• Increased levels of soluble CD27 in the cerebrospinal fluid are not diagnostic for leptomeningeal involvement by lymphoid malignancies.

• B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes.

• Down-regulation of candidate tumor suppressor genes within chromosome band 13q14.3 is independent of the DNA methylation pattern in B-cell

• Relationship between glutathione S-transferase M1, T1, and P1 polymorphisms and chronic lymphocytic leukemia.

• Molecular abnormalities in B-cell chronic lymphocytic leukaemia.

• Contribution of comparative genomic hybridization and fluorescence in situ hybridization to the detection of chromosomal abnormalities in

• Significance of chromosomal aberrations in CLL.

• Infectious complications in chronic lymphoid malignancy.

• Autoimmunity in chronic lymphocytic leukemia.

• Spontaneous remission of B-cell chronic lymphocytic leukemia associated with T lymphocytic hyperplasia in bone marrow.

• Chronic lymphocytic leukemia.

• Simultaneous occurrence of chronic lymphocytic leukaemia and acute lymphoblastic leukaemia.

• Subcapsular splenic rupture in a patient with chronic lymphocytic leukemia.

• Prolymphocytic leukemia or prolymphocytic transformation of mantle cell lymphoma.

• Response to fludarabine in B-cell chronic lymphocytic leukemia patients previously treated with chlorambucil as up-front therapy and a CHOP-like

• Chronic lymphocytic leukemia: case-based session.

• Integrin function in chronic lymphocytic leukemia.

• Chromosomal imbalances in familial chronic lymphocytic leukaemia: a comparative genomic hybridisation analysis.

• Deletion analysis of chromosome 13q14.3 and characterisation of an alternative splice form of LEU1 in B cell chronic lymphocytic leukemia.

• Chronic lymphocytic leukemia of the orbit.

• Nursing care of patients receiving Campath.

• Challenges in treating hematologic malignancies.

• The effects of anemia in hematologic malignancies: more than a symptom.

• Beneficial effects of rituximab on primary cold agglutinin disease refractory to conventional therapy.

• Molecular diversity of gammadelta T cells in peripheral blood from patients with B-cell chronic lymphocytic leukaemia.

• Evidence for distinct pathomechanisms in B-cell chronic lymphocytic leukemia and mantle cell lymphoma by quantitative expression analysis of

• T-cell responses against chronic lymphocytic leukemia cells: implications for immunotherapy.

• Chylothorax in chronic lymphocytic leukemia patient.

• Antioxidant enzyme activities and the production of MDA and 8-oxo-dG in chronic lymphocytic leukemia.

• Fulminant hepatic failure due to disseminated adenovirus infection in a patient with chronic lymphocytic leukemia.

1
UI - 11976819
AU - van den Bent MJ; Lamers CH; van 't Veer MB; Sillevis Smitt PA; Bolhuis
TI - RL; Gratama JW Increased levels of soluble CD27 in the cerebrospinal fluid are not diagnostic for leptomeningeal involvement by lymphoid malignancies.
SO - Ann Hematol 2002 Apr;81(4):187-91
AD - Department of Neuro-Oncology, University Hospital and Daniel den Hoed Cancer Center, P.O. Box 5201, 3008 AE Rotterdam, Netherlands. bent@neuh.azr.nl
Soluble CD27 (sCD27) reportedly is a sensitive and specific marker for leptomeningeal involvement (LI) of CD27-expressing lymphoproliferations such as B-cell non-Hodgkin's lymphoma (B-NHL) or chronic B-lymphocytic leukemia (B-CLL). Because morphological analysis of cerebrospinal fluid (CSF) in patients suspected of LI is false negative in one-third of patients, a diagnostic marker for LI by B-NHL or B-CLL would be very valuable. sCD27 was determined in the first CSF sample from each of 102 unselected patients submitted for (immuno)morphologic detection of malignant cells. The patients were considered to have LI if either (immuno)morphologic analyses showed tumor cells or if neuroradiological evaluation showed typical abnormalities consistent with LI. Patients were suspected of having LI if CSF samples revealed atypical lymphocytes and/or if clinical symptoms and signs suggestive of LI were present, but clinical follow-up was shorter than 3 months because of deterioration of the patient. LI was considered absent if (immuno)morphologic analyses of CSF samples were negative without evidence for LI during 3 months of clinical follow-up. In patients with chronic lymphoproliferative disorders [mainly B-non-Hodgkin's lymphoma (NHL)], sCD27 concentrations were significantly higher in the CSF samples of 16 patients with confirmed or suspected LI than in those of 46 patients without LI. However, sCD27 was also increased in a variety of other predominantly inflammatory neurological disorders including herpes simplex and zoster infections. The positive predictive value of sCD27 determination for LI was only 54%, but the negative predictive value was 92%. Normal sCD27 concentrations in CSF samples of patients with chronic lymphoproliferation makes LI unlikely, but the determination of CSF sCD27 is not sufficiently specific to serve as a reliable tumor marker.

2
UI - 12010811
AU - Damle RN; Ghiotto F; Valetto A; Albesiano E; Fais F; Yan XJ; Sison CP;
TI - Allen SL; Kolitz J; Schulman P; Vinciguerra VP; Budde P; Frey J; Rai KR; Ferrarini M; Chiorazzi N B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes.
SO - Blood 2002 Jun 1;99(11):4087-93
AD - North Shore-Long Island Jewish Research Institute, Manhasset, NY 11030, USA.
B-cell chronic lymphocytic leukemia (B-CLL) is considered an accumulative disease of antigen-naive CD5(+) B lymphocytes that circulate in the resting state. However, to evaluate the possibility that B-CLL cells resemble antigen-experienced and activated B cells, we analyzed the expression of markers of cellular activation and differentiation on CD5(+)CD19(+) cells from B-CLL patients and from age-matched healthy donors. The leukemic cells from all B-CLL patients, including those that lack significant numbers of V gene mutations, bear the phenotype of activated B cells based on the overexpression of the activation markers CD23, CD25, CD69, and CD71 and the underexpression of CD22, Fcgamma receptor IIb, CD79b, and immunoglobulin D that are down-regulated by cell triggering and activation. Furthermore, these leukemic cells resemble antigen-experienced lymphocytes in the underexpression of molecules that are down-regulated by cell triggering and in the uniform expression of CD27, an identifier of memory B cells. A comparison of the phenotypes of B-CLL patients with and without immunoglobulin V gene mutations suggests that the 2 subgroups differ both in specific marker expression (CD69, CD71, CD62 L, CD40, CD39, and HLA-DR) and in the time since antigenic stimulation, based on the reciprocal relationship of CD69 and CD71 expression. These findings imply that the leukemic cells from all B-CLL cases (irrespective of V gene mutations) exhibit features of activated and of antigen-experienced B lymphocytes and that the B-CLL cells that differ in immunoglobulin V genotype may have different antigen-encounter histories.

3
UI - 12010815
AU - Mertens D; Wolf S; Schroeter P; Schaffner C; Dohner H; Stilgenbauer S;
TI - Lichter P Down-regulation of candidate tumor suppressor genes within chromosome band 13q14.3 is independent of the DNA methylation pattern in B-cell chronic lymphocytic leukemia.
SO - Blood 2002 Jun 1;99(11):4116-21
AD - Abteilung "Organisation komplexer Genome," Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Loss of genomic material from chromosomal band 13q14.3 is the most common genetic imbalance in B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma, pointing to the involvement of this region in a tumor suppressor mechanism. From the minimally deleted region, 3 candidate genes have been isolated, RFP2, BCMS, and BCMSUN. DNA sequence analyses have failed to detect small mutations in any of these genes, suggesting a different pathomechanism, most likely haploinsufficiency. We, therefore, tested B-CLL patients for epigenetic aberrations by measuring expression of genes from 13q14.3 and methylation of their promotor region. RB1, CLLD7, KPNA3, CLLD6, and RFP2 were down-regulated in B-CLL patients as compared with B cells of healthy donors, with RFP2 showing the most pronounced loss of expression. To test whether this loss of gene expression is associated with methylation of CpG islands in the respective promotor regions, we performed methylation-sensitive quantitative polymerase chain reaction analyses and bisulfite sequencing on DNA from B-CLL patients. No difference in the methylation patterns could be detected in any CpG island of the minimally deleted region. Down-regulation of genes within chromosomal band 13q14.3 in B-CLL is in line with the concept of haploinsufficiency, but this tumor-specific phenomenon is not associated with DNA methylation.

4
UI - 12010828
AU - Yuille M; Condie A; Hudson C; Kote-Jarai Z; Stone E; Eeles R; Matutes E;
TI - Catovsky D; Houlston R Relationship between glutathione S-transferase M1, T1, and P1 polymorphisms and chronic lymphocytic leukemia.
SO - Blood 2002 Jun 1;99(11):4216-8
AD - Academic Department of Haematology and Cytogenetics, and the Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
Interindividual differences in susceptibility to hematologic malignancies may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The glutathione S-transferases (GSTs) have been implicated as susceptibility genes in this context for a number of cancers. The aim of this study was to examine whether polymorphic variation in GSTs confers susceptibility to chronic lymphocytic leukemia (CLL). GSTM1, GSTT1, and GSTP1 genotypes were determined in 138 patients and 280 healthy individuals. The frequency of both GSTM1 and GSTT1 null genotypes and the GSTP1-Ile allele was higher in cases than in controls. There was evidence of a trend in increasing risk with the number of putative "high-risk" alleles of the GST family carried (P =.04). The risk of CLL associated with possession of all 3 "high-risk" genotypes was increased 2.8-fold (OR = 2.8, 95% confidence interval: 1.1-6.9). Our findings suggest that heritable GST status may influence the risk of developing CLL.

5
UI - 11553053
AU - Fegan C
TI - Molecular abnormalities in B-cell chronic lymphocytic leukaemia.
SO - Clin Lab Haematol 2001 Jun;23(3):139-48
AD - Department of Haematology, Bordesley Green East, Birmingham, UK. FeganC@heartsol.wmids.nhs.uk
Chronic lymphocytic leukaemia is the commonest adult leukaemia, however the pathogenesis is largely unknown. Since the 1980s specific chromosomal abnormalities have been identified, of which the commonest are deletions of chromosomes 6q, 11q23, 13q14 and 17q13 and trisomy 12. The search for the responsible oncogenes at these sites has proved to be extremely frustrating. There are many oncogenes at 11q23 but the exact gene(s) responsible have yet to be identified. Germline abnormalities of the ATM gene occur in about 18% of patients compared to a normal population carriage of 0.5% but not all studies agree that ATM is the gene responsible. Unfortunately, despite the identification of various minimally deleted regions and the full sequencing of 13q14 no oncogenes have been identified. All original studies suggested the presence of a autosomally recessive tumour suppressor gene at this site but more recent studies suggest this may not be the case and the pathogenesis is more complex than first thought. Similarly, no genes have been identified at 6q or on chromosome 12. We know that the p53 tumour suppressor gene at 17p13 is an important prognostic indicator but it occurs in a minority of patients (about 15%), usually in patients with advanced disease, and therefore probably is not of aetiological importance.

6
UI - 11441283
AU - Jarosova M; Jedlickova K; Holzerova M; Urbanova R; Papajik T; Raida L;
TI - Pikalova Z; Lakoma I; Prekopova I; Kropackova J; Indrak K Contribution of comparative genomic hybridization and fluorescence in situ hybridization to the detection of chromosomal abnormalities in B-cell chronic lymphocytic leukemia.
SO - Onkologie 2001 Feb;24(1):60-5
AD - Department of Hematology/Oncology, Palacky University Hospital, Olomouc (Czech Republic). marie.jarosova@fnol.cz
BACKGROUND: B-chronic lymphocytic leukemia (B-CLL), the most common type of leukemia in Western Europe and the United States, is characterized by clonal chromosomal abnormalities detected in almost half of the studied patients. The precise determination of chromosomal changes helps to indicate the prognosis and to understand the pathogenesis of CLL. METHODS AND PATIENTS: We applied conventional cytogenetics (CC), FISH and comparative genomic hybridization (CGH) to the investigation of clonal abnormalities in 88 B-CLL patients at the time of diagnosis. RESULTS: By using CC of bone marrow cells without any stimulation, non-random chromosomal changes were found in 17 (19%) of 88 patients.The employment of FISH and CGH revealed chromosomal changes in additional 33 patients, thus increasing the detection rate of chromosomal abnormalities to 57%. The most common abnormalities detected in our patients included deletions of 13q in 16 cases (18%), followed by trisomy of chromosome 12 in 12 patients (13%), deletions of 11q in 10 patients (11%) and deletions of 17p in 10 patients (11%). A statistically significant correlation between higher disease activity and the presence of deletions 11q and 17p was observed. CONCLUSION: The addition of FISH and CGH to CC in 88 B-CLL patients improved the detection of clonal chromosomal changes from 19 to 57%. The most frequent chromosomal change was deletion of 13q14 (18%). Deletions of 11q23 and 17p13 were found in patients with higher clinical disease activity. Our results underline the importance of employing FISH and CGH techniques in CLL patients. CC without any stimulation has a low detection rate and is not suggested for detection of chromosomal changes in CLL. Copyright 2001 S. Karger GmbH, Freiburg

7
UI - 11476076
AU - Bergmann L
TI - Significance of chromosomal aberrations in CLL.
SO - Onkologie 2001 Apr;24(2):176

8
UI - 12057123
AU - Egerer G; Hensel M; Ho AD
TI - Infectious complications in chronic lymphoid malignancy.
SO - Curr Treat Options Oncol 2001 Jun;2(3):237-44
AD - Department of Internal Medicine V, University of Heidelberg, Hospitalstrasse 3, 69115 Heidelberg, Germany.
Taking steps to minimize, prevent, and treat infection in patients with chronic lymphoid malignancies, especially chronic lymphocytic leukemia, has always been a challenge. As more patients with these diseases live longer and lead productive lives upon successful initial treatment, strategies for preventing infections have become more important. Distinguishing patients at low risk for infection from those at high risk is a crucial but challenging issue. Unfortunately, there are hardly any data on the use of prophylactic antibiotics for patients with chronic lymphoid malignancy (CLL). If patients cannot be enrolled in a clinical trial, antibiotics with co-trimoxazole should be administered when steroids are warranted. They should also be administered in patients who have had a documented infection early in the treatment course and during neutropenia. Viral infections remain another controversial issue in patients with CLL receiving treatment, especially a purine analogue. Very low CD4 counts (less than 50 cells/mL) might predict for reactivation for herpes zoster. Outside of depleted CD4 counts, there are no other means of identifying a high-risk group. Based on limited data, it would be reasonable to administer herpes zoster prophylaxis to patients with CD4 counts that are severely depleted or to patients with a prior episode of zoster. Controversial issues still remain regarding immunoglobulin treatment, specifically cost, scarcity of the product, and adequate dose, which has not yet been established. We would consider intravenous immunoglobulin (Ig) replacement in patients with marked hypogammaglobulinemia (IgG less than 400 mg/dL) with more than two recent severe infections [1]. Lower Ig doses (240 mg/kg) have been shown to be equivalent to higher ones in this trial [1].

9
UI - 12057125
AU - Ward JH
TI - Autoimmunity in chronic lymphocytic leukemia.
SO - Curr Treat Options Oncol 2001 Jun;2(3):253-7
AD - Department of Internal Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, 2000 Circle of Hope, Suite 2100, Salt Lake City, UT 84112-5550, USA.
Chronic lymphocytic leukemia (CLL) is associated with the immune-mediated disorders autoimmune hemolytic anemia and immune thrombocytopenia. Initial treatment with corticosteroids is often successful in controlling these manifestations, but splenectomy should be considered if a rapid and complete response is not obtained. For those with persistent anemia or thrombocytopenia after splenectomy, treatment directed against the underlying CLL may be considered, although the use of purine analogues has also precipitated autoimmune hemolytic anemia. Pure red cell aplasia has been reported in CLL, and usually responds to immunosuppressive therapy.

10
UI - 12081222
AU - Upshaw JD Jr; Callihan TR
TI - Spontaneous remission of B-cell chronic lymphocytic leukemia associated with T lymphocytic hyperplasia in bone marrow.
SO - South Med J 2002 Jun;95(6):647-9
AD - Memphis Cancer Center, Tenn 38119, USA.
Spontaneous remissions in B-cell chronic lymphocytic leukemia (B-CLL) are rare and none of them has been studied with immunophenotyping (by flow cytometry and immunohistochemistry) and genotyping. In this patient, studied after spontaneous remission had occurred, there was a residual T-lymphocytic hyperplasia in the bone marrow with a normal CD4:CD8 ratio. Absolute CD4 and CD8 counts and CD4:CD8 ratio in the peripheral blood were normal. Flow cytometry revealed no B-CLL cells in the peripheral blood and less than 2% B-CLL cells in the bone marrow.

11
UI - 12057068
AU - Andritsos L; Khoury H
TI - Chronic lymphocytic leukemia.
SO - Curr Treat Options Oncol 2002 Jun;3(3):225-31
AD - Division of Oncology, Section of Bone Marrow Transplantation and Leukemia, Washington University, 660 South Euclid Avenue, Campus Box 8056, St. Louis, MO 63110, USA. andritsosl@earthlink.net
Historically, treatment of chronic lymphocytic leukemia (CLL) essentially had been palliative. During the past two decades, effective new therapies for the treatment of CLL have emerged. The advent of fludarabine, a purine analog with activity against chlorambucil-resistant CLL, showed promising results with high response rates in previously untreated patients. These improvements in response and delays in disease progression have not translated into a survival benefit, indicating that chlorambucil may be the preferred first-line therapy when treatment is indicated. Allogeneic hematopoietic stem cell transplantation, by combining the cytoreductive effects of conditioning with a potent graft-versus-tumor effect, is the only treatment modality with the prospect of cure for patients with CLL. However, conventional hematopoietic stem cell transplantation can be offered only to select patients with CLL because of older age and comorbid conditions. Novel methods of transplantation exploiting the graft-versus-leukemia effect while reducing the toxicity of the pretransplant conditioning are promising approaches that may enable more patients to benefit from this therapy. Monoclonal antibodies such as rituximab or alemtuzumab (Campath-1H; llex Pharmaceuticals, San Antonio, TX) are agents with activity in untreated and resistant CLL. Efforts are being focused on combining these monoclonal antibodies with chemotherapy and the development of rationally designed drugs.

12
UI - 11940498
AU - Bueno J; Irriguible MD; Palacio C
TI - Simultaneous occurrence of chronic lymphocytic leukaemia and acute lymphoblastic leukaemia.
SO - Haematologica 2002 Apr;87(4):EIM11
AD - Servicio de Hematologia. Hospital Universitario Vall d Hebron. P Vall d Hebron 119-129. 08035 Barcelona. Spain. jabueno@hg.vhebron.es

13
UI - 11940499
AU - del Agua C; Real E; Cunat A; Pastor E; Grau E
TI - Subcapsular splenic rupture in a patient with chronic lymphocytic leukemia.
SO - Haematologica 2002 Apr;87(4):EIM12
AD - Department of Hematology, Hospital Lluis Alcanyis, Xativa, Spain.

14
UI - 11710698
AU - Veillon DM; Nordberg ML; Glass J; Sattar T; Cotelingam JD
TI - Prolymphocytic leukemia or prolymphocytic transformation of mantle cell lymphoma.
SO - Am J Clin Pathol 2001 Nov;116(5):781-2

15
UI - 11694402
AU - Liso V; Molica S; Capalbo S; Pogliani E; Battista C; Broccia G; Montillo
TI - M; Cuneo A; Leoni P; Specchia G; Castoldi G Response to fludarabine in B-cell chronic lymphocytic leukemia patients previously treated with chlorambucil as up-front therapy and a CHOP-like regimen as second line therapy.
SO - Haematologica 2001 Nov;86(11):1165-71
AD - Institute of Hematology, University of Bari, Italy. ematba@cimedoc.uniba.it
BACKGROUND AND OBJECTIVES: Fludarabine (FAMP) is the most active single agent in relapsed and refractory patients with B-cell chronic lymphocytic leukemia (B-CLL). However, it is not clear whether it should be used immediatly after failure of chlorambucil (CLB). We addressed such an issue retrospectively analyzing a series of patients in whom FAMP was used as third-line therapy after a sequential use of CLB and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP-like regimen, respectively. DESIGN AND METHODS: On a retrospective basis, 57 B-CLL patients fulfilling the above mentioned criteria and followed-up in seven different hematologic institutions, were evaluated. RESULTS: Of 57 patients who were evaluated for response, 3 (5.2%) achieved a complete response (CR), 30 (52.6%) had a partial response (PR) and the remaining 24 (42.1%) failed to respond to FAMP. Overall median survival from the start of FAMP therapy was 30 months. Survival by tumor response did not show any difference between responders and non-responders (p = 0.536). The survival was significantly shorter in the group of patients with progressive disease than in all other patients included in our study (p = 0.05). Using each patient as his own control (McNemar test) we attempted to evaluate the value of FAMP in inducing a therapeutic response after failure of previous therapies. Among the 37 patients resistant to CLB the response rate was 40.3% with FAMP (p = 0.037) and only 17.5% with CHOP (p = 1.0). Among 35 patients resistant to a CHOP-like regimen, the response rate was 29.8% (p = 0.066) after FAMP therapy. INTERPRETATION AND CONCLUSIONS: From our results, it seems that FAMP works better than a CHOP-like regimen in patients resistant to CLB although results do not translate into a survival advantage for responders.

16
UI - 11722982
AU - Rai KR; Dohner H; Keating MJ; Montserrat E
TI - Chronic lymphocytic leukemia: case-based session.
SO - Hematology (Am Soc Hematol Educ Program) 2001;():140-56
AD - Division of Hematology-Oncilogy, Long Island Jewish Medical Center, New Hyde Park, NY 11040, USA.
Drs. Hartmut Dohner, Michael J. Keating, Kanti R. Rai and Emili Montserrat form the panel to review chronic lymphocytic leukemia (CLL) while focusing on the clinical features of a particular patient. The pace of progress in CLL has accelerated in the past decade. The pathophysiological nature of this disease, as had been known in the past, was based largely on the intuitive and empiric notions of two leaders in hematology, William Dameshek and David Galton. Now the works of a new generation of leaders are providing us with the scientific explanations of why CLL is a heterogeneous disease, perhaps consisting of at least two separate entities. In one form of CLL, the leukemic lymphocytes have a surface immunoglobulin (Ig) variable region gene that has undergone somatic mutations, with tell-tale markers suggesting that these cells had previously traversed the germinal centers. Such patients have a distinctly superior prognosis than their counterparts whose leukemic lymphocytes IgV genes have no mutations (these are indeed immunologically naive cells), who have a worse prognosis. The introduction of fluorescence in situ hybridization (FISH) technique has provided us with new insights into the diverse chromosomal abnormalities that can occur in CLL, and which have significant impact on the clinical behavior and prognosis of patients with this disease. Major advances in therapeutics of CLL also have occurred during the past decade. Two monoclonal antibodies, Campath-1H (anti-CD52) and rituximab (anti-CD20), and one nucleoside analogue, fludarabine, have emerged as three agents of most promise in the front-line treatment of this disease. Studies currently in progress reflect our attempts to find the most effective manner of combining these agents to improve the overall survival statistics for CLL patients. As in many other hematological malignancies, high dose chemotherapy followed by autologous or HLA-compatible allogeneic stem cells rescue strategies are under study as a salvage treatment for a relatively younger age group of CLL patients with poor prognosis characteristics.

17
UI - 8639849
AU - Vincent AM; Cawley JC; Burthem J
TI - Integrin function in chronic lymphocytic leukemia.
SO - Blood 1996 Jun 1;87(11):4780-8
AD - Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK.
Integrins are central to many aspects of the tissue localization of normal and malignant lymphocytes. We examined how integrin function, rather than simple expression, might determine disease behavior in chronic lymphocyte leukemia (CLL). Using fluorescence-activated cell sorting (FACS) and immunoprecipitation, we first established the precise integrin heterodimer expression of a representative group of CLL patients (beta1 consistently present, with variable alpha 3, alpha 4, and alpha 5; alpha 4 beta 7 often expressed; alpha L beta 2 high; alpha V beta 3 absent). Regarding function, we initially examined the ability of CLL cells to interact with endothelium, because such interaction is the initial event determining the entry of CLL lymphocytes into tissues. The abnormal lymphocytes were shown to bind at low levels to unstimulated endothelium via beta 2/intercellular adhesion molecule (ICAM). However, when the endothelium was stimulated, markedly enhanced interaction with endothelium was observed in approximately half the cases; in these patients, the neoplastic population expressed alpha 4 beta 1, which conferred the ability to adhere strongly to stimulated endothelium via the alpha 4 beta 1 ligand, vascular cellular adhesion molecule-1 (VCAM-1). In relation to the migration of CLL cells within tissues, the abnormal lymphocytes showed differential binding to various adhesive proteins; they did not attach to basement membrane components, but displayed variable adhesion to fibronectin (FN). Finally, we examined the role of cell activation in these processes, and showed that activated CLL lymphocyte populations showed an increased capacity to adhere to both endothelium and matrix. Moreover, ex vivo CLL cells showed no capacity to migrate through endothelium/stroma, but were able to do so after cytokine stimulation. These studies show how the constitutive integrin expression/function, the intrinsic activation state of the cell, and the capacity of cytokines to modify integrin-mediated function all combine to determine the different patterns of clinical disease observed in CLL.

18
UI - 12094247
AU - Summersgill B; Thornton P; Atkinson S; Matutes E; Shipley J; Catovsky D;
TI - Houlston RS; Yuille MR Chromosomal imbalances in familial chronic lymphocytic leukaemia: a comparative genomic hybridisation analysis.
SO - Leukemia 2002 Jul;16(7):1229-32
AD - UK Co-ordinating Centre for the Study of Familial Chronic Lymphocytic Leukaemia, Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, UK.
A subset of B cell chronic lymphocytic leukaemia (CLL) is familial. Lack of large families makes it attractive to exploit methods in addition to genetic linkage analysis for the identification of a susceptibility locus. One strategy that can localise regions of the genome that may harbour tumour suppressor genes is to identify regions of chromosomal imbalance using comparative genomic hybridisation (CGH) analysis. We examined 24 familial CLL cases by CGH analysis. Losses that are documented as arising frequently in sporadic CLL were observed at a comparable frequency in familial CLL. However, gains and losses in two regions of the X chromosome - Xp11.2-p21 and Xq21-qter - appear more common in familial CLL than in sporadic CLL. This suggests these regions may harbour a susceptibility locus for CLL. There is also some evidence that chromosome regions 2p12-p14 and 4q11-q21 may harbour predisposition genes.

19
UI - 12094250
AU - Rowntree C; Duke V; Panayiotidis P; Kotsi P; Palmisano GL; Hoffbrand AV;
TI - Foroni L Deletion analysis of chromosome 13q14.3 and characterisation of an alternative splice form of LEU1 in B cell chronic lymphocytic leukemia.
SO - Leukemia 2002 Jul;16(7):1267-75
AD - Department of Academic Haematology Royal Free and University College of London (Royal Free Campus), UK.
Heterozygous and homozygous deletions of chromosome 13q14.3 are found in 50% of patients with B cell CLL, suggesting the presence of one or more tumour suppressor genes within the deleted region. To identify candidate genes from the region, we constructed a map of 13q14.3 using a combination of genomic and cDNA library screening. The incidence of deletions in CLL patients was 51.5% encompassing a 265 kb region of minimal deletion (RMD) telomeric to markers D13S319. Two CpG islands were identified within the RMD, the telomeric of which is fully methylated whilst the more centromeric is unmethylated. A novel transcript was identified within the RMD that represents an alternative splice version of Leu1. The nine exons of this transcript span a genomic of 436 kb with exon 1 of Leu1 being the common first exon. The remaining exons were shown to be more frequently deleted than Leu1 itself. All splice forms of this transcript were detectable by RT-PCR but Leu1 detected the most abundant message on Northern blotting. Sequence analysis failed to reveal inactivating mutations in patients with heterozygous deletion of 13q14.3, although a polymorphic T to A variant was identified within exon 1 of Leu1 in leukemic and normal controls. As no mutations have been detected for Leu1 or any other transcript so far described, we cannot exclude the existence of control elements within the RMD that may regulate expression of genes lying in this region.

20
UI - 12096979
AU - Hatton MP; Rubin PA
TI - Chronic lymphocytic leukemia of the orbit.
SO - Arch Ophthalmol 2002 Jul;120(7):990-1
AD - Department of Oculoplastics, Orbit, and Cosmetic Surgery, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114, USA.

21
UI - 11998606
AU - Seeley K; DeMeyer E
TI - Nursing care of patients receiving Campath.
SO - Clin J Oncol Nurs 2002 May-Jun;6(3):138-43
AD - seelkm@stlo.smhs.com
Monoclonal antibodies are focused therapies with unique infusion-related complications. Campath (alemtuzumab, Berlex Laboratories, Richmond, CA) is indicated for the treatment of refractory chronic lymphocytic leukemia and has a complicated administration schedule, severe infusion-related toxicity, and profound immunosuppressive capability. Ambulatory cancer care is challenging simply because of the complex nature of the disease. Management of complicated therapies, such as Campath, stretches resources and requires a coordinated effort by the healthcare team for successful patient outcomes.

22
UI - 12082652
AU - Voliotis D; Diehl V
TI - Challenges in treating hematologic malignancies.
SO - Semin Oncol 2002 Jun;29(3 Suppl 8):30-9
AD - Clinic I for Internal Medicine, University of Cologne, Cologne, Germany.
During the past 40 years substantial progress has been made in the treatment of hematologic malignancies, particularly in some subgroups of patients. Today, cure is attainable for patients with Hodgkin's disease and a considerable proportion of patients with high-grade non-Hodgkin's lymphoma. Prognosis is improving in patients with acute promyelocytic leukemia and, to some extent, those with acute lymphoblastic and myeloid leukemias. However, the majority of patients who suffer from a hematologic malignancy live with incurable disease. In CLL, outside the setting of a clinical trial, it is advisable to postpone treatment until the manifestation of clinical symptoms. It is yet to be determined whether treatment strategies based on new prognostic parameters such as cytogenetics can change the course of disease. In indolent lymphomas, cure is not attainable for the vast majority of patients; the median survival of 9 to 10 years has remained unchanged for several decades. Nevertheless, there has been a dramatic change in therapeutic paradigms in the past few years. For the first time, with the use of new cytostatic drugs and recombinant monoclonal antibodies, it is possible to achieve molecular remissions. Whether this will translate into cure or prolonged survival is still to be determined. In Hodgkin's disease, which is curable when treated with radiotherapy, chemotherapy, or combined therapy, depending on the stage of disease, the focus of future studies must be on prevention of early relapse and on primary resistant disease, both of which present a very poor prognosis. Finally, regardless of underlying malignancy and prognosis, the preservation of quality of life is of major consideration in the setting of hematologic malignancies. Copyright 2002, Elsevier Science (USA). All rights reserved.

23
UI - 12082653
AU - Littlewood T; Mandelli F
TI - The effects of anemia in hematologic malignancies: more than a symptom.
SO - Semin Oncol 2002 Jun;29(3 Suppl 8):40-4
AD - Department of Haematology, John Radcliffe Hospital, Oxford, UK.
Anemia is a common complication in patients with hematologic malignancies, and is caused by a variety of mechanisms, including neoplastic cell infiltration into the bone marrow, hemolysis, nutritional deficiencies, and defects in erythropoiesis as a result of the disease itself or cytotoxic therapy. The anemia associated with multiple myeloma is caused by inadequate erythropoietin levels consequent to renal impairment and the effect of inflammatory cytokines. The degree of anemia can have prognostic importance, as is the case with multiple myeloma, or be a significant indicator of disease stage, as noted with chronic lymphocytic leukemia. Anemia results in fatigue, exhaustion, dizziness, headache, dyspnea, and decreased motivation, seriously affecting a patient's quality of life. Since anemia is so prevalent in hematologic malignancy patients, its treatment must be an integral part of disease management, to improve quality of life and to possibly increase potential survival. Clinical studies have shown that effectively treating anemia and increasing hemoglobin levels using recombinant human erythropoietin (rHuEPO, epoetin alfa) has a significant effect on transfusion requirements and quality of life. Copyright 2002, Elsevier Science (USA). All rights reserved.

24
UI - 12071942
AU - Mori A; Tamaru J; Sumi H; Kondo H
TI - Beneficial effects of rituximab on primary cold agglutinin disease refractory to conventional therapy.
SO - Eur J Haematol 2002 Apr;68(4):243-6
AD - Department of Medicine, Shimizu Kohsei Hospital, Shizuoka, Japan.
A case is reported of lymphoplasmacytoid lymphoma (LPL) associated with a monoclonal immunoglobulin (Ig) M and cold agglutinin disease (CAD) that was successfully treated with rituximab. A 52-yr-old male was admitted with a direct antiglobulin test positive haemolytic anaemia and thrombocytopenia associated with monoclonal IgM. Bone marrow examinations disclosed the marked infiltration of medium-sized lymphoma cells with plasmacytoid differentiation that indicated non-Hodgkin's lymphoma of B-cell origin (LPL). Prednisolone and combination chemotherapy were temporarily effective for both anaemia and thrombocytopenia, although these strategies became refractory and bone marrow lymphoplasmacytosis persisted. CAD ameliorated, and the serum level of IgM decreased in association with the disappearance of lymphoma cells and clonal rearrangement of the Ig heavy chains in the bone marrow after treatment with rituximab. Rituximab played a significant role in the treatment of refractory CAD associated with LPL.

25
UI - 12088111
AU - Bartkowiak J; Kulczyck-Wojdala D; Blonski JZ; Robak T
TI - Molecular diversity of gammadelta T cells in peripheral blood from patients with B-cell chronic lymphocytic leukaemia.
SO - Neoplasma 2002;49(2):86-90
AD - Department of Oncology, Medical University of Lodz, Poland. j.bartkowiak@pro.onet.pl
To characterize circulating gammadelta T cell subpopulations in B chronic lymphocytic leukaemia patients (n=30), TCR Vgamma and Vdelta gene-segment use was analyzed by RT-PCR using a panel of subfamily-specific oligonucleotide primers. All results were compared with those obtained with specimens from healthy donors (n=10). The cells expressing Vdelta1+ TCR displayed the highest relative increase in B-CLL patients (particularly observed in 60% of cases), but Vdelta3+ T lymphocytes also expanded in leukaemic peripheral blood (10% of studied cases). Both mentioned gammadelta T cell subsets were significantly more frequent in the most severe stages of disease--Rai III+IV. The analysis of Vgamma region usage in TCR formation revealed that gammadelta T cells from B-CLL patients predominantly expressed a Vgamma9 segment (26 of 30 cases), usually linked to Cgamma1 region. It should be noticed that the dominant TCR genes expression in a 50% of healthy donors was Vdelta2+/Vgamma9+, however, Vgamma4 and Vgamma8 transcripts were also observed (2 and 3 of 10 cases, respectively). The above results indirectly indicate that gammadelta T lymphocyte expansion was driven by the oligo- or polyclonal proliferation and can reflect specific response against the autologous tumor cells.

26
UI - 12036888
AU - Korz C; Pscherer A; Benner A; Mertens D; Schaffner C; Leupolt E; Dohner
TI - H; Stilgenbauer S; Lichter P Evidence for distinct pathomechanisms in B-cell chronic lymphocytic leukemia and mantle cell lymphoma by quantitative expression analysis of cell cycle and apoptosis-associated genes.
SO - Blood 2002 Jun 15;99(12):4554-61
AD - Abteilung Molekulare Genetik and Zentrale Einheit Biostatistik, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
The B-cell lymphoproliferative malignancies B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL) share characteristics, including overlapping chromosomal aberrations with deletions on chromosome bands 13q14, 11q23, 17p13, and 6q21 and gains on chromosome bands 3q26, 12q13, and 8q24. To elucidate the biochemical processes involved in the pathogenesis of B-CLL and MCL, we analyzed the expression level of a set of genes that play central roles in apoptotic or cell proliferation pathways and of candidate genes from frequently altered genomic regions, namely ATM, BAX, BCL2, CCND1, CCND3, CDK2, CDK4, CDKN1A, CDKN1B, E2F1, ETV5, MYC, RB1, SELL, TFDP2, TNFSF10, and TP53. Performing real-time quantitative reverse transcription polymerase chain reaction in a panel of patients with MCL and B-CLL and control samples, significant overexpression and underexpression was observed for most of these genes. Statistical analysis of the expression data revealed the combination of CCND1 and CDK4 as the best classifier concerning separation of both lymphoma types. Overexpression in these malignancies suggests ETV5 as a new candidate for a pathogenic factor in B-cell lymphomas. Characteristic deregulation of multiple genes analyzed in this study could be combined in a comprehensive picture of 2 distinctive pathomechanisms in B-CLL and MCL. In B-CLL, the expression parameters are in strong favor of protection of the malignant cells from apoptosis but did not provide evidence for promoting cell cycle. In contrast, in MCL the impairment of apoptosis induction seems to play a minor role, whereas most expression data indicate an enhancement of cell proliferation.

27
UI - 12070023
AU - Krackhardt AM; Harig S; Witzens M; Broderick R; Barrett P; Gribben JG
TI - T-cell responses against chronic lymphocytic leukemia cells: implications for immunotherapy.
SO - Blood 2002 Jul 1;100(1):167-73
AD - Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Chronic lymphocytic leukemia (CLL) cells are ineffective antigen-presenting cells (APCs) although CD40-activated CLL cells can stimulate proliferation of autologous and allogeneic T cells. We examined the antigen-presenting capacity of CD40-activated CLL cells as well as dendritic cells pulsed with apoptotic bodies of CLL cells to generate autologous and allogeneic immune responses against CLL cells. Both APC types were capable of generating T-cell lines that proliferate specifically in response to unstimulated CLL cells. Whereas cytotoxic responses against stimulated and unstimulated CLL cells could be repeatedly generated by allogeneic healthy donors, autologous cytotoxic immune responses against CD40-activated and native CLL cells were rarely detected. However, T cells isolated from patients with CLL could recognize and lyse allogeneic stimulated and unstimulated CLL cells, demonstrating that cytotoxic T cells from these tumor-bearing patients are functionally intact.

28
UI - 12111770
AU - Doerr CH; Staats BA; Markovic SN
TI - Chylothorax in chronic lymphocytic leukemia patient.
SO - Am J Hematol 2002 Jul;70(3):237-40
AD - Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. doerr.clinton@mayo.edu
Chronic lymphocytic leukemia (CLL) is rarely complicated by chylothorax: we present a 93-year-old woman with CLL who developed recurrent pleural effusions that were ultimately found to be chylous in nature. Despite eight repeated thoracenteses, she continued to experience re-accumulation of fluid, and therefore, video-assisted thoracotomy with mass ligation of the thoracic duct region plus pleurodesis was performed to resolve the chylothorax. Despite her age and underlying disease, she did well during follow-up. The etiology and management of chylothorax are also reviewed. Copyright 2002 Wiley-Liss, Inc.

29
UI - 11368926
AU - Oltra AM; Carbonell F; Tormos C; Iradi A; Saez GT
TI - Antioxidant enzyme activities and the production of MDA and 8-oxo-dG in chronic lymphocytic leukemia.
SO - Free Radic Biol Med 2001 Jun 1;30(11):1286-92
AD - Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Valencia, Valencia, Spain.
Chronic lymphocytic leukemia (CLL) is a neoplastic disease susceptible to antioxidant enzyme alterations and oxidative stress. We have examined the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and the oxidized/reduced glutathione (GSSG/GSH) ratio together with the levels of malondialdehyde (MDA) and 8-oxo-2'-deoxyguanosine (8-oxo-dG) in lymphocytes of CLL patients and compared them with those of normal subjects of the same age. SOD and CAT activity decreased in CLL lymphocytes while GPx activity increased. GSH content of CLL lymphocytes also increased, and GSSG concentration remained constant. Thus, a reduced GSSG/GSH ratio was obtained. The oxidation product MDA, and the damaged DNA base 8-oxo-dG were also increased in CLL. The observed changes in enzyme activities, GSSG/GSH ratio, and MDA were significantly enhanced as the duration of the disease increased in years. The results support a predominant oxidative stress status in CLL lymphocytes and emphasize the role of the examined parameters as markers of the disease evolution.

30
UI - 12060822
AU - Haura EB; Winden MA; Proia AD; Trotter JE
TI - Fulminant hepatic failure due to disseminated adenovirus infection in a patient with chronic lymphocytic leukemia.
SO - Cancer Control 2002 May-Jun;9(3):248-53
AD - Thoracic Oncology and xperimental Therapeutics Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

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