RESUMEN
INTRODUCTION: Adults with acute myeloid leukemia (AML) have a high rate of remission; however, more than 50% relapse. C-kit is expressed in approximately 60% of patients with de novo AML and represents a potential therapeutic target. MATERIALS AND METHODS: Patients with newly diagnosed AML received 12 months of imatinib mesylate as maintenance therapy after the completion of post-remission therapy. The primary objective was to determine whether this approach improved progression-free survival (defined as no relapse and no death) compared with historical controls. RESULTS: The median progression-free survival of patients < 60 years of age was 52.1 months (historical control, 13 months) and for patients ≥ 60 years of age was 10.7 months (historical control, 8 months). The median level of AF1q expression was high (9.59), and 84% of patients had moderate or high levels of drug-resistance factors. CONCLUSIONS: Imatinib maintenance therapy may improve the outcome of newly diagnosed patients with AML who are < 60 years of age.
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Mesilato de Imatinib/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Mesilato de Imatinib/efectos adversos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Quimioterapia de Mantención/métodos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas c-kit/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Previous studies suggest isolated distal deep vein thrombosis (IDDVT) has a self-limited clinical course. However, these studies excluded cancer patients, who remain a high-risk population. In addition, studies to evaluate the long-term clinical outcomes of IDDVT in cancer patients have been limited. Here, we report outcomes from our experience in treating cancer-associated IDDVT versus proximal venous thromboembolism (VTE). METHODS: We prospectively evaluated a cohort of patients referred to our cancer-associated thrombosis clinic from August 2014 through May 2018. We compared clinical characteristics, anticoagulation prescription, VTE recurrence, overall survival, major bleeding, and subsequent hospital admission between cancer patients with IDDVT and proximal VTE. A propensity score matching method was used to reduce bias from confounding variables. RESULTS: Of 1100 patients referred to the clinic, 124 IDDVT and 178 proximal VTE events were analyzed. After propensity score matching, 96 patients were included in each cohort. There was no difference in the rate of recurrent VTE between cancer patients with proximal VTE vs IDDVT, with or without matching (matched: hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.31-1.92; P = .58). There was no difference in overall survival between cancer patients with proximal VTE vs. IDDVT with or without matching (matched: HR, 1.18; 95% CI, 0.77-1.82; P = .45). Furthermore, subsequent hospital admissions and major bleeding events were similar between patients with proximal VTE events versus IDDVT. CONCLUSIONS: Cancer patients with IDDVT have similar outcomes as their proximal counterparts, including rate of recurrence and overall survival. These findings suggest treatment of cancer-associated IDDVT should mirror treatment of proximal events.
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Neoplasias , Tromboembolia Venosa , Trombosis de la Vena , Anticoagulantes/uso terapéutico , Coagulación Sanguínea , Hemorragia , Humanos , Neoplasias/complicaciones , Recurrencia , Factores de Riesgo , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/tratamiento farmacológicoAsunto(s)
Anticoagulantes/uso terapéutico , Neoplasias/complicaciones , Tromboembolia Venosa/tratamiento farmacológico , Tromboembolia Venosa/etiología , Anciano , Instituciones de Atención Ambulatoria/economía , Anticoagulantes/economía , Femenino , Costos de la Atención en Salud , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Tromboembolia Venosa/economíaRESUMEN
BACKGROUND: Myelodysplastic syndrome (MDS) continues to cause major morbidity and mortality; thus, novel treatments are needed. The mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) inhibits cellular pathways important to MYC protein stability and cell growth. Pharmacodynamic biomarkers could be useful in distinguishing between (1) disease resistance that occurs even though mTOR is successfully inhibited (suggesting a need for a different treatment strategy) and (2) resistance that might respond to changes in drug dosage or schedule. PATIENTS AND METHODS: This was a small phase II trial of RAD001 in patients with low- and intermediate-1-risk MDS (n = 7). Protein S6K1 (S6) is downstream of mTOR, whereas protein kinase B (AKT) is upstream of mTOR. Therefore, to evaluate the pharmacodynamic effects of RAD001, S6 and AKT phosphorylation (pS6, pAKT) were measured by peripheral blood flow cytometry. RESULTS: Sequential weeks of RAD001 produced a decrease in pS6, whereas pAKT was maintained or increased. There were no clinical responses despite the biomarker evidence of intended pharmacodynamic effect. CONCLUSION: The pS6:pAKT ratio could be useful as a biomarker of target inhibition by RAD001 (clinicaltrials.gov identifier: NCT00809185).
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Biomarcadores/metabolismo , Síndromes Mielodisplásicos/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas S6 Ribosómicas/metabolismo , Sirolimus/análogos & derivados , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Esquema de Medicación , Disnea/inducido químicamente , Everolimus , Fatiga/inducido químicamente , Femenino , Fiebre/inducido químicamente , Citometría de Flujo , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/metabolismo , Neutropenia/inducido químicamente , Fosforilación/efectos de los fármacos , Sirolimus/efectos adversos , Sirolimus/farmacología , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/metabolismo , Resultado del TratamientoRESUMEN
The c-kit receptor is expressed in 95% of relapsed acute myeloid leukemias (AMLs) and mediates leukemic proliferation. We conducted a Phase 1 study of the c-kit inhibitor, imatinib mesylate (IM), in combination with cytarabine and daunorubicin (7+3) in c-kit+ relapsed AML. IM was dose escalated using a 3 by 3 design. Phosphorylated STAT5 was absent to minimally present in residual blasts on day 14 bone marrows. The maximum tolerated dose of IM was 300 mg. The dose-limiting toxicity was Grade 3-4 hepatic toxicity. The CR/CRp rate was 57%. Cytotoxic therapy that includes IM for relapsed AML is well-tolerated and effective.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Mieloide Aguda/prevención & control , Proteínas Proto-Oncogénicas c-kit , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzamidas , Citarabina/administración & dosificación , Citarabina/efectos adversos , Daunorrubicina/administración & dosificación , Daunorrubicina/efectos adversos , Femenino , Humanos , Mesilato de Imatinib , Leucemia Mieloide Aguda/metabolismo , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Fosforilación/efectos de los fármacos , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Recurrencia , Factor de Transcripción STAT5/metabolismoRESUMEN
We evaluated patients with newly diagnosed ALL treated at the Cleveland Clinic during the years 1996 through 2005. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of complete remission, overall survival and progression-free survival. On univariate analysis, significant prognostic factors included: age at diagnosis (per 10-year increase), poor risk cytogenetics, time to white blood count recovery, and time from induction chemotherapy (IC) to post-remission therapy (PRT). In patients age <60 years without poor risk cytogenetics, time from IC to PRT (per week increase) was a significant prognostic factor by multivariate analysis and was associated with a decreased progression-free survival [HR 1.27, CI (1.04-1.55), p = 0.019] and decreased overall survival [HR 1.34, CI (1.08-1.67), p = 0.009]. Delayed time from IC to PRT (> or =6.6 weeks) was associated with a statistically worse progression-free and overall survival.
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Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Adolescente , Adulto , Factores de Edad , Anciano , Análisis Citogenético , Humanos , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Inducción de Remisión , Estudios Retrospectivos , Análisis de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Cytogenetic analysis at the time of diagnosis predicts outcome in patients with acute myelogenous leukemia (AML). For those patients with favorable risk cytogenetics, stem cell transplant can be delayed until the time of relapse. For those patients with nonfavorable cytogenetic risk profiles, stem cell transplant may be required for optimal survival benefit. We treated patients with de novo AML and age less than 60 years first with etoposide, mitoxantrone, cytarabine, and G-CSF (EMA-G) to induce remission. Patients in complete remission were assigned to treatment with chemotherapy alone if they had favorable risk cytogenetics defined as the identification of a core-binding factor translocation. Patients with any other cytogenetic profile were assigned to treatment with either autologous or allogeneic stem cell transplant depending on the availability of an HLA-matched donor. Following EMA-G, 33 of 40 patients (83%) achieved CR. Of the 25 patients who actually were treated with postremission chemotherapy, 21 were treated with their assigned risk-adapted therapy. Of the 33 patients in remission, 5 year relapse-free survival (RFS) and overall survival (OS) was 46 and 38%, respectively. Our intensive and risk-adapted, stem cell transplant approach to the treatment of patients with AML requires a better definition of risk and does not appear to substantially improve results compared with more standard approaches.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Aberraciones Cromosómicas/clasificación , Estudios de Cohortes , Terapia Combinada , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Esquema de Medicación , Etopósido/administración & dosificación , Femenino , Humanos , Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Inducción de Remisión/métodosRESUMEN
C-kit, a tyrosine kinase receptor, is expressed on most myeloid blasts and is thought to be important in the pathogenesis of AML. Activation of the c-kit receptor leads to phosphorylation and activation of downstream signaling proteins, which are important for cell survival and proliferation. Here, we discuss the prognostic impact of c-kit intensity, measured using the mean fluorescent index (MFI) in patients with newly diagnosed AML. On multivariate analysis, c-kit MFI>20.3 correlated with a decreased progression-free survival and overall survival, independent of known prognostic factors (age, white blood count at diagnosis and cytogenetics). Whether inhibiting c-kit in patients with AML will alter prognosis is the basis of ongoing clinical trials.
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Citometría de Flujo , Leucemia Mieloide Aguda/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Adolescente , Adulto , Anciano , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Fluorescencia , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Telmisartan, a highly selective angiotensin-II-receptor antagonist, used for the treatment of hypertension, acts as a partial agonist of the PPAR-gamma (peroxisome proliferator-activated receptor-gamma) receptor, which is involved in the regulation of glucose and lipid metabolism. In the present study the effect of Telmisartan on hypertension, parameters of glucose and lipid metabolism was investigated in 670 patients with the metabolic syndrome. There was a significant (p < 0,05) improvement regarding all parameters involved in the diagnosis of the metabolic syndrome, namely hypertension (systolic: 161,7 +/- 16,3 vs. 136,7 +/- 11,7 mmHg, diastolic: 93,3 +/- 10,1 vs. 80,7 +/- 10,5 mmHg), fasting blood glucose (133,2 +/- 44,1 vs. 116,0 +/- 31,5 mg/dl), triglycerides (227,2 +/- 170,1 vs. 187,8 +/- 94,8 mg/dl), HDL-cholesterin (women: 48,9 +/- 13,1 vs. 51,8 +/- 12,9 mg/dl) and abdominal circumference (women: 101,2 +/- 12,4 vs. 99,3 +/- 12,9 mg/dl, men: 111,9 +/- 14,7 vs. 109,5 +/- 14,4 mg/dl). The number of patients diagnosed with the metabolic syndrome was significantly reduced over the 3 months study duration (38%). The medication was well tolerated and adverse effects were minimal. Thus, Telmisartan can be regarded as an appropriate medication for the therapy of hypertension in patients with the metabolic syndrome with possible additive effects on parameters of glucose and lipid metabolism.
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Bencimidazoles/administración & dosificación , Benzoatos/administración & dosificación , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/epidemiología , Medición de Riesgo/métodos , Anciano , Antihipertensivos/uso terapéutico , Austria/epidemiología , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Atención Primaria de Salud/estadística & datos numéricos , Factores de Riesgo , Telmisartán , Resultado del TratamientoRESUMEN
Obesity is a chronic disease with a worldwide increasing incidence. The mainstay of therapy consists in modification of behaviour related to obesity such as overeating and physical inactivity. When these life-style modifying attempts fail, the use of anti-obesity drugs is warranted. The two available drugs, orlistat and sibutramine, are capable of reducing body weight by 10%. Failure of these medications in a subset of patients to achieve adequate weight loss and limited overall efficacy have led to an extensive research on novel anti-obesity agents. This review presents an overview on the current drugs available as well as on potential future candidates.
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Depresores del Apetito/uso terapéutico , Obesidad/tratamiento farmacológico , Depresores del Apetito/efectos adversos , Peso Corporal/efectos de los fármacos , Ensayos Clínicos como Asunto , Ciclobutanos/efectos adversos , Ciclobutanos/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Humanos , Lactonas/efectos adversos , Lactonas/uso terapéutico , Orlistat , Respuesta de Saciedad/efectos de los fármacos , Resultado del TratamientoRESUMEN
Obesity is a chronic disease with a worldwide increasing incidence. The mainstay of therapy consists in modification of behaviour related to obesity such as overeating and physical inactivity. When these life-style modifying attempts fail, the use of anti-obesity drugs is warranted. Public health efforts and current anti-obesity agents have not controlled the increasing epidemic of obesity, which has led to an extensive research on novel anti-obesity agents. This review presents an overview on potential future candidates.