bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epidemiology and 15-Year Follow up after Cladribine Treatment of Patients with Hairy Cell Leukemia (HCL): Population-Based Swedish Data and Long-Term Follow-up of Scandinavian Study Patients Identify Older Patients with Poorer Outcome
Authors: Samuelsson Henrik , Heldal Dag , Jerkeman Mats , Juliusson Gunnar 
Published: April 2020

Abstract
HCL has been considered to be a disease of predominantly young males with, after the introduction of effective treatment, excellent prognosis. However, although very effective, these therapies introduced in the 1980’s are not curative. The Swedish Lymphoma Registry records all patients diagnosed since year 2000, with a 96 % coverage compared to the Swedish Cancer Registry, which is compulsory since 60 years. In contrast, previously published studies include patients highly selected for inclusion in treatment studies or referral to major medical centers. The Swedish registry data confirms the high male to female ratio, with yearly incidences of 5.3 males and 1.1 females per million. However, the median age at diagnosis was 62 years (range 30–92). The incidence in males rise with age as follows: 3 (30–49 yrs), 11 (50–69 yrs), 16 (70–79 yrs), and 20/million (80–95yrs). The 5-year overall survival of these unselected patients was 81%. Age and performance status had strong influence on survival. If HCL was diagnosed before age 60 the 5-year survival was 94%, whereas it was 70% for patients over 60 years. We also performed a 15-year follow-up of patients included in our first cladribine trials in the early 1990’s. The progression-free survival at 10 years was 60% and at 15 years 55%, irrespective of age. However, the 10 year and 15 year overall survivals were 91% and 82% for patients &lt;60 yrs, in contrast to 65% and 42% for those with diagnosis after age 60 years. We conclude that there is a proportion of older patients with HCL with a similar progressionfree survival after cladribine treatment as the younger, but poorer overall survival. Further analyses, including epidemiology of unselected total populations diagnosed since 1987, age-adjusted survival estimates, and incidence of secondary cancers among the HCL patients will be presented.
Quantitative Gene Expression Analysis of Surrogate Markers for Genetic Risk Groups and Survival in CLL
Authors: Kienle Dirk , Benner Axel , Winkler Dirk , Hensel Manfred , Dalla-Favera Riccardo , Lichter Peter , Stilgenbauer Stephan , Döhner Hartmut 
Published: April 2020

Abstract
In CLL, a variety of surrogate markers for individual genetic features, mostly the VH mutation status, were proposed from gene expression analyses. However, their detailed relation to specific genetic subsets such as V3-21 usage, del11q22-q23 (11q−), and del17p13 (17p−), and their prognostic value in relation to established factors is not elucidated yet. Gene expression markers (ADAM29, ATM, CLLU1, DMD, GLO1, HS1, KIAA0977, LPL, MGC9913, PCDH9, PEG10, SEPT10, TCF7, TP53, Vimentin, ZAP-70, ZNF2) were evaluated using real-time quantitative RT-PCR (RQ-PCR) in purified samples of 151 patients. VH sequencing and FISH screening for genomic aberrations were carried out for all cases, survival information was available for 133 cases. Logistic regression was performed to test the predictive value of gene expression for genetic risk groups, Cox proportional hazards statistics for survival analysis. VH mutation status was best assigned by LPL and ZAP70, followed by TCF7, a marker with a characteristic overexpression in VH mutated CLL patients (correct VH prediction in 83%, 83%, and 75% of the patients, respectively). A similar rate of correct VH assignments was achieved in the subgroup of patients with 11q− or 17p− when using these markers (88%, 86%, and 79%, respectively). In contrast to LPL and TCF7, most of the patients with V3-21 usage were recognized as risk patients by ZAP70 independently of the VH status. Therefore, ZAP70 yielded the best results for the overall recognition of patients with a genetic risk constellation (VH unmutated or V3-21 usage or 11q− or 17p−). Comparison of ZAP-70 determination by RQPCR and flow cytometry was performed for 72 patients and revealed 30% of discordant cases. Thereof, the majority was VH unmutated (including several cases with 11q− or 17p−) showing ZAP-70 negativity by FACS and positivity by RQ-PCR. In multivariate analysis of time to first treatment (TFT), ADAM29 was an independent prognostic factor besides the VH status and Binet stage. In overall survival analysis including the gene expression variables only, LPL was the strongest predictor for overall survival. When genetic and clinical factors were added to this analysis, V3-21 usage, 17p−, age, binet stage, and expression of ATM, ADAM29, SEPT10, and TCL1 were identified as significant prognostic factors. In conclusion, novel gene expression markers allow screening for patients at risk but can not fully substitute for the genetic factors, which should therefore at present remain the basis for risk stratification approaches. Some of the novel markers appear to have a prognostic relevance independently of the established factors, which points to relevant biologic and clinical implications demanding further investigation.
Elevated Serum Level of Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor Correlates with Stage of Chronic Lymphocytic Leukemia and Resistance to Treatment
Authors: Bakirov Bulat , Sgibneva Anastasiya , Bakirov Akhat 
Published: April 2020

Abstract
Background: B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in western world with an incidence of 3,36/100,000 in European males. It is characterized by a clonal growth of long lived, slowly proliferating mature B lymphoid cells in the bone marrow (BM), peripheral blood (PB), and lymphoid tissues. Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) is a pleiotropic cytokine that plays a role in hematopoiesis and apoptosis. Angiogenesis may have a role in a pathophysiology of leukemias and antiangiogenesis therapy could have an anticancer effect.
Aim: analyze the clinical significance of serum levels of angiogenic factors and how it’s correlate with clinical stage and survival in patients with B-CLL
Methods: the enzyme-linked immunosorbent assays (ELISAs) for VEGF and bFGF were performed in 78 CLL patients and 29 healthy person as a control group. The patients was divided on low-risk disease (44 patients) and high-risk disease (34 patients).
Results: VEGF and bFGF serum levels were significantly increased in patient with high-risk disease, the median serum VEGF level was 185.66 pg/ml, compared with 72.67 pg/ml in patient with a low-risk and in control, it was 48.62 pg/ml. The difference in the VEGF levels was significant for the comparison between low- and high-risk disease (p&lt;0.001). VEGF levels correlate with high white blood cell/lymphocyte counts, short period of time to begin treatment, disease progression, lymphocyte doubling time and worse answer to chemotherapy. No significant increase was found in bFGF serum level between low- and high-risk disease (34.06 pg/ml and 35.84 pg/ml, respectevely), but between patient and control group it was differences in serum level of bFGF (34.85 pg/ml and 7.77 pg/ml, respectively) (p&lt;0.001).
Conclusion: as we found, serum levels of bFGF and VEGF were significantly higher in the patients with B-CLL than in controls. High serum level of VEGF and bFGF associated with poor prognosis and worse answer on treatment. In summary, our data suggest that angiogenic factors play a significant role in the leukemic process and may suggest novel therapeutic approaches in B-CLL.
Formin-Like Gene Expression in Chronic Lymphocytic Leukemia Is Associated with Unfavorable Prognostic Factors and Clinical Outcome
Authors: Calpe Eva , Martinez Antonio , Favaro Patricia , Crespo Marta , Codony Carles , Baptista Ma.ÂJoao Gomes , Gine Eva , Montserrat Emili , Bosch Francesc 
Published: April 2020

Abstract
Formin proteins are large proteins evolutionarily conserved that govern cell shape, adhesion, cytokinesis, and morphogenesis by remodeling the actin and microtubule cytoskeletons. The human leukocyte formin, named as FMNL1, corresponds to an extended cDNA of the 5′-truncated KW-13 which was reported as a tumor-associated antigen in CLL, using a serologic identification by recombinant expression cloning (SEREX). In addition, FMNL1 co-immunoprecipitates with P-Akt in CLL cells, suggests that this protein may contribute to regulate cell survival. The aim of this study was to analyze the expression of FMNL1 in normal B-cell subsets and in a series of 73 patients (median age, 59 years; male/female 40/33; Binet A: 90.2%) with CLL. FMNL1 expression was analyzed by Western Blot, Immunohistochemistry and by Real-Time RT-PCR using expression in Jurkat as baseline. In normal lymphocytes subsets, FMNL1 was only expressed in memory B-cells, and in T-cells, whereas germinal center lymphocytes were negative. Among lymphoid B-cell malignancies, FMNL1 was expressed in mantle-cell lymphomas, Burkitt’s lymphomas and in DLBCL of GCB-type. In CLL cases mean of FMNL1 expression by QRT-PCR was 2.18 AU (SD, 1.01 AU). Using an arbitrary cut-off of 3.2 AU, cases with increased expression of FMNL1 were associated with a younger age at diagnosis (&lt; 50 yrs), elevated lymphocyte count, high serum β2-microglobulin (β2-m) levels, increased ZAP-70 and CD38 expression, shorter time to progression, and shorter survival as compared to cases with low FMNL1 expression. No relationship was observed with genetic abnormalities. In summary, increased expression of FMNL1 gene couples with adverse clinical and biological parameters in patients with CLL. Finally, the interaction between FMNL1 and AKT protein in lymhoproliferative disorders is under investigation.
Angiopoietin-2 mRNA Expression Is Elevated in Chronic Lymphocytic Leukemia Patients with Poor Prognostic Features
Authors: Vrbacky Filip , Smolej Lukas , Vroblova Vladimira , Pekova Sona , Hrudkova Monika , Pecka Miroslav , Maly Jaroslav 
Published: April 2020

Abstract
Several studies have demonstrated potential prognostic importance of angiogenesis in chronic lymphocytic leukemia (CLL). Elevated expression of angiogenic activator angiopoietin-2 (Ang-2) was recently reported in CLL but data regarding prognostic significance of Ang-2 in CLL is limited. Therefore, we evaluated potential relationship between Ang-2 expression and other prognostic factors in patients with CLL. Ang-2 mRNA was quantified by real-time quantitative PCR in purified mononuclear cells of 33 untreated CLL patients. Ang-2 transcript levels were further analyzed with regard to clinical stage, disease course, IgVH mutation status, CD38 and ZAP-70 expression. Elevated Ang-2 mRNA was detected in 12 cases; twenty-one patients had very low or undetectable levels of Ang-2 transcript. High Ang-2 mRNA levels were significantly associated with unmutated IgVH genes (p=0.010) and high CD38 expression (p=0.011) but not with ZAP-70 expression (p=0.784), Rai stage (p=0.305) or stable vs. progressive clinical course (p=0.443). Interestingly, there was a trend towards shorter progression-free survival in patients with high Ang-2 expression, but it did not reach statistical significance (median 15 months vs. not reached; p=0.090). In conclusion, our data show that Ang-2 mRNA is differentially expressed in patients with CLL and its increased expression appears to be associated with poor prognostic features.
Serum CD26 (Dipeptidyl Peptidase IV, DPP IV) compared with Immunoglobulin Heavy-Chain Mutation Status, ZAP-70 and CD38 as a Predictor of Time to First Treatment in Early B-CELL Chronic Lymphocytic Leukemia
Authors: Molica Stefano , Vitelli Gaetano , Cutrona Giovanna , Mirabelli Rosanna , Digiesi Giovanna , Giannarelli Diana , Sperduti Isabella , Morabito Fortunato , Ferrarini Manlio 
Published: April 2020

Abstract
We analyzed the correlation between well-established biological parameters of prognostic relevance in B-chronic lymphocytic leukemia [CLL] (i.e, mutational status of the immunoglobulin heavy chain variable region [IgVH], ZAP-70- and CD38-expression) and serum levels of CD26 (dipeptidyl peptidase IV, DPP IV) by evaluating the impact of these variables on the time to first treatment [TFT] in a series of 69 previously untreated Binet stage A B-CLL patients. By using a commercial ELISA (Human DPPIV/CD26 Quantikine R D Systems, USA) we found that circulating levels of CD26 did not reflect Rai sub-stages (P=0.52), β2-microglobulin (P=0.68), LDH (P=0.06), mutational status of IgVH (P=0.28), ZAP-70 (P=0.52) and CD38 (P=0.48). We used an optimal cut-point search to determine how to best split soluble CD26 data. Maximally selected logrank statistics plots identified a CD26 serum concentration of 371 ng/mL as the best cut-off. Accordingly, patients who had CD26 levels higher than 371 ng/mL experienced a shorter TFT (median 40 months) in comparison to patients whose CD26 levels were lower than 371 ng/mL (median 120 months; P=0.003). The univariate Cox proportional hazard model identified higher serum concentration of CD26 and absence of mutation in IgVH as predictor of shorter TFT. Again in multivariate analysis all these parameters maintained their discriminating power: mutational status of IgVH (HR= 0.23; CI 95% 0.10−0.51, P&lt;0.0001), soluble CD26 (HR= 0.38; CI 95% 0.17−0.85, P=0.02). The effects of CD26 on TFT were masked by mutational status of IgVH in patients with unmutated IgVH. In contrast, serum levels of CD26 and mutational status of IgVH had a joint effect on TFT in patients with mutated IgVH which translates into a segregation of patients with mutated IgVH in two sub-groups with different TFT according to CD26 levels (HR= 0.18; CI 95% 0.05−0.60, P=0.005). Our results indicate that in early B-cell CLL biological profile including among other parameters soluble CD26 may provide a useful insight into the complex interrelationship of prognostic variables. Furthermore, CD26 along with mutational status of IgVH can be adequately used to predict clinical behaviour of patients with low biological risk.
Alemtuzumab Administered by Subcutaneous Route Is Less Effective Than Intravenous Route for First Line Therapy of T-Cell Prolymphocytic Leukaemia: Results of a Pilot Study (UKCLL05)
Authors: Khot Ami t S , Matutes Estella , Kaczmarek Pawel A , Hamblin Mike , Roy Ashok , Grand Effie , Ethell Mark E , Dearden Claire E 
Published: April 2020

Abstract
T-cell prolymphocytic leukaemia (T-PLL) is a rare aggressive post thymic lymphoid disorder with distinctive clinical and pathological features. It is resistant to conventional chemotherapy and has a short median survival of 7 months. Intravenous (IV) alemtuzumab is an effective and well tolerated therapy for this disease, inducing remission in 76% of patients in the relapsed and refractory setting and increasing median survival to 24 months in responders. The aim of this study was to determine the efficacy of subcutaneous (SC) administration of alemtuzumab in previously untreated T-PLL patients. After an initial week of dose escalation, patients were treated with a dose of 30 mg 3 times weekly. Patients could be switched to the IV route if they had local side effects or showed a lack of response. Nine patients were enrolled. Male: female ratio was 2:1; median age was 61 years. All cases were centrally reviewed and confirmed to have a diagnosis of T-PLL. Eight had an immunophenotype typical of T-PLL (CD2, CD3, CD4, CD5 and CD 7 positive). One patient was unusually CD7 negative and also did not have an abnormality of chromosome 14. Seven had a complex karyotype and 8 had chromosome 14 abnormalities. Patients were treated on trial for a median of 7 weeks (range 3–13 weeks); 55% required a change to IV treatment due to a lack of response. This resulted in an increase in overall response (OR) from 33% (1 complete response [CR], 2 partial response [PR]) to 44 %.(2 CR, 2 PR). Five patients required addition of pentostatin to alemtuzumab at a dose of 4 mg/m2 IV weekly to augment response. This increased OR to 77% (1 additional CR and 2 PR). 5 patients had haemopoietic progenitor cell transplants (HPCT) as consolidation; 1 was autologous and 4 were allogeneic. Median overall survival was 20 months (range 1–26 months) and disease free survival was 12 months (range 0–20 months). The treatment was well tolerated; however 2 patients had skin reactions to the SC injections. One patient required treatment for CMV reactivation and 2 patients had grade 4 haematologic toxicity which was related to disease and not treatment. Four patients remain alive and well in CR with a follow up of between 12 and 23 months, of whom 3 had allogeneic HPCT. The study was terminated early as a data safety monitoring review felt that SC treatment was not efficacious and patients should not be offered SC treatment. This pilot study suggests that the SC route of administration of alemtuzumab is not as effective as IV in the treatment of T-PLL; our series of 16 patients receiving first line therapy with IV alemtuzumab has shown an OR of 94% with 88% CR. It is therefore advisable that IV treatment should be used. Pentostatin is an effective agent to augment response. Allogeneic HPCT should be used as consolidation therapy when possible.
Assessment of Targeted Systemic Exposure Based on Ex-Vivo Concentrations of Bendamustine and Chlorambucil and Related Clinical Outcomes
Authors: Darwish Mona , Brown Peter , Bensen-Kennedy Debra M , Young Lauren 
Published: April 2020

Abstract
The alkylating agent bendamustine (100 mg/m2 iv) was recently shown to be superior to chlorambucil (0.8 mg/kg po) in the treatment of patients with chronic lymphocytic leukemia, in respect to both overall response rate and progression-free survival (Knauf et al 2007). In order to better understand the greater activity exhibited by bendamustine, the ex-vivo potencies of these two drugs against primary CLL cells were compared with the peak plasma concentrations obtained in patients. Published studies indicate that ex-vivo bendamustine treatment results in a mean LD50 (dose causing 50% cell death) of 7.4 and 4.3 μg/ml in CLL cells from chemo-naive and previously-treated patients respectively (Schwanen et al 2002). This is comparable to the Cmax attained in patients: a 120 mg/m2 dose of bendamustine infused over 60 min resulted in a mean Cmax of 5.6 μg/ml in a study of lymphoma patients. In contrast, the corresponding LD50 values for chlorambucil were reported to be 12.3 and 26.2 μg/ml for chemo-naive and previously-treated CLL patients (Silber et al 1994). These concentrations are considerably higher than the plasma concentrations attained with oral administration of chlorambucil: an oral dose of 60 mg (~0.8 mg/kg) resulted in a mean Cmax of 2.2 μg/ml of parent compound and 1.1 μg/ml of the active phenylacetic acid metabolite. A higher dose of 70 mg did not result in higher plasma exposure (Hartvig et al 1988). The ability to achieve adequate therapeutic concentrations of bendamustine in CLL patients may explain, in part, the greater activity observed with this novel chemotherapy as compared to chlorambucil.
The Effects of BCR/ABL on DNA Damage and Repair Are Dependent on Apoptosis Competence
Authors: Burke Beth A , Carroll Martin 
Published: April 2020

Abstract
Chronic myeloid leukemia (CML) is a two-stage disease associated with the t(9;22) translocation. This translocation fuses the BCR gene with the ABL tyrosine kinase, forming the BCR/ABL oncogene. BCR/ABL is a constitutively activated tyrosine kinase, which causes the first stage of CML, chronic phase. However, it is still unknown why patients progress to the second phase, blast crisis, a phase marked by increased chromosomal abnormalities. Previous data from our lab suggests that cells expressing BCR/ABL have an increase in chromosomal translocations after DNA repair compared to control cells, as assessed by spectral karyotyping. We hypothesized that BCR/ABL alters the apoptotic threshold in response to DNA damage, and we sought to determine if cells lacking BCR/ABL that were unable to undergo apoptosis would show similar responses in DNA damage and repair assays to BCR/ABL expressing cells. In order to study this question we have used an interleukin 3 (IL3) dependent cell line that lacks expression of the pro-apoptotic proteins, Bax and Bak. These cells grow in the presence of IL3 but do not undergo apoptosis after cytokine withdrawal or genotoxic stress. We have generated a subclone of these cells that expresses BCR/ABL. This cell line, designated DBA, grows in the absence of IL3. As expected, growth of the cells in the absence of IL3 is suppressed by the ABL kinase inhibitor, dasatinib. BCR/ABL expressing and control cells proliferate at similar rates following DNA damage. After damage, both control cells and DBA cells have a delay in the G2/M phase of the cell cycle, which is modestly prolonged in BCR/ABL expressing cells. Both control and BCR/ABL expressing cells have a similar amount of DNA damage after irradiation as assessed by pulsed field gel electrophoresis. Additionally, the rate of repair of DNA double strand breaks is not significantly different in the two cell types. Spectral karyotype analysis is ongoing to determine whether error prone DNA repair in BCR/ABL cells is secondary to the effects of BCR/ABL on inhibition of apoptosis or reflects other proposed mechanisms of action of the oncogene.