MedWorm: Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia

Clinical Care Options Oncology - Leukemia — Tue, 07 Feb 2012 15:36:47 +0100

Learning Module - In this CME-certified slideset, John C. Byrd, MD, and Kanti Rai, MD, explore the most compelling data in chronic lymphocytic leukemia presented in San Diego. (Source: Clinical Care Options Oncology - Leukemia)

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Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia

Blood — Thu, 02 Feb 2012 05:00:00 +0100

Chronic lymphocytic leukemia (CLL) demonstrates a global down-regulation of miR-15a and miR-16 and a selective silencing of the related miR-29b in aggressive disease. Deletions in chromosome 13 [del(13q14)] partially account for the loss of expression of miR-15a and miR-16, but the mechanisms by which miR-29b becomes silenced is unknown. In the present study, we show that the histone deacetylases (HDACs) are overexpressed in CLL and mediate the epigenetic silencing of miR-15a, miR-16, and miR-29b. HDAC inhibition triggered the accumulation of the transcriptionally activating chromatin modification H3K4me2 and restored the expression of miR-15a, miR-16, and miR-29b in approximately 35% of samples. Ectopic expression of miR-15a and miR-16 and HDAC inhibition–induced expression of miR-1...

The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo

Blood — Thu, 02 Feb 2012 05:00:00 +0100

In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13). PCI-32765 also down-regulated secretion of BCR-dependent chemokines (CCL3, CCL4) by the CLL cells, both in vitro and in vivo. In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 affected disease progression. In this model, PCI-32765 caused a transient early lymphocytosis, and profoundly inhibited CLL progression, as assessed by weight, development, and extent of hepatospenomegaly, and survival. Our data demonstrate that PCI-32765 effectively inhib...

Pathologic and Molecular Genetic Features of Chronic Lymphocytic Leukemia

Seminars in Oncology — Wed, 01 Feb 2012 05:00:00 +0100

Chronic lymphocytic leukemia (CLL) is an indolent B-cell leukemia. While many patients may not require therapy, some patients will suffer a progressive course and die of their disease. This clinical heterogeneity is reflected in the molecular genetic heterogeneity that is becoming apparent through studies of immunoglobulin heavy chain gene mutational status, chromosomal numerical abnormalities, microRNA abnormalities, and genetic abnormalities identified by whole genome sequencing. Indeed, many of these studies are becoming routine in the assessment of patients with CLL or being incorporated into clinical trials to further stratify patients for appropriate therapies. Here, we will review the morphologic, immunophenotypic, and molecular genetic features of CLL and touch upon the concept of ...

IGHV gene mutational status and 17p deletion are independent molecular predictors in a comprehensive clinical-biological prognostic model for overall survival prediction in chronic lymphocytic leukemia

Journal of Translational Medicine — Mon, 30 Jan 2012 05:00:00 +0100

Conclusions: Data indicate that IGHV mutational status and 17p deletion may be integrated with clinical-demographic variables in new prognostic tools to estimate overall survival. (Source: Journal of Translational Medicine)

Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL

Blood — Thu, 26 Jan 2012 05:00:00 +0100

Hedgehog (HH) signaling is activated in various lymphoid malignancies, but conflicting results exist about its role in chronic lymphocytic leukemia (CLL). Here, we demonstrate that the expression of essential HH pathway components like GLI1, PTCH1, and the HH ligands is highly diverse in CLL. A subset of 36.7% of 60 tested CLL samples responded to all 3 SMOOTHENED (SMO) inhibitors, whereas 40% were completely resistant. Responsiveness correlated with elevated GLI1 and PTCH1 transcript levels and the presence of trisomy 12, whereas no other karyotype correlated with responsiveness. All trisomy 12 CLLs displayed constitutive HH pathway activation driven by autocrine DESERT HH (DHH) ligand secretion, which could be blocked by the HH-blocking Ab 5E1. Cocultures with DHH-expressing BM stromal c...

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Flavopiridol treatment of patients aged 70 or older with refractory or relapsedchronic lymphocytic leukemia is a feasible and active therapeutic approach.

Haematologica — Sun, 22 Jan 2012 05:00:00 +0100

Authors: Stephens D, Ruppert AS, Blum K, Jones J, Flynn J, Johnson A, Ji J, Phelps M, Grever M, Byrd J Abstract Older chronic lymphocytic leukemia patients have poor outcomes with standard treatments and are underrepresented in clinical trials. We retrospectively reviewed outcomes of refractory chronic lymphocytic leukemia patients in two age categories [≥70, <70 years] treated with single-agent flavopiridol, a drug active in genomically high-risk patients, during two trials. No significant difference between older and younger patients was observed in response rates (43% versus 47%) or progression-free survival (median=8.7 versus 9.9 months, p>0.80). Although overall survival was worse in older patients (median=2.1 versus 2.4 years, p=0.02), when adjusted for other factors,...

“Best of ASH” Features Two Studies with Contributions from US Oncology Research 01-20-2012

McKesson News — Fri, 20 Jan 2012 23:06:24 +0100

Studies focused on treatment of Chronic Lymphocytic Leukemia (CLL) recognized by the American Society of Hematology (Source: McKesson News)

Longitudinal genome-wide analysis of patients with chronic lymphocytic leukemia reveals complex evolution of clonal architecture at disease progression and at the time of relapse

Leukemia — Fri, 20 Jan 2012 05:00:00 +0100

Authors: E Braggio, N E Kay, S VanWier, R C Tschumper, S Smoley, J E Eckel-Passow, T Sassoon, M Barrett, D L Van Dyke, J C Byrd, D F Jelinek, T D Shanafelt & R Fonseca (Source: Leukemia)

Composite Hodgkin lymphoma and chronic lymphocytic leukemia: A rare case

Journal of Cancer Research and Therapeutics — Thu, 19 Jan 2012 05:00:00 +0100

Krishnakumar Rathnam, Shashidhar Karpurmath, Sanju Cyriac, Sagar Tenali Gnana, Shirley SundersinghJournal of Cancer Research and Therapeutics 2011 7(4):484-485 (Source: Journal of Cancer Research and Therapeutics)

An Increased Number of Individuals with Clinically Recognized Monoclonal B-Cell Lymphocytosis Characterizes a Recent Database of Chronic Lymphocytic Leukemia Rai Stage 0.

Acta Haematologica — Thu, 19 Jan 2012 05:00:00 +0100

Authors: Molica S, Gentile M, Mauro FR, Brugiatelli M, Federico M, Sperduti I, Neri A, Ferrarini M, Foà R, Morabito F Abstract No abstract available. PMID: 22262125 [PubMed - as supplied by publisher] (Source: Acta Haematologica)

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Quantification of subclonal distributions of recurrent genomic aberrations in paired pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia

Leukemia — Thu, 19 Jan 2012 05:00:00 +0100

Authors: S J L Knight, C Yau, R Clifford, A T Timbs, E Sadighi Akha, H M Dréau, A Burns, C Ciria, D G Oscier, A R Pettitt, S Dutton, C C Holmes, J Taylor, J-B Cazier & A Schuh (Source: Leukemia)

Expression of natural killer cell activating receptors in patients with chronic lymphocytic leukaemia

Immunology — Tue, 17 Jan 2012 11:21:23 +0100

(Source: Immunology)

The assessment of minimal residual disease in chronic lymphocytic leukaemia: comparison of multi-colour flow cytometry and bone marrow trephine biopsy

Journal of Hematopathology — Tue, 17 Jan 2012 07:07:47 +0100

Abstract We investigated the value and degree of agreement between a sensitive four-colour flow cytometry (FC) method and bone marrow trephine (BMT) biopsy for detecting minimal residual disease (MRD) in 82 chronic lymphocytic leukaemia (CLL) cases. Concordance was 85%, with 15% of cases discrepant (six BMT-positive/FC-negative and six BMT-negative/FC-positive cases). FC-positive/BMT-negative cases had a low-level MRD by FC (0.05–0.9%), whereas BMT-positive/FC-negative cases had significant residual nodular disease. We conclude that FC and BMT biopsy are complementary investigations for MRD assessment in CLL, and both should be considered in the routine setting to assess MRD in CLL. Content Type Journal ArticleCategory Original ArticlePages 1-5DOI 10.1007/s12308-011-...

Genetics: Splicing the pieces of the chronic lymphocytic leukemia puzzle

Nature Clinical Practice Oncology — Tue, 17 Jan 2012 05:00:00 +0100

Nature Reviews Clinical Oncology 9, 66 (2012). doi:10.1038/nrclinonc.2011.216 Author: M. Teresa Villanueva B-cell chronic lymphocytic leukemia (CLL) is the most common type of leukemia and it is characterized by the accumulation of impaired mature B lymphocytes in the blood and bone marrow. Although it progresses slowly in many cases and these patients may have normal active lives (Source: Nature Clinical Practice Oncology)

Outcome of patients with relapsed or refractory chronic lymphocytic leukemia treated with flavopiridol: impact of genetic features

Leukemia — Fri, 13 Jan 2012 05:00:00 +0100

Authors: J A Woyach, G Lozanski, A S Ruppert, A Lozanski, K A Blum, J A Jones, J M Flynn, A J Johnson, M R Grever, N A Heerema & J C Byrd (Source: Leukemia)

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A role for Danazol in chronic lymphocytic leukemia

Leukemia — Fri, 13 Jan 2012 05:00:00 +0100

Authors: S Tung & D E Spaner (Source: Leukemia)

SOCS1 is significantly up-regulated in Nutlin-3-treated p53wild-type B chronic lymphocytic leukemia (B-CLL) samples and shows an inverse correlation with miR-155

Investigational New Drugs — Thu, 12 Jan 2012 06:43:03 +0100

Summary The basal SOCS1 mRNA levels were significantly lower in p53mutated BJAB and MAVER leukemic cell lines with respect to p53wild-type SKW6.4 and JVM-2 leukemic cell lines, p53wild-type primary B chronic lymphocytic leukemia (B-CLL) cells and primary normal peripheral blood mononuclear cells (PBMC). Moreover, the MDM2 small molecule inhibitor Nutlin-3 significantly increased the levels of SOCS1 mRNA in both primary p53wild-type B-CLL cells as well as in p53wild-type B leukemic cell lines, but not in p53mutated B leukemic cell lines nor in primary PBMC. Of note, a significant inverse correlation was observed between SOCS1 mRNA and miR-155 levels in Nutlin-3-treated primary B-CLL cells and PBMC, suggesting that the miRNA-155/SOCS1 axis represents a potentially important the...

NOTCH1 mutations in CLL associated with trisomy 12

Blood — Thu, 12 Jan 2012 05:00:00 +0100

Two recent studies reported wholegenome sequencing of chronic lymphocytic leukemia (CLL) samples and found repeated mutations in the XPO1 and NOTCH1 genes. XPO1 was found mutated in 2.4% of cases, while NOTCH1 was found mutated in 12.2% or 15.1% of CLL samples. Here we report the results of sequencing of XPO1 and NOTCH1 in 186 CLL cases. Our results confirmed frequency of XPO1 mutations. However, we found only 5 NOTCH1 mutations in 127 IGVH unmutated/ZAP70+ CLL samples (4%), and one mutation was found in IGVH mutated/ZAP70– CLL for a total percentage of 1.5%. Because 4 of 6 mutated samples also showed trisomy 12, we sequenced NOTCH1 in an additional 77 cases with trisomy 12 CLLs, including 47 IGVH unmutated/ZAP70+ cases. Importantly, we found 41.9% NOTCH1 mutation frequency in aggres...

Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia

Blood — Thu, 12 Jan 2012 05:00:00 +0100

Analysis of the chronic lymphocytic leukemia (CLL) coding genome has recently disclosed that the NOTCH1 proto-oncogene is recurrently mutated at CLL presentation. Here, we assessed the prognostic role of NOTCH1 mutations in CLL. Two series of newly diagnosed CLL were used as training (n = 309) and validation (n = 230) cohorts. NOTCH1 mutations occurred in 11.0% and 11.3% CLL of the training and validation series, respectively. In the training series, NOTCH1 mutations led to a 3.77-fold increase in the hazard of death and to shorter overall survival (OS; P < .001). Multivariate analysis selected NOTCH1 mutations as an independent predictor of OS after controlling for confounding clinical and biologic variables. The independent prognostic value of NOTCH1 mutations was externally confirmed...

Mechanisms and consequences of the loss of PHLPP1 phosphatase in chronic lymphocytic leukemia (CLL)

Leukemia — Thu, 12 Jan 2012 05:00:00 +0100

Authors: M O'Hayre, M Niederst, J F Fecteau, V M Nguyen, T J Kipps, D Messmer, A C Newton & T M Handel (Source: Leukemia)

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Can Prognostic Factors Be Used to Direct Therapy in Chronic Lymphocytic Leukemia?

Current Hematologic Malignancy Reports — Wed, 11 Jan 2012 17:56:53 +0100

Abstract Chronic lymphocytic leukemia (CLL) shows a heterogeneous clinical course, which can be explained in part by prognostic factors. Most patients do not need treatment at the time of first diagnosis. The identification of prognostic factors is of major interest if strategies can be devised to treat patients according to their individual risk profile or biological subgroup. Currently, in spite of a wealth of prognostic factors, individualized treatment approaches in different genetic or risk groups are the exemption in CLL. This review summarizes the most important prognostic and predictive factors in CLL, with particular emphasis on factors affecting treatment decisions in clinical trials and routine practice. Content Type Journal ArticleCategory Chronic Lymphocyt...

Mantle cell lymphoma displays a homogenous methylation profile: A comparative analysis with chronic lymphocytic leukemia

American Journal of Hematology — Wed, 11 Jan 2012 05:00:00 +0100

AbstractMantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are mature CD5+ B‐cell malignancies with different biological/clinical characteristics. We recently reported an association between different prognostic subgroups of CLL (i.e. IGHV mutated and unmutated) and genomic methylation pattern. However, the relationship between DNA methylation and prognostic markers, such as the proliferation gene expression signature, has not been investigated in MCL. We applied high‐resolution methylation microarrays (27,578 CpG sites) to assess the global DNA methylation profiles in 20 MCL (10 each with high/low proliferation signature) and 30 CLL (15 poor‐prognostic IGHV unmutated subset #1 and 15 good‐prognostic IGHV mutated subset #4) samples. Notably, MCL and each CLL subset d...

Chronic Lymphocytic Leukemia

Clinical Care Options Oncology - Leukemia — Wed, 11 Jan 2012 00:00:00 +0100

CCO Slideset - In this downloadable slideset, John C. Byrd, MD, and Kanti Rai, MD, review the most compelling data in the treatment of chronic lymphocytic leukemia presented at the 2011 American Society of Hematology Annual Meeting. (Source: Clinical Care Options Oncology - Leukemia)

Treatment of Older Patients with Chronic Lymphocytic Leukemia

Current Hematologic Malignancy Reports — Tue, 10 Jan 2012 16:49:22 +0100

Abstract Chronic lymphocytic leukemia (CLL) is typically a disease of older individuals. Yet most of the literature on various chemotherapeutic regimens includes patients who are 10 to 15 years younger than the median age at diagnosis of this disease. The older patient population is grossly underrepresented in clinical trials. Currently available therapies are often too toxic for this older patient population, so their efficacy is reduced. This review discusses some of the results of treatment in older patients with CLL. A discussion of factors that often affect outcome, such as comorbidities, renal function, bone marrow reserve, and infection, are also reviewed, along with quality of life. Content Type Journal ArticleCategory Chronic Lymphocytic Leukemia (S O'Bri...

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Population Pharmacokinetics of Rituximab in Patients With Chronic Lymphocytic Leukemia.

The Journal of Clinical Pharmacology — Tue, 10 Jan 2012 05:00:00 +0100

Authors: Li J, Zhi J, Wenger M, Valente N, Dmoszynska A, Robak T, Mangat R, Joshi A, Visich J Abstract This retrospective analysis characterizes rituximab population pharmacokinetics in combination with fludarabine and cyclophosphamide and its effect on fludarabine and cyclophosphamide disposition in chronic lymphocytic leukemia (CLL) patients. Rituximab concentration data were well described by a 2-compartment model comprising a time-varying clearance component related to the target-mediated clearance pathway and a constant clearance component reflecting catabolic elimination pathway. Marked differences were observed compared to pharmacokinetic parameters for non-Hodgkin lymphoma (NHL) obtained previously: in CLL, time-varying clearance at time zero (CL(2)) was faster, volumes of ...

Hepatitis B reactivation despite entecavir prophylaxis in a patient with chronic lymphocytic leukaemia receiving bendamustine

Journal of Antimicrobial Chemotherapy — Tue, 10 Jan 2012 05:00:00 +0100

(Source: Journal of Antimicrobial Chemotherapy)

Histone Deacetylase in Chronic Lymphocytic Leukemia.

Oncology — Tue, 10 Jan 2012 05:00:00 +0100

Conclusions: These results suggest: (1) in CLL, elevated HDAC isoenzyme activity is not restricted to one class, and therefore, HDACi therapy may need to be directed to more than one specific class of HDAC; (2) higher HDAC expression activity may indicate a poor prognosis and more advanced disease stage (through indirect evidence), since higher values were found in patients with ZAP-70+ and higher CD44 expression levels. PMID: 22237050 [PubMed - as supplied by publisher] (Source: Oncology)

Hematological cancer in 2011: New therapeutic targets and treatment strategies

Nature Clinical Practice Oncology — Tue, 10 Jan 2012 05:00:00 +0100

Authors: Paula Cramer & Michael Hallek 2011 saw improvements in our understanding of B-cell malignancies: insights into the genomic basis of chronic lymphocytic leukemia were achieved; reduced treatment intensity caused fewer toxic effects in early-stage Hodgkin lymphoma; first-line rituximab maintenance therapy improved outcome in follicular lymphoma; and selected patients with diffuse large-cell lymphoma benefited from the addition of bortezomib. (Source: Nature Clinical Practice Oncology)

Immune Reconstitution in Chronic Lymphocytic Leukemia

Current Hematologic Malignancy Reports — Mon, 09 Jan 2012 19:39:48 +0100

This article reviews the immune defect in CLL and discusses strategies aimed at repairing or circumventing this defect. In particular, it focuses on recent developments in the areas of CD40 ligand (CD40L/CD154) gene therapy, immunomodulatory agents such as lenalidomide, and adoptive transfer of T cells bearing chimeric antigen receptors. Content Type Journal ArticleCategory Chronic Lymphocytic Leukemia (S O'Brien, Section Editor)Pages 1-8DOI 10.1007/s11899-011-0106-xAuthors John C. Riches, Barts Cancer Institute, Queen Mary University of London, 3rd Floor John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ UKAlan G. Ramsay, Barts Cancer Institute, Queen Mary University of London, 3rd Floor John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ UKJohn G. Gribbe...

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Monoclonal B‐cell lymphocytosis is closely related to chronic lymphocytic leukaemia and may be better classified as early‐stage CLL

British Journal of Haematology — Mon, 09 Jan 2012 05:00:00 +0100

This study analysed 298 MBL patients by multi‐parameter flow cytometry, chromosome banding analysis (CBA)/fluorescence in situ hybridization (FISH), and IGHV mutation status and compared them with 356 CLL patients. In MBL, CBA more frequently revealed a normal karyotype and FISH identified less frequently del(6q), del(13q) (as sole alterations), and del(17)(p13). Within the MBL cohort, a shorter time to treatment (TTT) was found for ZAP‐70‐positivity, 14q32/IGH‐translocations (CBA), del(11)(q22·3) (FISH) and unmutated IGHV status. Higher CD38 and ZAP‐70 expression, del(11)(q22·3) (FISH), trisomy 12 (FISH), and 14q32/IGH‐translocations (CBA) were correlated with a shorter TTT in the combined cohort (MBL + CLL); a sole del(13)(q14) (FISH) correlated with longer TTT. Regardi...

Chronic lymphocytic leukaemia with 17p deletion: a retrospective analysis of prognostic factors and therapy results

British Journal of Haematology — Mon, 09 Jan 2012 05:00:00 +0100

SummaryPatients with chronic lymphocytic leukaemia (CLL) whose tumour cells harbour a 17p deletion (17p‐) are universally considered to have a poor prognosis. The deletion can be detected at diagnosis or during the evolution of the disease, particularly in patients who have received chemotherapy. We sought to evaluate the natural history of patients with 17p‐ CLL, identify predictive factors within this prognostic subgroup, and evaluate the results of different therapeutic approaches. Data from 294 patients with 17p‐ CLL followed up at 20 different institutions was retrospectively collected and analysed. Median age was 68 (range 27–98) years at the time of fluorescence in situ hybridization analysis. After 17p‐ documentation, 52% received treatment, achieving an overall response ...

Individualized Fludarabine-Based Regimen in Elderly Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

Advances in Therapy — Mon, 09 Jan 2012 05:00:00 +0100

CONCLUSION: The individual regimen of fludarabine combined with rituximab demonstrated marked clinical efficacy and acceptable toxicity in elderly patients with CLL/SLL. PMID: 22249944 [PubMed - as supplied by publisher] (Source: Advances in Therapy)

Histone deacetylase inhibitors are unable to synergize with ABT-737 in killing primary chronic lymphocytic leukaemia cells in vitro

Leukemia — Fri, 06 Jan 2012 05:00:00 +0100

Authors: R Ralli, K M Banks, A P Wiegmans, D Carney, J F Seymour, R W Johnstone & A E Alsop (Source: Leukemia)

Monoclonal antibodies against ROR1 induce apoptosis of chronic lymphocytic leukemia (CLL) cells

Leukemia — Fri, 06 Jan 2012 05:00:00 +0100

Authors: A H Daneshmanesh, M Hojjat-Farsangi, A S Khan, M Jeddi-Tehrani, M M Akhondi, A A Bayat, R Ghods, A-R Mahmoudi, R Hadavi, A Österborg, F Shokri, H Rabbani & H Mellstedt (Source: Leukemia)

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The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells

Leukemia — Fri, 06 Jan 2012 05:00:00 +0100

The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells Leukemia advance online publication, January 6, 2012. doi:10.1038/leu.2011.369 Authors: A Zucchetto, T Vaisitti, D Benedetti, E Tissino, V Bertagnolo, D Rossi, R Bomben, M Dal Bo, M I Del Principe, A Gorgone, G Pozzato, G Gaidano, G Del Poeta, F Malavasi, S Deaglio & V Gattei (Source: Leukemia)

Surface IgM stimulation induces MEK1/2-dependent MYC expression in chronic lymphocytic leukemia cells

Blood — Thu, 05 Jan 2012 05:00:00 +0100

Although long considered as a disease of failed apoptosis, it is now clear that chronic lymphocytic leukemia (CLL) cells undergo extensive cell division in vivo, especially in progressive disease. Signaling via the B-cell receptor is thought to activate proliferation and survival pathways in CLL cells and also has been linked to poor outcome. Here, we have analyzed the expression of the proto-oncoprotein MYC, an essential positive regulator of the cell cycle, after stimulation of surface IgM (sIgM). MYC expression was rapidly increased after sIgM stimulation in a subset of CLL samples. The ability of sIgM stimulation to increase MYC expression was correlated with sIgM-induced intracellular calcium fluxes. MYC induction was partially dependent on the MEK/ERK signaling pathway, and MYC and p...

Tcl1 interacts with Atm and enhances NF-{kappa}B activation in hematologic malignancies

Blood — Thu, 05 Jan 2012 05:00:00 +0100

The T-cell leukemia/lymphoma 1 (TCL1) oncogene is a target of chromosomal translocations and inversions at 14q31.2, and its rearrangement in T cells causes T-cell prolymphocytic leukemias. TCL1 dysregulation in B cells is responsible for the development of an aggressive form of chronic lymphocytic leukemia (CLL), the most common human leukemia. We have investigated the mechanisms underlying the oncogenic functions of Tcl1 protein using a mass spectrometry approach and have identified Atm (ataxia-telangiectasia mutated) as a candidate Tcl1-interacting protein. The Tcl1-Atm complex formation was validated by coimmunoprecipitation experiments. Importantly, we show that the association of Atm with Tcl1 leads to enhanced IBα phosphorylation and ubiquitination and subsequent activation of ...

Expression of ERp5 and GRP78 on the membrane of chronic lymphocytic leukemia cells: association with soluble MICA shedding

Cancer Immunology, Immunotherapy — Wed, 04 Jan 2012 06:47:57 +0100

In conclusion, these results uncover a molecular mechanism which regulates MICA protein shedding and immune evasion in CLL. Content Type Journal ArticleCategory Original ArticlePages 1-10DOI 10.1007/s00262-011-1195-zAuthors Leticia Huergo-Zapico, Functional Biology Department. Instituto Universitario Oncologico del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, SpainAna P. Gonzalez-Rodriguez, Hematology Department, Hospital Cabueñes, Gijón, SpainJuan Contesti, Hematology Department, Hospital Cabueñes, Gijón, SpainEsther Gonzalez, Hematology Department, Hospital Cabueñes, Gijón, SpainAlejandro López-Soto, Functional Biology Department. Instituto Universitario Oncologico del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, SpainAzahara Fernandez-G...

ATM and chronic lymphocytic leukemia: mutations, and not only deletions, matter.

Haematologica — Sun, 01 Jan 2012 05:00:00 +0100

Authors: Rossi D, Gaidano G PMID: 22210328 [PubMed - in process] (Source: Haematologica)

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New Class of Drug May Vanquish CLLNew Class of Drug May Vanquish CLL

Medscape Today Headlines — Thu, 29 Dec 2011 23:06:42 +0100

The novel small molecule navitoclax blocks the function of Bcl-2, a protein essential for the growth of chronic lymphocytic leukemia cells, and may represent a "revolution" in the treatment of CLL. Medscape Medical News (Source: Medscape Today Headlines)

Bone marrow stromal cell-derived vascular endothelial growth factor (VEGF) rather than chronic lymphocytic leukemia (CLL) cell-derived VEGF is essential for the apoptotic resistance of cultured CLL cells.

Molecular Medicine — Thu, 29 Dec 2011 07:24:03 +0100

In this study, the VEGF status in CLL was assessed by enzyme-linked immunosorbent assay and immunofluorescence. VEGF receptor 2 (VEGFR2) phosphorylation was determined flow cytometrically and by immunofluorescence. For co-culture, CLL cells were cultivated on a monolayer of the bone marrow-derived stromal cell (BMSC) line HS5. Secreted VEGF was neutralized using the monoclonal antibody mAb293 (R&D Systems, Minneapolis, MN, USA). To block protein secretion, we used Brefeldin A. VEGF was downregulated in BMSCs by small interfering RNA (siRNA), and we assessed survival by annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. CLL cells express and secrete VEGF and possess phosphorylated VEGFR2. This positive VEGF status is not sufficient to prevent spontaneous apoptos...

Chronic lymphocytic leukemia and prolymphocytic leukemia with MYC translocations: a subgroup with an aggressive disease course

Annals of Hematology — Thu, 29 Dec 2011 06:42:41 +0100

In conclusion, CLL/PLL with MYC translocations is a rare entity, which seems to be associated with adverse prognostic features and unfavorable outcome. Content Type Journal ArticleCategory Original ArticlePages 1-11DOI 10.1007/s00277-011-1393-yAuthors Natalie Put, Center for Human Genetics, Catholic University of Leuven, Herestraat 49, 3000 Leuven, BelgiumKatrien Van Roosbroeck, Center for Human Genetics, Catholic University of Leuven, Herestraat 49, 3000 Leuven, BelgiumPeter Konings, Department of Electrical Engineering/IBBT-K.U. Leuven Future Health Department, Catholic University of Leuven, Leuven, BelgiumPeter Meeus, Center for Human Genetics, Catholic University of Leuven, Herestraat 49, 3000 Leuven, BelgiumCaroline Brusselmans, Department of Clinical Biology, University Hospit...

NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL.

Haematologica — Thu, 29 Dec 2011 05:00:00 +0100

Authors: Del Giudice I, Rossi D, Chiaretti S, Marinelli M, Tavolaro S, Gabrielli S, Laurenti L, Marasca R, Rasi S, Fangazio M, Guarini A, Gaidano G, Foa' R Abstract Trisomy 12, the third most frequent chromosomal aberration in chronic lymphocytic leukemia (CLL), confers an intermediate prognosis. In our cohort of 104 untreated patients carrying +12, NOTCH1 mutations occurred in 24% of cases and were associated to unmutated IGHV genes (p=.003) and +12 as a sole cytogenetic abnormality (p=.008). NOTCH1 mutations in +12 CLL associated with a ~2.4 fold increase in the death risk, a significant survival shortening (p<.001) and proved an independent predictor of survival in multivariate analysis. Analogous to +12 CLL with TP53 disruption or del(11q), NOTCH1 mutations in +12 CLL confer...

Physical contact with endothelial cells through β1- and β2- integrins rescues chronic lymphocytic leukemia from spontaneous and drug-induced apoptosis and induces a peculiar gene expression profile on leukemic cells.

Haematologica — Thu, 29 Dec 2011 05:00:00 +0100

ConclusionOur study supports the notion that endothelial cells are major players in chronic lymphocytic leukemia microenvironment. Adhesion to endothelium strongly sustains survival, protects from drug-induced apoptosis and widely modifies gene expression profile of leukemic cells. PMID: 22207686 [PubMed - as supplied by publisher] (Source: Haematologica)

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Multiple myeloma shows no intra-disease clustering of immunoglobulin heavy chain genes.

Haematologica — Thu, 29 Dec 2011 05:00:00 +0100

Conclusions. Analysis of multiple myeloma immunoglobulin repertoire does not support a pathogenetic role for antigen selection in this tumor. PMID: 22207685 [PubMed - as supplied by publisher] (Source: Haematologica)

Spliceosome mutations in hematopoietic malignancies

Nature Genetics — Tue, 27 Dec 2011 05:00:00 +0100

Authors: Christopher N Hahn & Hamish S Scott Recent studies, including two in this issue, report heterozygous missense mutations in the U2AF1 and SF3B1 genes that encode spliceosome subunits. U2AF1 is frequently mutated in myeloid hematopoietic malignancies, especially in myelodysplastic syndrome (MDS), and SF3B1 is frequently mutated in both MDS and chronic lymphocytic leukemia (CLL). (Source: Nature Genetics)

High-throughput VDJ sequencing for quantification of minimal residual disease in chronic lymphocytic leukemia and immune reconstitution assessment [Medical Sciences]

Proceedings of the National Academy of Sciences — Tue, 27 Dec 2011 05:00:00 +0100

The primary cause of poor outcome following allogeneic hematopoietic cell transplantation (HCT) for chronic lymphocytic leukemia (CLL) is disease recurrence. Detection of increasing minimal residual disease (MRD) following HCT may permit early intervention to prevent clinical relapse; however, MRD quantification remains an uncommon diagnostic test because of logistical and financial barriers to widespread use. Here we describe a method for quantifying CLL MRD using widely available consensus primers for amplification of all Ig heavy chain (IGH) genes in a mixture of peripheral blood mononuclear cells, followed by high-throughput sequencing (HTS) for disease-specific IGH sequence quantification. To achieve accurate MRD quantification, we developed a systematic bioinformatic methodology to a...

Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness

Blood — Thu, 22 Dec 2011 05:00:00 +0100

The genetic lesions identified in chronic lymphocytic leukemia (CLL) do not entirely recapitulate the disease pathogenesis and the development of serious complications, such as chemorefractoriness. While investigating the coding genome of fludarabine-refractory CLL, we observed that mutations of SF3B1, encoding a splicing factor and representing a critical component of the cell spliceosome, were recurrent in 10 of 59 (17%) fludarabine-refractory cases, with a frequency significantly greater than that observed in a consecutive CLL cohort sampled at diagnosis (17/301, 5%; P = .002). Mutations were somatically acquired, were generally represented by missense nucleotide changes, clustered in selected HEAT repeats of the SF3B1 protein, recurrently targeted 3 hotspots (codons 662, 666, and 700),...

[Rare association between chronic lymphocytic leukemia and systemic lupus erythematosus.]

Presse Medicale — Thu, 22 Dec 2011 05:00:00 +0100

Authors: Dieval C, Herrador C, Guiboux AL, Haramburu F, Mercié P PMID: 22197401 [PubMed - as supplied by publisher] (Source: Presse Medicale)

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Expansion of a CD8+PD-1+ replicative senescence phenotype in early stage CLL patients is associated with inverted CD4:CD8 ratios and disease progression.

Clinical Cancer Research — Wed, 21 Dec 2011 05:00:00 +0100

CONCLUSIONS: Our data show that the emergence of CD8+PD-1+ replicative senescence phenotype in early stage CLL patients is associated with more aggressive clinical disease. Importantly, these findings were independent of tumor cell prognostic markers and could not be accounted for by patient age, changes in regulatory T cell frequency or cytomegalovirus serostatus. PMID: 22190592 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)

Diagnostic Usefulness and Prognostic Impact of CD200 Expression in Lymphoid Malignancies and Plasma Cell Myeloma.

American Journal of Clinical Pathology — Tue, 20 Dec 2011 15:14:08 +0100

Authors: Alapat D, Coviello-Malle J, Owens R, Qu P, Barlogie B, Shaughnessy JD, Lorsbach RB Abstract The membrane glycoprotein MRC OX-2 (CD200) is expressed in several lymphoid malignancies. However, the diagnostic usefulness and potential prognostic importance of CD200 expression have not been rigorously examined. We show that CD200 is uniformly expressed in chronic lymphocytic leukemia (CLL) and absent in mantle cell lymphoma (MCL). It is important to note that expression of CD200 is retained even in CLLs with immunophenotypic aberrancies, making CD200 a particularly useful marker for discrimination between these cases and MCL. CD200 is expressed in nearly all precursor B-lymphoblastic leukemias, with aberrant overexpression or underexpression compared with normal B-cell progenit...

Characteristics of chronic lymphocytic leukemia with somatically acquired mutations in NOTCH1 exon 34

Leukemia — Tue, 20 Dec 2011 05:00:00 +0100

Authors: K Shedden, Y Li, P Ouillette & S N Malek (Source: Leukemia)

NEJM study finds leukaemia DNA mutations

Pharmacy Europe — Mon, 19 Dec 2011 12:07:00 +0100

Results may aid treatment decisions in chronic lymphocytic leukaemia (Source: Pharmacy Europe)

Downregulation of BCL2 by AT‐101 enhances the antileukaemic effect of lenalidomide both by an immune dependant and independent manner

British Journal of Haematology — Fri, 16 Dec 2011 10:18:32 +0100

SummaryOver‐expression of anti‐apoptotic BCL2 has been reported in chronic lymphocytic leukaemia (CLL), but targeting BCL2 alone did not yield appreciable clinical results. However, it was demonstrated that BCL2 inhibitors enhanced the clinical efficacy of chemo and immunotherapeutics. Lenalidomide, an immunomodulator, is clinically effective in CLL and can enhance the anti‐CLL effects of CD20 targeting monoclonal antibody, rituximab. Here, we investigated the mechanism of immune‐directed killing of lenalidomide in CLL and evaluated if concurrent targeting of CD20 and BCL2 can enhance this effect. In vitro treatment with lenalidomide enhanced the antibody‐mediated cellular cytotoxicity (ADCC) directed by rituximab in autologous leukaemic cells. Furthermore, peripheral blood monon...

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The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin1 in B-cell lymphomas through CD22 up-regulation and PKC-βII depletion.

Haematologica — Fri, 16 Dec 2011 05:00:00 +0100

Conclusions:Our data suggest that the combination of Bryostatin1 with antibodies directed against CD22 is a potent drug combination for the treatment of low and high-grade B-cell lymphoma. PMID: 22180432 [PubMed - as supplied by publisher] (Source: Haematologica)

Enhancement of fludarabine sensitivity by all-trans retinoic acid in chronic lymphocytic leukemia cells.

Haematologica — Fri, 16 Dec 2011 05:00:00 +0100

Conclusions. Improvement of ex vivo fludarabine sensitivity in chronic lymphocytic leukemia cells is associated with increased hCNT3 activity after all-trans-retinoic acid treatment. PMID: 22180426 [PubMed - as supplied by publisher] (Source: Haematologica)

ASH: Btk Inhibitor Shines in Early Trials (CME/CE)

MedPage Today Hematology/Oncology — Fri, 16 Dec 2011 03:13:13 +0100

SAN DIEGO (MedPage Today) -- Small trials with a first-in-class compound that inhibits the Bruton's tyrosine kinase have shown substantial efficacy with low toxicity in poor-prognosis chronic lymphocytic leukemia and mantle cell lymphoma, researchers said here. (Source: MedPage Today Hematology/Oncology)

Rituximab Plus Lenalidomide Active, Well Tolerated in Both Younger and Older Patients With Previously Untreated Chronic Lymphocytic Leukemia

Clinical Care Options Oncology - Leukemia — Thu, 15 Dec 2011 10:43:42 +0100

Capsule Summary - In this nonrandomized phase II trial, ORR and CR rates were higher in patients younger than 65 years of age compared with patients 65 years of age or older. (Source: Clinical Care Options Oncology - Leukemia)

Defining the prognosis of early stage chronic lymphocytic leukaemia patients

British Journal of Haematology — Thu, 15 Dec 2011 05:00:00 +0100

SummaryApproximately 70% of chronic lymphocytic leukaemia (CLL) patients present with early stage disease, therefore defining which patients will progress and require treatment is a major clinical challenge. Here, we present the largest study of prognostic markers ever carried out in Binet stage A patients (n = 1154) with a median follow‐up of 8 years. We assessed the prognostic impact of lymphocyte doubling time (LDT), immunoglobulin gene (IGHV) mutation status, CD38 expression, ZAP‐70 expression and fluorescence in situ hybridization (FISH) cytogenetics with regards to time to first treatment (TTFT) and overall survival (OS). Univariate analysis revealed LDT as the most prognostic parameter for TTFT, with IGHV mutation status most prognostic for OS. CD38 expression, ZAP‐70 ex...

General population low-count CLL-like MBL persists over time without clinical progression, although carrying the same cytogenetic abnormalities of CLL

Blood — Thu, 15 Dec 2011 05:00:00 +0100

This study indicates that (1) the risk of progression into CLL for low-count population-screening CLL-like MBL is exceedingly rare and definitely lower than that of clinical MBL and (2) chromosomal abnormalities occur early in the natural history and are possibly associated with the appearance of the typical phenotype. (Source: Blood)

Diagnostic Radiation Exposure Risk in a Contemporary Cohort of Male Patients With Germ Cell Tumor

The Journal of Urology — Thu, 15 Dec 2011 05:00:00 +0100

Conclusions: At a tertiary care center with experience with managing testicular cancer 78% of patients with more than 5 years of followup exceeded current national and standard safety limits for radiation exposure. Imaging should be done judiciously in this population at high risk for radiation overexposure. (Source: The Journal of Urology)

CC-5013-CLL-009: Lenalidomide Active, Well Tolerated at Different Starting Doses in Relapsed or Refractory Chronic Lymphocytic Leukemia

Clinical Care Options Oncology - Leukemia — Wed, 14 Dec 2011 16:15:45 +0100

Capsule Summary - In this interim analysis at a median of 3 lenalidomide cycles, only 2 cases of serious tumor lysis syndrome have been reported, and more than one half of enrolled patients remain on treatment. (Source: Clinical Care Options Oncology - Leukemia)

Lenalidomide and Rituximab Combination Therapy Active With Durable Responses in Relapsed/Refractory Chronic Lymphocytic Leukemia

Clinical Care Options Oncology - Leukemia — Wed, 14 Dec 2011 15:47:29 +0100

Capsule Summary - In this single-arm phase II trial, patients with fludarabine-refractory disease experienced lower response rates to lenalidomide plus rituximab compared with patients whose disease was not refractory to fludarabine; however, this subgroup analysis was limited by low patient numbers. (Source: Clinical Care Options Oncology - Leukemia)

ASH: Novel BTK Inhibitor PCI-32765 Shows Promise to Change the Paradigm for Treatment of CLL

Cancer Network — Wed, 14 Dec 2011 12:00:00 +0100

Updated findings from a multicenter phase Ib/II clinical trial suggest that the novel Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 may be an important new targeted treatment approach for patients with chronic lymphocytic leukemia. (Source: Cancer Network)

Treatment Decisions In Chronic Lymphocytic Leukemia Aided By Massive DNA Search

Health News from Medical News Today — Wed, 14 Dec 2011 08:00:00 +0100

The most comprehensive search to date of DNA abnormalities in chronic lymphocytic leukemia (CLL) has unearthed several new altered genes that drive this common blood cancer, a finding that could potentially help doctors predict whether an individual patient's disease will progress rapidly or remain indolent for years, say scientists from Dana-Farber Cancer Institute and the Broad Institute. Using powerful "next-generation" DNA sequencing, the teams identified nine frequently mutated genes across 91 patients. Catherine J... (Source: Health News from Medical News Today)

Chronic Lymphocytic Leukemia Patients May Benefit From Novel Export-Inhibitor

Health News from Medical News Today — Wed, 14 Dec 2011 08:00:00 +0100

An experimental drug that works by blocking the export of key control molecules from the nucleus of cancer cells shows promise as a treatment for chronic lymphocytic leukemia (CLL) and other incurable B-cell malignancies, according to a new study by researchers at the Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James). The agent, called KPT-SINE, belongs to a new class of drugs called selective inhibitors of nuclear export (SINE). The agent was developed by Karyopharm Therapeutics Inc... (Source: Health News from Medical News Today)

Novel Experimental Agent Is Highly Active In Chronic Lymphocytic Leukemia Patients, Interim Study Shows

Health News from Medical News Today — Tue, 13 Dec 2011 08:00:00 +0100

An interim analysis of a phase Ib/II clinical trial indicates that a novel experimental agent for chronic lymphocytic leukemia (CLL) is highly active and well tolerated in patients who have relapsed and are resistant to other therapy. The agent, called PCI-32765, is the first drug designed to target Bruton's tyrosine kinase, a protein essential for CLL-cell survival and proliferation. CLL is the most common form of leukemia, with about 15,000 new cases annually in the U.S. About 4,400 Americans die of the disease each year. Study co-leader Dr. John C... (Source: Health News from Medical News Today)

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B Cell Receptor Inhibitor Causes Chronic Lymphocytic Leukemia Remission

Health News from Medical News Today — Tue, 13 Dec 2011 08:00:00 +0100

PCI-32765 applies molecularly aimed attack to disease usually treated with chemotherapy combinations A new, targeted approach to treating chronic lymphocytic leukemia has produced durable remissions in a Phase I/II clinical trial for patients with relapsed or resistant disease, investigators report at the 53rd Annual Meeting of the American Society of Hematology... (Source: Health News from Medical News Today)

Dysregulation of TNFα-induced necroptotic signaling in chronic lymphocytic leukemia: suppression of CYLD gene by LEF1

Leukemia — Tue, 13 Dec 2011 05:00:00 +0100

Dysregulation of TNFα-induced necroptotic signaling in chronic lymphocytic leukemia: suppression of CYLD gene by LEF1 Leukemia advance online publication, December 13, 2011. doi:10.1038/leu.2011.357 Authors: P Liu, B Xu, W Shen, H Zhu, W Wu, Y Fu, H Chen, H Dong, Y Zhu, K Miao, W Xu & J Li (Source: Leukemia)

Identification of three MICA alleles in the genotype of a patient with chronic lymphocytic leukemia

Tissue Antigens — Mon, 12 Dec 2011 23:45:39 +0100

Major histocompatibility complex (MHC) class I‐related chain A gene (MICA) sequence‐based genotyping (SBT) was attempted on a peripheral blood sample collected from a patient evaluated for hematopoietic stem cell retransplant. The electropherogram pattern of MICA SBT indicated the possibility of carrying more than two MICA alleles. Subsequent cloning and sequencing of the polymerase chain reaction products revealed the presence of three distinct MICA alleles: MICA*008:01/:04 (A5.1), MICA*007:01(A4), and MICA*002:01 (A9) in the genotype of this patient. The origin of the third extra MICA allele could not be determined and would require MICA genotyping information from other family members, which is unavailable. (Source: Tissue Antigens)

ASH: Nine Genes Drive CLL (CME/CE)

MedPage Today Hematology/Oncology — Mon, 12 Dec 2011 18:32:28 +0100

SAN DIEGO (MedPage Today) -- Using massively parallel genetic analysis, researchers have found nine genes that appear to be the drivers of chronic lymphocytic leukemia (CLL). (Source: MedPage Today Hematology/Oncology)

SF3B1 and Other Novel Cancer Genes in Chronic Lymphocytic Leukemia

New England Journal of Medicine — Mon, 12 Dec 2011 18:30:27 +0100

New England Journal of Medicine, Volume 0, Issue 0, Ahead of Print. (Source: New England Journal of Medicine)

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Novel export-inhibitor shows promise for treating CLL

EurekAlert! - Medicine and Health — Mon, 12 Dec 2011 05:00:00 +0100

(Ohio State University Medical Center) An experimental drug that works by blocking the export of key control molecules from the nucleus of cancer cells shows promise as a treatment for chronic lymphocytic leukemia and other incurable B-cell malignancies, according to a new study. The agent, a nuclear-export inhibitor, may represent an entirely new therapeutic strategy for treating cancer by restoring multiple normal cell-death pathways. (Source: EurekAlert! - Medicine and Health)

Massive DNA search uncovers new mutations driving blood cancer

EurekAlert! - Cancer — Mon, 12 Dec 2011 05:00:00 +0100

(Dana-Farber Cancer Institute) The most comprehensive search to date of DNA abnormalities in chronic lymphocytic leukemia has unearthed several new altered genes that drive this common blood cancer, a finding that could potentially help doctors predict whether an individual patient's disease will progress rapidly or remain indolent for years, say scientists from Dana-Farber Cancer Institute and the Broad Institute. (Source: EurekAlert! - Cancer)

B Cell Receptor Inhibitor Causes Chronic Lymphocytic Leukemia Remission

M. D. Anderson Cancer Center - News Releases — Mon, 12 Dec 2011 05:00:00 +0100

A new, targeted approach to treating chronic lymphocytic leukemia has produced durable remissions in a Phase I/II clinical trial for patients with relapsed or resistant disease, investigators report at the 53rd Annual Meeting of the American Society of Hematology. (Source: M. D. Anderson Cancer Center - News Releases)

Novel Compound Holds Promise in High-Risk CLLNovel Compound Holds Promise in High-Risk CLL

Medscape Today Headlines — Mon, 12 Dec 2011 01:17:36 +0100

An experimental compound showed high efficacy and low toxicity in relapsed/refractory patients with chronic lymphocytic leukemia. Medscape Medical News (Source: Medscape Today Headlines)

Celgene reports encouraging data from CLL investigational study

Drug Development Technology — Mon, 12 Dec 2011 00:00:00 +0100

Celgene International has announced interim results of CLL-009 followed by step-wise dose escalation as tolerated in patients with chronic lymphocytic leukemia (CLL) who received at least one prior therapy. (Source: Drug Development Technology)

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B cell receptor inhibitor causes chronic lymphocytic leukemia remission

EurekAlert! - Medicine and Health — Sun, 11 Dec 2011 05:00:00 +0100

(University of Texas M. D. Anderson Cancer Center) A new, targeted approach to treating chronic lymphocytic leukemia has produced durable remissions in a Phase I/II clinical trial for patients with relapsed or resistant disease, investigators report at the 53rd Annual Meeting of the American Society of Hematology. (Source: EurekAlert! - Medicine and Health)

Novel experimental agent is highly active in CLL patients, interim study shows

EurekAlert! - Medicine and Health — Sun, 11 Dec 2011 05:00:00 +0100

(Ohio State University Medical Center) An interim analysis of a phase Ib/II clinical trial indicates that a novel experimental agent for chronic lymphocytic leukemia is highly active and well tolerated in patients who have relapsed and are resistant to other therapy. The agent is the first drug designed to target Bruton's tyrosine kinase, a protein essential for CLL-cell survival and proliferation. CLL is the most common form of leukemia. (Source: EurekAlert! - Medicine and Health)

Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia

Nature Genetics — Sun, 11 Dec 2011 05:00:00 +0100

Authors: Víctor Quesada, Laura Conde, Neus Villamor, Gonzalo R Ordóñez, Pedro Jares, Laia Bassaganyas, Andrew J Ramsay, Sílvia Beà, Magda Pinyol, Alejandra Martínez-Trillos, Mónica López-Guerra, Dolors Colomer, Alba Navarro, Tycho Baumann, Marta Aymerich, María Rozman, Julio Delgado, Eva Giné, Jesús M Hernández, Marcos González-Díaz, Diana A Puente, Gloria Velasco, José M P Freije, José M C Tubío, Romina Royo, Josep L Gelpí, Modesto Orozco, David G Pisano, Jorge Zamora, Miguel Vázquez, Alfonso Valencia, Heinz Himmelbauer, Mónica Bayés, Simon Heath, Marta Gut, Ivo Gut, Xavier Estivill, Armando López-Guillermo, Xose S Puente, Elías Campo & Carlos López-Otín Here we...

Post-transcriptional silencing of Notch2 mRNA in chronic lymhocytic leukemic cells of B-CLL patients.

Molecular Biology Reports — Sat, 10 Dec 2011 05:00:00 +0100

In this study, we focused on the inhibition of Notch2 function in B-cell chronic lymphocytic leukemia (B-CLL) by AS-ODN (phosphorothioate oligomers) targeted to the initiation codon region of the Notch2 mRNA. We investigated the in vitro ability of four such oligomers to reduce the expression of Notch2 gene in peripheral blood mononuclear cells from B-CLL patients. Our findings implicate that AS-ODNs specifically designed for the region of 314-333 neucleotides (AS1) of Notch2 inhibits its gene expression better than other AS-ODNs designed for other regions and respond in a dose dependent manner. The results of cell proliferation assay for the evaluation of AS1 in gene silencing, infer that the number of cells were reduced to 80% (P < 0.001). Our results implicate that using the AS-ODN...

Richter Syndrome and Brain Involvement: Low-Grade Lymphoma Relapsing as Cerebral High-Grade Lymphoma.

Acta Haematologica — Sat, 10 Dec 2011 05:00:00 +0100

This report extends the literature of central nervous system RS and particularly highlights the importance of a thorough diagnostic evaluation of patients with low-grade NHL presenting with neurological symptoms. PMID: 22156510 [PubMed - as supplied by publisher] (Source: Acta Haematologica)

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A new genetic abnormality leading to TP53 gene deletion in chronic lymphocytic leukaemia

British Journal of Haematology — Fri, 09 Dec 2011 05:00:00 +0100

This report describes the clinical and pathological characteristics of four CLL patients showing a new recurrent chromosomal abnormality dic(8;17)(p11;p11), that implied loss of the TP53 gene in all cases. In addition, TP53 gene was mutated in three out of four patients. Mechanically, Low Copy Repeats (LCR) in 17p12 and 8p11 may explain the origin of the translocation by non‐allelic homologous recombination (NAHR). Isolated dic(8;17)(p11;p11) in patients with mutated IGHV genes status may not have the same prognostic impact as other mutations or deletions affecting the TP53 gene. Larger series are needed to better evaluate the clinical impact of this chromosomal aberration during the course of the disease. (Source: British Journal of Haematology)

An Italian retrospective study on the routine clinical use of low‐dose alemtuzumab in relapsed/refractory chronic lymphocytic leukaemia patients

British Journal of Haematology — Fri, 09 Dec 2011 05:00:00 +0100

SummaryLow‐dose alemtuzumab has shown a favourable toxicity profile coupled with good results in terms of efficacy in relapsed/refractory chronic lymphocytic leukaemia (CLL). We conducted a multicentre retrospective study on the routine clinical use of low‐dose alemtuzumab in this patient setting. One hundred and eight relapsed/refractory CLL patients from 11 Italian centres were included in the analysis. All patients had an Eastern Cooperative Oncology Group performance status ≤2 and the majority (84%) had adenopathies <5cm. Low‐dose alemtuzumab was defined as a total weekly dose ≤45 mg and a cumulative dose ≤600 mg given for up to 18 weeks. The overall response rate was 56% (22% complete remissions). After a median follow‐up of 42·2 months, the median overall su...

Janssen Biotech, Inc. Announces Collaborative Development And Worldwide License Agreement For Investigational Anti-Cancer Drug, PCI-32765 (Dec 8, 2011)

Johnson and Johnson — Thu, 08 Dec 2011 09:33:05 +0100

HORSHAM, PA, (December 8, 2011) – Janssen Biotech, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson (NYSE:JNJ), announced today that it has executed an agreement with Pharmacyclics, Inc. (Nasdaq: PCYC) to jointly develop and market the anti-cancer compound, PCI-32765. A number of Phase 1 and 2 studies with PCI-32765 are ongoing across a panel of B-cell malignancy disorders, including chronic lymphocytic leukemia, mantle cell lymphoma, and diffuse large B-cell lymphoma. Interim data were reported at the 2011 American Society of Clinical Oncology Annual Meeting and oral presentations on two separate Phase 2 studies will be presented at the upcoming American Society of Hematology Meeting in December, along with several other poster presentations..... (S...

Behind the scenes of non‐nodal MCL: downmodulation of genes involved in actin cytoskeleton organization, cell projection, cell adhesion, tumour invasion, TP53 pathway and mutated status of immunoglobulin heavy chain genes

British Journal of Haematology — Thu, 08 Dec 2011 05:00:00 +0100

SummaryMantle cell lymphoma (MCL) is an aggressive neoplasm with a short survival. Cases with leukaemic MCL and splenomegaly without adenopathies (non‐nodal MCL) may have a more indolent course. To gain insights into the biological features underlying this presentation, we investigated the gene expression profile (GEP) and the IGHV mutational status in a cohort of leukaemic MCL cases. Comparison of MCL with other lymphoproliferative disorders (i.e. splenic marginal zone lymphoma, follicular lymphoma, chronic lymphocytic leukaemia) revealed a MCL signature enriched for the following gene categories: mitochondrion, oxidoreductase activity, response to stress, to DNA damage and TP53‐pathway. Furthermore, GEP analysis revealed that non‐nodal MCL cases were characterized by the down‐mod...

The cumulative amount of serum-free light chain is a strong prognosticator in chronic lymphocytic leukemia

Blood — Thu, 08 Dec 2011 05:00:00 +0100

Identification of patients at risk of early disease progression is the mainstay of tailored management in chronic lymphocytic leukemia (CLL). Although application of established biomarkers is limited by intrinsic detection/readout complexities, abnormality of and serum-free light chain ratio [sFLC (/)] was proposed as a straightforward prognosticator in CLL. By analyzing 449 therapy-naive patients, we show that an abnormal sFLC(/), along with CD38, ZAP-70, IGHV mutations, cytogenetics and stage, independently predicts treatment-free survival (TFS) but becomes prognostically irrelevant if the cumulative amount of clonal and nonclonal FLCs [sFLC( + )], a variable associated with cytogenetic risk, exceeds the threshold of 60.6 mg/mL. Patients with sFLC( + ) above cut-off displayed a poorer TF...

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Chemotherapy: New FluCam combination therapy has familiar limitations

Nature Clinical Practice Oncology — Tue, 06 Dec 2011 05:00:00 +0100

Authors: Jennifer A. Woyach & John C. Byrd A new phase III study shows superior efficacy of fludarabine plus alemtuzumab combination therapy over fludarabine alone in the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL). However, the study has limitations and the findings can not be generalized to the majority of patients with CLL. (Source: Nature Clinical Practice Oncology)

4‐1BB ligand modulates direct and Rituximab‐induced NK‐cell reactivity in chronic lymphocytic leukemia

European Journal of Immunology — Mon, 05 Dec 2011 05:00:00 +0100

AbstractNK cells play an important role in tumor immunosurveillance and largely contribute to the therapeutic success of anti‐tumor antibodies like Rituximab. Here we studied the role of the TNF family member 4‐1BB ligand (4‐1BBL) during the interaction of NK cells with chronic lymphocytic leukemia (CLL) cells. 4‐1BBL was highly expressed on patient CLL B cells in all 56 investigated cases. Signaling via 4‐1BBL following interaction with 4‐1BB, which was detected on NK cells of CLL patients but not healthy individuals, led to the release of immunoregulatory cytokines including TNF by CLL cells. CLL patient sera contained elevated levels of TNF and induced 4‐1BB upregulation on NK cells, which in turn impaired direct and Rituximab‐induced NK reactivity against 4‐1BBL‐exp...

The prognostic difference of monoallelic versus biallelic deletion of 13q in chronic lymphocytic leukemia

Cancer — Fri, 02 Dec 2011 05:00:00 +0100

CONCLUSIONS:Except for inconsequential differences in albumin and ZAP70 expression, there was no difference in the baseline characteristics between patients with CLL who had monoallelic or biallelic deletion of 13q. In addition, there was no significant difference in endpoints, including time to treatment. Cancer 2011. © 2011 American Cancer Society. (Source: Cancer)

The Cytokine Midkine and Its Receptor RPTPζ Regulate B Cell Survival in a Pathway Induced by CD74.

Journal of Immunology — Fri, 02 Dec 2011 05:00:00 +0100

In this study, we describe a novel biological mechanism essential for survival and homeostasis of normal peripheral mature B cells and chronic lymphocytic leukemia cells, regulated by the heparin-binding cytokine, midkine (MK), and its proteoglycan receptor, the receptor-type tyrosine phosphatase ζ (RPTPζ). We demonstrate that MK initiates a signaling cascade leading to B cell survival by binding to RPTPζ. In mice lacking PTPRZ, the proportion and number of the mature B cell population are reduced. Our results emphasize a unique and critical function for MK signaling in the previously described MIF/CD74-induced survival pathway. Stimulation of CD74 with MIF leads to c-Met activation, resulting in elevation of MK expression in both normal mouse splenic B and chronic lymphocytic leukemia ...

miR-15a and miR-16-1 inhibit the proliferation of leukemic cells by down-regulating WT1 protein level

Journal of Experimental and Clinical Cancer Research — Thu, 01 Dec 2011 05:00:00 +0100

Conclusion: These data suggest that miR-15a/16-1 may function as a tumor suppressor to regulate leukemic cell proliferation potentially by down-regulating the WT1 oncogene. However WT1 is not directly targeted by miR-15a/16-1 through miRNA-mRNA base pairing, therefore more study are required to understand the mechanism by which miR-15a/16-1 downregulate WT1. (Source: Journal of Experimental and Clinical Cancer Research)

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AP-1 elements and TCL1 protein regulate expression of the gene encoding protein tyrosine phosphatase PTPROt in leukemia

Blood — Thu, 01 Dec 2011 05:00:00 +0100

We previously demonstrated that the gene encoding PTPROt, the truncated form of protein tyrosine phosphatase receptor type O expressed predominantly in hematopoietic cells, is a candidate tumor suppressor and is down-regulated in chronic lymphocytic leukemia (CLL). Here, we show that PTPROt expression is significantly reduced in CD19+ spleen B cells from Eμ-T cell leukemia 1 (TCL1) transgenic mice relative to the wild-type mice. Strikingly, as much as a 60% decrease in PTPROt expression occurs at 7 weeks independently of promoter methylation. To elucidate the potential mechanism for this early suppression of PTPROt in these mice, we explored the role of activating protein-1 (AP-1) in its expression. We first demonstrate that AP-1 activation by 12-O-tetradecanoylphorbol-13-acetate induce...

CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death

Blood — Thu, 01 Dec 2011 05:00:00 +0100

Extracellular adenosine (ADO), generated from ATP or ADP through the concerted action of the ectoenzymes CD39 and CD73, elicits autocrine and paracrine effects mediated by type 1 purinergic receptors. We have tested whether the expression of CD39 and CD73 by chronic lymphocytic leukemia (CLL) cells activates an adenosinergic axis affecting growth and survival. By immunohistochemistry, CD39 is widely expressed in CLL lymph nodes, whereas CD73 is restricted to proliferation centers. CD73 expression is highest on Ki-67+ CLL cells, adjacent to T lymphocytes, and is further localized to perivascular areas. CD39+/CD73+ CLL cells generate ADO from ADP in a time- and concentration-dependent manner. In peripheral blood, CD73 expression occurs in 97/299 (32%) CLL patients and pairs with CD38 and ZAP...

Systematic review of purine analogue treatment for chronic lymphocytic leukemia: lessons for future trials.

Haematologica — Thu, 01 Dec 2011 05:00:00 +0100

Conclusions. Purine analogs, particularly combined with cyclophosphamide, significantly improve progression free survival but not survival. Some groups, such as the elderly, may not see the same benefits and maximising doses may be important for all treatments, including chlorambucil. Longer follow-up, consistent definitions and detailed reporting of trials should be encouraged. PMID: 22133773 [PubMed - as supplied by publisher] (Source: Haematologica)

Clonal diversity analysis using SNP microarray: a new prognostic tool for chronic lymphocytic leukemia

Cancer Genetics and Cytogenetics — Thu, 01 Dec 2011 05:00:00 +0100

In conclusion, SNP microarray studies with simultaneous evaluation of genomic alterations and mosaic distribution of clones can be used to assess apparent clonal evolution via analysis of clonal diversity. Since clonal evolution in CLL is strongly correlated with disease progression, whole genome SNP microarray analysis provides a new comprehensive and reliable prognostic tool for CLL patients. (Source: Cancer Genetics and Cytogenetics)

Intracerebral Infiltration As the Unique Cause of the Clinical Presentation of Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia [DIAGNOSIS IN ONCOLOGY]

Journal of Clinical Oncology — Tue, 29 Nov 2011 05:00:00 +0100

(Source: Journal of Clinical Oncology)

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Tipping the Noxa/Mcl-1 balance overcomes ABT-737 resistance in chronic lymphocytic leukemia.

Clinical Cancer Research — Tue, 29 Nov 2011 05:00:00 +0100

CONCLUSIONS: Thus, the Noxa/Mcl-1 balance determines sensitivity to ABT-737 in CD40-stimulated CLL cells. These data provide a rationale to investigate the combination of drugs which enhance the Noxa/Mcl-1 balance with ABT-737 in order to eradicate CLL in chemoresistant niches. PMID: 22128299 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)

Advances in the Clinical Staging of Chronic Lymphocytic Leukemia [Citation Classic]

Clinical Chemistry — Mon, 28 Nov 2011 05:00:00 +0100

(Source: Clinical Chemistry)

Soluble BAFF Levels Inversely Correlate with Peripheral B Cell Numbers and the Expression of BAFF Receptors.

Journal of Immunology — Mon, 28 Nov 2011 05:00:00 +0100

Authors: Kreuzaler M, Rauch M, Salzer U, Birmelin J, Rizzi M, Grimbacher B, Plebani A, Lougaris V, Quinti I, Thon V, Litzman J, Schlesier M, Warnatz K, Thiel J, Rolink AG, Eibel H Abstract The TNF family member protein BAFF/BLyS is essential for B cell survival and plays an important role in regulating class switch recombination as well as in the selection of autoreactive B cells. In humans, increased concentrations of soluble BAFF are found in different pathological conditions, which may be as diverse as autoimmune diseases, B cell malignancies, and primary Ab deficiencies (PAD). Because the mechanisms that regulate BAFF levels are not well understood, we newly developed a set of mAbs against human BAFF to study the parameters that determine the concentrations of soluble BAFF in c...

[Articles] Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial

The Lancet Oncology — Mon, 28 Nov 2011 02:01:45 +0100

SummaryBackgroundChronic lymphocytic leukaemia (CLL) is an incurable and chronic disorder, with worsening prognosis for patients as their disease progresses. We compared the efficacy and safety of the combination of fludarabine and alemtuzumab with fludarabine monotherapy in previously treated patients with relapsed or refractory CLL.MethodsPatients (aged ≥18 years) with CLL Binet stage A, B, or C or Rai stages I–IV were randomly assigned in a 1:1 ratio according to a computer-generated allocation schedule to open-label combination treatment (fludarabine 30 mg/m2 per day and alemtuzumab 30 mg per day on days 1–3) or monotherapy (fludarabine 25 mg/m2 on days 1–5) by use of an interactive voice response system. (Source: The Lancet Oncology)

A case of community acquired pseudomonas aeruginosa necrotising fasciitis on a background of chronic lymphocytic leukaemia and review of current literature

Journal of Infection — Fri, 25 Nov 2011 11:05:45 +0100

Necrotizing fasciitis is a relatively uncommon, but severe, infection involving subcutaneous soft tissues, especially the super ficial and deep fascia. It can be caused by a mixture of anaerobic and aerobic organisms or more classically Lance-field group A streptococci. Typical progression is from an initial poorly demarcated swollen, erythematous area, the skin gradually breaks down further with colour change and often formation of dark, fluid filled bullae. The surrounding tissue becomes nectrotic and a compartment syndrome-like process may develop. Rapid diagnosis and surgical inter- vention, alongside appropriate antimicrobials, is the main- stay of treatment. In some cases gas production can also be seen. Most commonly Pseudomonas aeruginosa is isolated as part of a mixed microbial fl...

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A case of community acquired Pseudomonas aeruginosa necrotising fasciitis on a background of chronic lymphocytic leukaemia and review of current literature: Category: Clinical lesson

Journal of Infection — Fri, 25 Nov 2011 11:05:45 +0100

Necrotizing fasciitis is a relatively uncommon, but severe, infection involving subcutaneous soft tissues, especially the superficial and deep fascia. It can be caused by a mixture of anaerobic and aerobic organisms or more classically Lancefield group A streptococci. Typical progression is from an initial poorly demarcated swollen, erythematous area, the skin gradually breaks down further with colour change and often formation of dark, fluid filled bullae. The surrounding tissue becomes nectrotic and a compartment syndrome-like process may develop. Rapid diagnosis and surgical intervention, alongside appropriate antimicrobials, is the mainstay of treatment.In some cases gas production can also be seen. Most commonly Pseudomonas aeruginosa is isolated as part of a mixed microbial flora, on...

Reproductive factors and lymphoid neoplasms in Europe: findings from the EpiLymph case–control study

Cancer Causes and Control — Thu, 24 Nov 2011 17:48:46 +0100

Conclusion These data support the hypothesis that increased parity confers a protective effect against lymphoma. Less clearly, our results also indicate that hormonal contraceptives could play a role. Content Type Journal ArticleCategory Original paperPages 1-12DOI 10.1007/s10552-011-9869-6Authors Laura Costas, Unit of Infections and Cancer (UNIC), Cancer Epidemiology Research Programme, Institut Català d’ Oncologia, IDIBELL, Av. Gran Via de l’Hospitalet 199-203, 08908 L’ Hospitalet de Llobregat, Barcelona, SpainDelphine Casabonne, Unit of Infections and Cancer (UNIC), Cancer Epidemiology Research Programme, Institut Català d’ Oncologia, IDIBELL, Av. Gran Via de l’Hospitalet 199-203, 08908 L’ Hospitalet de Llobregat, Barcelona, SpainYolanda Benavente, U...

Alemtuzumab therapy in T-cell prolymphocytic leukemia: comparing efficacy in a series treated intravenously and a study piloting the subcutaneous route

Blood — Thu, 24 Nov 2011 05:00:00 +0100

This study is registered at www.eudract.ema.europa.eu as #2004-004636-31. (Source: Blood)

Inhibiting B-Cell Receptor Signaling Pathways in Chronic Lymphocytic Leukemia

Current Hematologic Malignancy Reports — Mon, 21 Nov 2011 18:08:46 +0100

This article reviews key biologic aspects of BCR-associated kinases in CLL and other B cell neoplasias, and develops perspectives for future development of this exciting new class of kinase inhibitors. Content Type Journal ArticleCategory Chronic Lymphocytic Leukemia (S O’Brien, Section Editor)Pages 1-8DOI 10.1007/s11899-011-0104-zAuthors Jan A. Burger, Department of Leukemia, Unit 428, The University of Texas M.D. Anderson Cancer Center, P.O. Box 301402, Houston, TX 77230-1402, USA Journal Current Hematologic Malignancy ReportsOnline ISSN 1558-822XPrint ISSN 1558-8211 (Source: Current Hematologic Malignancy Reports)

Flow cytometric analysis of surface light chain expression patterns in B-cell lymphomas using monoclonal and polyclonal antibodies.

American Journal of Clinical Pathology — Mon, 21 Nov 2011 13:30:31 +0100

Authors: Horna P, Olteanu H, Kroft SH, Harrington AM Abstract Light chain (LC) expression by flow cytometry (FC) in B cell non-Hodgkin lymphomas (B-NHLs) can occasionally be detected with one anti-LC antibody but not with another. We retrospectively analyzed 564 four-color FC files from B-NHLs, assessing LC staining with monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs). Discrepancies in LC expression between mAbs and pAbs were present in 9.2% of cases, mainly in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; 11.1%), diffuse large B-cell lymphoma (DLBCL; 10.2%), follicular lymphoma (9.5%), and mantle cell lymphoma (11.1%) and most frequently in body fluids. Equal proportions of cases were LC+ only with pAbs (4.8%) or mAbs (4.4%). Negative LC expressio...

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Genetics of Chronic Lymphocytic Leukemia

Clinics in Laboratory Medicine — Mon, 21 Nov 2011 05:00:00 +0100

In general, chronic lymphocytic leukemia (CLL) is easy to diagnose; a peripheral blood sample for blood count, blood smear, and flow cytometry are sufficient. Whereas morphology and the immunophenotype of CLL cells are quite homogenous, there is a marked heterogeneity in the clinical course. The majority of patients do not require extended therapy, and the disease impacts them minimally; a distinct subgroup of patients, however, experiences rapid progression and insufficient response to treatment. The Binet and Rai staging systems are accepted prognostic factors in CLL but these systems are not able to differentiate between good and bad prognosis, especially in the early stage. Cytogenetics provides a better insight into the pathogenesis of the disease and helps to estimate a patient's pro...

t(14;19)(q32;q13)-associated B-cell neoplasms—a review

Journal of Hematopathology — Fri, 18 Nov 2011 06:56:27 +0100

Abstract The t(14;19)(q32;q13) is a rare cytogenetic abnormality that occurs in <0.1% of all B-cell neoplasms. The majority of these cases has been categorised as “atypical” chronic lymphocytic leukaemia (CLL). Although the clinical presentation is similar to CLL, these patients are often younger, with a stronger male predominance and the disease is reported to have a more aggressive clinical course. The peripheral blood/bone marrow aspirate morphology is “atypical”, but these differences are not recognised on bone marrow or lymph node histology. The immunoprofile is CD5 positive and usually CD23 dim/negative with a low Matutes CLL score. Fluorescence in situ hybridisation confirms the presence of the translocation giving rise to IGH/BCL3 fusion. Many cases also...

Phenotypic Complexity of T Regulatory Subsets in Patients with B-Chronic Lymphocytic Leukemia

Modern Pathology AOP — Fri, 18 Nov 2011 05:00:00 +0100

Authors: Angélique Biancotto, Pradeep K Dagur, John C Fuchs, Adrian Wiestner, C Bruce Bagwell & J Philip McCoy (Source: Modern Pathology AOP)

PIM2 inhibition as a rational therapeutic approach in B-cell lymphoma

Blood — Thu, 17 Nov 2011 05:00:00 +0100

In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification. (Source: Blood)

Combination of flavopiridol and embelin effectively inhibit cell growth in hepatocellular carcinoma depending on regulatory relationship between CDK6 and XIAP

Medicinal Chemistry Research — Wed, 16 Nov 2011 18:00:01 +0100

Abstract Flavopiridol, as a cyclin-dependent kinase (CDK) inhibitor, has entered into phase II study of clinical trial in chronic lymphocytic leukemia. In our study, flavopiridol decreased cell viability, significantly arrested cell cycle in G1 phase and induced cell apoptosis in HepG2/2.2.1 cells. Flavopiridol also inhibited protein expression of cyclin D1, cyclin-dependent kinase 4 (CDK4), cyclin-dependent kinase 6 (CDK6), and downregulated X-linked IAP (XIAP) expression in a dose-dependent manner. Further studies using HepG2/2.2.1 cells transfected with CDK6 siRNA or expression vector demonstrated that CDK6 modulates expression of XIAP. Finally, treatment of HepG2/2.2.1 cells with combination of flavopiridol and embelin, as a XIAP specific inhibitor, could inhibit cell ...

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Evaluation of chronic lymphocytic leukemia by oligonucleotide-based microarray analysis uncovers novel aberrations not detected by FISH or cytogenetic analysis

Molecular Cytogenetics — Wed, 16 Nov 2011 05:00:00 +0100

Conclusions: Our results show that microarray analysis will detect known aberrations, including microscopic and cryptic alterations. In addition, novel genomic changes will be uncovered that may become important prognostic predictors or treatment targets for CLL in the future. (Source: Molecular Cytogenetics)

Vaccination with dendritic cells loaded with tumor apoptotic bodies (Apo-DC) in patients with chronic lymphocytic leukemia: effects of various adjuvants and definition of immune response criteria

Cancer Immunology, Immunotherapy — Tue, 15 Nov 2011 16:57:01 +0100

In conclusion, vaccination with Apo-DC + GM-CSF and cyclophosphamide was safe and elicited anti-CLL immune responses that correlated inversely with Tregs levels. Lack of clinical responses highlights the necessity to develop more potent vaccine strategies in B cell malignancies. Content Type Journal ArticleCategory Original articlePages 1-15DOI 10.1007/s00262-011-1149-5Authors Marzia Palma, Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, SwedenLotta Hansson, Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, SwedenAniruddha Choudhury, Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, SwedenBarbro Näsman-Glaser, Department of Oncology and ...

Can ex vivo evaluation (testing) predict the sensitivity of CLL cells to therapy with purine analogs in conjunction with an alkylating agent? A comparison of in vivo and ex vivo responses to treatment

Medical Oncology — Tue, 15 Nov 2011 16:49:59 +0100

This study demonstrated that the in vivo responses of malignant cells from CLL patients after administration of purine analogs (cladribine/fludarabine) with cyclophosphamide vary significantly. For comparative purposes, the sensitivity of leukemic cells obtained from the same CLL patients to conventional purine analogs and the selective CDK inhibitor R-roscovitine (ROSC) was determined, with and without the addition of an alkylating agent, prior to the onset of in vivo therapy. The kinetics and rate of spontaneous and drug-induced apoptosis of CLL cells under ex vivo conditions differed significantly between patients, mirroring the variability observed during in vivo treatment. Interestingly, individual patients’ leukemic cells were comparably sensitive to the drugs under both cond...

Relevance of IgVH Gene Somatic Hypermutation and Interphase Cytogenetics in Lymphomatous Presentation of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

International Journal of Surgical Pathology — Tue, 15 Nov 2011 05:00:00 +0100

Conclusion. The authors’ attempt to compare CLL with SLL with regards to cytogenetic and IgVH mutational status shows no statistically significant difference. (Source: International Journal of Surgical Pathology)

Actinic granuloma occurring in an unusual association with cutaneous B‐cell chronic lymphocytic leukemia

Journal of Cutaneous Pathology — Sat, 12 Nov 2011 05:00:00 +0100

We report a case of a 65‐year‐old woman with B‐cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who presented with multiple, tender, firm pink papules on the face, upper trunk and upper extremities 6 years after diagnosis of CLL. Biopsy revealed both palisading granulomatous dermatitis consistent with actinic granuloma and a dense perivascular lymphocytic infiltrate consistent with the patient's known history of leukemia. This is an unusual manifestation of cutaneous B‐cell CLL that is rarely seen.Kauffman JA, Ivan DS, Cutlan JE, Hymes SR. Actinic granuloma occurring in an unusual association with cutaneous B‐cell chronic lymphocytic leukemia. (Source: Journal of Cutaneous Pathology)

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Therapy-related myeloid neoplasms following fludarabine, cyclophosphamide, and rituximab (FCR) treatment in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

Modern Pathology AOP — Fri, 11 Nov 2011 05:00:00 +0100

Therapy-related myeloid neoplasms following fludarabine, cyclophosphamide, and rituximab (FCR) treatment in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma Modern Pathology advance online publication, November 11, 2011. doi:10.1038/modpathol.2011.158 Authors: Yi Zhou, Guilin Tang, L Jeffrey Medeiros, Timothy J McDonnell, Michael J Keating, William G Wierda & Sa A Wang (Source: Modern Pathology AOP)

Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study

Blood — Thu, 10 Nov 2011 05:00:00 +0100

Ofatumumab, the human CD20 monoclonal antibody that binds a distinct epitope from rituximab, has demonstrated clinical benefit as monotherapy for patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab (FA-ref) and patients refractory to fludarabine with bulky (> 5 cm) lymph nodes (BF-ref). To potentially gain insight into outcomes in patients previously treated with or refractory to rituximab, we performed an ad hoc retrospective analysis in the final 96 FA-ref and 111 BF-ref patients. There were 117 patients previously treated with rituximab (98 rituximab-refractory); 89 patients were rituximab-naive. For rituximab-treated, rituximab-refractory, and rituximab-naive patients, overall response rate was 43%, 44%, and 53%; median progression-free survival was ...

CD40 stimulation sensitizes CLL cells to lysosomal cell death induction by type II anti-CD20 mAb GA101

Blood — Thu, 10 Nov 2011 05:00:00 +0100

Sensitivity of chronic lymphocytic leukemia (CLL) cells to anti-CD20 mAbs is low and, therefore, the efficacy of monotherapy with current anti-CD20 mAbs is limited. At present, it is not known whether sensitivity of CLL cells to CD20 mAbs is modulated by microenvironmental stimuli. We have shown previously that in vitro CD40 stimulation of peripheral blood–derived CLL cells results in resistance to cytotoxic drugs. In the present study, we show that, in contrast, CD40 stimulation sensitizes CLL cells to the recently described novel type II anti-CD20 mAb GA101. Cell death occurred without cross-linking of GA101 and involved a lysosome-dependent mechanism. Combining GA101 with various cytotoxic drugs resulted in additive cell death, not only in CD40-stimulated CLL cells, but also in p5...

Identification of outcome-correlated cytokine clusters in chronic lymphocytic leukemia

Blood — Thu, 10 Nov 2011 05:00:00 +0100

Individual cytokines and groups of cytokines that might represent networks in chronic lymphocytic leukemia (CLL) were analyzed and their prognostic values determined. Serum levels of 23 cytokines were measured in 84 patients and 49 age-matched controls; 17 levels were significantly elevated in patients. Unsupervised hierarchical bicluster analysis identified 3 clusters (CLs) of highly correlated but differentially expressed cytokines: CL1 (CXCL9, CXCL10, CXCL11, CCL3, CCL4, CCL19, IL-5, IL-12, and IFN), CL2 (TNFα, IL-6, IL-8, and GM-CSF), and CL3 (IL-1β, IL-2, IL-4, IL-15, IL-17, and IFNα). Combination scores integrating expression of CL1/CL2 or CL1/CL3 strongly correlated (P < .005) with time-tofirst-treatment and overall survival (OS), respectively. Patients with the ...

Chronic Lymphocytic Leukemia and Hairy-Cell Leukemia

Cancer Network — Wed, 09 Nov 2011 12:00:00 +0100

This management guide covers the epidemiology, etiology and risk factors, signs and symptoms, laboratory features, cytogenetic and molecular findings, staging and prognosis, and treatment of chronic lymphocytic leukemia, as well as the treatment of hairy-cell leukemia. (Source: Cancer Network)

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Leflunomide induces apoptosis in Fludarabine-resistant and clinically refractory CLL cells.

Clinical Cancer Research — Wed, 09 Nov 2011 05:00:00 +0100

CONCLUSION: We thus demonstrate that A771726 overcomes CD40L/IL4-mediated resistance to Fludarabine in CLL cells of untreated as well as clinically refractory CLL cells. We present a possible novel therapeutic principle for attacking chemoresistant CLL cells. PMID: 22072733 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)

Involvement of T2677T multidrug resistance gene polymorphism in Interleukin 22 plasma concentration in B-chronic lymphocytic leukemia patients.

Acta Oncologica — Wed, 09 Nov 2011 05:00:00 +0100

Authors: Musolino C, Allegra A, Ferraro M, Aguennouz M, Russo S, Alonci A, Saitta S, Gangemi S PMID: 22070651 [PubMed - as supplied by publisher] (Source: Acta Oncologica)

Oral high-dose glucocorticoids and Ofatumumab in fludarabine-resistant Chronic Lymphocytic Leukemia

Leukemia — Tue, 08 Nov 2011 05:00:00 +0100

Leukemia advance online publication, November 8, 2011. doi:10.1038/leu.2011.329 Author: D E Spaner (Source: Leukemia)

Glucocorticoid-induced TNFR-related protein (GITR) ligand modulates cytokine release and NK cell reactivity in chronic lymphocytic leukemia (CLL)

Leukemia — Tue, 08 Nov 2011 05:00:00 +0100

Authors: C Buechele, T Baessler, S Wirths, J U Schmohl, B J Schmiedel & H R Salih (Source: Leukemia)

Combination of cellular population data and CytoDiff™ analyses for the diagnosis of lymphocytosis

Clinical Chemistry and Laboratory Medicine — Sat, 05 Nov 2011 20:10:01 +0100

Conclusions: The analysis of CPD in combination with CytoDiff analysis shows promise for the rapid and accurate identification of lymphocyte pathologies in routine practice. (Source: Clinical Chemistry and Laboratory Medicine)

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Analysis of CD38 and ZAP70 mRNA expression among cytogenetic subgroups of Iranian chronic-lymphocytic-leukemia patients.

Genetics and Molecular Research — Fri, 04 Nov 2011 22:25:04 +0100

Analysis of CD38 and ZAP70 mRNA expression among cytogenetic subgroups of Iranian chronic-lymphocytic-leukemia patients. Genet Mol Res. 2011;10(4):2415-23 Authors: Teimori H, Akbari MT, Hamid M, Forouzandeh M, Bibordi E Abstract Chromosomal abnormalities and ZAP70 expression profile are two major independent prognostic markers in B-cell chronic lymphocytic leukemia. We investigated a possible correlation between these two markers. ZAP70 expression using real-time RT-PCR was examined in 20 B-cell chronic lymphocytic leukemia patients with del13q14, 13 patients with del11q22, 15 patients with trisomy 12, and 16 patients with no detected chromosomal abnormalities. Molecular analysis revealed that ZAP70 expression in the del13q subgroup was the same as in the control group, whi...

Th17 and non-Th17 IL-17-expressing cells in chronic lymphocytic leukemia: delineation, distribution, and clinical relevance.

Haematologica — Fri, 04 Nov 2011 04:00:00 +0100

Conclusions. Th17 cells are elevated in chronic lymphocytic leukemia patients with better prognostic markers and correlate with longer survival. Furthermore, non-Th17 IL-17A-expressing cells exist in chronic lymphocytic leukemia spleens as maturing granulocytes and mature mast cells, suggesting the microenvironmental milieu in leukemic spleens promotes the recruitment and/or expansion of Th17 and other IL-17-expressing cells. The pathophysiology of Th17 and non-Th17 IL 17A-producing cells in chronic lymphocytic leukemia and their distributions and roles in this disease merit further study. PMID: 22058222 [PubMed - as supplied by publisher] (Source: Haematologica)

AMD3100 disrupts the cross-talk between chronic lymphocytic leukemia cells and a mesenchymal stromal or nurse-like cell -based microenvironment: preclinical evidence for its association with chronic lymphocytic leukemia treatments.

Haematologica — Fri, 04 Nov 2011 04:00:00 +0100

Conclusions. Altogether, these data demonstrate that interfering with the SDF-1α/CXCR4 axis, by using AMD3100, inhibited chronic lymphocytic leukemia cell trafficking and microenvironment-mediated protective effects. Combining AMD3100 with other drugs may thus represent a promising therapeutic approach to enhance chronic lymphocytic leukemia cell killing. PMID: 22058221 [PubMed - as supplied by publisher] (Source: Haematologica)

Membrane microdomain sphingolipids are required for anti-CD20-induced death of chronic lymphocytic leukemia B cells.

Haematologica — Fri, 04 Nov 2011 04:00:00 +0100

Conclusion: B cells diverge from one chronic lymphocytic leukemia patient to another with respect to their membrane lipid organization. In practice, given the relevance of the membrane lipid distribution to the efficacy of biotherapies, such observations are of potential importance. PMID: 22058197 [PubMed - as supplied by publisher] (Source: Haematologica)

Association of an increased frequency of CD14+HLA‐DRlo/neg monocytes with decreased time to progression in chronic lymphocytic leukaemia (CLL)

British Journal of Haematology — Thu, 03 Nov 2011 04:00:00 +0100

(Source: British Journal of Haematology)

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Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias

Blood — Thu, 03 Nov 2011 04:00:00 +0100

We report the findings from the first 10 patients with chemotherapy-refractory chronic lymphocytic leukemia (CLL) or relapsed B-cell acute lymphoblastic leukemia (ALL) we have enrolled for treatment with autologous T cells modified to express 19-28z, a second-generation chimeric antigen (Ag) receptor specific to the B-cell lineage Ag CD19. Eight of the 9 treated patients tolerated 19-28z+ T-cell infusions well. Three of 4 evaluable patients with bulky CLL who received prior conditioning with cyclophosphamide exhibited either a significant reduction or a mixed response in lymphadenopathy without concomitant development of B-cell aplasia. In contrast, one patient with relapsed ALL who was treated in remission with a similar T-cell dose developed a predicted B-cell aplasia. The short-term per...

Enhanced levels of both the membrane-bound and soluble forms of IgM Fc receptor (Fc{mu}R) in patients with chronic lymphocytic leukemia

Blood — Thu, 03 Nov 2011 04:00:00 +0100

We examined the expression of the recently identified FcμR by B and T cells in CLL patients using receptor-specific monoclonal antibodies. CLL B cells (CD5+/CD19+) expressed much higher levels of FcμR on their cell surface than B cells from healthy donors. Such enhanced expression was more evident in immunoglobulin heavy chain variable region (IGHV)–mutated, CD38– or early Rai-stage CLL than in IGHV-unmutated, CD38+, or advanced Rai-stage CLL. Intriguingly, surface FcμR levels also were significantly elevated in the non-CLL B cells (CD5–/CD19+) and T cells (CD5+/CD19–), especially in IGHV-mutated CLL. CLL patients also had high serum titers of FcμR compared with healthy donors, and serum FcμR levels correlated significantly with circulating lymphocyte...

SU2C IRG Profile: Dr. Catherine Wu

Stand Up 2 Cancer — Wed, 02 Nov 2011 19:24:59 +0100

Stand Up To Cancer Innovative Research Grant recipient Dr. Catherine Wu discusses her work in Chronic Lymphocytic Leukemia. (Source: Stand Up 2 Cancer)

Analysis of p53 Tumor Suppressor Pathway Genes in Chronic Lymphocytic Leukemia

DNA and Cell Biology — Wed, 02 Nov 2011 15:07:20 +0100

DNA and Cell Biology , Vol. 0, No. 0. (Source: DNA and Cell Biology)

Activation of DNA damage response pathways in human mesenchymal stem cells exposed to cisplatin or gamma-irradiation.

Cell Cycle — Tue, 01 Nov 2011 04:00:00 +0100

Authors: Prendergast AM, Cruet-Hennequart S, Shaw G, Barry FP, Carty MP Abstract DNA damaging agents are widely used in treatment of hematogical malignancies and solid tumors. While effects on hematopoietic stem cells have been characterized, less is known about the DNA damage response in human mesenchymal stem cells (hMSCs) in the bone marrow stroma, progenitors of osteoblasts, chondrocytes and adipocytes. To elucidate the response of undifferentiated hMSCs to gamma-irradiation and cisplatin, key DNA damage responses have been characterised in hMSCs from normal adult donors. Cisplatin and gamma-irradiation activated the DNA damage response in hMSCs, including induction of p53 and p21, and activation of PI3 kinase-related protein kinase (PIKK)-dependent phosphorylation of histone H...

Chronic Herpes Zoster Duplex Bilateralis.

Acta Dermato-Venereologica — Tue, 01 Nov 2011 04:00:00 +0100

We describe here a patient with chronic lymphocytic leukaemia, who presented simultaneously non-contiguous bilateral and chronic herpes zoster lasting for more than 2 months, with resistance to aciclovir. To our knowledge, this is the first report of chronic herpes zoster duplex bilateralis. Physicians should be aware of and recognize these atypical manifestations of varicella zoster virus. PMID: 22041917 [PubMed - as supplied by publisher] (Source: Acta Dermato-Venereologica)

Aberrant Activation of the Hedgehog Signaling Pathway in Hematological Neoplasms.

The American Journal of Pathology — Tue, 01 Nov 2011 04:00:00 +0100

Authors: Ok CY, Singh RR, Vega F Abstract The hedgehog (HH) signaling pathway is a highly regulated signaling pathway that is important not only for embryonic development, tissue patterning, and organogenesis but also for tissue repair and the maintenance of stem cells in adult tissues. In the adult hematopoietic system, HH signaling regulates intrathymic T-cell development, and it is one of the survival signals provided by follicular dendritic cells to prevent apoptosis in germinal center B cells. HH signaling is required for primitive hematopoiesis; however, conflicting data have been reported regarding the role of the HH pathway in adult hematopoiesis. Inappropriate activation of the HH signaling pathway occurs in several human cancers, including hematopoietic neoplasms. Emergin...

Frequency and prognostic impact of the aberrant CD8 expression in 5,523 patients with chronic lymphocytic leukemia

Cytometry Part B: Clinical Cytometry — Tue, 01 Nov 2011 04:00:00 +0100

Conclusions:This study confirms that CD8‐expression is a recurrent albeit rare phenomenon in patients with CLL and suggests that CD8 expression has an adverse prognostic impact. Therefore, CD8 expression should be further investigated for its potential to contribute to risk stratification in patients with CLL. © 2011 International Clinical Cytometry Society (Source: Cytometry Part B: Clinical Cytometry)

Multivariable Model for Time to First Treatment in Patients With Chronic Lymphocytic Leukemia [Hematologic Malignancies]

Journal of Clinical Oncology — Fri, 28 Oct 2011 04:00:00 +0100

Conclusion We developed a multivariable model that incorporates traditional and newer prognostic factors to identify patients at high risk for progression to treatment. This model may be useful to identify patients for early interventional trials. (Source: Journal of Clinical Oncology)

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A case of cutaneous Scedosporium infection in an immunocompromised patient

Journal of Cutaneous Pathology — Fri, 28 Oct 2011 04:00:00 +0100

Scedosporium apiospermum, the asexual stage of Pseudoallescheria boydii, is a fungus ubiquitous in soil as well as organically polluted areas, where nitrogen‐containing compounds are abundant. It is an emerging opportunistic pathogen that can range from cutaneous to disseminated infection and can be fatal within months of diagnosis. Here we present a case of disseminated S. apiospermum infection with cutaneous manifestations in a 59‐year‐old woman with myelodysplastic syndrome, in remission from chronic lymphocytic leukemia, presented with pneumonia and deteriorating mental status. An X‐ray computed tomography scan showed three non‐contrast‐enhancing hypodensities affecting the brain. Many erythematous, indurated skin lesions, measuring 3–5 mm in diameter, were noted on her c...

Stromal cells and CD40 ligand (CD154) alter the miRNome and induce miRNA clusters including, miR-125b/miR-99a/let-7c and miR-17-92 in chronic lymphocytic leukaemia

Leukemia — Tue, 25 Oct 2011 04:00:00 +0100

Stromal cells and CD40 ligand (CD154) alter the miRNome and induce miRNA clusters including, miR-125b/miR-99a/let-7c and miR-17-92 in chronic lymphocytic leukaemia Leukemia advance online publication, October 25, 2011. doi:10.1038/leu.2011.299 Authors: S Willimott & S D Wagner (Source: Leukemia)

Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma [Medical Sciences]

Proceedings of the National Academy of Sciences — Tue, 25 Oct 2011 04:00:00 +0100

Squamous cell carcinomas (SCCs) are one of the most frequent forms of human malignancy, but, other than TP53 mutations, few causative somatic aberrations have been identified. We identified NOTCH1 or NOTCH2 mutations in ∼75% of cutaneous SCCs and in a lesser fraction of lung SCCs, defining a spectrum for the most prevalent tumor suppressor specific to these epithelial malignancies. Notch receptors normally transduce signals in response to ligands on neighboring cells, regulating metazoan lineage selection and developmental patterning. Our findings therefore illustrate a central role for disruption of microenvironmental communication in cancer progression. NOTCH aberrations include frameshift and nonsense mutations leading to receptor truncations as well as point substitutions in key func...

Hodgkin lymphoma as Richter transformation in chronic lymphocytic leukaemia: a retrospective analysis of world literature

British Journal of Haematology — Mon, 24 Oct 2011 04:00:00 +0100

SummaryRichter transformation in chronic lymphocytic leukaemia (CLL) represents an entity of considerable genetic, molecular, immunological and clinical heterogeneity. A rare occurrence, Hodgkin variant of Richter syndrome, has not been comprehensively characterized or systematized to date. We conducted a retrospective analysis of the existing cases of Hodgkin lymphoma as Richter syndrome reported in the medical literature in the previous three and a half decades. Our search identified 86 such patients; this entity affects predominantly older men and the most common histological subtype is mixed cellularity. Interval between the diagnosis of CLL and subsequent development of Hodgkin lymphoma is circa 4·3 years. The overall survival of patients was approximately 1·7 years in our analy...