bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Pharmacokinetic & Pharmacodynamic Study of Oral Lenalidomide in Patients with Low- or Intermediate-1-Risk Myelodysplastic Syndromes.
Authors: Wu Anfan , List Alan , Lush Richard , Bretz Kelly , Knight Robert , Zeldis Jerry , Lau Henry 
Published: April 2020

Abstract
Twelve patients diagnosed with low- or intermediate-1-risk myelodysplastic syndromes (MDS) were administered a single, 10 mg dose of lenalidomide followed by 24-hour blood and urine sampling on one occasion, and again at Day 14 of multiple dosing, followed by 5-hours of blood and urine sampling. Patients then continued into a combined treatment phase in which recombinant EPO was administered with lenalidomide. Table 1 describes the pharmacokinetic profiles of lenalidomide found for the first 12 MDS patients.
Following the single oral 10 mg dose, lenalidomide had an average renal clearance of 7.48 ± 1.74 L/hr. Greater than half of the dose (65.6% ± 6.9%) was excreted unchanged in the urine over 24 hours.
Conclusions: Among these MDS patients, the single and multiple dose pharmacokinetics of lenalidomide were similar, suggesting no accumulation of lenalidomide with multiple dosing. After 24 hours, 65.6% of the dose is eliminated in the urine as the parent compound. No relationship was apparent between the total number of adverse events normalized per day or Grade’s 3+4 adverse events and the drug exposure.
Table 1. Pharmacokinetics (Mean ± SD) in MDS Patients After a Single and Multiple 10 mg Oral Dose of Lenalidomide Parameter Single Dose Multiple Dose 1 Cmax and tmax are presented on Day 14; 2 median (min, max); NA = Not Applicable Cmax1 188 ± 59.5 168 ± 55.4 AUCt 852.3 ± 272 NA AUCss,0–5 NA 553.1 ± 205.6 T½,z 3.72 ± 0.75 NA tmax1,2 1.00 (0.5, 2.00) 0.75 (0.75, 2.50)
High Level of Pretransplant Leukemic Blasts and the Absence of Chronic Graft-Versus-Host Disease Provide Negative Effects on Clinical Outcome of Transplantation with Fludarabine-Busulfex Based Reduced Intensity Conditioning for Patients with the De Novo Myelodysplastic Syndrome According to WHO Criteria.
Authors: Cho Seok-Goo , Cho Byung-Sik , Kim Yoo-Jin , Kim Sung-Yong , Eom Ki-Seong , Kim HeeJe , Lee Seok , Min Chang-Ki , Kim Dong-Wook , Lee Jong-Wook , Min Woo-Sung , Kim Chun-Choo 
Published: April 2020

Abstract
Background: Allogeneic hematopoietic cell transplantation (HSCT) is the only curative potential for patients with MDS. HSCT following reduced-intensity conditioning (RIST) have enabled the extension of transplantation to include older or medically infirm patients with myeloid malignancies. However, it is very difficult to determine the value of outcomes of RIST for myelodysplastic syndrome (MDS) because of the heterogeneity of diseases included in most trials and the small number of MDS.
Method: Twenty-two patients with de novo MDS classified by WHO criteria received an allograft using a Fludarabine (30 mg/m2/day for 5 days)/Busulfex (3.2 mg/kg/day for 2 days) (14 patients) or Fludarabine (30 mg/m2/day for 5 days)/Busulfex (3.2 mg/kg/day for 2 days)/ATG (2.5 mg/kg/day for 2 days) (8 patients). The median age of patients was 43 years (range, 16–55). Donors were HLA-compatible sibling (n = 19) or matched unrelated (n = 3).
Result: Nineteen patients (86.4%) achieved engraftment. At a median follow-up of 18.9 months (range, 13.1–24.8 months), the estimated 2-year overall survival (OS), event-free survival (EFS), transplantation-related mortality and relapse incidence were 78.7%, 67.7%, 12.6%, and 22.5%, respectively. Acute GVHD greater than grade II was developed in 3 patients (15.8%). Chronic GVHD were developed in 10 patients (55.6%) and all of them did not receive ATG as conditioning. Variables influencing EFS were chronic GVHD (None/Limited [20.8%] versus Extensive [100%], P = 0.001), marrow blasts before transplantation (&lt;10% [85.1%] versus &gt;10% [20.8%], P = 0.006), and WHO criteria (RA [100%] versus RCMD [75%] versus RAEB-1 [80%] versus RAEB-2 [20.8%], P = 0.043).
Conclusion: These observations indicate that high level of pretransplant leukemic blasts and the absence of chronic graft-versus-host disease provide negative effects on clinical outcome of transplantation with Fludarabine-Busulfex based reduced intensity conditioning for patients with the de novo myelodysplastic syndrome according to WHO criteria.
Detection of the JAK2 V617F Mutation by Real Time PCR in Granulocytes and Platelets of ET Patients.
Authors: Bellosillo Beatriz , Gimeno Eva , Longaron Raquel , Florensa Lourdes , Salar Antonio , Espinet Blanca , Sole Francesc , Serrano Sergio , Besses Carlos 
Published: April 2020

Abstract
Introduction. The JAK2 V617F mutation has been detected in 23%–57% of ET patients by direct sequencing or allele-specific (AS) PCR. It remains unknown, however, if the mutation detected in the granulocyte population, may be equally detected in platelets from these patients.
Objective. To compare the detection of the JAK2V617F mutation in granulocytes and platelets from ET patients by real time AS RT-PCR.
Patients and methods. Platelets and granulocytes from 50 ET patients from a single institution were studied. Patients were diagnosed according to the WHO criteria. At the time when JAK2 mutation was analyzed 16/50 patients were receiving platelet-lowering therapy ± ASA, 14/50 patients only received ASA and 20/50 received no specific treatment. JAK2 mutation was analyzed by real-time AS RT-PCR with probes specific for the mutated and the wild type form.
Results. The V617F JAK2 mutation was detected in 18 out of 50 patients in both granulocytes and platelets by real time AS RT-PCR, and was negative in both cell populations in the remaining 32 patients. In the V617F JAK2 positive cases, the mean Ct(V617FJAK2)/Ct(wild type JAK2) ratio was 1.074±0.062 for granulocytes and 1.038±0.039 for platelets (p=0.048). These values corresponded to a 17.79 ±7.4% of mutated population when granulocytes were analyzed, whereas, a significantly higher percentage of mutated population was observed, 23.45±7.78 %, when platelets were analyzed (p=0.032).
Conclusions. The results of V617FJAK2 mutation detection by AS RT-PCR were the same in granulocytes and platelets (either positive or negative). The percentage of clonal population detected in ET patients was significantly higher in platelets than in granulocytes.
Tyk2 Mutation Homologous to V617F Jak2 Is Not Found in Essential Thrombocythaemia, Although It Induces Constitutive Signaling and Growth Factor Independence.
Authors: Shide Kotaro , Shimoda Kazuya , Kamezaki Kenjirou , Kakumitsu Haruko , Kumano Takashi , Oku Seido , Numata Akihiko , Ishikawa Fumihiko , Takenaka Katsuto , Harada Mine 
Published: April 2020

Abstract
A single somatic mutation, V617F, in the pseudokinase domain of the Jak2 is the cause of the majority of polycythaemia vera (PV) cases and one-third of essential thrombocythaemia (ET) cases. PV is characterized by an increase in RBC and erythropoiesis is regulated by erythropoietin (EPO). ET is characterized by the elevation of megakaryopoiesis and platelet numbers, while thrombopoietin (TPO) is a primary regulator of thrombopoiesis. EPO selectively activates Jak2, whereas TPO selectively activates Jak2 and Tyk2. As valine 617 of Jak2 is conserved as valine 678 of Tyk2, we examined the effect of a homologous mutation in Tyk2 (V678F Tyk2) on cell growth. V678F Tyk2 augumented the transcriptional activity of Stat3 and Stat5 in 293T cells. The expression of V678F Tyk2 in Ba/F3 cells induced the phosphorylation of Tyk2 and Stat5 in the absence of cytokine stimulation and induced autonomous cell growth. Ba/F3 cells harboring V678F Tyk2 showed hyper-responsiveness to IL-3. As V678F Tyk2 might cause MPD, we examined the somatic mutation of Tyk2 in 6 ET patients lacking the V617F Jak2 mutation. No cases harbored the Tyk2 mutation. It requires a two-base-pair change to substitute phenylalanine for valine in Tyk2, and the enhancing effects of V678F Tyk2 on cell growth are less dramatic than those of V617F Jak2. The lesser effect of V678F Tyk2 on cell proliferation, together with the lower incidence of VF mutations in Tyk2, might explain why mutations in Tyk2 are rare in ET patients.
Endothelial Dysfunction Is Independent of the JAK2 V617F Mutation in Polycythemia Vera.
Authors: Gisslinger Heinz , Gwechenberger Marianne , Neunteufl Thomas , Bachofner Nicol , Gisslinger Bettina , Kralovics Robert 
Published: April 2020

Abstract
In polycythemia vera (PV) thrombotic events are the major cause of morbidity and mortality. Although in PV vascular complications encompass the whole spectrum of thrombembolic events, arterial occlusions (stroke, TIA, myocardial infarction and peripheral arterial disease) play a major role. In a large retrospective analysis arterial thromboses accounted for about 75% of all thrombotic complications while venous thrombotic events were less frequent and accounted only for a quarter of vascular complications. As a preclinical sign of arterial thrombosis we observed in a previous study a significantly more pronounced endothelial dysfunction in PV compared to a sex and age matched control group with even a higher cardiovascular risk profile. So far the pathogenesis of this predisposition to endothelial dysfunction and arterial thrombosis in PV remains poorly understood and no clear association with any laboratory parameter could be established. The V617F mutation in the JAK2 kinase gene (JAK2-V617F) showed an association with thrombosis in essential thrombocythemia. Virtually all patients with PV acquire JAK2-V617F although the abundance of myeloid cells carrying the V671F mutation varies greatly among patients. Therefore, we quantified the presence of the mutated allele of JAK2 (%V617F) in granulocytes using a quantitative allele-specific PCR-assay and examined the endothelial function as a preclinical indicator for arterial vascular disease in 27 patients with PV. Endothelium-dependent flow-mediated vasodilatation (FMD) was measured using high-resolution ultrasound of the brachial artery. We did not observe a correlation between the FMD values and %V617F in our cohort of PV patients (P=0.48). A similar lack of correlation was observed when only patients with low and high %V617F were compared (P=0.60). To date the low FMD values in PV have not been associated with any laboratory or genetic parameters. Thus, a unique V617F-independent pathogenetic mechanism is likely to play a role in endothelial dysfunction in PV.
The Clinical Implications of JAK2V617F Mutation in 137 Chinese Patients with Myeloproliferative Diseases.
Authors: Zhang Ri , Fei Hairong , Chen Suning , Pei De 
Published: April 2020

Abstract
A single acquired mutation in the JAK2 gene has recently been described in the classic myeloproliferative diseases(MPDs) including 65–97% of patients with polycythemia vera (PV), 23–57% of those with essential thrombocythemia (ET) and 35–57% of those with idiopathic myelofibrosis (IMF). The understanding of the molecular mechanisms has been considered a point mutation in exon 12 of the JAK2 gene, a key hematopoietic regulator, resulting in substitution of valine for phenylalanine at amino acid position 617 in the JH2 domain. In order to clarify the frequency and some clinical implication of JAK2V617F mutation in the Chinese patients with MPDs, we investigated this mutation in 137 Chinese patients aged 15 to 65 years. There are 57 patients with PV, 68 with ET, and 12 with IMF and the diagnosis of MPDs was defined according to published criteria. Genomic DNA samples obtained from all three MPDs and twenty cases of healthy people as negative control and the HEL, an erythroleukemic cell line, as positive control was screened by allele-specific PCR and gel electrophoresis for JAK2V617F mutation described by Baxter EJ et al.
The results indicated that 65.69% of heterozygous JAK2V617F mutation was shown in 137 patients of over all MPDs, 73.68% in PV (42/57), 58.82% in ET (40/68), 66.67% in IMF (8/12). Sequence analysis of PCR products from selected patients confirmed existence of both mutant and wild-type alleles in patients with JAK2V617F mutation. A higher prevalence was observed in older patients with MPDs, and the WBC count of ET patients with JAK2V617F mutation is higher than that of ET patients without JAK2V617F mutation, and the difference has a statistical significance (P&lt;0.05). The HGB concentration and platelet number of MPDs patients with JAK2V617F mutation were higher than those without JAK2V617F patients, but the difference did not achieve a statistical significance(P&gt;0.05).
Cytogenetic analyses were performed in 115 of the 137 MPDs patients. The chromosomal karyotype was normal in 108 of the 115 patients. Among them, JAK2V617F mutation was detected in 74 patients (68.51%) as compared with 5 of the 7 patients with karyotypic abnormalities (71.4%). Three patients with detective bcr/abl low expression assayed by FISH and real-time PCR techniques, two have JAK2V617F mutation. Our datas suggest that JAK2V617F mutation also occurs in a significant percentage of Chinese patients with the myeloproliferative diseases.
Relationship between Autoimmune Phenomena and Disease Stage and Therapy in B-Cell Chronic Lymphocytic Leukaemia.
Authors: Barcellini Wilma , Capalbo Silvana , Agostinelli Rosa M. , Mauro Francesca R. , Ambrosetti Achille , Calori Rossella , Cortelezzi Agostino , Laurenti Luca , Pogliani Enrico M. , Pedotti Paola , Liso Vincenzo , Mandelli Franco , Zanella Alberto 
Published: April 2020

Abstract
Autoimmune haemolytic anaemia (AIHA) and thrombocytopenia (AITP) are known complications of B-cell chronic lymphocytic leukaemia (B-CLL), whereas there are only few reports on other autoimmune diseases and on serological markers of autoimmunity. In this multicentric GIMEMA study we investigated the presence of different autoimmune phenomena in B-CLL (haematological cytopenias, other autoimmune diseases, and serological markers of autoimmunity) and their relationship with B-CLL stage and therapy by multivariate analysis.
Among the 194 cases recorded, the more frequent complication was AIHA (66%), followed by AITP (18%) and other autoimmune diseases (16%). The occurrence of autoimmune complications was associated with advanced and multi-treated disease, as demonstrated by multivariate analysis, which identified age over the median, stage C and I and II line therapy as independent risk factors for autoimmune complications. The distribution of the autoimmune diseases was different with respect to stage and therapy, in that AIHA and AITP were typically present in advanced and multi-treated disease, whereas the non-haematological autoimmune complications were mostly observed in early B-CLL. Interestingly, fludarabine treatment was not associated with an increased risk of AIHA. In addition, 41% of B-CLL patients, mostly in stage A, showed positive serological markers of autoimmunity.
Non-haematological autoimmune complications, although usually less severe than haematological ones, should be carefully searched for, particularly in early B-CLL patients. The distribution of autoimmune diseases with respect to stage and therapy suggest the existence of different pathogenic mechanisms underlying haematological and non-haematological autoimmune phenomena in B-CLL.
Distribution of autoimmune phenomena grouped as haematological complications (AIHA and AITP, ▪), non-haematological disease (***), and serological autoantibodies only (□), χ2 test: p&lt;0.001 Distribution of autoimmune phenomena grouped as haematological complications (AIHA and AITP, ▪), non-haematological disease (***), and serological autoantibodies only (□), χ2 test: p&lt;0.001
CD20 Antigen Expression Is Increased in Trisomy 12 CLL as Compared to Other Cytogenetic Subtypes.
Authors: Tam Constantine S. , Otero-Palacios Joselle , Lerner Susan , Abruzzo Lynne V. , Jorgensen Jeffrey L. , Ferrajoli Alessandra , Wierda William G. , O’Brien Susan , Keating Michael J. 
Published: April 2020

Abstract
CD20, a B-cell specific 297-amino acid transmembrane phosphoprotein and the target of the monoclonal antibody rituximab, is expressed at lower levels in malignant cells from patients with CLL as compared to other indolent B-cell malignancies. Anecdotal observations have suggested that CLL patients with trisomy 12 may have higher cell-surface CD20 expression than other cytogenetic subtypes. In order to test this hypothesis, we analyzed bone marrow (n=454) and peripheral blood (n=56) samples from 510 chemotherapy-naïve patients using a Vysis FISH panel and a flow cytometric quantitative CD20 antigen assay. FISH studies identified 99 patients (19%) with trisomy 12. Compared to non-trisomy 12 patients, patients with trisomy 12 were older (p=0.002) and were more likely to have increased serum B2-microglobulin (p&lt;0.001), LDH (p&lt;0.001), splenomegaly (p=0.007), and hepatomegaly (p=0.01). Mean CD20 antigen sites were significantly higher in patients with trisomy 12 in both peripheral blood and bone marrow samples (log mean 4.64 vs. 4.03 for PB, p&lt;0.001; log mean 4.36 vs. 3.99 for BM, p&lt;0.001). Mean CD20 antigen expression by Döhner subtypes were (per cell): trisomy 12 24,255; 17p deletion 11,114; negative FISH 10,557; 13q deletion 10,431; and 11q deletion 6,391. A multivariate analysis confirmed trisomy 12 as the only significant predictor of increased CD20 expression. To date, 11 CLL patients with trisomy 12 have received rituximab and GMCSF as initial therapy, and partial response was achieved in 8 of 9 (89%) assessable patients. Increased CD20 antigen expression in CLL patients with trisomy 12 provides a rationale for exploration of rituximab-based regimens in these patients.
Cytogenetic Aberrations and Ig VH Gene Mutations of Clinically Benign CD5-Monoclonal B-Cell Lymphocytosis (MLUS).
Authors: Wang Chen , Amato Dominick , Oscier David G. , Davis Zadie , Mould Sarah , Kolomietz Elena , Zheng Jianing 
Published: April 2020

Abstract
Clonal expansion of lymphocytes is a hallmark of lymphoproliferative disorders. However, the finding of clonal lymphocytes may not be diagnostic of a defined lymphoid malignancy. In this study, we had an opportunity to identify and characterize a series of 7 patients with clinically benign clonal B-cell lymphocytosis. The clonal lymphocytes were clearly of CD5− and non-CLL phenotype. All patients were elderly and identified with a mild to moderate absolute lymphocytosis (lymphocytes range 3.6–9.4 ×109/L). The clonal population accounted for 95–99% of total B cells. For a follow-up period of 4–16 years, clonal lymphocytosis was persistent but virtually not progressing. All patients remained clinically stable and totally asymptomatic. The clonal CD5− B cells were shown to have somatic hypermutations of VH gene in 6 of the 7 patients, indicating a cell origin of germinal center B lymphocytes. Karyotypic aberrations were found in 5 of 6 patients examined. Two clones were found to have an isochromosome 17q, one as the sole abnormality and one as part of a complex karyotype. The loss of the short arm of chromosome 17 resulted in loss of p53, which was confirmed by the FISH analysis in both cases. The finding of p53 loss is unusual in such a benign condition. Two other clones were shown to have 7q abnormalities; one 7q31–34 deletion and one t(2;7)(p11;q22), the latter is impliated in dysregulation of the CDK6 gene. Even though deletion of 7q is strongly associated with, and t(2;7) is confined to splenic marginal zone lymphoma (SMZL), neither patients were hematologically or clinically diagnostic for SMZL. It remains to be determined whether additional cytogenetic and molecular changes may occur to lead to progression to a clinical malignancy. The patients in this study differ from those clonal CD5− monoclonal B-cell populations identified by sensitive flow cytometry in the normal population, by the presence of absolute lymphocytosis. In addition, the phenotypic profile is distinct from that of benign variant CLL. These clinically benign lymphocytoses may represent an intermediate between covert clonal expansion and overt malignancy.
The t(14;19)(q32;q13) Translocation in B Lymphoproliferative Disorders: A Continuum from Chronic Lymphocytic Leukemia (CLL) to Marginal Zone Lymphoma (MZL)?.
Authors: Nguyen-Khac Florence , Chapiro Elise , Radford-Weiss Isabelle , Bastard Christian , Dominique Leroux , Callet-Bauchu Evelyne , Talmant Pascaline , Luquet Isabelle , Marie-Joelle Mozziconacci , Michel Lessard , Sophie Raynaud D. , Davi Frederic , Merle-Beral Helene , Berger Francoise , Berger Roland 
Published: April 2020

Abstract
Translocation t(14;19)(q32;q13) juxtaposing BCL3 in 19q13 with IGH in 14q32, is a rare recurrent event found in patients with B-cell malignancies. So far, a few cases of well-documented B-cell neoplasm have been reported. We analyzed 34 patients with t(14;19) and 1 patient with a variant t(2;19)(p11;q13) collected by the Groupe Francophone de Cytogenetique Hematologique on the basis of cytogenetic abnormality. Clinico-biological data, morphological review, immunophenotyping with Matutes’ score, conventional karyotype and FISH analysis with BCL3, IGH, CEP12, 13q14, ATM, TP53, 6q21 probes, and IgVH mutational status were recorded. The sex ratio was 22M/13F, the median age at diagnosis was 61 [39–89], the lymphocyte count was &gt; 4×109/l in 96% of patients, and spleen enlargement was found in 47%. 31% (11/35) were morphologically classified CLL, 37% (13/35) atypical CLL, 20% (7/35) MZL; 79% had features of disease progression; 3 of the 4 latter were Diffuse Large B Cell Lymphoma, possibly transformed from MZL. 87% were CD5+, 72% had a Matutes’ score &lt; 3. The IgVH genes were unmutated in 9/11 cases. The time to treatment was &lt; 1 year in 68% of patients. The BCL3 locus involvement was confirmed by FISH analysis in all cases. 46% of cases showed complex karyotype. The chromosomal abnormalities associated with t(14;19) were +12 (57%), 6q- (27%), +3 (15%), 11q- (15%), 13q- (13%), 17p- (12%), +18 (12%), 7q- (12%). Comparison with published cytogenetic CLL data shows that deletion 6q was frequent and deletion 13q uncommon. Trisomies 3 and 18, and 7q deletion are less common than in published MZL. The independent analysis of our series of CLL/atypical CLL and MZL gave the same tendency. The chromosomal abnormalities associated with t(14;19) are not specific, but their frequencies are between those of typical CLL and MZL suggesting an intermediary status between the 2 malignancies. The t(14;19) identifies a subgroup of B-disorders CD5+ and Matutes’ score &lt; 3, which could be of poor prognosis, based on progressive disease and unmutated status.