pinecone/core-2020-05-10-deduplication huggingface dataset:
Residual vein thrombosis for assessing duration of anticoagulation after unprovoked deep vein thrombosis of the lower limbs: the extended DACUS study.

Abstract\ud
The safest duration of anticoagulation after idiopathic deep vein thrombosis (DVT) is unknown. We conducted a prospective study to assess the optimal duration of vitamin K antagonist (VKA) therapy considering the risk of recurrence of thrombosis according to residual vein thrombosis (RVT). Patients with a first unprovoked DVT were evaluated for the presence of RVT after 3 months of VKA administration; those without RVT suspended VKA, while those with RVT continued oral anticoagulation for up to 2 years. Recurrent thrombosis and/or bleeding events were recorded during treatment (RVT group) and 1 year after VKA withdrawal (both groups). Among 409 patients evaluated for unprovoked DVT, 33.2% (136 of 409 patients) did not have RVT and VKA was stopped. The remaining 273 (66.8%) patients with RVT received anticoagulants for an additional 21 months; during this period of treatment, recurrent venous thromboembolism and major bleeding occurred in 4.7% and 1.1% of patients, respectively. After VKA suspension, the rates of recurrent thrombotic events were 1.4% and 10.4% in the no-RVT and RVT groups, respectively (relative risk = 7.4; 95% confidence interval = 4.9-9.9). These results indicate that in patients without RVT, a short period of treatment with a VKA is sufficient; in those with persistent RVT, treatment extended to 2 years substantially reduces, but does not eliminate, the risk of recurrent thrombosis
Cancer patients requiring interruption of long-term warfarin because of surgery\ud
or chemotherapy induced thrombocytopenia: the use of fixed sub-therapeutic doses \ud
of low-molecular weight heparin.

No data are available regarding the management of cancer patients requiring interruption of long-term vitamin-K antagonist (VKA) therapy. For this purpose, we tested the efficacy and safety of fixed doses of low-molecular weight heparin (LMWH) in substitution of VKA because of invasive procedures or chemotherapy-induced thrombocytopenia. In cancer patients on VKA, therapy was discontinued 5 ± 1 days before surgery or chemotherapy. Heparin was given at prophylactic dosage in patients at low risk and at fixed subtherapeutic doses (3,800 or 4,000 UI anti-FXa, b.i.d.) in those at high-risk for thrombosis. LMWH was reinitiated 12 hr after surgery and VKA the day after. In patients receiving chemotherapy, LMWH was reinitiated 12/24 hr after obtaining a stable platelet count ≥ 30,000 mmc(3) and VKA after a stable platelet count ≥ 50,000 mmc(3) . Thromboembolism and major bleeding events were recorded from the time of VKA suspension to 30 ± 2 days postprocedure or until the next chemotherapy. Overall, 156 patients (56.4% at low risk and 43.5% at high risk for thrombosis) were enrolled; 34.6% underwent major surgery, 40.4% nonmajor surgery, and 25% chemotherapy. Thrombotic events occurred in five patients [3.2%, 95% confidence interval (CI): 1.41-7.27], four belonging to the high-risk and one to the low-risk group. Major bleeding occurred in five patients (3.2%, 95 CI: 1.41-7.27), all belonging to the high-risk group (three during major surgery and two during chemotherapy). In conclusion, LMWH given at fixed subtherapeutic is a feasible and relatively safe approach for bridging therapy in cancer patients on long-term VK
The hope and reality of long‐acting hemophilia products

Recombinant DNA technology and protein engineering are creating hope that we can address ongoing challenges in hemophilia care such as reducing the costs of therapy, increasing the availability to the developing world, and improving the functional properties of these proteins. Technological advances to improve the half‐life of recombinant clotting factors have brought long‐acting clotting factors for hemophilia replacement therapy closer to reality. Preclinical and clinical trial results are reviewed as well as the potential benefits and risks of these novel therapies. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc
Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progression-free survival in multiple myeloma

Despite the good response of stem cell transplant (SCT) in the treatment of multiple myeloma (MM), most patients relapse or do not achieve complete remission, suggesting that additional treatment is needed. We assessed the impact of thalidomide in maintenance after SCT in untreated patients with MM. A hundred and eight patients (&lt;70 years old) were randomized to receive maintenance with dexamethasone (arm A; n = 52) or dexamethasone with thalidomide (arm B; n = 56; 200 mg daily) for 12 months or until disease progression. After a median follow-up of 27 months, an intention to treat analysis showed a 2-year progression-free survival (PFS) of 30% in arm A (95% CI 2238) and 64% in arm B (95% CI 5771; P = 0.002), with median PFS of 19 months and 36 months, respectively. In patients who did not achieve at least a very good partial response, the PFS at 2 years was significantly higher when in use of thalidomide (19 vs. 59%; P = 0.002). Overall survival at 2 years was not significantly improved (70 vs. 85% in arm A and arm B, respectively; P = 0.27). The addition of thalidomide to dexamethasone as maintenance improved the PFS mainly in patients who did not respond to treatment after SCT. Am. J. Hematol. (c) 2012 Wiley Periodicals, Inc.FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)CNPq (Conselho Nacional do Desenvolvimento Cientifico e Tecnologico)Conselho Nacional do Desenvolvimento Cientifico e Tecnologico (CNPq)FAPERJ (Fundacao de Apoio a Pesquisa do Estado do Rio de Janeiro)FAPERJ (Fundacao de Apoio a Pesquisa do Estado do Rio de Janeiro
Chromosome 2p gain in monoclonal B-cell lymphocytosis and in early stage chronic lymphocytic leukemia.

Recent studies have described chromosome 2p gain as a recurrent lesion in chronic lymphocytic leukemia (CLL). We investigated the 2p gain and its relationship with common prognostic biomarkers in a prospective series of 69 clinical monoclonal B-cell lymphocytosis (cMBL) and 218 early stage (Binet A) CLL patients. The 2p gain was detected by FISH in 17 patients (6%, 16 CLL, and 1 cMBL) and further characterized by single nucleotide polymorphism-array. Overall, unfavorable cytogenetic deletions, i.e., del(11)(q23) and del(17)(p13) (P = 0.002), were significantly more frequent in 2p gain cases, as well as unmutated status of IGHV (P < 1 × 10(-4) ) and CD38 (P < 1 × 10(-4) ) and ZAP-70 positive expression (P = 0.003). Furthermore, 2p gain patients had significantly higher utilization of stereotyped B-cell receptors compared with 2p negative patients (P = 0.009), and the incidence of stereotyped subset #1 in 2p gain patients was significantly higher than that found in the remaining CLLs (P = 0.031). Transcriptional profiling analysis identified several genes significantly upregulated in 2p gain CLLs, most of which mapped to 2p. Among these, NCOA1 and ROCK2 are known for their involvement in tumor progression in several human cancers, whereas among those located in different chromosomes, CAV1 at 7q31.1 has been recently identified to play a critical role in CLL progression. Thus, 2p gain can be present since the early stages of the disease, particularly in those cases characterized by other poor prognosis markers. The finding of genes upregulated in the cells with 2p gain provides new insights to define the pathogenic role of this lesion. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc
Total body computed tomography scan in the initial work-up of binet stage a chronic lymphocytic leukemia patients: results of the prospective, multicenter o-cll1-gisl study

Total body computed tomography (TB-CT) scan is not mandatory in the diagnostic/staging algorithm of chronic lymphocytic leukemia (CLL). The aim of this study was to determine the value and prognostic significance of TB-CT scan in early stage CLL patients. Baseline TB-CT scan was performed in 240 Binet stage A CLL patients (179 Rai low- and 61 Rai intermediate-risk) included in a prospective multicenter observational study (clinicaltrial.gov ID:NCT00917549). The cohort included 69 clinical monoclonal B lymphocytosis (cMBLs). Patients were restaged considering only radiological data. Following TB-CT scans, 20% of cases reclassified as radiologic Binet (r-Binet) stage B. r-Binet B patients showed a higher incidence of unfavorable cytogenetic abnormalities (P = 0.027), as well as a shorter PFS (P = 0.001). At multivariate analysis, r-Binet stage [HR = 2.48; P = 0.004] and IGHV mutational status [HR = 3.01; P = 0.002] retained an independent predictive value for PFS. Among 179 Rai low-risk cases, 100 were redefined as r-Rai intermediate-risk based upon TB-CT scan data, showing a higher rate of cases with higher ZAP-70 (P = 0.033) and CD38 expression (P = 0.029) and β2-microglobulin levels (P < 0.0001), as well as a shorter PFS than those with r-Rai low-risk (P = 0.008). r-Rai stage [HR = 2.78; P = 0.046] and IGHV mutational status [HR = 4.25; P = 0.009] retained a significant predictive value for PFS at multivariate analysis. Forty-two percent of cMBL patients were reclassified as r-small lymphocytic lymphomas (r-SLLs) by TB-CT scan. TB-CT scan appears to provide relevant information in early stage CLL related to the potential and the timing of patients to progress towards the more advanced disease stages
X-linked sideroblastic anemia due to ALAS2 intron 1 enhancer element GATA-binding site mutations

Contains fulltext :
                  137231.pdf (publisher's version ) (Open Access)X-linked sideroblastic anemia (XLSA) is the most common form of congenital sideroblastic anemia. In affected males, it is uniformly associated with partial loss-of-function missense mutations in the erythroid-specific heme biosynthesis protein 5-aminolevulinate synthase 2 (ALAS2). Here, we report five families with XLSA owing to mutations in a GATA transcription factor binding site located in a transcriptional enhancer element in intron 1 of the ALAS2 gene. As such, this study defines a new class of mutations that should be evaluated in patients undergoing genetic testing for a suspected diagnosis of XLSA. Am. J. Hematol. 89:315-319, 2014. (c) 2013 Wiley Periodicals, Inc
Genetic Variants at HbF-Modifier Loci Moderate Anemia and Leukocytosis in Sickle Cell Disease in Tanzania.

Fetal hemoglobin (HbF) is a recognized modulator of sickle cell disease (SCD) severity. HbF levels are strongly influenced by genetic variants at three major genetic loci, Xmn1-HBG2, HMIP-2, and BCL11A, but the effect of these loci on the hematological phenotype in SCD, has so far not been investigated. In a cohort of individuals with SCD in Tanzania (HbSS and HbS/β° thalassemia, n = 726, aged 5 or older), HbF levels were positively correlated with hemoglobin, red blood cell (RBC) indices, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH), and negatively with white blood cell (WBC) and platelet counts (all P < 0.0001). We subsequently assessed the contribution of the three HbF modifier loci and detected diverse effects, including a reduction in anemia, leukocytosis, and thrombocytosis associated with certain HbF-promoting alleles. The presence of the 'T' allele at Xmn1-HBG2 led to a significant increase in hemoglobin (P = 9.8 × 10(-3) ) but no changes in cellular hemoglobin content. Xmn1-HBG2 'T' also has a weak effect decreasing WBC (P = 0.06) and platelet (P = 0.06) counts. The BCL11A variant (rs11886868-'C') increases hemoglobin (P = 2 × 10(-3) ) and one of the HBS1L-MYB variants decreases WBC values selectively (P = 2.3 × 10(-4) ). The distinct pattern of effects of each variant suggests that both, disease alleviation through increased HbF production, and 'pleiotropic' effects on blood cells, are involved, affecting a variety of pathways
Registry studies on myelodysplastic syndrome and secondary acute myeloid leukemia

The aims were (I) to describe a European lower risk MDS population and the use of erythropoietin stimulation agents (ESA), (II) to describe the AML population in Sweden 1997-2006 with emphasis on secondary AML (s-AML) and therapy-related AML (t-AML), (III) to investigate the use and effect of allogeneic hematopoietic stem cell transplantation (HSCT) in the AML population in Sweden 1997-2013, and (IV) to merge  patients from the Swedish AML Registry 2009-14 with patients from the Swedish MDS Registry 2009-14 in order to describe the patients with s-AML after MDS from time of MDS diagnosis and AML diagnosis. Patients, methods and results: (I) ESA treatment were given to 45.6% patients with lower risk MDS, median duration 27.5 months. A propensity model, comparing ESA-treated and untreated was used. Median time to first post-ESA treatment transfusion was 6.1 months in patients transfused before ESA treatment compared to 23.3 months in non-transfused patients (p<0,0001), showing that ESAs can significantly delay the onset of a regular transfusion need in patients with lower-risk MDS. (II) Of 3,363 AML patients with induction therapy, 73.6% were de novo AML, 18.7% had antecedent hematological disease (AHD-AML), and 7.7% had t-AML. S-AML-patients were older compared to de novo AML and had higher cytogenetic risk scores. Multivariate analysis showed that AHD-AML and t-AML were independent risk factors for inferior survival in the younger age groups. (III) Of 3337 intensively treated patients, 21% underwent HSCT at any stage of the disease. Five-year survival without and with allogeneic HSCT were 0% vs 50% for MPN-AML, 3% vs 39% for MDS-AML, 8% vs. 48% for t-AML and 24% vs. 57% for de novo AML-patients. Presence of any chronic graft versus host disease (cGvHD) compared to no cGvHD and a GvHD grade 1 or lower was significantly associated to better survival in a multivariable analysis. Allogeneic HSC is the only option for cure in S-AML. (IV)We found 257 patients with sufficient information from both AML and MDS registries for further examination. 72.2% had high risk cytogenetics and 66.8%, had performance status 0-1 at AML diagnosis. Median time from MDS diagnosis to AML diagnosis was 10.8 months. Median survival time for S-AML was 4.93 months. Allogeneic HSCT improves survival significantly in the younger age groups
Genome-wide association study follow-up identifies cyclin A2 as a regulator of the transition through cytokinesis during terminal erythropoiesis

Genome-wide association studies (GWAS) hold tremendous promise to improve our understanding of human biology. Recent GWAS have revealed over 75 loci associated with erythroid traits, including the 4q27 locus that is associated with red blood cell size (mean corpuscular volume, MCV). The close linkage disequilibrium block at this locus harbors the CCNA2 gene that encodes cyclin A2. CCNA2 mRNA is highly expressed in human and murine
erythroid progenitor cells and regulated by the essential erythroid transcription factor GATA1. To understand the role of cyclin A2 in erythropoiesis, we have reduced expression of this gene using short hairpin RNAs in a primary murine erythroid culture system. We demonstrate that cyclin A2 levels affect erythroid cell size by regulating the passage through cytokinesis during the final cell division of terminal erythropoiesis. Our study provides new insight into cell cycle regulation during terminal erythropoiesis and more generally illustrates the value of functional GWAS follow-up to gain mechanistic insight into hematopoiesis.German Academic Scholarship FoundationNational Institutes of Health (U.S.) (Grant  P01 HL032262
Complex karyotype, older age, and reduced first-line dose intensity determine poor survival in core binding factor acute myeloid leukemia patients with long-term follow-up

Approximately 40% of patients affected by core binding factor (CBF) acute myeloid leukemia\ud
(AML) ultimately die from the disease. Few prognostic markers have been identified. In this\ud
study we reviewed 192 patients with core binding factor acute myeloid leukemia (AML),\ud
treated with curative intent (age, 15-79 years) in 11 Italian institutions. Overall, 10-year\ud
overall survival (OS), disease-free survival (DFS), and event-free survival were 63.9%,\ud
54.8%, and 49.9%, respectively; patients with the t(8;21) and inv(16) chromosomal\ud
rearrangements exhibited significant differences at diagnosis. Despite similarly high\ud
complete remission (CR) rate, patients with inv(16) experienced superior DFS and a high\ud
chance of achieving a second CR, often leading to prolonged OS also after relapse. We\ud
found that a complex karyotype (ie, ≥4 cytogenetic anomalies) affected survival; the KIT\ud
D816 mutation predicted worse prognosis only in patients with the t(8;21) rearrangement,\ud
whereas FLT3 mutations had no prognostic impact. We then observed increasingly better\ud
survival with more intense first-line therapy, in some high-risk patients including autologous\ud
or allogeneic hematopoietic stem cell transplantation. In multivariate analysis, age, severe\ud
thrombocytopenia, elevated lactate dehydrogenase levels, and failure to achieve CR after\ud
induction independently predicted longer OS, whereas complex karyotype predicted shorter\ud
OS only in univariate analysis. The achievement of minimal residual disease negativity\ud
predicted better OS and DFS. Long-term survival was also observed in a minority of elderly\ud
patients who received intensive consolidation treatment. All considered, we identified also\ud
among CBF AML patients a subgroup with poorer prognosis who might benefit from more\ud
intense first-line treatment
Monoclonal anti-transferrin antibody: A paradigm for better understanding of iron metabolism.

International audienceA 82 years old patient was admitted for persisting abnormalities of iron metabolismparameters in the context IgG kappa monoclonal gammopathy, discovered 12 years before,and classified as MGUS (monoclonal gammopathy of undetermined significance). Serum ironand transferrin concentration were constantly extremely high (96.9 μmol/L and 5.0 g/L,respectively), transferrin saturation was elevated (77.5% ; N<45%) and serum ferritinmoderately increased (608μg/L ; N<300 μg/L). Hemochromatosis was ruled out(1) : no tissueiron overload was present and genetic studies searching for mutations in HFE and non HFEgenes, were negative (p.Cys282Tyr mutation, HJV (HFE2), HAMP, TFR2, BMP6, SLC40A1 andFTL)
Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia.

he introduction of second-generation tyrosine-kinase inhibitors (TKIs) has generated a lively debate on the choice of first-line TKI in chronic phase, chronic myeloid leukemia (CML). Despite the TKIs have different efficacy and toxicity profiles, the planned use of two TKIs has never been investigated. We report on a phase 2 study that was designed to evaluate efficacy and safety of a treatment alternating nilotinib and imatinib, in newly diagnosed BCR-ABL1 positive, chronic phase, CML patients. One hundred twenty-three patients were enrolled. Median age was 56 years. The probabilities of achieving a complete cytogenetic response, a major molecular response, and a deep molecular response (MR 4.0) by 2 years were 93%, 87%, and 61%, respectively. The 5-year overall survival and progression-free survival were 89%. Response rates and survival are in the range of those reported with nilotinib alone. Moreover, we observed a relatively low rate of cardiovascular adverse events (5%). These data show that the different efficacy and toxicity profiles of TKIs could be favorably exploited by alternating their us
Hematopoietic deletion of transferrin receptor 2 in mice leads to a block in erythroid differentiation during iron-deficient anemia

Iron metabolism and erythropoiesis are inherently interlinked physiological processes. Regulation of iron metabolism is mediated by the iron-regulatory hormone hepcidin. Hepcidin limits the amount of iron released into the blood by binding to and causing the internalization of the iron exporter, ferroportin. A number of molecules and physiological stimuli, including erythropoiesis, are known to regulate hepcidin. An increase in erythropoietic demand decreases hepcidin, resulting in increased bioavailable iron in the blood. Transferrin receptor 2 (TFR2) is involved in the systemic regulation of iron metabolism. Patients and mice with mutations in TFR2 develop hemochromatosis due to inappropriate hepcidin levels relative to body iron. Recent studies from our laboratory and others have suggested an additional role for TFR2 in response to iron-restricted erythropoiesis. These studies used mouse models with perturbed systemic iron metabolism: anemic mice lacking matriptase-2 and Tfr2, or bone marrow transplants from iron-loaded Tfr2 null mice. We developed a novel transgenic mouse model which lacks Tfr2 in the hematopoietic compartment, enabling the delineation of the role of Tfr2 in erythroid development without interfering with its role in systemic iron metabolism. We show that in the absence of hematopoietic Tfr2 immature polychromatic erythroblasts accumulate with a concordant reduction in the percentage of mature erythroid cells in the spleen and bone marrow of anemic mice. These results demonstrate that erythroid Tfr2 is essential for an appropriate erythropoietic response in iron-deficient anemia. These findings may be of relevance in clinical situations in which an immediate and efficient erythropoietic response is required
Iron deficiency across chronic inflammatory conditions: international expert opinion on definition, diagnosis, and management

Iron deficiency, even in the absence of anemia, can be debilitating, and exacerbate any underlying chronic disease, leading to increased morbidity and mortality. Iron deficiency is frequently concomitant with chronic inflammatory disease; however, iron deficiency treatment is often overlooked, partially due to the heterogeneity among clinical practice guidelines. In the absence of consistent guidance across chronic heart failure, chronic kidney disease and inflammatory bowel disease, we provide practical recommendations for iron deficiency to treating physicians: definition, diagnosis, and disease-specific diagnostic algorithms. These recommendations should facilitate appropriate diagnosis and treatment of iron deficiency to improve quality of life and clinical outcomes