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Gordon W Dewald

Publications and source records attributed to Gordon W Dewald.

At least 55 records · Page 3Linked to original sources
PubMed2003

Comparison of interphase FISH and metaphase cytogenetics to study myelodysplastic syndrome: an Eastern Cooperative Oncology Group (ECOG) study.

Cytogenetic analysis can be important in determining the prognosis and diagnosis of a number of hematological disorders, including myelodysplastic syndromes (MDS). Here, we compared metaphase chromosomal analyses on bone marrow aspirates from MDS patients with interphase fluorescence in situ hybridization (FISH) using probes specific for chromosomes nos. 5, 7, 8, 11, 13 and 20. Forty-three patients enrolled in ECOG protocol E1996 for low risk MDS and five patients enrolled in ECOG protocol E3996 for high risk MDS were studied by both metaphase chromosomal analysis and interphase FISH. Excluding those with a clonal loss of the Y chromosome, an abnormal clone was detected by cytogenetic analysis in 18 of 48 samples (37.5%). In comparison, our FISH panel detected an abnormal clone in 17 of 48 samples (35.4%). Twenty-nine of 30 samples with apparently normal karyotypes, including those with a missing Y chromosome, were also normal by our FISH panel. One patient had an occult deletion of chromosome 11 that was detected by FISH. These results indicate that around 60% of patients with MDS do not have abnormalities that are detectable by either chromosomal or FISH studies. In addition, it appears that interphase FISH studies are nearly as sensitive as cytogenetic analyses and can be a useful tool in studying bone marrow aspirates where cytogenetic analysis is not possible.

Antineoplastic Agents↗
PubMed2003

New highly sensitive fluorescence in situ hybridization method to detect PML/RARA fusion in acute promyelocytic leukemia.

We investigated a new fluorescence in situ hybridization (FISH) method to detect PML/RARA fusion and/or anomalies of the RARA gene (alias RARalpha) in interphase nuclei from patients with acute promyelocytic leukemia (APL). This method uses a commercially available product with two different colored fluorescent probes to detect both PML/RARA gene fusion products (double fusion signal or dual-color fluorescence in situ hybridization [D-FISH]). A total of 82 bone marrow specimens were studied, including 30 from normal bone marrow transplant donors, 33 from patients with untreated APL, 14 from patients with treated APL, and 5 from APL patients with known translocation variants or alternate translocations. The signal patterns and percentage of abnormal nuclei were determined in a blinded study on 500 interphase nuclei for each specimen. Based on 25 normal specimens, the normal cutoff was >0.6% and >1.6% for t(15;17) and t(17;var), respectively. The clinical sensitivity for this series of patients was 98% and the clinical specificity was 100%. The results suggest that the new D-FISH probe set can detect all t(15;17)(q22;q21) and all variant forms of this translocation associated with PML and RARA. In addition, this FISH method can detect all alternate translocations involving RARA and not PML. This FISH method can be used both for the accurate diagnosis of APL and to monitor low levels of disease in treated patients.

Bone Marrow Cells↗
PubMed2003

Cytogenetics of chronic myeloproliferative disorders and related myelodysplastic syndromes.

The only MPD associated with any specific chromosome anomaly is CML, which is linked with t(9;22)(q34;q11.2) or a variant of this anomaly. An association exists for del(13)(q12q14) and CIMF; t(5;12)(q33;p13) and CEL; and del(20q11), +8, and +9 and PV, but these anomalies can be seen in various hematologic malignancies. The most common chromosomal anomalies among MPD in order of frequency are t(9;22)(q34;q11.2), -Y, +8, +9, -7, del(20) (q11q13), del(13)(q12q14), del(5)(q13q33), and del(12)(p12). FISH techniques are useful for MPD to study inadequate bone marrow or blood specimens and to monitor disease status among patients with known chromosome anomalies, but they are not more sensitive than conventional chromosome studies.

Chromosome Aberrations↗
PubMed2003

Chromosome anomalies detected by interphase fluorescence in situ hybridization: correlation with significant biological features of B-cell chronic lymphocytic leukaemia.

Fluorescence in situ hybridization (FISH) was used to detect 6q-, 11q-, +12, 13q-, 17p- and translocations involving 14q32 in interphase nuclei from blood and/or bone marrow from 113 patients with B-cell chronic lymphocytic leukaemia (B-CLL). A total of 87 patients (77%) had a FISH anomaly: 13q- x 1 was most frequent (64%) followed by 13q- x 2 (28%), +12 (25%), 11q- (15%), 17p- (8%) and 6q- (0%). FISH results for blood and bone marrow cells in 38 patients were similar. Purified CD5+/CD19+ cells from blood were studied in eight patients and results indicate that in some patients not all B cells have FISH anomalies. We used a defined set of hierarchical FISH risk categories to compare FISH results by stable versus progressive disease, age, sex, Rai stage, CD38+ expression and IgVH mutational status. Significant differences in FISH risk distributions were associated with Rai stage, disease status and CD38+, but not by age, sex or IgVH mutational status. To look for baseline factors associated with high-risk disease, multivariate analysis of age, sex, Rai stage, CD38+ and disease status versus FISH risk category was performed. Importantly, only CD38+ was significantly associated with high-risk FISH categories (+12, 11q- and 17p-) after adjustment for the effects of other variables.

ADP-ribosyl Cyclase↗
PubMed2002

Both B and T lymphocytes may be clonally involved in myelofibrosis with myeloid metaplasia.

A combination of magnetic cell sorting (MACS) and fluorescent in situ hybridization (FISH) techniques was used to detect clonal cytogenetic markers in different myeloid and lymphoid cell types of the peripheral blood from 4 patients with myelofibrosis with myeloid metaplasia (MMM) that was associated with either a 13q- or a 20q- karyotypic abnormality. Interphase cytogenetics studies demonstrated abnormal clonal FISH signal patterns in neutrophil, myeloid, erythroid, megakaryocyte, and B- and T-cell preparations in 3 of the 4 patients. In one patient, FISH results were within normal limits in T cells and slightly abnormal in B cells. In general, the percentage of abnormal nuclei was variable in both lymphocyte populations but always higher in B lymphocytes compared with T lymphocytes. The current study provides direct evidence for the clonal involvement of both B and T lymphocytes in MMM. A larger study is needed to clarify the relevance of the observed interpatient heterogeneity in clonal constitution.

Antigens, CD↗
PubMed2002

Genomic abnormalities in monoclonal gammopathy of undetermined significance.

Translocations involving immunoglobulin (Ig) loci and chromosome 13 monosomy (Delta 13) are frequent cytogenetic findings in multiple myeloma (MM). Similar chromosomal aberrations have been identified in the monoclonal gammopathy of undetermined significance (MGUS), but their prevalence and significance remain uncertain. Bone marrow from 72 patients with MGUS (n = 62) and smoldering MM (n = 10) was evaluated for translocations between the Ig heavy chain (IgH) and chromosomes 4, 11, and 16, translocations involving Ig light chain-lambda (IgL-lambda, and Delta 13. Fluorescence in situ hybridization (FISH) analysis was done on clonal plasma cells (PCs) detected by immunofluorescence (cIg-FISH) of the cytoplasmic light chain. We also studied cells for cyclin D1 and FGFR3 up-regulation by immunohistochemistry and immunofluorescence, respectively. Twenty-seven (46%) of 59 patients had IgH translocations, and 4 (11%) of 37 had an IgL-lambda translocation. A t(11;14)(q13;q32) was found in 15 (25%) of 59 patients, a t(4;14)(p16.3;q32) in 9% of patients, and a t(14;16)(q32;q23) in 5% of patients. All patients with t(4;14)(p16.3;q32) tested (n = 3) had intense cytoplasmic fluorescence with an anti-FGFR3 antibody. PC nuclear staining of cyclin D1 was only observed in patients with t(11;14)(q13;q32); Delta 13 was detected in the clonal PCs in 50% of patients. The percentage of abnormal PCs varied with any given abnormality. No obvious clinical or biologic correlations were associated with these chromosome abnormalities. Similar translocations are found in both MGUS and MM, including t(4;14)(p16.3;q32) and t(14;16)(q32;q23). Moreover, Delta 13 is common in MGUS and unlikely to play a predominant role in the evolution of MGUS to MM.

Aneuploidy↗
PubMed2002

Phase 2 trial of imatinib mesylate in myelofibrosis with myeloid metaplasia.

In a phase 2 study, 23 patients with myelofibrosis with myeloid metaplasia were treated with imatinib mesylate at a constant dose of 400 mg/d. Treatment was held in 16 patients (70%), after 1 to 12 weeks, because of side effects (neutropenia, 6 patients; musculoskeletal pain, 5 patients; thrombocytosis, 4 patients; edema, 3 patients; diarrhea and hyperbilirubinemia, 1 patient). Including patients in whom retreatment at a reduced dose was possible, 11 patients (48%) were able to continue treatment beyond 3 months. None of the patients experienced a response in anemia, and only 2 had partial responses in splenomegaly. A greater than 50% increase in platelet count was documented in 11 (48%) patients, but not in those with baseline platelet counts of less than 100 x 10(9)/L. In vitro, imatinib mesylate caused variable degrees of growth suppression of myeloid and erythroid progenitors that unfortunately did not translate into clinical benefit.

Adult↗
PubMed2002

Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients.

The t(11;14)(q13;q32) results in up-regulation of cyclin D1 and is the most common translocation detected in multiple myeloma, where it is also associated with a lymphoplasmacytic morphology. We performed an interphase fluorescent in situ hybridization (FISH) study to determine the clinical and biologic significance of the abnormality when testing a large cohort of myeloma patients. Bone marrow slides from multiple myeloma patients entered into the Eastern Cooperative Oncology Group phase III clinical trial E9486 and associated laboratory correlative study E9487 were analyzed using interphase FISH combined with immune-fluorescent (cytoplasmic immunoglobulin-FISH) detection of clonal plasma cells. We used FISH probes that hybridize to the 14q32 and 11q13 chromosomal loci. The t(11;14)(q13;q32) was correlated with known biologic and prognostic factors. Of 336 evaluable patients, 53 (16%) had abnormal FISH patterns compatible with the t(11;14)(q13;q32). These patients appeared to be more likely to have a serum monoclonal protein of less than 10 g/L (1 g/dL) (28% vs 15%, P =.029) and a lower plasma cell labeling index (P =.09). More strikingly, patients were less likely to be hyperdiploid by DNA content analysis (n = 251, 14% vs 62%, P <.001). Patients with the t(11;14)(q13;q32) appeared to have better survival and response to treatment, although this did not reach statistical significance. Multiple myeloma with the t(11;14)(q13;q32) is a unique subset of patients, not only characterized by cyclin D1 up-regulation and a lymphoplasmacytic morphology, but is also more frequently associated with small serum monoclonal proteins and is much less likely to be hyperdiploid. These patients do not have a worsened prognosis as previously thought.

Adult↗
PubMed2002

Biological and prognostic significance of interphase fluorescence in situ hybridization detection of chromosome 13 abnormalities (delta13) in multiple myeloma: an eastern cooperative oncology group study.

Chromosome 13 abnormalities (Delta13) have been associated with an unfavorable prognosis in patients with multiple myeloma (MM). The significance of this has been unresolved because of diverse methods of detection and heterogeneous groups of patients. We conducted a study of Delta13 in patients entered into the Eastern Cooperative Oncology Group trial E9486/E9487. Patients with newly diagnosed MM (median follow-up of survivors >100 months) were studied for Delta13, using bone marrow samples obtained at study enrollment. We used interphase fluorescence in situ hybridization with the probes LSI13 (Rb)/D13S319 with simultaneous immunofluorescence detection of bone marrow plasma cells (PCs). We detected Delta13 in 176 of 325 (54%) evaluable patients. Patients with Delta13 were more likely to have a serum monoclonal protein at a concentration < or =1 g/dl (22 versus 13%; P = 0.04), light-chain-only MM (19.3 versus 10.8%; P = 0.04), gamma light chain (42 versus 28%; P = 0.027), stage III (56 versus 42%; P = 0.014), and be female (60 versus 50%; P = 0.087). The PC labeling index and Delta13 correlated (P = 0.03). Patients with Delta13 were less likely to respond to treatment (74 versus 63%; P = 0.041) and had a significantly shorter median overall survival (34.9 versus 51 months; P = 0.021). The association of Delta13 and survival remained an independent prognostic variable in a regression model. Among patients with Delta13, those receiving IFN had a worse overall survival that those not receiving the medication (P = 0.03). The presence of Delta13 is an important and independent adverse prognostic factor in newly diagnosed MM and is associated with specific biological features.

Adult↗
PubMed2002

Cytogenetic and FISH studies in myelodysplasia, acute myeloid leukemia, chronic lymphocytic leukemia and lymphoma.

Conventional cytogenetic studies are widely used today to diagnose and manage patients with hematological malignancies. The application of fluorescence in situ hybridization (FISH) with chromosome-specific DNA probes helps to further define molecular subclasses and cytogenetic risk categories for patients with these disorders. Moreover, FISH permits analysis of proliferating (metaphase cells) and non-proliferating (interphase nuclei) cells, and is useful in establishing the percentage of neoplastic cells before and after therapy (minimal residual disease). For patients with myelodysplasia or acute myeloid leukemia, these chromosome techniques are important for accurate diagnosis and classification of disease and to help decide treatment and monitor response to therapy. Conventional cytogenetic studies have been problematic in chronic lymphocytic leukemia because the neoplastic cells divide infrequently. However, interphase FISH studies now permit detection of chromosome anomalies with prognostic significance in chronic lymphocytic leukemia. The World Health Organization recognizes that genetic anomalies are one of the most reliable criteria for classification of malignant lymphomas. New methods to extract individual nuclei from paraffin-embedded tissue are now available which permit the use of interphase FISH to detect important chromosome anomalies in lymphoma.

Acute Disease↗
PubMed2002

A new method to extract nuclei from paraffin-embedded tissue to study lymphomas using interphase fluorescence in situ hybridization.

Fluorescence in situ hybridization (FISH) is difficult to accomplish using thin-sections of paraffin-embedded lymphoid tissue because of the high cellularity and truncated cells that interfere with accurate scoring of individual nuclei. We modified and tested a new technique to isolate individual nuclei from tissue cores of paraffin-embedded tissue processed with xylene, proteinase K, citric acid, and pepsin. The efficacy of this method to study paraffin-embedded tissue was investigated in six normal lymph nodes or tonsils and 32 malignant lymphomas including five mantle cell, five follicular, five Burkitt, five extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue, five anaplastic large-cell, and seven diffuse large B-cell. Fusion of CCND1 and IgH, BCL2 and IgH, c-myc and IgH, and MALT1 and API2 were detected using probes with a dual-fusion FISH strategy. Anomalies involving ALK and BCL6 were detected using break-apart FISH probes. FISH studies were successful for each of the 38 specimens. Chromosome anomalies were detected in each malignant specimen, but not in the normal lymphoid tissue. The correct chromosome anomaly was detected in 22 of 22 specimens with genetic abnormalities that were established by other genetic techniques. This FISH technique is useful to detect chromosome anomalies with high sensitivity and specificity in paraffin-embedded tissue and may provide important diagnostic and prognostic genetic information.

Burkitt Lymphoma↗
PubMed2002

Mucosa-associated lymphoid tissue lymphomas with t(11;18)(q21;q21) and mucosa-associated lymphoid tissue lymphomas with aneuploidy develop along different pathogenetic pathways.

t(11;18)(q21;q21) and aneuploidy are recurrent chromosomal aberrations in mucosa-associated lymphoid tissue (MALT) lymphomas. To investigate their relationship and clinical significance, we developed a two-color fluorescence in situ hybridization (FISH) technique to detect t(11;18) and aneuploidy in nuclei isolated from paraffin-embedded tissue. Thirty-seven MALT lymphomas (all previously evaluated for t(11;18) by reverse transcriptase-polymerase chain reaction), 1 large cell lymphoma (LCL) arising subsequent to MALT lymphoma, and 16 controls were tested by FISH using the t(11;18) probe set and multiple centromeric probes. t(11;18)(q21;q21) was present by FISH in 11 of 12 polymerase chain reaction-positive MALT lymphomas (92%). The LCL and its clonally identical antecedent MALT lymphoma both showed t(11;18). The LCL had trisomy 12, and a small subset of MALT lymphoma cells had trisomy 3 and/or 12. Only one other MALT lymphoma with t(11;18) showed aneuploidy (trisomy 3) in a small clone, whereas 15 of 25 t(11;18)-negative MALT lymphomas (60%) showed trisomy of chromosomes 18 (n = 12), 3 (n = 8), 7 (n = 2), and/or 11 (n = 1). t(11;18) and aneuploidy are primarily mutually exclusive events, suggesting different pathogenetic pathways in the development of MALT lymphomas. Both t(11;18) and aneuploidy were seen disproportionately in lung, and both were associated with recurrent disease.

Adult↗
PubMed2002

Primary myelodysplastic syndrome with normal cytogenetics: utility of 'FISH panel testing' and M-FISH.

The myelodysplastic syndromes (MDS) are a clinically heterogeneous group of hematologic disorders. Cytogenetic analysis is crucial as it can provide both diagnostic and prognostic information. Herein, 32 cytogenetically normal patients with primary MDS were analyzed both by multiple FISH probes on interphase nuclei (FISH panel testing) and by M-FISH (metaphase nuclei). One patient had a chromosome 13q-arm deletion, while the remaining 31 patients had normal results. These findings confirm standard cytogenetics as an excellent technique in identifying the common chromosomal abnormalities associated with MDS and suggest limited utility for either a FISH panel test or M-FISH in primary MDS.

Anemia, Refractory, with Excess of Blasts↗
PubMed2002

Correlation of three methods of measuring cytogenetic response in chronic myelocytic leukemia.

Change in proportion of metaphases with a Ph chromosome is often used to measure effect of treatment in chronic myelocytic leukemia, but this method requires analysis of dividing cells. Dual-color fluorescence in situ hybridization (D-FISH) analysis of bone marrow (BM) or blood (PB), can be used to establish the proportion of interphase nuclei with BCR/ABL fusion. We studied the correlation of these three measures with each other and with response classification categories. In a clinical trial to test rIFN(-) versus rIFN(-) +Ara-C (N = 65 patients), we defined for each cytogenetic and FISH parameter, the patient's "best response" over time and at any given time. The strength and nature of agreement among the three measurements were determined by regression, correlation, and kappa statistic. Correlations between cyBM versus D-FISH-BM, cyBM versus D-FISH-PB and D-FISH-BM vs. D-FISH-PB were fairly strong. Regression showed cyBM values were significantly higher than those of D-FISH-PB or D-FISH-BM. No difference between D-FISH-PB and D-FISH-BM was apparent. When numerical responses (BR%) were classified into response categories (CR, PR, MR, NR), levels of agreement were weak to moderate. We observed a trend toward disagreement between cyBM and each D-FISH method, with cyBM tending to "downgrade" response category. Whether analyzed using actual numerical values or classified into response categories, cyBM differed from D-FISH-BM or D-FISH-PB. The results indicate that mixing data of different methods to measure treatment response within or between patients may be misleading clinical index.

Bone Marrow Cells↗
PubMed2002

The prognostic significance of trisomy 8 in patients with acute myeloid leukemia.

Recent therapeutic outcomes for patients with acute myeloid leukemia and trisomy 8 (+8) who were seen at our institution were investigated. Complete remission was achieved in 85% with isolated +8, 100% with +8 and chromosomal abnormalities predictive of a favorable outcome, and 47% of patients with +8 and other, mostly complex chromosomal abnormalities. Median relapse-free and overall survivals in months were 5.5 and 12 (isolated +8), 20 and 25 (+8 and favorable karyotype), and 7.5 and 6 (+8 and unfavorable karyotype). Despite an encouraging rate of complete remission, the relapse-free and overall survivals for patients with isolated +8 were not significantly different from those of patients with +8 and unfavorable karyotypes. The presence of +8 did not appear to adversely affect the outcome of patients with favorable karyotypes.

Acute Disease↗
PubMed2002

Chronic lymphocytic leukemia.

This update of early stage B-cell chronic lymphocytic leukemia (B-CLL) embraces current information on the diagnosis, biology, and intervention required to more fully develop algorithms for management of this disease. Emphasis on early stage is based on the rapid advancement in our understanding of the disease parameters and our increasing ability to predict for a given early stage patient whether there is a need for more aggressive management. In Section I, Dr. Terry Hamblin addresses the nature of the disease, accurate diagnostic procedures, evidence for an early "preclinical" phase, the use of newer prognostic features to distinguish who will be likely to progress or not, and whether it is best to watch or treat early stage disease. In Section II, Dr. Neil Kay and colleagues address the biologic aspects of the disease and how they may relate to disease progression. Review of the newer insights into gene expression, recurring genetic defects, role of cytokines/autocrine pathways, and the interaction of the CLL B cell with the microenvironment are emphasized. The relationship of these events to both trigger disease progression and as opportunities for future therapeutic intervention even in early stage disease is also considered. In Section III, Dr. John Byrd and colleagues review the historical and now current approaches to management of the previously untreated progressive B-CLL patient. They discuss what decision tree could be used in the initial decision to treat a given patient. The use of single agents versus newer combination approaches such as chemoimmunotherapy are discussed here. In addition, the place of marrow transplant and some of the newer antibodies available for treatment of B-CLL are considered. Finally, a challenge to utilize our growing knowledge of the biology of B-CLL in the early stage B-CLL is proffered.

Antineoplastic Agents↗
PubMed2002

Primer on medical genomics part I: History of genetics and sequencing of the human genome.

In comparison with most other disciplines of science, the field of genetics is still in its youth. The majority of scientific work in genetics has been done in the past 150 years. The successful preliminary sequencing of the human genome was announced in 2001. Nonetheless, interest in heredity and in other concepts within the field of genetics has existed since the beginning of humanity. This article provides an account of the history of genetics, spanning from humankind's initial attempts to understand and influence heredity, to the early scientific work in the field of genetics, and subsequently to the advancements in modern genetics. Additionally, the Human Genome Project is summarized, from inception to publication of the 'first draft" of the human genome sequence.

Forecasting↗