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Gastric cancer (GC) is the fifth most common cancer worldwide with a varied geographic distribution and an aggressive behavior. In Spain, the incidence is lower and GC represents the tenth most frequent tumor and the seventh cause of cancer mortality. Molecular biology knowledge allowed to better profile patients for a personalized therapeutic approach. In the localized setting, the multidisciplinary team discussion is fundamental for planning the therapeutic approach. Endoscopic resection in very early stage, perioperative chemotherapy in locally advanced tumors, and chemoradiation + surgery + adjuvant immunotherapy for the GEJ are current standards. For the metastatic setting, biomarker profiling including Her2, PD-L1, MSS status is needed. Chemotherapy in combination with checkpoint inhibitors had improved the outcomes for patients with PD-L1 expression. Her2 positive patients should receive antiHer2 therapy added to chemotherapy. We describe the different evidences and recommendations based on the literature.
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Several hepatic disorders are influenced by gut microbiota, but its role in idiosyncratic drug-induced liver injury (iDILI), whose main causative agent is amoxicillin-clavulanate, remains unknown. This pioneering study aims to unravel particular patterns of gut microbiota composition and associated metabolites in iDILI and iDILI patients by amoxicillin-clavulanate (iDILI-AC). Thus, serum and fecal samples from 46 patients were divided into three study groups: healthy controls (n = 10), non-iDILI acute hepatitis (n = 12) and iDILI patients (n = 24). To evaluate the amoxicillin-clavulanate effect, iDILI patients were separated into two subgroups: iDILI non-caused by amoxicillin-clavulanate (iDILI-nonAC) (n = 18) and iDILI-AC patients (n = 6). Gut microbiota composition and fecal metabolome plus serum and fecal bile acid (BA) analyses were performed, along with correlation analyses. iDILI patients presented a particular microbiome profile associated with reduced fecal secondary BAs and fecal metabolites linked to lower inflammation, such as dodecanedioic acid and pyridoxamine. Moreover, certain taxa like Barnesiella, Clostridia UCG-014 and Eubacterium spp. correlated with significant metabolites and BAs. Additionally, comparisons between iDILI-nonAC and iDILI-AC groups unraveled unique features associated with iDILI when caused by amoxicillin-clavulanate. In conclusion, specific gut microbiota profiles in iDILI and iDILI-AC patients were associated with particular metabolic and BA status, which could affect disease onset and progression.
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Combinación Amoxicilina-Clavulanato de Potasio , Ácidos y Sales Biliares , Enfermedad Hepática Inducida por Sustancias y Drogas , Heces , Microbioma Gastrointestinal , Metaboloma , Humanos , Microbioma Gastrointestinal/efectos de los fármacos , Heces/microbiología , Ácidos y Sales Biliares/metabolismo , Combinación Amoxicilina-Clavulanato de Potasio/efectos adversos , Masculino , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Femenino , Metaboloma/efectos de los fármacos , Persona de Mediana Edad , Adulto , AncianoRESUMEN
Although the treatment landscape has rapidly evolved over the last years, hepatocellular carcinoma (HCC) is one of the most lethal cancers. With recent advances, both immunotherapy and tyrosine kinase inhibitors (TKIs)-based chemotherapy constitute the standard treatment for advanced HCC. A systematic search of randomized clinical trials employing TKIs was performed in 17 databases, obtaining 25 studies evaluating the prognosis, tumor response, and presence of adverse events (AEs) related to TKIs in HCC. Overall effect sizes were estimated for the hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI), either extracted or calculated with the Parmar method, employing STATA 16. Heterogeneity was assessed by Chi-square-based Q-test and inconsistency (I2) statistic; source of heterogeneity by meta-regression and subgroup analysis; and publication bias by funnel plot asymmetry and Egger's test. The research protocol was registered in PROSPERO (CRD42023397263). Meta-analysis revealed a correlation between survival and tumor response parameters and TKI treatment vs. placebo, despite detecting high heterogeneity. Combined TKI treatment showed a significantly better objective response rate (ORR) with no heterogeneity, whereas publication bias was only detected with time to progression (TTP). Few gastrointestinal and neurological disorders were associated with TKI treatment vs. placebo or with combined treatment. However, a higher number of serious AEs were related to TKI treatment vs. sorafenib alone. Results show positive clinical benefits from TKI treatment, supporting the approval and maintenance of TKI-based therapy for advanced HCC, while establishing appropriate strategies to maximize efficacy and minimize toxicity.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Inhibidores de Proteínas Quinasas , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Medición de Riesgo , Resultado del Tratamiento , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéuticoRESUMEN
BACKGROUND: Retrospective data suggest an association between bevacizumab efficacy and the incidence of arterial hypertension (AHT). Additionally, epigenetic mechanisms have been related to AHT. METHODS: This prospective observational study conducted by GEICAM Spanish Breast Cancer Research Group included metastatic breast (MBC) or colorectal (mCRC) cancer patients treated with bevacizumab-containing chemotherapy as first-line treatment. Blood pressure (BP) levels were measured (conventional and 24-h Holter monitoring) at baseline and up to cycle 3. Primary endpoint assessed BP levels increase as predictive factor for progression-free survival (PFS). Germline DNA methylation profile was explored in pre-treatment blood samples; principal component analysis was used to define an epigenetic predictive score for increased BP levels. RESULTS: From Oct-2012 to Jul-2016, 143 (78 MBC and 65 mCRC) patients were included. The incidence of AHT according to guidelines was neither predictive of PFS nor of best overall tumor response (BOR). No statistically significant association was observed with systolic BP nor diastolic BP increment for PFS or BOR. Grade 3 and 4 adverse events were observed in 37 and 5% of patients, respectively. We identified 27 sites which baseline methylation status was significantly associated to BP levels increase secondary to bevacizumab-containing chemotherapy. CONCLUSIONS: Neither the frequency of AHT nor the increase of BP levels were predictive of efficacy in MBC and mCRC patients treated with bevacizumab-containing chemotherapy. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov Identifier: NCT01733628.
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Bevacizumab , Neoplasias de la Mama , Neoplasias Colorrectales , Hipertensión , Humanos , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Femenino , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Persona de Mediana Edad , Hipertensión/inducido químicamente , Estudios Prospectivos , Anciano , Masculino , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Supervivencia sin Progresión , Metilación de ADNRESUMEN
BACKGROUND: The prognostic value of the Systemic Inflammation Response Index (SIRI) in advanced pancreatic cancer is recognized, but its correlation with patients´ nutritional status and outcomes remains unexplored. AIM: To study the prognostic significance of SIRI and weight loss in metastatic pancreatic cancer. METHODS: The PANTHEIA-Spanish Society of Medical Oncology (SEOM) study is a multicentric (16 Spanish hospitals), observational, longitudinal, non-interventional initiative, promoted by the SEOM Real World-Evidence work group. This pilot study sought to analyze the association between weight loss and inflammatory status as defined by SIRI. The cohort stems from a proof-of-concept pilot study conducted at one of the coordinating centers. Patients with pathologically confirmed metastatic pancreatic adenocarcinoma, treated from January 2020 to January 2023, were included. The index was calculated using the product of neutrophil and monocyte counts, divided by lymphocyte counts, obtained within 15 days before initiation chemotherapy. This study evaluated associations between overall survival (OS), SIRI and weight loss. RESULTS: A total of 50 patients were included. 66% of these patients were male and the median age was 66 years. Metastasis sites: 36% liver, 12% peritoneal carcinomatosis, 10% lung, and 42% multiple locations. Regarding the first line palliative chemotherapy treatments: 50% received gemcitabine plus nab-paclitaxel; 28%, modified fluorouracil, leucovorin, irinotecan and oxaliplatin, and 16% were administered gemcitabine. 42% had a weight loss > 5% in the three months (mo) preceding diagnosis. 21 patients with a SIRI ≥ 2.3 × 103/L exhibited a trend towards a lower median OS compared to those with a SIRI < 2.3 × 103/L (4 vs 18 mo; P < 0.000). Among 21 patients with > 5% weight loss before diagnosis, the median OS was 6 mo, in contrast to 19 mo for those who did not experience such weight loss (P = 0.003). Patients with a weight loss > 5% showed higher SIRI levels. This difference was statistically significant (P < 0.000). For patients with a SIRI < 2.3 × 103/L, those who did not lose > 5% of their weight had an OS of 20 mo, compared to 11 mo for those who did (P < 0.001). No association was found between carbohydrate antigen 19-9 levels ≥ 1000 U/mL and weight loss. CONCLUSION: A higher SIRI was correlated with decreased survival rates in patients with metastatic pancreatic cancer and associated with weight loss. An elevated SIRI is suggested as a predictor of survival, emphasizing the need for prospective validation in the upcoming PANTHEIA-SEOM study.
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In the original publication [...].
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BACKGROUND: Sequential nab-paclitaxel plus gemcitabine followed by modified FOLFOX-6 (oxaliplatin, leucovorin, and 5-fluorouracil) (nab-P/Gem-mFOLFOX) showed a good safety and clinical profile in metastatic pancreatic ductal adenocarcinoma (mPDAC) in the phase I SEQUENCE trial. METHODS: The safety and efficacy of sequential nab-P/Gem-mFOLFOX was compared with standard nab-paclitaxel plus gemcitabine (nab-P/Gem) as first-line treatment in a multi-institutional, randomized, open-label, phase II trial in patients with untreated mPDAC. We randomly assigned patients in a 1:1 ratio to receive nab-P/Gem on days 1, 8, and 15 followed by mFOLFOX on day 29 of a 6-week cycle (experimental group) or nab-P/Gem on days 1, 8, and 15 of a 4-week cycle (control group). The primary end point was the 12-month overall survival rate. RESULTS: A total of 157 patients were randomly assigned: 78 to nab-P/Gem-mFOLFOX and 79 to nab-P/Gem. Patients receiving nab-P/Gem-mFOLFOX had a 12-month overall survival of 55.3% (95% confidence interval [CI], 44.2 to 66.5) versus 35.4% (95% CI, 24.9 to 46) in the control group (P=0.02). Similarly, the 24-month survival was 22.4% (95% CI, 13 to 31.8) with nab-P/Gem-mFOLFOX versus 7.6% (95% CI, 1.8 to 13.4) with control treatment. The median overall survival was 13.2 months (95% CI, 10.1 to 16.2) with nab-P/Gem-mFOLFOX and 9.7 months (95% CI, 7.5 to 12) with nab-P/Gem (hazard ratio for death, 0.68; 95% CI, 0.48 to 0.95). The safety profile showed a higher incidence of grade 3 or higher neutropenia (35 of 76 vs. 19 of 79 patients, P=0.004), grade 3 or higher thrombocytopenia (18 of 78 vs. 6 of 79 patients, P=0.007), and two treatment-related deaths (2.6%) with nab-P/Gem-mFOLFOX compared with none with control treatment. CONCLUSIONS: Sequential nab-P/Gem-mFOLFOX showed a significantly higher 12-month survival when compared with the standard nab-P/Gem treatment; this came with greater treatment toxicity. (Funded by Celgene; EuCT number, 2014-005350-19; ClinicalTrials.gov number, NCT02504333.)
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Albúminas , Gemcitabina , Neoplasias Pancreáticas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Desoxicitidina/efectos adversos , Paclitaxel/efectos adversos , Neoplasias Pancreáticas/tratamiento farmacológicoRESUMEN
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.
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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
BACKGROUND: Gastroesophageal adenocarcinoma in young adults (GCYA) counts for 10-15% of diagnoses. Previous studies have mainly focused on surgical outcomes in patients with resectable tumors; however, systemic therapy for advanced GCYA remains under-evaluated. This study aims to assess the efficacy-related outcomes and safety of first-line chemotherapy (CT) in younger versus older patients with advanced gastroesophageal adenocarcinoma. METHODS: Patients with advanced gastroesophageal adenocarcinoma from the AGAMENON-SEOM registry treated with first-line polychemotherapy between January 2008 and October 2022 were included. We compared clinicopathological features, therapies received, efficacy-related outcomes, and toxicity between individuals aged < and ≥ 45 years. RESULTS: Out of 3386 patients, 263 (7.8%) were < 45 years. Young patients exhibited a higher proportion of females affected, lower ECOG-PS ≥ 2, fewer comorbidities, and more aggressive disease-related features, such as higher proportion of diffuse subtype, signet-ring cells, plastic linitis, grade 3, peritoneal metastases and metastatic disease at diagnosis. They received more triple-agent combinations and underwent more surgeries in metastatic setting. No significant differences were observed between groups in overall response rate (53.1% vs. 52.3% in < and ≥ 45 years, respectively, p = 0.579), progression-free survival (6.1 vs. 6.83 months, p = 0.158) and overall survival (11.07 vs. 10.81 months, p = 0.82), even after adjusting for potential confounding factors. Grade 3-4 adverse events were comparable in both groups, although toxicity leading to treatment discontinuation was more frequent in older patients. CONCLUSIONS: In the AGAMENON-SEOM registry, younger patients with GCYA exhibited more aggressive clinicopathological features, and despite receiving more aggressive treatments, similar efficacy outcomes and toxicity profiles were achieved compared to their older counterparts. In the AGAMENON-SEOM registry, GEAC in < 45 years showed more aggressive clinicopathological features and, although treated with more intense first-line CT regimens, similar efficacy outcomes and toxicity were achieved compared to older patients.
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Adenocarcinoma , Neoplasias Gástricas , Femenino , Adulto Joven , Humanos , Anciano , Neoplasias Gástricas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Progresión , Adenocarcinoma/patología , Sistema de RegistrosRESUMEN
In the original publication [...].
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Glenohumeral internal rotation deficit (GIRD) is one of the most important factors influencing injury risk in the arm of overhead athletes. Some studies have shown that the GIRD of athletes with shoulder pain was higher than those without shoulder pain, establishing a relation between shoulder pain and GIRD. However, there are no studies that relate to GIRD and shoulder pain or the risk factors that affect GIRD in the population with this ailment. This study aimed to: determine if GIRD could be found clinically and between which values it oscillates in patients with shoulder pain, and explore if there are any potential associations between GIRD and some sociodemographic data, and orthopedic or radiological findings. A descriptive observational study design was adopted to determine if GIRD could be found clinically in patients with shoulder pain and to gain further evidence in the potential associations between GIRD and sociodemographic data, and orthopedic or radiological findings. All those patients without exclusion criteria between October 1,2020 and March 31,2021 were included. Exclusion criteria consisted of being under 18 years old but younger than 80 years old, showing shoulder pain in both shoulders and having a joint prosthesis in at least one of the 2 shoulders, tumor, or infection. A total of 67 patients aged between 25 and 75 years (52.7â ±â 11.8 years, 36 male and 31 female). More than 82% of patients with shoulder pain showed a GIRD higher than 20º. The mean GIRD was 37.6â ±â 17.09º. The 95th percentile was 66.22º. From sociodemographic data could be extracted that: patients who have children showed a lower GIRD, patients with right shoulder pain, or whose dominance coincided with a painful shoulder showed a higher GIRD. The orthopedic findings revealed that patients with a positive Jobe test showed a lower GIRD. The linear model considering both sociodemographic and orthopedic findings showed that GIRD was reduced by having children and by BMI. GIRD shows a high incidence in patients with shoulder pain. The descendant, BMI, and positive Jobe test were negatively associated with the GIRD.
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Articulación del Hombro , Dolor de Hombro , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atletas , Rango del Movimiento Articular , Factores de Riesgo , Hombro , Dolor de Hombro/epidemiología , Dolor de Hombro/etiologíaRESUMEN
This study's main purpose involves exploring the relationship between the social values of nursing staff and the perception they have of their professional lives. A further aim is to examine how their terms of employment and tenure of service relate to the quality of their careers and their social values. The research consisted of a non-experimental quantitative approach of a descriptive nature involving 380 nursing staff at four public hospitals in Madrid (Spain). The values were appraised by means of the Schwarz Value Survey (SVS) and the quality of their careers was measured through the Quality of Professional Life (QPL-35) questionnaire. The results reveal significant correlations between the two, highlighting the significance of such values as universalism, benevolence, achievement and power depending on their terms of employment, on the one hand, and all the values in the Schwartz model according to the length of their tenure on the other. The findings suggest that terms of employment and tenure are significantly related to the axiological profile of nursing staff and the quality of their professional lives. This study provides major empirical evidence that contributes to our understanding of how social values and the quality of professional lives are interwoven within the field of nursing in Spain.
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BACKGROUND: Maladaptation can provoke important alterations in the arthrokinematics such as an internal rotation reduction in the dominant shoulder compared with the nondominant shoulder known as glenohumeral internal rotation deficit (GIRD). Though the number of studies investigating GIRD in athletic population, there are not studies reporting the efficacy of the GIRD treatment in the nonathlete population, a kind of study required to improve our understanding of patient care with this pathology. This study aimed to describe the efficacy of the GIRD treatment in nonathlete population with shoulder pain. METHODS: An open single-arm trial with 35 patients was adopted for evaluating the efficacy of GIRD treatment in patients with shoulder pain. All patients with shoulder pain who attended the consultation, accepted, and agreed to participate in the study between October 2020 and March 2021 were included. A treatment sequence including joint manual therapy techniques and soft tissue release techniques was applied in the consultation. Then, patients were instructed to adapt the daily active biological stimulus at home. The IR before (IR0) and after (IR1) the treatment was considered the outcome measure. The GIRD was calculated as the difference between the IR of the non-painful shoulder and the IR of the painful shoulder before (GIRD0) and after treatment (GIRD1). A paired Student t test was used to compare the GIRD of each patient before and after the treatment. RESULTS: Treatment of the patients significantly increased the IR of the painful shoulder in all the patients (P-value < .0001) So, the mean IR0 was 26.09 ± 14.46º (23.64-28.53), and after the treatment the mean IR1 was 67.98 ± 15.03º (65.48-70.52). The mean difference after the treatment (IR1-IR0) was 41.89 ± 14.74º (39.4-44.39). The treatment also significantly reduced GIRD (P-value < .0001). So, the mean GIRD0 was 42.95 ± 16.26º (40.2-45.7), and after the treatment the mean GIRD1 was -1.05 ± 17.18º (-3.96 to 1.85). CONCLUSIONS: The treatment administrated in this study significantly increased the internal rotation of the treated and painful shoulder and reduced the GIRD from the first consultation. LEVEL OF EVIDENCE: Level 3.
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Osteopatía , Dolor de Hombro , Humanos , Dolor de Hombro/terapia , Isótopos de Oxígeno , Derivación y ConsultaRESUMEN
Exosome release varies depending on the physiological state of the cell, so they could play a fundamental role in obesity, the biggest pandemic in today's societies. The beneficial effects that physical activity has both on weight and cardiovascular parameters may be mediated by exosomes released in response to exercise. Thus, we aimed (I) to study the influence of a 12-week CT intervention on exosome cargo modifications in men with obesity and (II) to determine whether changes in exosomes after the intervention were related to changes in cardiometabolic health parameters in our cohorts. An experimental, controlled design was performed in twelve (nine with valid data) adult male obese patients (mean values: 41.6 years old, 97.6 kg and 32.4 kg/m2) who were randomly divided into a control group (n = 4) and a training group (n = 5), which completed 36 sessions of CT (concurrent training) for 12 weeks. Before and after the training period, cardiometabolic health parameters were evaluated and blood samples to measure exosomes and proteins were drawn. No changes were observed in the levels of any exosomal markers and proteins; however, associations of changes between CD81 and both fat mass and weight, Flot-1 and VO2max, HSP70 and both CRP and left ventricle diastolic diameter or CD14 and leptin were found (all p ≤ 0.05). Although the current CT was not able to clearly modify the exosome cargo, a certain medium to large clinical effect was manifested considering the nature of this study. Moreover, the associations found between the promoted changes in cardiometabolic parameters and exosome-carried proteins could indicate a relationship to be considered for future treatments in patients with obesity.
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Enfermedades Cardiovasculares , Exosomas , Adulto , Humanos , Masculino , Obesidad/terapia , Ejercicio Físico , Terapia por EjercicioRESUMEN
Introduction: Eccentric-overload (EO) resistance training emerges as an alternative to more optimally prescribe intensity relative to the force generation capabilities of the eccentric muscle contraction. Given the difficulties to individually prescribe absolute eccentric loads relative to each person's eccentric ability, setting the load relative to the concentric one-repetition maximum (1-RM) is the most used EO training approach. Therefore, we investigated the effects of submaximal and supramaximal (i.e., eccentric loads above 100% of 1-RM) accentuated eccentric training on changes in lean mass, anabolic hormonal responses and muscle function. Methods: Physically active university students (n = 27) were randomly assigned to two training groups. Participants in the training groups performed dominant leg isotonic training twice a week for 10 weeks (four sets of eight repetitions). Isotonic resistance was generated by an electric-motor device at two different percentages of 1-RM for the eccentric phase; 90% submaximal load, SUB group) and 120% (supramaximal load, SUPRA group). Concentric load was the same for both groups (30% of 1-RM). Changes in total thigh lean mass (TTLM), anabolic hormonal responses (growth hormone, IGF-1, IL-6, and total testosterone), unilateral leg-press 1-RM, maximal voluntary isometric contractions (MVIC), local muscle endurance (XRM), muscle power at 40 (PP40), 60 (PP60) and 80% (PP80) of the 1-RM, and unilateral vertical jump height before and after training were compared between groups. Results: After training, both SUB and SUPRA groups showed similar increases (p < 0.05) in MVIC (19.2% and 19.6%), XRM (53.8% and 23.8%), PP40 (16.2% and 15.7%), TTLM (2.5% and 4.2%), IGF-1 (10.0% and 14.1%) and IL-6 (58.6% and 28.6%). However, increases in 1-RM strength (16.3%) and unilateral vertical jump height (10.0%-13.4%) were observed for SUPRA only. Indeed, SUPRA was shown to be more favorable than SUB training for increasing 1-RM [ES = 0.77 (1.49-0.05)]. Unilateral muscle power at medium and high intensity (10.2% and 10.5%) also increased in SUB but without significant differences between groups. Discussion: Similar functional and structural effects were demonstrated after 10 weeks EO training with submaximal and supramaximal eccentric loads. Although supramaximal loading might be superior for increasing 1-RM, the use of this approach does not appear to be necessary in healthy, active individuals.
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BACKGROUND: The results of the Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD)-1402 phase II randomized trial suggested that adding aflibercept to modified fluorouracil, oxaliplatin, and leucovorin (mFOLFOX6) induction, followed by chemoradiation and surgery, could increase the pathological complete response (pCR) rate in patients with high-risk, locally advanced rectal cancer. Here we update results up to 3 years of follow-up and evaluate the predictive value of consensus molecular subtypes identified with immunohistochemistry (IHC). METHODS: Patients with magnetic resonance imaging-defined T3c-d and/or T4 and/or N2 rectal adenocarcinoma in the middle or distal third were randomly assigned to mFOLFOX6 induction, with aflibercept (mF+A; n = 115) or without aflibercept (mF; n = 65), followed by capecitabine plus radiotherapy and surgery. The risk local relapse, distant metastases, disease-free survival (DFS), and overall survival (OS) were estimated at 3 years. Selected samples were classified via IHC into immune-infiltrate, epithelial, or mesenchymal subtypes. RESULTS: mF+A and mF had 3-year DFS of 75.2% (95% confidence interval [CI] = 66.1% to 82.2%) and 81.5% (95% CI = 69.8% to 89.1%), respectively; 3-year OS of 89.3% (95% CI = 82.0% to 93.8%) and 90.7% (95% CI = 80.6% to 95.7%), respectively; 3-year cumulative local relapse incidences of 5.2% (95% CI = 1.9% to 11.0%) and 6.1% (95% CI = 1.7% to 15.0%), respectively; and 3-year cumulative distant metastases rates of 17.3% (95% CI = 10.9% to 25.5%) and 16.9% (95% CI = 8.7% to 28.2%), respectively. pCRs were achieved in 27.5% (n = 22 of 80) and 0% (n = 0 of 10) of patients with epithelial and mesenchymal subtypes, respectively. CONCLUSION: Adding aflibercept to mFOLFOX6 induction was not associated with improved DFS or OS. Our findings suggested that consensus molecular subtypes identified with IHC subtypes could be predictive of pCR with this treatment.
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Terapia Neoadyuvante , Neoplasias del Recto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/patología , Fluorouracilo/uso terapéutico , Capecitabina/uso terapéutico , Quimioradioterapia/métodos , Recurrencia , Estadificación de NeoplasiasRESUMEN
This article examines the jurisprudential arguments elaborated in David Dyzenhaus's The Long Arc of Legality. In particular, it looks into the main claim of the book: that the fact of 'very unjust laws' is central to illuminating the idea of law's authority, the elaboration of which Dyzenhaus takes to be the purpose of legal theory. The article analyses Dyzenhaus's own normative proposal in this matter, which consists of a version of legal positivism committed to Lon Fuller's principles of the internal morality of law, with the corollary of a conception of the judicial role as bound to a duty to apply these internal principles of legality when exercising their main function. While I cast some doubts on the feasibility of constructing the judge's function that way, in the end I celebrate Dyzenhaus's attempt at refining legal positivism's identity, especially in light of the ongoing debate with contemporary anti-positivism.
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BACKGROUND AND AIMS: Extracellular vesicles (EVs) have emerged as a potential source of circulating biomarkers in liver disease. We evaluated circulating AV+ EpCAM+ CD133+ EVs as a potential biomarker of the transition from simple steatosis to steatohepatitis. METHODS: EpCAM and CD133 liver proteins and EpCAM+ CD133+ EVs levels were analysed in 31 C57BL/6J mice fed with a chow or high fat, high cholesterol and carbohydrates diet (HFHCC) for 52 weeks. The hepatic origin of MVs was addressed using AlbCrexmT/mG mice fed a Western (WD) or Dual diet for 23 weeks. Besides, we assessed plasma MVs in 130 biopsy-proven NAFLD patients. RESULTS: Hepatic expression of EpCAM and CD133 and EpCAM+ CD133+ EVs increased during disease progression in HFHCC mice. GFP+ MVs were higher in AlbCrexmT/mG mice fed a WD (5.2% vs 12.1%) or a Dual diet (0.5% vs 7.3%). Most GFP+ MVs were also positive for EpCAM and CD133 (98.3% and 92.9% respectively), suggesting their hepatic origin. In 71 biopsy-proven NAFLD patients, EpCAM+ CD133+ EVs were significantly higher in those with steatohepatitis compare to those with simple steatosis (286.4 ± 61.9 vs 758.4 ± 82.3; p < 0.001). Patients with ballooning 367 ± 40.6 vs 532.0 ± 45.1; p = 0.01 and lobular inflammation (321.1 ± 74.1 vs 721.4 ± 80.1; p = 0.001), showed higher levels of these EVs. These findings were replicated in an independent cohort. CONCLUSIONS: Circulating levels of EpCAM+ CD133+ MVs in clinical and experimental NAFLD were increased in the presence of steatohepatitis, showing high potential as a non-invasive biomarker for the evaluation and management of these patients.