Incidence and management of hepatic venoocclusive disease in 237 patients undergoing reduced-intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT).
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Adult↗
Biomedical subjects
S Devereux
Publications and source records attributed to S Devereux.
Lamivudine prophylaxis and treatment of hepatitis B Virus-exposed recipients receiving reduced intensity conditioning hematopoietic stem cell transplants with alemtuzumab.
Individuals with past exposure to hepatitis B virus (HBV) may reactivate HBV following bone marrow transplantation. Alemtuzumab (CAMPATH)-based reduced intensity conditioning bone marrow transplantation has been associated with a high incidence of viral infections. Lamivudine prophylaxis for HBV should be instituted in this setting. The management of 240 CAMPATH-based reduced intensity conditioning bone marrow transplantation, carried out over an 8-year period at Kings College Hospital, was reviewed. Hepatitis B core total antibody (anti-HBc) testing identified recipients and donors with previous HBV exposure. Fifteen donor-recipient pairs were identified as being at risk of HBV reactivation. Eight recipients of anti-HBc negative donors were HBsAg negative, anti-HBc positive pre-transplantation. Five anti-HBc negative recipients received transplants from HBsAg negative, anti-HBc positive donors. Two HBV carrier recipients had one anti-HBc negative and one positive donor, respectively. Pre-transplant lamivudine prophylaxis was given to 8/10 (80%) anti-HBc positive recipients. Although HBsAg and HBV DNA were detected 4 months after bone marrow transplantation in one patient who did not receive prophylaxis, a good antiviral response was documented on starting lamivudine. The two HBV carrier recipients had stopped lamivudine at 8 and 31 months post-bone marrow transplantation, respectively, and died of liver failure with a sharp rise in HBV DNA levels. The five anti-HBc negative recipients with anti-HBc positive donors remained HBsAg and HBV DNA negative. Although lamivudine prophylaxis prevented HBV reactivation, it is unclear at what stage post-transplantation prophylaxis can be discontinued. Close monitoring of liver function tests (LFTs), HBsAg, and HBV DNA must be undertaken even after stopping antiviral prophylaxis.
Adolescent↗
Increase in allergy following donor lymphocyte infusions.
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Adult↗
Prolonged remission in a case of Richter's transformation of B-cell chronic lymphocytic leukaemia following adoptive immunotherapy.
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Alemtuzumab↗
Koebnerizing sclerodermatous graft-versus-host disease caused by donor lymphocyte infusion and interferon-alpha.
Graft-versus-host disease (GvHD) is a common sequel to allogeneic bone marrow transplants, which may be accompanied by desirable graft-versus-tumour effects. Sclerodermatous GvHD is a rare subtype that is very difficult to treat. We report the first case of sclerodermatous GvHD as part of the Koebner phenomenon. We propose that donor lymphocyte infusion and interferon-alpha were involved in the pathogenesis of this case.
Adult↗
Tumor supernatant from myeloid malignancies inhibits T-cell apoptosis and cell cycle entry independently.
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Apoptosis↗
PNP with Waldenström's macroglobulinaemia.
We describe a 65-year-old Caucasian man with Waldenstrom's macroglobulinaemia who developed paraneoplastic pemphigus (PNP) 3 years after his haematological diagnosis. This is a very rare malignancy that is associated with PNP. The evolution of PNP in this patient appears to exhibit the postulated immunological phenomenon of epitope spreading.
Aged↗
Cardiac presentation of ALK positive anaplastic large cell lymphoma.
Cardiac involvement as an initial presentation of malignant lymphoma is a rare occurrence. We report the case of an immunocompetent 29-year-old male who presented with syncope and arrythmias secondary to a ventricular cardiac mass. Transcutaneous cardiac biopsy was non-diagnostic, therefore an open cardiac biopsy was performed from which a provisional diagnosis of a cardiac inflammatory pseudotumour was made. Six months after presentation, he developed several subcutaneous lesions with systemic symptoms. Histological and immunophenotypic review of the initial cardiac biopsy revealed features consistent with a diagnosis of CD30, ALK1 positive anaplastic large cell lymphoma (ALCL). Despite intensive treatment with combination chemotherapy, there was significant progression of disease, and he died 11 months after diagnosis. The overall prognosis of cardiac lymphoma remains poor, which may be due to the often late presentation of the tumour. To our knowledge, this is the first reported case of a cardiac ALK positive ALCL. Although rare, cardiac presentation of ALCL should be added to the list of differential diagnoses of cardiac lymphomas.
Activin Receptors, Type I↗
Patient, carer and health service outcomes of nurse-led early discharge after breast cancer surgery: a randomised controlled trial.
Patients with breast cancer who require axillary clearance traditionally remain in hospital until their wound drains are removed. Early discharge has been shown to improve clinical outcomes, but there has been little assessment of the psychosocial and financial impact of early discharge on patients, carers and the health service. This study aimed to evaluate the effectiveness of a nurse-led model of early discharge from hospital. Main outcome measures were quality of life and carer burden. Secondary outcomes included patient satisfaction, arm morbidity, impact on community nurses, health service costs, surgical cancellations and in-patient nursing dependency. A total of 108 patients undergoing axillary clearance with mastectomy or wide local excision for breast cancer were randomised to nurse-led early discharge or conventional stay. Nurse-led early discharge had no adverse effects on quality of life or patient satisfaction, had little effect on carer burden, improved communication between primary and secondary care, reduced cancellations and was safely implemented in a mixed rural/urban setting. In total, 40% of eligible patients agreed to take part. Nonparticipants were significantly older, more likely to live alone and had lower emotional well being before surgery. This study provides further evidence of the benefits of early discharge from hospital following axillary clearance for breast cancer. However, if given the choice, most patients prefer to stay in hospital until their wound drains are removed.
Aged↗
Reduced-intensity rituximab-BEAM-CAMPATH allogeneic haematopoietic stem cell transplantation for follicular lymphoma is feasible and induces durable molecular remissions.
The indolent non-Hodgkin's lymphomas are theoretically curable through allogeneic haematopoietic stem cell transplantation (allo-HSCT). The applicability of standard conditioning allo-HSCT is, however, restricted by its toxicity. Recently, reduced-intensity conditioning regimens have demonstrated efficacy with significantly reduced early morbidity and mortality. We examined the safety and efficacy of rituximab-BEAM-CAMPATH as reduced-intensity conditioning for allo-HSCT in follicular lymphomas. Minimal residual disease was assessed by polymerase chain reaction (PCR) for bcl-2/IgH translocations, and chimerism by X,Y-FISH or PCR amplification of short tandem repeat sequences. At a median follow-up of 521 days (371-719), four of five patients were alive and three were in complete molecular remission. Three patients required pre-emptive treatment for CMV reactivation. One succumbed to a perforated viscus and one had slowly progressive disease. A graft-versus-lymphoma effect was demonstrable and quantitative PCR for bcl-2/IgH may allow better accuracy in scheduling post-allograft rituximab and/or donor lymphocyte infusions. Although follow-up is short, reduced-intensity allo-HSCT with BEAM-CAMPATH conditioning appears to be safe, effective in inducing a molecular remission and is potentially curative. Further recruitment and much longer follow-up will be necessary to determine if this impacts favourably upon disease-free and overall survival.
Adult↗
Fatal donor-derived Epstein-Barr virus-associated post-transplant lymphoproliferative disorder following reduced intensity volunteer-unrelated bone marrow transplant for myelodysplastic syndrome.
Post-transplant lymphoproliferative disorders (PTLD) are a well recognised complication of conventional haemopoietic stem cell transplantation (HSCT). Reduced intensity HSCT involves intensive immunosuppression to permit engraftment. Thirty reduced intensity transplants with the FBC (fludarabine 150 mg/m2, busulphan 8 mg/m2, CAMPATH-1H 100 mg) protocol have been performed at our centre, with one confirmed EBV-positive PTLD. The female recipient developed a perforated viscus day +191 following HSCT from a volunteer unrelated male donor. A large caecal mass and a retroperitoneal abscess were excised, revealing an EBV-positive diffuse large B cell lymphoma confirmed by FISH to be of donor origin. More experience is required before the risk of PTLD in this setting can be assessed.
Epstein-Barr Virus Infections↗
The retinoblastoma family member, p107, is active in non-dividing monocyte-derived dendritic cells.
A member of the retinoblastoma family of cell cycle regulatory proteins, p107, is not normally expressed in non-cycling cells. We demonstrate here that p107 is expressed in monocytes as they differentiate into dendritic cells under the influence of granulocyte-macrophage colony-stimulating factor and interleukin 4, a process shown not to involve cellular proliferation. We show that p107 is localized to the nucleus of these cells and is active, in that it binds an E2F-DNA binding site, together with E2F transcription factors. These findings suggest a hitherto unknown role for p107 in non-proliferating dendritic cells that warrants further investigation.
Blotting, Western↗
Granulocyte transfusion: a review.
Neutrophils are the body's main defence against invasion by bacteria and fungi and, below a level of 1 x 10(9)/l, there is a direct relationship between their circulating number and the risk of systemic infection. Despite advances in supportive care, such as improved broad-spectrum antibiotics and the haemopoietic growth factors, neutropenia following myelosuppressive chemotherapy for malignant disease remains the most important cause of treatment-related morbidity and mortality and its most important dose-limiting toxicity. Although there is clear theoretical, experimental and anecdotal clinical evidence supporting the use of transfused granulocytes to prevent and treat infection in neutropenia, early attempts at exploiting this clinically were unsuccessful, mainly because of difficulties in collecting a sufficient number of cells. Improvements in the technology of collection, including the use of red cell sedimenting agents, glucocorticoids and, more recently, granulocyte-colony-stimulating factor, now allow granulocyte doses within the therapeutic range to be routinely collected. Preliminary evidence suggests clinical efficacy. However, well-designed trials with clinically relevant end-points will be required before granulocyte transfusion can become part of routine clinical practice.
Blood Component Transfusion↗
In vivo CAMPATH-1H prevents GvHD following nonmyeloablative stem-cell transplantation.
BACKGROUND: We have investigated a novel nonmyeloablative conditioning regimen in 44 patients with hematological malignancies. The median patient age was 41 years. Many of the patients had high-risk features, including 19 patients with a previous failed transplant. METHODS: Recipient conditioning consisted of CAMPATH-1H 20 mg/day on Days -8 to -4, fludarabine 30 mg/m(2) on Days -7 to -3 and melphalan 140 mg/m(2) on Day -2. Thirty-six recipients received unmanipulated G-CSF mobilized PBSC from HLA identical siblings and eight received unmanipulated BM from MUD. GvHD prophylaxis was with CYA alone for 38 patients and CYA plus MTX for six sibling recipients. RESULTS: Forty-two of the 43 evaluable patients had sustained engraftment. Results of chimerism analysis using microsatellite PCR indicate that 18 of 31 patients studied were full donor chimeras, while the other patients were mixed chimeras in one or more lineages. At a median follow-up of 9 months (range, 3-29 months) 33 patients remain alive in CR, or with no evidence of disease progression. Seven patients relapsed or progressed post-transplant and four of them subsequently died. Four patients died from regimen-related complications. There were no cases of Grades III-IV acute GvHD. Only two patients developed Grade II acute GvHD and only one had chronic GvHD. The estimated probability of non-relapse mortality at 1 year was 11%.Results: Although longer follow-up is needed to establish the long-term remission rates, this study demonstrates that this nonmyeloablative preparative regimen is associated with durable engraftment, minimal toxicity and low incidence of GvHD.
Adolescent↗
The role of apoptosis, proliferation, and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS.
Bone marrow CD34(+) cell apoptosis (annexin V), proliferation (Ki-67), and Bcl-2-related protein expression was evaluated by flow cytometry in 102 patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia secondary to MDS (MDS-AML) and in 30 normal donors (NBM). Apoptosis was significantly increased in refractory anemia (RA)/RA with ringed sideroblasts (RARS) (56.9% [20.4%-93.6%]) and refractory anemia with excess blasts (RAEB) (51.2% [25.2%-76. 6%]) compared with NBM (16.7% [3.4%-35.3%], P <.0001). In RA/RARS, apoptosis always exceeded proliferation (Ki-67-positivity, 26.1% [9.5%-47.8%]; apoptosis:proliferation ratio 2.08 [1.15-3.63]); whereas in RAEB, this ratio equalized (1.14 [0.93-2.08]) due to increased proliferation (40.4% [22%-69.5%]). Progression to RAEB in transformation (RAEB-t)/MDS-AML was associated with a significant reduction in apoptosis (22.3% [2.1%-53.2%]; P <.0001) and proliferation (16.8% [1.9%-75.8%); P =.04; ratio 1.69 [0.16-12.21]). Pro-apoptotic (Bax/Bad) versus anti-apoptotic (Bcl-2/Bcl-X) Bcl-2-related protein ratios were increased in RA/RARS compared with NBM (2.57 [1.93-9.42] versus 1.89 [0.65-4.1]; P =.06), whereas disease progression was associated with significantly reduced ratios (1.16 [0.06-3.32]; P <.0001) due primarily to increased Bcl-2 expression. Apoptosis and Bax/Bad:Bcl-2/Bcl-X ratio were inversely correlated with both International Prognostic Scoring System score and cytogenetic risk group; highest levels observed in patients with low score and/or good risk cytogenetics. There was a trend toward an association between Bcl-2-related protein expression and apoptosis (P =.07). This study indicates that MDS progression arises through multiple hits that alter levels of CD34(+) cell apoptosis and proliferation. Early disease is associated with excessive apoptosis and elevated ratio of apoptosis to proliferation. Increased proliferative rates are observed in RAEB, whereas leukemic transformation arises through inhibition of apoptosis rather than excessive cell growth. Although disease progression is accompanied by a fall in pro-apoptotic versus anti-apoptotic Bcl-2-related protein ratios, heterogeneity in patterns of protein expression indicates that factors additional to Bcl-2 family members play a role in the deregulated apoptosis in MDS. (Blood. 2000;96:3932-3938)
Acute Disease↗
In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation.
A novel nonmyeloablative conditioning regimen was investigated in 44 patients with hematologic malignancies. The median patient age was 41 years. Many of the patients had high-risk features, including 19 patients with a previous failed transplant. Recipient conditioning consisted of CAMPATH-1H, 20 mg/day on days -8 to -4; fludarabine, 30 mg/m(2) on days -7 to -3; and melphalan, 140 mg/m(2) on day -2. Thirty-six recipients received unmanipulated granculocyte colony-stimulating factor-mobilized peripheral blood stem cells from HLA-identical siblings, and 8 received unmanipulated marrow from matched unrelated donors. GVHD prophylaxis was with cyclosporine A alone for 38 patients and cyclosporine A plus methotrexate for 6 sibling recipients. Forty-two of the 43 evaluable patients had sustained engraftment. Results of chimerism analysis using microsatellite polymerase chain reaction indicate that 18 of 31 patients studied were full-donor chimeras while the other patients were mixed chimeras in one or more lineages. At a median follow-up of 9 months (range 3 to 29 months), 33 patients remain alive in complete remission or with no evidence of disease progression. Seven patients relapsed or progressed post-transplantation, and 4 of them subsequently died. Four patients died of regimen-related complications. There were no cases of grades III-IV acute GVHD. Only 2 patients developed grade II acute GVHD, and only 1 had chronic GVHD. The estimated probability of nonrelapse mortality was 11%. Although longer follow-up is needed to establish the long-term remission rates, this study demonstrates that this nonmyeloablative preparative regimen is associated with durable engraftment, minimal toxicity, and low incidence of GVHD.
Adolescent↗
The PI3 kinase, p38 SAP kinase, and NF-kappaB signal transduction pathways are involved in the survival and maturation of lipopolysaccharide-stimulated human monocyte-derived dendritic cells.
As a dendritic cell (DC) matures, it becomes more potent as an antigen-presenting cell. This functional change is accompanied by a change in DC immunophenotype. The signal transduction events underlying this process are poorly characterized. In this study, we have investigated the signal transduction pathways involved in the lipopolysaccharide (LPS)-induced maturation of human monocyte-derived DCs (MoDCs) in vitro. We show that exposure of immature MoDCs to LPS activates the p38 stress-activated protein kinase (p38SAPK), extracellular signal-regulated protein kinase (ERK), phosphoinositide 3-OH kinase (PI3 kinase)/Akt, and nuclear factor (NF)-kappaB pathways. Studies using inhibitors demonstrate that PI3 kinase/Akt but not the other pathways are important in maintaining survival of LPS-stimulated MoDCs. Inhibiting p38SAPK prevented activation of the transcription factors ATF-2 and CREB and significantly reduced the LPS-induced up-regulation of CD80, CD83, and CD86, but did not have any significant effect on the LPS-induced changes in macropinocytosis or HLA-DR, CD40, and CD1a expression. Inhibiting the NF-kappaB pathway significantly reduced the LPS-induced up-regulation of HLA-DR as well as CD80, CD83, and CD86. Inhibiting the p38SAPK and NF-kappaB pathways simultaneously had variable effects depending on the cell surface marker studied. It thus appears that different aspects of LPS-induced MoDC maturation are regulated by different and sometimes overlapping pathways.
Cell Differentiation↗
Effect of changes in expression of the amphotropic retroviral receptor PiT-2 on transduction efficiency and viral titer: implications for gene therapy.
The aim of this study was to quantify the impact of amphotropic retroviral receptor (PiT-2) levels on susceptibility to transduction and to determine whether the low level of PiT-2 found on CD34+ hematopoietic cells is within the range likely to compromise gene transfer. Receptor-deficient Chinese hamster ovary (CHO) cells were transfected with a PiT-2 construct that could be induced by the removal of tetracycline. The level of PiT-2 expression measured by virus binding in uninduced and in fully and partially induced transfectants correlated with the efficiency of transduction by an amphotropic retroviral reporter vector. Fully induced CHO-PiT-2 cells gave apparent viral titers similar to NIH 3T3 fibroblasts while addition of tetracycline reduced titers by up to 140-fold. Binding of the same vector preparation to purified CD34+ peripheral blood stem cells (PBSCs) was always less than to uninduced CHO-PiT-2 transfectants even after preincubation in 10-ng/ml concentrations of IL-3, IL-6, and stem cell factor, which increased retroviral binding by an average of 35%. The level of expression of the amphotropic retroviral receptor PiT-2 thus significantly limits transduction efficiency within the range observed in target cells of importance in human gene therapy.
3T3 Cells↗