Daniel Catovsky

..We aimed to establish whether this treatment combination provided greater survival benefit than did chlorambucil or fludarabine...

..It remains a useful drug for patients unfit to receive more intensive combinations. However, both the dose and duration of treatment are important...

..CLL risk increased with increasing numbers of risk alleles (P(trend) = 1.40 x 10(-15)), consistent with a polygenic model of disease susceptibility. These data validate the relationship between common variation and risk of CLL...

..We aimed to address the frequency and prognostic value of TP53 abnormalities in patients with CLL in the context of a prospective randomized trial...

..These four SNPs map to a 3 kb region of the 3'-UTR of IRF4, consistent with the causal basis of the association being mediated through differential IRF4 expression...

..Our analysis provides no evidence that common variation in CXCR4 defined by rs228014 influences the risk of CLL, but that functional coding mutations in CXCR4 may contribute to familial CLL...

..In conclusion, DAT status at the time of initiation of therapy provides a new prognostic indicator, although FC may protect against AHA. This trial was registered at http://isrctn.org as no. 58585610...

..They continue to be effective at second- and even third-line therapy; however, alternative treatments are needed for patients who are or have become refractory to these agents or whose remissions are shorter with each course of therapy...

..Overall only eight patients died of HCL-related causes. Patients achieving a CR can expect a normal lifespan...

..006). The combination of a purine analog with rituximab was safe and effective for patients with recurrent HCL. The results suggest an added benefit compared with single-agent purine analog therapy...

..32 (rs11083846, PRKD2; P = 3.96 x 10(-9)). These data provide the first evidence for the existence of common, low-penetrance susceptibility to a hematological malignancy and new insights into disease causation in CLL...

..99 (95% CI: 0.85 - 1.16) and 0.91 (95% CI: 0.74 - 1.11) for heterozygotes and TT homozygotes, respectively. These data suggests variation at SMAD7 does not significantly contribute to an inherited susceptibility to CLL...

..2 (rs783540, CPEB1; OR = 1.18; P = 3.67 x 10(-6)) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 x 10(-6)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy...

..To the authors' knowledge, there is no standard treatment for patients with T-cell large granular lymphocyte (LGL) leukemia. Available data are limited by patient numbers and coexisting pathologies...

..27; P = 7.75 × 10(-3)), rs2456449 (OR = 1.31; P = 3.14 × 10(-3)), and rs735665 (OR = 1.63; P = 6.86 × 10(-6)). Collectively, these data provide support for genetic variation influencing CLL risk through predisposition to MBL...

..Simultaneous analysis of ZAP-70, CD38 and IGHV mutations in CLL provides more discriminatory prediction of TFI than any factor alone...

..These data provide further evidence for the involvement of common genetic variants in CLL risk and insight into the biological basis of disease development...

..001*). These findings support the recommendation to begin treatment when patients experience symptomatic disease, to improve HRQoL...

..To facilitate the identification of prognostic markers through pooled analyses, we have made all data from our analysis publicly available...

..Overall, only eight patients have died of HCL-related causes. Patients with HCL who achieve a CR can expect a normal lifespan...

..Alemtuzumab delivered intravenously, but not subcutaneously, remains the treatment of choice for previously untreated T-PLL. This study is registered at www.eudract.ema.europa.eu as #2004-004636-31...

..These observations provide evidence that familial CLL is essentially indistinguishable from sporadic CLL, favoring a genetic basis to disease development in general rather than a simple environmental etiology...

..None of the SNPs were individually significantly associated with risk of CLL and there was no evidence for epistatic interaction between loci. Our study does not support the postulate that variants of ARLTS1 influence the risk of CLL...

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..Here, we review the current status of knowledge about inherited susceptibility to CLL...

..Fluorescence in-situ hybridization (FISH) analysis also provides prognostic information, chiefly by detecting 17 (p53 locus) and 11q deletion, and may determine the type of therapy...

..In atypical CLL, histology and/or molecular genetics may be required to exclude other B-cell disorders...

..Differences seen between MCL and CLL in spleen size, and in response of the leucocytosis suggest a central role for the spleen in the evolution of MCL with leukaemia...

..Our results indicate that quantitative analysis of CD34 and CD117 may be useful to detect minimal residual disease (MRD) and could be tested in a future to monitor therapy in AML...

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..Alternatively, the frequent loss of the p53 gene could be associated with the deletion of an adjacent gene, which could be involved in the pathogenesis of these diseases...

..We have investigated the roles of interleukin-6 and other gp130-dependent ligands on the proliferation of macrophage-lineage hemopoietic progenitor cells...

..Splenectomy is a useful treatment option in this group of patients...

..In this work we analyze diagnostic criteria for BAL...

..To augment the limited literature on bone marrow (BM) appearances in T-cell large granular lymphocyte (LGL) leukaemia and to identify a histological signature to aid in diagnosis of this condition...

..Thus, 13q14.3 deletions could contribute to the development of overt leukaemia in T-PLL, but the involvement of more than one gene in the region cannot be excluded...

..We discuss the significance of this for CLL tumorigenesis and for genomewide hypomethylation in CLL...

..Transformation to large cell is seen in 6% of patients. The inferior survival in HCL-variant compared with typical HCL cases may reflect the chemotherapy resistance...

..This is the first case documented by molecular methods of the transformation of the pre-existing clone...

..We suggest that the relatively high incidence of transformation in this series may be due to immunosuppression mainly related to fludarabine, although other agents and prior therapies may have also contributed...

..Deletion at 17p13 did not show prognostic impact in this series. CD38, positive in two-thirds of cases, was associated with male gender and nodal disease but not with any cytogenetic abnormality, or with survival...

..No overt pathogenic mutations were identified. These findings indicate that germline mutations in RAD51, RAD51AP1, RAD51L1, RAD51L3, RAD52 and RAD54L are unlikely to be causal of an inherited predisposition to CLL...

..Here we review the current status of knowledge relating to inherited susceptibility to CLL and the strategies that are being employed to identify disease-causing mutations...

..002). None of the regions coincided with areas of common chromosomal abnormalities frequently observed in CLL. These findings provide direct evidence for Mendelian predisposition to CLL and evidence for the location of disease loci...

..Disruption of the amino-terminus of BCL7A defines a new mechanism in the pathogenesis of a subset of high-grade B-NHL...

..True cure in HCL remains elusive, but the addition of monoclonal antibodies may be beneficial. Our results suggest that achieving CR should remain the main goal of treatment...

..This article reviews current knowledge relating to inherited susceptibility to CLL and strategies that are being used to identify disease-causing mutations...

..02). In particular, amplification of 2p and deletion of 6q were both more frequent. Cases with >20%TP53-deleted cells had the worst prognosis in the LRF CLL4 trial...

..Our data confirm the value of combining cytogenetic, FISH and molecular analyses to define the incidence and precise nature of MLL and 11q23 abnormalities in AML...

..Common ATM missense mutations were not overrepresented. The data support previous observations that ATM mutation is associated with B-CLL. However, ATM mutations do not account for familial clustering of the disease...

..00001). CONCLUSIONS: The current findings suggested that both ZAP-70 and CD38 should be tested prospectively in all patients with early-stage CLL...

..B-PLL appears biologically heterogeneous regarding IgVH mutations, ZAP-70 and CD38 expression, showing a pattern distinct from that of other lymphoproliferative disorders...

..This revision updates those guidelines and covers the areas of diagnosis, treatment and assessment of response to therapy...

..68, P = .0006), CHEK2 I157T (OR = 14.83, P = .0008), BRCA2 N372H (OR = 1.45, P = .0032), and BUB1B Q349R (OR = 1.42, P = .0038). Our findings implicate variants in the ATM-BRCA2-CHEK2 DNA damage-response axis with risk of CLL...

..The structures of the ATM duplications suggest they may arise from an error in somatic hypermutation. We suggest that aberrant components of somatic hypermutation may contribute to the defective DSB repair characteristic of cancer...

..Anthracyclines did not appear to influence survival or disease relapses when given as front-line therapy in our series. The role of anthracyclines should be further evaluated in large randomised studies...

..It has clinically significant activity with an acceptable toxicity profile. Lack of renal toxicity makes DHAX an attractive cytoreductive regimen before high-dose chemotherapy...

..Grade 3 or 4 nonhaematological toxicity was minimal and stem cell mobilisation was not inhibited. GEM-P is an effective salvage regimen and its use prior to autologous stem cell transplant warrants further investigation...

..Further characterization of the genetic rearrangements in U937 may lead to the isolation of genes important in leukemogenesis and provide an in vitro system for their study...

..01). None of the regions coincided with areas of common chromosomal abnormalities frequently observed for CLL. These findings strengthen the argument for an inherited predisposition to CLL and related B-cell LPDs...

..80-1.31). A meta-analysis of this study and five other smaller published studies provides no evidence of relationship between this P2X7 polymorphism and risk of CLL (odds ratio = 0.99, 95% confidence interval: 0.74-1.32)...

..97 (95% CI, 0.79-1.18) and 0.88 (95% CI, 0.62-1.24), respectively. This data indicate that the MTHFR polymorphisms C677T and A1298C do not significantly contribute to an inherited genetic susceptibility to CLL...

..This suggests these regions may harbour a susceptibility locus for CLL. There is also some evidence that chromosome regions 2p12-p14 and 4q11-q21 may harbour predisposition genes...

..The EPIC regimen has equivalent activity to other reported cisplatin based regimens used in the treatment of recurrent lymphoma, but is associated with lower treatment related morbidity and mortality...

..In conclusion, our study demonstrates that MSI does not have a prominent role in the pathogenesis of B-CLL...

..These data suggest that BCL9 may be the target of translocation in some B-cell malignancies with abnormalities of 1q21 and that deregulated BCL9 expression may be important in their pathogenesis...

..However CD123 does not allow the distinction between HCL-variant and SLVL, as both are CD123 negative...

..Despite its efficacy the combination is not easily manageable because of the high rate of opportunistic infections...

..This study demonstrates that HDMP alone or in combination with other agents is a useful treatment strategy in refractory CLL including patients with p53 abnormalities...

..The patient has twice achieved a good response to pentostatin after failure of combination chemotherapy. This is the first report of the successful use of the purine analogue pentostatin in the management of GSSD...

..9-80.5%). In conclusion, GEM-P is a novel combination salvage therapy for poor-prognostic primary progressive or multiply relapsed lymphoma patients. It has clinically significant activity with a favourable toxicity profile...

..001 for SLVL deaths). We conclude that SLVL is mainly a disease of the elderly with a relatively benign course but, when treatment is required, splenectomy is beneficial...

..We find no evidence against a diagnosis of MCL in the nonnodal group and suggest that mutated IgVH genes may help identify patients with indolent disease...

..However, a role for RFP2 in the pathogenesis of MM cannot yet be excluded, given that alternative mechanisms such as haploinsufficiency remain possible...

..Our results indicate that marginal zone lymphomas at different anatomical localizations may derive from a similar B-cell subset...

..We conclude that 7% may be a more useful threshold for disease progression than higher values of CD38...

..These cases illustrate the importance of tissue diagnosis with cyclin D1 staining and fluorescence in situ hybridization analysis in B-cell leukaemia with prolymphocytic features...

..The objective of this retrospective study was to compare the outcomes of patients with SMZL who received treatment with rituximab, rituximab plus chemotherapy, or chemotherapy alone...

..However, these neoplasms also differ from CLL cytologically and in their immunophenotype...

..We highlight the resistant nature of the LGL clone and discuss the relative merits of immunomodulatory type therapy in this disease...

..This case further illustrates the value of M-FISH in combination with fusion probes in elucidating complex cytogenetic abnormalities...

..These cases serve to highlight the biological and cytogenetic heterogenity of DLBL and emphasize the need for complementary investigations in the characterization of this entity...

..No candidate gene has been linked to the high incidence of CLL (10%) seen in families of patients with this disease...

..Assessment of cDNA array profiles should further help us to design a working model for SMRT involvement in non-Hodgkin lymphoma transformation as a novel, nonclassical tumor suppressor...

..The presence of a high incidence of abnormalities in the established hotspot areas and in particular the finding of biallelic deletions is indicative of the existence of genes important for the pathogenesis of SLVL in these areas...

..This study aimed to assess the frequency, relationship and impact of p53 abnormalities and those of its inhibitor mdm2 in blastoid and non-blastoid MCL in leukemic phase...

..Pending the outcome of such trials, treatment decisions outside the context of a clinical trial still should be based on guidelines established by the most recent National Cancer Institute-sponsored Working Group...

..The detection of CLL-phenotype cells provides a surrogate marker of carrier status, potentially facilitating gene identification through mapping in families and direct analysis of isolated CLL-phenotype cells...

..4% (95% confidence interval, 2.5-24%). No analysed potential risk factor was predictive for MDS/AML development. We hypothesise that potential causative factors are fludarabine, low cell dose and transplant conditioning...

..This is to our knowledge the first description of amplification of the CCND1/IGH fusion gene in a human neoplasm, which may have played a role in the fulminating course of the disease in this patient...

..Detectable molecular disease by PCR was highly predictive of disease recurrence. It is of concern that 5 of 65 (8%) patients developed posttransplant acute myeloid leukemia/myelodysplastic syndrome...

..Our data suggest that SMZL constitute a genetically heterogeneous disease where gain of 3q25 and loss of 7q31 are the most likely imbalances to be involved in the pathogenesis of the disease...

..DNA sequencing adds little to these methods in identifying the population at risk...

..FMC7 is of greater diagnostic value than CD20 for distinguishing CLL from other B-cell disorders; we recommend its continued use for this purpose...

..The incidence of the latter two events was, however, higher than previously reported. Deletion of the TP53 gene predicted resistance to chemotherapy, highlighting its importance in this disease process...

..During follow-up post-treatment, seven delayed responses (54%) were observed, improving the initial overall response rate of 61% to a final response rate of 77%...

..Pregnancy thus appears to have a beneficial effect on neutrophil count in T-cell LGL leukaemia...