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1.
ESMO Open ; 7(6): 100606, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36327757

RESUMEN

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers; ∼20% of patients have metastases at diagnosis, and 50%-60% subsequently develop metachronous metastases. Bone involvement, despite being rare, is usually associated with higher disease burden, worse prognosis, impaired quality of life, and significant health-related cost. In the last few years, following the positive results of the TRIBE and TRIBE2 trials, the association of FOLFOXIRI plus bevacizumab has become the new standard of care for metastatic CRC. Despite being highly efficacious in all subgroups, little is known about the activity of this regimen in patients with bone metastases. PATIENTS AND METHODS: We carried out a pooled analysis of TRIBE and TRIBE2 studies focusing on patients with skeletal deposits. RESULTS: Our analyses on the whole population showed that patients with baseline bone involvement reported shorter overall survival [OS; 14.0 versus 26.2 months; hazard ratio (HR) 2.04, 95% confidence interval (CI) 1.46-2.87; P < 0.001] and progression-free survival (PFS; 6.2 versus 11.1 months; HR 1.96, 95% CI 1.42-2.69; P < 0.001) compared with those without bone metastases; no significant interaction with the treatment was reported for PFS (P = 0.094) and OS (P = 0.38). Bone metastases had a negative prognostic implication in the multivariate analysis (HR 2.24, 95% CI 1.54-3.26; P < 0.001). Furthermore, patients with bone lesions at first radiological progression (including those with baseline bone metastases) had a shorter OS compared with those who progressed in other sites (10.4 versus 13.2 months; HR 1.48, 95% CI 1.15-1.91; P = 0.002). A trend toward inferior OS (7.5 versus 11 months, HR 1.50, 95% CI 0.92-2.45; P = 0.10) appeared in patients with basal skeletal deposits compared with those with bone involvement at first radiological progression. CONCLUSIONS: Our study confirmed the negative prognostic impact of bone metastases in CRC. Furthermore, we demonstrated for the first time that the survival advantage of triplet chemotherapy plus bevacizumab is maintained even in this prognostically unfavorable subgroup.


Asunto(s)
Neoplasias Óseas , Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Neoplasias Colorrectales/patología , Calidad de Vida , Camptotecina/uso terapéutico , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Pronóstico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Óseas/tratamiento farmacológico
2.
Diabetologia ; 45(8): 1172-81, 2002 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12189448

RESUMEN

AIMS/HYPOTHESIS: This study aimed to evaluate the effects of hyperglycaemia on the evolution of myocardial infarction and the expression of the transcriptional factor for angiogenesis hypoxia-inducible factor 1alpha (HIF-1alpha) in the rat. METHODS: We studied the effects of streptozotocin induced diabetes on infarct size and HIF-1 alpha gene expression. These parameters were also evaluated in isolated hearts of non-diabetic rat, in condition of high glucose concentration. RESULTS: In streptozotocin (STZ)-diabetic rats (in vivo study), myocardial infarct size was greater (p<0.01) in hyperglycaemic rats (22 mmol/l) than in normoglycaemic (7 mmol/l) or non-diabetic rats. In euglycaemic conditions, basal expression of HIF-1alpha mRNA was not appreciable, but increased steadily after ischaemia (762+/-86%, p<0.001); this response was blunted in hyperglycaemic STZ-rats (6.8+/-6% of the control, p<0.001) and improved in euglycaemic STZ-rats (58+/-10%). The changes in myocardial Rac1 mRNA expression paralleled those of HIF-1alpha. In isolated hearts from non-diabetic rats (in vitro study), perfusion with high glucose (33 mmol/l) produced an infarct size (58+/-2% of the area at risk) not different from that obtained in hyperglycaemic STZ-rats (57+/-2%). Similar changes in the expression of HIF-1alpha and Rac1, which were prevented by glutathione infusion (0.3 mmol/l) were also observed. CONCLUSION/INTERPRETATION: Both hyperglycaemia and high glucose concentrations increased basal HIF-1alpha and Rac1 expression, suggesting a state of pseudohypoxia. These findings show that myocardial infarct size in the rat is increased in hyperglycaemic conditions and is associated with a reduced expression of the HIF-1alpha gene. These changes are reversed, totally or partially, by normoglycaemia or glutathione suggesting a role for reactive oxygen species generation brought about by hyperglycaemia.


Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Angiopatías Diabéticas/metabolismo , Angiopatías Diabéticas/patología , Hiperglucemia/etiología , Infarto del Miocardio/etiología , Infarto del Miocardio/metabolismo , Factores de Transcripción , Animales , Glucemia/análisis , Proteínas de Unión al ADN/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/fisiopatología , Hemodinámica , Factor 1 Inducible por Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Masculino , Infarto del Miocardio/patología , Miocardio/metabolismo , Miocardio/patología , Proteínas Nucleares/metabolismo , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Proteína de Unión al GTP rac1/metabolismo
3.
Diabetologia ; 44(4): 464-70, 2001 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11357477

RESUMEN

AIMS/HYPOTHESIS: To investigate cardiac repolarization time in streptozotocin-induced diabetic rats and isolated hearts perfused with high glucose concentration. METHODS: We studied the effects of streptozotocin-induced diabetes on the cardiac repolarisation time (Q-T interval) in Sprague-Dawley rats during a 4-day period of hyperglycaemia and a subsequent 4-day period of normoglycaemia. The Q-T interval was also evaluated in isolated hearts of non-diabetic rats, in condition of high glucose concentration. RESULTS: Hyperglycaemia in streptozotocin rats increased mean blood pressure and led to a significant (p < 0.001) prolongation of Q-T values, which normalized after 4 days of normoglycaemia with intravenous insulin infusion. Perfusion of isolated hearts in condition of high glucose concentration caused a significant prolongation of Q-T values and increased coronary perfusion pressure (p < 0.001). The effects of high glucose were completely prevented by glutathione and almost completely by L-arginine, the natural precursor of nitric oxide. In a condition of normal glucose, L-NAME, an inhibitor of endogenous nitric oxide synthesis, increased both Q-T and CPP values to levels similar to those induced by high glucose (p < 0.001). Verapamil completely prevented Q-T lengthening and reduced by about two-thirds CPP values (p < 0.001). CONCLUSION/INTERPRETATION: Streptozotocin-diabetes in rats produces significant haemodynamic and electric perturbations that are reversed by normoglycaemia. Moreover, high glucose increases Q-T and CPP values in the isolated hearts of non-diabetic rats. The latter effects are reversed by glutathione and L-arginine, partially reversed by verapamil and mimicked by L-NAME. By increasing the production of free radicals, high glucose could reduce nitric oxide availability to target cells inducing a state of increased vasomotor tone and ventricular instability.


Asunto(s)
Corazón/fisiopatología , Hiperglucemia/complicaciones , Sistema Vasomotor/fisiopatología , Animales , Arginina/farmacología , Presión Sanguínea , Circulación Coronaria , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/fisiopatología , Electrocardiografía , Inhibidores Enzimáticos/farmacología , Glutatión/farmacología , Corazón/efectos de los fármacos , Frecuencia Cardíaca , Ventrículos Cardíacos/fisiopatología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley
4.
Diabetes Care ; 23(5): 658-63, 2000 May.
Artículo en Inglés | MEDLINE | ID: mdl-10834426

RESUMEN

OBJECTIVE: The aim of the present study was to evaluate the hemodynamic effects of acute hyperglycemia in type 2 diabetic patients and to see whether these effects are related to changes in nitric oxide (NO) availability. RESEARCH DESIGN AND METHODS: Twenty newly diagnosed complication-free diet-treated type 2 diabetic patients participated in the study. All patients underwent 3 hyperglycemic glucose clamps in random order: 1) the control study was performed with plasma glucose clamped at 18 mmol/l for 2 h; 2) the octreotide study with plasma insulin blocked at basal levels during the clamp; and 3) the L-arginine study with L-arginine (1 g/min) infused during the last 30 min of the clamp. A group of 8 patients also underwent a glutathione infusion (600 mg as an intravenous bolus followed by 5 mg/min infusion) during the clamp. RESULTS: During hyperglycemia, there were significant increments of systolic (sBP) (from 115.5 +/- 9.1 to 120.3 +/- 8.2 mmHg, P < 0.01) and diastolic (dBP) (from 70.3 +/- 7.8 to 79.7 +/- 5.3 mmHg, P < 0.01) blood pressure, as well as heart rate (from 75.2 +/- 7.8 to 80.8 +/- 5.4 beats/min, P < 0.01) and plasma catecholamines (P < 0.05). Squatting ratios, a measure of the baroreflex activity, significantly deteriorated after hyperglycemia (P < 0.01). The infusion of octreotide, used to avoid the possible confounding influence of insulin, did not change the hemodynamic effects of hyperglycemia. Glutathione, a free radical scavenger, completely prevented the vascular effects of hyperglycemia. L-Arginine produced a fall in sBP and dBP to baseline values and normalized squatting ratios. CONCLUSIONS: Acute hyperglycemia in newly diagnosed type 2 diabetic patients causes significant hemodynamic changes that are independent of endogenous insulin and are prevented by glutatione and reversed by L-arginine, suggesting an interference with endogenous NO availability. These observations could help explain the adverse cardiovascular effects of hyperglycemic spikes.


Asunto(s)
Diabetes Mellitus Tipo 2/fisiopatología , Hemodinámica , Hiperglucemia/fisiopatología , Adulto , Arginina , Presión Sanguínea , Volumen Sanguíneo , Diabetes Mellitus Tipo 2/complicaciones , Epinefrina/sangre , Femenino , Técnica de Clampeo de la Glucosa , Glutatión , Frecuencia Cardíaca , Humanos , Hiperglucemia/complicaciones , Insulina/sangre , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Octreótido
5.
JAMA ; 281(22): 2113-8, 1999 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-10367822

RESUMEN

CONTEXT: Increased levels of homocysteine are associated with risk of cardiovascular disease. Homocysteine may cause this risk by impairing endothelial cell function. OBJECTIVE: To evaluate the effect of acute hyperhomocysteinemia with and without antioxidant vitamin pretreatment on cardiovascular risk factors and endothelial functions. DESIGN AND SETTING: Observer-blinded, randomized crossover study conducted at a university hospital in Italy. SUBJECTS: Twenty healthy hospital staff volunteers (10 men, 10 women) aged 25 to 45 years. INTERVENTIONS: Subjects were given each of 3 loads in random order at 1-week intervals: oral methionine, 100 mg/kg in fruit juice; the same methionine load immediately following ingestion of antioxidant vitamin E, 800 IU, and ascorbic acid, 1000 mg; and methionine-free fruit juice (placebo). Ten of the 20 subjects also ingested a placebo load with vitamins. MAIN OUTCOME MEASURES: Lipid, coagulation, glucose, and circulating adhesion molecule parameters, blood pressure, and endothelial functions as assessed by hemodynamic and rheologic responses to L-arginine, evaluated at baseline and 4 hours following ingestion of the loads. RESULTS: The oral methionine load increased mean (SD) plasma homocysteine level from 10.5 (3.8) micromol/L at baseline to 27.1 (6.7) micromol/L at 4 hours (P<.001). A similar increase was observed with the same load plus vitamins (10.0 [4.0] to 22.7 [7.8] micromol/L; P<.001) but no significant increase was observed with placebo (10.1 [3.7] to 10.4 [3.2] micromol/L; P=.75). Coagulation and circulating adhesion molecule levels significantly increased after methionine ingestion alone (P<.05) but not after placebo or methionine ingestion with vitamins. While the mean (SD) blood pressure (-7.0% [2.7%]; P<.001), platelet aggregation response to adenosine diphosphate (-11.4% [4.5%]; P=.009) and blood viscosity (-3.0% [1.2%]; P=.04) declined in these parameters 10 minutes after an L-arginine load (3 g) following placebo, the increase after methionine alone (-2.3% [1.5%], 4.0% [3.0%], and 1.5% [1.0%], respectively; P<.05), did not occur following methionine load with vitamin pretreatment (-6.3% [2.5%], -7.9% [3.5%], and -1.5% [1.0%], respectively; P=.24). CONCLUSION: Our data suggest that mild to moderate elevations of plasma homocysteine levels in healthy subjects activate coagulation, modify the adhesive properties of endothelium, and impair the vascular responses to L-arginine. Pretreatment with antioxidant vitamin E and ascorbic acid blocks the effects of hyperhomocysteinemia, suggesting an oxidative mechanism.


Asunto(s)
Antioxidantes/metabolismo , Ácido Ascórbico/metabolismo , Enfermedades Cardiovasculares/epidemiología , Endotelio Vascular/fisiología , Hemodinámica/fisiología , Homocisteína/sangre , Metionina/metabolismo , Vitamina E/metabolismo , Enfermedad Aguda , Adulto , Antioxidantes/farmacología , Arginina/metabolismo , Arginina/farmacología , Ácido Ascórbico/farmacología , Coagulación Sanguínea , Viscosidad Sanguínea , Enfermedades Cardiovasculares/metabolismo , Estudios Cruzados , Femenino , Homocisteína/metabolismo , Humanos , Masculino , Metionina/farmacología , Agregación Plaquetaria , Factores de Riesgo , Método Simple Ciego , Vitamina E/farmacología
6.
Am J Physiol ; 273(3 Pt 1): E606-12, 1997 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-9316452

RESUMEN

The objective of this study was to assess the role of L-arginine, the natural precursor of nitric oxide, for testing endothelial function in physiological and pathophysiological conditions. In an initial study of 20 healthy subjects, mean blood pressure decreases in response to increasing doses of L-arginine (1, 2, 3, and 5 g) were 1.1 +/- 1.3, 2.6 +/- 1.5, 7.6 +/- 1.3, and 7.7 +/- 2 mmHg, respectively, P < 0.01. The enantiomer D-arginine (3 g) did not produce any change in mean blood pressure and platelet aggregation (n = 10), whereas the infusion of the L-arginine analog NG-monomethyl-L-arginine (6 mg/min) reduced by 70% the vascular effects of L-arginine. In the whole population of 52 healthy subjects, there was an inverse correlation between age and blood pressure or platelet aggregation changes after L-arginine. Compared with matched controls (n = 20), the changes in mean blood pressure and platelet aggregation after L-arginine were significantly lower in non-insulin-dependent diabetic (n = 20) and hypercholesterolemic (n = 16), but not in hypertensive (n = 20), subjects. Changes in blood viscosity were significantly lower only in hypercholesterolemic subjects. Our findings suggest that an intravenous bolus of 3 g L-arginine may be a simple and useful tool to assess the endothelial control of blood pressure and platelet activity in health and disease.


Asunto(s)
Arginina/farmacología , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Tipo 2/fisiopatología , Hipercolesterolemia/fisiopatología , Hipertensión/fisiopatología , Adenosina Difosfato/farmacología , Adulto , Factores de Edad , Glucemia/análisis , Viscosidad Sanguínea , Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Diástole , Femenino , Humanos , Hipercolesterolemia/sangre , Hipertensión/sangre , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Agregación Plaquetaria/efectos de los fármacos , Valores de Referencia , Análisis de Regresión , Fumar , Estereoisomerismo , Sístole , omega-N-Metilarginina/administración & dosificación , omega-N-Metilarginina/farmacología
7.
Circulation ; 95(7): 1783-90, 1997 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-9107164

RESUMEN

BACKGROUND: Acute hyperglycemia may increase vascular tone in normal humans via a glutathione-sensitive, presumably free radical-mediated pathway. The objective of this study was to investigate whether or not the vascular effects of hyperglycemia are related to reduced availability of nitric oxide. METHODS AND RESULTS: Acute hyperglycemia (15 mmol/L, 270 mg/dL) was induced in 12 healthy subjects with an artificial pancreas. Systolic and diastolic blood pressures, heart rate, and plasma catecholamines showed significant increases (P < .05) starting after 30 minutes of hyperglycemia; leg blood flow decreased significantly (15%; P < .05) at 60 and 90 minutes. Platelet aggregation to ADP and blood viscosity also showed significant increments (P < .05). The infusion of L-arginine (n = 7, 1 g/min) but not D-arginine (n = 5, 1 g/min) or L-lysine (n = 5, 1 g/min) in the last 30 minutes of the hyperglycemic clamp completely reversed all hemodynamic and rheological changes brought about by hyperglycemia. Infusion of NG-monomethyl-L-arginine (L-NMMA; 2 mg/min) to inhibit endogenous nitric oxide synthesis in 8 normal subjects produced vascular effects qualitatively similar to those of hyperglycemia but quantitatively higher (P < .05); however, heart rate and plasma catecholamine levels decreased during L-NMMA infusion, presumably as a consequence of baroreflex activation. Infusion of L-NMMA during hyperglycemia produced changes not different from those obtained during infusion of L-NMMA alone. CONCLUSIONS: The results show that acute hyperglycemia in normal subjects causes significant hemodynamic and rheological changes that are reversed by L-arginine. Moreover, the effects of hyperglycemia are mimicked to a large extent, but not entirely, by infusion of L-NMMA. This suggests that hyperglycemia may reduce nitric oxide availability in humans.


Asunto(s)
Arginina/farmacología , Hiperglucemia/fisiopatología , Óxido Nítrico/fisiología , Vasoconstricción/efectos de los fármacos , Enfermedad Aguda , Adulto , Viscosidad Sanguínea/efectos de los fármacos , Catecolaminas/sangre , Femenino , Radicales Libres , Glucosa , Glutatión/fisiología , Hemodinámica/efectos de los fármacos , Humanos , Insulina/sangre , Lisina/farmacología , Masculino , Óxido Nítrico/biosíntesis , Agregación Plaquetaria/efectos de los fármacos , omega-N-Metilarginina/farmacología
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