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BACKGROUND: A standard of care and optimal duration of therapy have not been established for patients with multiply relapsed or refractory follicular lymphoma. The aim of this study was to evaluate epcoritamab, a novel CD3â×âCD20 bispecific antibody, in the third-line and later setting of follicular lymphoma. METHODS: EPCORE NHL-1 is a multicohort, single-arm, phase 1-2 trial conducted at 88 sites across 15 countries. Here, we report the primary analysis of patients with relapsed or refractory follicular lymphoma in the phase 2 part of the trial, which included the pivotal (dose expansion) cohort and the cycle 1 optimisation cohort. Eligible patients were aged 18 years or older, had relapsed or refractory CD20+ follicular lymphoma (grade 1-3A), an Eastern Cooperative Oncology Group performance status of up to 2, and had received at least two previous lines of therapy (including an anti-CD20 monoclonal antibody and an alkylating agent or lenalidomide). Patients were treated with subcutaneous epcoritamab 48 mg in 28-day cycles: weekly in cycles 1-3, biweekly in cycles 4-9, and every 4 weeks until disease progression or unacceptable toxicity. To mitigate the risk and severity of cytokine release syndrome, in the pivotal cohort, cycle 1 consisted of a step-up dosing regimen of a 0·16-mg priming dose on day 1 and a 0·80-mg intermediate dose on day 8, followed by subsequent 48-mg full doses and prophylactic prednisolone 100 mg; in the cycle 1 optimisation cohort, a second intermediate dose of 3 mg on day 15, adequate hydration, and prophylactic dexamethasone 15 mg were evaluated during cycle 1 to further reduce risk and severity of cytokine release syndrome. Primary endpoints were independently reviewed overall response rate for the pivotal cohort and the proportion of patients with grade 2 or worse and any-grade cytokine release syndrome for the cycle 1 optimisation cohort. Analyses were done in all enrolled patients who had received at least one dose of epcoritamab. This study is registered with ClinicalTrials.gov, NCT03625037, and is ongoing. FINDINGS: Between June 19, 2020, and April 21, 2023, 128 patients (median age 65 years [IQR 55-72]; 49 [38%] female and 79 [62%] male) were enrolled and treated in the pivotal cohort (median follow-up 17·4 months [IQR 9·1-20·9]). The overall response rate was 82·0% (105 of 128 patients; 95% CI 74·3-88·3), with a complete response rate of 62·5% (80 of 128; 95% CI 53·5-70·9). The most common grade 3-4 treatment-emergent adverse event was neutropenia in 32 (25%) of 128 patients. Grade 1-2 cytokine release syndrome was reported in 83 (65%) of 128 patients; grade 3 cytokine release syndrome was reported in two (2%). Immune effector cell-associated neurotoxicity syndrome was reported in eight (6%) of 128 patients (five [4%] grade 1; three [2%] grade 2). Between Oct 25, 2022, and Jan 8, 2024, 86 patients (median age 64 years [55-71]; 37 [43%] female and 49 [57%] male) were enrolled and treated in the cycle 1 optimisation cohort. The incidence of cytokine release syndrome was 49% (42 of 86 patients; eight [9%] grade 2; none of grade 3 or worse), with no reported immune effector cell-associated neurotoxicity syndrome. INTERPRETATION: Epcoritamab monotherapy showed clinically meaningful activity in patients with multiply relapsed or refractory follicular lymphoma, and had a manageable safety profile. FUNDING: Genmab and AbbVie.
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Anticuerpos Biespecíficos , Linfoma Folicular , Humanos , Linfoma Folicular/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Biespecíficos/efectos adversos , AdultoRESUMEN
Late toxicities can impact survivorship in patients with classical Hodgkin lymphoma (cHL) with pulmonary toxicity after bleomycin-containing chemotherapy being a concern. The incidence of pulmonary diseases was examined in this Danish population-based study. A total of 1474 adult patients with cHL treated with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or BEACOPP (bleomycin, vincristine, etoposide, doxorubicin, cyclophosphamide, procarbazine and prednisone) between 2000 and 2018 were included along with 7370 age- and sex-matched comparators from the background population. Median follow-up was 8.6 years for the patients. Patients with cHL had increased risk of incident pulmonary diseases (HR 2.91 [95% CI 2.30-3.68]), with a 10-year cumulative risk of 7.4% versus 2.9% for comparators. Excess risks were observed for interstitial lung diseases (HR 15.84 [95% CI 9.35-26.84]) and chronic obstructive pulmonary disease (HR 1.99 [95% CI 1.43-2.76]), with a 10-year cumulative risk of 4.1% and 3.5% respectively for patients. No excess risk was observed for asthma (HR 0.82 [95% CI 0.43-1.56]). Risk factors for interstitial lung diseases were age ≥60 years, the presence of B-symptoms and low albumin. These findings document a significant burden of pulmonary diseases among patients with cHL and emphasize the importance of diagnostic work-up of pulmonary symptoms.
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Protocolos de Quimioterapia Combinada Antineoplásica , Enfermedad de Hodgkin , Enfermedades Pulmonares , Humanos , Enfermedad de Hodgkin/epidemiología , Enfermedad de Hodgkin/tratamiento farmacológico , Femenino , Masculino , Adulto , Dinamarca/epidemiología , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedades Pulmonares/inducido químicamente , Enfermedades Pulmonares/epidemiología , Enfermedades Pulmonares/etiología , Anciano , Bleomicina/efectos adversos , Bleomicina/administración & dosificación , Adulto Joven , Incidencia , Procarbazina/efectos adversos , Procarbazina/administración & dosificación , Vincristina/efectos adversos , Vincristina/uso terapéutico , Vincristina/administración & dosificación , Estudios de Cohortes , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Adolescente , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Doxorrubicina/administración & dosificaciónRESUMEN
ABSTRACT: Despite improvements in treatment of mantle cell lymphoma (MCL), most patients eventually relapse. In this multicenter phase 1b/2 trial, we evaluated safety and efficacy of minimal residual disease (MRD)-driven venetoclax, lenalidomide, and rituximab (venetoclax-R2) in relapsed/refractory (R/R) MCL and explored the feasibility of stopping treatment in molecular remission. The primary end point was overall response rate (ORR) at 6 months. After dose escalation, the recommended phase 2 dose was lenalidomide 20 mg daily, days 1 to 21; venetoclax 600 mg daily after ramp-up; and rituximab 375 mg/m2 weekly for 4 weeks, then every 8 weeks. MRD monitoring by RQ-PCR was performed every 3 months. When MRD-negativity in the blood was reached, treatment was continued for another 3 months; if MRD-negativity was then confirmed, treatment was stopped. In total, 59 patients were enrolled, with a median age of 73 years. At 6 months, the ORR was 63% (29 complete remission [CR], 8 partial remission [PR]), and 40% (4 CR, 2 PR) for patients previously failing a Bruton tyrosine kinase (BTK) inhibitor. Median progression-free survival (PFS) was 21 months, with median overall survival of 31 months. TP53 mutation was associated with inferior PFS (P < .01). Overall, 28 patients (48%) discontinued treatment in molecular remission, and 25 remain MRD negative after a median of 17.4 months. Hematological toxicity was frequent, with 52 of 59 (88%) patients with G3-4 neutropenia and 21 of 59 (36%) patients with G3-4 thrombocytopenia. To conclude, MRD-driven venetoclax-R2 is feasible and tolerable and shows efficacy in R/R MCL, also after BTK inhibitor failure. This trial was registered at www.ClinicalTrials.gov as #NCT03505944.
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Compuestos Bicíclicos Heterocíclicos con Puentes , Linfoma de Células del Manto , Sulfonamidas , Anciano , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Lenalidomida/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasia Residual/tratamiento farmacológico , Rituximab/uso terapéuticoRESUMEN
Background: Parsaclisib is a potent and highly selective PI3Kδ inhibitor that has shown clinical benefit in patients with relapsed/refractory (R/R) B-cell malignancies. In this phase 2 study (CITADEL-205; NCT03235544, EudraCT 2017-003148-19), the efficacy and safety of parsaclisib was evaluated in patients with R/R mantle cell lymphoma (MCL). Methods: Patients ≥18 years old with pathologically confirmed R/R MCL and prior treatment with 1-3 systemic therapies, with (cohort 1) or without (cohort 2) previous Bruton kinase inhibitor (BTKi) treatment, received oral parsaclisib 20 mg once-daily (QD) for 8 weeks, then either parsaclisib 20 mg once-weekly (weekly dosing group [WG]) or parsaclisib 2.5 mg QD (daily dosing group [DG]). The primary endpoint was objective response rate (ORR). Findings: At the primary analysis data cutoff on January 15, 2021, 53 patients in cohort 1 (BTKi-experienced) (WG, n = 12; DG: n = 41) and 108 patients in cohort 2 (BTKi-naive) (WG, n = 31; DG: n = 77) had received parsaclisib monotherapy. The BTKi-experienced cohort was closed after an interim analysis demonstrated limited clinical benefit. In the BTKi-naive cohort, the ORR (95% CI) for DG (dosing selected for further study) was 70.1% (58.6%-80.0%), with a complete response rate (95% CI) of 15.6% (8.3%-25.6%) and a median duration of response (95% CI) of 12.1 (9.0-not evaluable) months. Treatment-emergent adverse events (TEAEs) occurred among 90.7% (98/108) of all treated patients in the BTKi-naive cohort. Grade ≥3 TEAEs occurred among 62.0% (67/108) of patients, including diarrhoea (13.9%, 15/108) and neutropenia (8.3%, 9/108). Parsaclisib interruption, reduction, or discontinuation due to TEAEs occurred among 47.2% (51/108), 8.3% (9/108), and 25.0% (27/108) of patients, respectively. Fatal TEAEs were experienced by six patients and determined to be treatment-related in one patient. Interpretation: Parsaclisib, a potent, highly selective, PI3Kδ inhibitor demonstrated meaningful clinical benefits and a manageable safety profile (25.0% discontinuation rate, low incidences of individually reported grade ≥3 or serious adverse events) in R/R MCL patients with no prior BTKi therapy. Limited clinical benefit was observed with parsaclisib monotherapy in patients who had previously received BTKi treatment. Future development of PI3K inhibitors for NHL will require further investigation of dose optimisation to improve safety and long-term survival. Funding: Incyte Corporation.
RESUMEN
We analysed a large cohort of Hodgkin lymphoma (HL) patients in order to characterize: (1) the pattern of late recurrence of lymphoid malignancies (LR) after initial treatment for HL over a 35-year period; (2) the clinicopathological parameters influencing the risk of LR; and (3) the outcome of patients experiencing LR. We reviewed data of 3350 HL patients diagnosed in Denmark between 1982 and 2018 and registered in the Danish National Lymphoma Registry (LYFO). LR was defined as a recurrence of lymphoid malignancy at least five years after initial diagnosis. LR occurred in 58 patients, with a cumulative incidence at 10, 15 and 20 years of 2.7%, 4.0% and 5.4% respectively. LR was more frequently observed in patients with nodular lymphocyte-predominant HL (NLPHL) [hazard ratio (HR) 4.5; 95% confidence interval (CI): 2.4-8.4, p < 0.001]. In classical HL (cHL) patients, older age and lymphocytopenia were risk factors for LR with HRs of 1.04 per additional year (95% CI: 1.02-1.06) and 5.6 (95% CI: 2.7-11.5) respectively. Mixed cellularity histological subtype was a risk factor for LR, but only in females, with a HR of 5.4 (95% CI: 1.4-20.4, p = 0.014). In contrast to what was observed in NLPHL, LR in cHL was associated with an almost threefold increased risk of death compared with patients in continuous complete remission. Approximately one fifth (22.4%) of patients with LR experienced a second relapse.
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Enfermedad de Hodgkin , Linfoma , Dinamarca/epidemiología , Femenino , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/epidemiología , Enfermedad de Hodgkin/terapia , Humanos , Recurrencia Local de Neoplasia , Sistema de RegistrosRESUMEN
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of aggressive non-Hodgkin lymphomas, the majority of which have high relapse rates following standard therapy. Despite use of consolidative stem cell transplant (SCT) following frontline therapy, there remains no consensus on its utility. The double-blind randomized phase 3 ECHELON-2 study (#NCT01777152; clinicaltrials.gov) demonstrated improved progression-free survival (PFS) and overall survival with frontline brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP). Herein, we conducted an exploratory subgroups analysis of the impact of consolidative SCT on PFS in patients with previously untreated CD30+ PTCL (ALK- anaplastic large cell lymphoma [ALCL] and non-ALCL) who were in complete response (CR) after frontline treatment with A+CHP or cyclophosphamide, doxorubicin, vincristine, and prednisone. Median PFS follow-up was 47.57 months. The PFS hazard ratio was 0.36, equating to a 64% reduction in the risk of a PFS event in patients who underwent SCT. The median PFS in patients who underwent SCT was not reached, vs 55.66 months in patients who did not undergo SCT. PFS results favored the use of SCT in both ALK- ALCL and non-ALCL subgroups. These data support the consideration of consolidative SCT in patients with CD30+PTCL who achieve CR following treatment with A+CHP.
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Trasplante de Células Madre Hematopoyéticas , Linfoma Anaplásico de Células Grandes , Brentuximab Vedotina , Ciclofosfamida/efectos adversos , Doxorrubicina/efectos adversos , Humanos , Antígeno Ki-1 , Linfoma Anaplásico de Células Grandes/inducido químicamente , Linfoma Anaplásico de Células Grandes/terapia , Recurrencia Local de Neoplasia , Prednisona/efectos adversos , Vincristina/efectos adversosRESUMEN
BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas. METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152. FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54-0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group. INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile. FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoconjugados/administración & dosificación , Factores Inmunológicos/administración & dosificación , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Brentuximab Vedotina , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Método Doble Ciego , Doxorrubicina/administración & dosificación , Femenino , Humanos , Inmunoconjugados/efectos adversos , Factores Inmunológicos/efectos adversos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Vincristina/administración & dosificaciónAsunto(s)
Linfoma/mortalidad , Modelos Biológicos , Factores de Edad , Anciano , Dinamarca/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Linfoma/diagnóstico , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Curva ROC , Sistema de Registros/estadística & datos numéricos , Factores de Riesgo , Factores de TiempoRESUMEN
BACKGROUND: The Danish National Lymphoma Register (LYFO) prospectively includes information on all lymphoma patients newly diagnosed at hematology departments in Denmark. The validity of the clinical information in the LYFO has never been systematically assessed. AIM: To test the coverage and data quality of the LYFO. METHODS: The coverage was tested by merging data of the LYFO with the Danish Cancer Register and the Danish National Patient Register, respectively. The validity of the LYFO was assessed by crosschecking with information from medical records in subgroups of patients. A random sample of 3% (N = 364) was made from all patients in the LYFO. In addition, four subtypes of lymphomas were validated: CNS lymphomas, diffuse large B-cell lymphomas, peripheral T-cell lymphomas, and Hodgkin lymphomas. A total of 1,706 patients from the period 2000-2012 were included. The positive predictive values (PPVs) and completeness of selected variables were calculated for each subgroup and for the entire cohort of patients. RESULTS: The comparison of data from the LYFO with the Danish Cancer Register and the Danish National Patient Register revealed a high coverage. In addition, the data quality was good with high PPVs (87% to 100%), and high completeness (92% to 100%). CONCLUSION: The LYFO is a unique, nationwide clinical database characterized by high validity, good coverage and prospective data entry. It represents a valuable resource for future lymphoma research.
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Linfoma/epidemiología , Sistema de Registros/estadística & datos numéricos , Exactitud de los Datos , Dinamarca/epidemiología , Femenino , Humanos , Masculino , Vigilancia de la Población , Sistema de Registros/normasRESUMEN
Multiple myeloma (MM) lytic bone disease (LBD) is caused by osteoclast activation and osteoblast inhibition. RANK/RANKL/OPG play central roles in osteoclast activation and Wnt inhibitor DKK1 in osteoblast inhibition. The role of other Wnt inhibitors is less clear. We evaluated gene expression of osteoclast regulators (RANK, RANKL, OPG, TRAIL, MIP1A), Wnt inhibitors (DKK1, SFRP2, SFRP3, sclerostin, WIF1) and osteoblast transcription factors (RUNX2, osterix) by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) in the bone marrow (BM) microenvironment using snap-frozen BM biopsies, thereby achieving minimal post-sampling manipulation, and gene expression profiling (GEP) data, reflecting the in vivo situation. We analyzed 110 biopsies from newly diagnosed patients with MM and monoclonal gammopathy of unknown significance (MGUS) and healthy volunteers. LBD was evaluated using standard radiographs and the bone resorption marker CTX-1. Protein levels were evaluated by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. Among Wnt inhibitors, only SFRP3 and DKK1 were significantly overexpressed in advanced LBD, correlating with protein levels. SFRP3 correlated with CTX-1. Our findings support osteoblast inhibition as the driving force behind MM LBD.
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Regulación Neoplásica de la Expresión Génica , Mieloma Múltiple/genética , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Microambiente Tumoral/genética , Adulto , Anciano , Médula Ósea/patología , Biología Computacional , Femenino , Perfilación de la Expresión Génica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Mieloma Múltiple/diagnóstico , Estadificación de Neoplasias , Osteólisis/etiologíaRESUMEN
The JAK2 V617F mutation is a frequent genetic event in the three classical Philadelphia-chromosome negative chronic myeloproliferative disorders (Ph(neg.)-CMPD), polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Its occurrence varies in frequency in regards to phenotype. The mutation is found in the majority of patients with PV and about half of the patients with ET and IMF. These diseases are clonal stem cell disorders arising in an early stem cell progenitor. The level in the stem cell hierarchy on which the initiating genetic events and the JAK2 V617F mutation occurs is not known. The mutation has so far been detected in all cells of the myeloid lineage, whereas the potential clonal involvement of the lymphoid lineage is controversial. In this study, we detected the JAK2 V617F mutation by real-time quantitative PCR (qPCR) in both B-lymphocytes and T-lymphocytes in a subgroup of patients with Ph(neg.)-CMPDs. These results demonstrate the origin of the JAK2 V617F positive disorders in an early stem cell with both lymphoid and myeloid differentiation potential.
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Linfocitos B/patología , Janus Quinasa 2/genética , Mutación , Trastornos Mieloproliferativos/genética , Linfocitos T/patología , Anciano , Análisis Mutacional de ADN/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/inmunología , Cromosoma Filadelfia , Policitemia Vera/genética , Policitemia Vera/inmunología , Reacción en Cadena de la Polimerasa/métodos , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/inmunología , Trombocitemia Esencial/genética , Trombocitemia Esencial/inmunologíaRESUMEN
PRV-1 is a new molecular marker within the Ph-negative chronic myeloproliferative disorders. PRV-1 is a useful, highly sensitive and specific marker in the differentiation between polycythaemia vera (PV) and secondary erythrocytosis (ET), and seems to identify those PV patients presenting in the early phase of the disease with dominating thrombocytosis and thus a clinical phenotype of ET. These PRV-1 positive ET patients can be regarded as having "masked" PV or, more accurately, as having early PV. Moreover, PRV-1 positivity may be associated with a particular risk of thromboembolic complications. The biological role of PRV-1 and the significance of alterations in PRV-1 gene expression levels during treatment remain to be clarified.
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Biomarcadores/sangre , Isoantígenos/genética , Glicoproteínas de Membrana/genética , Mutación , Trastornos Mieloproliferativos/genética , Receptores de Superficie Celular/genética , Análisis Mutacional de ADN , Diagnóstico Diferencial , Proteínas Ligadas a GPI , Expresión Génica , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/tratamiento farmacológico , Cromosoma Filadelfia , Policitemia Vera/diagnóstico , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/genética , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/genética , Pronóstico , Trombocitosis/sangre , Trombocitosis/diagnóstico , Trombocitosis/tratamiento farmacológico , Trombocitosis/genéticaRESUMEN
The Philadelphia-negative chronic myeloproliferative disorders feature autonomous myeloid hyperproliferation and hypersensitivity to a number of growth factors, which most recently have been shown to be explained by a guanine-to-thymidine mutation in the Janus tyrosine kinase (JAK2) gene, implicating that phenylalanine is substituted with valine in position 617 (V617F mutation). JAK2 is of particular importance to haematopoiesis, since JAK2 proteins are activated mainly by the haematopoietic growth factors. The JAK2 mutation is present in most patients with polycythaemia vera and about 50% of patients with essential thrombocytosis and idiopathic myelofibrosis. The identification of the JAK2 mutation is a major molecular breakthrough in the understanding of the pathobiology of these disorders, and it is a new molecular marker to be used in the future classification of the diseases as well as a simple and rapid diagnostic test. The mutated JAK2 tyrosine kinase is an obvious potential target for a small-molecule inhibitor of tyrosine kinase activity.
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Biomarcadores/sangre , Mutación , Trastornos Mieloproliferativos/genética , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Análisis Mutacional de ADN , Humanos , Janus Quinasa 2 , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/tratamiento farmacológico , Cromosoma Filadelfia , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/enzimología , Policitemia Vera/genética , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/genética , Pronóstico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Transducción de Señal , Trombocitosis/diagnóstico , Trombocitosis/tratamiento farmacológico , Trombocitosis/genéticaRESUMEN
INTRODUCTION: The aim was to describe the prevalence and to estimate the prognosis of congenital hydrocephalus (HC) in fetuses and children. MATERIAL AND METHODS: Data for the study were taken from the Eurocat Register of Congenital Malformations for the County of Funen and from medical records. The study includes liveborn, intrauterine deaths, and induced abortions. All cases with HC born in the County of Funen in the years 1986-1998 were included. The followup period is three years after birth. RESULTS: The prevalence of HC was 0.4/1,000 births. There were 29 cases of HC, out of which 21 were liveborn. 41% had associated malformations, syndromes and/or chromosome abnormalities, and mortality of these compared to cases with isolated HC were significantly increased (p < 0.05). 18 children had shunt surgery and 12 children had one or more reoperations. At the age of three, four children had died, 12 had neurological problems related to their HC, and five children were described as normal. DISCUSSION: We found high mortality and morbidity in fetuses and children with HC. Mortality was significantly increased if associated malformations, syndromes and/or chromosome abnormalities were present. After prenatal diagnosis of HC it is important to look carefully for other malformations and to perform a karyotype before information about the prognosis of the fetus is given to the parents.