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S J Proctor

Publications and source records attributed to S J Proctor.

At least 55 records · Page 3Linked to original sources
PubMed1998

Cytokine gene polymorphisms associating with severe acute graft-versus-host disease in HLA-identical sibling transplants.

It is now well known that the initial phase of graft-versus-host disease (GVHD) involves cytokine release during preconditioning of the recipient of an allogeneic bone marrow transplant (BMT). Tumor necrosis factor (TNF), in particular, has been implicated in pathological damage and is released pretransplant due to irradiation and cytotoxic preconditioning regimens. Interleukin-10 (IL-10), a natural immunosuppressant of TNF, may be involved in downregulation of these responses, which may be an individual patient-specific effect. In this study, we determined the genotype for polymorphisms associated with TNF and IL-10 in 80 potential allo-BMT recipients and correlated the genotype with the severity of GVHD in 49 patients for whom clinical data relating to GVHD was available. The widely studied TNF -308 polymorphism does not show any significant associations, but the d3 homozygous allele of the TNFd microsatellite is preferentially associated with grade III/IV GVHD (7 of 11 patients) compared with its occurrence in 8 of 38 patients with grade 0/II GVHD (P =.006). Alleles of the IL-10 (-)1064 promoter region microsatellite polymorphism that possess greater numbers of dinucleotide (CA) repeats also significantly associate with more severe GVHD. This region has been demonstrated to be important in the regulation of the IL-10 promoter. Eighteen of 38 patients with grade 0-II GVHD possessed alleles with greater numbers (12 or more) of dinucleotide repeats, compared with 9 of 11 cases with grade III-IV GVHD (P <.02). Of the 38 patients with grade 0-II GVHD, 3 of 38 had a both TNFd3/d3 and IL-10 (12-15) genotype, compared with 6 of 11 patients with grade III-IV GVHD (P <.001). There was no association of either the TNFd or IL-10 microsatellite polymorphisms with mortality (P =.43 and.51, respectively). Our results suggest that patient cytokine gene polymorphism genotypes may influence GVHD outcome by affecting cytokine activation during the pretransplant conditioning regimens, and these results are the first to suggest a genetic predisposition to this important transplant-related complication.

Acute Disease↗
PubMed1998

Predicting graft-versus-host disease in HLA-identical bone marrow transplant: a comparison of T-cell frequency analysis and a human skin explant model.

BACKGROUND: Graft-versus-host disease (GVHD) occurring after HLA-identical sibling bone marrow transplantation (BMT) is considered to be mainly caused by minor histocompatibility antigen (mHag) disparities between the recipient and donor. In our laboratory, a human skin explant model has been successfully used to predict acute GVHD in HLA-identical sibling BMT. More recently, the frequency analysis of host-reactive helper and cytotoxic T lymphocyte precursors (HTLp and CTLp, respectively) has been shown to have potential application for predicting GVHD. In the present study, HTLp and CTLp frequency analysis and the skin explant model were directly compared for their ability to predict acute GVHD in HLA-identical sibling BMT. METHODS: Host-reactive HTLp and CTLp frequencies were determined using a combined limiting dilution assay. A human skin explant model was used to detect graft-versus-host reactions in vitro. The results from the skin explant model (graft-versus-host reaction grades I-IV) and T cell frequency analysis (>/< 1:100,000) were correlated with posttransplant GVHD outcome, respectively. RESULTS: The skin explant model correctly predicted GVHD outcome in 77% of cases (P=0.03). HTLp frequencies were very low in all patient/donor pairs tested. None of them exceeded 1:100,000, although 9/18 recipients developed GVHD (> or =clinical grade II) after transplant. In all patients tested, the relationship between either high (>1:100,000) or low (<1:100,000) CTLp frequency and occurrence of GVHD appeared to be random (P=1.0). CONCLUSIONS: HTLp and CTLp frequency analysis did not predict the occurrence of acute GVHD after HLA-identical sibling BMT. The human skin explant model, however, remained an accurate indicator of acute GVHD and probably detects mHag disparities.

Acute Disease↗
PubMed1998

Cellular alloreactivity of human cord blood cells detected by T-cell frequency analysis and a human skin explant model.

BACKGROUND: Recent clinical data have demonstrated the success of allogeneic stem cell transplantation using HLA-mismatched unrelated human umbilical cord blood (CB). The incidence and severity of acute graft-versus-host disease (GVHD) in these mainly pediatric transplants is low. The immunological mechanisms by which CB transplants may result in reduced GVHD is not completely clear. In this study, the functional cellular alloreactivity of CB cells was investigated, by measuring the frequency of alloreactive helper and cytotoxic T lymphocyte precursors (HTLp and CTLp, respectively) in CB and detecting the ability of CB cells to induce graft-versus-host (GVH) type alloreactivity in vitro. METHODS: A human skin explant model was used to measure GVH type alloreactivity in vitro. A combined limiting dilution assay was carried out in parallel to determine alloreactive HTLp and CTLp frequencies. The cellular alloreactivity was compared between cord and HLA-haploidentical parental blood cells against the same HLA-mismatched unrelated stimulator. RESULTS: The results demonstrated that alloreactive CTLp frequency in CB mononuclear cells (CBMCs) was significantly lower (mean, 1:35,694, range, 1:1,667-<1:500,000) than that in adult peripheral blood mononuclear cells (PBMCs) (mean, 1:5,333, range, 1:544-1:47,619). Alloreactive HTLp frequencies, however, were comparable for CBMCs and PBMCs (mean, 1:7,586, range, 1:1,359-1:200,000; and mean, 1:5,976, range, 1:385-1:50,000, respectively). A significantly decreased ability to induce in vitro GVH type alloreactivity was observed for CBMCs and that was strongly associated with low alloreactive CTLp frequencies (P=0.001). CONCLUSIONS: The present study provides the first clear in vitro evidence to suggest that CBMCs are less able than PBMCs to induce skin GVH type alloreactivity in HLA-mismatched pairs. The severity of in vitro GVH type alloreactivity (graded as I-IV) was strongly associated with the levels of alloreactive CTLp frequencies. The low cellular alloreactivity of CBMCs detected in vitro suggests that in a proportion of cases HLA-mismatched unrelated CB may not give rise to severe GVHD in vivo after transplantation.

Blood Cells↗
PubMed1998

Molecular remission in Philadelphia-positive adult acute lymphoblastic leukaemia rapidly induced by conventional-dose chemotherapy.

This report describes a patient presenting with Ph-positive ALL. RT-PCR analysis of diagnostic marrow revealed the presence of three bcr/abl transcripts; the ALL type ela2 along with the CML types, b2a2 and b3a2. After initial induction therapy, bcr/abl transcripts were only detectable after two rounds of PCR but after MIDAC consolidation, remission samples were two-round negative. The relationship between the unusual molecular biological profile of this leukaemia and the rapid attainment of molecular remission is discussed.

Adult↗
PubMed1998

Collection of Philadelphia-negative peripheral blood progenitor cells in unselected patients with chronic granulocytic leukaemia. Northern Regional Haematology Group.

Thirty unselected patients with chronic granulocytic leukaemia (CGL), age range 22-59 years, were treated with intensive chemotherapy and G-CSF to mobilize peripheral blood progenitor cells (PBPC). Chemotherapy was well tolerated and PBPC were collected by leukapheresis early during white cell recovery. PBPC collections considered adequate for engraftment were collected in 21 patients. Cytogenetic analysis of all collections in these patients showed >75% Ph negativity (range 79-100%) in 10. Successful collections, ie those >75% Ph negative and with total cell count of >1 x 10(6) CD34+ve cells/kg or >20 x 10(4) CFU-GM/kg were further analysed by Southern blot or RT-PCR. All samples were positive for the bcr/abl transcript. Patients with a low Sokal score (<0.8) were more likely to achieve a successful collection. In contrast, there was no association between transcript expression and likelihood of successful collection. We have confirmed that it is possible to mobilize and collect Ph-negative enriched PBPC in unselected patients with CGL. This procedure is more likely to be successful earlier rather than later in the course of the disease. Whether such collections will give an advantage over unmanipulated autologous bone marrow transplantation in CGL requires further study, but our experience suggests that suitable material for autologous rescue can be obtained from approximately one third of eligible, unselected young patients.

Adult↗
PubMed1998

Hodgkin's disease: a population-adjusted clinical epidemiology study (PACE) of management at presentation. Northern Region Lymphoma Group.

Between January 1991 and December 1993, all newly-diagnosed patients with Hodgkin's disease in the Northern Health Region (population 3.08 million) were entered into a prospective population-based (PACE) study to assess the accuracy of staging at diagnosis, and to evaluate treatment and outcome. On histological review, 202 patients were confirmed to have Hodgkin's disease, an incidence of 2.2 per 100,000 per annum. Radiological review revealed that only 12% of patients were staged to recognized guidelines. In early-stage disease, treatment outcome was comparable to published results in Stage IA disease, but disappointing for Stage IIA. This was partly due to inadequate or inaccurate staging. In-built audit in the process was followed by the introduction and implementation of improved guidelines. Of younger patients (15-55 years) with 'poor-risk disease', 75% of the eligible population were entered into the appropriate randomized controlled trial. This intensive treatment has led to improved survival in this group over that which might be expected on four-drug therapy. The results of the randomized trial are not discussed as it is currently ongoing. This combined research/audit programme has resulted in greater standardization of care across a whole region, and confirms that the PACE (population-adjusted clinical epidemiology) approach facilitates the flow of information from research into practice and vice versa.

Adolescent↗
PubMed1997

CHOP-based chemotherapy is as effective as alternating PEEC/CHOP chemotherapy in a randomised trial in high-grade non-Hodgkin's lymphoma. Scotland and Newcastle Lymphoma Group.

The aim of this study was to test whether survival for patients with high-grade non-Hodgkin's lymphoma (NHL) can be improved with a non-cross-resistant regimen as compared to a CHOP-based regimen. This is a multicentre study comprising 325 adult patients, median age 58 years, with high-grade non-Hodgkin's lymphoma: patients of any age and performance status were eligible provided they were able to receive the drugs in the regimens. Patients were randomised to either B-CHOP-M (bleomycin, cyclophosphamide, doxorubicin, vincristine, prednisolone and methotrexate) or PEEC-M (methylprednisolone, vindesine, etoposide, chlorambucil and methotrexate) alternating with B-CHOP-M. At a median follow-up of 9 years, there was no significant difference in overall survival or disease-free survival between the two arms. Toxicities for the two regimens were equivalent. This study confirms that for relatively unselected patients with high-grade non-Hodgkin's lymphoma, an alternating multidrug regimen does not improve upon the results obtained with B-CHOP-M.

Adult↗
PubMed1997

Umbilical cord blood collection and separation for haematopoietic progenitor cell banking.

Cord blood transplantation has been proven to be a suitable form of treatment for a variety of diseases in childhood and more recently in an increasing number of adult patients. Banks of cord blood cryopreserved after HLA testing are required in order to provide various HLA types for unrelated transplantation. To optimize storage space cord blood needs to be stored as a separated product. Several early methods of cord blood separation resulted in a significant loss of progenitor cells. We used a separation procedure where the donation was separated by centrifugation into a buffy coat fraction, a red cell fraction, and a plasma fraction. Twenty-five samples, (mean initial volume 81 ml) were assessed. Nucleated cells were recovered in the buffy coat fraction. Recoveries of nucleated cell count, total progenitors and CD34-positive cells in the buffy coat were 90%, 88% and 100%, respectively. The buffy fraction was tested for sterility by aerobic and anaerobic culture. Using this closed bag system, volume reduction was achieved while maintaining sterility and retaining progenitor cells in a final mean buffy coat volume of 44 ml. Red cell and plasma fractions were available for ABO grouping, virology testing and cryopreservation. The results show that cord blood can be effectively volume-reduced using simple and readily available blood banking techniques.

Adult↗
PubMed1997

The use of an all oral chemotherapy (idarubicin and etoposide) in the treatment of acute myeloid leukaemia in the elderly: a report of toxicity and efficacy.

Acute myeloid leukaemia (AML) is predominantly a disease of the elderly but such patients are not always appropriate candidates for intensive intravenous (i.v.) based treatment regimens. The development of the anthracycline idarubicin which is highly effective in the treatment of AML and is active when given orally has made it possible to design anti-leukaemic regimens which may be given orally and be particularly useful in those elderly patients with AML considered unsuitable for standard intensive aggressive treatments. We have assessed an oral regimen combining idarubicin 30 mg/m2 and etoposide 80 mg/m2 for 3 consecutive days as initial treatment in 28 elderly patients with AML (median age 69 years, range 56-81) who were not considered suitable for more intensive i.v. chemotherapy schedules. Following informed consent, two patients died before treatment began and one patient withdrew prior to treatment. Twenty-five patients underwent one to four courses of treatment. The schedule was well tolerated with minor nonhaematological toxicity. The first course was given in hospital, eight of 21 subsequent courses of treatment were given entirely as an out-patient. Eleven patients responded to treatment with nine (36%) achieving complete remission (CR). The median survival for all patients was 3 months, but for the nine who achieved a CR it is 9 months with six patients still alive, five in first CR and one in second CR. We conclude that a combination of idarubicin and etoposide given orally as first-line treatment in elderly patients with AML is safe and effective. In some patients this means treatment and follow-up can be given entirely on an out-patient basis.

Acute Disease↗
PubMed1997

Low incidence of myelodysplastic syndrome following transplantation using autologous non-cryopreserved bone marrow.

Between May 1984 and October 1995 we performed 114 autologous stem cell transplants for lymphoma in our centre; 77/114 (68%) were transplanted after primary therapy. The conditioning regimen varied according to diagnosis; 26 patients were conditioned with melphalan and total body irradiation, 66 received melphalan and etoposide and the remainder (50) were conditioned with melphalan alone. The median follow-up is 62 months. Only two new haematological malignancies have occurred, both in patients with Hodgkin's disease. One patient developed Ph+ chronic myeloid leukaemia 18 months post-transplant. In this case, because of the timing of the haematological disorder, we considered the malignancy to be concurrent with or to have preceded the transplant. A second patient developed acute myeloid leukaemia 20 months post-transplant. She had been treated for Hodgkin's disease for 10 years and was transplanted in third complete remission. Cytogenetic analysis in this case showed trisomy 11. We believe this to have been an unequivocal second malignancy. Our finding of a 1.1% incidence of secondary haematological malignancy (95% CI 0.02-4.96) from a census population adds weight to the hypothesis that haematological problems post-transplant reflects prior chemotherapy rather than toxicity from the transplant procedure itself.

Adolescent↗
PubMed1997

Early high dose chemotherapy intensification with autologous bone marrow transplantation in lymphoma associated with retention of fertility and normal pregnancies in females. Scotland and Newcastle Lymphoma Group, UK.

As more centres consider autologous bone marrow and peripheral blood stem cell transplantation for patients with high risk Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) in first complete remission (CR1) the long term sequelae of such treatments have to be considered. One of the most important side effects of such intensive treatment is loss of fertility. Sperm banking before treatment commences is available for males but unfortunately cryopreservation of ova/ovarian tissue is not yet possible for females. We have transplanted 30 women, 23 were under 40 years and report ten females who have had successful pregnancies (including two twin pregnancies and one triplet pregnancy), leading to live births following autologous bone marrow transplantation (ABMT) for poor prognosis HD and NHL in first or second complete remission. None of these children have shown evidence of birth defects (median follow up of two years). Of the twenty one pregnancies reported to the European Bone Marrow Transplantation Registry (EBMTR) following ABMT for lymphoma, eight of the seventeen unassisted cases came from our centres. The Newcastle/SNLG autotransplant differs from the approach in many EBMTR centres in that it uses melphalan or melphalan/etoposide alone instead of the more common four drug containing regimens and yet sustained complete remission rates indicate that the non-ablative approach is equally effective as more aggressive regimens on the disease with the huge advantage of preserved fertility in females. This approach to conditioning for ABMT should be considered when treating women in the reproductive age group.

Adult↗
PubMed1996

Detection and quantification of melphalan-DNA adducts at the single cell level in hematopoietic tumor cells.

Bifunctional alkylating agents, such as melphalan, are widely used in the treatment of hematological malignancies. The effects of these drugs on particular types of hematological cells and the causes of treatment failure are poorly understood. The aim of this work was to establish an ability to measure the extent to which melphalan reacts with the DNA of individual tumor cells, thereby creating new possibilities for molecular pharmacological studies on clinical samples. A novel approach for staining drug-DNA adducts is described in which cells were embedded in agarose and then lysed. The DNA from each cell remained in an ideal state for quantitative immunofluorescent staining using a previously described monoclonal antibody. Immunofluorescence and DNA-Hoechst dye fluorescence were quantified using a cooled slow scan charge coupled device camera and image analysis procedures. Immunofluorescence of drug-treated cells from a human leukemia cell line was partially correlated with DNA content. Mean integrated immunofluorescence of 50 to 100 cells was dependent on drug concentration and was linearly related to adduct levels. In these cells and in chronic lymphocytic leukemia cells obtained from patients, there was considerable intercell heterogeneity in apparent adduct levels. This was also seen in peripheral blood mononuclear cells isolated from a patient after melphalan therapy.

Antineoplastic Agents, Alkylating↗