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G W Dewald

Publications and source records attributed to G W Dewald.

At least 37 records · Page 2Linked to original sources

Fish demonstrates treatment-related chromosome damage in myeloid but not plasma cells in primary systemic amyloidosis.

Conventional cytogenetic analysis is limited in the evaluation of plasma cell disorders because, relative to normal hematopoietic elements, plasma cells divide slowly. Moreover, it is difficult to know whether abnormal metaphases originate from malignant plasma cells or myeloid cells harboring other abnormalities. We studied a patient with primary systemic amyloidosis who had previously been treated with an alkylating agent. Bone marrow cells were analyzed by cytoplasmic-immunoglobulin fluorescent staining combined with fluorescent in situ hybridization (cIg-FISH). Both chromosome enumeration probes for chromosome 1 and 7 and loci-specific probes for the short and long arm of chromosome 7 were used. Cytogenetic analysis disclosed the following abnormality: +der(1;7)(q10;p10). On cIg-FISH, the myeloid cells had fusion signals between chromosome enumeration probes for chromosomes 1 and 7, whereas plasma cells had the normal appearance of two pairs of signals. There was a second clone of abnormal myeloid cells with monosomy of chromosome 7. The bone marrow did not show any evidence of myelodysplasia. Interphase cIg-FISH is a useful technique for assigning the lineage of chromosomal abnormalities in plasma cell disorders.

Amyloidosis↗

Cytogenetic abnormalities correlate with the plasma cell labeling index and extent of bone marrow involvement in myeloma.

Chromosomal abnormalities have biologic and prognostic significance in multiple myeloma, especially among patients with relapsed disease. We report the relationship between chromosomal abnormalities and known prognostic factors such as plasma cell labeling index (PCLI) and bone marrow plasma cell involvement in 75 consecutive patients undergoing autologous stem cell transplantation for relapsed or refractory myeloma. Thirty of 70 patients (43%) had a chromosomally abnormal clone in their bone marrow, and in most cases the karyotype was complex (> 3 abnormalities). Patients with an abnormal clone on cytogenetic analysis had a higher PCLI (median, 1.4) than patients with a normal karyotype (0.2) (P < 0.001). Bone marrow plasma cell percentage also differed: median 48% versus 20%, respectively (P < 0.001). The PCLI and bone marrow plasma cell percentage correlated positively with the percentage of abnormal metaphases on conventional cytogenetic analysis: rho 0.60 (P < 0.001) and 0.46 (P < 0.001), respectively. We categorized patients into those with 20% or more abnormal metaphases, less than 20% abnormal metaphases, and only normal metaphases. The median PCLI values were 3.3, 1.1, and 0.3, respectively (P < 0.001). The bone marrow plasma cell percentage median values were 62%, 40%, and 25%, respectively (P = 0.003). Chromosomal abnormalities may offer a proliferative advantage to the neoplastic plasma cell, thereby leading to an unfavorable outcome.

Adult↗

Cytogenetic abnormalities in multiple myeloma.

There is an increasing understanding that chromosomal abnormalities play a major role in the pathogenesis of multiple myeloma. Furthermore, they seem to predict the clinical outcome of patients according to the specific abnormalities detected. It is likely that in the future, knowledge of the cytogenetic composition will be an integral part of the evaluation of myeloma patients.

Chromosome Aberrations↗

Isolated isochromosome 17q: a distinct type of mixed myeloproliferative disorder/myelodysplastic syndrome with an aggressive clinical course.

A clinicopathologic study was performed on 15 patients with haematological malignancies in which isochromosome 17q [i(17q)] was the sole structural chromosome abnormality identified in bone marrow. The data indicated that an isolated i(17q) is associated with a distinct type of mixed chronic myeloproliferative/myelodysplastic disorder with an aggressive clinical course. The patients ranged in age from 37 to 83 years (median 60) with a M:F ratio of 3:1. All cases were chronic myeloid disorders with mixed proliferative and dysplastic features, making classification difficult. 11 patients tested for BCR/ABL gene fusion were normal. A low bone marrow blast count (<5%) at presentation was a typical finding. All cases had severe myeloid dysplasia which included non-segmented neutrophils and an increase in the monocyte/macrophage lineage. Fluorescence in situ hybridization (FISH) analysis of one case showed the i(17q) to involve all myeloid lineages, but not the lymphocytes. For cases with complete follow-up (n = 11) the median survival was 2.5 years (range 0.83-5.25) and 64% progressed to AML prior to death. The following features were identified which defined the haematological disorder associated with an isolated i(17q): (1) adult patient, (2) chronic myeloid disorder with clonal involvement of all myeloid lineages, (3) mixed chronic myeloproliferative/myelodysplastic features, (4) severe hyposegmentation of neutrophil nuclei, (5) prominence of the monocyte/macrophage lineage, (6) high risk for progression to AML, and (7) median survival of 2.5 years.

Adult↗

Atypical BCR and ABL D-FISH patterns in chronic myeloid leukemia and their possible role in therapy.

D-FISH uses DNA probes with fluorescence in situ hybridization to detect two fusion signals in cells with a t(9;22)(q34;q11.2) from patients with chronic myeloid leukemia (CML). Using D-FISH, 147 patients with CML were studied and considerable macro genetic variation was observed among their Ph-chromosomes. Typical D-FISH signal patterns were observed for 81% of patients, but three different atypical patterns were seen in 19% of patients. Atypical patterns among Ph-chromosomes were consistent with loss of the 3' portion of BCR that is usually translocated to chromosome 9, or loss of the 5' segment of ABL that usually remains on chromosome 9, or loss of both the 3' translocated BCR and 5' residual ABL hybridization sites. Atypical patterns were associated with all forms of Ph-chromosomes including t(9;22)(q34;q1.2), complex translocations and masked. The normal range for 500 interphase nuclei for patients with typical patterns is < 1%. By comparison, the normal range for patients with either of two atypical patterns was < or = 1.8% and for patients with the other atypical pattern was < or = 23%. Thus, special scoring criteria are needed to detect and quantify nuclei with atypical patterns using D-FISH. The proportion of patients that responded to therapy with interferon alpha-2b or interferon alpha-2b and ara-C for 36 patients with typical patterns was similar to 7 patients with atypical patterns.

Antineoplastic Combined Chemotherapy Protocols↗

Extensive analysis of mosaicism in a case of Turner syndrome: the experience of 287 cytogenetic laboratories. College of American Pathologists/American College of Medical Genetics Cytogenetics Resource Committee.

OBJECTIVE: To assemble and interpret karyotype data provided as part of the College of American Pathologists/American College of Medical Genetics Cytogenetics Proficiency Testing Program. DATA SOURCES, EXTRACTION, AND SYNTHESIS: The Cytogenetics Resource Committee requested data on all cells analyzed in a 1994 whole-blood specimen challenge. In that study, 287 participating laboratories analyzed a total of 14297 cells derived from a sample drawn from an adult donor with Turner syndrome. This individual had previously been found to have mosaicism, including cell lines with X structural anomalies along with monosomy X, making this an excellent challenge for a multicenter cytogenetic survey. RESULTS AND CONCLUSIONS: Analysis of the data from this extensive study revealed mosaicism of up to 10 different sex chromosome complements involving the X chromosome with and without a small ring X or a derivative X chromosome. In the routine cytogenetic analysis performed by the participating laboratories, cell lines observed, in decreasing order of prevalence, included 45,X (n = 8357 cells), 46,X,r(X) (n = 3597), 46,X,der(X)t(X;X) (n = 2237), 46,XX (n = 93), 47,X,r(X),r(X) (n = 5), 47,X,der (X)t(X;X),der(X)t(X;X) (n = 3), 47,XX,r(X) (n = 2), and one observation each of 47,XX,der(X)t(X;X), 47,X,der(X)t (X;X),r(X), and 47,XXX. Our molecular cytogenetic data, as well as detailed analysis of G-banded chromosomes, suggest the nomenclature for these 2 abnormal X chromosomes as r(X)(p11.3q21.3) and der(X)t(X;X)(p11.3;q21.3), and we discuss models for the concomitant formation of these 2 entities. Both the degree of analysis and the extensive mosaicism that was discovered in this study are exceptional, and similar reported cases as well as possible mechanisms for the observed X chromosome instability are reviewed.

Adult↗

A special fluorescent in situ hybridization technique to study peripheral blood and assess the effectiveness of interferon therapy in chronic myeloid leukemia.

Using a highly sensitive fluorescence in situ hybridization method with probes for BCR and ABL1 (D-FISH), we studied 37 paired sets of bone marrow and blood specimens, collected within 24 to 96 hours of each other, from 10 patients before and during treatment for chronic myeloid leukemia (CML). The normal range for 500 interphase nuclei was </=4 (</=0.8%) nuclei based on 10 bone marrow and 10 blood specimens from normal individuals. The percentage of neoplastic nuclei was usually lower in blood than bone marrow. However, changes in the percentage of neoplastic nuclei in blood and bone marrow tracked closely over the course of therapy and with the results of quantitative cytogenetic studies on bone marrow. This result indicates that D-FISH is useful to test blood from patients with CML to monitor therapy. Moreover, by analysis of 6,000 nuclei with D-FISH, residual disease was identified in bone marrow and blood for patients in complete cytogenetic remission. Consequently, D-FISH analyses of interphase nuclei from blood could substitute for Q-cytogenetic studies on bone marrow. Thus, it may not be necessary to collect bone marrow samples so frequently to monitor therapy in CML.

Antimetabolites, Antineoplastic↗

Highly sensitive fluorescence in situ hybridization method to detect double BCR/ABL fusion and monitor response to therapy in chronic myeloid leukemia.

We investigated a new method using fluorescence in situ hybridization and DNA probes that span the common breakpoints of t(9;22)(q34;q11.2) and that detect double BCR/ABL fusion (D-FISH) in bone marrow cells with this translocation, one on the abnormal chromosome 9 and one on the Philadelphia chromosome (Ph chromosome). D-FISH patterns were abnormal in 30 of 30 specimens with classic, simple, complex, and masked Ph chromosomes. Based on 200 nuclei from each of 30 normal specimens, the mean percentage of false-positive cells was 0.25 +/- 0.39. Thirty-seven specimens from 10 patients were studied before treatment and two or more times at 4-month intervals after treatment with interferon-alpha2b (IFN-alpha2b) with or without ara-C. Based on 200 nuclei, the results of D-FISH in these specimens correlated closely with quantitative cytogenetics and accurately quantified disease within a few percent. We studied 6, 000 nuclei for each of six specimens, three normal and three from patients with chronic myeloid leukemia (CML) in cytogenetic remission. The normal cutoff for 6,000 nuclei was 0.079% and patients in cytogenetic remission had residual disease ranging from 7 (0.117%) to 53 (0.883%) Ph-positive nuclei. We conclude that D-FISH can detect the Ph chromosome and its variant translocations and accurately quantify disease in CML at diagnosis and at all times after treatment, including cytogenetic remission.

Chromosomes, Human, Pair 22↗

Prenatal detection of aneuploidy by directly labeled multicolored probes and interphase fluorescence in situ hybridization.

OBJECTIVE: To detect aneuploidy of chromosomes 13, 18, 21, X, and Y with use of new, directly labeled, multicolored, commercially available DNA probes from interphase cells of amniotic fluid (AF). MATERIAL AND METHODS: The hybridization sites of the five probes were validated by metaphase analysis. The fluorescence in situ hybridization (FISH) normal range was determined from a series of normal AF specimens and tested on a series of normal and abnormal specimens. RESULTS: The hybridization efficiencies of the five probes were 100%. The mean AF interphase disomic signal patterns for chromosomes 13, 18, 21, XX, and XY were 95.9%, 89.1%, 94.3%, 94.7%, and 98.7%, respectively. Of a total of 508 cases analyzed, 211 were aneuploid. All cases were correctly identified and no false results occurred (in comparison with karyotypic analysis), although maternal cell contamination was relatively common. CONCLUSION: Clinical screening for aneuploidy of chromosomes 13, 18, 21, X, and Y from interphase AF cells is possible with use of these probes and FISH. Cases of maternal cell contamination and mosaicism necessitate cautious interpretation. The FISH procedure is recommended for screening of common aneuploidies, followed by a complete chromosome analysis to detect anomalies.

Amniotic Fluid↗

A novel three-color, clone-specific fluorescence in situ hybridization procedure for monoclonal gammopathies.

We have developed a three-color cytoplasmic immunoglobulin (cIg) and fluorescence in situ hybridization (FISH) technique to detect plasma cell chromosomal aneuploidy in patients with multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and amyloidosis (AL). Immunofluorescent-labeled antibodies to detect light chain expression and six directly labeled alpha-satellite chromosome specific enumeration probes (CEP) were used simultaneously to detect aneuploidy of the plasma cells. The six probes were specific for chromosomes 7, 9, 11, 15, 18, and X. The technique was tested in 12 consecutive patient samples (5 MM, 2 MGUS, 3 SMM, and 2 AL). Based on the alpha-satellite signals, we found trisomic clones for CEP 7 (4 of 12), CEP 11 (4 of 12), CEP X (1 of 12), CEP 9 (8 of 12), CEP 15 (7 of 12), and CEP 18 (5 of 12). Trisomic clones of at least one of the six chromosomes were present in 9 of 12 patients. We believe that this technique efficiently identifies monotypic plasma cells and permits simultaneous analysis of numeric chromosome anomalies by FISH in emerging neoplastic cells. We are in the process of applying this technique to a series of about 100 newly diagnosed monoclonal gammopathy patients.

Adult↗

Detection of RB1 deletions by fluorescence in situ hybridization in malignant hematologic disorders.

We evaluated the usefulness of fluorescence in situ hybridization (FISH) using different-colored commercial RB1 and 13qter DNA probes to identify RB1 deletions in interphase nuclei of bone marrow from 24 patients with agnogenic myeloid metaplasia (AMM), 20 patients with multiple myeloma (MM), 21 patients with other hematologic malignancies, and 25 normal bone marrow transplant (BMT) donors. Based on the 25 normal BMT donors, the upper boundary for the normal percentage of nuclei with one RB1 signal was 6.5%. Based on eight specimens known to have a deletion of 13q14 by cytogenetic studies, the lower limit of abnormal for the percentage of nuclei with one RB1 signal was 12.5%. More than 12.5% of nuclei had a single RB1 signal in 7/24 (29%) patients with AMM and 3/20 (15%) patients with MM. None of the 21 patients with hematologic malignancies other than AMM or MM had more than 12.5% nuclei with loss of RB1. The results of this study suggest that FISH with RB1 probes is useful to detect loss of RB1 in interphase nuclei from patients with hematologic disorders who have chromosome abnormalities involving 13q14. Thus, FISH with probes for RB1 is efficacious to investigate the pathogenesis of RB1 in malignant neoplasms and is a useful adjunct to conventional cytogenetic studies in clinical practice when abnormalities of 13q14 are involved.

Adult↗

Chromosomal abnormalities in systemic amyloidosis.

Primary systemic amyloidosis (AL) is a plasma cell disorder characterized by deposition of monoclonal light chains in different organ systems. Although multiple and complex numerical chromosomal abnormalities have been described in patients with multiple myeloma, it is currently unknown whether such changes occur in systemic amyloidosis. Bone marrow samples from 21 patients with AL were studied by standard cytogenetics and interphase fluorescence in situ hybridization (FISH) for the presence of numerical chromosomal abnormalities. We tested for six chromosomes (7, 11, 9, 15, 18 and X) using centromere-specific probes. The monoclonal plasma cells were identified by simultaneous fluorescent staining of the monotypic cytoplasmic immunoglobulin. We compared these results with those obtained from 19 patients with monoclonal gammopathy of undetermined significance (MGUS) and normal controls. Multiple numerical chromosomal abnormalities were detected in AL by interphase FISH, including trisomy of chromosomes 7 (42%), 9 (52%), 11 (47%), 15 (39%), 18 (33%) and X (13% in women and 54% in men). Monosomy of chromosome 18 was seen in 72% of cases. Previous exposure to alkylator therapy did not appear to correlate with these abnormalities. No significant difference was observed in the prevalence of these abnormalities between AL and MGUS. Multiple chromosomal numerical abnormalities were detected by interphase FISH analysis in patients with AL, especially monosomy of chromosome 18. Aneuploidy in the monotypic plasma supports a neoplastic nature for the disorder.

Adult↗

Acute myeloid leukemia with minimal differentiation. A multiple parameter study.

Acute myeloid leukemia with minimal differentiation (AML-M0) is a recently described entity, and few large studies are available to characterize its clinical and pathologic features. We reviewed blood and bone marrow morphology, cytochemistry, immunophenotyping, and cytogenetics, as well as the clinical findings, of 17 patients with AML-M0. Most patients were male, with a median age of 62 years. Minimal background myelodysplastic features were identified in only 5 of 15 patients. Cytochemical stains for myeloperoxidase and alpha-naphthyl butyrate esterase were negative in the leukemic blasts of all specimens. Positivity for one or both myeloid-associated antigens, CD13 and CD33, was seen in all patients. Both CD34 and HLA-DR were positive in all tested cases. Lymphoid-associated antigens were identified in seven patients; these antigens were typically dim or weak in intensity. Terminal deoxynucleotidyltransferase positivity was seen in 14 of 14 tested patients; monoclonal anti-myeloperoxidase reactivity was seen in the blasts of 2 patients. Abnormal clonal karyotypes were found in 6 of 14 patients. Abnormalities of chromosomes 7 and 13 were the most common findings, most frequently manifested by monosomy 7 and trisomy 13. The median follow-up was 8 months. Eight patients died of their disease, three are alive with disease, and six are in first or second remission (including three patients treated with bone marrow transplantation). When narrowly defined, AML-M0 appears to be a homogeneous entity that affects older and predominantly male patients. It has no single karyotypic abnormality, but complex karyotypes with monosomy 7 and trisomy 13 are commonly found. Acute myeloid leukemia with minimal differentiation is relatively resistant to chemotherapy; however, bone marrow transplantation may provide a better outcome for eligible patients.

Adult↗

The erythroid leukemias: a comparative study of erythroleukemia (FAB M6) and Di Guglielmo disease.

Pure erythroid malignancies, such as Di Guglielmo disease (DG), in which the predominant immature elements are proerythroblasts, are excluded from the French-American-British (FAB) classification for acute leukemia and do not fit neatly into any of the categories of myelodysplasia. This retrospective review compares the clinical and laboratory features of DG and erythroleukemia (FAB M6) among 37 cases treated at a single institution over a 7-year period. DG was defined as >30% proerythroblasts and the absence of a myeloblastic component. Clinical and laboratory features were similar in both subtypes. High proportions of secondary leukemias and prior myelodysplastic syndromes (MDS) were noted (M6, 13 of 26 cases; DG, five of 11 cases; p = 0.85). Pancytopenia was common at presentation in both groups [median white blood cells (WBC), 2,600/mm3; HgB, 8.65 gm/dl; platelets, 38,000/microl]. Two-thirds of studied cases had chromosomal abnormalities typified by major karyotypic abnormalities (MAKA) involving three or more chromosomes. Abnormalities involving chromosome 5 and/or 7 occurred in 47% (48% M6 and 45% DG). Both erythroid malignancies carried a poor prognosis (M6, 6.0-month median survival; DG, 4-month survival; p = 0.74). Among those patients choosing aggressive rather than palliative therapy, higher remission rate (80 versus 25%) and survival advantage (11.5 versus 2.5 months) were seen in M6 compared to DG. However, only two long-term survivors exist. The similar clinical and laboratory features, cytogenetic patterns, and poor survival data suggest that the FAB classification schema should be modified to include DG.

Adolescent↗

Long-term survival of patients with acute myeloid leukemia: a third follow-up of the Fourth International Workshop on Chromosomes in Leukemia.

BACKGROUND: In 1982, the Fourth International Workshop on Chromosomes in Leukemia reviewed data prospectively collected on 716 patients with acute myeloid leukemia (AML) diagnosed between 1980 and 1982. The present study examined the extended follow-up on these patients. METHODS: The analyses included cytogenetic and clinical data, with a median follow-up of 14.7 years, from 54 patients with treatment-associated AML and 628 with de novo AML. Of these patients, 291 received induction therapy that would be considered standard by today's criteria; no patient received high-dose cytarabine (HiDAC) intensification. RESULTS: Among the patients with treatment-associated AML, the only long-term survivor in retrospect appears to have had de novo AML. Among the patients with de novo AML, achievement of complete remission and survival varied significantly based on cytogenetic classification among all 628 patients as well as among those who did and did not receive standard induction therapy. The remission rate and survival were significantly better with standard induction therapy for patients with t(15;17) and normal cytogenetics. Multivariate analyses showed that karyotype was an independent predictor of survival for all patients and those receiving standard induction therapy. Only 8.9% of patients were alive 5 years following diagnosis, but 5 years of continuous remission was synonymous with cure. Even among 5-year survivors who had suffered a previous relapse, 41% appeared to be cured. Survival among patients in continuous remission for > or = 10 years varied significantly by cytogenetic classification. In the absence of HiDAC intensification, no complete responders with t(8;21) and only 7% with normal cytogenetics survived continuously 10 years disease free. CONCLUSIONS: Cure of AML following specific therapies must be evaluated in the context of cytogenetics. A meta-analysis incorporating cytogenetic data is indicated for patients with > or = 10 years of follow-up.

Acute Disease↗

Cytogenetic and molecular genetic methods for diagnosis and treatment response in chronic granulocytic leukemia.

Today, laboratory geneticists help clinical hematologists diagnose chronic granulocytic leukemia (CGL) and monitor the response of patients undergoing treatment. The most common genetic tests for CGL include quantitative cytogenetic studies, fluorescence in situ hybridization with probes for BCR and ABL, Southern blot analysis, and reverse transcriptase polymerase chain reaction. No single genetic testing procedure fulfills all the needs of clinicians who care for patients who have CGL. Thus, it has become important to use combinations of testing methods that are both accurate and cost-effective for any given clinical situation in the diagnosis and treatment of patients with CGL.

Antineoplastic Agents↗

Chronic granulocytic leukemia: recent information on pathogenesis, diagnosis, and disease monitoring.

Current evidence strongly implicates the chromosome translocation t(9;22)(q34;q11.2) as the cause of chronic granulocytic leukemia. Therefore, identification of this genetic abnormality through either cytogenetic or molecular methods has become a requirement for diagnosis. Intense investigation of the mechanism by which t(9;22) transforms normal hematopoietic progenitors into malignant cells is ongoing. Recent advances in molecular diagnostic methods have allowed refined qualitative and quantitative methods of detecting t(9;22), which are useful for monitoring response status and detecting minimal residual disease. The current understanding of the pathogenesis of chronic granulocytic leukemia and the application of new diagnostic methods are discussed.

Blotting, Southern↗