RESUMEN
BACKGROUND: Hydroxyethyl starch (HES) is reportedly associated with an increased risk of renal failure and death when used for fluid resuscitation in critically ill patients. HES can be used during therapeutic leukocytapheresis (TL) procedures to enhance cell separation. The purpose of this study was to evaluate the occurrence of adverse events associated with HES during TL procedures. STUDY DESIGN AND METHODS: We performed a retrospective review of patients who underwent TL with and without HES in the period 2009 to 2013 at six academic medical institutions. RESULTS: A difference-in-difference regression analysis was used to estimate the mean change before and after TL in selected outcomes in the HES group relative to the average change in the non-HES group. Selected outcomes included serum creatinine, estimated glomerular filtration rate (eGFR), and white blood cell (WBC) count. A total of 195 patients who underwent 278 TL procedures were studied. We found no significant differences in serum creatinine levels and eGFR on Days 1 and 7 after TL procedure between patients who received and those who did not receive HES. The rate of adverse events and overall and early mortality were similar in both groups. Patients with acute myeloid leukemia who received HES had greater WBC reduction when HES was used. Additionally, patients who received HES had improvement in pulmonary leukostasis symptoms. CONCLUSION: HES, used at low doses during TL procedures, was not associated with adverse events previously ascribed to its use as a volume expander.
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Lesión Renal Aguda/etiología , Derivados de Hidroxietil Almidón/efectos adversos , Leucaféresis/métodos , Creatinina/sangre , Femenino , Tasa de Filtración Glomerular , Humanos , Leucemia Mieloide Aguda/terapia , Recuento de Leucocitos , Leucostasis , Masculino , Persona de Mediana Edad , Sustitutos del Plasma/efectos adversos , Estudios RetrospectivosRESUMEN
Plasmablastic lymphoma (PBL) is a challenging diagnosis given its rarity and lack of expression of markers that are usually used by pathologists in establishing hematopoietic lineage. However, knowledge of the characteristic clinical setting, sites of involvement, and morphologic features of plasmablastic lymphoma can aid in the correct diagnosis of a suspected large cell lymphoma that is negative for B-cell- and T-cell-specific antigens. Herein, we review the clinical and pathologic features of plasmablastic lymphoma with an emphasis on the differential diagnosis of hematolymphoid neoplasms with immunoblastic morphology and/or evidence of plasmacytic differentiation by immunophenotype.
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Linfocitos B/patología , Células Plasmáticas/patología , Linfoma Plasmablástico/diagnóstico , Antígenos CD20/metabolismo , Linfocitos B/metabolismo , Diagnóstico Diferencial , Humanos , Inmunofenotipificación , Factor de Transcripción PAX5/metabolismo , Células Plasmáticas/metabolismo , Linfoma Plasmablástico/metabolismo , Linfoma Plasmablástico/terapia , Pronóstico , Análisis de SupervivenciaRESUMEN
B-cell non-Hodgkin lymphomas with plasmacytic differentiation are a diverse group of entities with extremely variable morphologic features. Diagnostic challenges can arise in differentiating lymphoplasmacytic lymphoma from marginal zone lymphoma and other low-grade B-cell lymphomas. In addition, plasmablastic lymphomas can be difficult to distinguish from diffuse large B-cell lymphoma or other high-grade lymphomas. Judicious use of immunohistochemical studies and molecular testing can assist in appropriate classification.
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Linfoma de Células B/diagnóstico , Macroglobulinemia de Waldenström/diagnóstico , Diagnóstico Diferencial , Humanos , Inmunofenotipificación , Linfoma de Células B/inmunología , Linfoma de Células B/patología , Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma de Células B de la Zona Marginal/inmunología , Linfoma de Células B de la Zona Marginal/patología , Plasmacitoma/diagnóstico , Plasmacitoma/inmunología , Plasmacitoma/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Macroglobulinemia de Waldenström/inmunología , Macroglobulinemia de Waldenström/patologíaRESUMEN
Langerhans cell histiocytosis (LCH) comprises a wide spectrum of clinical disorders that have in common a proliferation of Langerhans-type cells with characteristic morphologic, immunophenotypic, and ultrastructural features. In part because of the diverse clinical manifestations of LCH, there has long been controversy over whether LCH is best considered a reactive process or a neoplasm. Herein, we discuss the clinical and pathologic features of LCH, including recent advances in the understanding of the molecular pathogenesis of this disease that support its categorization as a neoplasm. We also review the implications that these recently described molecular characteristics may have on risk stratification and treatment of LCH.
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Histiocitosis de Células de Langerhans/diagnóstico , Células de Langerhans/patología , Antígenos CD1/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Diagnóstico Diferencial , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/metabolismo , Humanos , Células de Langerhans/metabolismo , MAP Quinasa Quinasa 1/genética , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas S100/metabolismoRESUMEN
BACKGROUND: Widespread reports of high stress levels and mental health problems among university student populations indicate the use of interventions to facilitate stress reduction and support student resilience and wellbeing. There is growing evidence that regular mindfulness practice may confer positive health benefits and reduced stress levels. OBJECTIVES: The aim of this pilot project was to explore the impact of a seven-week stress management and mindfulness program as a learning support and stress reduction method for nursing and midwifery students. SETTING: The program was conducted at a large regional university in Australia. PARTICIPANTS: Fourteen first-year undergraduate nursing and midwifery students agreed to attend the program and to participate in a follow-up focus group. METHOD AND DESIGN: A descriptive qualitative design was utilised to examine the impact of the program. A semi-structured focus group interview was conducted with a thematic analysis undertaken of the transcript and process notes. RESULTS: Ten students completed the research component of this project by participating in the focus group interview. Three main themes capture the participants' experience: attending to self, attending to others and attending to program related challenges. Data indicate a positive impact on sleep, concentration, clarity of thought and a reduction in negative cognitions. Participants also identified challenges related to timetabling, program structure and venue. CONCLUSIONS: Overall, this pilot program enhanced the participants' sense of well-being. Despite the challenges, benefits were identified on a personal and professional level. Valuable feedback was provided that will be used to further develop and expand stress management and mindfulness programs offered to students attending this university.
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Bachillerato en Enfermería , Retroalimentación , Atención Plena/educación , Estrés Psicológico , Estudiantes de Enfermería/psicología , Adulto , Australia , Femenino , Grupos Focales , Humanos , Persona de Mediana Edad , Partería/educación , Investigación en Educación de Enfermería , Proyectos Piloto , Investigación Cualitativa , Adulto JovenRESUMEN
OBJECTIVE: Patients with nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) have poorer survival than those with functional PNETs. Our objective was to identify risk factors for recurrence after resection to better define surveillance parameters to improve long-term outcomes. METHODS: A retrospective analysis was performed for NF-PNET patients who underwent resection at the University of Michigan from 1995 to 2012. Immunohistochemical staining of tissues from patients with and without disease recurrence was performed for Ki-67 and the macrophage marker CD68, as tumor-associated macrophages are important for PNET development and progression. Clinicopathological factors and patient outcomes were measured. RESULTS: Ninety-seven NF-PNET patients underwent surgical resection. There was a recurrence rate of 14.4% (14/97). The median time to recurrence was 0.61 years, with 10 (71%) patients recurring within the first 2 years. Six of 7 patients (86%) monitored at 6-month surveillance intervals were diagnosed with recurrence on their first computed tomographic scan or during the intervening intervals. By Cox proportional hazards analysis, the most significant independent risk factors for recurrence were higher grade, stage, and intraoperative blood loss. High CD68 score and Ki-67 index correlated with recurrence risk, and Ki-67 index inversely correlated with time to recurrence. In patients who otherwise had few risk factors, a high CD68 score was a significant prognostic factor for recurrence. CONCLUSIONS: In patients with NF-PNETs, risk factors associated with recurrence were high EBL, grade, stage, CD68 score, and Ki-67 index. The CD68 score was an important prognostic factor in patients who otherwise had few clinicopathological risk factors; therefore, the CD68 score should be considered when planning surveillance strategies. We recommend that NF-PNET patients at high risk of recurrence undergo initial surveillance every 3 months for 2 years after surgery.
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Biomarcadores de Tumor/metabolismo , Macrófagos/patología , Recurrencia Local de Neoplasia/diagnóstico , Pancreatectomía , Neoplasias Pancreáticas/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Colangiopancreatografia Retrógrada Endoscópica , Endosonografía , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Incidencia , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/metabolismo , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Pronóstico , Estudios Retrospectivos , Factores de Tiempo , Tomografía Computarizada por Rayos X , Estados Unidos/epidemiología , Adulto JovenRESUMEN
PURPOSE: We investigated potential biomarkers of efficacy in a phase III trial of sunitinib versus interferon-alpha (IFN-α), first-line in metastatic renal cell carcinoma (mRCC), by analyzing plasma levels of vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGF receptor-3 (sVEGFR-3) and interleukin (IL)-8. METHODS: Seven hundred and fifty mRCC patients were randomized to oral sunitinib 50 mg/day in repeated cycles of a 4-week on/2-week off schedule or IFN-α 9 million units subcutaneously thrice weekly. Plasma samples collected from a subset of 63 patients on days 1 and 28 of cycles 1-4 and at end of treatment were analyzed by ELISA. RESULTS: Baseline characteristics of biomarker-evaluated patients in sunitinib (N = 33) and IFN-α (N = 30) arms were comparable to their respective intent-to-treat populations. By univariate Cox regression analysis, low baseline soluble protein levels were associated with lower risk of progression/death (all P < 0.05): in both treatment arms, baseline VEGF-A and IL-8 were associated with overall survival (OS) and baseline VEGF-C with progression-free survival (PFS); in the sunitinib arm, baseline VEGF-A was associated with PFS and baseline sVEGFR-3 with PFS and OS; in the IFN-α arm, baseline IL-8 was associated with PFS. In multivariate analysis, baseline sVEGFR-3 and IL-8 remained independent predictors of OS in the sunitinib arm, while no independent predictors of outcome remained in the IFN-α arm. Pharmacodynamic changes were not associated with PFS or OS for any plasma protein investigated. CONCLUSIONS: Our findings suggest that, in mRCC, baseline VEGF-A and IL-8 may have prognostic value, while baseline sVEGFR-3 may predict sunitinib efficacy.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/uso terapéutico , Interferón-alfa/uso terapéutico , Interleucina-8/sangre , Neoplasias Renales/tratamiento farmacológico , Pirroles/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 3 de Factores de Crecimiento Endotelial Vascular/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Carcinoma de Células Renales/sangre , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/secundario , Femenino , Humanos , Neoplasias Renales/sangre , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , SunitinibRESUMEN
BACKGROUND: Sunitinib inhibits vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors, and stem cell factor receptor (KIT). The ability of soluble (s)KIT, VEGF-A, sVEGFR-2, and sVEGFR-3 to predict clinical outcome was analyzed in 61 patients with previously treated metastatic breast cancer (MBC) in a phase II study of sunitinib monotherapy (ClinicalTrials.gov NCT00078000). METHODS: Plasma concentrations of soluble proteins were measured at baseline and during treatment with sunitinib 50 mg/day (4 weeks on treatment, 2 weeks off treatment). Baseline concentrations and maximal percent change during the first two treatment cycles were stratified by median values and evaluated for correlation with median time to tumor progression (TTP) and overall survival (OS). This latter fixed time period was chosen to avoid bias accruing from patients who were on study for longer periods of time. RESULTS: TTP was significantly longer in patients having median or higher maximal percent sKIT change compared with patients with less than the median change (21.7 vs. 7.9 weeks; p < 0.0001). Similarly, OS was significantly longer in patients having median or higher sKIT change versus less than the median change (53.7 vs. 25.7 weeks; p = 0.018). Significant prolongation of OS (62.6 vs. 32.3 weeks; p = 0.032), but not TTP, was observed in patients with a median or higher maximal percent VEGF-A change compared with less than the median change. Maximal percent change of sVEGFR-2 or sVEGFR-3 concentrations and baseline concentrations of all four proteins were not predictive of clinical outcome. CONCLUSIONS: This exploratory analysis suggests that changes in sKIT and possibly VEGF-A early during sunitinib treatment may be predictive of clinical outcome in MBC.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/tratamiento farmacológico , Indoles/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/sangre , Pirroles/uso terapéutico , Adulto , Anciano , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Sunitinib , Resultado del TratamientoRESUMEN
PURPOSE: To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes. EXPERIMENTAL DESIGN: Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore cross-over impact. Circulating levels of angiogenesis biomarkers were analyzed. RESULTS: In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 vs. 64.9 weeks; HR, 0.876; P = 0.306) as expected, given the cross-over design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262-1.134; P = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome. CONCLUSIONS: The cross-over design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following cross-over, there was no statistical difference in OS. RPSFT analysis modeled the absence of cross-over, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events.
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Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Indoles/efectos adversos , Indoles/uso terapéutico , Pirroles/efectos adversos , Pirroles/uso terapéutico , Adulto , Anciano , Benzamidas , Biomarcadores de Tumor/sangre , Estudios Cruzados , Femenino , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Neovascularización Patológica/sangre , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Placebos , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Retratamiento , Sunitinib , Análisis de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Several proteins that promote angiogenesis are overexpressed in hepatocellular carcinoma (HCC) and have been implicated in disease pathogenesis. Sunitinib has antiangiogenic activity and is an oral multitargeted inhibitor of vascular endothelial growth factor receptors (VEGFRs)-1, -2, and -3, platelet-derived growth factor receptors (PDGFRs)-α and -ß, stem-cell factor receptor (KIT), and other tyrosine kinases. In a phase II study of sunitinib in advanced HCC, we evaluated the plasma pharmacodynamics of five proteins related to the mechanism of action of sunitinib and explored potential correlations with clinical outcome. METHODS: Patients with advanced HCC received a starting dose of sunitinib 50 mg/day administered orally for 4 weeks on treatment, followed by 2 weeks off treatment. Plasma samples from 37 patients were obtained at baseline and during treatment and were analyzed for vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGFR-2 (sVEGFR-2), soluble VEGFR-3 (sVEGFR-3), and soluble KIT (sKIT). RESULTS: At the end of the first sunitinib treatment cycle, plasma VEGF-A levels were significantly increased relative to baseline, while levels of plasma VEGF-C, sVEGFR-2, sVEGFR-3, and sKIT were significantly decreased. Changes from baseline in VEGF-A, sVEGFR-2, and sVEGFR-3, but not VEGF-C or sKIT, were partially or completely reversed during the first 2-week off-treatment period. High levels of VEGF-C at baseline were significantly associated with Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease control, prolonged time to tumor progression (TTP), and prolonged overall survival (OS). Baseline VEGF-C levels were an independent predictor of TTP by multivariate analysis. Changes from baseline in VEGF-A and sKIT at cycle 1 day 14 or cycle 2 day 28, and change in VEGF-C at the end of the first off-treatment period, were significantly associated with both TTP and OS, while change in sVEGFR-2 at cycle 1 day 28 was an independent predictor of OS. CONCLUSIONS: Baseline plasma VEGF-C levels predicted disease control (based on RECIST) and were positively associated with both TTP and OS in this exploratory analysis, suggesting that this VEGF family member may have utility in predicting clinical outcome in patients with HCC who receive sunitinib. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00247676.
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Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/tratamiento farmacológico , Proteínas de Neoplasias/sangre , Pirroles/uso terapéutico , Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma Hepatocelular/cirugía , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/cirugía , Masculino , Análisis Multivariante , Curva ROC , Sunitinib , Factores de Tiempo , Resultado del Tratamiento , Factor C de Crecimiento Endotelial Vascular/sangreRESUMEN
OBJECTIVES: Sunitinib is an oral, multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors with proven clinical benefit in patients with metastatic renal cell carcinoma (RCC). This phase I/II study investigated sunitinib in combination with an epidermal growth factor receptor inhibitor, gefitinib, in patients with metastatic RCC. METHODS: In phase I, patients received sunitinib 37.5 or 50 mg in 6-week cycles (4 weeks on treatment, 2 off) plus gefitinib 250 mg, both once daily, to determine the sunitinib maximum tolerated dose (MTD). Pharmacokinetics was assessed for both drugs. In phase II, patients received sunitinib MTD plus gefitinib to evaluate the safety and antitumor activity of this combination. RESULTS: Forty-two patients were enrolled: 11 in phase I, and 31 in phase II. In phase I, 2 dose-limiting toxicities were observed with sunitinib 50 mg (grade 2 left ventricular ejection fraction decline and grade 3 fatigue), and 37.5 mg was declared the MTD. Thirteen patients treated at the MTD achieved a partial response (objective response rate: 37%; 95% confidence interval, 22-55) and 12 (34%) had stable disease. Median progression-free survival was 11 months (95% confidence interval, 6-17). The most commonly reported grade 3/4 treatment-related adverse event was diarrhea (14%), the only grade 3/4 adverse event to occur in >2 patients. Pharmacokinetic analyses did not indicate any drug-drug interactions. CONCLUSIONS: In metastatic RCC, sunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapy with an acceptable safety profile. Dosing, pharmacokinetic profile, and safety support study of sunitinib plus an epidermal growth factor receptor inhibitor in other tumor types.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Renales/mortalidad , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Gefitinib , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Neoplasias Renales/mortalidad , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Pirroles/administración & dosificación , Pirroles/efectos adversos , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Sunitinib , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate changes in circulating levels of soluble KIT (sKIT) extracellular domain as a potential biomarker for clinical outcome in gastrointestinal stromal tumor patients treated with the multitargeted tyrosine kinase inhibitor sunitinib following imatinib failure in a previously reported phase III study. EXPERIMENTAL DESIGN: Patients received sunitinib 50 mg/d (n = 243) or placebo (n = 118) daily in 6-week cycles (4 weeks on, 2 weeks off treatment). Plasma sKIT levels were sampled every 2 weeks in cycle 1 and on days 1 and 28 of subsequent cycles; analyzed by ELISA; and evaluated using Prentice criteria, Cox proportional hazards models, and proportion of treatment effect (PTE) analysis. RESULTS: From 4 weeks on treatment and onward, significant differences were shown between treatment groups (P < 0.0001) in sKIT level changes from baseline (median levels decreased with sunitinib and increased with placebo). Decreases in sKIT levels were a significant predictor of longer time to tumor progression (TTP). Patients with reduced levels at the end of cycle 2 had a median TTP of 34.3 weeks versus 16.0 weeks for patients with increased levels [hazard ratio, 0.71; 95% confidence interval (95% CI), 0.61-0.83; P < 0.0001], and changes in sKIT levels replaced treatment as a stronger predictor of TTP (PTE, 0.80; 95% CI, 0.34-3.70), showing even greater surrogacy on cycle 3 day 1 (PTE, 0.98; 95% CI, 0.39-3.40). CONCLUSIONS: The results suggest that circulating plasma sKIT levels seem to function as a surrogate marker for TTP in gastrointestinal stromal tumor patients. Additional studies are warranted to confirm and expand these findings.
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Biomarcadores de Tumor/sangre , Tumores del Estroma Gastrointestinal/sangre , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Indoles/administración & dosificación , Proteínas Proto-Oncogénicas c-kit/sangre , Pirroles/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Mesilato de Imatinib , Indoles/farmacología , Masculino , Persona de Mediana Edad , Piperazinas/administración & dosificación , Proteínas Proto-Oncogénicas c-kit/genética , Pirimidinas/administración & dosificación , Pirroles/farmacología , Solubilidad , Sunitinib , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) tumour spread is partly dependent on neoangiogenesis. In this open-label, multicentre, phase II trial done in Europe and Asia, sunitinib, a multitargeted tyrosine-kinase inhibitor with anti-angiogenic properties, was assessed in patients with advanced unresectable HCC. METHODS: Between February and July, 2006, eligible patients were enrolled and treated with repeated cycles of oral sunitinib (50 mg/day for 4 weeks, followed by 2 weeks off treatment). The primary endpoint of this Simon two-stage phase II trial was objective response rate according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria, with an expected response rate of 15%. This trial is registered with ClinicalTrials.gov, number NCT00247676. FINDINGS: Of 37 patients enrolled, one (2.7%) patient experienced a confirmed partial response, giving an overall objective response rate of 2.7% (95% CI 0.1-14.2); on the basis of this, the trial did not proceed to the second stage. 13 (35%) of 37 patients achieved stable disease for over 3 months. Commonly observed grade 3 and 4 adverse events included thrombocytopenia (14 of 37; 37.8%), neutropenia (nine of 37; 24.3%), asthenia (five of 37; 13.5%), hand-foot syndrome (four of 37; 10.8%), and anaemia (four of 37; 10.8%). There were four deaths among the 37 patients (10.8%) that were possibly related to treatment. INTERPRETATION: Sunitinib showed pronounced toxicities at a dose of 50 mg/day in patients with unresectable HCC. The response rate was low, and the study did not meet the primary endpoint based on RECIST criteria. FUNDING: Pfizer Oncology.
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Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Pirroles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/mortalidad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , SunitinibRESUMEN
PURPOSE: To assess the safety and efficacy of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma (mRCC) and explore biomarkers for sunitinib response. PATIENTS AND METHODS: Patients with mRCC and disease progression after bevacizumab-based therapy received oral sunitinib 50 mg once daily in 6-week cycles on a 4/2 schedule (4 weeks with treatment followed by 2 weeks without treatment) in a phase II multicenter study. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), duration of response (DR), overall survival (OS), and safety. Plasma soluble proteins (vascular endothelial growth factor [VEGF]-A, VEGF-C, soluble VEGF receptor [sVEGFR]-3, and placental growth factor [PlGF]) levels were measured. RESULTS: Sixty-one patients were enrolled. The ORR was 23.0% (95% CI, 13.2% to 35.5%), median PFS was 30.4 weeks (95% CI, 18.3 to 36.7 weeks), median DR was 44.1 weeks (95% CI, 25.0 to 102.7 weeks), and median OS was 47.1 weeks (95% CI, 36.9 to 79.4 weeks). Mean plasma VEGF-A and PlGF levels significantly increased whereas VEGF-C and sVEGFR-3 levels decreased with sunitinib treatment. Lower baseline levels of sVEGFR-3 and VEGF-C were associated with longer PFS and ORR. Most treatment-related adverse events were of mild-to-moderate intensity and included fatigue, hypertension, and hand-foot syndrome. CONCLUSION: Sunitinib has substantial antitumor activity in patients with bevacizumab-refractory mRCC and modulates circulating VEGF pathway biomarkers. These data support the hypothesis that sunitinib inhibits signaling pathways involved in bevacizumab resistance. Baseline levels of sVEGFR-3 and VEGF-C may have potential utility as biomarkers of clinical efficacy in this setting.
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Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Biomarcadores de Tumor/sangre , Carcinoma de Células Renales/tratamiento farmacológico , Resistencia a Antineoplásicos , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Pirroles/uso terapéutico , Administración Oral , Adulto , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales Humanizados , Bevacizumab , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Neoplasias Renales/metabolismo , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Factor de Crecimiento Placentario , Proteínas Gestacionales/sangre , Estudios Prospectivos , Pirroles/administración & dosificación , Pirroles/efectos adversos , Sunitinib , Factores de Tiempo , Insuficiencia del Tratamiento , Estados Unidos , Factor A de Crecimiento Endotelial Vascular/sangre , Factor C de Crecimiento Endotelial Vascular/sangre , Receptor 3 de Factores de Crecimiento Endotelial Vascular/sangreRESUMEN
The discovery and structure-activity relationship of first-generation small-molecule malonyl-CoA decarboxylase (MCD; CoA = coenzyme A) inhibitors are reported. We demonstrated that MCD inhibitors increased malonyl-CoA concentration in the isolated working rat hearts. Malonyl-CoA is a potent, endogenous, and allosteric inhibitor of carnitine palmitoyltransferase-I (CPT-I), a key enzyme for mitochondrial fatty acid oxidation. As a result of the increase in malonyl-CoA levels, fatty acid oxidation rates were decreased and the glucose oxidation rates were significantly increased. Demonstration of in vivo efficacy of methyl 5-(N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)morpholine-4-carboxamido)pentanoate (6u) in a pig ischemia model indicated that MCD inhibitors may be useful for treating ischemic heart diseases.
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Carboxiliasas/antagonistas & inhibidores , Morfolinas/síntesis química , Compuestos de Fenilurea/síntesis química , Animales , Metabolismo Energético/efectos de los fármacos , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Técnicas In Vitro , Masculino , Malonil Coenzima A/metabolismo , Morfolinas/química , Morfolinas/farmacología , Isquemia Miocárdica/tratamiento farmacológico , Miocardio/enzimología , Miocardio/metabolismo , Oxidación-Reducción , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , PorcinosRESUMEN
Abnormally high rates of fatty acid oxidation and low rates of glucose oxidation are important contributors to the severity of ischemic heart disease. Malonyl coenzyme A (CoA) regulates fatty acid oxidation by inhibiting mitochondrial uptake of fatty acids. Malonyl CoA decarboxylase (MCD) is involved in the decarboxylation of malonyl CoA to acetyl CoA. Therefore, inhibition of MCD may decrease fatty acid oxidation and protect the ischemic heart, secondary to increasing malonyl CoA levels. Ex vivo working rat hearts aerobically perfused in the presence of newly developed MCD inhibitors showed an increase in malonyl CoA levels, which was accompanied by both a significant decrease in fatty acid oxidation rates and an increase in glucose oxidation rates compared with controls. Using a model of demand-induced ischemia in pigs, MCD inhibition significantly increased glucose oxidation rates and reduced lactate production compared with vehicle-treated hearts, which was accompanied by a significant increase in cardiac work compared with controls. In a more severe rat heart global ischemia/reperfusion model, glucose oxidation was significantly increased and cardiac function was significantly improved during reperfusion in hearts treated with the MCD inhibitor compared with controls. Together, our data show that MCD inhibitors, which increase myocardial malonyl CoA levels, decrease fatty acid oxidation and accelerate glucose oxidation in both ex vivo rat hearts and in vivo pig hearts. This switch in energy substrate preference improves cardiac function during and after ischemia, suggesting that pharmacological inhibition of MCD may be a novel approach to treating ischemic heart disease.
Asunto(s)
Carboxiliasas/antagonistas & inhibidores , Cardiotónicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Isquemia Miocárdica/tratamiento farmacológico , Miocardio/metabolismo , Acetilcoenzima A , Animales , Cardiotónicos/farmacología , Metabolismo Energético , Inhibidores Enzimáticos/farmacología , Ésteres/metabolismo , Glucólisis , Malonil Coenzima A/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Modelos Animales , Isquemia Miocárdica/metabolismo , Oxidación-Reducción , Ratas , Ratas Sprague-Dawley , PorcinosRESUMEN
OBJECTIVE: Clinical trials in patients with stable angina show that drugs that partially inhibit myocardial fatty acid oxidation reduce the symptoms of demand-induced ischemia, presumably by reducing lactate production and improving regional systolic function. We tested the hypothesis that partial inhibition of fatty acid oxidation with oxfenicine (a carnitine palmitoyl transferase-I inhibitor) reduces lactate production and increases regional myocardial power during demand-induced ischemia. METHODS: Demand-induced ischemia was produced in anesthetized open-chest swine by reducing flow by 20% in the left anterior descending coronary artery and increasing heart rate and contractility with dobutamine (15 microg kg(-1) min(-1) i.v.) for 20 min. Glucose and fatty acid oxidation were measured with an intracoronary infusion of [U-14C] glucose and [9,10-3H] oleate, and hearts were treated with oxfenicine (2 mmol l(-1); n=7) or vehicle (n=7). Regional anterior wall power was assessed from the left ventricular pressure-anterior free wall segment length loops. RESULTS: During demand-induced ischemia, the oxfenicine group had a higher rate of glucose oxidation (6.9+/-1.1 vs. 4. 7+/-0.8 micromol min(-1); P<0.05), significantly lower fatty acid uptake, but no change in total or active PDH activity. The oxfenicine group had significantly lower lactate output integrals (1.11+/-0.23 vs. 0.60+/-0.11 mmol) and glycogen depletion (66+/-6 vs. 43+/-8%), and higher anterior wall power index (0.95+/-0.17 vs. 1.30+/-0.11%) and anterior wall energy efficiency index (91+/-17 vs. 129+/-10%). CONCLUSIONS: Partial inhibition of fatty acid oxidation reduced non-oxidative glycolysis and improved regional contractile power and efficiency during demand-induced ischemia.