Current methods for the detection of IgVH mutational status in chronic lymphocytic leukemia (CLL), which identifies 2 subgroups of patients with significantly different outcomes, are laborious, expensive and do not lend themselves to a routine diagnostic setting. With the introduction of BIOMED-2 primers, a rapid protocol is now available. This study evaluated the protocol by examining DNA from 100 CLL patients. Conventional methods using RNA, and fluorescence in-situ hybridization (FISH) analysis for recurring chromosomal abnormalities, were carried out on 30 and 60 of these patients, respectively. There was complete concordance between the BIOMED-2 protocol and the RNA based method, both in mutational status and gene usage, whilst unmutated IgVH genes showed association with 17p13 and 11q23 deletions, and trisomy 12, associated with poor and intermediate outcomes, respectively. This study demonstrates that it is feasible to use the BIOMED-2 protocol in the diagnostic profile of CLL patients, obviating the need for inclusion of surrogate markers such as ZAP-70.
Chromosomal translocations affecting the immunoglobulin loci, particularly immunoglobulin heavy chain (IGH) genes complex at 14q32, are a hallmark of B cell malignancies.1,2 They usually result in deregulated expression of involved oncogenes (eg, BCL1, CMYC, and PAX5) juxtaposed to the regulatory elements of IGH. As some of these translocations are associated with specific subtypes of mature B cell lymphoma and have prognostic significance, their detection is of clinical importance. In daily practice, IGH translocations have been routinely analyzed by fluorescence in situ hybridization (FISH) using either a common LSI IGH dual-color, break-apart rearrangement assay or dual-color, dual-fusion oncogene-specific probe, such as LSI IGH/CCND1, IGH/ BCL2, and IGH/CMYC.The IGH-mediated translocations are relatively rare in B cell chronic lymphocytic leukemia (CLL), [3][4][5] which is the most common form of leukemia in adults and shows a highly variable clinical course. The CLL cells display a phenotype of mature activated B lymphocytes expressing CD19, CD5, and CD23 and having reduced levels of membrane IgM, IgD, and CD79b. The co-expression of CD19 and CD5, however, is also characteristic for mantle cell lymphoma (MCL), which, in contrast to CLL, is usually an aggressive disease hallmarked by the t(11;14)(q13; q32)/IGH-CCND1 rearrangement. Differential diagnosis between CLL and leukemic MCL is sometimes challenging. 5 Given that up to 30% of MCL cases have immunophenotypic features characteristic of B-CLL, albeit usually with atypical, pleomorphic morphology, 6 immunophenotyping alone is insufficient to exclude a diagnosis of MCL. Therefore, in the Belfast City Hospital (Belfast, Northern Ireland) all suspected CLL cases have been routinely examined by rapid interphase FISH with the LSI IGH/CCND1 assay to identify t(11;14)-positive MCL cases, in addition to examination for CLL typical cytogenetic aberrations. During this analysis, a subset of CLL
Bone marrow necrosis is most frequently diagnosed at postmortem examination. Antemortem diagnosis is still uncommon. In a recent review of world literature, we have found 133 cases of bone marrow necrosis diagnosed during life. It has been observed during the course of a wide variety of diseases, most commonly in association with acute and chronic leukemia, carcinoma, malignant lymphoma, infections, and sickle cell disease. We report two intravitally diagnosed cases of bone marrow necrosis occurring in two patients with high-grade B-cell lymphoproliferative disease. These cases are unusual in that both patients had a triad of bone marrow necrosis, high-grade B-cell lymphoproliferative disease, and hypercalcemia. Despite chemotherapy, both cases ultimately proved fatal, with progressive involvement of the central nervous system.
Two P-glycoprotein (P-gp) genes, MDR-1 (ABCB1) and MDR-3 (ABCB4), have been identified in humans. This study was designed to investigate whether associations exist between expression of MDR-1 and MDR-3 P-gp and other markers of poor prognosis and/or prior exposure to therapeutic agents in chronic lymphocytic leukemia (CLL). IgVH mutational status, gene usage, CD38 positivity, FISH analysis and clinical information were available on all patients. Twenty-one of 101 patients tested showed MDR-3 P-gp positivity. Associations with markers of poor prognosis or prior chemotherapy did not reach statistical significance, but MDR-3 P-gp positive patients had significantly shorter survivals than MDR-3 P-gp negative patients. MDR-1 P-gp expression (18/25) showed a strong association with unmutated IgVH genes and adverse prognosis cytogenetics (p = 0.015, p = 0.014, respectively), but was independent of prior exposure to chemotherapeutic agents. These results suggest a role for MDR-1 and MDR-3 in chemoresistant disease. This study highlights the value of determining MDR phenotype in CLL patients prior to treatment, to allow the design of novel drug regimens containing agents that reverse MDR function.
Morbidity and mortality from cardiovascular disease are more common in colder seasons, especially in elderly people. Previous studies have shown higher fibrinogen levels in old people in the winter months. The present studies of haemostatic factors in relation to age and season have shown that fibrinogen, tissue plasminogen activator (tPA), protein S and protein C levels are higher in old (aged 75 years and over) than young (aged 25-30 years) subjects while antiplasmin levels are lower in old people. Antiplasmin and protein C levels are lower in winter in both young and old while plasminogen activator inhibitor (PAI) is higher, and tPA higher in old people only. This study illustrates the complex interrelationships of the haemostatic system and may suggest that in 'successful' elderly people the fibrinolytic system may alter to maintain the delicate balance between thrombogenic and fibrinolytic activity. Nevertheless, the results presented here suggest that both old age and cold weather may increase the risk of atherothrombotic disease.
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