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Article ; Online: Should we move to a genomic classification of neutrophilic myeloid neoplasms?

Carreño-Tarragona, Gonzalo / Álvarez-Larrán, Alberto / Hernández-Boluda, Juan Carlos / Ayala, Rosa / Cross, Nicholas C P

Blood advances

2023 Volume 7, Issue 21, Page(s) 6705–6706

MeSH term(s)	Humans ; Neoplasms ; Myeloproliferative Disorders/genetics ; Genomics
Language	English
Publishing date	2023-09-04
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023011103
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Article: Multidisciplinary management in chronic myeloid leukemia improves cardiovascular risk measured by SCORE.

Blanco Sánchez, Alberto / Gil Manso, Rodrigo / Carreño-Tarragona, Gonzalo / Paredes Ruiz, Diana / González Olmedo, Jesús / Martínez-López, Joaquín / Díaz Pedroche, Carmen / Ayala, Rosa

Frontiers in pharmacology

2023 Volume 14, Page(s) 1206893

Abstract: Introduction: ...

Abstract	Introduction:
Language	English
Publishing date	2023-07-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2023.1206893
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Article ; Online: DNMT3A/TET2/ASXL1 Mutations are an Age-independent Thrombotic Risk Factor in Polycythemia Vera Patients: An Observational Study.

Segura-Díaz, Adrián / Stuckey, Ruth / Florido, Yanira / Sobas, Marta / Álvarez-Larrán, Alberto / Ferrer-Marín, Francisca / Pérez-Encinas, Manuel / Carreño-Tarragona, Gonzalo / Fox, María L / Tazón Vega, Barbara / Cuevas, Beatriz / López Rodríguez, Juan F / Sánchez-Farías, Nuria / González-Martín, Jesús M / Gómez-Casares, María T / Bilbao-Sieyro, Cristina

Thrombosis and haemostasis

2024

Abstract: Background: Polycythemia vera (PV) patients are classified as high or low thrombotic risk based on age and prior history of thrombosis. Despite adherence to treatment recommendations, vascular events remain frequent, leading us to question whether ... ...

Abstract	Background: Polycythemia vera (PV) patients are classified as high or low thrombotic risk based on age and prior history of thrombosis. Despite adherence to treatment recommendations, vascular events remain frequent, leading us to question whether thrombotic risk stratification could be improved. We previously reported an association between thrombotic events and mutations in DTA genes ( Methods: PV patients with a minimum follow-up of 3 years were recruited from 8 European centers. Medical history was searched for thrombotic event recorded at any time and next-generation sequencing carried out with a myeloid panel. Multivariable logistic regression evaluated the impact of variables on thrombotic risk. Kaplan-Meier thrombosis-free survival curves were compared by the log rank test. Associations in the total cohort were confirmed in a case-control study to exclude selection bias. Results: Of the 136 patients recruited, 74 (56.1%) had a thrombotic event, with an incidence density of 2.83/100 person-years. In multivariable analysis, DTA mutation was a risk factor for thrombotic event, being predictive for shorter thrombosis-free survival in the whole cohort ( Conclusion: Our results support the use of molecular testing at diagnosis to help predict which PV patients are at higher risk of developing thrombosis.
Language	English
Publishing date	2024-01-30
Publishing country	Germany
Document type	Journal Article
ZDB-ID	518294-3
ISSN	2567-689X ; 0340-6245
ISSN (online)	2567-689X
ISSN	0340-6245
DOI	10.1055/a-2239-9265
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Article: Cell Count Differentials by Cytomorphology and Next-Generation Flow Cytometry in Bone Marrow Aspirate: An Evidence-Based Approach.

Ríos-Tamayo, Rafael / Sánchez, María José / Gómez-Rojas, Sandra / Rodríguez-Barranco, Miguel / Segura, Gloria Pérez / Redondo-Sánchez, Daniel / Carreño-Tarragona, Gonzalo / Nicolás, Antonio Rodríguez / Ruiz-Cabello, Francisco / Jiménez, Pilar / Alonso, Rafael / Lahuerta, Juan José / Martínez-López, Joaquín / Duarte, Rafael F

Diagnostics (Basel, Switzerland)

2023 Volume 13, Issue 6

Abstract: Despite a lack of evidence, a bone marrow aspirate differential of 500 cells is commonly used in the clinical setting. We aimed to test the performance of 200-cell counts for daily hematological workup. In total, 660 consecutive samples were analyzed ... ...

Abstract	Despite a lack of evidence, a bone marrow aspirate differential of 500 cells is commonly used in the clinical setting. We aimed to test the performance of 200-cell counts for daily hematological workup. In total, 660 consecutive samples were analyzed recording differentials at 200 and 500 cells. Additionally, immunophenotype results and preanalytical issues were also evaluated. Clinical and statistical differences between both cutoffs and both methods were checked. An independent control group of 122 patients was included. All comparisons between both cutoffs and both methods for all relevant types of cells did not show statistically significant differences. No significant diagnostic discrepancies were demonstrated in the contingency table analysis. This is a real-life study, and some limitations may be pointed out, such as a different sample sizes according to the type of cell in the immunophenotype analysis, the lack of standardization of some preanalytical events, and the relatively small sample size of the control group. The comparisons of differentials by morphology on 200 and 500 cells, as well as by morphology (both cutoffs) and by immunophenotype, are equivalent from the clinical and statistical point of view. The preanalytical issues play a critical role in the assessment of bone marrow aspirate samples.
Language	English
Publishing date	2023-03-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662336-5
ISSN	2075-4418
ISSN	2075-4418
DOI	10.3390/diagnostics13061071
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Article ; Online: Janus kinase inhibitor ruxolitinib in combination with nilotinib and prednisone in patients with myelofibrosis (RuNiC study): A phase Ib, multicenter study.

Ayala, Rosa / Fernández, Rafael Alonso / García-Gutiérrez, Valentín / Alvarez-Larrán, Alberto / Osorio, Santiago / Sánchez-Pina, Jose M / Carreño-Tarragona, Gonzalo / Álvarez, Noemi / Gómez-Casares, María Teresa / Duran, Antonia / Gorrochategi, Julian / Hernández-Boluda, Juan Carlos / Martínez-López, Joaquín

EJHaem

2023 Volume 4, Issue 2, Page(s) 401–409

Abstract: This phase Ib, non-randomized, open-label study evaluates the safety and tolerability of ruxolitinib in combination with nilotinib and prednisone in patients with naïve or ruxolitinib-resistant myelofibrosis (MF). A total of 15 patients with primary or ... ...

Abstract	This phase Ib, non-randomized, open-label study evaluates the safety and tolerability of ruxolitinib in combination with nilotinib and prednisone in patients with naïve or ruxolitinib-resistant myelofibrosis (MF). A total of 15 patients with primary or secondary MF received the study treatment; 13 patients had received prior ruxolitinib treatment (86.7%). Eight patients completed seven cycles (53.3%) and six patients completed twelve cycles of treatment (40%). All the patients experienced at least one adverse event (AE) during the study (the most common AEs were hyperglycemia, asthenia, and thrombocytopenia), and 14 patients registered at least one treatment-related AE (the most common treatment-related AEs were hyperglycemia (22.2%; three grade 3 cases). Five treatment-related serious AEs (SAEs) were reported in two patients (13.3%). No deaths were registered throughout the study. No dose-limiting toxicity was observed. Four out of fifteen (27%) patients experienced a 100% spleen size reduction at Cycle 7, and two additional patients achieved a >50% spleen size reduction, representing an overall response rate of 40% at Cycle 7. In conclusion, the tolerability of this combination was acceptable, and hyperglycemia was the most frequent treatment-related AE. Ruxolitinib in combination with nilotinib and prednisone showed relevant clinical activity in patients with MF. This trial was registered with EudraCT Number 2016-005214-21.
Language	English
Publishing date	2023-04-16
Publishing country	United States
Document type	Journal Article
ISSN	2688-6146
ISSN (online)	2688-6146
DOI	10.1002/jha2.685
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Article ; Online: Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia.

Morales, María Luz / García-Vicente, Roberto / Rodríguez-García, Alba / Reyes-Palomares, Armando / Vincelle-Nieto, África / Álvarez, Noemí / Ortiz-Ruiz, Alejandra / Garrido-García, Vanesa / Giménez, Alicia / Carreño-Tarragona, Gonzalo / Sánchez, Ricardo / Ayala, Rosa / Martínez-López, Joaquín / Linares, María

Leukemia

2023 Volume 37, Issue 8, Page(s) 1649–1659

Abstract: Despite the approval of several drugs for AML, cytarabine is still widely used as a therapeutic approach. However, 85% of patients show resistance and only 10% overcome the disease. Using RNA-seq and phosphoproteomics, we show that RNA splicing and ... ...

Abstract	Despite the approval of several drugs for AML, cytarabine is still widely used as a therapeutic approach. However, 85% of patients show resistance and only 10% overcome the disease. Using RNA-seq and phosphoproteomics, we show that RNA splicing and serine-arginine-rich (SR) proteins phosphorylation were altered during cytarabine resistance. Moreover, phosphorylation of SR proteins at diagnosis were significantly lower in responder than non-responder patients, pointing to their utility to predict response. These changes correlated with altered transcriptomic profiles of SR protein target genes. Notably, splicing inhibitors were therapeutically effective in treating sensitive and resistant AML cells as monotherapy or combination with other approved drugs. H3B-8800 and venetoclax combination showed the best efficacy in vitro, demonstrating synergistic effects in patient samples and no toxicity in healthy hematopoietic progenitors. Our results establish that RNA splicing inhibition, alone or combined with venetoclax, could be useful for the treatment of newly diagnosed or relapsed/refractory AML.
MeSH term(s)	Humans ; Cytarabine/pharmacology ; Cytarabine/therapeutic use ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Sulfonamides/pharmacology ; Sulfonamides/therapeutic use ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use ; RNA Splicing ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use
Chemical Substances	Cytarabine (04079A1RDZ) ; venetoclax (N54AIC43PW) ; Sulfonamides ; Bridged Bicyclo Compounds, Heterocyclic
Language	English
Publishing date	2023-07-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-023-01963-4
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Article ; Online: MPL S505C enhances driver mutations at W515 in essential thrombocythemia.

Varghese, Leila N / Carreño-Tarragona, Gonzalo / Levy, Gabriel / Gutiérrez-López de Ocáriz, Xabier / Rapado, Inmaculada / Martínez-López, Joaquín / Ayala, Rosa / Constantinescu, Stefan N

Blood cancer journal

2021 Volume 11, Issue 11, Page(s) 188

MeSH term(s)	Aged, 80 and over ; Amino Acid Substitution ; Female ; Humans ; Mutation, Missense ; Receptors, Thrombopoietin/genetics ; Receptors, Thrombopoietin/metabolism ; Thrombocythemia, Essential/genetics ; Thrombocythemia, Essential/metabolism
Chemical Substances	Receptors, Thrombopoietin ; MPL protein, human (143641-95-6)
Language	English
Publishing date	2021-11-29
Publishing country	United States
Document type	Case Reports ; Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	2600560-8
ISSN	2044-5385 ; 2044-5385
ISSN (online)	2044-5385
ISSN	2044-5385
DOI	10.1038/s41408-021-00583-4
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Article ; Online: Monitoring of clonal evolution of acute myeloid leukemia identifies the leukemia subtype, clinical outcome and potential new drug targets for post-remission strategies or relapse.

Onecha, Esther / Rapado, Inmaculada / Luz Morales, María / Carreño-Tarragona, Gonzalo / Martinez-Sanchez, Pilar / Gutierrez, Xabier / Sáchez Pina, José María / Linares, María / Gallardo, Miguel / Martinez-López, Joaquín / Ayala, Rosa

Haematologica

2021 Volume 106, Issue 9, Page(s) 2325–2333

Abstract: In cases of treatment failure in acute myeloid leukemia (AML), the utility of mutational profiling in primary refractoriness and relapse is not established. We undertook a perspective study using next-generation sequencing (NGS) of clinical follow-up ... ...

Abstract	In cases of treatment failure in acute myeloid leukemia (AML), the utility of mutational profiling in primary refractoriness and relapse is not established. We undertook a perspective study using next-generation sequencing (NGS) of clinical follow-up samples (n=91) from 23 patients with AML with therapeutic failure to cytarabine plus idarubicin or fludarabine. Cases of primary refractoriness to treatment were associated with a lower number of DNA variants at diagnosis than cases of relapse (median 1.67 and 3.21, respectively, p=0.029). The most frequently affected pathways in patients with primary refractoriness were signaling, transcription and tumor suppression, whereas methylation and splicing pathways were mainly implicated in relapsed patients. New therapeutic targets, either by an approved drug or within clinical trials, were not identified in any of the cases of refractoriness (0/10); however, 8 potential new targets were found in 5 relapsed patients (5/13) (p=0.027): 1 IDH2, 3 SF3B1, 2 KRAS, 1 KIT and 1 JAK2. Sixty-five percent of all variants detected at diagnosis were not detected at complete response (CR). Specifically, 100% of variants in EZH2, RUNX1, VHL, FLT3, ETV6, U2AF1, PHF6 and SF3B1 disappeared at CR, indicating their potential use as markers to evaluate minimal residual disease (MRD) for follow-up of AML. Molecular follow-up using a custom NGS myeloid panel of 32 genes in the post-treatment evaluation of AML can help in the stratification of prognostic risk, the selection of MRD markers to monitor the response to treatment and guide post-remission strategies targeting AML, and the selection of new drugs for leukemia relapse.
MeSH term(s)	Clonal Evolution/genetics ; Humans ; Leukemia, Myeloid, Acute/diagnosis ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Neoplasm, Residual ; Pharmaceutical Preparations ; Prognosis ; Recurrence
Chemical Substances	Pharmaceutical Preparations
Language	English
Publishing date	2021-09-01
Publishing country	Italy
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2020.254623
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Article ; Online: A typical acute lymphoblastic leukemia JAK2 variant, R683G, causes an aggressive form of familial thrombocytosis when germline.

Carreño-Tarragona, Gonzalo / Varghese, Leila N / Sebastián, Elena / Gálvez, Eva / Marín-Sánchez, Alberto / López-Muñoz, Nieves / Nam-Cha, Syonghyun / Martínez-López, Joaquín / Constantinescu, Stefan N / Sevilla, Julián / Ayala, Rosa

Leukemia

2021 Volume 35, Issue 11, Page(s) 3295–3298

MeSH term(s)	Adult ; Child ; Female ; Germ-Line Mutation ; Humans ; Janus Kinase 2/genetics ; Male ; Pedigree ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Thrombocytosis/etiology ; Thrombocytosis/metabolism ; Thrombocytosis/pathology ; Young Adult
Chemical Substances	JAK2 protein, human (EC 2.7.10.2) ; Janus Kinase 2 (EC 2.7.10.2)
Language	English
Publishing date	2021-04-12
Publishing country	England
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-021-01239-9
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Article: DNMT3A/TET2/ASXL1 Mutations are an Age-independent Thrombotic Risk Factor in Polycythemia Vera Patients: An Observational Study

Segura-Díaz, Adrián / Stuckey, Ruth / Florido, Yanira / Sobas, Marta / Álvarez-Larrán, Alberto / Ferrer-Marín, Francisca / Pérez-Encinas, Manuel / Carreño-Tarragona, Gonzalo / Fox, María L. / Tazón Vega, Barbara / Cuevas, Beatriz / López Rodríguez, Juan F. / Sánchez-Farías, Nuria / González-Martín, Jesús M. / Gómez-Casares, María T. / Bilbao-Sieyro, Cristina

Thrombosis and Haemostasis

2024

Abstract	Background: Polycythemia vera (PV) patients are classified as high or low thrombotic risk based on age and prior history of thrombosis. Despite adherence to treatment recommendations, vascular events remain frequent, leading us to question whether thrombotic risk stratification could be improved. We previously reported an association between thrombotic events and mutations in DTA genes ( DNMT3A, TET2, and ASXL1 ). The objective of this study was to confirm this observation in a larger series of PV patients. Methods: PV patients with a minimum follow-up of 3 years were recruited from 8 European centers. Medical history was searched for thrombotic event recorded at any time and next-generation sequencing carried out with a myeloid panel. Multivariable logistic regression evaluated the impact of variables on thrombotic risk. Kaplan–Meier thrombosis-free survival curves were compared by the log rank test. Associations in the total cohort were confirmed in a case–control study to exclude selection bias. Results: Of the 136 patients recruited, 74 (56.1%) had a thrombotic event, with an incidence density of 2.83/100 person-years. In multivariable analysis, DTA mutation was a risk factor for thrombotic event, being predictive for shorter thrombosis-free survival in the whole cohort ( p = 0.007), as well as in low-risk patients ( p = 0.039) and older patients ( p = 0.009), but not for patients with a prediagnostic event. A gender- and age-matched case–control study confirmed the increased risk of thrombotic event for PV patients with a DTA mutation. Conclusion: Our results support the use of molecular testing at diagnosis to help predict which PV patients are at higher risk of developing thrombosis.
Keywords	myeloproliferative neoplasm ; cardiovascular event ; next-generation sequencing ; prognosis ; CHIP
Language	English
Publishing date	2024-01-08
Publisher	Georg Thieme Verlag KG
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	518294-3
ISSN	2567-689X ; 0340-6245
ISSN (online)	2567-689X
ISSN	0340-6245
DOI	10.1055/a-2239-9265
Database	Thieme publisher's database

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