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A S Jack

Publications and source records attributed to A S Jack.

At least 19 recordsLinked to original sources
PubMed2006

Flow cytometric protein expression profiling as a systematic approach for developing disease-specific assays: identification of a chronic lymphocytic leukaemia-specific assay for use in rituximab-containing regimens.

Depletion of disease below the levels detected by sensitive minimal residual disease (MRD) assays is associated with prolonged survival in chronic lymphocytic leukaemia (CLL). Flow cytometric MRD assays are now sufficiently sensitive and rapid to guide the duration of therapy in CLL, but generally rely on assessment of CD20 expression, which cannot be accurately measured during and after therapeutic approaches containing rituximab. The aim of this study was to use analytical software developed for microarray analysis to provide a systematic approach for MRD flow assay development. Samples from CLL patients (n=49), normal controls (n=21) and other B-lymphoproliferative disorders (n=12) were assessed with a panel of 66 antibodies. The DNA-Chip analysis program was used to identify discriminating antibodies, with hierarchical cluster analysis to identify complementary combinations. An iterative process was used: increasing numbers of patients were assessed with smaller, more targeted antibody panels until a highly specific combination (CD81/CD22/CD19/CD5) was identified. This combination was as sensitive and specific as previously reported assays and potentially applicable to blood and marrow samples from patients treated with current therapeutic approaches including rituximab. This approach to the identification of disease-specific antibody combinations for MRD analysis is readily applicable to a variety of haematological disorders.

Antibodies, Monoclonal↗
PubMed2004

Cutaneous B-cell lymphoma: pathological spectrum and clinical outcome in 51 consecutive patients.

The clinical behavior and optimal treatment of patients presenting with skin infiltration by B-cell lymphoma have not been established. To clarify this we assessed the clinical and laboratory features of 51 patients presenting with cutaneous infiltration by B-cell lymphoma. Follow-up data was available for 46 patients with a median age of 68 years (range 16-89 years) and a median follow-up of 32.5 months (range 5-123 months). Thirty-three of 51 (65%) patients had diffuse large B-cell lymphoma (DLBCL), and 15/51 (29%) had marginal zone lymphoma (MZL). The remaining 3 patients had follicular lymphoma, CLL, and post-transplant lymphoproliferative disease. Of the 33 patients with DLBCL, follow-up was available in 29; 24/29 (83%) had primary cutaneous disease, which was unifocal in 17/24 (71%). Following treatment, 8/24 (33%) of the primary cases relapsed. Of the 8 who relapsed, 7 had received local forms of treatment only. Follow-up data was available in 14/15 patients with MZL. 11/14 (79%) had primary cutaneous disease, which was unifocal in 8 (73%). Following treatment, 4 of these cases relapsed (36%); all had received local therapy only. It is evident from this study that a significant proportion ( reverse similar 20%) of patients who present with cutaneous infiltration by B-cell lymphoma have systemic disease. Staging is therefore mandatory in these patients. Approximately 1/3 patients with primary cutaneous DLBCL or MZL ultimately relapse, and relapse rates appear higher in those patients receiving local therapy only. Systemic or combined modality therapy may therefore be the most appropriate treatment at presentation. This should be assessed prospectively in randomized trials.

Adolescent↗
PubMed2003

The classification of lymphomas: a new beginning or the end of an era?

The World Health Organisation Classification of Tumours of the Haematopoietic and Lymphoid Tissues has recently been published. This is the latest in a long line of classifications of haematological malignancies and will be the international standard. It is now possible to achieve high levels of diagnostic accuracy for the main types of lymphoma. However, many of the entities encompass a wide spectrum of clinical outcomes and this approach to classification may be insufficiently precise for the future needs of haematological oncology. Rapid progress in targeted therapies may require further developments in tumour classification based on pathogenic features rather than arbitrary morphological criteria.

Humans↗
PubMed2003

The development of integrated haematopathology laboratories: a new approach to the diagnosis of leukaemia and lymphoma.

The diagnosis and monitoring of leukaemia and lymphoma requires the effective integration of a wide range of diagnostic techniques and expertise. The need to develop this type of service that crosses traditional boundaries of laboratory specialities is being recommended in national guidance. The Haematological Malignancy Diagnostic Service based within the Leeds Teaching Hospitals NHS Trust was established in 1993 to provide specialist laboratory services for the diagnosis of haematological malignancy for Yorkshire and Humberside in the UK. The department uses a wide range of methodologies including morphology, immunocytochemistry, flow cytometry and molecular genetics [fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR)] in a systematic and co-ordinated way. We describe how the department was established, its current working practices and highlight the advantages of an integrated laboratory for diagnosis of tumours of the haematopoietic system.

Algorithms↗
PubMed2001

Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy.

Previous studies have suggested that the level of residual disease at the end of therapy predicts outcome in chronic lymphocytic leukemia (CLL). However, available methods for detecting CLL cells are either insensitive or not routinely applicable. A flow cytometric assay was developed that can differentiate CLL cells from normal B cells on the basis of their CD19/CD5/CD20/CD79b expression. The assay is rapid and can detect one CLL cell in 10(4) to 10(5) leukocytes in all patients. We have compared this assay to conventional assessment in 104 patients treated with CAMPATH-1H and/or autologous transplant. During CAMPATH-1H therapy, circulating CLL cells were rapidly depleted in responding patients, but remained detectable in nonresponders. Patients with more than 0.01 x 10(9)/L circulating CLL cells always had significant (> 5%) marrow disease, and blood monitoring could be used to time marrow assessments. In 25 out of 104 patients achieving complete remission by National Cancer Institute (NCI) criteria, the detection of residual bone marrow disease at more than 0.05% of leukocytes in 6 out of 25 patients predicted significantly poorer event-free (P =.0001) and overall survival (P =.007). CLL cells are detectable at a median of 15.8 months (range, 5.5-41.8) posttreatment in 9 out of 18 evaluable patients with less than 0.05% CLL cells at end of treatment. All patients with detectable disease have progressively increasing disease levels on follow-up. The use of sensitive techniques, such as the flow assay described here, allow accurate quantitation of disease levels and provide an accurate method for guiding therapy and predicting outcome. These results suggest that the eradication of detectable disease may lead to improved survival and should be tested in future studies.

Adult↗
PubMed2001

Autoimmune thrombocytopenia in Waldenström's macroglobulinemia.

Autoimmune phenomena are well-recognised complications of Waldenström's macroglobulinemia (WM) and IgM monoclonal gammopathy. Peripheral neuropathy and cold agglutinin hemolytic anemia are the most common reported and occur in 5-10% of patients. Autoimmune thrombocytopenia has been rarely reported in WM and its incidence is not known. In this study we report the case of a 67-year-old man who presented with autoimmune thrombocytopenia who was subsequently found to have WM. Laboratory investigation demonstrated that platelet-associated IgM (PAIgM) but not PAIgG was clearly elevated compared to normal controls. In addition the patient's serum reacted strongly with a panel of donor platelets analysed with an indirect platelet immunofluorescence assay utilising an anti-IgM secondary antibody. Glycoprotein specificity could not however be demonstrated by ELISA techniques for platelet glycoproteins IIbIIIa, IaIIa, IbIXa, and IV. We also reviewed the case records of 104 additional cases of WM diagnosed at our institution between 5/93 and 5/99. Three further cases with clinically significant autoimmune thrombocytopenia were identified. The overall incidence of autoimmune thrombocytopenia (4/105, 3.8%) in this cohort of patients was similar to the incidence of peripheral neuropathy (7/105, 6.7%) and cold agglutinins (3/105, 2.9%).

Aged↗
PubMed2001

Insertional events as well as translocations may arise during aberrant immunoglobulin switch recombination in a patient with multiple myeloma.

The majority of patients with multiple myeloma have translocations involving the immunoglobulin heavy chain switch regions on chromosome 14q32 and a promiscuous range of partner chromosomes. We describe a patient with an insertion of 132 bp of chromosome 22q12 sequence into the 5' region flanking S(mu) on chromosome 14q32. The 132 bp region from chromosome 22q12 contains the whole of exon 3 from a novel gene of unknown function in man. The significance of such insertional events remains unclear. The description of insertional events occurring as a result of abnormal switch recombination suggests that, in myeloma, dysregulation of oncogenes may occur by a mechanism other than chromosomal translocation.

Base Sequence↗
PubMed2001

In multiple myeloma, only a single stage of neoplastic plasma cell differentiation can be identified by VLA-5 and CD45 expression.

The nature of the proliferating fraction in myeloma is still not known and understanding the characteristics of this fraction is central to the development of effective novel therapies. However, myeloma plasma cells typically show a very low rate of proliferation and this complicates accurate analysis. Although the level of CD45 and/or VLA-5 has been reported to identify proliferating 'precursor' plasma cells, there are discrepancies between these studies. We have therefore used a rigorous sequential gating strategy to simultaneously analyse cycle status and immunophenotype with respect to CD45, VLA-5 and a range of other integrin molecules. In 11 presentation myeloma patients, the proliferative fraction was distributed evenly between CD45+ and CD45- cells, however, cycling plasma cells were consistently VLA-5-. There was close correlation between the expression of VLA-5 and a range of other integrin molecules (CD11a, CD11c, CD103), as well as the immunoglobulin-associated molecules CD79a/b (Spearman, n = 10, P < 0.0001). In short-term culture, cells that were initially VLA-5-showed increasing VLA-5 expression with time. However, simultaneous analysis of the DNA-binding dye 7-amino-actinomycin D demonstrated that this was not as a result of differentiation, as VLA-5+ plasma cells were all non-viable. This was confirmed in freshly explanted plasma cells from nine patients. Discrete stages of plasma cell differentiation could not be distinguished by the level of CD45 or VLA-5 expression. The results indicate that there is a single stage of plasma cell differentiation, with the phenotype CD38+CD138+VLA-5-. These findings support the hypothesis that neoplastic bone marrow plasma cells represent an independent, self-replenishing population.

Antigens, CD↗
PubMed2001

Analysis of CD34+ cell subsets in stem cell harvests can more reliably predict rapidity and durability of engraftment than total CD34+ cell dose, but steady state levels do not correlate with bone marrow reserve.

In peripheral blood stem cell transplantation (PBSCT), the number of CD34+ cells transplanted has been shown to correlate well with both rapidity and durability of engraftment. However, it is clear that engraftment does not necessarily correlate with total CD34+ cell numbers in some patients. Consequently, there is increasing interest in evaluating the role of CD34+ subsets in haemopoietic recovery as a more accurate marker of harvest quality. We analysed the numbers of CD34+ cell subsets, namely Thy-1+, L-Selectin+ and CD38-, and correlated this with engraftment in 86 patients undergoing PBSCT. Adequate engraftment was defined as being a platelet count greater than 50 x 10(9)/l and a neutrophil count greater than 1.0 x 10(9)/l. CD34+L-Selectin+ provided the best prediction of engraftment rapidity, although the improvement over total CD34+ cell dose was minor. Only the dose of CD34+Thy-1+ cells transplanted correlated with durable engraftment. The probability of adequate 3-month engraftment increased with the dose of CD34+ cells transplanted, but 10% of patients receiving > 5 x 10(6)/kg still showed poor engraftment at 3 months. However, all patients receiving > 2.5 x 10(5)/kg CD34+Thy-1+ showed adequate engraftment at this time point. We also demonstrated that CD34+Thy-1+ progenitors were restricted to the bone marrow under normal conditions and, during stem cell mobilization, their kinetics generally paralleled total CD34+ numbers.

ADP-ribosyl Cyclase↗
PubMed2001

Waldenström macroglobulinemia. Development of diagnostic criteria and identification of prognostic factors.

To establish whether a combination of morphologic and immunophenotypic criteria could be developed to more precisely define Waldenström macroglobulinemia (WM) and prognostic factors, we retrospectively assessed the clinical and laboratory features of 111 cases of WM. Bone marrow infiltration by small lymphocytes was documented in each case; and diffuse, interstitial, nodular, and paratrabecular patterns of infiltration were documented in 58%, 32%, 6%, and 4% of cases, respectively. Ninety percent were characterized by a surface immunoglobulin-positive, CD19+CD20+CD5-CD10-CD23- immunophenotype. The median overall survival from diagnosis was 60 months; univariate analysis revealed the following adverse prognostic factors: older than 60 years, performance status more than 1, platelet count less than 100 x 10(3)/microL (< 100 x 10(9)/L), pancytopenia, and diffuse bone marrow infiltration. Associated median survival was 40, 38, 46, 28, and 59 months, respectively. Multivariate analysis revealed age, performance status, and platelet count as prognostically significant, but stratification of patients according to the International Prognostic Index had limited value. We suggest defining WM by the following criteria: IgM monoclonal gammopathy; bone marrow infiltration by small lymphocytes, plasmacytoid cells, and plasma cells in a diffuse, interstitial, or nodular pattern; and a surface immunoglobulin-positive, CD19+CD20+CD5-CD10-CD23- immunophenotype.

Adult↗
PubMed2000

The interleukin-6 receptor alpha-chain (CD126) is expressed by neoplastic but not normal plasma cells.

Interleukin-6 (IL-6) is reported to be central to the pathogenesis of myeloma, inducing proliferation and inhibiting apoptosis in neoplastic plasma cells. Therefore, abrogating IL-6 signaling is of therapeutic interest, particularly with the development of humanized anti-IL-6 receptor (IL-6R) antibodies. The use of such antibodies clinically requires an understanding of IL-6R expression on neoplastic cells, particularly in the cycling fraction. IL-6R expression levels were determined on plasma cells from patients with myeloma (n = 93) and with monoclonal gammopathy of undetermined significance (MGUS) or plasmacytoma (n = 66) and compared with the levels found on normal plasma cells (n = 11). In addition, 4-color flow cytometry was used to assess the differential expression by stage of differentiation and cell cycle status of the neoplastic plasma cells. IL-6R alpha chain (CD126) was not detectable in normal plasma cells, but was expressed in approximately 90% of patients with myeloma. In all groups, the expression levels showed a normal distribution. In patients with MGUS or plasmacytoma, neoplastic plasma cells expressed significantly higher levels of CD126 compared with phenotypically normal plasma cells from the same marrow. VLA-5(-) "immature" plasma cells showed the highest levels of CD126 expression, but "mature" VLA-5(+) myeloma plasma cells also overexpressed CD126 when compared with normal subjects. This study demonstrates that CD126 expression is restricted to neoplastic plasma cells, with little or no detectable expression by normal cells. Stromal cells in the bone marrow microenvironment do not induce the overexpression because neoplastic cells express higher levels of CD126 than normal plasma cells from the same bone marrow in individuals with MGUS. (Blood. 2000;96:3880-3886)

Aged↗
PubMed2000

The relationship between typical and atypical B-cell chronic lymphocytic leukemia. A comparative genomic hybridization-based study.

B-cell chronic lymphocytic leukemia (CLL) can be classified as typical or atypical based on morphologic and immunophenotypic features. The relationship between these 2 groups is uncertain, and there is some evidence they may be different entities. We used comparative genomic hybridization (CGH) to explore the cytogenetic relationship between typical and atypical B-cell CLL. Results showed a similar pattern of chromosome gains and losses detected in typical and atypical B-cell CLL, suggesting they are related disorders. Gain on chromosome 12 material occurred in cases that were apparently normal by interphase fluorescence in situ hybridization (FISH). The common region mapped to chromosome 12q21. Gains on chromosome 4 were present in 74% (32) of cases analyzed and were confirmed by interphase FISH in 30% (13) of cases. We previously have shown the strong association between trisomy 12 as detected by FISH and CD11a expression in atypical B-cell CLL. In the present study, CGH demonstrated additional gains on 12p and 12q outside the common amplified region of 12q21 in these patients.

Aged↗
PubMed2000

Clinicopathological correlates of IgM paraproteinemias.

IgM paraproteinemia is considered to be the major defining feature of Waldenström's macroglobulinemia (WM), but it may also occur in other B-cell lymphoproliferative disorders. In this study we have reviewed the final pathological diagnosis of 106 patients with IgM paraproteinemia investigated in our laboratories between April 1993 and May 1999. In 22 of the 106 patients (20.8%), there was no clinical or laboratory evidence of an underlying lymphoproliferative disorder, and a diagnosis of monoclonal gammopathy of undetermined significance (MGUS) was therefore made. In 60 cases (56.6%), a diagnosis of WM was made, while in the remaining 24 patients, the final diagnosis was chronic lymphocytic leukemia (n = 10), diffuse large B-cell lymphoma (n = 5), extranodal marginal-zone lymphoma (n = 3), follicular lymphoma (n = 3), and mantle-cell lymphoma (n = 3). The median paraprotein concentration in patients with WM, MGUS, and "other" lymphoproliferative disorders was 13 g/L (range, 2-54), 6 g/L (range, 3-30), and 4.5 g/L (range, 3-61), respectively. It is clear that IgM paraproteins are demonstrable in all subtypes of peripheral B-cell disorders and, although paraprotein concentrations are generally higher in WM, there is considerable overlap. Immunophenotypic criteria are therefore essential for the accurate diagnosis of WM.

Adult↗
PubMed1999

FICTION-TSA analysis of the B-cell compartment in myeloma shows no significant expansion of myeloma precursor cells.

Studies utilizing flow cytometry and PCR have shown that the B-cell compartment in myeloma contains cells which are clonally related to the myelomatous plasma cells. Current data, however, remains inconclusive regarding the extent of this involvement. By combining fluorescent immunophenotyping, tyramine signal amplification and fluorescence in-situ hybridization (FICTION-TSA), we have used the presence of numerical chromosomal abnormalities within plasma cells as a clonal marker to examine the CD20+ B-cell compartment for the presence of aneuploidy. A series of 54 cases of myeloma were screened for the presence of numerical abnormalities of chromosomes 3 and 11. FICTION-TSA was performed on 13 cases with either trisomy 3 or 11 and on a control group of six cases known to be disomic for the two chromosomes. B-cell numbers were reduced in the myeloma cases compared to the normal controls (median 1.8% v 3.0%, P = 0.05). In the cases with a chromosomal marker, three signals were seen in a median of 1.88% of CD20+ B cells compared to 2.58% within the control group. Comparison of the two groups using a Wilcoxon-Mann-Whitney U test showed no statistical significant difference. Using this data set, it was possible to exclude a 3.03% expansion of clonally related B cells (95% confidence level). We conclude that the B-cell compartment in myeloma does not represent the major site of clonal expansion, and if clonally related cells are present then the numbers are few.

Aneuploidy↗
PubMed1998

The development of haematopathology laboratories: a possible model for other pathology services.

The diagnosis of haematological malignancies has undergone major conceptual changes in the past decade. Accurate diagnosis now depends on a combination of morphological examination, cell marker studies, and molecular biological techniques. Specialist haematopathology diagnostic services are best provided in an integrated laboratory, able to carry out the full range of techniques and staffed by pathologists and scientists with expertise in the investigation of leukaemia and lymphoma.

England↗