Drug companies' lobbying of ministers has little effect on NICE.
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Drug Industry↗
Biomedical subjects
Andrew Jack
Publications and source records attributed to Andrew Jack.
Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial.
We evaluated the role of rituximab (R) both in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). A total of 465 patients were randomized to induction with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (every 3 weeks) or R-CHOP (R: 375 mg/m(2) intravenously, day 1). Those in complete remission (CR) or partial remission (PR) were randomized to maintenance with R (375 mg/m(2) intravenously once every 3 months for a maximum of 2 years) or observation. R-CHOP induction yielded an increased overall response rate (CHOP, 72.3%; R-CHOP, 85.1%; P < .001) and CR rate (CHOP, 15.6%; R-CHOP, 29.5%; P < .001). Median progression-free survival (PFS) from first randomization was 20.2 months after CHOP versus 33.1 months after R-CHOP (hazard ratio [HR], 0.65; P < .001). Rituximab maintenance yielded a median PFS from second randomization of 51.5 months versus 14.9 months with observation (HR, 0.40; P < .001). Improved PFS was found both after induction with CHOP (HR, 0.30; P < .001) and R-CHOP (HR, 0.54; P = .004). R maintenance also improved overall survival from second randomization: 85% at 3 years versus 77% with observation (HR, 0.52; P = .011). This is the first trial showing that in relapsed/resistant FL rituximab maintenance considerably improves PFS not only after CHOP but also after R-CHOP induction.
Adult↗
Organisation of neoplastic haematopathology services: a UK perspective.
The diagnosis of haematological malignancies has begun to emerge as a distinct pathological discipline in the United Kingdom. This has been driven by the recommendation of the National Institute for Clinical Excellence that diagnosis of leukaemia and lymphoma should take place in a specialist laboratory and in most cases this should be organised on a regional basis. The reason for this guidance was the perception that there was a considerable level of diagnostic inaccuracy and that this could be improved by better integration of the currently available technologies. This is one of a number of major changes in the way that services to patients are being delivered, all of which are centred on the development of multidisciplinary teams responsible for the provision of local services. The introduction of the WHO classification of haematological malignancy provides a structure for the development of integrated haemtopathology laboratories, with its emphasis on definition of disease entities based on clinical, morphological, phenotypical and molecular features. This means that these diagnostic modalities can be used systematically and in parallel to provide effective cross validation of a diagnosis. One of the challenges raised by this approach is the selection of the most informative panels of investigations both at presentation and subsequent follow up from the wide range of options that are now available. The introduction of specialist haematopathology services in the United Kingdom has highlighted a number of scientific and organisational issues that in time may have a wider impact on diagnostic laboratories in general. These include the relationship between size and cost effectiveness and the future role of clinical scientists and medically trained pathologists. Integrated laboratories of the type being developed challenge the prevailing model for delivery of pathological services in the United Kingdom, which is based around the traditional pathology disciplines. These speciality boundaries will become less relevant as long established diagnostic techniques are replaced by the new generation of diagnostic technologies and it is important to establish frameworks of service delivery that can deploy these developments for the benefit of patients.
Flow Cytometry↗
Demonstration of a germinal center immunophenotype in lymphomas by immunocytochemistry and flow cytometry.
The germinal center plays an important role in the pathogenesis of B-cell lymphomas, and evidence exists to suggest that most cases are germinal center or postgerminal center derived. Burkitt lymphoma and follicular lymphoma are derived from the germinal center stage of differentiation. It has been shown that diffuse large B-cell lymphomas with a germinal center-type pattern of RNA expression or a germinal center cell phenotype using immunocytochemistry have a more favorable outcome compared with those with a postgerminal center/activated profile. Microarray technology may not be available in many diagnostic laboratories, and antibody-based methods are much simpler and cheaper and are therefore more applicable to the routine setting. Immunocytochemistry has the advantage that the cells of interest are identified morphologically, and it is applicable retrospectively to fixed tissue. The main disadvantage is that only single-color staining is currently used in the routine setting. Flow cytometry allows one to obtain a more precise definition of individual cell types. The cells of interest are identified by a combination of physical characteristics and by the use of multiple antibodies labeled with different fluorochromes. Flow cytometry has the major advantage of being able to analyze very large numbers of cells, and results can be obtained within a few hours of the specimen being taken. The methods described allow B-cell lymphomas to be crudely divided into two groups, those with a germinal center phenotype and those that are mainly postgerminal center tumors. As knowledge of the normal biology of the germinal center develops, it will become possible to use immunophenotypic methods to more precisely classify all types of mature B-cell malignancies.
Antibodies, Monoclonal↗
CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma.
The combination of cyclophosphamide, vincristine, and prednisone (CVP) is one of several standard treatment options for advanced follicular lymphoma. This, like similar chemotherapeutic regimens, induces response rates of 60% to 80%, with a median response duration of under 2 years. Rituximab, a chimeric monoclonal antibody against CD20, is active in follicular lymphoma, both as monotherapy and in combination with chemotherapy. Previously untreated patients with stages III to IV follicular lymphoma were randomly assigned to receive either 8 cycles of CVP plus rituximab (R-CVP; n = 162) or CVP (n = 159). Overall and complete response rates were 81% and 41% in the R-CVP arm versus 57% and 10% in the CVP arm, respectively (P < .0001). At a median follow-up of 30 months, patients treated with R-CVP had a very significantly prolonged time to progression (median 32 months versus 15 months for CVP; P < .0001). Median time to treatment failure was 27 months in patients receiving R-CVP and 7 months in the CVP arm (P < .0001). Rituximab did not add significantly to the toxicity of CVP. The addition of rituximab to the CVP regimen significantly improves the clinical outcome in patients with previously untreated advanced follicular lymphoma, without increased toxicity.
Adult↗
Gastric marginal zone lymphoma is associated with polymorphisms in genes involved in inflammatory response and antioxidative capacity.
Gastric marginal zone lymphoma (GMZL) is strongly associated with Helicobacter pylori infection, which induces a chronic inflammatory response. Inflammation can result in DNA damage related to its severity, the cellular antioxidant capacity, and the integrity of DNA repair mechanisms. Interleukin-1 (IL-1) polymorphisms have been shown to be important mediators of inflammation, while glutathione S-transferase GST T1 and GST M1 polymorphisms are believed to affect cellular antioxidant capacity. We aimed to determine whether polymorphisms at the IL-1 and GST T1 and GST M1 loci modulate the risk of developing GMZL. Blood and biopsy samples were obtained for a historical series of 66 GMZL cases, whereas blood samples were available from 163 healthy controls. Genotypes were obtained for GST T1, GST M1, IL-1 RN, and IL-1B-31 using PCR-based techniques. H pylori infection was found in 86.0% of cases, whereas in the control population only 37.4% tested positive. The IL-1 RN 2/2 genotype was significantly associated with risk of GMZL (odds ratio [OR], 5.51; 95% confidence interval [CI] 2.16-14.07), but not the IL-1B-31 genotype. Likewise, the GST T1 null genotype was strongly associated with risk of GMZL (OR, 9.51; 95% CI 4.57-19.81), but not the GST M1 genotype. Evidence was found of effect modification between the IL-1 RN and GST T1 genotypes (P =.02). The combination of the IL-1 RN 2/2 and GST T1 null genotype was most strongly associated with risk of GMZL (OR, 32.29; 95% CI 6.92-150-63). These results support the hypothesis that the risk of developing GMZL is influenced by inter-individual variation in the cellular inflammatory immune responses to H pylori infection, and to antioxidative capacity.
Adult↗
An evaluation of a low-density DNA microarray using cytochrome P450 inducers.
The aim of this study was to validate a low-density DNA microarray "Rat HepatoChip", which contains 59 genes from a range of potential toxic markers and drug metabolism-related genes. Liver mRNA was isolated from rats dosed with six different chemicals, dexamethasone, troleandomycin, miconazole, clotrimazole, and methylclofanapate, which are all known to induce different cytochrome P450 genes, and isoniazid, which does not cause histopathological changes. Replicate microarrays were used to measure the variability in the chips and in the process. The average variability in signal between different chips observed in triplicate experiments was 33% ranging from 21 to 39% depending on genes. We also demonstrated a strong correlation between the liver histopathology and the gene expression profiles indicating that the gene expression profile reflects histopathological changes. These results suggest that the Rat HepatoChip microarray may provide a fast and effective tool for assessing the toxicity profile of developmental drug candidates during the drug discovery process.
Administration, Oral↗
Isolation and characterization of bone marrow multipotential mesenchymal progenitor cells.
OBJECTIVE: There is an increased interest in rheumatology in mesenchymal progenitor/stem cells (MPCs) and their roles in rheumatic diseases, but little is known about the phenotype of these cells in vivo. The aim of this study was to isolate and characterize human bone marrow (BM) MPCs. METHODS: Fluorescence microscopy was used to identify putative MPCs among adherent BM cells. To purify them, a positive selection with antifibroblast microbeads was used, combined with fluorescence-activated cell sorting (FACS) for microbead+,CD45(low) cells. A more detailed phenotype of these cells was determined using 4-color flow cytometry, and standard chondrogenic, osteogenic, and adipogenic assays were used to investigate their differentiation potentials. RESULTS: Putative MPCs microscopically identified as large, fibroblast-like, D7-FIB+ cells were purified using positive selection with D7-FIB-conjugated (antifibroblast) microbeads followed by FACS for specifically bound microbead+,CD45(low) cells. These cells represented 0.01% of mononuclear cells in the BM. They were uniformly positive for CD105, LNGFR, HLA-DR, CD10, CD13, CD90, STRO-1, and bone morphogenetic protein receptor type IA (BMPRIA) and were negative for CD14, CD34, CD117, and CD133. Only cells with this phenotype could proliferate and produce adherent cell monolayers capable of chondrogenic, osteogenic, and adipogenic differentiation. D7-FIB- cells in the BM lacked any MPC activity. Uncultured skin fibroblasts had a phenotype similar to that of BM MPCs, but were negative for LNGFR, STRO-1, HLA-DR, and BMPRIA. CONCLUSION: This study shows the distinct phenotype, morphology, and method of isolation of BM MPCs. The findings may have implications for defining the physiologic roles of MPCs in arthritis, bone diseases, and joint regeneration.
Adolescent↗