolase activities were both observed, the failure of a known inhibitor of ribonucleotide reductase (hydroxyurea) to produce toxicity, and the inability of deoxycytidine (CdR) to achieve a rescue effect, point to another mechanism, possibly inhibition of trans-methylation or ATP depletion being the more likely causes of toxicity in resting lymphocytes. The same mechanism may well account for the rapid and severe lymphopenia in patients treated with dCF. On the other hand, in cultured lymphoblasts in the exponential phase of growth. AdR and dCF produced marked inhibition of growth and cell death both in a Thy-ALL line and in a c-ALL line, in the absence of significant inhibition of SAH hydrolase, but with a substantial elevation in dATP concentrations and depressed levels of the other dNTP. Minor toxicity occurred in a proliferating B lymphoblast line despite almost complete inactivation of SAH hydrolase. These observations indicate inhibition of ribonucleotide reductase as the more likely mechanism of toxicity in rapidly proliferating lymphocytes. Other T-cells actively synthesizing DNA, such as PHA-stimulated or MLC activated lymphocytes and T-lymphoid colony forming cells, are also likely to be affected by the same mechanism. Indeed in PHA-stimulated lymphocytes, deoxycytidine caused significant although incomplete rescue from toxicity due to dCF and AdR. In patients with ADA deficiency or treated with ADA inhibitors, both mechanisms could be operative. These observations are also relevant to the possible use of dCF and AdR as immunosuppressive agents and for the removal of T-cells or residual Thy-ALL blasts from bone marr

Adenosine Deaminase Inhibitors↗
PubMed1984

A and B blood group antigen expression on mixed colony cells and erythroid precursors: relevance for human allogeneic bone marrow transplantation.

Using anti-A and anti-B blood group monoclonal antibodies and fluorescent activated cell sorting of human bone marrow, A (or B) blood group antigen was shown to be on 5.2 +/- 5.9 (mean +/- SD) % of CFU-GEMM and 12.5 +/- 19.6% of the erythroid burst forming cells (designated BFU-GEMM) as defined by the mixed colony assay, and 49.5 +/- 20% of the BFU-E and 83.5 +/- 9.9% of the CFU-E as defined by the erythroid colony assay. This antigen expression on the BFU-GEMM is consistent with the concept that erythroid bursts stimulated by leucocyte conditioned medium are less mature, and are closer in development to the pluripotent stem cell than the BFU-E. These results help to explain the delayed erythropoiesis, and perhaps impaired engraftment of all cell lineages, that may occur in some recipients of ABO incompatible bone marrow transplants with persistent and high anti-A titres.

ABO Blood-Group System↗
PubMed1984

Herpes virus infections: clinical manifestations and therapeutic strategies in immunocompromised patients.

Herpesvirus infections are a major cause of morbidity and mortality in immunosuppressed patients. Bone marrow and organ transplant recipients are model patient populations for studying the natural history of herpesvirus infections because the infections occur predictably after transplantation. Herpes simplex virus infections occur within the first month after transplantation and may cause severe mucocutaneous disease. Cytomegalovirus infections occur one to three months after transplantation and are the major viral cause of morbidity and mortality. Varicella-zoster virus infections occur four to five months after transplantation and rarely cause life-threatening infection. Further studies of Epstein-Barr virus are necessary to determine its significance as a pathogen. The development of new antiviral agents has introduced effective therapeutic approaches for herpes simplex virus infections and varicella-zoster virus infections. Efforts to treat or prevent cytomegalovirus infections in transplant recipients have had limited success. However, new therapeutic strategies may lead to therapies which may reduce the severity of these infections and lead to increased survival in bone marrow transplant and organ transplant recipients.

Antiviral Agents↗
PubMed1984

Mitoxantrone in relapsed and refractory acute leukemia.

Mitoxantrone is a relatively new synthetic anthracenedione derivative with intercalating properties. An in vitro study with established leukemia cell lines indicated that DNA strand breaks were caused by mitoxantrone; when these were progressive after the initial insult, the cell line was sensitive to the drug. Clinical trials involved patients with relapsed and/or refractory acute leukemia. None of the patients receiving a single slow infusion of mitoxantrone achieved a complete remission. A five day treatment regimen produced an overall response rate of 48% with a complete remission rate of 25%. Toxicity in these preliminary studies was limited compared to that expected with the anthracycline antibiotics. Alopecia and nausea were the only commonly observed side effects. The trials were too short, however, to evaluate possible cardiac toxicity. Mitoxantrone is an acute and relatively nontoxic agent that merits further study to identify its role in the first line therapy of acute leukemia; such studies are underway.

Acute Disease↗
PubMed1984

Infection prophylaxis in the patient with bone marrow failure.

The last two decades have seen some significant advances made in the recognition of infection problems in the immunocompromised host and in their prevention in a rapidly expanding population. Many areas urgently await much-needed improvements, particularly anti-bacterial decontamination and fungal and viral prophylaxis. Despite interesting pilot studies there has been a failure to fully evaluate potential strategies in properly designed trials. Now is the time for large studies which control for the multitudinous variables of patient population such as disease status, protective environment, degree of diet sterility, and types of GI and mucocutaneous decontamination. Meanwhile, it is impossible to make hard and fast rules for prophylaxis for all circumstances. Clearly, most of the measures which we have discussed are applicable only where there is profound immunosuppression. Practice should be based on a careful evaluation of the local flora and fauna. Table 6 details an outline of the Royal Free prophylaxis schedule concurrently used during the treatment of acute non-lymphoblastic leukaemia and following marrow transplantation. This type of protocol is an attempt at short-term 'total' decontamination which appears justifiable in this very high-risk group where the invading organisms are a greater immediate risk than the disease under treatment. Our hope is that the scientific foundations for such regimens will rest on firmer ground in the future.

Anti-Bacterial Agents↗
PubMed1983

High-dose melphalan with autologous bone marrow transplant. Treatment of poor prognosis tumors.

Seventeen patients were treated with high-dose melphalan with autologous bone marrow transplant (ABMT) and cyclophosphamide pretreatment. All of the patients had marrow reconstitution. Although there was one death caused by infection, high-dose melphalan with ABMT causes toxicity that is generally acceptable, and can achieve a high-response rate, but with responses of short duration in tumors resistant to standard-dose combination chemotherapy. In other poor-prognosis tumors that are sensitive to chemotherapy, or can be debulked surgically, or locally irradiated, high-dose melphalan with ABMT given as late intensification therapy may significantly prolong time to relapse, and ultimately prolong survival.

Adult↗