RESUMO
The consensus panel 2 (CP2) of the 11th International Workshop on Waldenström's macroglobulinemia (IWWM-11) has reviewed and incorporated current data to update the recommendations for treatment approaches in patients with relapsed or refractory WM (RRWM). The key recommendations from IWWM-11 CP2 include: (1) Chemoimmunotherapy (CIT) and/or a covalent Bruton tyrosine kinase (cBTKi) strategies are important options; their use should reflect the prior upfront strategy and are subject to their availability. (2) In selecting treatment, biological age, co-morbidities and fitness are important; nature of relapse, disease phenotype and WM-related complications, patient preferences and hematopoietic reserve are also critical factors while the composition of the BM disease and mutational status (MYD88, CXCR4, TP53) should also be noted. (3) The trigger for initiating treatment in RRWM should utilize knowledge of patients' prior disease characteristics to avoid unnecessary delays. (4) Risk factors for cBTKi related toxicities (cardiovascular dysfunction, bleeding risk and concurrent medication) should be addressed when choosing cBTKi. Mutational status (MYD88, CXCR4) may influence the cBTKi efficacy, and the role of TP53 disruptions requires further study) in the event of cBTKi failure dose intensity could be up titrated subject to toxicities. Options after BTKi failure include CIT with a non-cross-reactive regimen to one previously used CIT, addition of anti-CD20 antibody to BTKi, switching to a newer cBTKi or non-covalent BTKi, proteasome inhibitors, BCL-2 inhibitors, and new anti-CD20 combinations are additional options. Clinical trial participation should be encouraged for all patients with RRWM.
Assuntos
Antineoplásicos , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética , Fator 88 de Diferenciação Mieloide/genética , Consenso , Recidiva Local de Neoplasia/induzido quimicamente , Recidiva Local de Neoplasia/tratamento farmacológico , Antineoplásicos/uso terapêuticoRESUMO
Heparanase, endo-beta-D-glucuronidase, degrades heparan sulfate glycosaminoglycans - the principal polysaccharide of the basement membrane and extracellular matrix. Heparanase activity plays a decisive role in biological processes associated with remodeling of the extracellular matrix, such as cancer metastasis, angiogenesis and inflammation. In the hematopoietic system, heparanase is thought to be associated with normal differentiation and function of myeloid cells and platelets. We investigated heparanase polymorphisms in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), Hodgkin's disease (HD) and multiple myeloma (MM). Significant correlation was found between rs11099592 and rs6535455 heparanase gene (HPSE) single nucleotide polymorphisms (SNPs) and ALL (chi2(1d.f.)=4.96, P=0.026). Genotype frequency comparisons revealed a significant association with rs4693602 (chi2(2d.f.)=7.276, P=0.026) in MM patients and rs4364254 (chi2(2d.f.)=6.226, P=0.044) in AML patients. Examination of HPSE gene mRNA expression by real-time RT-PCR indicated a significant low HPSE gene expression level in ALL patients and a high expression level in MM and AML patients, compared to healthy controls. Moreover, statistically significant correlation was found between heparanase mRNA expression level and three HPSE gene SNPs (rs4693608, rs11099592 and rs4364254) among healthy individuals. These data suggest that certain HPSE gene SNPs may contribute to basal heparanase gene expression and that alterations in this gene are an important determinant in the pathogenesis of ALL, AML and MM.
Assuntos
Regulação Neoplásica da Expressão Gênica , Glucuronidase/genética , Neoplasias Hematológicas/genética , Polimorfismo de Nucleotídeo Único , Alelos , Matriz Extracelular/metabolismo , Frequência do Gene , Doença de Hodgkin/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Modelos Genéticos , Mieloma Múltiplo/genética , Síndromes Mielodisplásicas/genética , Polimorfismo de Fragmento de RestriçãoRESUMO
OBJECTIVE: Deximune soft-gelatin capsules (Dexcel Ltd., Hadera, Israel), the test preparation and Sandimmun Neoral (Novartis Inc., Basel, Switzerland), the reference preparation, are two cyclosporine (CyA) formulations widely used after stem cells and solid organ transplantation. A post-marketing, retrospective, parallel, comparative, multicenter survey study in transplant patients receiving these two formulations after transplantation was carried out in order to compare the toxicity profile and bioavailability. MATERIALS AND METHODS: The study was conducted in the five main leading transplantation centers in Israel and included 174 patients. A total of 1-3 CyA serum levels at different periods after transplantation were measured in each subject and the bioavailability, efficacy and toxicity profile were assessed. The blood concentrations were compared using a statistical model after adjustment for type of transplantation, dose and time after transplantation as confounding factors. RESULTS: No distinct differences were observed between the two CyA formulations. Using model-derived least squares means (LSM) of the CyA blood levels and adjusting for relevant confounding factors, no significant difference could be found between the blood levels of the test and reference formulations. Most of the side effects were mild and transient with both formulations, whereas 23% of the patients reported serious adverse events (mainly hypertension, 15%). 20% of the patients developed infectious complications during the therapy. CONCLUSIONS: Deximune administration is safe. The toxicity profile of the product, incidence and type of side effects and bioavailability are similar to those of Sandimmun Neoral.
Assuntos
Ciclosporina/efeitos adversos , Ciclosporina/farmacocinética , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Transplante de Órgãos , Transplante de Células-Tronco , Adolescente , Adulto , Disponibilidade Biológica , Cápsulas , Criança , Pré-Escolar , Ciclosporina/sangue , Monitoramento de Medicamentos , Feminino , Gelatina , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/sangue , Lactente , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Halofuginone, a low molecular weight plant alkaloid, inhibits collagen alpha1 (I) gene expression in several animal models and in patients with fibrotic disease, including scleroderma and graft-versus-host disease. In addition, halofuginone has been shown to inhibit angiogenesis and tumor progression. It was demonstrated recently that halofuginone inhibits transforming growth factor-beta (TGF-beta), an important immunomodulator. The present study was undertaken to explore the effects of halofuginone on activated T cells. Peripheral blood T cells were activated by anti-CD3 monoclonal antibodies in the absence and presence of halofuginone and assessed for nuclear factor (NF)-kappaB activity, production of tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma), T cell apoptosis, chemotaxis, and phosphorylation of p38 mitogen-activated protein kinase (MAPK). A delayed-type hypersensitivity (DTH) model was applied to investigate the effect of halofuginone on T cells in vivo. Preincubation of activated peripheral blood T cells with 10-40 ng/ml halofuginone resulted in a significant dose-dependent decrease in NF-kappaB activity (80% inhibition following incubation with 40 ng halofuginone, P = 0.002). In addition, 40 ng/ml halofuginone inhibited secretion of TNF-alpha, IFN-gamma, interleukin (IL)-4, IL-13, and TGF-beta (P < 0.005). Similarly, halofuginone inhibited the phosphorylation of p38 MAPK and apoptosis in activated T cells (P = 0.0001 and 0.005, respectively). In contrast, T cell chemotaxis was not affected. Halofuginone inhibited DTH response in mice, indicating suppression of T cell-mediated inflammation in vivo. Halofuginone inhibits activated peripheral blood T cell functions and proinflammatory cytokine production through inhibition of NF-kappaB activation and p38 MAPK phosphorylation. It also inhibited DTH response in vivo, making it an attractive immunomodulator and anti-inflammatory agent.
Assuntos
NF-kappa B/metabolismo , Quinazolinas/farmacologia , Linfócitos T/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Apoptose , Quimiotaxia , Citocinas/imunologia , Relação Dose-Resposta a Droga , Humanos , Ativação Linfocitária , Fosforilação , Piperidinas , Quinazolinonas , Transdução de Sinais , Linfócitos T/fisiologiaRESUMO
Multiple myeloma (MM) is a common hematological malignancy that has widespread manifestations in multiple organs, including bones and joints. This retrospective study aimed to evaluate the involvement of the temporomandibular joint (TMJ) in patients with MM. Consecutive subjects with a diagnosis of MM who presented to the oral and maxillofacial surgery clinic for routine evaluation between 2008 and 2014 were identified. Patients who had a computed tomography (CT) scan of the TMJs as part of their MM staging were included in the study. Outcome variables were the presence of TMJ myelomatous changes on CT and the presence of TMJ symptoms. Of the 88 patients included in the study, 28 demonstrated TMJ myelomatous lesions on CT scans and 10 patients complained of TMJ pain or dysfunction. The CT scans of seven of the 10 symptomatic patients demonstrated myelomatous involvement of the TMJ area. Myelomatous involvement of the TMJ is common in MM patients and the majority of lesions are asymptomatic. An MM patient complaining of temporomandibular symptoms is relatively highly likely to having a lesion in the TMJ. Diagnosing the myelomatous lesions in the TMJ is important for accurate hemato-oncologic staging and providing treatment without delay.
Assuntos
Mieloma Múltiplo/complicações , Transtornos da Articulação Temporomandibular/complicações , Transtornos da Articulação Temporomandibular/diagnóstico por imagem , Articulação Temporomandibular/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
Hypophosphatemia complicating parathyroidectomy for secondary hyperparathyroidism in renal failure is usually corrected by the oral or intravenous routes. We present a case in which those methods of treatment were not possible, and the phosphate was administered intraperitoneally. Phosphate was added as one molar sodium diphosphate solution to the dialysis fluid. In our case the procedure was well tolerated, phosphate blood levels were rapidly corrected, no alterations in calcium, magnesium or other parameters were detected and the patient was discharged in good condition. In selected cases of hungry bone syndrome after parathyroidectomy, intraperitoneal phosphate can be used safely.
Assuntos
Difosfatos/administração & dosagem , Paratireoidectomia/efeitos adversos , Diálise Peritoneal , Fosfatos/sangue , Adulto , Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , Soluções para Diálise , Difosfatos/uso terapêutico , Feminino , Humanos , Hiperparatireoidismo Secundário/cirurgia , Falência Renal Crônica/complicaçõesRESUMO
BACKGROUND: Behcet's disease (BD) is an inflammatory disorder of unknown cause, associated with vasculitis. Arterial or venous thrombosis occurs in about 25% of BD patients. Familial Mediterranean fever (FMF) is another inflammatory disorder, which stems from mutations in the FMF gene (MEFV) and shares a number of features with BD. OBJECTIVE: MEFV analysis in patients with BD suggests that mutated MEFV may act as a susceptibility gene in BD. We studied the rate and the clinical correlates of MEFV mutations in Israeli BD patients. METHODS: Included were 54 BD patients who satisfied the International Study Group criteria for BD. All BD patients were genotyped using polymerase chain reaction (PCR) and restriction enzyme analysis for the three most common MEFV mutations (M694V, V726A, and E148Q). The association between BD manifestations and MEFV alleles was analysed. RESULTS: Twenty-one BD patients were found to carry a single MEFV mutation and three additional patients were compound heterozygotes, a frequency significantly higher than that expected for ethnically matched healthy individuals. There were no statistically significant differences between carriers and non-carriers with respect to gender, frequency of HLA B5 antigen, cutaneous lesions, joint disease, and severity score. However, carriers did experience thrombosis more often [54% vs. 17%, p<0.005, odds ratio (OR) = 6.9, 95% confidence interval (CI) 1.75-26.9] and uveitis less often (20% vs. 40%, p<0.05, OR = 0.2, 95% CI 0.04-0.92). CONCLUSIONS: MEFV appears to be a susceptibility and modifier gene in BD.
Assuntos
Síndrome de Behçet/genética , Proteínas do Citoesqueleto/genética , Trombose Venosa/genética , Adulto , Alelos , Síndrome de Behçet/complicações , Síndrome de Behçet/etnologia , Feminino , Predisposição Genética para Doença , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Mutação , Pirina , Fatores de RiscoRESUMO
A multicentre study was undertaken to determine whether side effects induced by hypotensive drugs could be reduced by replacement with low dose captopril. There were 100 patients on combinations of drugs, including diuretics, beta-blocking agents, methyldopa, clonidine and vasodilators. A questionnarie to obtain information on quality of life was completed by the patients. Each patient had major drugs, possibly responsible for side effects, withdrawn. Captopril was added at an initial dose of 12.5 up to 25 mg b.i.d. and titrated to a maximum of 50 mg t.i.d., until the blood pressure was equal to or lower than the level on entry into the study. Blood pressure was measured every two weeks and questionnaries were completed a number of times during the treatment period and scored at random, not in chronological order. A marked drop in blood pressure was obtained: mean systolic blood pressure went down from 173.4 +/- 2 to 154.5 +/- 2 mm Hg and diastolic blood pressure dropped from 104.5 +/- 11 to 9l.5 +/- 12 mm Hg. Neither tachycardia nor orthostasis was observed. Side effects, including inability to concentrate, nightmares, dizziness and sexual dysfunction, were reduced in 36% of the patients. Captopril itself produced no significant additional adverse reactions. It is concluded that captopril is a safe and effective drug, which can replace antihypertensive drugs that have deleterious side effects.
Assuntos
Captopril/uso terapêutico , Hipertensão/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Platelets are intimately involved in atherosclerosis, and hypertension is a known risk factor for coronary artery disease. The angiotensin-converting enzyme (ACE) inhibitors were demonstrated to reduce hypertension and attenuate atherosclerosis. Because increased platelet aggregation was shown in hypertensive patients, the effect of a new ACE inhibitor, fosinopril, on platelet aggregation was studied. Fosinopril therapy (10 mg/day for 4 weeks) in 18 male hypertensive patients showed > or = 31% reduction in ADP-induced platelet aggregation. In vitro studies showed that fosinopril had similar inhibitory effect on ADP-induced platelet aggregation. No inhibitory effect could be detected with collagen as the aggregating agent. Finally, inhibition of platelet aggregation by fosinopril was less effective in platelets derived from hypertensive patients as compared with platelets derived from normal subjects. We conclude that fosinopril possesses a significant inhibitory activity on ADP-induced platelet aggregation both in vitro and in vivo.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Plaquetas/efeitos dos fármacos , Fosinopril/farmacologia , Hipertensão/sangue , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Difosfato de Adenosina/sangue , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Fosinopril/uso terapêutico , Humanos , Hipertensão/tratamento farmacológico , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêuticoRESUMO
BACKGROUND: Venous and arterial thromboses occur in patients with Behçet's disease and are associated with significant morbidity and mortality. Studies on a possible association between the occurrence of thrombosis and thrombophilia in patients with this disease have been controversial. OBJECTIVE: To determine the prevalence of the most common thrombophilias and dyslipidaemia in patients with Behçet's disease with and without thrombosis. METHODS: Blood samples from 107 patients with Behçet's disease who had or did not have thrombosis were analysed for factor V Leiden, prothrombin G20210A polymorphism, methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, factor VIII level, homocysteine and C reactive protein concentrations, dyslipidaemia, and plasma glucosylceramide. RESULTS: There was no difference between patients with and without thrombosis in the prevalence of prothrombin G20210A polymorphism, factor V Leiden, homozygous MTHFR C677T, or plasma concentrations of homocysteine, C reactive protein, or glucosylceramide. In contrast, patients with thrombosis were found to have significantly higher mean levels of factor VIII, total cholesterol, triglycerides, VLDL cholesterol, and apolipoproteins B-100, C-II, and C-III than those without thrombosis. Multistepwise logistic regression analysis showed that triglyceride concentration was the best marker associated with thrombosis (p = 0.008), with an estimated odds ratio of 1.58 (95% confidence interval, 1.09 to 2.30) for a difference of 40 mg/dl. CONCLUSIONS: Thrombophilia does not seem to play a major role in the tendency to thrombosis in Behçet's disease. However, dyslipidaemia, predominantly hypertriglyceridaemia, might be a risk factor.