Penelope R. A. Taylor

Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: a prospective study of a population-based cohort of 245 patients.

Summary. The true incidence and prognosis of autoimmune thrombocytopenic purpura (ITP) in adults is unknown. We present the results of a prospective study in a population‐based cohort of newly presenting adults (≥ 16 years) with ITP and platelet count of < 50 × 109/l, which took place between 1 January 1993 and 31 December 1999 in the former Northern Health Region in the UK (population 3·08 million). A total of 245 cases were confirmed by bone marrow examination with a median follow‐up of 60 months (range 6–78 months). There were 134 females/111 males (1·2:1). Overall incidence was 1·6 per 105 per annum. Absolute incidence was similar for both sexes, with highest age‐specific incidence in those aged > 60 years. Thirty patients (12%) presented with frank bleeding, and 28% were asymptomatic. Forty‐five patients (18%) received no treatment, and 135 (55%) received first‐line treatment only. Thirty patients (12%) underwent splenectomy. There were four deaths (1·6%) from bleeding and/or the complications of therapy in this cohort, but only one was in the acute phase of the illness. The majority of patients (155 out of 245) achieved remission (platelet count > 100 × 109/l), with a further 59 (24%) in partial remission with no symptoms (platelet count 30–100 × 109/l). This population‐based study suggests that the traditional view of adult ITP as being a predominantly chronic disease that preferentially affects females needs to be modified.

Hodgkin's disease in the elderly: a population‐based study

Summary. This study evaluated the incidence and outcome of Hodgkins disease (HD) in older patients using a population‐based approach. In total, 102 patients (52 men, 50 women) aged ≥ 60 years presented in the Northern Health Region of England (population of 3·09 million) between 1 January 1991 and 31 December 1998 and were studied prospectively. The age‐specific incidence was 1·97/100 000 for those aged 60–69 years, and 2·18/100 000 for those aged 70 years or over. The median age of the cohort was 70 years (range 60–91) and the median follow up was 63 months (range 20–113). Out of 95 treated patients, 70 (74%) obtained complete or good partial (> 90% response) remissions. In the 60 to 69‐year‐old group, the disease‐specific survival at 5 years was 100% for those presenting with early stage disease and 52% for those with advanced stage disease. In patients aged >70 years the 5 year disease‐specific survival was 36% in patients with early stage and 14% for patients with advanced stage disease. The survival of patients with Epstein–Barr virus (EBV)‐positive tumours was significantly poorer than that of patients with EBV‐negative tumours (P = 0·007); median survival in the former group was 20 months versus undefined in the latter group. In total, 43 deaths were due to progressive HD and five were treatment‐related. This study defined the incidence of HD in our population and demonstrated that the prognosis of elderly patients, particularly those with advanced stage disease, has not improved concurrently with that of patients aged < 60 years old. Novel approaches to assessment and treatment are necessary.

The Scotland and Newcastle epidemiological study of Hodgkin’s disease: impact of histopathological review and EBV status on incidence estimates

Aims: The epidemiological and pathological features of Hodgkin lymphoma (HL) are complex. The Epstein-Barr virus (EBV) is consistently associated with a proportion of cases, and these cases are thought to represent a distinct aetiological subgroup of HL. The aim of the present analysis was to determine the age and sex specific incidence of EBV associated and non-associated HL, analysed separately, using data derived from a population based study–the Scotland and Newcastle epidemiological study of Hodgkin’s disease (SNEHD). This study also provided a unique opportunity to evaluate accuracy in the current diagnosis and classification of HL. Methods: SNEHD analysed consecutive cases of HL diagnosed in the study area between 1993 and 1997. Diagnostic biopsy material was retrieved, EBV status of tumours was determined, and histological review was performed. Results: In total, 622 cases were eligible for the study, and EBV studies and histopathological review were performed on biopsy material from 537 and 549 cases, respectively. Accuracy in the overall diagnosis of HL and classification of nodular sclerosis HL was good, but diagnosis of HL in the elderly and classification of other subtypes was less reliable. One third of classic HL cases were EBV associated, and age specific incidence curves for EBV associated and non-associated cases were distinct. Conclusions: Comparison of age specific incidence curves for EBV associated and non-associated HL supports the hypothesis that these are two distinct aetiological entities. Accuracy in the diagnosis of HL is generally good, but certain subgroups of cases continue to present diagnostic difficulties.

Tumour necrosis factor receptor type II 196M/R genotype correlates with circulating soluble receptor levels in normal subjects and with graft-versus-host disease after sibling allogeneic bone marrow transplantation1

Background. A single nucleotide polymorphism in the tumor necrosis factor type II receptor (TNFRII) gene, codon 196, results in the substitution of arginine (R allele) for methionine (M allele). The 196R allele is reportedly associated with an increased susceptibility to autoimmune disease, and donor 196R allele carriage correlates with increased severity of acute graft-versus-host disease (GVHD) after matched unrelated bone marrow transplantation (BMT). Methods. We investigated the impact of donor and recipient TNFRII genotype on GVHD incidence and severity among 104 adult recipients of myeloablative sibling BMTs. Results. 196R allele frequency was 0.28 among recipients, donors, and controls. There was an increased incidence of acute GVHD among 196R-positive recipients (odds ratio [OR] 3.6, P =0.05). This association was confirmed in multivariate analysis (relative risk 4, P =0.04), correcting for previously established clinical and genetic risk factors. Donor 196R homozygosity was associated with an increased incidence of extensive chronic GVHD (OR 18.5, P =0.02). This association was also confirmed in multivariate analysis (OR 11, P =0.02). To investigate the functional impact of the TNFRII 196 M/R polymorphism, 79 volunteer blood donors were genotyped at this locus, by polymerase chain reaction and single-strand conformational polymorphism analysis, and plasma soluble TNFRII (sTNFRII) levels were measured by ELISA. Mean plasma sTNFRII levels (pg/mL: ±SEM) were 1224 (±26) and 1063 (±65) for 196M-postive (196 M homozygous or heterozygous) individuals and 196R homozygotes, respectively (P =0.02). Conclusions. Because sTNFRIIs can act as TNF antagonists, the association between recipient and donor TNFRII 196R allele status and acute or extensive chronic GVHD incidence, respectively, may reflect reduced circulating sTNFRII.

Predicting graft-versus-host disease in HLA-identical bone marrow transplants : 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.

Effect of IL‐6 promoter polymorphism on incidence and outcome in Hodgkin's lymphoma

A single nucleotide polymorphism (SNP) is present at position ‐174 of the human interleukin‐6 gene. The risk of developing Hodgkins lymphoma (HL) in young adults decreases with an increasing number of C alleles at this position. We analysed the effect of this SNP on incidence and outcome in HL. DNA samples from 408 cases and 349 controls were screened and analysed following stratification by age, histological subtype and Epstein–Barr virus status. Although the risk of classical HL in young adults decreased with increasing C alleles, case–control differences were not significant. An excess of G alleles was observed for nodular lymphocyte predominant HL in young adults (n = 21), which was significant.

Micro-vessel density and the expression of vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PdEGF) in classical Hodgkin lymphoma (HL)

There is little information to date regarding the role of angiogenesis in Hodgkin lymphoma (HL). The present study examines micro-vessel density and the expression of vascular endothelial growth factor (VEGF) and platelet-derived endothelial growth factor (PdEGF) in lymph node biopsies of patients with HL at presentation and relapse. Using immunohistochemistry, the degree of new blood vessel formation and the expression of VEGF and PdEGF was assessed in Hodgkin-rich tissue. The micro-vessel density (MVD) increased with disease progression in seven out of 11 cases. Expression of VEGF was observed in endothelial cells (EC) of some micro-vessels and also in follicular dendritic cells. The Hodgkin/Reed-Sternberg (H-RS) cells as well as the inflammatory lymphocytes were negative for VEGF. Cytoplasmic or cytoplasmic and nuclear expression of PdEGF by the H-RS cells was observed in five of the 11 presentation cases. The expression of PdEGF increased with disease progression in seven cases. In conclusion, Hodgkin tissue shows prominent vascularization. The increased MVD and PdEGF expression with disease progression merits further investigation.

Early High Dose Chemotherapy Intensification with Autologous Bone Marrow Transplantation in Lymphoma Associated with Retention of Fertility and Normal Pregnancies in Females

As more centres consider autologous bone marrow and peripheral blood stem cell transplantation for patients with high risk Hodgkins disease (HD) and non-Hodgkins 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.

Quantification improves the prognostic value of CD38 expression in B-cell chronic lymphocytic leukaemia

Summary. Recent studies have shown that CD38 expressed as a percentage of the antigen positivity can predict prognosis and disease progression in patients with B‐cell chronic lymphocytic leukaemia (B‐CLL). The present study showed that quantification of CD38 expressed as antibody‐binding capacity (ABC) improves the prognostic value of the percentage of CD38 positivity in B‐CLL. In a cohort of 81 patients with B‐CLL, a level of CD38 expression of ≥ 30% and an ABC value of 250 proved statistically valid cut‐off points to predict disease progression (% CD38: P=0·0027; ABC: P < 0·0001). There was a positive and significant correlation between the percentage of CD38 expression and ABC (r=0·7; P < 0·0001). There was a better discrimination of survival using ABC rather than percentage CD38 positivity (P < 0·0001 compared with P=0·0027). Only ABC predicted for survival in patients under 60 years of age (P=0·0076) or with stage A disease (P=0·0195). Both percentage CD38 and ABC discriminated between time to first treatment for all patients but only ABC predicted time to treatment for stage A patients (P=0·0004). In conclusion, CD38 positivity is an important prognostic factor in B‐CLL. However, quantification of CD38 is superior to the percentage positivity and should be used clinically in conjunction with other variables of predictive value to identify B‐CLL patients that are likely to progress.

Phenotype and frequency of Epstein–Barr virus-infected cells in pretreatment blood samples from patients with Hodgkin lymphoma

An accumulating body of data suggests that the Epstein–Barr virus (EBV), a lymphotropic herpesvirus, is involved in the pathogenesis of a proportion of cases of Hodgkin lymphoma (HL). In this study, we showed that the frequency of circulating EBV‐infected cells was significantly higher (P < 0·001) in pretreatment blood samples from EBV‐associated cases when compared with non‐EBV‐associated cases. We further showed that in patients with EBV‐associated disease, the virus persisted in the peripheral blood in memory B cells. This phenotype is consistent with that seen in healthy seropositive controls, post‐transplant patients and patients with acute infectious mononucleosis. The data suggest that an increased frequency of EBV carrying B cells in peripheral blood is associated with EBV‐associated HL.