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Biomedical subjects

G W Dewald

Publications and source records attributed to G W Dewald.

At least 19 recordsLinked to original sources
PubMed2006

FIP1L1-PDGFRA in eosinophilic disorders: prevalence in routine clinical practice, long-term experience with imatinib therapy, and a critical review of the literature.

We previously studied clinico-pathologic features of 89 consecutive adult patients with moderate-to-severe eosinophilia, and reported a FIP1L1-PDGFRA prevalence of 12%. In that series, all 11 FIP1L1-PDGFRA+ patients receiving imatinib achieved a complete response. We now extend our observations through a study of 741 unselected patients with eosinophilia for FIP1L1-PDGFRA, and present longer term follow up data for the imatinib-treated cohort. We also include data for three previously unreported FIP1L1-PDGFRA+ patients. Among the 741 requests, only 21 (3%) were found to carry the FIP1L1-PDGFRA mutation. While all 14 FIP1L1-PDGFRA+ patients receiving imatinib achieved a complete response, the 4 patients who attempted to discontinue imatinib all relapsed. We also find that it is possible to maintain patients in clinical remission with an empirically derived schedule of low-dose (50-100 mg), intermittent (once daily to once weekly) imatinib. Lastly, we present a comprehensive review of the literature pertaining to FIP1L1-PDGFRA in order to address several key aspects of this mutation from a clinical standpoint.

Adult↗
PubMed2005

Interphase fluorescence in situ hybridization with an IGH probe is important in the evaluation of patients with a clinical diagnosis of chronic lymphocytic leukaemia.

Translocations involving IGH are common in some lymphoid malignancies but are believed to be rare in chronic lymphocytic leukaemia (CLL). To study the clinical utility of fluorescence in situ hybridization (FISH) for IGH translocations, we reviewed 1032 patients with a presumptive diagnosis of CLL. Seventy-six (7%) patients had IGH translocations. Pathology and clinical data were available for the 24 patients evaluated at the Mayo Clinic. Ten (42%) patients had IGH/cyclin D1 fusion and were diagnosed with mantle cell lymphoma (MCL). The immunophenotype was typical of MCL in three of these patients and atypical for MCL in seven patients. One patient had biclonal disease with typical MCL and CLL with IGH/BCL-2. Eleven (46%) patients had IGH/BCL-2 fusion including the patient with biclonal disease. Two of these patients had leukaemic phase follicular lymphoma and nine patients had CLL. The median progression-free survival of patients with CLL and IGH/BCL-2 translocation was 20.6 months. The two patients with IGH/BCL-3 fusion (one of these also had IGH/BCL-11a) had rapid disease progression. The IGH partner gene was not identified in two patients. We conclude that use of an IGH probe in FISH analysis of monoclonal B-cell lymphocytosis improves diagnostic precision and could have prognostic value in patients with CLL.

B-Cell Lymphoma 3 Protein↗
PubMed2004

Primary pulmonary MALT lymphomas show frequent and heterogeneous cytogenetic abnormalities, including aneuploidy and translocations involving API2 and MALT1 and IGH and MALT1.

API2-MALT1 fusion and aneuploidy are common chromosomal abnormalities in MALT lymphoma. In studying their incidence and relationship in primary pulmonary MALT lymphomas, a translocation involving MALT1 and IGH was also identified. In all, 28 primary pulmonary MALT lymphomas were studied by fluorescence in situ hybridization using an API2-MALT1 probe and multiple centromeric probes, as well as IGH-BCL2, IGH-MALT1, and MALT1 breakapart probes in selected cases. Seven (25%) had API2-MALT1 fusion; all seven lacked aneuploidy except for two with trisomy 3 in a small clone. Three (11%) had IGH-MALT1 fusion; two also showed trisomy 3 and 12. A total of 11 (39%) had aneuploidy only, with trisomy 3 and 18 being the most common. Ectopic nuclear bcl-10 expression, which has been previously associated with API2-MALT1, was seen by immunohistochemistry in 86% of API2-MALT1 fusion-positive cases, one IGH-MALT1 fusion-positive case, two aneuploidy-only cases, and two normal cases. In primary pulmonary MALT lymphomas, cytogenetic abnormalities are common (75%) and heterogeneous, encompassing API2-MALT1 and IGH-MALT1, which are mutually exclusive, as well as aneuploidy, which may be present in the latter but is rare in the former. Ectopic nuclear bcl-10 expression is associated with API2-MALT1 but may also be seen in IGH-MALT1 fusion-positive, aneuploidy-only, and normal cases.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Secondary myelodysplastic syndrome and acute myelogenous leukemia are significant complications following autologous stem cell transplantation for lymphoma.

Secondary myelodysplastic syndrome (sMDS) and acute myelogenous leukemia (AML) have been recognized with increasing frequency following autologous stem cell transplantation (ASCT). A retrospective analysis of 230 consecutive patients with Hodgkin's lymphoma (HL, 64) and non-Hodgkin's lymphoma (NHL, 166) who underwent ASCT was conducted to assess the incidence and risk factors for the development of sMDS/AML. At a median follow up of 41 months (range 0.1-177 months), 10 of 230 patients (4.3%) developed sMDS/AML. The 5-year-actuarial incidence of sMDS/AML was 13.1% and 5-year cumulative incidence by competing risk analysis was 4.2%. The median time to development of sMDS/AML was 39.9 months from the time of ASCT (range 12.1-62.0 months). Complex karyotypes at diagnosis of sMDS/AML included structural anomalies and/or loss of chromosome 5 (eight patients), 7 (five patients), 17 (two patients) and 20 (two patients). All patients subsequently died, at a median of 6.8 months (range 0-39.9) from diagnosis of sMDS/AML. Fluorescent in situ hybridization (FISH) analysis for -5/5q- and -7/7q- were normal in all six patients whose pre-ASCT bone marrow was available for testing. Five of the six had samples available for testing at diagnosis of sMDS/AML and all had abnormal FISH results. By univariate statistical analysis, male gender (P=0.01), prior alkylating agents (mechlorethamine for HL, P=0.001 and cyclophosphamide for NHL, P=0.05) and the number of prior treatment regimens (P=0.04) were significantly associated with the development of sMDS/AML. Given the relatively low incidence rate of sMDS/AML, these analyses are primarily exploratory in nature but provide some insight into relevant risk factors and illustrate the risk of developing sMDS/AML after myeloablative conditioning and ASCT for lymphoma.

Adult↗
PubMed2003

Chromosome abnormalities clustering and its implications for pathogenesis and prognosis in myeloma.

The nonrandom recurrent nature of chromosome abnormalities in myeloma suggests a role for them in disease pathogenesis. We performed a careful cytogenetic analysis of patients with abnormal karyotypes (n = 254), to discern patterns of association, search for novel abnormalities and elucidate clinical implications. Patients with karyotypic abnormalities suggestive of myelodysplasia/acute leukemia were excluded. In this study we compared survival by abnormality only between patients with abnormal karyotypes. Patients with abnormalities were more likely to have features of aggressive disease as compared to all other patients without abnormalities entered into the myeloma database (lower hemoglobin, higher beta(2)-microglobulin, labeling-index and plasmocytosis; all P < 0.0001). Several groups of patients could be readily identified; hypodiploid (22%), pseudodiploid (36%), hyperdiploid (31%) and near-tetraploid (11%). Clustering associations were seen among several trisomies and monosomy of chromosome 13 and 14. Several monosomies (-2, -3, -13, -14 and -19), 1p translocations/ deletions, and hypodiploidy were associated with a significantly shorter survival. Trisomy of chromosome 13 was rare ( <2%). Even among patients with abnormal karyotypes, specific chromosome abnormalities can impart biologic variability in myeloma, including several monosomies, hypodiploidy and abnormalities of 1p.

Adolescent↗
PubMed2002

Agnogenic myeloid metaplasia associated with Klinefelter syndrome: a case report.

Klinefelter syndrome is the most commonly diagnosed sex chromosome disorder among males. It is usually associated with 47 chromosomes, including two Xs and one Y. The formal cytogenetic designation for Klinefelter syndrome is 47, XXY; the extra sex chromosome is due to meiotic chromosomal nondisjunction. Increased risk of various malignant diseases has been recognized among patients with different congenital chromosomal abnormalities. Since the early 1960s, numerous reports have appeared of an increased risk of malignant neoplasms among patients with Klinefelter syndrome. Evidence suggests a correlation with increased incidences of germ cell tumors and breast cancers. Whether these patients are at an increased risk of hematologic malignant disease, especially acute leukemia, is still uncertain. This report describes a patient with agnogenic myeloid metaplasia and Klinefelter syndrome, an association not previously reported.

Cytogenetic Analysis↗
PubMed2002

B-CLL cells are capable of synthesis and secretion of both pro- and anti-angiogenic molecules.

Initial work has shown that clonal B cells from B-chronic lymphocytic leukemia (B-CLL) are able to synthesize pro-angiogenic molecules. In this study, our goal was to study the spectrum of angiogenic factors and receptors expressed in the CLL B cell. We used ELISA assays to determine the levels of basic fibroblast growth factors (bFGF), vascular endothelial growth factor (VEGF), endostatin, interferon-alpha (IFN-alpha) and thrombospondin-1 (TSP-1) secreted into culture medium by purified CLL B cells. These data demonstrated that CLL B cells spontaneously secrete a variety of pro- and anti-angiogenic factors, including bFGF (23.9 pg/ml +/- 7.9; mean +/- s.e.m.), VEGF (12.5 pg/ml +/- 2.3) and TSP-1 (1.9 ng/ml +/- 0.3). Out of these three factors, CLL B cells consistently secreted bFGF and TSP-1, while VEGF was expressed in approximately two-thirds of CLL patients. Of interest, hypoxic conditions dramatically upregulated VEGF expression at both the mRNA and protein levels. We also employed ribonuclease protection assays to assay CLL B cell expression of a variety of other angiogenesis-related molecules. These analyses revealed that CLL B cells consistently express mRNA for VEGF receptor 1 (VEGFR1), thrombin receptor, endoglin, and angiopoietin. Further analysis of VEGFR expression by RT-PCR revealed that CLL B cells expressed both VEGFR1 mRNA and VEGFR2 mRNA. In summary, these data collectively indicate that CLL B cells express both pro- and anti-angiogenic molecules and several vascular factor receptors. Because of the co-expression of angiogenic molecules and receptors for some of these molecules, these data suggest that the biology of the leukemic cells may also be directly impacted by angiogenic factors as a result of autocrine pathways of stimulation.

Angiogenesis Inhibitors↗
PubMed2001

Phase II study of combination human recombinant GM-CSF with intermediate-dose cytarabine and mitoxantrone chemotherapy in patients with high-risk myelodysplastic syndromes (RAEB, RAEBT, and CMML): an Eastern Cooperative Oncology Group Study.

A Phase II study of GM-CSF with intermediate-dose cytarabine and mitoxantrone was conducted in patients with high-risk myelodysplastic syndrome. It was designed to evaluate if priming with growth factor could increase the efficiency of chemotherapy. In this older population only two of 10 patients achieved a bone marrow CR, including one patient whose leukemic blasts had an "S" phase increase of 2.55x at 48 hr. Unexpected hepatotoxicity was noted. This regimen cannot be recommended for this elderly population of patients.

Aged↗
PubMed2001

Chronic neutrophilic leukemia (CNL): a clinical, pathologic and cytogenetic study.

This report describes a single institution's recent experience with six patients fulfilling the diagnostic criteria of chronic neutrophilic leukemia. No patient had the Philadelphia chromosome or the BCR/ABL fusion gene. None of the common cytogenetic abnormalities characteristic of myeloid disorders were detected. Two patients demonstrated clonal evolution during the course of the disease. All responded initially to therapy with hydroxyurea with control of leukocytosis and reduction in splenomegaly. Three patients eventually became refractory to hydroxyurea, manifesting progressive neutrophilia without blastic transformation. Aggressive chemotherapy to control progressive leukocytosis resulted in death due to cytopenias in two of these patients. The third patient received less intensive chemotherapy and died of progressive disease. One patient died after transformation of the disease into undifferentiated acute myeloid leukemia. Two patients remain alive with stable disease on hydroxyurea therapy, 12 and 54 months after initial diagnosis. Chronic neutrophilic leukemia is a rare clinicopathologic entity that can be distinguished from chronic myelogenous leukemia, the recently described neutrophilic-chronic myelogenous leukemia, and myelodysplastic syndrome. The clinical course is heterogeneous, with a definite risk of death from either blastic transformation or progressive neutrophilic leukocytosis. Continued study and reporting of these cases must be encouraged.

Humans↗
PubMed2001

Deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q arm or monosomy.

Deletions of the long arm of chromosome 13 (13q-) are observed in patients with multiple myeloma (MM), are rarely observed in the monoclonal gammopathy of undetermined significance (MGUS) and have been associated with a worsened prognosis in MM. However, no minimally deleted region in the 13q arm has been defined at 13q, and consequently no tumor suppressor genes have yet been identified that are important for disease pathogenesis. We attempted to characterize these chromosome 13q deletions at the molecular cytogenetic level. We studied 351 newly diagnosed patients, entered into the E9486/E9487 clinical study of the Eastern Cooperative Oncology Group. Fluorescent in situ hybridization (FISH) combined with immune fluorescent detection (cIg-FISH) of clonal plasma cells (PC) and cytomorphology were used to analyze interphase, bone marrow (BM) cell, cytospin slides. We simultaneously used DNA probes for the following locus specific probes (LSI); LSI 13 (Rb) and D13S319, which hybridize to 13q14. We subsequently studied distal deletions using the D13S25 probe (13q14.3) and a subtelomeric probe (13qSTP) for the 13q-arm (D13S327) in 40 cases with documented LSI 13 (Rb)/D13S319 deletion and 40 without deletion of these loci. Of 325 evaluable patients, we found 13q deletions in 176 (54%) using LSI 13 (Rb) and D13S319 probes. Of 40 patients with LSI 13 (Rb)/D13S319 deletions, 34 (85%) had coexistent deletion of both D13S25/13qSTP. These results indicate that chromosome 13 deletions in MM involve loss of most if not all of the 13q arm perhaps even indicating monosomy. In six cases the 13qSTP signal was conserved, but D13S25 was lost indicating large interstitial deletions involving 13q14. In 39 of the 40 cases without LSI 13 (Rb)/D13S319 deletions, the normal pattern of two pairs of signals was observed for D13S25/13qSTP. Deletions involving 13q14 are very common in MM as detected by cIg-FISH. These deletions appear to predominantly involve loss of large segments of the 13q arm or monosomy 13, and only occasionally represent an interstitial deletion.

Adult↗
PubMed2001

Cytogenetic findings and their clinical relevance in myelofibrosis with myeloid metaplasia.

The prognostic significance of bone marrow cytogenetic lesions in myelofibrosis with myeloid metaplasia (MMM) was investigated in a retrospective series of 165 patients. An abnormal karyotype was demonstrated in 57% of patients. At diagnosis (n = 92), 48% of the patients had detectable cytogenetic abnormalities, and clonal evolution was frequently demonstrated in sequential studies. More than 90% of the anomalies were represented by 20q-, 13q-, +8, +9, 12p-, and abnormalities of chromosomes 1 and 7. Of these, 20q-, 13q- and +8 were the most frequent sole abnormalities, each occurring in 15-25% of the abnormal cases. Trisomy 9 and abnormalities of chromosomes 1 and 7 were equally prevalent but were usually associated with additional cytogenetic lesions. Chromosome 5 abnormalities were infrequent but were over-represented in the group of patients exposed to genotoxic therapy. In a multivariate analysis that incorporated other clinical and laboratory variables, the presence of an abnormal karyotype did not carry an adverse prognosis. Instead, +8, 12p-, advanced age and anaemia were independent prognostic determinants of inferior survival. In particular, survival was not adversely affected by the presence of either 20q- or 13q-.

Adult↗
PubMed2001

Comparison of peripheral blood interphase cytogenetics with bone marrow karyotype analysis in myelofibrosis with myeloid metaplasia.

In a prospective study of 42 patients with myelofibrosis with myeloid metaplasia (MMM), peripheral blood (PB) and bone marrow (BM) interphase cytogenetics and PB CD34 enumeration were performed concomitantly with BM karyotype analysis. Interphase cytogenetics was performed with a panel of fluorescence in situ hybridization (FISH) probes that were capable of detecting most of the known recurrent cytogenetic lesions in MMM. There was a close concordance in the results of interphase cytogenetics between PB and BM, regardless of the PB CD34 count. In general, FISH-detectable abnormalities were also detected by BM karyotype. Although complementary, interphase cytogenetics may not always provide the necessary karyotypic information in MMM.

Adult↗
PubMed2001

Analysis of clonal B-cell CD38 and immunoglobulin variable region sequence status in relation to clinical outcome for B-chronic lymphocytic leukaemia.

Recent reports suggest that the expression of germline (GL) Ig variable region heavy-chain genes (VH) is a negative prognostic factor for B-cell chronic lymphocytic leukaemia (B-CLL) patients and that CLL B-cell CD38 expression may be a surrogate marker of Ig VH gene status. Currently, however, the usefulness of this surrogate marker is controversial. Therefore, our goal was to study the ability of CD38 to act as a surrogate marker for Ig VH somatic mutation (SM), and to identify differences in overall survival (OS), progression-free survival (PFS) and response in B-CLL patients based on these two markers. We first assessed the relationship between CD38 expression and Ig VH status on 131 B-CLL patients, including 66 patients enrolled in three North Central Cancer Treatment Group Trials. Although the mean percentages of CD38+ clonal B cells were significantly higher for patients classified as GL versus SM, CD38 was not a reliable marker for clonal B-cell SM. Overall, GL patients exhibited significantly shorter OS and PFS times than SM patients. Despite the inability of clonal B-cell CD38 expression to predict Ig VH mutation status, patients with < or =30% CD38+ cells did have shorter PFS and OS times than did CLL patients with < 30% CD38+ cells. Thus, the relationship between CD38 expression and Ig VH mutation status in B-CLL is not straightforward. Nevertheless, analysis in a co-operative group clinical trial setting suggests that both B-cell markers alone or in combination may have clinical usefulness. These data strongly encourage the study of these biological markers as they relate to disease heterogeneity in B-CLL.

ADP-ribosyl Cyclase↗
PubMed2000

Diagnostic utility of fluorescence in situ hybridization in mantle-cell lymphoma.

Mantle-cell lymphoma (MCL) has a poorer prognosis than other small B-cell lymphomas, thus a definitive diagnosis is essential. The t(11;14)(q13;q32) associated with MCL juxtaposes portions of CCND1 (11q13) and IGH (14q32), resulting in over-expression of cyclin D1. In this study, a highly sensitive two-colour fluorescence in situ hybridization (FISH) method was developed to detect t(11;14)(q13;q32) in nuclei isolated from paraffin-embedded tissue. Twenty-three MCLs, 13 normal controls and nine small B-cell lymphomas other than MCL were studied by FISH. Each MCL had been previously investigated to detect genomic IGH-CCND1 fusion by polymerase chain reaction (PCR) using DNA extracted from frozen tissue. The IGH-CCND1 fusion detection rate in the MCLs was 96% by FISH compared with 35% by PCR. By FISH, one MCL and three small B-cell lymphomas other than MCL harboured abnormalities involving only IGH. Less than 1% of cells showed false-positive IGH-CCND1 fusion in normal specimens by FISH. Thus, this highly sensitive FISH assay is very useful in confirming the diagnosis of MCL, has wide applicability as it may be performed on both paraffin-embedded and fresh tissue, and may also facilitate detection of translocations involving these loci in tumours other than MCL.

Case-Control Studies↗
PubMed2000

Optimizing preparation of normal dendritic cells and bcr-abl+ mature dendritic cells derived from immunomagnetically purified CD14+ cells.

The goal of this work was to optimize dendritic cell (DC) preparations obtained from patients suffering from chronic myeloid leukemia (CML) and compare them with DC prepared from normal CD14+ mononuclear cells (MNC). We studied normal DC and bcr-abl+ leukemic DC (CML-DC) yields, expression of membrane molecules, differentiation status, and ability to stimulate T cells. We isolated DC precursors from PBMC by CD14-specific immunoadsorption and cultured them for 7 days in GM-CSF and IL-4, followed by a 3-day incubation to fully differentiate the cells. We evaluated cultures of CML-DC using RPMI 1640 medium supplemented with FBS and X-VIVO 15 medium containing human AB serum. In contrast to cells matured in RPMI 1640, virtually all cells incubated in X-VIVO 15 expressed CD83, a marker of mature DC. CML-DC and normal DC were indistinguishable in expression of CD83, resulting in the highest percentage reported so far. The yields of normal DC and CML-DC from CD14+ cells were indistinguishable. The percentage of bcr-abl+ cells in PBMC varied among patients between 65% and 97% and the final CML-DC preparations were >98% bcr-abl+ the highest purity of bcr-abl+ cells to date. Normal DC and CML-DC were equally effective in stimulating proliferation of allogeneic and autologous T cells. These techniques provide highly enriched, mature, functional CML-DC.

Cell Division↗
PubMed2000

The (11;14)(q13;q32) translocation in multiple myeloma. A morphologic and immunohistochemical study.

We identified 24 cases of multiple myeloma with the t(11;14)(q13;q32). In 22 cases, the t(11;14)(q13;q32) was part of a complex karyotype, and in 2 cases it was an isolated abnormality. All patients had clinical and laboratory features consistent with multiple myeloma. The median degree of plasma cell involvement in the bone marrow was 60%, and in 10 cases, the plasma cells had a lymphoplasmacytoid appearance. Of the 24 cases, 21 had intermediate or high proliferative rates based on labeling index studies. Immunohistochemical studies performed on all bone marrow biopsy specimens showed strong cyclin D1 nuclear positivity in 19 cases. There also was strong cyclin D1 nuclear positivity found in 6 of 30 additional cases without the t(11;14)(q13;q32) demonstrated by routine cytogenetics. The t(11;14)(q13;q32) in multiple myeloma results in overexpression of the cyclin D1 protein, which can be demonstrated by immunohistochemical stain. The cyclin D1 stain results in the additional cases of multiple myeloma suggest that the t(11;14)(q13;q32) may be more common than previously thought and may be missed by routine cytogenetics, particularly if the proliferative rate is low.

Adult↗