PubMed Health⌕ Search

Biomedical subjects

D E Horsman

Publications and source records attributed to D E Horsman.

At least 19 recordsLinked to original sources
PubMed2006

Leukocyte count as a predictor of death during remission induction in acute myeloid leukemia.

Acute myeloid leukemia (AML) presenting with a high leukocyte count has been associated with an increase in induction mortality and poor results in a number of other survival measures. However, the level at which an elevated leukocyte count has prognostic significance in AML remains unclear. In this report on a series of 375 adult (non-M3) AML patients undergoing induction chemotherapy at a single institution, leukocyte count analyzed as a continuous variable is shown to be a better predictor of induction death (ID) and overall survival (OS) than a leukocyte count of > or = 100 x 10(9)/L, a value characteristically associated with "hyperleukocytosis" (HL). In this patient cohort, a presenting leukocyte count of > or = 30 x 10(9)/L had high sensitivity and specificity for predicting ID, and both performance status (PS) and leukocyte count more accurately predicted for ID than age. Considering these parameters in newly-diagnosed AML patients may facilitate the development of strategies for reducing induction mortality.

Adolescent↗
PubMed2005

Concurrent translocation of BCL2 and MYC with a single immunoglobulin locus in high-grade B-cell lymphomas.

B-cell leukaemia or lymphoma with a combination of t(8;14)(q24;q32) of Burkitt leukaemia/lymphoma and t(14;18)(q32;q21) of follicular lymphoma may present clinically as de novo acute lymphoblastic leukaemia or transformation of follicular lymphoma to aggressive histology diffuse lymphoma. A number of cell lines have been reported with a complex t(8;14;18) with fusion of MYC, IGH and BCL2 on the same derivative 8 chromosome. The objective of this study was to determine the frequency and chromosomal features of this der(8)t(8;14;18) in a series of acute leukaemias and malignant lymphomas. A database of 1350 leukaemia and lymphoma karyotypes was searched for cases with structural alterations affecting both 8q24 and 18q21. A total of 55 cases were identified, of which eight revealed a complex der(8)t(8;14;18) with an MYC-IGH-BCL2 rearrangement resulting from translocation of BCL2 and MYC with a single disrupted IGH allele. Molecular cytogenetic investigation is essential to identify cases of high-grade leukaemia/lymphoma with concurrent translocations affecting the BCL2 and MYC loci.

Adult↗
PubMed2002

Fulminant tumour lysis syndrome in acute myelogenous leukaemia with inv(16)(p13;q22).

Tumour lysis syndrome (TLS) is caused by rapid breakdown of malignant cells resulting in electrolyte disturbances and acute renal failure. TLS has rarely been described in patients with acute myelogenous leukaemia (AML). Between November 1997 and July 2001, 114 consecutive adult AML patients aged <60 yr received induction chemotherapy consisting of cytosine arabinoside 1.5 g m(-2) q 12 h x 12 doses and daunorubicin 45 mg m(-2) d(-1) x 3 doses. During induction chemotherapy (CT), seven patients (6.1%, 95% CI 2.5-12.2) developed fulminant TLS, resulting in acute renal failure; five of these seven patients had inversion of chromosome 16 [inv(16)(p13;q22)], and one patient had a biological equivalent [t(16,16)(p13;q22)]. Four of the TLS patients underwent leukapheresis for a presenting white blood cell (WBC) count > 100 x 10(9) L(-1) prior to commencing chemotherapy, and six patients subsequently required haemodialysis for a median of 2 (range 1-8) wk. One TLS patient died of intracerebral hemorrhage on day 10 and another patient of multiorgan failure on day 17. Of the other five patients, all entered a complete remission (CR) and recovered normal renal function. Four patients remain in continuous CR [median follow-up 20 (range 12-25) months]. One patient relapsed at 12 months and again developed TLS on re-induction. In univariate analysis, TLS patients were more likely to have an elevated presentation and pre-chemotherapy WBC counts, elevated serum creatinine, and uric acid levels at presentation, as well as an inv(16). In multivariate analysis, only serum creatinine and inv(16) remained statistically significant (P < 0.001 for each). Patients with an inv(16) are a unique AML subgroup at high risk for fulminant TLS.

Adolescent↗
PubMed2002

Establishment and comprehensive analysis of a new human transformed follicular lymphoma B cell line, Tat-1.

A spontaneously EBV transformed follicular lymphoma (FL) cell line, Tat-1, was established from the lymph node biopsy specimen of a patient with B cell FL, grade 1 in transformation to high grade disease. Tat-1 cells expressed lymphoid markers and developed tumor masses in immunodeficient mice. Bcl-2, Bcl-X(L), Bax and p53 protein expression was revealed by Western blotting. Flow cytometric analysis confirmed P-gp expression. Cytogenetically, the Tat-1 cell line showed identical chromosomal alterations to that of the initial biopsy specimen, among which the most notable were the t(14;18) typical of FL and additional abnormalities involving chromosomes 1, 8 and 13. Multicolor FISH analysis delineated all abnormalities, including a t(1p;8q), a der(8)(8q24::14q32::18q21) and a der(13)(13q32::8q24::14q32::18q21). Further FISH investigations using a locus-specific probe cocktail containing c-myc, IgH and bcl-2 revealed fusion of these three loci on the derivatives 8 and 13, in addition to the derivative 14 IgH/bcl-2 fusion and an extra copy of c-myc on derivative chromosome 1. These results demonstrate an additional example of the deregulation of bcl-2 and c-myc expression through recombination with a single IgH enhancer region. The unusual molecular features of the Tat-1 cell line render it a unique tool for studies focused on cytogenetic alterations, expression of multidrug resistance phenotype and expression of anti-apoptotic proteins in FL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Bcl-3/IgH translocation (14;19)(q32;q13) in non-Hodgkin's lymphomas.

The recurrent cytogenetic (CG) abnormality t(14;19)(q32;q13) involving the oncogene BCL3 is described in patients with atypical chronic lymphocytic leukemia (CLL). We report four patients with non-Hodgkin's lymphoma (NHL) bearing t(14;19). All cases were female and their age ranged from 62 to 91. Histologically, there were two cases of small lymphocytic lymphoma (SLL), both CD11c positive with atypical morphology, one case of Burkitt like lymphoma (BLL), and one case of diffuse large cell lymphoma (DLC-L). One SLL patient showed t(14;19) as the sole abnormality and experienced a benign course for 8 years. The other three cases showed secondary CG progression, including tetraploidy, del(6q), t(8;22) and del(13q). These cases were aggressive in clinical behavior, including an SLL case which transformed to DLC lymphoma in 4 months. Southern analysis and long distance PCR confirmed BCL3/IgH Calpha translocation in one case. We propose that NHLs with t(14;19) may have evolved from the same spectrum of disease as atypical CLL. The poor prognosis of t(14;19) disease is associated with the occurrence of recurrent secondary CG changes, commonly found in B cell lymphoproliferative diseases.

Aged↗
PubMed2001

Cyclin D3 is a target gene of t(6;14)(p21.1;q32.3) of mature B-cell malignancies.

Chromosomal translocation t(6;14)(p21.1;q32.3) has been reported as a rare but recurrent event not only in myeloma and plasma cell leukemia but also in diffuse large B-cell non-Hodgkin lymphoma (B-NHL) (diffuse large B-cell lymphoma [DLBCL]) and splenic lymphoma with villous lymphocytes (SLVL); however, the nature of the target gene(s) has not been determined. This study identified t(6;14)(p21.1;q32.3) in 3 cases of transformed extranodal marginal zone B-NHL, in 1 case of SLVL, and in 1 case of a low-grade B-cell lymphoproliferative disorder. In a sixth case, a CD5(+) DLBCL, the translocation was identified by molecular cloning in the absence of cytogenetically detectable change. Two chromosomal translocation breakpoints were cloned by using long-distance inverse polymerase chain reaction methods. Comparison with the genomic sequence for chromosome 6p21.1 showed breakpoints approximately 59 and 73.5 kilobases 5' of the cyclin D3 (CCND3) gene with no other identifiable transcribed sequences in the intervening region. Although Southern blotting with derived genomic 6p21.1 probes failed to detect other rearrangements, fluorescent in situ hybridization assays, using BAC (bacterial artificial chromosome) clones spanning and flanking the CCND3 locus, along with probes for IGH confirmed localization of 6p21.1 breakpoints within the same region, as well as fusion of the CCND3 and IGH loci. Furthermore, in all cases, high-level expression of CCND3 was demonstrated at RNA and/or protein levels by Northern and Western blotting and by immunohistochemistry. These data implicate CCND3 as a dominant oncogene in the pathogenesis and transformation in several histologic subtypes of mature B-cell malignancies with t(6;14)(p21.1;q32.3) and suggest that CCND3 overexpression seen in about 10% of DLBCL cases may have a genetic basis.

Adult↗
PubMed2001

Comparative genomic hybridization detects multiple chromosomal amplifications and deletions in undifferentiated embryonal sarcoma of the liver.

Undifferentiated embryonal sarcoma (UES) is the third most common hepatic malignancy in children. Previous reports have described a broad range of complex cytogenetic abnormalities in individual cases of hepatic UES. Herein we report the cytogenetic findings of six cases of hepatic UES at our institution analyzed by conventional cytogenetic methods and comparative genomic hybridization (CGH). The CGH demonstrated several chromosomal gains and deletions in each case, but there was no specific abnormality seen in every case. Patterns of chromosomal changes included gains of chromosome 1q (four cases), 5p (four cases), 6q (four cases), 8p (three cases), and 12q (three cases), and losses of chromosome 9p (two cases), 11p (two cases), and chromosome 14 (three cases). The three cases in which CGH showed gains in the 12q region were studied specifically for amplifications of MDM2 and CDK4, two genes that have been shown to be amplified in other soft tissue sarcomas. However, Southern analysis showed no amplification of MDM2 or CDK4 in these three cases. Further analysis will be needed to determine the critical events in the pathogenesis of these malignant pediatric liver tumors.

Blotting, Southern↗
PubMed2001

Partial deletions of the long and short arm of chromosome 3 point to two tumor suppressor genes in uveal melanoma.

Uveal melanoma is the most common form of primary eye cancer. Monosomy 3, which is an unusual finding in tumors but is present in approximately 50% of uveal melanomas, is significantly correlated with metastatic disease. To obtain positional information on putative tumor suppressor genes on this chromosome, we have investigated tumors from 333 patients by comparative genomic hybridization, microsatellite analysis, or conventional karyotype analysis. A partial deletion of the long arm was found in eight tumors, and the smallest region of deletion overlap (SRO) spans 3q24-q26. We found six tumors with a partial deletion of the short arm and were able to define a second SRO of about 2.5 Mb in 3p25. This SRO does not overlap with the VHL gene. Our finding suggests a role for two tumor suppressor genes in metastasizing uveal melanoma and may explain the loss of an entire chromosome 3 in these tumors.

Chromosome Deletion↗
PubMed2001

Analysis of secondary chromosomal alterations in 165 cases of follicular lymphoma with t(14;18).

Follicular lymphoma is characterized by the t(14;18) in up to 85% of cases. Almost all cases display evidence of secondary chromosomal alterations at initial diagnosis. The influence of recurrent secondary changes on disease progression has not been fully determined. The purpose of this study was to define the full spectrum of recurrent karyotypic events present at diagnosis in a large cohort of cases and to evaluate the sequence of cytogenetic evolution in relation to morphologic progression. A total of 165 cases of follicular lymphoma with t(14;18) were ascertained for which complete clinical information, histopathology, immunophenotype, and karyotype were available. One hundred sixty cases showed secondary alterations with an average of 7.9 additional changes per case. Recurrent alterations seen at the 10% or greater level included +X, +1q21-q44, +7, +12q, +18q, del(1)(p36), del(6q), del(10)(q22-q24), the development of polyploidy and sidelines, and the presence of extra marker chromosomes and chromosomal additions. Changes that correlated with morphologic progression included del(1)(p36), del(6q), del(10)(q22-q24), +7, the total number of abnormalities, the number of markers and additions, and the presence of polyploidy. The most frequent second event arising after the t(14;18) was duplication of the der(18)t(14;18). This study demonstrates that the number and type of secondary chromosomal alterations in follicular lymphoma is highly variable between cases, but that a relatively small number of changes are seen repeatedly in different combinations. A consistent pattern of cytogenetic evolution could not be identified. Potentially significant gene duplications or amplifications may be disguised within marker chromosomes and additions. Additional cytogenetic investigation is required to decipher the karyotypic complexity associated with the progression of follicular lymphoma.

Adult↗
PubMed2000

Clinical significance of the t(14;18) and BCL2 overexpression in follicular large cell lymphoma.

Follicular large cell lymphoma (FLCL) is an aggressive disease that responds to anthracycline-containing chemotherapy much like diffuse large B-cell lymphoma (DLBCL). Since the t(14;18) and/or bcl2 protein expression are less common in FLCL than in its low-grade counterparts, we sought to determine whether these features were predictive of survival as in DLBCL. We studied 50 patients with FLCL who were treated with curative intent. The t(14;18) was found by cytogenetic analysis in 56% of the patients and bcl2 protein was expressed by the tumor cells in 73%, but neither was predictive of survival. However, abnormalities of chromosome 17p and the presence of trisomy 21 were adverse predictors of survival, as were a number of clinical features. We conclude that neither the absence of the t(14;18) nor the lack of bcl2 expression explain the good response of a subset of patients with FLCL to curative therapy.

Aged↗
PubMed1999

Bcl-6 and Bcl-2 protein expression in diffuse large B-cell lymphoma and follicular lymphoma: correlation with 3q27 and 18q21 chromosomal abnormalities.

The bcl-2 gene on chromosome 18 at q21 and the bcl-6 gene on chromosome 3 at q27 are both highly regulated during B-cell differentiation and show an inverse relationship of expression in the normal secondary lymphoid follicle. The objective of this study was to investigate the relationship between bcl-2 and bcl-6 protein expression and the relationship between protein expression and the corresponding chromosomal alterations in malignant lymphomas, including those associated with the germinal center. Expression of bcl-2 and bcl-6 proteins was studied in 55 cases of diffuse large B-cell lymphoma (DLBCL) and 21 cases of follicular lymphoma (FL), and the results correlated with the presence of t(14;18) and 3q27 abnormalities in a subset of 52 cases with cytogenetic analysis. These cases were selected to represent a spectrum of nodal and extranodal lymphomas, including those with and without a t(14;18). It was shown that the neoplastic cells in 71% of DLBCLs and 100% of FLs expressed bcl-6 protein. Expression of bcl-6 was seen more frequently in diffuse large B-cell lymphomas with large noncleaved morphology compared with immunoblastic morphology (82% v 27%, P = .0015), but failed to correlate with 3q27 abnormalities. Thirty-eight percent of cases with 3q27 abnormalities were bcl-6 protein negative, whereas 85% of cases without a 3q27 abnormalities were bcl-6 protein positive. Expression of bcl-2 protein was shown in 51% DLBCLs (nodal v extranodal, 71% v 30%, P = .012). bcl-2 protein was expressed in 89% of FLs with t(14;18), in contrast to 25% of FLs without t(14;18) (P = .016). In DLBCL and FL with t(14;18), the most common pattern of expression was bcl-2+/bcl-6+. In lymphomas without t(14;18), there was not an inverse relationship between bcl-2 and bcl-6 protein expression. In conclusion, these data suggest that mechanisms other than gene rearrangements can deregulate bcl-2 and bcl-6 expression in lymphomas, and there does not appear to be an inverse relationship between these two proteins as seen in the normal germinal center.

Chromosome Aberrations↗
PubMed1999

Concurrent chromosomal alterations at 3q27, 8q24 and 18q21 in B-cell lymphomas.

Recurrent chromosomal translocations in malignant lymphomas most commonly involve 18q21(bcl-2), 8q24 (c-myc) and 3q27 (bcl-6), with an incidence of 27%, 11% and 6%, respectively. Individual cases concurrently harbouring two of these three rearrangements have been previously reported. This report describes four patients with cytogenetic alterations affecting all three loci, which was confirmed by molecular analysis in one case. Clinically, each patient had aggressive B-cell lymphoma with disseminated disease often involving the central nervous system, poor response to chemotherapy and short survival. Activation of c-myc in association with deregulation of bcl-2, bcl-6 or both confers high-grade disease with a poor prognosis.

Adult↗
PubMed1998

Cytogenetic abnormalities in primary myelodysplastic syndrome are highly predictive of outcome after allogeneic bone marrow transplantation.

Allogeneic bone marrow transplantation (BMT) is the only curative therapy available for patients with myelodysplastic syndrome (MDS). In an attempt to identify prognostic factors influencing outcome, we collected data retrospectively on 60 consecutive adult patients who had undergone BMT at our center for primary MDS or acute myelogenous leukemia evolving from preexisting primary MDS (sAML). Patients were divided into subgroups according to cytogenetic abnormalities based on a recently described International MDS Workshop categorization system. The 7-year actuarial event-free survival (EFS), relapse rate, and nonrelapse mortality (NRM) for all patients were 29% (95% confidence interval [CI], 16% to 43%), 42% (CI, 24% to 67%), and 50% (CI, 37% to 64%), respectively. The EFS for the good-, intermediate-, and poor-risk cytogenetic subgroups were 51% (CI, 30% to 69%), 40% (CI, 16% to 63%), and 6% (CI, 0% to 24%), respectively (P = .003). The corresponding actuarial relapse rates were 19% (CI, 6% to 49%), 12% (CI, 2% to 61%), and 82% (CI, 48% to 99%), respectively (P = . 002) with no difference in NRM between the subgroups. Univariate analysis showed cytogenetic category, French-American-British (FAB) subtype, and graft-versus-host disease (GVHD) prophylaxis used to be predictive of relapse and EFS. In multivariate analysis, only the cytogenetic category was predictive of EFS, with the relative risk of treatment failure for the good-, intermediate-, and poor-risk cytogenetic subgroups being 1.0, 1.5, and 3.5, respectively (P = . 004). For adults with primary MDS and sAML, even after BMT, poor-risk cytogenetics are predictive of an unfavorable outcome; novel treatment strategies will be required to improve results with allogeneic BMT in this patient population.

Adolescent↗
PubMed1998

Correlation of cytogenetic abnormalities with the outcome of patients with uveal melanoma.

BACKGROUND: Cytogenetic investigations of choroid and ciliary body melanomas have revealed that the majority of cases are characterized by recurrent clonal abnormalities involving chromosomes 3, 6, and 8. The authors sought to determine whether these abnormalities were associated with outcome. METHODS: Fifty-four patients who underwent enucleation for untreated uveal melanoma between 1988 and 1996 were subjected to complete cytogenetic analysis. The most recent follow-up data from the time of enucleation was obtained. Patient outcomes were divided into two groups: 1) alive with metastases or dead of disease, and 2) alive without known metastases or dead of other causes. The relative risk (RR) and 95% confidence interval (CI) of a poor outcome were calculated for each chromosomal abnormality and clinical characteristic. RESULTS: Patients were followed for a median of 38 months. No patients were lost to follow-up. Abnormalities of chromosomes 3 and 8 were associated with a poor prognosis, but only when these two chromosomal abnormalities were present together (RR = 4.1, 95% CI = 1.7-9.9). The presence of a chromosome 6 abnormality was predictive of a good outcome (RR = 0.2, 95% CI = 0.1-0.8), even in the presence of chromosome 3 and 8 abnormalities. The only clinical factor associated with a poor outcome was the presence of extrascleral extension. CONCLUSIONS: In this group of patients with large posterior uveal melanomas, the concurrent presence of cytogenetic abnormalities of chromosomes 3 and 8 was associated with a poor outcome. An abnormality of chromosome 6 appeared to have a protective effect. These data suggest that cytogenetic analysis may provide prognostic information on patients with uveal melanoma and that further investigation of the contributions of these chromosomal aberrations to disease progression is warranted.

Chromosome Aberrations↗
PubMed1998

Acquired homozygosity (isodisomy) of chromosome 3 in uveal melanoma.

Cytogenetic investigation of uveal melanoma (UM) has revealed that monosomy 3 is the most frequent karyotypic abnormality, present in approximately 60% of cases. We investigated a cohort of 41 cases of UM, 19 of which retained two apparently normal copies of chromosome 3. Investigation of loss of heterozygosity (LOH) status was undertaken in an attempt to detect subcytogenetic loss of genetic material in those cases with two copies of chromosome 3. DNA from peripheral blood lymphocytes and fresh frozen or paraffin-embedded tumor tissue from 19 patients was amplified by the polymerase chain reaction for polymorphic loci on chromosome 3, including dinucleotide repeats, a tetranucleotide repeat, and polymorphic restriction enzyme sites. Three tumors showed LOH at multiple informative loci on both short and long arms of chromosome 3. Two additional tumors showed localized LOH on 3q, which corresponded to large deletions seen by cytogenetic analysis. The remaining 16 tumors showed retention of heterozygosity at all informative loci. This study did not detect the presence of cryptic deletions but revealed instead complete chromosomal homozygosity or functional monosomy, which probably occurred by loss and then duplication of the remaining chromosome 3. The demonstration of acquired isodisomy (functional monosomy) in a subset of UM increases the percentage of cases with monosomy 3 and provides further evidence for a central role of chromosome 3 loss in the molecular pathogenesis of uveal melanoma.

Autoradiography↗
PubMed1998

Myelodysplastic syndrome with hypereosinophilia and a nonrandom chromosomal abnormality dic(1;7): confirmation of eosinophil clonal involvement by fluorescence in situ hybridization.

We report a case of de novo myelodysplastic syndrome (MDS) with hypereosinophilia and dic(1;7) in which eosinophil clonal involvement was confirmed by fluorescence in situ hybridization. There have been two previous reports in the literature of eosinophilic MDS with dic(1;7) or t(1;7) in which eosinophil clonality was demonstrated. The specific breakpoints on chromosomes 1 and 7 differ in the three cases, making it difficult to implicate disruption of a single gene as causative; nevertheless, the nonrandom occurrence of t(1;7) or dic(1;7) with malignant eosinophilic proliferations suggests that this chromosomal rearrangement is involved in the etiology of the disease.

Aged↗