Search PubMed⌕ Search

Biomedical subjects

S J Proctor

Publications and source records attributed to S J Proctor.

At least 73 records · Page 4Linked to original sources
PubMed1996

Frequency analysis of recipient-reactive helper and cytotoxic T lymphocyte precursors using a combined single limiting dilution assay.

In the present study, in order to simplify the procedure of helper T lymphocyte precursor (HTLp) and cytotoxic T lymphocyte precursor (CTLp) assays, reduce the sample size required and compare the sensitivity of HTLp and CTLp assays in the detection of alloreactive responses, the same set of limiting dilution mixed lymphocyte cultures was used and evaluated for both HTLp and CTLp frequencies. Ninety-four normal volunteer or patient/donor pairs were tested. High frequencies of HTLp (1:385 to 1:28,571) and CTLp (1:554 to 1:25,000) were detected for HLA unmatched unrelated individuals. The range of HTLp and CTLp frequencies of HLA identical siblings was 1:67,000 to 1:1,000,000 and 1:3700 to 1:1,000,000, respectively. In HLA matched unrelated pairs both HTLp and CTLp frequencies ranged from 1:1000 to 1:500,000, overlapping the values obtained from the former two groups. High CTLp and HTLp frequencies were found in 73% and 84% of HLA matched unrelated patient/donor pairs, respectively, suggesting that these in vitro functional assays may provide additional and essential information for the selection of unrelated bone marrow donors. The results of this study support the hypothesis that the combined single limiting dilution system is an efficient and informative method to quantitatively analyse HTLp and CTLp frequencies against major and minor histoincompatibilities with the advantage of being less time-consuming, less laborious and requiring fewer lymphocytes. The results also suggest that the HTLp assay is at least as efficient as the CTLp assay for the detection of alloreactivity other than of HLA identical siblings and may be useful for predicting graft-versus-host disease after bone marrow transplantation using HLA matched unrelated donors. The clinical value of this modified limiting dilution assay to predict graft-versus-host disease in bone marrow transplantation using HLA identical sibling donors and matched unrelated donors is being assessed.

Blood Donors↗
PubMed1996

Effects of interferon-alpha therapy on immune parameters in immune thrombocytopenic purpura.

Interferon-alpha (IFN alpha) has been shown to increase platelet numbers in patients with immune thrombocytopenic purpura (ITP), but the basis for this effect is not known. In this study changes in immune function were monitored following administration of IFN alpha to seven patients whose ITP had proved refractory to conventional therapy. Patients' peripheral blood mononuclear cells were cultured with phytohaemagglutinin and culture supernatants assayed for cytokine production. Production of the Th1 cytokines IL-2 and IFN-gamma was low in patients compared to healthy controls, and amounts of these tended to increase after IFN alpha therapy. In two patients high levels of IL-10 were detectable in culture, and these were reduced after IFN alpha. In patients who had high serum concentrations of IL-4 or IL-10, these were also decreased following therapy. Natural killer cell activity, which was low in the patients prior to therapy, was increased following administration of IFN alpha. In those patients with detectable platelet-associated autoantibody to gpIIb/IIIa, the amounts were reduced after treatment. Two patients had an unusually high percentage of T cells expressing the gamma delta T cell receptor, which decreased after therapy. The findings are consistent with an increase in Th 1 activity and a decrease in autoantibody production following IFN alpha therapy, which may be related to the beneficial effects of this cytokine.

Adult↗
PubMed1996

Non-Hodgkin's lymphoma and hepatitis C virus infection.

The hepatitis C virus (HCV) is a recently described and important cause of acute and chronic liver disease. A hallmark of HCV is its propensity to become chronic, some patients with chronic HCV progressing to cirrhosis and hepatocellular carcinoma (HCC). HCV is also lymphotrophic and we report 2 patients with HCV cirrhosis who developed non-Hodgkins lymphoma (NHL). These cases raise the possibility that chronic HCV infection of lymphocytes plays an aetiological role in this malignancy. However screening of a further 63 consecutive patients over the age of 50 years with NHL for HCV antibody by second generation enzyme linked immunoassay (ELISA) failed to identify any patients with evidence of HCV infection. This suggests that HCV is an uncommon contributory factor for the development of non-Hodgkins lymphoma in the United Kingdom.

Aged↗
PubMed1995

Bone marrow examination in newly diagnosed Hodgkin's disease: current practice in the United Kingdom.

In the UK Hodgkin's disease is usually treated by either clinical oncologists or haematologists. A national study of the performance of bone marrow examination in newly diagnosed Hodgkin's disease was undertaken to establish current practice. A total of 620 questionnaires were despatched, and replies were received from 60% of consultants (45% of clinical oncologists and 70% of haematologists). Bone marrow examination was performed in all new cases significantly more often by haematologists than by clinical oncologists (74% vs 40%, P < 0.001). Among haematologists, there was no correlation between the number of new patients seen annually and practice, however clinical oncologists were even less likely to perform routine bone marrow biopsies if they saw more than ten patients per year (P < 0.02). Where bone marrow examination was performed selectively, the most common criteria used were peripheral blood cytopenia and advanced-stage disease. These criteria were applied in the same way by both clinical oncologists and haematologists. Bone marrow biopsy, an invasive and often painful procedure, is currently performed more frequently in Hodgkin's disease than can be recommended on the basis of recent studies in the literature and associated guidelines. There is a significant difference in practice between clinical oncologists and haematologists, and this raises the wider issue of the influence of hospital specialisation on patient management.

Bone Marrow Examination↗
PubMed1995

Corticosteroid resistance is increased in lymphoblasts from adults compared with children: preliminary results of in vitro drug sensitivity study in adults with acute lymphoblastic leukaemia.

The prognosis of acute lymphoblastic leukaemia (ALL) in adults is poor compared with children in terms of complete remission (CR) and leukaemia-free survival. In children in vitro resistance of leukaemic cells to various cytotoxic agents is an independent poor prognostic marker, but the relevance of in vitro drug resistance in adults to poor prognosis has not been described. Lymphoblasts from 16 adults and 32 children with ALL at initial presentation were assayed for in vitro drug sensitivity in a short-term culture system using the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) as an indicator of cell viability. The following drugs were tested: prednisolone, daunorubicin, mitozantrone, etoposide, melphalan and 6-thioguanine. At initial presentation, lymphoblasts from adults demonstrated a significantly higher degree of in vitro resistance to prednisolone than those from children (P < 0.01). Glucocorticoid resistance may be a fundamental difference between adult and childhood ALL which may underlie different biological aspects and also explain the difference in prognosis. Lymphoblasts from adults who achieved CR were more sensitive in vitro to prednisolone (P = 0.07), daunorubicin (P < 0.05), mitozantrone (P < 0.01) and melphalan (P < 0.05) than cells from those who did not. The MTT assay can predict response to induction chemotherapy in adults and therefore discriminate between standard- and high-risk patients. The assay, however, is not suitable for selection of the most effective agent for treatment because of in vitro cross-resistance of lymphoblasts to various drugs tested.

Adrenal Cortex Hormones↗
PubMed1995

c-MYC gene abnormalities in high grade and centroblastic-centrocytic non-Hodgkins lymphoma.

Fifty nine cases of high grade and centroblastic-centrocytic (cc) Non Hodgkins Lymphoma (NHL) were investigated for mutations and gross gene rearrangements in the 5' region of the c-MYC gene. Mutations in this region, and the presence of hypermutated c-MYC genes, have been associated with poor prognostic groups. All cases showed normal c-MYC gene organisation on Southern blot analysis indicating absence of gross gene rearrangements. PCR amplification and restriction digest analysis of the exon 1/intron 1 region revealed point mutations in 7 cases. No evidence for hypermutation was found. Mutations were relatively more common in high grade NHL (6/39) than in cc-NHL (1/20). There was no correlation with disease status at presentation or relapse or the presence of extranodal disease. The cc-NHL case with a c-MYC mutation subsequently transformed to high grade disease. These data suggest that hypermutation of the c-MYC gene is a relatively rare event in cc-NHL and high grade NHL and does not contribute to the aetiology in the majority of cases. Mutation of c-MYC in cc-NHL may predict transformation to high grade disease.

Adolescent↗
PubMed1995

De novo acute myeloid leukaemia in patients over 55-years-old: a population-based study of incidence, treatment and outcome. Northern Region Haematology Group.

A 4-year prospective study of de novo acute myeloid leukaemia in patients aged 56 years and over was undertaken in the Northern Region of England (population 3.09 million). The study was conducted to assess the incidence and outcome of treatment in all elderly patients diagnosed between January 1, 1988 and December 31, 1991. Two hundred cases de novo AML were confirmed, giving an incidence of 6.05/10(5) per annum (age specific population) (95% Cl, 5.2-6.9). Acute promyelocytic leukaemia was rare. Erythroleukaemia, monocytic leukaemia and AML with trilineage myelodysplasia were more common than in younger patients. Karyotypic abnormalities classically associated with response to therapy were present in only six of 91 patients where cytogenetic data was available. Treatment was at the discretion of the physician in charge: if given, specific treatment was recorded and clinical outcome assessed. Only 84 (42%) of patients received treatment with curative intent. Forty-four of 84 achieved a complete remission, usually of brief duration. A normal karyotype in leukaemic cells was associated with a survival advantage in this group (p < 0.05). Actuarial overall survival at 4 years for the entire group was 2.5%. Even with aggressive treatment, the outcome is poor. The pattern of disease and its lack of response to conventional treatment would support the hypothesis that AML in the elderly may differ biologically from that observed in younger patients. Karyotyping appears to predict those patients likely to benefit from intensive therapy and decisions about management in otherwise fit patients should, if possible, be delayed until a result is obtained. Every effort should be made to give such patients optimal treatment. However, most patients are unsuitable for aggressive treatment and, since long-term survival is rare, cure should not be offered as an inducement to accept such treatment and improving quality of life outside hospital should be the aim of treatment in this group.

Acute Disease↗
PubMed1995

Cytokine treatment of human bone marrow activates anti-leukaemia effector cells: monitoring of purging by polymerase chain reaction and DNA analysis.

The aims of this study were to investigate the role of cytokines (tumour necrosis factor alpha (TNF alpha), interferon gamma (IFN gamma) and interleukin-2 (IL-2) in augmenting graft-versus-leukaemia (GVL). We have investigated the effector cells involved in GVL, by studying the role of these cells in purging of the cell line K562 in short-term bone marrow cultures. The effect of the addition in vitro of rGCSF was also studied. Monitoring of purging was achieved by cytotoxicity assays, DNA analysis and the use of the polymerase chain reaction for the detection of bcr/abl transcripts in the Philadelphia positive (Ph+) K562 cell line. Supernatants from IL-2-treated and non-treated bone marrow were tested for cytokine production (TNF alpha and IFN gamma). The results have shown that the main cytotoxic effector cells in the bone marrow generated by IL-2 have the CD56+ CD8+ phenotype. Overnight incubation of bone marrow was sufficient to generate cytotoxic cells as measured by Chromium51 (Cr51) release assays. Measurable levels of TNF alpha but not IFN gamma were also detected in supernatants. Addition of TNF alpha and IFN gamma to the IL-2 in the bone marrow cultures augmented the cytotoxicity but tended to inhibit progenitor cell growth as measured by granulocyte-macrophage colony-forming unit (GM-CFU) and erythroid blast-forming unit (BFU-e) assays. An estimate of the purging of the marrow could also be achieved by DNA analysis of K562 DNA in bone marrow. The bcr/abl transcript could still be detected by PCR analysis in marrow containing 1% K562 and treated with IL-2 for 24 h, but by 6 days of incubation the bcr/abl transcript was weak or undectable. The results suggest that although reduction in the proportion of leukaemia in contaminated marrow can be detected after incubation with IL-2 for 24 h, complete elimination of minimal residual disease requires longer incubation times.

Biomarkers, Tumor↗
PubMed1995

Evaluation of the impact of allogenic transplant in first remission on an unselected population of patients with acute myeloid leukaemia aged 15-55 years. The Northern Regional Haematology Group.

The aim of this study was to collect prospectively unselected, population-based data on young adults with acute myeloid leukaemia (AML) over a 9-year period and to evaluate the impact on survival of the introduction of allogeneic transplantation performed in first remission. The population within the Northern Region of England is 3.09 million. During the study period a total of 149 de novo patients between 15 and 55 years old presented. The incidence of AML was 0.79 per 10(5) (age-specific population) in the 15-24-year-old group, 0.85 per 10(5) in the group 25-39 years old and 1.35 per 10(5) in the 40-55-year-old group. Remission induction success varied with age (74% for patients < 40 years and 58% for patients 40-55 years). In the 15-40 year old group 28 patients had an HLA-matched donor, 22 patients had a transplant (one syngeneic) and 24 patients in the 15-40-year-old group in remission at 6 months did not have a transplant. The allogeneic group < 40 years old had an event-free survival (EFS) at 4 years of 62%, whereas patients of the same age who received chemotherapy alone had an EFS at 4 years of 24%. A small heterogeneous group of 14 patients who had intensification with autotransplant are not included in this analysis. The population study approach demonstrates the difficulties of introducing uniform treatment strategy in this disease group. The study confirms the view that allogeneic transplant in first remission in the 15-40-year-old group is the treatment of choice. Unfortunately the overall impact of transplant on the population is not great since only 22 of 149 patients (14%) were able to receive an allograft in first remission.

Adolescent↗
PubMed1995

Role of target organ infection with cytomegalovirus in the pathogenesis of graft-versus-host disease.

Skin and rectal biopsy tissue from 34 allogeneic and 23 autologous BMT recipients was prospectively analysed for CMV using immunohistochemistry and PCR to investigate the hypothesis that target organ infection with CMV initiates and/or exacerbates GVHD. Biopsies were obtained prior to and at 3, 8 and 26 weeks after BMT and whenever GVHD was suspected. Surveillance specimens of peripheral blood leucocytes (PBL), urine and throat swabs were obtained every 2 weeks until 12 weeks after BMT, and whenever CMV was suspected. Cryostat sections were analysed immunohistochemically for CMV antigens and PBL and biopsies for CMV DNA by PCR. Of the 31 patients who engrafted, 28 (90%) developed GVHD clinically, confirmed histologically in 56 biopsies. GVHD proved clinically severe in 14 patients, 4 of whom had treatment-resistant GVHD. CMV was detected in PBL more frequently in patients with severe GVHD than in those with mild/moderate GVHD (29% vs. 7%). However, in all but one patient the onset of GVHD preceded detection of CMV. In biopsy specimens, CMV was detected in only 2 patients, 1 of whom had an exacerbation of GVHD temporally associated with CMV. Thus, despite a high incidence of GVHD in this series, with 56 episodes of GVHD in 28 patients, only 1 patient had CMV in biopsy tissue temporally associated with GVHD. This suggests that biopsy infection with CMV is not a major factor in initiating or exacerbating GVHD in this cohort. This study thus does not support a role for target organ infection with CMV in the pathogenesis of GVHD.

Adolescent↗
PubMed1995

Human herpes virus-6 infection in marrow graft recipients: role in pathogenesis of graft-versus-host disease. Newcastle upon Tyne Bone Marrow Transport Group.

To investigate the hypothesis that target organ infection with human herpes virus-6 (HHV-6) exacerbates the clinical severity of GVHD, skin and rectal biopsies from 34 allogeneic bone marrow transplant (BMT) recipients and 23 comparative autologous recipients were studied. Biopsies and heparinised blood samples were obtained from all patients prior to and at regular intervals after BMT, and whenever GVHD was suspected. HHV-6 antigen was detected in cryostat sections by immunohistochemistry, and HHV-6 DNA in peripheral blood leucocytes (PBL) and biopsies by nested PCR. Twenty-eight (90%) of the 31 patients who engrafted developed clinical GVHD, which was mild in five, moderately severe in nine and severe in 14. Overall, HHV-6 DNA was detected in PBl in 74% of autologous recipients and 76% of allogeneic recipients, and in biopsy tissue in 48% of autos and 71% of allos. However, HHV-6 DNA was detected in skin and/or rectal biopsies more frequently in allogeneic recipients with severe GVHD (92%) than in those with either moderate (55%) or mild GVHD (22%), suggesting an association (P = 0.004) between HHV-6 DNA in biopsy tissue and GVHD severity. A significant linear trend (P = 0.03) was identified between detection of HHV-6 DNA in biopsy tissue obtained prior to or concomitant with the onset of GVHD and increased GVHD severity, suggesting that HHV-6 was causally linked to GVHD rather than reactivated as a consequence of GVHD therapy. Thus this study supports a role for HHV-6 in the initiation and/or exacerbation of GVHD, and suggests that the presence of HHV-6 DNA in the skin or rectum may be a factor in determining GVHD severity. If confirmed, these findings may have implications for the management of allogeneic BMT recipients.

Adolescent↗
PubMed1994

Autologous bone marrow transplantation in acute lymphoblastic leukaemia.

There has been a great deal of interest in the use of high dose chemotherapy and/or radiotherapy, with autologous bone marrow/peripheral blood stem cell rescue, in the treatment of haematological malignancies including acute lymphoblastic leukaemia (ALL). In this review we assess the role of autologous bone marrow transplantation (ABMT) in ALL. The heterogeneity of this disease makes the analysis of treatment results in ALL difficult to interpret. There is some evidence that ABMT may be useful in second complete remission (CR) and increasing interest in ABMT as a therapeutic option in first CR in adults. At the moment there is little evidence that such an approach will have an impact in childhood ALL. ABMT is considerably less toxic than allogeneic bone marrow transplantation and the major cause of 'treatment failure' is disease relapse. There has been considerable effort put into purging autologous bone marrow of malignant stem cells but whether purging is effective remains controversial and not proven. Newer studies involving cytokines post-ABMT to stimulate an artificial 'graft versus leukaemia' effect may prove of value.

Adult↗