RESUMEN
BACKGROUND: Programmed death receptor ligand 1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden (TMB) are key predictive biomarkers for immune checkpoint inhibitor (ICI) efficacy in non-small-cell lung cancer (NSCLC). Data on their variation across multiple samples are limited. PATIENTS AND METHODS: Patients with NSCLC and multiple PD-L1 TPS and/or TMB assessments were included. Clinicopathologic and genomic data were analyzed according to PD-L1 and TMB variation. RESULTS: In total, 402 PD-L1 sample pairs and 413 TMB sample pairs were included. Concordance between pairs was moderate for PD-L1 (ρ = 0.53, P < 0.0001) and high for TMB (ρ = 0.80, P < 0.0001). Shorter time between biopsies correlated with higher concordance in PD-L1, but not in TMB. Major increases (ΔTPS ≥ +50%) and decreases (ΔTPS ≤ -50%) in PD-L1 were observed in 9.7% and 8.0% of cases, respectively. PD-L1, but not TMB, decreased with intervening ICI (P = 0.02). Acquired copy number loss of CD274, PDCD1LG2, and JAK2 were associated with major decrease in PD-L1 (q < 0.05). Among patients with multiple PD-L1 assessments before ICI, cases where all samples had a PD-L1 ≥1%, compared to cases with at least one sample with PD-L1 <1% and another with PD-L1 ≥1%, achieved improved objective response rate and progression-free survival (PFS). Among patients with at least one PD-L1 <1% and one ≥1% before ICI, cases where the most proximal sample was PD-L1 ≥1% had longer median PFS compared to cases where the most proximal PD-L1 was <1%. Among patients with multiple TMB assessments before ICI, patients with a TMB ≥10 mut/Mb based on the most recent assessment, as compared to those with a TMB <10 mut/Mb, achieved improved PFS and overall survival to ICI; instead, no differences were observed when patients were categorized using the oldest TMB assessment. CONCLUSIONS: Despite intrapatient concordance in PD-L1 and TMB, variation in these biomarkers can influence ICI outcomes, warranting consideration for reassessment before ICI initiation when feasible.
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Antígeno B7-H1 , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Mutación , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Antígeno B7-H1/genética , Antígeno B7-H1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/inmunología , Masculino , Femenino , Anciano , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Anciano de 80 o más Años , Adulto , Supervivencia sin Progresión , PronósticoRESUMEN
The development of a scheme for the safety evaluation of mechanical recycling processes for polyethylene terephthalate (PET) is described. The starting point is the adoption of a threshold of toxicological concern such that migration from the recycled PET should not give rise to a dietary exposure exceeding 0.0025 µg kg(-1) bw day(-1), the exposure threshold value for chemicals with structural alerts raising concern for potential genotoxicity, below which the risk to human health would be negligible. It is practically impossible to test every batch of incoming recovered PET and every production batch of recycled PET for all the different chemical contaminants that could theoretically arise. Consequently, the principle of the safety evaluation is to measure the cleaning efficiency of a recycling process by using a challenge test with surrogate contaminants. This cleaning efficiency is then applied to reduce a reference contamination level for post-consumer PET, conservatively set at 3 mg kg(-1) PET for a contaminant resulting from possible misuse by consumers. The resulting residual concentration of each contaminant in recycled PET is used in conservative migration models to calculate migration levels, which are then used along with food consumption data to give estimates of potential dietary exposure. The default scenario, when the recycled PET is intended for general use, is that of an infant weighing 5 kg and consuming every day powdered infant formula reconstituted with 0.75 L of water coming from water bottles manufactured with 100% recycled PET. According to this scenario, it can be derived that the highest concentration of a substance in water that would ensure that the dietary exposure of 0.0025 µg kg(-1) bw day(-1) is not exceeded, is 0.017 µg kg(-1) food. The maximum residual content that would comply with this migration limit depends on molecular weight and is in the range 0.09-0.32 mg kg(-1) PET for the typical surrogate contaminants.
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Contaminación de Alimentos/análisis , Embalaje de Alimentos , Análisis de Peligros y Puntos de Control Críticos/métodos , Tereftalatos Polietilenos/análisis , Tereftalatos Polietilenos/toxicidad , Reciclaje/métodos , Unión Europea , Contaminación de Alimentos/prevención & control , Embalaje de Alimentos/legislación & jurisprudencia , Humanos , Peso Molecular , Nivel sin Efectos Adversos Observados , Tereftalatos Polietilenos/química , Medición de RiesgoRESUMEN
A variety of melaware articles were tested for the migration of melamine into the food simulant 3% w/v acetic acid as a benchmark, and into other food simulants, beverages and foods for comparison. The results indicate that the acidity of the food simulant plays a role in promoting migration, but not by as much as might have been anticipated, since 3% acetic acid gave migration values about double those obtained using water under the same time and temperature test conditions. In contrast, migration into the fatty food simulant olive oil was not detectable and at least 20-fold lower than with the aqueous food simulants. This was expected given the solubility properties of melamine and the characteristics of the melaware plastic. Migration levels into hot acidic beverages (apple juice, tomato juice, red-fruit tea and black coffee) were rather similar to the acetic acid simulant when the same time and temperature test conditions are used, e.g. 2 h at 70°C. However, migration levels into foods that were placed hot into melaware articles and then allowed to cool on standing were much lower (6-14 times lower) than if pre-heated food was placed into the articles and then maintained (artificially) at that high temperature in the same way that a controlled time-temperature test using simulants would be conducted. This very strong influence of time and especially temperature was manifest in the effects seen of microwave heating of food or beverage in the melaware articles. Here, despite the short duration of hot contact, migration levels were similar to simulants used for longer periods, e.g. 70°C for 2 h. This is rationalized in terms of the peak temperature achieved on microwave heating, which may exceed 70°C, counterbalancing the shorter time period held hot. There was also evidence that when using melaware utensils in boiling liquids, as for stovetop use of spatulas, the boiling action of circulating food/simulant can have an additional effect in promoting surface erosion, increasing the plastic decomposition and so elevating the melamine release.
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Análisis de los Alimentos , Contaminación de Alimentos , Plásticos/química , Triazinas/análisis , Bebidas/análisis , Bebidas/efectos de la radiación , Seguridad de Productos para el Consumidor , Culinaria , Utensilios de Comida y Culinaria , Alimentos/efectos de la radiación , Manipulación de Alimentos/métodos , Embalaje de Alimentos , Formaldehído/química , Concentración de Iones de Hidrógeno , Microondas/efectos adversos , Modelos Químicos , Plásticos/efectos adversos , Plásticos/efectos de la radiación , Temperatura , Factores de Tiempo , Triazinas/químicaRESUMEN
For materials and articles intended to come in contact with food - particularly for substances from plastics (e.g., monomers, additives) - there are comprehensive European regulations based on toxicological evaluations. Other food contact materials, e.g., paper and rubber, are covered by resolutions established by the European Council without additional evaluations, while in Germany substances from these materials are toxicologically evaluated by the Federal Institute for Risk Assessment (BfR) and are included in the "BfR recommendations". Some further areas of food contact materials are not regulated by European or by national regulations (e.g., substances from printing inks). Recently, new European regulations for recycled plastics intended for food contact and for active and intelligent materials and articles have been released. Future challenges are the risk assessment of contaminants and reaction products from the production of food contact substances, which may migrate into the food in only tiny amounts, and of complex mixtures of substances, e.g., of hormone-like substances (endocrine disruptors).
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Defensa del Consumidor , Información de Salud al Consumidor/tendencias , Seguridad de Productos para el Consumidor , Inspección de Alimentos , Embalaje de Alimentos , Salud Pública/tendencias , Política Pública/tendencias , Administración de la Seguridad/tendencias , Europa (Continente) , AlemaniaRESUMEN
OBJECTIVES: Modular component separation following endovascular aortic repair is recognized as a potential source of late failure. The aim of this study was to establish the extent of component separation occurring in branched and fenestrated endografts and to ascertain any factors that predict its occurrence. DESIGN: An analysis of component relationships following fenestrated and branched endovascular aneurysm repair was conducted on all patients with >1 year of digital imaging data. A mathematical model was developed, and retrospectively applied, to determine the minimum stentgraft overlap required to preclude any risk of component separation. RESULTS: Of the 184 patients treated prior to 2006, data (for patients with greater than 1 year follow-up) were available for 106 patients. Fourteen (13%) had evidence of inter-component movement of which 8 developed component separation (<2 stent overlap). All 8 patients with component separation, in addition to 38% of the total cohort, were identified as being at risk for eventual component separation using the mathematical model. CONCLUSIONS: Component movement is commonly observed in modular devices, but clinical consequences are rare. The degree of overlap, aneurysm diameter, aneurysm length, and stentgraft diameter can be used to predict the risk of inter-component movement which may result in component separation.
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Aneurisma de la Aorta/cirugía , Implantación de Prótesis Vascular/instrumentación , Prótesis Vascular , Migración de Cuerpo Extraño/etiología , Falla de Prótesis , Stents , Algoritmos , Aneurisma de la Aorta/diagnóstico por imagen , Aortografía , Implantación de Prótesis Vascular/efectos adversos , Migración de Cuerpo Extraño/diagnóstico por imagen , Migración de Cuerpo Extraño/prevención & control , Humanos , Modelos Teóricos , Diseño de Prótesis , Estudios Retrospectivos , Medición de Riesgo , Tomografía Computarizada Espiral , Insuficiencia del TratamientoRESUMEN
PURPOSE: To evaluate a novel approach to preserve pelvic perfusion during endovascular AAA repair in patients with common iliac aneurysms extending to the iliac bifurcation. MATERIALS AND METHODS: A multicenter prospective analysis of patients undergoing implantation of a branched endograft designed to perfuse the internal iliac artery was conducted. All patients enrolled were considered high risk for open surgical repair and presented with common iliac artery aneurysms greater than 20mm and anatomy amenable to implant the branched device. Preoperative high resolution spiral CT, and follow-up CT studies in addition to abdominal radiographs were obtained at discharge, 1, 6, 12, and 24 months. RESULTS: Between 2003 and 2006, 52 patients (53 internal iliacs) were implanted with an investigational device. Mean common iliac aneurysm maximal diameter was 38 mm. The branch graft was combined with a proximal standard bifurcated component (61%), a fenestrated or a visceral branch component (33%), an aortouni-iliac component (2%), and alone in 2 patients (4%, following prior aortobi-iliac repair). Technical success was achieved in 94% of patients. Within the first month, 6 (11%) internal iliac branches occluded. No occlusions were noted after 1 month. The mean follow-up was 14.2 months. Common iliac aneurysm shrinkage was noted in 42% and 81% of patients at 6 and 12 months. There were no rupture, aneurysm related deaths or conversions, but there were 7 deaths during follow-up. CONCLUSIONS: The placement of endovascular prostheses that maintain antegrade perfusion of one or both internal iliac arteries is feasible, and early results provide evidence for optimism with regard to safety and efficacy.
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Aneurisma de la Aorta Abdominal/cirugía , Implantación de Prótesis Vascular/métodos , Prótesis Vascular , Aneurisma Ilíaco/cirugía , Anciano , Anciano de 80 o más Años , Femenino , Oclusión de Injerto Vascular , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Diseño de Prótesis , Ajuste de Prótesis , Grado de Desobstrucción VascularRESUMEN
The amended Council Directive 82/711/EEC will include the test conditions for plastic materials and articles intended to come into contact with foodstuffs at high temperature. The most stringent test condition (excluding susceptor materials) will be heating of the material for 2 h at 175 degrees C in a conventional oven. For fatty foodstuffs, olive oil (simulant D), synthetic triglycerides or sunflower oil shall be used for the test. If these simulants are found inappropriate, other simulants and conditions of time and temperature may be used. In order to perform a correct evaluation of such materials one must distinguish between volatile and non-volatile migrants, between additives and decomposition products, and between overall and specific migration. No universally applicable simulant has been found yet which is able to provide all the data needed for evaluation. The advantages and limitations of a high temperature-resistant simulant will be described.
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Utensilios de Comida y Culinaria/normas , Contaminación de Alimentos/análisis , Tecnología de Alimentos/legislación & jurisprudencia , Temperatura , Tecnología de Alimentos/normas , PolímerosRESUMEN
The genetic polymorphism of the single-locus probes pL159-1 (D18S17) and pL355-8 (D20S15) was investigated in 445 unrelated individuals using PstI as restriction enzyme. Fragment size calculations were obtained using the molecular weight size marker MW-SBH. The basic relationship between migration distance and molecular weight was transformed using an exponential function. Fragment size frequency data show 2 peaks for pL159-1 at 4.36kb (2.36%) and 4.67 kb (6.29%) and one peak for pL355-8 at 6.04 kb (5.73%). The rate of heterozygosity exceeded 70% for both probes.
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Sondas de ADN , Frecuencia de los Genes , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de Restricción , Secuencias Repetitivas de Ácidos Nucleicos , Alelos , Tamización de Portadores Genéticos , Alemania , Humanos , Peso Molecular , MutaciónRESUMEN
The activity of urease immobilized by adsorption on anodized sheet aluminium strongly depends on the method chosen for preparation of these carriers. If oxalic acid is applied as electrolyte, only the anodizing temperature significantly influences the activity of the preparations. In case of the well-known GS process, however, the activity is not only affected by the temperature, but also by other conditions of anodizing, for example the current density and the electrolyte concentration. For both methods the correlation between the topography of the carrier surfaces and the activity of enzyme immobilized to the surface is described.
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Enzimas Inmovilizadas/metabolismo , Ureasa/metabolismo , Aluminio , Cinética , Microscopía Electrónica de RastreoRESUMEN
Based on a concept of self-organization of older people and on the initiative of older Dortmund citizens a cooperative model of seniors' studies, the "Seniors" Academy is presented. The chances, but also the legal, organizational as well as the corporate difficulties of institutionalizing seniors' studies are identified.
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Anciano , Educación , Adulto , Alemania Occidental , Humanos , Persona de Mediana EdadRESUMEN
After application of SnCl2 and tin incorporated into baker's yeast, the effects on carbonic anhydrase (CA), glutathione peroxidase (GPx), lactate dehydrogenase (LDH), alkaline phosphatase (AP) and leucine aminopeptidase (LAP) were measured. The tin contents of liver and kidneys were determined. CA and GPx are not affected. AP and LAP are inhibited by high concentrations of tin (as SnCl2). Tin incorporated into yeast exerts no effect. Inorganic tin produces increases in liver and kidneys.
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Fluoruros/farmacología , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Saccharomyces cerevisiae/metabolismo , Fluoruros de Estaño/farmacología , Fosfatasa Alcalina/análisis , Fosfatasa Alcalina/antagonistas & inhibidores , Animales , Anhidrasas Carbónicas/análisis , Glutatión Peroxidasa/análisis , Riñón/enzimología , L-Lactato Deshidrogenasa/análisis , Dosificación Letal Mediana , Leucil Aminopeptidasa/análisis , Leucil Aminopeptidasa/antagonistas & inhibidores , Hígado/enzimología , Masculino , Ratas , Estaño , Fluoruros de Estaño/administración & dosificación , Fluoruros de Estaño/metabolismoRESUMEN
Tin incorporated in baker's yeast was applied to male Wistar rats over 21 days. The doses corresponded to 1/500 or 1/50 of LD50 of SnCl2 x 2H2O and 1/50 of LD50 of SnCl2 x 2H2O. The effects on activities of certain selected enzymes as well as on tin levels in liver and kidneys were tested. Some of the enzymes tested were found to reflect even exposures much below the point recordable from accumulation of the metal. Serum lactate-dehydrogenase is recommended as a sensitive indicator enzyme in the context of tin exposure.
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Saccharomyces cerevisiae/metabolismo , Estaño/toxicidad , Fosfatasa Alcalina/sangre , Animales , Anhidrasas Carbónicas/sangre , Glutatión Peroxidasa/sangre , Riñón/efectos de los fármacos , Riñón/metabolismo , L-Lactato Deshidrogenasa/sangre , Dosificación Letal Mediana , Leucil Aminopeptidasa/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratas , Estaño/metabolismoRESUMEN
Whole blood samples from 40 male and 40 female individuals were analyzed for zinc, copper, selenium and iron, and in part also for cadmium and lead. Correlations were established between the element contents and the activities of blood enzymes (carbo-anhydrase, leucine aminopeptidase, lactate dehydrogenase, alkaline phosphatase, glutathione peroxidase). The zinc-copper ratio exerted no effect on the zinc-dependent enzymes. There was a correlation between the glutathione peroxidase activity and the selenium content in whole blood (r greater than 0.73). A cluster analysis was performed. In women, the authors stated a significant effect of oral contraceptives especially on the zinc and copper balance. It was evidenced that detectable (more marked) changes in the mineral equilibrium are not produced in all cases by the contraceptives. Nevertheless, changes in the mineral equilibrium are likely to occur in 25% of all women. In the present study further changes (for example in enzymes) were observed in 50% of all women. The results obtained from the male individuals were indicative of certain relationships between the zinc-copper ratio and the content of total lipids or lipid fractions in human blood.
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Enzimas/sangre , Oligoelementos/sangre , Adulto , Fosfatasa Alcalina/sangre , Cadmio/sangre , Anhidrasas Carbónicas/sangre , Anticonceptivos Orales , Cobre/sangre , Femenino , Glutatión Peroxidasa/sangre , Humanos , Hierro/sangre , L-Lactato Deshidrogenasa/sangre , Plomo/sangre , Leucil Aminopeptidasa/sangre , Masculino , Selenio/sangre , Factores Sexuales , Oligoelementos/farmacología , Zinc/sangreRESUMEN
Clerical and administrative errors are the most common mistakes in blood banking, with errors of sample or patient identification accounting for the majority of mistakes. In an effort to reduce the incidence of human errors, three automated donor-recipient identification systems were developed and were evaluated under clinical conditions. After two years of development and bench testing, each set of equipment was tested, along with established procedures, at a large clinical center, a medium-sized community hospital and a regional donor center. Although none of the systems, as tested, proved acceptable under clinical conditions, a great deal was learned about prototype equipment testing in the clinical setting. Future development of identification systems for clinical use should respond to carefully defined problems, apply in all areas of the hospital or donor center, and be convenient and reliable. The development of the equipment should involve established manufacturers and be subject to exacting preclinical testing.