Nonrandom chromosomal abnormalities in malignant pleural mesothelioma

Cytogenetic studies were performed on tumor cells from specimens of 30 consecutive patients with malignant pleural mesothelioma. Metaphases for chromosomal G-banding analyses were obtained from 27 of these patients. Clonal abnormalities were detected in 19 patients. Karyotype findings were complex and heterogeneous: aneuploidy, polyploidy, structural abnormalities, and several subclones were seen. The most frequent chromosomal abnormalities were polysomy or partial polysomy 7, monosomy or partial monosomy 22, and rearrangements involving breakpoints at 1p11-22.     

The use of flow cytometry in the diagnosis and monitoring of malignant hematological disorders

Flow cytometry is a modality with ever increasing application in modern hematological practice. This is due to the rapidity of obtaining results, ease of use and increasing power to detect abnormal populations of cells. The major uses of flow cytometry in malignant hematology are in the diagnosis, classification and monitoring of diseases such as leukemia, lymphoma and myeloma. The technique is now used also to detect disease-specific populations of cells in paroxysmal nocturnal hemoglobinuria. This review describes the use of flow cytometry in many disease states.     

Characterization of chromosomal rearrangements in hematological diseases using spectral karyotyping.

Since chromosomal changes are used both as independent prognostic factors and for therapy design in hematological disorders, it is necessary to elucidate chromosomal changes as accurately as possible. We used spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) to further characterize chromosomal abnormalities in 35 patients with hematological disorders. SKY confirmed 149 aberrations, refined 117, and detected 11 hidden changes. Eighteen abnormalities were detected only by G-banding. Ten monosomies and two deletions described by G-banding were shown to be involved in translocations or ring chromosomes. These results demonstrate that SKY increases the accuracy of karyotype interpretation, which is important for proper diagnosis and management of hematological malignancies.     

Nonrandom t(1;22)(p12-p13;q13) in acute megakaryocytic malignant proliferation

A case of acute megakaryocytic leukemia (M7) and one of acute myeloid hemopathy affecting megakaryocytic and erythrocytic cell lineages in infants are reported. Both patients had t(1;22)(p12-p13;q13). This translocation was previously observed in a congenital M7 leukemia. These studies suggest that t(1;22) translocation can be nonrandom in M7.     

Nonrandom chromosome structural aberrations and oncogene loci in human malignant melanoma

Short-term cultures of 10 malignant melanomas derived from 8 patients were analyzed cytogenetically. The chromosome composition of the tumors was found to be similar in terms of modal number and structural and numerical aberrations, especially the nonrandom nature of breakpoints. Six chromosomes were consistently involved in marker formation. Aberrations of chromosomes #1 and #9 were identified in every tumor, whereas structural alterations of chromosome #2 were found in 9 tumors. In contrast, aberrations of chromosomes #6, #3, and #7 were identified in 7, 7, and 8 of the tumors, respectively. The nonrandom breakpoints on these chromosomes frequently coincided with known oncogenic loci and resulted in morphologically identical marker chromosomes. Consecutive lesions were obtained for two patients. Common markers were identified in both cases, indicating the clonal origin of the tumors. In addition, many marker chromosomes characteristic of the individual lesions were also identified. The presence of these lesion-specific markers indicates the nonrandom selective nature of the metastatic process and suggests the possible heterogeneity of the original tumor cell population.     

Multiple karyotypic abnormalities, including structural rearrangements of 11p, in cell lines from malignant melanomas

Cell lines were obtained from three malignant melanoma patients by culturing cell suspensions from tumor biopsies. A total of six lines (I to VI) were established. One line each was established from the first two cases. Lines III and IV were established from two different methyl cellulose colonies derived from the primary tumor of case 3; line III was from a non-pigmented and line IV from a pigmented colony. Cloning of line IV resulted in two highly malignant (IV Cl 1 and IV Cl 3) and one less malignant (IV Cl 2) clone. Clone IV Cl 1 was inoculated intracardially in nude mice and gave rise to adrenal and brain metastases. Lines V and VI were derived from such metastases. Multiple structural and/or numerical chromosome abnormalities were detected in all lines. Line I had 57-61 chromosomes, with structural changes affecting 1p, 2p, 3q, 7p, 7q, 11p, 14q, 17q, and 22q, as well as one unidentified marker. Line II had 40-48 chromosomes, with structural changes of 1p, 1q, 4q, 5p, 6p, 8p, 11p, 11q, 14p, 20p, and two unidentified markers. Line III had 45 chromosomes, 6q+, del(11p), and a centric fusion between chromosomes 14 and 15. Line IV had 45-46 chromosomes. The clonal changes included rearrangements of 1p, 9p, 11p, and the centric fusion of chromosomes 14 and 15. Line V was pseudodiploid and contained aberrations of 1p, 9p, 11p, 14q, 20q, an isochromosome for 21q, and an unidentified marker. Finally, the pseudodiploid line VI had changes of 9p, 11p, centric fusion of chromosomes 14 and 15, and an unidentified marker. Although no single identical aberration was shared by all six lines, structural abnormalities of 11p were invariably present and, hence, might constitute a common cytogenetic feature in melanoma development. The most consistent difference between the amelanotic and melanotic lines derived from case 3 was the presence of a 6q+ marker in the former and a 9p+ marker in the latter.     

Pneumococcal vaccination in splenectomized patients with hematological disorders

Seventy splenectomized patients were vaccinated with Pneumovax, a pneumococcal polysaccharide vaccine. Twenty-four of the patients had a malignant and 30 a nonmalignant hematological disorder. The remaining 16 were patients with no known hematological disorder, seven with intra-abdominal carcinomas and nine with non-malignant reasons for splenectomy. About 90% of the patients with non-malignant hematological disorders responded to vaccination with a rise in antibody titres, which was significantly higher than in the other two groups studied. Malignant hematological disorders lowered the response rate to 61-67%. Patients with no known hematological disorder but with intra-abdominal carcinomas also responded less frequently, while those in this group with other surgical reasons for splenectomy had a response rate comparable to healthy individuals. No serious side-effects were reported and we therefore conclude that all splenectomized patients should be vaccinated with a pneumococcal vaccine. However, it must always be born in mind that one third of the patients with malignant disease did not respond to vaccination.     

Malignant hematological disorders in children with Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome (WHS) is a rare chromosomal disorder attributable to a deletion at the short arm of chromosome 4. This syndrome is associated with characteristic facial appearance, multiple congenital abnormalities, mental retardation, feeding difficulties and failure to thrive. We report two girls with WHS who developed myelodysplastic syndrome (MDS). According to the "Category, Cytology, Cytogenetic (CCC)"classification of childhood MDS, patient 1 had refractory cytopenia with ring sideroblasts at the age of 6 years, while patient 2 had refractory cytopenia with dysplasia at the age of 5-1/2 years. Patient 1 progressed to refractory cytopenia with excess blasts within a year, while patient 2 progressed to acute lymphoblastic leukemia within 1 month of presentation. It is possible that allelic loss of a tumor suppressor gene such as WHSC1 and/or FGFR3 from the deleted segment 4p16.3 plays a critical role in the process of malignant transformation. To our knowledge, this is the first report of severe hematological complications like MDS and leukemia in children with WHS and may be an important genetic model for understanding malignant hematological transformation. This report also underscores the importance of evaluating children with WHS for hematopoietic dysfunction.     

Application of fluorescence in situ hybridization in hematological disorders.

In the present study, chromosome changes in bone marrow (BM) or peripheral blood (PB) cells from 13 patients with malignant hematologic disorders were analyzed by classical cytogenetic techniques (G-banding) and fluorescence in situ hybridization (FISH) procedures using centromere specific probes for chromosomes 1, 6, 7, 8, 9, 12, 18, 13/21, and X, and a DNA probe specific for the long arm of chromosome Y. The cytogenetic data obtained with G-banding were in accord with those obtained by FISH to metaphase chromosomes. Most significantly, FISH to interphase nuclei offered reliable results and in some cases provided important information concerning crucial chromosome anomalies which were not or could not be completely detected by analyzing metaphase chromosomes. Our results indicate that FISH could be clinically valuable in five major areas: 1) marker chromosome identification; 2) identification of trisomy consistent with certain specific hematological neoplasms; 3) clonal evaluation post observation of a single cell with trisomy; 4) clonal evaluation post-sex-mismatched bone marrow transplantation (BMT); and 5) residual disease detection following clinical remission.     

Clinical and microbiological characteristics of the infections in patients treated with rituximab for autoimmune and/or malignant hematological disorders

Introduction

Rituximab is commonly used for the treatment of hematological malignancies and autoimmune diseases. Despite a reputation for good tolerance, case-series and registries reported rituximab-related infections of variable severity including opportunistic infections. We aimed at describing the natural history of infectious events (IE) after treatment by rituximab providing clinical and microbiological features and outcome.

The peroxin Pex6p gene is impaired in peroxisomal biogenesis disorders of complementation group 6

Human genetic peroxisomal biogenesis disorders (PBDs), such as Zellweger syndrome, comprise 13 different complementation groups (CGs). Eleven peroxin genes, termed PEXs, responsible for PBDs have been identified, whereas pathogenic genes for PBDs of 2 CGs, CG-A (the same CG as CG8 in the United States and Europe) and CG6, remained unidentified. We herein provide several lines of novel evidence indicating that PEX6, the pathogenic gene for CG4, is impaired in PBD of CG6. Expression of PEX6 restored peroxisome assembly in fibroblasts from a CG6 PBD patient. This patient was a compound heterozygote for PEX6 gene alleles. Accordingly, by merging CG6 with CG4, human PBDs are now classified into 12 CGs. Received: December 25, 2000 / Accepted: February 5, 2001     

Pooled analysis of p53 mutations in hematological malignancies

A computerized database is described that contains information about 507 mutations in the p53 gene of hematologic tumors and corresponding cell lines. Analysis of these mutations indicated the following findings: First, mutational spectrum analysis in these tumors was found to be similar to the pattern found for other solid tumors. However, when the patterns of base substitutions were examined separately according to the types of hematologic malignancies, followed by subgroup analysis, notable differences (in some cases of statistical significance) emerged. Second, mutational pattern analysis indicates that about 48% of base substitutions in hematologic tumors are suspected to be associated with carcinogen exposure. Third, deletions and insertions are localized mainly to exons 5–8 and repeated DNA sequences. However, the unusual profile of variations in frequency within each type of tumor suggests that, in addition to endogenous damage to template DNA, there is the factor of exposure to environmental physical and chemical carcinogens/mutagens. Fourth, p53 protein alterations analysis indicate that most of the changes in the amino acids are “semiconservative,” presumably in order to avoid disrupting the structure of the p53 monomer. Consistent with this notion, structural mutations are more conservative than the binding mutations. Finally, molecular mechanisms that lead to p53 mutations, etiological factors that play a role in their formation, and the pathophysiological significance of consequent p53 protein alterations are discussed. Hum Mutat 12:4–18, 1998. © 1998 Wiley-Liss, Inc.     

Molecular basis of IIq23 rearrangements in hematopoietic malignant proliferations

Chromosomal abnormalities of the 11q23 band occur frequently in various hematopoietic malignant disorders. Because numerous partner chromosomes have been previously described, it is now important to determine the number of genes involved at 11q23 and to clarify the role of the partner genes. Recent efforts in several laboratories have identified a trithorax-related gene that is involved in most of the 11q23 abnormalities. The aim of this review is to summarize the recent data concerning these 11q23 rearrangements and the understanding of their consequences.     

Genomic rearrangements of the c-myc proto-oncogene in human malignant lymphomas

Southern blot analysis of EcoRI-digested DNAs was used to study the genomic configuration of the human proto-oncogene c-myc in tissue samples from a series of 28 human malignant T-cell and B-cell lymphomas. Rearrangements of c-myc were found in 12 (43 per cent) of the cases. In all but one of these the intensities of the hybridization signals from the aberrant c-myc-homologous fragments were much less than that from the 13 Kbp germ-line fragment, suggesting that only a subpopulation of the cells in the tumour carried rearranged myc gene sequences. No relationship was found between the rearrangement of c-myc and cell lineage or differentiation stage, though non-germ-line c-myc-homologous DNA fragments were more commonly found in tumours classed as high-grade according to National Cancer Institute criteria.