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Biomedical subjects

S J Proctor

Publications and source records attributed to S J Proctor.

At least 127 records · Page 7Linked to original sources
PubMed1990

An effective oral combination in advanced relapsed Hodgkin's disease prednisolone, etoposide, chlorambucil and CCNU.

Many patients with advanced Hodgkin's disease continue to need palliative therapy, but where there is no curative intent, patients and doctors may prefer oral treatment only. This paper describes the preliminary experience of such a schedule. A total of 15 patients with advanced relapsed Hodgkin's disease were treated with an oral regimen, PECC (prednisolone at 40 mg daily for 7 days, etoposide at 200 mg/m2 on days 1-3, chlorambucil at 20 mg/m2 on days 1-4 and CCNU at 100 mg/m2 on day 1 only), repeated every 4-6 weeks. 12 patients had been extensively pretreated. 11 patients had extranodal disease and 8 had B symptoms when treatment was started. Eight patients achieved a complete remission, with a median duration of 7+ months, and five achieved a partial remission; the overall response rate was 86%. Haematological toxicity was the major side effect. There were no treatment-related deaths. All patients tolerated treatment well and the oral route has particular advantages for those unwilling or unable to accept intravenous treatment.

Administration, Oral↗
PubMed1990

The potential use of thalidomide in the therapy of graft-versus-host disease--a review of clinical and laboratory information.

This article reviews the historical development of thalidomide as an immunosuppressive agent and the current state of knowledge of thalidomide as an anti-graft-versus-host disease (GVHD) agent. The evidence suggests that metabolites of thalidomide act at an early stage in the antigen recognition-activation pathway of graft T lymphocytes and down regulate normal lymphocyte responses. This effect seems to have beneficial effects in both acute and chronic GVHD, but the optimal mode of use in the clinical setting remains to be determined.

Acute Disease↗
PubMed1990

De novo Ph negative T-cell lymphoblastic leukaemia associated with bcr gene rearrangement.

One case of de novo Ph-negative T-cell acute lymphoblastic leukaemia has been found to have a classical breakpoint cluster region (bcr) rearrangement of the type seen in chronic granulocytic leukaemia. There were no haematological features to suggest a previous chronic phase. This case represents the first report of this rearrangement in Ph negative acute T-lymphoblastic leukaemia at presentation. The implications for various therapeutic options in such patients are discussed.

Adult↗
PubMed1990

Glutathione S-transferase (placental) as a marker of transformation in the human cervix uteri: an immunohistochemical study.

Using an indirect immunohistochemical technique on paraffin sections, employing a polyclonal antibody to the acidic (placental) form of glutathione-S-transferase (GST), we have evaluated cytoplasmic and nuclear staining in a series of 67 cervical biopsies including normal non neoplastic tissue, immature squamous metaplasia, all grades of cervical intraepithelial neoplasia (CIN) and invasive carcinomas of keratinising and non-keratinising types. No differences in cytoplasmic staining between the varied lesions studied were seen. However, there were marked differences in nuclear staining. While normal non-neoplastic stratified squamous epithelium showed weak staining of the lower one-third of the epithelium only, in immature squamous metaplasia and in all grades of CIN there was intense nuclear staining in all layers of the epithelium. Invasive carcinomas showed generally less intense nuclear staining than CIN lesions. Endocervical cell nuclei also showed intense nuclear staining. These findings indicate that GST is of limited use as a marker of transformation in the human cervix uteri.

Biomarkers, Tumor↗
PubMed1990

Purification and characterization of a pi class glutathione S-transferase from human leukaemic cells.

The glutathione S-transferases are a group of enzymes involved in the detoxification of a wide range of xenobiotics. Elevation of the level of activity of glutathione S-transferases within the cytosol has been associated with the development of resistance to a number of cytotoxic drugs, including some commonly used in the treatment of leukaemia. In this paper we describe the purification and characterization of an anionic (p class) form of the enzyme from the peripheral blood of patients with acute myeloid leukemia, chronic myeloid leukaemia, and acute lymphocytic leukaemia and the spleen of a patient with chronic lymphocytic leukaemia. We present evidence that the form of enzyme purified closely resembles pi class glutathione S-transferase purified from human placenta. Immunoblotting performed on cytosol from the leukaemic cells from a range of cases of leukaemia at presentation, or on treatment, demonstrated that this form of glutathione S-transferase was the predominant isoenzyme expressed in all cases studied. However, in the limited number of cases studied there was no correlation between the level of expression and response to chemotherapy, suggesting that increased expression of pi class GST is not the sole cause of resistance to bifunctional alkylating agent in human leukaemias.

Aged↗
PubMed1990

An in vitro predictive test for clinical graft-versus-host disease in allogeneic bone marrow transplant recipients.

An in vitro skin explant model has been used in an attempt to predict the severity of graft-versus-host disease (GVHD) in HLA-identical donor-recipient pairs. The skin explant model involves the use of donor lymphocytes which have been sensitized against recipient lymphocytes in vitro and then co-cultured with the recipient's skin. Thirteen patients were studied in a prospective manner and results from the skin explant model compared with the clinical status of the patient post-transplant showed good correlation (p less than 0.001). Results from T cell-depletion studies indicated a role for both CD4 and CD8 positive cells in GVHD. In conclusion the results confirmed that the skin explant assay is a useful and predictive test of GVHD in humans.

Adult↗
PubMed1989

Possible role of inhibition of glutathione S-transferase in the partial reversal of chlorambucil resistance by indomethacin in a Chinese hamster ovary cell line.

We have reported previously the isolation and characterization of a Chinese hamster ovary cell line, designated CHO-Chlr, which exhibits resistance to bifunctional nitrogen mustards while maintaining sensitivity to a range of other alkylating agents and chemotherapeutic drugs. This enhanced drug resistance is associated with a greater than 40-fold increase in the level of expression of an alpha class (YcYc) glutathione S-transferase (GST) as compared to the parental, CHO-K1, cell line. Here, we have purified GST from CHO-Chlr cells and show that the nonsteroidal antiinflammatory drug indomethacin acts as an inhibitor of enzyme activity. Indomethacin at 500 microM causes no significant decrease in colony forming ability of either CHO-K1 or CHO-Chlr cells. However, the cytotoxicity of chlorambucil is potentiated 5.5-fold in CHO-Chlr cells, but only 2.5-fold in CHO-K1 cells following preexposure to 500 microM indomethacin. In contrast, the antiinflammatory agent acetylsalicylic acid failed to inhibit the activity of purified GST and caused no potentiation of chlorambucil toxicity, suggesting that the potentiation by indomethacin is not due to the effects of this drug on prostaglandin synthesis. These studies provide further evidence that GSTs may be involved in the development of resistance to bifunctional alkylating agents and suggest that indomethacin, or agents with similar activities, may be of value as an adjunct to chemotherapy in some patients with tumors resistant to treatment with alkylating agents.

Animals↗
PubMed1989

Improvement of platelet counts in steroid-unresponsive idiopathic immune thrombocytopenic purpura after short-course therapy with recombinant alpha 2b interferon.

In 13 patients with severe steroid-refractory idiopathic immune thrombocytopenia (ITP), a short course of recombinant alpha 2b interferon (IFN), given at a dose of 3 MU for 12 doses, caused a significant increase in platelet count in 11 patients. The rise in platelet count occurred following completion of the short course of IFN in 10 patients and occurred during therapy in one patient. Three patients showed an increase to normal platelet counts within 14 days of discontinuing the drug, eight showed a partial response, with a platelet count increase from 30 to 100 x 10(9)/L, and two patients showed minimal response. One complete responder relapsed at 5 months from initial response, and a further course of alpha 2b IFN caused a second prompt response with a rise of platelet count to supranormal levels. Short-course alpha 2b IFN can be recommended as a therapy for severe ITP. Responses are seen in splenectomized and nonsplenectomized subjects, and thrombocytopenia is not exacerbated during treatment.

Autoimmune Diseases↗
PubMed1989

Severe renal toxicity due to intermediate-dose methotrexate.

Methotrexate (MTX) is a drug widely used in the treatment of patients with malignant disease. Its well-known side effects include myelosuppression, mucositis and renal damage. These problems are primarily dose-related, tending to occur more frequently when high doses (greater than 1 g/m2) are given. We present four cases in whom severe renal and mucosal toxicity occurred with intermediate doses (200 mg/m2) of MTX despite folinic acid rescue. Possible reasons for this occurrence are discussed and means of avoiding such toxicity are suggested. Three of four patients developed severe loin pain within a few hours of injection; the significance of this symptom in relation to subsequent renal toxicity has implications for early recognition of the problem.

Adult↗
PubMed1989

Mechanisms of drug resistance in acute leukaemia.

The development of resistance to chemotherapeutic agents is a frequent cause of treatment failure in acute myeloid and lymphocytic leukaemia. The mechanisms by which resistance develops in these patients are poorly understood, although a framework for their investigation has been provided by a range of studies using animal and human cell lines as model systems. In this review the basic concepts of drug resistance mechanisms are outlined, with special emphasis on studies using cells obtained from patients with resistant forms of leukaemia.

Acute Disease↗
PubMed1989

Expression of MHC class I and II antigens by keratinocytes and enterocytes in acute graft-versus-host disease. Newcastle Bone Marrow Transplant Group.

The expression of MHC class I and subgroups of class II antigens by keratinocytes and enterocytes has been investigated in patients receiving autologous and allogeneic bone marrow transplants. Allogeneic recipients with graft-versus-host disease (GVHD) expressed all the class II antigens HLA DR, DP and DQ more frequently than pretransplant patients, autologous or allogeneic recipients without GVHD post-BMT (p less than 0.01). Staining for DP and DQ was never detected without DR being present. Whenever there was a lymphocytic infiltrate in the epidermis or single cell necrosis in the gut, DR was expressed on the epithelium. There was no difference in class I expression in GVHD. This study further increases the immunopathological characterization of acute GVHD which may improve the understanding of its pathogenesis.

Acute Disease↗
PubMed1989

Detection of residual T-cells in T-cell depleted bone marrow: a comparison of immunofluorescence and limiting dilution culture techniques.

The quantitation of T lymphocytes in human bone marrow was assayed by a limiting dilution technique. Phytohaemagglutinin-responsive T cells were maintained in interleukin-2 containing medium with feeder cells for 16 days of culture. Each well was then scored microscopically as positive or negative, or by H3 thymidine incorporation as a measure of DNA synthesis. Minimum Chi square statistics were used to establish the best line of fit to calculate the T lymphocyte frequency in the sample. This method for enumeration of cells was applied to untreated samples of bone marrow, and marrow treated with monoclonal anti-T cell antibodies and rabbit complement. T cells in parallel samples were enumerated by membrane immunofluorescence and flow cytometry. The limiting dilution assay using microscopic analysis produced data consistent with single-hit kinetics, and was the method of choice for detecting T cells in T cell depleted human bone marrow.

Animals↗
PubMed1988

Suppression of human granulocyte-macrophage colony formation in vitro by natural killer cells.

This study has demonstrated the ability of human bone marrow natural killer (NK) cells to inhibit the formation of granulocyte-macrophage colonies from autologous bone marrow derived committed progenitors in vitro. NK cell activity was demonstrated in all marrow samples and could be significantly increased by pretreatment of the bone marrow mononuclear cells with IFN-alpha. Bone marrow preincubated with IFN-alpha produced significantly fewer colonies in both Day 7 and Day 14 colony assays compared with untreated marrow. Removal of active NK cells by Leu 11b and complement significantly increased the number of colonies observed in both Day 7 and Day 14 assays, but this was not the case when NK cell-depleted marrow was treated with IFN-alpha prior to the GM assays. These results have further shown that NK cells and IFN-alpha are involved in regulating granulopoiesis by demonstrating that IFN-alpha can inhibit granulocyte/macrophage colonies in the presence or absence of NK cells in the bone marrow.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1988

Hodgkin's disease involving the large bowel.

A case is described in which Hodgkin's disease occurred in the descending colon and adjacent mesenteric nodes as the only site of relapse. This rare presentation is discussed, with a review of the available literature.

Adult↗
PubMed1988

Class II antigen expression by keratinocytes and enterocytes--an early feature of graft-versus-host-disease.

HLA-DR expression by keratinocytes and enterocytes was studied in 23 patients undergoing BMT (12 autologous; 11 allogeneic). Two monoclonal antibodies were used to detect the HLA-DR antigen. Only in two patients before transplant and in one following autologous BMT was HLA-DR expressed on keratinocytes. Of 11 allogeneic recipients, 7 developed clinical GVHD, and HLA-DR-positive keratinocytes were seen in 6 of these. HLA-DR was expressed by enterocytes in 5 patients with GVHD and 4 of these also showed HLA-DR expression by keratinocytes. HLA-DR expression by keratinocytes correlated well with clinical GVHD. Expression of this antigen by enterocytes was associated with characteristic histological appearances of GVHD, even in the absence of intestinal symptoms. A combination of traditional and immunocytochemical techniques offers a sensitive and accurate method of confirming GVHD before it becomes florid.

Epidermal Cells↗
PubMed1988

A comparative study of combination chemotherapy versus marrow transplant in first remission in adult acute lymphoblastic leukaemia.

The results of conventional chemotherapy in adult acute lymphoblastic leukaemia (ALL) have not improved substantially in recent years. The present study is based on a flexible policy of marrow transplantation (allograft and autograft without marrow purging) in first remission compared with a group treated with standard maintenance therapy after a common induction sequence. The actuarial disease free survival (DFS) and actuarial overall survival (OS) at 3 years for autologous marrow grafted patients was 30% and 65% respectively. The allogeneic transplant group had DFS of 30% and OS at 3 years of 38% compared with DFS (12%) and OS (12%) for patients on 6-mercaptopurine and methotrexate maintenance. The actuarial disease free survival calculations include patients on protocol not entering remission, therefore, giving the worst possible result. We conclude that high dose chemo/radiotherapy with autologous marrow rescue in first remission followed by no maintenance provides better results in terms of overall survival and quality of life than standard ALL maintenance in adult patients. Results for allogeneic transplant in ALL are less good in terms of duration and quality of survival and the majority of deaths are related to causes other than leukaemic relapse.

Adolescent↗
PubMed1988

Histological features of skin and rectal biopsy specimens after autologous and allogeneic bone marrow transplantation.

The histological appearances of skin and rectal biopsy specimens were studied in 31 bone marrow transplant recipients (13 autologous, 18 allogeneic) before transplant, at 28 days, at six months, and as soon as graft versus host disease (GVHD) was clinically suspected. Grades I and II skin changes were commonly seen in patients before transplant and in the autologous group after transplant, as well as in most of the allogeneic recipients with suspected GVHD. Epidermal lymphocytic infiltration was seen only in allogeneic recipients, with clinical GVHD following transplant, but this was not a consistent finding and no other histological features were seen which would distinguish early GVHD from changes caused by cytotoxic agents. Rectal biopsy specimens, however, were normal in patients before transplant and in autologous recipients at 28 days; single cell necrosis of crypt cells was seen only in six of 13 allogeneic recipients studied after transplant with clinical skin GVHD but no gastrointestinal symptoms. Skin changes greater than I and II are required for the histological diagnosis of GVHD. Rectal changes are more specific and may be present despite a lack of intestinal symptoms.

Adolescent↗