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1.
Cochrane Database Syst Rev ; 7: CD003598, 2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-39082471

RESUMEN

BACKGROUND: The comparative effects of specific blood pressure (BP) lowering treatments on patient-important outcomes following kidney transplantation are uncertain. Our 2009 Cochrane review found that calcium channel blockers (CCBs) improved graft function and prevented graft loss, while the evidence for other BP-lowering treatments was limited. This is an update of the 2009 Cochrane review. OBJECTIVES: To compare the benefits and harms of different classes and combinations of antihypertensive drugs in kidney transplant recipients. SEARCH METHODS: We contacted the Information Specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 3 July 2024 using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs evaluating any BP-lowering agent in recipients of a functioning kidney transplant for at least two weeks were eligible. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risks of bias and extracted data. Treatment estimates were summarised using the random-effects model and expressed as relative risk (RR) or mean difference (MD) with 95% confidence intervals (CI). Evidence certainty was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) processes. The primary outcomes included all-cause death, graft loss, and kidney function. MAIN RESULTS: Ninety-seven studies (8706 participants) were included. One study evaluated treatment in children. The overall risk of bias was unclear to high across all domains. Compared to placebo or standard care alone, CCBs probably reduce all-cause death (23 studies, 3327 participants: RR 0.83, 95% CI 0.72 to 0.95; I2 = 0%; moderate certainty evidence) and graft loss (24 studies, 3577 participants: RR 0.84, 95% CI 0.75 to 0.95; I2 = 0%; moderate certainty evidence). CCBs may make little or no difference to estimated glomerular filtration rate (eGFR) (11 studies, 2250 participants: MD 1.89 mL/min/1.73 m2, 95% CI -0.70 to 4.48; I2 = 48%; low certainty evidence) and acute rejection (13 studies, 906 participants: RR 10.8, 95% CI 0.85 to 1.35; I2 = 0%; moderate certainty evidence). CCBs may reduce systolic BP (SBP) (3 studies, 329 participants: MD -5.83 mm Hg, 95% CI -10.24 to -1.42; I2 = 13%; low certainty evidence) and diastolic BP (DBP) (3 studies, 329 participants: MD -3.98 mm Hg, 95% CI -5.98 to -1.99; I2 = 0%; low certainty evidence). CCBs have uncertain effects on proteinuria. Compared to placebo or standard care alone, angiotensin-converting-enzyme inhibitors (ACEi) may make little or no difference to all-cause death (7 studies, 702 participants: RR 1.13, 95% CI 0.58 to 2.21; I2 = 0%; low certainty evidence), graft loss (6 studies, 718 participants: RR 0.75, 95% CI 0.49 to 1.13; I2 = 0%; low certainty evidence), eGFR (4 studies, 509 participants: MD -2.46 mL/min/1.73 m2, 95% CI -7.66 to 2.73; I2 = 64%; low certainty evidence) and acute rejection (4 studies, 388 participants: RR 1.75, 95% CI 0.76 to 4.04; I2 = 0%; low certainty evidence). ACEi may reduce proteinuria (5 studies, 441 participants: MD -0.33 g/24 hours, 95% CI -0.64 to -0.01; I2 = 67%; low certainty evidence) but had uncertain effects on SBP and DBP. Compared to placebo or standard care alone, angiotensin receptor blockers (ARB) may make little or no difference to all-cause death (6 studies, 1041 participants: RR 0.69, 95% CI 0.36 to 1.31; I2 = 0%; low certainty evidence), eGRF (5 studies, 300 participants: MD -1.91 mL/min/1.73 m2, 95% CI -6.20 to 2.38; I2 = 57%; low certainty evidence), and acute rejection (4 studies, 323 participants: RR 1.00, 95% CI 0.44 to 2.29; I2 = 0%; low certainty evidence). ARBs may reduce graft loss (6 studies, 892 participants: RR 0.35, 95% CI 0.15 to 0.84; I2 = 0%; low certainty evidence), SBP (10 studies, 1239 participants: MD -3.73 mm Hg, 95% CI -7.02 to -0.44; I2 = 63%; moderate certainty evidence) and DBP (9 studies, 1086 participants: MD -2.75 mm Hg, 95% CI -4.32 to -1.18; I2 = 47%; moderate certainty evidence), but has uncertain effects on proteinuria. The effects of CCBs, ACEi or ARB compared to placebo or standard care alone on cardiovascular outcomes (including fatal or nonfatal myocardial infarction, fatal or nonfatal stroke) or other adverse events were uncertain. The comparative effects of ACEi plus ARB dual therapy, alpha-blockers, and mineralocorticoid receptor antagonists compared to placebo or standard care alone were rarely evaluated. Head-to-head comparisons of ACEi, ARB or thiazide versus CCB, ACEi versus ARB, CCB or ACEi versus alpha- or beta-blockers, or ACEi plus CCB dual therapy versus ACEi or CCB monotherapy were scarce. No studies reported outcome data for cancer or life participation. AUTHORS' CONCLUSIONS: For kidney transplant recipients, the use of CCB therapy to reduce BP probably reduces death and graft loss compared to placebo or standard care alone, while ARB may reduce graft loss. The effects of ACEi and ARB compared to placebo or standard care on other patient-centred outcomes were uncertain. The effects of dual therapy, alpha-blockers, and mineralocorticoid receptor antagonists compared to placebo or standard care alone and the comparative effects of different treatments were uncertain.


Asunto(s)
Antihipertensivos , Bloqueadores de los Canales de Calcio , Hipertensión , Trasplante de Riñón , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Antihipertensivos/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Hipertensión/tratamiento farmacológico , Supervivencia de Injerto/efectos de los fármacos , Rechazo de Injerto/prevención & control , Causas de Muerte , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Sesgo , Adulto , Tasa de Filtración Glomerular/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos
2.
Blood ; 2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39046810

RESUMEN

The fifth edition of the WHO classification and the International Consensus Classification (ICC) both include a category "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions" (WHO, MLN-TK; ICC, M/LN-eo-TK). This rare group comprises phenotypically and prognostically heterogeneous disorders that present a significant diagnostic challenge. The rapid and reliable identification of patients with MLN-TK may be delayed due to genetic complexity and significant phenotypic differences, which include chronic phase and primary/secondary blast phase (BP) of myeloid, or lymphoid or mixed phenotype in the bone marrow (BP-BM) and/or at extramedullary sites (extramedullary disease, EMD). As a result, the entire armamentarium of conventional molecular genetic and cytogenetic techniques complemented by modern sequencing technologies such as RNA sequencing or whole genome sequencing are often required to identify an underlying TK fusion. TK inhibitors (TKIs) with variable efficacy are available for all fusion genes, but a long-term favorable clinical course under TKI monotherapy is currently only observed in MLN-PDGFRA/PDGFRB fusion genes on imatinib. Since primary/secondary BP-BM/EMD occur more frequently in MLN-FGFR1/JAK2/FLT3/ETV6::ABL1, a sequential combination of selective TKIs with or without prior intensive chemotherapy, rarely local local radiationradiotherapy and/or subsequent allogeneic hematopoietic cell transplantation should be considered.

4.
Phys Ther Sport ; 67: 19-24, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38457997

RESUMEN

OBJECTIVE: To determine return to running criteria currently used by physiotherapists following anterior cruciate ligament (ACL) injury. DESIGN: Self-reported online international survey. METHODS: An online survey of physiotherapists across Australia, the Netherlands and France. RESULTS: A total of 476 respondants participated in the survey across Australia (n = 153), the Netherlands (n = 162), and France (n = 161). For return to running criteria following a non-operative approach, the majority of respondents chose swelling (40.55%, n = 193/476), pain (38.24%, n = 182/476), knee extensor strength (34.34%, n = 163/476), single leg squat (31.93%, n = 152/476) and knee flexor strength (29.83%, n = 142/476). After ACL reconstruction, the highest responses were also swelling (41.18%, n = 196/476), pain (37.18%, n = 177/476), knee extensor strength (37.18%, n = 177/476) and single leg squat (33.19%, n = 158/476). From the identified themes the most common cutoff variables were pain between 0 and 3/10, swelling < grade 1+ and limb symmetry on strength and hop tests >70 %. CONCLUSION: Physiotherapists in Australia, France, and the Netherlands use many different return to running criteria and most of them use more than one criterion. Despite this, there was little consensus on the cut-off physiotherapists use to apply these criteria.


Asunto(s)
Lesiones del Ligamento Cruzado Anterior , Reconstrucción del Ligamento Cruzado Anterior , Fisioterapeutas , Volver al Deporte , Carrera , Humanos , Lesiones del Ligamento Cruzado Anterior/cirugía , Lesiones del Ligamento Cruzado Anterior/rehabilitación , Australia , Reconstrucción del Ligamento Cruzado Anterior/rehabilitación , Carrera/lesiones , Carrera/fisiología , Encuestas y Cuestionarios , Países Bajos , Francia , Masculino , Femenino , Adulto , Fuerza Muscular/fisiología
5.
Br J Haematol ; 204(4): 1325-1334, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38462984

RESUMEN

We report on a study of next-generation sequencing in 257 patients undergoing investigations for cytopenias. We sequenced bone marrow aspirates using a target enrichment panel comprising 82 genes and used T cells from paired blood as a control. One hundred and sixty patients had idiopathic cytopenias, 81 had myeloid malignancies and 16 had lymphoid malignancies or other diagnoses. Forty-seven of the 160 patients with idiopathic cytopenias had evidence of somatic pathogenic variants consistent with clonal cytopenias. Only 39 genes of the 82 tested were mutated in the 241 patients with either idiopathic cytopenias or myeloid neoplasms. We confirm that T cells can be used as a control to distinguish between germline and somatic variants. The use of paired analysis with a T-cell control significantly reduced the time molecular scientists spent reporting compared to unpaired analysis. We identified somatic variants of uncertain significance (VUS) in a higher proportion (24%) of patients with myeloid malignancies or clonal cytopenias compared to less than 2% of patients with non-clonal cytopenias. This suggests that somatic VUS are indicators of a clonal process. Lastly, we show that blood depleted of lymphocytes can be used in place of bone marrow as a source of material for sequencing.


Asunto(s)
Citopenia , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Neoplasias , Humanos , Síndromes Mielodisplásicos/genética , Mutación , Linfocitos T/patología , Trastornos Mieloproliferativos/genética
6.
Frontline Gastroenterol ; 15(2): 99-103, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38486672

RESUMEN

Objective: Endoscopic retrograde cholangiopancreatography (ERCP) is the mainstay of management for most patients with common bile duct stones (CBDS). Duct clearance at initial ERCP may not be achieved in a third of patients, many of whom may be elderly with multiple comorbidities rendering them at potentially high risk for further procedures. We aimed to quantify the rate of biliary sequelae and mortality among a large cohort undergoing a single ERCP with sphincterotomy and stent insertion without having undergone complete ductal clearance (permanent stent insertion, PSI), and to examine factors that may predispose to adverse outcomes. Design/method: Outcomes of all ERCPs undertaken on the intact papilla between February 2010 and January 2020 were distilled to identify a cohort who had undergone PSI for initially irretrievable CBDS. These were subjected to retrospective follow-up until the development of biliary sequelae, death or survival into 2023. Results: There were 2175 index ERCPs for CBDS, of whom 114 met the PSI criteria. Eleven did not survive their index hospitalisation, leaving 103 for follow-up. Of these, 25 (24%) developed late biliary sequelae, 19 (18%) required at least one further ERCP and 8 (8%) died from biliary sequelae. Adverse outcomes were found to be more common among those who had undergone cholecystectomy prior to ERCP, and those with periampullary diverticula. Conclusions: Long-term biliary stenting following sphincterotomy remains a valid option for selected patients with initially irretrievable bile duct stones who could be at high risk from repeat procedures.

7.
Cancers (Basel) ; 16(3)2024 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-38339343

RESUMEN

Within our nationwide registry, we identified a KIT D816V mutation (KIT D816Vpos.) in 280/299 (94%) patients with advanced systemic mastocytosis (AdvSM). Age, cytopenias and the presence of additional somatic mutations confer inferior overall survival (OS). However, little is known about the characteristics of KIT D816V-negative (D816Vneg.) AdvSM. In 19 D816Vneg. patients, a combination of clinical, morphological and genetic features revealed three subgroups: (a) KIT D816H- or Y-positive SM (KIT D816H/Ypos., n = 7), predominantly presenting as mast cell leukemia (MCL; 6/7 patients), (b) MCL with negative KIT sequencing (KITneg. MCL, n = 7) and (c) KITneg. SM with associated hematologic neoplasm (KITneg. SM-AHN, n = 5). Although >70% of patients in the two MCL cohorts (KIT D816H/Ypos. and KITneg.) were classified as low/intermediate risk according to prognostic scoring systems (PSS), treatment response was poor and median OS was shorter than in a KIT D816Vpos. MCL control cohort (n = 29; 1.7 vs. 0.9 vs. 2.6 years; p < 0.04). The KITneg. SM-AHN phenotype was dominated by the heterogeneous AHN (low mast cell burden, presence of additional mutations) with a better median OS of 4.5 years. We conclude that (i) in MCL, negativity for D816V is a relevant prognostic factor and (ii) PSS fail to correctly classify D816Vneg. patients.

8.
Br. j. haematol ; 204(1): 127-134, 20240101.
Artículo en Inglés | BIGG - guías GRADE | ID: biblio-1537641

RESUMEN

This document represents an update of the British Society for Haematology (BSH) guideline on myelofibrosis (MF) first published in 2012 and updated in 2015.1 This guideline aims to provide healthcare professionals with clear guidance on the diagnosis and prognostic evaluation of primary my-elofibrosis (PMF), as well as post-polycythaemia vera myelo-fibrosis (post-PV MF) and post-essential thrombocythaemia myelofibrosis (post-ET MF). A section on prefibrotic MF is also included. A separate BSH Guideline covers the manage-ment of MF and is published alongside this guideline.


Asunto(s)
Humanos , Mielofibrosis Primaria/diagnóstico , Pronóstico , Células Mieloides , Cariotipificación Espectral
9.
Br. j. haematol ; 204(1): 136-150, 20240101.
Artículo en Inglés | BIGG - guías GRADE | ID: biblio-1537635

RESUMEN

This document represents an update of the British Society for Haematology guideline on Myelofibrosis first published in 2012 and updated in 2015 These guidelines aim to pro-vide healthcare professionals with clear guidance on stratified management for primary myelofibrosis (PMF), as well as post-polycythaemia myelofibrosis (post-PV MF) and postessential thrombocythaemia myelofibrosis (post-ET MF). A separate BSH guideline covers the diagnosis and prognostic evaluation of myelofibrosis and is published alongside this guideline


Asunto(s)
Humanos , Tiamina/sangre , Mielofibrosis Primaria/diagnóstico , Janus Quinasa 1/sangre , Janus Quinasa 2/sangre , Mielofibrosis Primaria/terapia , Antineoplásicos/uso terapéutico
12.
Ann Surg ; 279(3): 462-470, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38084600

RESUMEN

OBJECTIVE: This study evaluated the postoperative mortality and morbidity outcomes following the different subtypes of gastrointestinal (GI) surgery over a 15-year period. BACKGROUND: Patients receiving chronic kidney replacement therapy (KRT) experience higher rates of general surgery compared with other surgery types. Contemporary data on the types of surgeries and their outcomes are lacking. KRT was defined as patients requiring chronic dialysis (hemodialysis or peritoneal dilaysis) or having a functioning kidney transplant long-term. METHODS: All incident and prevalent patients aged greater than 18 years identified in the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry as receiving chronic KRT were linked with jurisdictional hospital admission datasets between January 1, 2000 until December 31, 2015. Patients were categorized by their KRT modality [hemodialysis (HD), peritoneal dialysis (PD), home hemodialysis (HHD), and kidney transplant (KT)]. GI surgeries were categorized as upper gastrointestinal (UGI), bowel (small and large bowel), anorectal, hernia surgery, cholecystectomy, and appendicectomy. The primary outcome was the rates of the different surgeries, estimated using Poisson models. Secondary outcomes were risks of 30-day/in-hospital postoperative mortality risk and nonfatal outcomes and were estimated using logistic regression. Independent predictors of 30-day mortality were examined using comorbidity-adjusted Cox models. RESULTS: Overall, 46,779 patients on chronic KRT were linked to jurisdictional hospital datasets, and 9,116 patients were identified as having undergone 14,540 GI surgeries with a combined follow-up of 76,593 years. Patients on PD had the highest rates of GI surgery (8 per 100 patient years), with hernia surgery being the most frequent. Patients on PD also had the highest risk of 30-day postoperative mortality following the different types of GI surgery, with the risk being more than 2-fold higher after emergency surgery compared with elective procedures. Infective postoperative complications were more common than cardiac complications. This study also observed a U-shaped association between body mass index (BMI) and mortality, with a nadir in the 30 to 35 kg/m 2 group. CONCLUSIONS: Patients on chronic KRT have high rates of GI surgery and morbidity, particularly in those who receive PD, are older, or are either underweight or moderately obese.


Asunto(s)
Procedimientos Quirúrgicos del Sistema Digestivo , Fallo Renal Crónico , Humanos , Anciano , Fallo Renal Crónico/terapia , Estudios de Cohortes , Diálisis Renal/efectos adversos , Diálisis Renal/métodos , Terapia de Reemplazo Renal , Hernia/etiología
13.
Leukemia ; 37(11): 2150-2167, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37794101

RESUMEN

From the laboratory perspective, effective management of patients with chronic myeloid leukemia (CML) requires accurate diagnosis, assessment of prognostic markers, sequential assessment of levels of residual disease and investigation of possible reasons for resistance, relapse or progression. Our scientific and clinical knowledge underpinning these requirements continues to evolve, as do laboratory methods and technologies. The European LeukemiaNet convened an expert panel to critically consider the current status of genetic laboratory approaches to help diagnose and manage CML patients. Our recommendations focus on current best practice and highlight the strengths and pitfalls of commonly used laboratory tests.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Recurrencia
15.
Leukemia ; 37(9): 1860-1867, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37454239

RESUMEN

In a registry-based analysis of 135 patients with "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions" (MLN-TK; FIP1L1::PDGFRA, n = 78; PDGFRB, diverse fusions, n = 26; FGFR1, diverse, n = 9; JAK2, diverse, n = 11; ETV6::ABL1, n = 11), we sought to evaluate the disease-defining characteristics. In 81/135 (60%) evaluable patients, hypereosinophilia (>1.5 × 109/l) was observed in 40/44 (91%) FIP1L1::PDGFRA and 7/7 (100%) ETV6::ABL1 positive patients but only in 13/30 (43%) patients with PDGFRB, FGFR1, and JAK2 fusion genes while 9/30 (30%) patients had no eosinophilia. Monocytosis >1 × 109/l was identified in 27/81 (33%) patients, most frequently in association with hypereosinophilia (23/27, 85%). Overall, a blast phase (BP) was diagnosed in 38/135 (28%) patients (myeloid, 61%; lymphoid, 39%), which was at extramedullary sites in 18 (47%) patients. The comparison between patients with PDGFRA/PDGFRB vs. FGFR1, JAK2, and ETV6::ABL1 fusion genes revealed a similar occurrence of primary BP (17/104, 16% vs. 8/31 26%, p = 0.32), a lower frequency (5/87, 6% vs. 8/23, 35%, p = 0.003) of and a later progression (median 87 vs. 19 months, p = 0.053) into secondary BP, and a better overall survival from diagnosis of BP (17.1 vs. 1.7 years, p < 0.0008). We conclude that hypereosinophilia with or without monocytosis and various phenotypes of BP occur at variable frequencies in MLN-TK.


Asunto(s)
Eosinofilia , Linfoma , Trastornos Mieloproliferativos , Humanos , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Proteínas de Fusión Oncogénica/genética , Trastornos Mieloproliferativos/complicaciones , Eosinofilia/genética , Eosinofilia/complicaciones , Fusión Génica
16.
Ann Hematol ; 102(8): 2077-2085, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37012462

RESUMEN

We sought to evaluate the efficacy of the purine analogue cladribine in 79 patients with advanced systemic mastocytosis (AdvSM) using data from the 'German Registry on Disorders of Eosinophils and Mast Cells (GREM)'. The overall response rate according to modified Valent criteria (46 evaluable patients) for first- (1L) and second-line (2L) cladribine treatment was 41% (12/29) and 35% (6/17, P = 0.690), respectively, and the median overall survival (OS, all patients evaluable) was 1.9 years (n = 48) and 1.2 years (n = 31; P = 0.311). Univariate and multivariable analyses of baseline and on-treatment parameters identified diagnosis of mast cell leukemia (hazard ratio [HR] 3.5, 95% confidence interval [CI, 1.3-9.1], P = 0.012), eosinophilia ≥ 1.5 × 109/L (HR 2.9 [CI 1.4-6.2], P = 0.006) and < 3 cycles of cladribine (HR 0.4 [CI 0.2-0.8], P = 0.008) as independent adverse prognostic parameters for OS. There was no impact of other laboratory (anemia, thrombocytopenia, serum tryptase) or genetic markers (mutations in SRSF2, ASXL1 or RUNX1) on OS. In consequence, none of the recently established prognostic scoring systems (MARS, IPSM, MAPS or GPSM) was predictive for OS. Modified Valent criteria were superior to a single factor-based response assessment (HR 2.9 [CI 1.3-6.6], P = 0.026). In conclusion, cladribine is effective in 1L and 2L treatment of AdvSM. Mast cell leukemia, eosinophilia, application of < 3 cycles and a lack of response are adverse prognostic markers.


Asunto(s)
Leucemia de Mastocitos , Mastocitosis Sistémica , Humanos , Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/tratamiento farmacológico , Mastocitosis Sistémica/genética , Cladribina/uso terapéutico , Leucemia de Mastocitos/tratamiento farmacológico , Leucemia de Mastocitos/genética , Pronóstico , Sistema de Registros
17.
Sci Adv ; 9(16): eade9746, 2023 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-37083525

RESUMEN

Mosaic loss of the Y-chromosome (LOY) in peripheral blood leukocytes is the most common somatic alteration in men and linked to wide range of malignant and nonmalignant conditions. LOY is associated with age, smoking, and constitutional genetics. Here, we aimed to assess the relationships between LOY, serum biomarkers, and clonal hematopoiesis (CH). LOY in U.K. Biobank was strongly associated with levels of sex hormone binding globulin (SHBG), a key regulator of testosterone bioavailability. Mendelian randomization suggested a causal effect of SHBG on LOY but there was no evidence for an effect of LOY on SHBG. In contrast, age-related CH defined by somatic driver mutations was not associated with SHBG but was associated with LOY at clonal fractions above 30%. TET2, TP53, and CBL mutations were enriched in LOY cases, but JAK2 V617F was depleted. Our findings thus identify independent relationships between LOY, sex hormone levels, and CH.


Asunto(s)
Cromosomas Humanos Y , Dioxigenasas , Humanos , Masculino , Hematopoyesis Clonal , Dioxigenasas/genética , Proteínas de Unión al ADN/genética , Mosaicismo , Mutación , Globulina de Unión a Hormona Sexual/genética , Proteína p53 Supresora de Tumor/genética
18.
Blood Adv ; 7(9): 1672-1681, 2023 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-36375042

RESUMEN

Chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are rare myeloid disorders that are challenging with regard to diagnosis and clinical management. To study the similarities and differences between these disorders, we undertook a multicenter international study of one of the largest case series (CNL, n = 24; aCML, n = 37 cases, respectively), focusing on the clinical and mutational profiles (n = 53 with molecular data) of these diseases. We found no differences in clinical presentations or outcomes of both entities. As previously described, both CNL and aCML share a complex mutational profile with mutations in genes involved in epigenetic regulation, splicing, and signaling pathways. Apart from CSF3R, only EZH2 and TET2 were differentially mutated between them. The molecular profiles support the notion of CNL and aCML being a continuum of the same disease that may fit best within the myelodysplastic/myeloproliferative neoplasms. We identified 4 high-risk mutated genes, specifically CEBPA (ß = 2.26, hazard ratio [HR] = 9.54, P = .003), EZH2 (ß = 1.12, HR = 3.062, P = .009), NRAS (ß = 1.29, HR = 3.63, P = .048), and U2AF1 (ß = 1.75, HR = 5.74, P = .013) using multivariate analysis. Our findings underscore the relevance of molecular-risk classification in CNL/aCML as well as the importance of CSF3R mutations in these diseases.


Asunto(s)
Leucemia Mieloide Crónica Atípica BCR-ABL Negativa , Leucemia Neutrofílica Crónica , Enfermedades Mielodisplásicas-Mieloproliferativas , Humanos , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/diagnóstico , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Leucemia Neutrofílica Crónica/diagnóstico , Leucemia Neutrofílica Crónica/genética , Epigénesis Genética , Enfermedades Mielodisplásicas-Mieloproliferativas/genética , Mutación
19.
BMC Cancer ; 22(1): 1013, 2022 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-36153475

RESUMEN

BACKGROUND: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response. METHODS: ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability. DISCUSSION: Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421).


Asunto(s)
Enfermedades Mielodisplásicas-Mieloproliferativas , Calidad de Vida , Acetonitrilos , Citidina Desaminasa , ADN/uso terapéutico , Decitabina/uso terapéutico , Humanos , Metiltransferasas , Estudios Prospectivos , Pirazoles , Pirimidinas , Pirroles , Síndrome
20.
PLoS One ; 17(8): e0273371, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36006937

RESUMEN

BACKGROUND: Kidney transplantation is considered the ideal treatment for most people with kidney failure, conferring both survival and quality of life advantages, and is more cost effective than dialysis. Yet, current health systems may serve some people better than others, creating inequities in access to kidney failure treatments and health outcomes. AcceSS and Equity in Transplantation (ASSET) investigators aim to create a linked data platform to facilitate research enquiry into equity of health service delivery for people with kidney failure in New Zealand. METHODS: The New Zealand Ministry of Health will use patients' National Health Index (NHI) numbers to deterministically link individual records held in existing registry and administrative health databases in New Zealand to create the data platform. The initial data linkage will include a study population of incident patients captured in the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA), New Zealand Blood Service Database and the Australia and New Zealand Living Kidney Donor Registry (ANZLKD) from 2006 to 2019 and their linked health data. Health data sources will include National Non-Admitted Patient Collection Data, National Minimum Dataset, Cancer Registry, Programme for the Integration of Mental Health Data (PRIMHD), Pharmaceutical Claims Database and Mortality Collection Database. Initial exemplar studies include 1) kidney waitlist dynamics and pathway to transplantation; 2) impact of mental illness on accessing kidney waitlist and transplantation; 3) health service use of living donors following donation. CONCLUSION: The AcceSS and Equity in Transplantation (ASSET) linked data platform will provide opportunity for population-based health services research to examine equity in health care delivery and health outcomes in New Zealand. It also offers potential to inform future service planning by identifying where improvements can be made in the current health system to promote equity in access to health services for those in New Zealand.


Asunto(s)
Fallo Renal Crónico , Insuficiencia Renal , Servicios de Salud , Humanos , Almacenamiento y Recuperación de la Información , Fallo Renal Crónico/terapia , Nueva Zelanda/epidemiología , Calidad de Vida , Sistema de Registros , Diálisis Renal/métodos
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