RESUMEN
BACKGROUND: The optimal chemotherapy backbone for HER2-negative advanced esophagogastric cancer, either in combination with targeted therapies or as a comparator in clinical trials, is uncertain. The subtle yet crucial differences in platinum-based regimens' safety and synergy with combination treatments need consideration. METHODS: We analyzed cases from the AGAMENON-SEOM Spanish registry of HER2-negative advanced esophagogastric adenocarcinoma treated with platinum and fluoropyrimidine from 2008 to 2021. This study focused exclusively on patients receiving one of the four regimens: FOLFOX (5-FU and oxaliplatin), CAPOX (capecitabine and oxaliplatin), CP (capecitabine and cisplatin) and FP (5-FU and cisplatin). The aim was to determine the most effective and tolerable platinum and fluoropyrimidine-based chemotherapy regimen and to identify any prognostic factors. RESULTS: Among 1293 patients, 36% received either FOLFOX (n = 468) or CAPOX (n = 466), 20% CP (n = 252), and 8% FP (n = 107). FOLFOX significantly increased PFS (progression free survival) compared to CP, with a hazard ratio of 0.73 (95% CI 0.58-0.92, p = 0.009). The duration of treatment was similar across all groups. Survival outcomes among regimens were similar, but analysis revealed worse ECOG-PS (Eastern Cooperative Oncology Group-Performance Status), > 2 metastatic sites, bone metastases, hypoalbuminemia, higher NLR (neutrophil-to-lymphocyte ratio), and CP regimen as predictors of poor PFS. Fatigue was common in all treatments, with the highest incidence in FOLFOX (77%), followed by FP (72%), CAPOX (68%), and CP (60%). Other notable toxicities included neuropathy (FOLFOX 69%, CAPOX 62%), neutropenia (FOLFOX 52%, FP 55%), hand-foot syndrome in CP (46%), and thromboembolic events (FP 12%, CP 11%). CONCLUSIONS: FOLFOX shown better PFS than CP. Adverse effects varied: neuropathy was more common with oxaliplatin, while thromboembolism was more frequent with cisplatin.
Asunto(s)
Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Capecitabina , Cisplatino , Neoplasias Esofágicas , Fluorouracilo , Leucovorina , Oxaliplatino , Receptor ErbB-2 , Sistema de Registros , Neoplasias Gástricas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Femenino , Masculino , Persona de Mediana Edad , Anciano , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Fluorouracilo/uso terapéutico , Fluorouracilo/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Capecitabina/uso terapéutico , Capecitabina/administración & dosificación , Receptor ErbB-2/metabolismo , Leucovorina/uso terapéutico , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Oxaliplatino/uso terapéutico , Oxaliplatino/administración & dosificación , Cisplatino/uso terapéutico , Cisplatino/administración & dosificación , Adulto , Compuestos Organoplatinos/uso terapéutico , Compuestos Organoplatinos/administración & dosificación , Supervivencia sin Progresión , Unión Esofagogástrica/patología , Anciano de 80 o más Años , EspañaRESUMEN
A healthy dietary pattern and high quality nutrient intake reduce atherosclerotic cardiovascular disease risk. Red wine grape pomace (RWGP)-a rich natural source of dietary fiber and antioxidants-appears to be a potential functional food ingredient. The impact of a dietary supplementation with RWGP flour was evaluated in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice, a model of lethal ischemic heart disease. SR-B1 KO/ApoER61h/h mice were fed with atherogenic (high fat, cholesterol, and cholic acid, HFC) diet supplemented with: (a) 20% chow (HFC-Control), (b) 20% RWGP flour (HFC-RWGP), or (c) 10% chow/10% oat fiber (HFC-Fiber); and survival time was evaluated. In addition, SR-B1 KO/ApoER61h/h mice were fed for 7 or 14 days with HFC-Control or HFC-RWGP diets and plasma lipid levels, inflammation, oxidative damage, and antioxidant activity were measured. Atherosclerosis and myocardial damage were assessed by histology and magnetic resonance imaging, respectively. Supplementation with RWGP reduced premature death, changed TNF-α and IL-10 levels, and increased plasma antioxidant activity. Moreover, decreased atheromatous aortic and brachiocephalic plaque sizes and attenuated myocardial infarction and dysfunction were also observed. These results suggest that RWGP flour intake may be used as a non-pharmacological therapeutic approach, contributing to decreased progression of atherosclerosis, reduced coronary heart disease, and improved cardiovascular outcomes.
Asunto(s)
Antioxidantes/administración & dosificación , Aorta/metabolismo , Enfermedades de la Aorta/prevención & control , Aterosclerosis/prevención & control , Suplementos Dietéticos , Frutas/química , Isquemia Miocárdica/prevención & control , Miocardio/metabolismo , Estrés Oxidativo , Extractos Vegetales/administración & dosificación , Vitis/química , Alimentación Animal , Animales , Antioxidantes/aislamiento & purificación , Antioxidantes/metabolismo , Aorta/patología , Enfermedades de la Aorta/sangre , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Aterosclerosis/sangre , Aterosclerosis/genética , Aterosclerosis/patología , Biomarcadores/sangre , Dieta Aterogénica , Modelos Animales de Enfermedad , Femenino , Mediadores de Inflamación/sangre , Interleucina-10/sangre , Lípidos/sangre , Masculino , Ratones Noqueados para ApoE , Isquemia Miocárdica/sangre , Isquemia Miocárdica/genética , Isquemia Miocárdica/patología , Miocardio/patología , Extractos Vegetales/sangre , Extractos Vegetales/aislamiento & purificación , Placa Aterosclerótica , Receptores Depuradores de Clase B/deficiencia , Receptores Depuradores de Clase B/genética , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Wine grape pomace flour (WGPF) is a fruit byproduct that is high in fiber and antioxidants. We tested whether WGPF consumption could affect blood biochemical parameters, including oxidative stress biomarkers. In a three-month intervention study, 27 male volunteers, each with some components of metabolic syndrome, consumed a beef burger supplemented with 7% WGPF containing 3.5% of fiber and 1.2 mg gallic equivalents (GE)/g of polyphenols (WGPF-burger), daily, during the first month. The volunteers consumed no burgers in the second month, and one control-burger daily in the third month. At baseline and after these periods, we evaluated the metabolic syndrome components, plasma antioxidant status (i.e., 2,2-diphenyl-1-picrylhydrazyl radical scavenging capacity (DPPH), vitamin E, vitamin C), and oxidative damage markers (i.e., advanced oxidation protein products (AOPPs), oxidized low-density lipoproteins (oxLDLs), malondialdehyde (MDA)). The WGPF-burger intake significantly reduced glycemia and homeostatic model assessment-based measurement of insulin resistance. Vitamin C increased and decreased during the consumption of the WGPF-burger and control-burger, respectively. The WGPF-burger intake significantly decreased AOPP and oxLDL levels. Vitamin E and MDA levels showed no significant changes. In conclusion, the consumption of beef burgers prepared with WGPF improved fasting glucose and insulin resistance, plasma antioxidant levels, and oxidative damage markers. Therefore, this functional ingredient has potential as a dietary supplement to manage chronic disease risk in humans.
Asunto(s)
Fibras de la Dieta/administración & dosificación , Ingestión de Alimentos/fisiología , Harina , Síndrome Metabólico/sangre , Carne Roja , Vitis/química , Adulto , Productos Avanzados de Oxidación de Proteínas/sangre , Antioxidantes/metabolismo , Ácido Ascórbico/sangre , Glucemia/metabolismo , Suplementos Dietéticos , Ayuno/sangre , Humanos , Resistencia a la Insulina/fisiología , Lipoproteínas LDL/sangre , Estudios Longitudinales , Masculino , Malondialdehído/sangre , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Periodo Posprandial , Vitamina E/sangreRESUMEN
BACKGROUND: The choice of chemotherapy in HER2-negative gastric cancer is based on centre's preferences and adverse effects profile. No schedule is currently accepted as standard, nor are there any factors to predict response, other than HER2 status. We seek to evaluate whether Lauren type influences the efficacy of various chemotherapies and on patient overall survival (OS). METHODS: We have conducted a multicenter study in 31 hospitals. The eligibility criteria include diagnosis of stomach or gastroesophageal junction adenocarcinoma, HER2 negativity, and chemotherapy containing 2-3 drugs. Cox proportional hazards regression adjusted for confounding factors, with tests of 'treatment-by-histology' interaction, was used to estimate treatment effect. RESULTS: Our registry contains 1303 tumours analysable for OS end points and 730 evaluable for overall response rate (ORR). A decrease in ORR was detected in the presence of a diffuse component: odds ratio 0.719 (95% confidence interval (CI), 0.525-0.987), P=0.039. Anthracycline- or docetaxel-containing schedules increased ORR only in the intestinal type. The diffuse type displayed increased mortality with hazard ratio (HR) of 1.201 (95% CI, 1.054-1.368), P=0.0056. Patients receiving chemotherapy with docetaxel exhibited increased OS limited to the intestinal type: HR 0.65 (95% CI, 0.49-0.87), P=0.024, with no increment in OS for the subset having a diffuse component. With respect to progression-free survival (PFS), a significant interaction was seen in the effect of docetaxel-containing schedules, with better PFS limited to the intestinal type subgroup, in the comparison against any other schedule: HR 0.65 (95% CI, 0.50-0.85), P=0.015, and against anthracycline-based regimens: HR 0.64 (95% CI, 0.46-0.88), P=0.046. CONCLUSIONS: As a conclusion, in this registry, Lauren classification tumour subtypes predicted survival and responded differently to chemotherapy. Future clinical trials should stratify effect estimations based on histology.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sistema de Registros , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Antraciclinas/administración & dosificación , Chile , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Docetaxel , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Receptor ErbB-2 , España , Neoplasias Gástricas/clasificación , Taxoides/administración & dosificación , Resultado del TratamientoRESUMEN
Vascular smooth muscle cell proliferation and migration play an important role in the pathophysiology of several vascular diseases, including atherosclerosis. Prostaglandins that have been implicated in this process are synthesized by two isoforms of cyclooxygenase (COX), with the expression of the regulated COX-2 isoform increased in atherosclerotic plaques. Bradykinin (BK), a vasoactive peptide increased in inflammation, induces the formation of prostaglandins through specific receptor activation. We hypothesized that BK plays an important role in the regulation of COX-2, contributing to the increase in production of prostaglandins in vascular smooth muscle cells. Herein we examined the signaling pathways that participate in the BK regulation of COX-2 protein levels in primary cultured aortic vascular smooth muscle cells. We observed an increase in COX-2 protein levels induced by BK that was maximal at 24 h. This increase was blocked by a B2 kinin receptor antagonist but not a B1 receptor antagonist, suggesting that the B2 receptor is involved in this pathway. In addition, we conclude that the activation of mitogen-activated protein kinases p42/p44, protein kinase C, and nitric oxide synthase is necessary for the increase in COX-2 levels induced by BK because either of the specific inhibitors for these enzymes blocked the effect of BK. Using a similar approach, we further demonstrated that reactive oxygen species and cAMP were not mediators on this pathway. These results suggest that BK activates several intracellular pathways that act in combination to increase COX-2 protein levels. This study suggests a role for BK on the evolution of the atheromatous plaque by virtue of controlling the levels of COX-2.
Asunto(s)
Bradiquinina/farmacología , Ciclooxigenasa 2/biosíntesis , Inhibidores de Adenilato Ciclasa , Animales , Aorta/citología , Aorta/efectos de los fármacos , Antagonistas del Receptor de Bradiquinina B2 , Butadienos/farmacología , Células Cultivadas , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Didesoxiadenosina/análogos & derivados , Didesoxiadenosina/farmacología , Inducción Enzimática/efectos de los fármacos , Imidazoles/farmacología , Inmunohistoquímica , Isoquinolinas/farmacología , Masculino , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Nitrilos/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Bradiquinina B2/fisiología , Sulfonamidas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
In addition to the induction of cell proliferation and migration, bradykinin (BK) can increase c-fos mRNA expression, activate ERK 1/2 and generate reactive oxygen species (ROS) in vascular smooth muscle cells (VSMC). It is not known, however, whether BK can induce cellular proliferation and extracellular matrix production via redox-sensitive signaling pathways. We investigated the role(s) of ROS in proliferation, migration and collagen synthesis induced by BK in VSMC derived from Sprague Dawley rat aorta. BK (10 nM) increased VSMC proliferation by 30% (n=5); this proliferation was inhibited by the antioxidants N-acetylcysteine (20 mM) and alpha-lipoic acid (LA, 250 mM). In addition, BK induced an increase in cell migration and in collagen levels that were blocked by LA. ROS production induced by BK (n=10) was significantly inhibited by bisindolylmaleimide (4microM) and by PD98059 (40microM). These results suggest that: 1) ROS participate in the mechanism(s) used by bradykinin to induce cellular proliferation; 2) bradykinin induces ROS generation through a pathway that involves the kinases PKC and MEK; and 3) ROS participate in the pathways mediating cell migration and the production of collagen as a response to treatment with bradykinin. To our knowledge, this is the first report describing mechanisms to explain the participation of ROS in the cellular proliferation and extracellular matrix pathway regulated by BK.
Asunto(s)
Antioxidantes/farmacología , Bradiquinina/farmacología , Proliferación Celular/efectos de los fármacos , Músculo Liso Vascular/citología , Especies Reactivas de Oxígeno , Animales , Aorta/citología , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Colágeno/biosíntesis , Colágeno/efectos de los fármacos , Masculino , Músculo Liso Vascular/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
In addition to the induction of cell proliferation and migration, bradykinin (BK) can increase c-fos mRNA expression, activate ERK 1/2 and generate reactive oxygen species (ROS) in vascular smooth muscle cells (VSMC). It is not known, however, whether BK can induce cellular proliferation and extracellular matrix production via redox-sensitive signaling pathways. We investigated the role(s) of ROS in proliferation, migration and collagen synthesis induced by BK in VSMC derived from Sprague Dawley rat aorta. BK (10 nM) increased VSMC proliferation by 30 % (n=5); this proliferation was inhibited by the antioxidants N-acetylcysteine (20 mM) and a-lipoic acid (LA, 250 mM). In addition, BK induced an increase in cell migration and in collagen levels that were blocked by LA. ROS production induced by BK (n=10) was significantly inhibited by bisindolylmaleimide (4mM) and by PD98059 (40mM). These results suggest that: 1) ROS participate in the mechanism(s) used by bradykinin to induce cellular proliferation; 2) bradykinin induces ROS generation through a pathway that involves the kinases PKC and MEK; and 3) ROS participate in the pathways mediating cell migration and the production of collagen as a response to treatment with bradykinin. To our knowledge, this is the first report describing mechanisms to explain the participation of ROS in the cellular proliferation and extracellular matrix pathway regulated by BK.