RESUMO
BACKGROUND: Data on outcome for patients in different body mass index (BMI) categories in young adults with acute lymphoblastic leukemia (ALL) are scarce. We explored survival and toxicities in different BMI categories in young adults with ALL. MATERIAL AND METHODS: Patients aged 18-45 years, diagnosed with ALL between July 2008 and June 2022 in the Nordic countries, Estonia, or Lithuania, and treated according to the NOPHO ALL2008 protocol, were retrospectively enrolled and classified into different BMI categories. Endpoints were overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse as well as incidence rate ratio (IRR) of severe predefined toxic events, and treatment delays. RESULTS: The group comprised 416 patients, of whom 234 (56%) were stratified to non-high-risk (non-HR) treatment. In the non-HR group, patients with severe obesity, BMI ≥35 kg/m2 had worse EFS due to relapses but there was no effect on toxicity or treatment delays compared with the healthy-weight patients. There was no association between BMI category and OS, overall toxicity, or treatment delays in the patients with high-risk treatment. CONCLUSION: Severe obesity is associated with worse EFS in young adults treated according to the non-HR arms of the NOPHO ALL2008 protocol. Poorer outcome is explained with a higher risk of relapse, possibly due to under treatment, and not caused by excess therapy-related mortality.
Assuntos
Obesidade Mórbida , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Adulto Jovem , Índice de Massa Corporal , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Estudos Retrospectivos , Recidiva , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resultado do TratamentoRESUMO
Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 × 10-8) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 × 10-9) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms.
Assuntos
Metotrexato/análogos & derivados , Recidiva Local de Neoplasia/patologia , Peptídeo Sintases/genética , Ácido Poliglutâmico/análogos & derivados , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Tetra-Hidrofolato Desidrogenase/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Masculino , Metotrexato/administração & dosagem , Metotrexato/metabolismo , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Ácido Poliglutâmico/administração & dosagem , Ácido Poliglutâmico/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Prognóstico , Adulto JovemRESUMO
Thromboembolism frequently occurs during acute lymphoblastic leukemia (ALL) therapy. We prospectively registered thromboembolic events during the treatment of 1772 consecutive Nordic/Baltic patients with ALL aged 1 to 45 years who were treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol (July 2008-April 2017). The 2.5-year cumulative incidence of thromboembolism (N = 137) was 7.9% (95% confidence interval [CI], 6.6-9.1); it was higher in patients aged at least 10 years (P < .0001). Adjusted hazard ratios (HRas) were associated with greater age (range, 10.0-17.9 years: HRa, 4.9 [95% CI, 3.1-7.8; P < .0001]; 18.0-45.9 years: HRa, 6.06 [95% CI, 3.65-10.1; P < .0001]) and mediastinal mass at ALL diagnosis (HRa, 2.1; 95% CI, 1.0-4.3; P = .04). In a multiple absolute risk regression model addressing 3 thromboembolism risk factors, age at least 10 years had the largest absolute risk ratio (RRage, 4.7 [95% CI, 3.1-7.1]; RRenlarged lymph nodes, 2.0 [95% CI, 1.2-3.1]; RRmediastinal mass, 1.6 [95% CI, 1.0-2.6]). Patients aged 18.0 to 45.9 years had an increased hazard of pulmonary embolism (HRa, 11.6; 95% CI, 4.02-33.7; P < .0001), and patients aged 10.0 to 17.9 years had an increased hazard of cerebral sinus venous thrombosis (HRa, 3.3; 95% CI, 1.5-7.3; P = .003) compared with children younger than 10.0 years. Asparaginase was truncated in 38/128 patients with thromboembolism, whereas thromboembolism diagnosis was unassociated with increased hazard of relapse (P = .6). Five deaths were attributable to thromboembolism, and patients younger than 18.0 years with thromboembolism had increased hazard of dying compared with same-aged patients without thromboembolism (both P ≤ .01). In conclusion, patients aged at least 10 years could be candidates for preemptive antithrombotic prophylaxis. However, the predictive value of age 10 years or older, enlarged lymph nodes, and mediastinal mass remain to be validated in another cohort.
Assuntos
Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Asparaginase/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Tromboembolia/induzido quimicamente , Tromboembolia/prevenção & controle , Adolescente , Adulto , Fatores Etários , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto JovemRESUMO
OBJECTIVES: Cure rates improve when adolescents and young adults with acute lymphoblastic leukemia (ALL) are treated according to pediatric protocols. Assumed risks of toxicities and associated delays in treatment have played a role in setting upper age limits. The aim of this study was to examine the toxicity profile and treatment delays in NOPHO ALL2008 comparing children and adults. METHODS: We collected information on 19 treatment-related toxicities, systematically captured at 3-month intervals throughout therapy, and time intervals between 12 consecutive treatment phases for 1076 patients aged 1-45 yrs treated according to the Nordic/Baltic ALL2008 protocol. RESULTS: No adults died during induction. The duration of induction therapy and postinduction treatment phases did not differ between children and adults, except for patients 18-45 yrs being significantly delayed during two of nine high-risk blocks (median number of days for patients 1-9, 10-17, and 18-45 yrs; the glucocorticosteroid/antimetabolite-based block B1: 24, 26, and 29 d, respectively, P = 0.001, and Block 5 (in most cases also a B block): 29, 29, and 37 d, respectively, P = 0.02). A higher incidence of thrombosis with increasing age was found; highest odds ratio 5.4 (95% CI: (2.6;11.0)) for patients 15-17 yrs compared with children 1-9 yrs (P < 0.0001). Risk of avascular osteonecrosis was related to age with the highest OR for patients 10-14 yrs (OR = 10.4 (95% CI: (4.4;24.9)), P < 0.0001). CONCLUSION: Adults followed and tolerated the NOPHO ALL2008 protocol virtually as well as children, although thrombosis and avascular osteonecrosis was most common among adolescents.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Osteonecrose/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Trombose/diagnóstico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Metotrexato/administração & dosagem , Metotrexato/toxicidade , Pessoa de Meia-Idade , Osteonecrose/induzido quimicamente , Osteonecrose/genética , Osteonecrose/patologia , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prednisona/administração & dosagem , Prednisona/toxicidade , Prognóstico , Indução de Remissão , Trombose/induzido quimicamente , Trombose/genética , Trombose/patologia , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/toxicidadeRESUMO
BACKGROUND: Congenital thrombotic thrombocytopenic purpura (TTP) is a rare, hereditary disorder. Clinically it presents as episodic microangiopathic haemolytic anaemia and thrombocytopenia with varying degrees of damage to internal organs. The condition may present in neonates, but can also present for the first time in adulthood. The prevalence of congenital TTP is particularly high in Norway, and it is therefore important for Norwegian doctors to be aware of the condition. In this article we review the main characteristics of the disease, including its diagnosis and management, and introduce potential new treatments for the future. METHOD: The article is based on a literature search in PubMed as well as the authors' own research and clinical experience. RESULTS: There was great variation in the severity of congenital TTP: from neonatal mortality to disease-free intervals of several years. Episodes are generally precipitated by a trigger. Acute episodes are treated with plasma infusions, and approximately half of all patients experience frequent episodes and require prophylactic infusions to avoid organ damage. The risk of episodes is greatest in neonates, during pregnancy and in association with infections. INTERPRETATION: There is little research-based evidence regarding long-term prognosis in congenital TTP. There is also a need for guidelines to help identify candidates for prophylactic treatment. An international patient registry would provide useful information and form the basis for better guidelines on the monitoring and treatment of these patients.
Assuntos
Púrpura Trombocitopênica Trombótica , Proteína ADAMTS13/genética , Algoritmos , Transfusão de Sangue , Humanos , Noruega/epidemiologia , Púrpura Trombocitopênica Trombótica/congênito , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/epidemiologia , Púrpura Trombocitopênica Trombótica/terapiaRESUMO
BACKGROUND: The prognosis of acute lymphoblastic leukemia is poorer in adults than in children. Studies have indicated that young adults benefit from pediatric treatment, although no upper age limit has been defined. DESIGN AND METHODS: We analyzed 749 patients aged 1-45 yr treated by the NOPHO ALL-2008 protocol. Minimal residual disease (MRD) on days 29 and 79, immunophenotype, white blood cell count (WBC), and cytogenetics were used to stratify patients to standard-, intermediate-, or high-risk treatment with or without hematopoietic stem cell transplantation. RESULTS: Adults aged 18-45 had significantly lower WBCs at diagnosis compared with children aged 1-9 and 10-17 yr, but significantly more adults were stratified to high-risk chemotherapy (8%, 14%, 17%; P < 0.0001) or high-risk chemotherapy with transplantation (4%, 13%, 19%; P < 0.0001). This age-dependent skewing of risk grouping reflected more T-ALL (11%, 27%, 33%, P < 0.0001), poorer MRD response day 29 (MRD < 0.1%: 75%, 61%, 52%; P < 0.0001), and more MLL gene rearrangements (3%, 3%, 10%; P = 0.005) in older patients. CONCLUSIONS: Even if identical diagnostics, treatment, and risk stratification are implemented, more adults will be stratified to high-risk therapy, which should be considered when comparing pediatric and adult outcomes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Análise Citogenética , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Quimioterapia de Indução , Lactente , Masculino , Adesão à Medicação , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prednisona/administração & dosagem , Sistema de Registros , Resultado do Tratamento , Vincristina/administração & dosagem , Adulto JovemAssuntos
Doença de Erdheim-Chester , Idoso , Ascite/etiologia , Tosse/etiologia , Quimioterapia Combinada , Doença de Erdheim-Chester/complicações , Doença de Erdheim-Chester/diagnóstico , Doença de Erdheim-Chester/diagnóstico por imagem , Doença de Erdheim-Chester/tratamento farmacológico , Feminino , Febre/etiologia , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico , Cintilografia , Sirolimo/uso terapêutico , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: There are no data on the effect of low-dose anticoagulation as secondary prophylaxis for venous thromboembolism (VTE) in cancer patients. We assessed the efficacy and safety of low-dose apixaban for 30 months, after initial 6 months of full-dose treatment. METHODS: We included 298 patients with cancer and any type of VTE in a single arm interventional clinical trial. All patients were treated with full-dose apixaban (5 mg twice daily) for 6 months. Total 196 patients with active cancer after 6 months treatment continued with apixaban 2.5 mg twice daily for another 30 months. The main endpoints were recurrent VTE, major bleeding and clinically relevant non-major bleeding. RESULTS: During the 30 months of treatment with low-dose apixaban 14 (7.6%; 95% confidence interval (CI) 4.0%-11.7%) patients experienced recurrent VTE, six (3.1%; 95% CI 1.1%-6.5%) experienced major bleeding and 16 (8.1%, 95% CI: 4.7%-12.8%) experienced clinically relevant non-major bleeding. The incidence rate per person month of recurrent VTE was 0.8% (95% CI 0.41-1.6) at 2-6 months with full-dose apixaban, and 1.0% (95% CI 0.5-1.9) at 7-12 months with low-dose apixaban. The incidence rate of major bleeding was 1.1% (95% CI 0.6-2.0) at 2-6 months, and 0.3% (95% CI 0.1-1.0) at 7-12 months. Between 12 and 36 months the incidence rate of recurrent VTE and major bleedings remained low. CONCLUSION: Dose reduction of apixaban to 2.5 mg twice daily seems safe after 6 months of full-dose treatment. After 12 months the incidence rate of recurrent VTE and major bleeding remained low.
Assuntos
Neoplasias , Tromboembolia Venosa , Anticoagulantes/uso terapêutico , Seguimentos , Hemorragia/epidemiologia , Humanos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Pirazóis , Piridonas , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/prevenção & controleRESUMO
Cerebral sinovenous thrombosis (CSVT) is a serious complication during asparaginase therapy in patients with acute lymphoblastic leukaemia (ALL). We identified 46 patients with CSVT among 2651 patients (1â45 years) treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2008 and 2018. CSVT cases were prospectively registered in the NOPHO database with retrospective updates. We examined the frequency of asparaginase re-exposure after CSVT, potential factors associated with asparaginase truncation, and sequelae after CSVT. This work was supported by the Danish Cancer Society and the Danish Childhood Cancer Foundation. The 2.5-year cumulative incidence of CSVT was 1.9% (95% confidence interval 1.4%-2.5%). The majority of patients (74%, n = 31) were re-exposed to asparaginase (with low-molecular-weight heparin coverage), one of whom had a second CSVT, without neurological sequelae. Patients re-exposed to asparaginase were earlier in ALL treatment and lacked more asparaginase doses than non-re-exposed patients at CSVT diagnosis (median 50 vs. 81 days, p = 0.03; mean 11.2 vs. 8.4 asparaginase doses, p = 0.04). No other examined factors had an impact on asparaginase re-exposure. At the last follow-up (median 4.5 years after CSVT), 61% of patients had normal neurological status, and 57% had complete recanalisation of CSVT, with no significant difference between patients re-exposed and non-re-exposed to asparaginase. Our results indicate that re-exposure to asparaginase is safe after CSVT during anticoagulation.
RESUMO
Endothelial dysfunction has not previously been investigated as a thrombogenic risk factor among patients with acute lymphoblastic leukemia (ALL), known to be at high risk of thromboembolism. We retrospectively explored the association between three circulating biomarkers of endothelial dysfunction (thrombomodulin, syndecan-1, VEGFR-1) measured in prospectively collected blood samples and risk of thromboembolism in 55 cases and 165 time-matched controls, treated according to the NOPHO ALL2008 protocol. In age-, sex-, and risk group-adjusted analysis, increasing levels of thrombomodulin and VEGFR-1 were independently associated with increased odds of developing thromboembolism (OR 1.37 per 1 ng/mL [95% CI 1.20â1.56, P < 0.0001] and OR 1.21 per 100 pg/mL [95% CI 1.02â1.21, P = 0.005], respectively). These associations remained significant when including only samples drawn >30 days before thromboembolic diagnosis. Thrombomodulin levels were on average 3.2 ng/mL (95% CI 2.6-8.2 ng/mL) higher in samples with measurable asparaginase activity (P < 0.0001). Among single nucleotide variants located in or neighboring coding genes for the three biomarkers, none were significantly associated with odds of thromboembolism. If results are validated in another cohort, thrombomodulin and VEGFR-1 could serve as predictive biomarkers, identifying patients in need of preemptive antithrombotic prophylaxis.
Assuntos
Asparaginase/metabolismo , Endotélio Vascular/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Tromboembolia/patologia , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Tromboembolia/enzimologia , Tromboembolia/etiologia , Adulto JovemRESUMO
Methotrexate/6-mercaptopurine maintenance therapy improves acute lymphoblastic leukemia (ALL) outcome. Cytotoxicity is mediated by DNA incorporation of thioguanine nucleotides (DNA-TG). We investigated the association of DNA-TG to relapse risk in 1 910 children and young adults with non-high risk ALL. In a cohort-stratified Cox regression analysis adjusted for sex, age, and white cell count at diagnosis, the relapse-specific hazard ratio (HRa) per 100 fmol/µg increase in weighted mean DNA-TG (wmDNA-TG) was 0.87 (95% CI 0.78-0.97; p = 0.013) in the 839 patients who were minimal residual disease (MRD) positive at end of induction therapy (EOI), whereas this was not the case in EOI MRD-negative patients (p = 0.76). Validation analysis excluding the previously published Nordic NOPHO ALL2008 pediatric cohort yielded a HRa of 0.92 (95% CI 0.82-1.03; p = 0.15) per 100 fmol/µg increase in wmDNA-TG in EOI MRD-positive patients. If also excluding the United Kingdom cohort, in which samples were taken non-randomly in selected patients, the HRa for the EOI MRD-positive patients was 0.82 (95% CI 0.68-0.99; p = 0.044) per 100 fmol/µg increase in wmDNA-TG. The importance of DNA-TG as a biomarker for maintenance therapy intensity calls for novel strategies to increase DNA-TG, although its clinical value may vary by protocol backbone.
Assuntos
Ensaios Clínicos como Assunto/estatística & dados numéricos , DNA de Neoplasias/metabolismo , Recidiva Local de Neoplasia/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Tioguanina/metabolismo , Adulto , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Prognóstico , Adulto JovemRESUMO
Extracorporeal photopheresis (ECP), an immunomodulatory therapy for the treatment of chronic graft-versus-host disease (cGvHD), exposes isolated white blood cells to photoactivatable 8-methoxypsoralen (8-MOP) and UVA light to induce the apoptosis of T-cells and, hence, to modulate immune responses. However, 8-MOP-ECP kills diseased and healthy cells with no selectivity and has limited efficacy in many cases. The use of 5-aminolevulinic acid (ALA) and light (ALA-based photodynamic therapy) may be an alternative, as ex vivo investigations show that ALA-ECP kills T-cells from cGvHD patients more selectively and efficiently than those treated with 8-MOP-ECP. The purpose of this phase I-(II) study was to evaluate the safety and tolerability of ALA-ECP in cGvHD patients. The study included 82 treatments in five patients. One patient was discharged due to the progression of the haematological disease. No significant persistent changes in vital signs or laboratory values were detected. In total, 62 adverse events were reported. Two events were severe, 17 were moderate, and 43 were mild symptoms. None of the adverse events evaluated by the internal safety review committee were considered to be likely related to the study medication. The results indicate that ALA-ECP is safe and is mainly tolerated well by cGvHD patients.
RESUMO
PURPOSE: Osteonecrosis is a burdensome treatment-related toxicity that is mostly diagnosed during or soon after 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy for acute lymphoblastic leukemia (ALL), possibly indicating a pathogenic role of these drugs. METHODS: We prospectively registered symptomatic osteonecrosis during treatment of 1234 patients aged 1.0-45.9 years treated according to the Nordic Society of Hematology and Oncology (NOPHO) ALL2008 protocol. MTX/6MP metabolites were measured as part of the NOPHO ALL2008 maintenance therapy study. RESULTS: After a median follow-up of 5.6 years [interquartile range (IQR) 3.6-7.5], 68 patients had been diagnosed with symptomatic osteonecrosis. The cumulative incidence was 2.7% [95% confidence interval (CI) 1.6-3.8%] for patients aged < 10 years, 14.9% (95% CI 9.7-20.2%) for patients aged 10.0-17.9 years, and 14.4% (95% CI 8.0-20.8%) for patients aged ≥ 18 years. The median time from diagnosis of ALL to diagnosis of osteonecrosis in these age groups was 1.0 year (IQR 0.7-2.0), 2.0 years (IQR 1.1-2.4), and 2.2 years (IQR 1.8-2.8), respectively (p = 0.001). With 17,854 blood samples available for MTX and 6MP metabolite analysis, neither erythrocyte levels of 6-thioguanine (TG) nucleotides (p > 0.99), methylated 6MP metabolites (p = 0.37), MTX polyglutamates (p = 0.98) nor DNA-TG (p = 0.53) were significantly associated with the hazard of osteonecrosis in Cox models stratified by the three age groups and adjusted for sex. CONCLUSION: Maintenance therapy intensity determined by 6MP and MTX metabolites was not associated with the risk of developing osteonecrosis in the NOPHO ALL2008 cohort.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Mercaptopurina/efeitos adversos , Metotrexato/efeitos adversos , Osteonecrose/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Criança , Pré-Escolar , Adutos de DNA/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Feminino , Humanos , Lactente , Masculino , Mercaptopurina/administração & dosagem , Mercaptopurina/farmacocinética , Metotrexato/administração & dosagem , Metotrexato/análogos & derivados , Metotrexato/metabolismo , Metotrexato/farmacocinética , Pessoa de Meia-Idade , Ácido Poliglutâmico/análogos & derivados , Ácido Poliglutâmico/metabolismo , Ácido Poliglutâmico/farmacocinética , Estudos Prospectivos , Tioguanina/metabolismo , Adulto JovemRESUMO
BACKGROUND: An explanation for the increased risk of myocardial infarction and stroke in patients with venous thrombosis is lacking. The objective of this study was to investigate whether risk factors for arterial cardiovascular disease also increase the risk of venous thrombosis. DESIGN AND METHODS: Cases who had a first venous thrombosis (n=515) and matched controls (n=1,505) were identified from a population-based, nested, case-cohort study (the HUNT 2 study) comprising 71% (n=66,140) of the adult residents of Nord-Trøndelag County in Norway. RESULTS: The age- and sex-adjusted odds ratio of venous thrombosis for subjects with concentrations of C-reactive protein in the highest quintile was 1.6 (95% confidence interval: 1.2-2.2) compared to subjects with C-reactive protein in the lowest quintile. This association was strongest in subjects who experienced venous thrombosis within a year after blood sampling with a three-fold increased risk of participants in the highest versus the lowest quintile. Having first degree relatives who had a myocardial infarction before the age of 60 years was positively associated with venous thrombosis compared to not having a positive family history [odds ratio 1.3 (95% confidence interval: 1.1-1.6)]. Subjects with blood pressure in the highest quintile had half the risk of developing venous thrombosis compared to subjects whose blood pressure was in the lowest quintile. There were no associations between the risk of venous thrombosis and total cholesterol, low density lipoprotein-cholesterol, high density lipoprotein-cholesterol, triglycerides, glucose or smoking. We confirmed the positive association between obesity and venous thrombosis. CONCLUSIONS: C-reactive protein and a family history of myocardial infarction were positively associated with subsequent venous thrombosis. Blood pressure was inversely correlated to venous thrombosis. These findings should be confirmed by further investigations.
Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Vigilância da População , Trombose Venosa/sangue , Trombose Venosa/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/etiologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Estudos Prospectivos , Fatores de Risco , Trombose Venosa/etiologiaRESUMO
PURPOSE OF REVIEW: Randomized trials have suggested that the beneficial effects of statins could extend to mechanisms beyond cholesterol reduction. Investigations have shown that statins are associated with reduced plasma markers of inflammation, reduced T-cell and monocyte activation, and reduced blood clotting. These effects could be explained by the inhibition of L-mevalonic acid synthesis, thus affecting cell-signalling pathways. However, it has been difficult to evaluate whether the nonlipid effects of statins translate into clinically meaningful outcomes. RECENT FINDINGS: Inflammation, as measured by C-reactive protein (CRP), has been established as an independent cardiovascular risk factor, even in persons with low-density lipoprotein (LDL)-cholesterol. Statins have anti-inflammatory effects, and lower CRP. Reducing both LDL-cholesterol and CRP is important in order to decrease the risk of cardiovascular events. Statins significantly reduce the risk of venous thrombosis. It is probable that this effect goes beyond lipid lowering. The clinical benefit of statin therapy in infectious diseases remains to be determined by randomized controlled trials. SUMMARY: Statins have anti-inflammatory properties that are clinically important in lowering cardiovascular risk. It is probable, but not definitely proven, that some of the benefits of statins are due to their nonlipid effects.
Assuntos
Anticolesterolemiantes/uso terapêutico , Proteína C-Reativa/efeitos dos fármacos , LDL-Colesterol/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação/tratamento farmacológico , Anticolesterolemiantes/farmacologia , Biomarcadores Farmacológicos , Doenças Transmissíveis/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamação/fisiopatologia , Ácido Mevalônico , Monócitos/efeitos dos fármacos , Medição de Risco , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Trombose Venosa/tratamento farmacológicoRESUMO
PURPOSE: Asparaginase-associated pancreatitis (AAP) is common in patients with acute lymphoblastic leukemia (ALL), but risk differences across age groups both in relation to first-time AAP and after asparaginase re-exposure have not been explored. PATIENTS AND METHODS: We prospectively registered AAP (n = 168) during treatment of 2,448 consecutive ALL patients aged 1.0-45.9 years diagnosed from July 2008 to October 2018 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. RESULTS: Compared with patients aged 1.0-9.9 years, adjusted AAP hazard ratios (HRa) were associated with higher age with almost identical HRa (1.6; 95% CI, 1.1 to 2.3; P = .02) for adolescents (10.0-17.9 years) and adults (18.0-45.9 years). The day 280 cumulative incidences of AAP were 7.0% for children (1.0-9.9 years: 95% CI, 5.4 to 8.6), 10.1% for adolescents (10.0 to 17.9 years: 95% CI, 7.0 to 13.3), and 11.0% for adults (18.0-45.9 years: 95% CI, 7.1 to 14.9; P = .03). Adolescents had increased odds of both acute (odds ratio [OR], 5.2; 95% CI, 2.1 to 13.2; P = .0005) and persisting complications (OR, 6.7; 95% CI, 2.4 to 18.4; P = .0002) compared with children (1.0-9.9 years), whereas adults had increased odds of only persisting complications (OR, 4.1; 95% CI, 1.4 to 11.8; P = .01). Fifteen of 34 asparaginase-rechallenged patients developed a second AAP. Asparaginase was truncated in 17/21 patients with AAP who subsequently developed leukemic relapse, but neither AAP nor the asparaginase truncation was associated with increased risk of relapse. CONCLUSION: Older children and adults had similar AAP risk, whereas morbidity was most pronounced among adolescents. Asparaginase re-exposure should be considered only for patients with an anticipated high risk of leukemic relapse, because multiple studies strongly indicate that reduction of asparaginase treatment intensity increases the risk of relapse.
Assuntos
Asparaginase/administração & dosagem , Pancreatite/epidemiologia , Polietilenoglicóis/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Adolescente , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Asparaginase/efeitos adversos , Criança , Pré-Escolar , Estônia/epidemiologia , Feminino , Humanos , Incidência , Lactente , Lituânia/epidemiologia , Masculino , Pessoa de Meia-Idade , Pancreatite/induzido quimicamente , Polietilenoglicóis/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Países Escandinavos e Nórdicos/epidemiologia , Adulto JovemRESUMO
INTRODUCTION: Known genetic variants with reference to preeclampsia only explain a proportion of the heritable contribution to the development of this condition. The association between preeclampsia and the risk of cardiovascular disease later in life has encouraged the study of genetic variants important in thrombosis and vascular inflammation also in relation to preeclampsia. The von Willebrand factor-cleaving protease, ADAMTS13, plays an important role in micro vascular thrombosis, and partial deficiencies of this enzyme have been observed in association with cardiovascular disease and preeclampsia. However, it remains unknown whether decreased ADAMTS13 levels represent a cause or an effect of the event in placental and cardiovascular disease. METHODS: We studied the distribution of three functional genetic variants of ADAMTS13, c.1852C>G (rs28647808), c.4143_4144dupA (rs387906343), and c.3178C>T (rs142572218) in women with preeclampsia and their controls in a nested case-control study from the second Nord-Trøndelag Health Study (HUNT2). We also studied the association between ADAMTS13 activity and preeclampsia, in serum samples procured unrelated in time of the preeclamptic pregnancy. RESULTS: No differences were observed in genotype, allele or haplotype frequencies of the different ADAMTS13 variants when comparing cases and controls, and no association to preeclampsia was found with lower levels of ADAMTS13 activity. CONCLUSION: Our findings indicate that ADAMTS13 variants and ADAMTS13 activity do not contribute to an increased risk of preeclampsia in the general population.