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Biomedical subjects

T Andrew Lister

Publications and source records attributed to T Andrew Lister.

At least 19 recordsLinked to original sources
PubMed2006

Number of CD4+ cells and location of forkhead box protein P3-positive cells in diagnostic follicular lymphoma tissue microarrays correlates with outcome.

PURPOSE: To examine the immune microenvironment in diagnostic follicular lymphoma (FL) biopsies and evaluate its prognostic significance. PATIENTS AND METHODS: Immunohistochemistry was used to study numbers and location of cells staining positive for immune cell markers CD4, CD7, CD8, CD25, CD68, forkhead box protein P3 (FOXP3), T-cell intracellular antigen-1, and Granzyme B in tissue microarrays of paraffin-embedded, diagnostic lymph node biopsies taken from 59 FL patients who lived less than 5 years (short-survival group; n = 34) and more than 15 years (long-survival group; n = 25). RESULTS: CD4 and FOXP3 expression were significantly different between the two groups. Samples from the long-survival group were more likely than those from the short-survival group to have CD4+ staining cells and to have FOXP3-positive cells in a perifollicular location. CONCLUSION: This study has identified differences in immune cell composition of the diagnostic FL lymph node immune microenvironment and these have the potential for use as prognostic biomarkers in a routine histopathology setting.

CD4-Positive T-Lymphocytes↗
PubMed2006

Multicenter phase II trial of immunotherapy with the humanized anti-CD22 antibody, epratuzumab, in combination with rituximab, in refractory or recurrent non-Hodgkin's lymphoma.

PURPOSE: A multicenter, single-arm study examining efficacy and toxicity of epratuzumab combined with rituximab was conducted in patients with recurrent or refractory non-Hodgkin's lymphoma. PATIENTS AND METHODS: Sixty-five patients were enrolled; 34 patients with follicular lymphoma (FL), 15 patients with diffuse large B-cell lymphoma (DLBCL), and 16 patients with other lymphomas. The patients had received a median of two prior therapies (range, 1 to 4); 23% had received rituximab. Epratuzumab was given at 360 mg/m2 intravenously over 60 minutes followed by infusion of 375 mg/m2 rituximab, weekly for 4 consecutive weeks. RESULTS: Combination therapy was well tolerated without greater toxicity than rituximab alone. The objective response (OR) rate was 47% (30 of 64) in assessable patients (46%; 30 of 65 in all patients), being highest in FL (64%; 21 of 33) and DLBCL (47%; seven of 15), and with 24% (eight of 33) and 33% (five of 15) achieving complete response (CR) or complete response unconfirmed (CRu) in these two groups, respectively. Two of six patients with marginal zone lymphoma responded to treatment (one CR). There was a trend for the response rates to be higher in patients with low prognostic index scores (statistically significant with respect to the Follicular Lymphoma International Prognostic Index score in FL patients), with 12 FL patients and three DLBCL patients in groups 0 to 1 having OR (CR/CRu) rates of 83% (33%) and 100% (100%), respectively. The median duration of response was 16 months for FL, with five patients currently progression free for 18 months to 30 months, and 6 months for DLBCL, with two patients currently progression free for 12 months and 18 months. CONCLUSION: Epratuzumab combined with rituximab was well tolerated, demonstrating promising antilymphoma activity that warrants additional study.

Adult↗
PubMed2006

Bortezomib therapy in patients with relapsed or refractory lymphoma: potential correlation of in vitro sensitivity and tumor necrosis factor alpha response with clinical activity.

PURPOSE: To determine the efficacy of bortezomib in patients with lymphoid malignancy, correlating clinical response with effect on plasma cytokines and in vitro activity in primary cultures. PATIENTS AND METHODS: Patients received bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11 of a 3-week cycle. Plasma tumor necrosis factor alpha (TNF-alpha) and interleukin-6 were measured before each treatment, and bortezomib activity was examined in patient samples grown in primary culture. RESULTS: Fifty-one patients received a total of 193 cycles of treatment. Twenty-four patients had mantle cell lymphoma (MCL), 13 had follicular lymphoma (FL), six had lymphoplasmacytic lymphoma, six had Hodgkin's disease (HD), and one each had diffuse large B-cell lymphoma and adult T-cell leukemia/lymphoma. Patients were heavily pretreated with a median of four previous therapies. Significant grade 3 to 4 toxicities were thrombocytopenia (n = 22), fatigue (n = 10), and peripheral neuropathy (n = 3). Seven patients with MCL responded to treatment (one complete response, six partial responses [PRs]; overall response rate, 29%). Two patients with FL achieved a late PR 3 months after discontinuing therapy. Two patients with Waldenström's macroglobulinemia and one patient with HD achieved a PR. MCL primary cultures demonstrated greater sensitivity to bortezomib than FL (median 50% effective concentration for viability, 209 nmol/L v 1,311 nmol/L, respectively; P = .07), which correlated with clinical response. A median reduction in plasma TNF-alpha of 98% was observed in six patients with MCL who responded to bortezomib compared with a reduction of 38% in six nonresponders (P = .07). CONCLUSION: Bortezomib demonstrates encouraging efficacy in MCL in heavily pretreated individuals. Response was associated with a reduction in plasma TNF-alpha and in vitro sensitivity in a small number of patients.

Adult↗
PubMed2005

AML engraftment in the NOD/SCID assay reflects the outcome of AML: implications for our understanding of the heterogeneity of AML.

The nonobese diabetic/severe combined immunodeficient (NOD/SCID) assay is the current model for assessment of human normal and leukemic stem cells. We explored why 51% of 59 acute myeloid leukemia (AML) patients were unable to initiate leukemia in NOD/SCID mice. Increasing the cell dose, using more permissive recipients, and alternative tissue sources did not cause AML engraftment in most previously nonengrafting AML samples. Homing of AML cells to the marrow was the same between engrafters and nonengrafters. FLT3 internal tandem duplication (ITD) and nucleophosmin mutations occurred at a similar frequency in engrafters and nonengrafters. The only variable that was related to engraftment ability was the karyotypically defined risk stratification of individual AML cases. Of interest, follow-up of younger patients with intermediate-risk AML revealed a significant difference in overall survival between NOD/SCID engrafting and nonengrafting AMLs. Hence, the ability of AML to engraft in the NOD/SCID assay seems to be an inherent property of AML cells, independent of homing, conditioning, or cell frequency/source, which is directly related to prognosis. Our results suggest an important difference between leukemic initiating cells between engrafting and nonengrafting AML cases that correlates with treatment response.

Age Factors↗
PubMed2005

Association between acquired uniparental disomy and homozygous gene mutation in acute myeloid leukemias.

Genome-wide single nucleotide polymorphism analysis has revealed large-scale cryptic regions of acquired homozygosity in the form of segmental uniparental disomy in approximately 20% of acute myeloid leukemias. We have investigated whether such regions, which are the consequence of mitotic recombination, contain homozygous mutations in genes known to be mutational targets in leukemia. In 7 of 13 cases with uniparental disomy, we identified concurrent homozygous mutations at four distinct loci (WT1, FLT3, CEBPA, and RUNX1). This implies that mutation precedes mitotic recombination which acts as a "second hit" responsible for removal of the remaining wild-type allele, as has recently been shown for the JAK2 gene in myeloproliferative disorders.

Acute Disease↗
PubMed2005

A novel K509I mutation of KIT identified in familial mastocytosis-in vitro and in vivo responsiveness to imatinib therapy.

KIT mutation has been implicated in sporadic mastocytosis, yet clusters in only a few sites in the molecule. For those malignancies associated with KIT mutation or over-expression, imatinib offers a specific therapeutic option, yet it has no effect on D816V mutation commonly seen in sporadic mastocytosis. The majority of cases of familial mastocytosis seem to lack KIT mutation. We report a kindred with mastocytosis in whom in vitro and in vivo sensitivity to imatinib was demonstrated. Mutation analysis of the KIT coding region in this family identified a novel A>T mutation at nucleotide 1547 [K509I] in exon 9 in both of the affected patients.

Antineoplastic Agents↗
PubMed2005

Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia.

Human hematopoietic stem cells (HSCs) are generally regarded as being devoid of the markers expressed by differentiated blood cells, the lineage-specific antigens. However, recent work suggests that genes associated with the myeloid lineage are transcribed in mouse HSCs. Here, we explore whether myeloid genes are actually translated in human HSCs. We show that CD33, CD13, and CD123, well-established myeloid markers, are expressed on human long-term repopulating cells from cord blood and bone marrow. In addition, we demonstrate that nonobese diabetic/severe combined immunodeficiency (NOD/SCID) leukemia-initiating cells (SL-ICs) are restricted to the CD33+ fraction in 11 of 12 acute myeloid leukemia (AML) samples studied, indicating that leukemic stem cells (LSCs) express this antigen. This study changes our view of HSCs and the process of differentiation. Furthermore, based on the phenotypic similarity of HSCs and LSCs, our data provide support for the hypothesis that AML derives from an HSC. Our findings also provide a challenge to contemporary attempts to improve the outcome of AML using myeloid antigen-targeted therapies, given the potential for HSC killing.

Animals↗
PubMed2005

Genome-wide single nucleotide polymorphism analysis reveals frequent partial uniparental disomy due to somatic recombination in acute myeloid leukemias.

Genome-wide analysis of single nucleotide polymorphisms in 64 acute myeloid leukemias has revealed that approximately 20% exhibited large regions of homozygosity that could not be accounted for by visible chromosomal abnormalities in the karyotype. Further analysis confirmed that these patterns were due to partial uniparental disomy (UPD). Remission bone marrow was available from five patients showing UPD in their leukemias, and in all cases the homozygosity was found to be restricted to the leukemic clone. Two examples of UPD11p were shown to be of different parental origin as indicated by the methylation pattern of the H19 gene. Furthermore, a previously identified homozygous mutation in the CEBPA gene coincided with a large-scale UPD on chromosome 19. These cryptic chromosomal abnormalities, which seem to be nonrandom, have the characteristics of somatic recombination events and may define an important new subclass of leukemia.

Acute Disease↗
PubMed2005

Lymphoma metastasizing to the pituitary: an unusual presentation of a treatable disease.

Lymphoma involving the pituitary gland is particularly rare. We present two cases of patients with pituitary lymphoma, both of whom were symptomatic from pituitary dysfunction. The first patient demonstrated pituitary involvement on imaging, with mild biochemical diabetes insipidus but clear hypoadrenalism. Both adrenals were grossly enlarged on CT scanning and biopsy of one of the adrenal masses confirmed the diagnosis of diffuse large B cell lymphoma. The second patient presented with clinical diabetes insipidus but with no obvious abnormalities on pituitary imaging. CT scanning of abdomen and pelvis, however, revealed widespread lymphadenopathy. Lymph node biopsy revealed a T cell-rich B cell lymphoma. Review of the English-language literature of all published cases of pituitary lymphoma in the presence of generalised disease in immunocompetent patients revealed 13 cases. Most patients had large B cell non-Hodgkin's lymphoma. Involvement of the anterior lobe of the pituitary was more frequently seen than in patients developing pituitary metastases from solid tumour primaries. Patients with advanced lymphoma including the pituitary also appear to have a better prognosis than patients presenting with pituitary metastases. This is an important diagnosis to make as rapidly as possible to allow the early institution of effective therapy.

Diabetes Insipidus↗
PubMed2005

The clinical course of follicular lymphoma.

Follicular lymphoma serves as a paradigm for the other subtypes of non-Hodgkin's lymphoma previously collectively known as 'indolent' or 'low-grade'. As such, its clinical course (that is, the natural history as influenced by conventional therapy) can act as a useful baseline against which the efficacy of new approaches may be assessed. The illness is characterised by repeated responsiveness to treatment but typically this is transient and incomplete. Death occurs at a median of 9-10 years after diagnosis, generally as a consequence of resistant disease, transformation to diffuse large B cell pathology or as a result of side effects of therapy. It has been demonstrated that there is no survival advantage associated with starting treatment prior to there being a clinical need to do so. It is hoped that the advent of new treatment modalities will alter the inexorable pattern of recurrence.

Cell Transformation, Neoplastic↗
PubMed2005

Secondary central nervous system lymphoma: risk factors and prophylaxis.

Patients diagnosed with diffuse large-cell lymphoma, peripheral T-cell non-Hodgkin's lymphoma or mantle cell lymphoma (either with a high serum lactate dehydrogenase level), more than one extranodal site, or who are a high risk according to the international Prognostic Index, should receive central nervous system prophylaxis either with intrathecal or high-dose systemic chemotherapy. The appropriateness of the same prophylaxis at relapse needs to be addressed in further studies.

Antibiotics, Antineoplastic↗
PubMed2005

Development of a human acute myeloid leukaemia screening panel and consequent identification of novel gene mutation in FLT3 and CCND3.

A study was undertaken to develop an acute myeloid leukaemia (AML) screening panel to uncover novel recurring gene mutations. Analysis was performed on six genes known to be mutated in AML (RUNX1, FLT3, KIT, CEBPA, PTPN11 and NRAS) and an additional two candidate genes (CCND3 and FES) in a panel of 175 primary human AML samples that included all French-American-British types except M3, and all cytogenetic risk groups. One hundred and fifteen mutations were identified in 97 (55%) patients comprising 81 patients (46%) with one mutation, 14 patients (8%) with two mutations and two patients (1%) with three mutations. Fifty-five of 88 (63%) patients with normal karyotype AML had at least one mutation. Correlation was observed between KIT mutation and 'favourable risk' cytogenetics (P <0.001), CEBPA mutation and 'intermediate risk' cytogenetics (P=0.045), and PTPN11 mutation and 'poor risk' disease (P <0.001). The frequency of individual gene mutation was in accordance with previously published studies. Three novel mutations of FLT3 were detected (Y589D, D839G, Y842H) that would have been overlooked by conventional gel electrophoresis. A 51-bp deletion was detected in CCND3 in a patient with normal karyotype AML. This validated panel now provides an important tool to evaluate other candidate genes in the genesis of myeloid malignancy.

Acute Disease↗
PubMed2005

Molecular diagnosis of lymphoma: outcome prediction by gene expression profiling in diffuse large B-cell lymphoma.

This chapter describes the illness diffuse large B-cell lymphoma (DLBCL) and why research has and continues to focus on creating accurate predictors of response to treatment to allow individual risk assessment for a patient and individualization of treatment choice to maximize the chances of cure. Microarray technology has the promise to bring these objectives within reach. The first papers attempting to identify molecular signatures of response and outcome using microarray technology were generated using DLBCL samples and are described. The different types of microarray platform and data analysis tools are reviewed followed by a detailed step-by-step guide to data generation using the Affymetrix chip system from RNA extraction to laser scanning of the hybridized and stained chips.

Artificial Intelligence↗
PubMed2004

Mutation of CEBPA in familial acute myeloid leukemia.

We describe a family in whom three members affected by acute myeloid leukemia (AML) had an identical, 212delC mutation in CEBPA, the gene encoding the granulocytic differentiation factor C/EBPalpha. Unaffected family members did not have this mutation. Latent periods of 10, 18, and 30 years elapsed before the onset of overt leukemia in the three patients. One of them had a second CEBPA mutation, but only at the time of diagnosis. All three patients are currently well, with no abnormalities in the bone marrow. CEBPA mutation is apparently the primary event in the development of AML in this family.

Adolescent↗
PubMed2004

Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells.

BACKGROUND: Patients with follicular lymphoma may survive for periods of less than 1 year to more than 20 years after diagnosis. We used gene-expression profiles of tumor-biopsy specimens obtained at diagnosis to develop a molecular predictor of the length of survival. METHODS: Gene-expression profiling was performed on 191 biopsy specimens obtained from patients with untreated follicular lymphoma. Supervised methods were used to discover expression patterns associated with the length of survival in a training set of 95 specimens. A molecular predictor of survival was constructed from these genes and validated in an independent test set of 96 specimens. RESULTS: Individual genes that predicted the length of survival were grouped into gene-expression signatures on the basis of their expression in the training set, and two such signatures were used to construct a survival predictor. The two signatures allowed patients with specimens in the test set to be divided into four quartiles with widely disparate median lengths of survival (13.6, 11.1, 10.8, and 3.9 years), independently of clinical prognostic variables. Flow cytometry showed that these signatures reflected gene expression by nonmalignant tumor-infiltrating immune cells. CONCLUSIONS: The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.

Adult↗