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BACKGROUND: In patients with heart failure and reduced ejection fraction, sleep-disordered breathing, comprising obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is associated with increased morbidity, mortality, and sleep disruption. We hypothesised that treating sleep-disordered breathing with a peak-flow triggered adaptive servo-ventilation (ASV) device would improve cardiovascular outcomes in patients with heart failure and reduced ejection fraction. METHODS: We conducted a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial of peak-flow triggered ASV in patients aged 18 years or older with heart failure and reduced ejection fraction (left ventricular ejection fraction ≤45%) who were stabilised on optimal medical therapy with co-existing sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥15 events/h of sleep), with concealed allocation and blinded outcome assessments. The trial was carried out at 49 hospitals in nine countries. Sleep-disordered breathing was stratified into predominantly OSA with an Epworth Sleepiness Scale score of 10 or lower or predominantly CSA. Participants were randomly assigned to standard optimal treatment alone or standard optimal treatment with the addition of ASV (1:1), stratified by study site and sleep apnoea type (ie, CSA or OSA), with permuted blocks of sizes 4 and 6 in random order. Clinical evaluations were performed and Minnesota Living with Heart Failure Questionnaire, Epworth Sleepiness Scale, and New York Heart Association class were assessed at months 1, 3, and 6 following randomisation and every 6 months thereafter to a maximum of 5 years. The primary endpoint was the cumulative incidence of the composite of all-cause mortality, first admission to hospital for a cardiovascular reason, new onset atrial fibrillation or flutter, and delivery of an appropriate cardioverter-defibrillator shock. All-cause mortality was a secondary endpoint. Analysis for the primary outcome was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01128816) and the International Standard Randomised Controlled Trial Number Register (ISRCTN67500535), and the trial is complete. FINDINGS: The first and last enrolments were Sept 22, 2010, and March 20, 2021. Enrolments terminated prematurely due to COVID-19-related restrictions. 1127 patients were screened, of whom 731 (65%) patients were randomly assigned to receive standard care (n=375; mean AHI 42·8 events per h of sleep [SD 20·9]) or standard care plus ASV (n=356; 43·3 events per h of sleep [20·5]). Follow-up of all patients ended at the latest on June 15, 2021, when the trial was terminated prematurely due to a recall of the ASV device due to potential disintegration of the motor sound-abatement material. Over the course of the trial, 41 (6%) of participants withdrew consent and 34 (5%) were lost to follow-up. In the ASV group, the mean AHI decreased to 2·8-3·7 events per h over the course of the trial, with associated improvements in sleep quality assessed 1 month following randomisation. Over a mean follow-up period of 3·6 years (SD 1·6), ASV had no effect on the primary composite outcome (180 events in the control group vs 166 in the ASV group; hazard ratio [HR] 0·95, 95% CI 0·77-1·18; p=0·67) or the secondary endpoint of all-cause mortality (88 deaths in the control group vs. 76 in the ASV group; 0·89, 0·66-1·21; p=0·47). For patients with OSA, the HR for all-cause mortality was 1·00 (0·68-1·46; p=0·98) and for CSA was 0·74 (0·44-1·23; p=0·25). No safety issue related to ASV use was identified. INTERPRETATION: In patients with heart failure and reduced ejection fraction and sleep-disordered breathing, ASV had no effect on the primary composite outcome or mortality but eliminated sleep-disordered breathing safely.
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Síndromes da Apneia do Sono/complicações , Função Ventricular Esquerda , Volume Sistólico , Insuficiência Cardíaca/complicaçõesRESUMO
Ants patrol foliage and exert a strong selective pressure on herbivorous insects, being their primary predators. As ants are chemically oriented, some organisms that interact with them (myrmecophiles) use chemical strategies mediated by their cuticular hydrocarbons (CHCs) to deal with ants. Thus, a better understanding of the ecology and evolution of the mutualistic interactions between myrmecophiles and ants depends on the accurate recognition of these chemical strategies. Few studies have examined whether treehoppers may use an additional strategy called chemical camouflage to reduce ant aggression, and none considered highly polyphagous pest insects. We analyzed whether the chemical similarity of the CHC profiles of three host plants from three plant families (Fabaceae, Malvaceae, and Moraceae) and the facultative myrmecophilous honeydew-producing treehopper Aetalion reticulatum (Hemiptera: Aetalionidae), a pest of citrus plants, may play a role as a proximate mechanism serving as a protection against ant attacks on plants. We found a high similarity (>80%) between the CHCs of the treehoppers and two of their host plants. The treehoppers acquire CHCs through their diet, and the chemical similarity varies according to host plant. Chemical camouflage on host plants plays a role in the interaction of treehoppers with their ant mutualistic partners.
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PURPOSE: This Delphi panel study assessed the level of consensus between medical oncologists on the clinical management of patients with early-stage EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: A modified two-round Delphi approach was used. A scientific committee comprised of medical oncologists developed an online questionnaire. Delphi panel experts rated their level of agreement with each questionnaire statement on a 9-point Likert scale. The questionnaire included 36 statements from 3 domains (clinical management of early-stage NSCLC: 15 statements; role of adjuvant therapy in early-stage NSCLC: 9 statements; and role of adjuvant therapy in early-stage NSCLC with sensitizing EGFR mutation: 12 statements). RESULTS: In round 1, consensus was reached for 24/36 statements (66.7%). Nine statements that did not achieve consensus after the first round were evaluated in round 2, and none of them reached consensus. Overall, 84.4% of the panelists agreed that EGFR mutation testing should be done after surgery. Consensus was not achieved on whether the implementation of EGFR mutation testing in resected early-stage NSCLC could limit the use of adjuvant osimertinib. The panelists recognized the rationale for the use of osimertinib in the adjuvant scenario (88%) and 72% agreed that it may change the treatment paradigm in stage IB-IIIA EGFR-mutated NSCLC. Consensus was not reached on the inconvenience of prolonged duration of osimertinib. CONCLUSIONS: This Delphi study provides valuable insights into relevant questions in the management of early-stage EGFR-mutated NSCLC. However, specific issues remain unresolved. The expert consensus emphasizes the role of adjuvant treatment with osimertinib in this scenario.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Espanha , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamento farmacológico , Técnica Delphi , Receptores ErbB/genética , Receptores ErbB/uso terapêuticoRESUMO
The treatment of head and neck and salivary gland tumours is complicated and evolves constantly. Prognostic and predictive indicators of response to treatment are enormously valuable for designing individualized therapies, which justifies their research and validation. Some biomarkers, such as p16, Epstein-Barr virus, PD-L1, androgen receptors and HER-2, are already used routinely in clinical practice. These biomarkers, along with other markers that are currently under development, and the massively parallel sequencing of genes, ensure future advances in the treatment of these neoplasms. In this consensus, a group of experts in the diagnosis and treatment of tumours of the head and neck and salivary glands were selected by the Spanish Society of Pathology (Sociedad Española de Anatomía Patológica-SEAP) and the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica-SEOM) to evaluate the currently available information and propose a series of recommendations to optimize the determination and daily clinical use of biomarkers.
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Infecções por Vírus Epstein-Barr , Neoplasias de Cabeça e Pescoço , Neoplasias das Glândulas Salivares , Biomarcadores Tumorais , Consenso , Herpesvirus Humano 4 , Humanos , OncologiaRESUMO
The arrival of the coronavirus in 2020 brought major changes to education, with the rapid transition to online classes being the most significant. In the case of university students, the pandemic meant returning to their homes, which can be interpreted as a temporary destudentification. This manuscript analyses and interprets the motivations of university students from Temuco (Chile) to change their social relations and place of residence as a consequence of the COVID-19 pandemic. Through a quantitative methodology that used more than 800 online surveys and a principal component analysis, it was concluded that the psychological well-being and the security provided by the family were the main causes for changing accommodation; but a total of four main components related to material conditions, economic aspects, family and psychological and physical well-being were identified. Similarly, although with the pandemic the family was the most reinforced dimension in terms of social relations, there were groups of students who were more connected to friends and colleagues or neighbours. The results point to a partial and temporary destudentification, explainable by the nature of the lease contract and the dependent role of the students with respect to the landlords.
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BACKGROUND: 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA), the main benzoxazinoid found in corn, elicits variable larval responses from different pest moths. For the widespread and highly polyphagous Spodoptera frugiperda (Lepidoptera: Noctuidae), the fall-armyworm (FAW), DIMBOA acts as a feeding stimulant and improves larval growth at low concentrations. The FAW present two host plant-related strains, corn and rice strains, related to host preference on corn and other Graminae or rice. Based on both host preference and strain divergence of the FAW on corn, a cereal containing DIMBOA, and rice, lacking this compound, we question if corn and rice strains larvae respond equally toward DIMBOA. We evaluated differential expression in the transcriptome of both midgut and fat body larval tissues of the two strains reared on either DIMBOA-enriched artificial diet or control diet and inferred Bayesian networks. RESULTS: We found differences in performance between corn and rice strain larvae reared on DIMBOA, as well as several differentially regulated contigs annotated as esterases, peptidases, transferases and reductases, all of them known for being related to responses of lepidopterans and other insects to DIMBOA. We also found a UDP-glucuronosyltransferase very similar to others found in many lepidopterans occupying a central hub within a transferase Bayesian network, suggesting that it is essential to an effective response to DIMBOA in FAW. CONCLUSION: Our results suggest that there is an intrinsic cost for FAW rice strain larvae to metabolize corn-originated hydroxamic acids, which could have resulted in the partial host-associated genetic isolation found at FAW field populations.
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Benzoxazinas , Transcriptoma , Animais , Teorema de Bayes , Spodoptera/genética , Zea mays/genéticaRESUMO
In order to evaluate the geographic mosaic theory of coevolution, it is crucial to investigate geographical variation on the outcome of ecological interactions and the functional traits which dictate these outcomes. Plant populations are attacked by specialist and non-specialist herbivores and may have different types of chemical and biotic defences. We investigated geographical and seasonal variation in the interaction between the plant Crotalaria pallida and its two major herbivores (the specialist Utetheisa ornatrix and the non-specialist Etiella zinckenella). We first showed that attack by the two herbivores and a chemical and a biotic defence vary greatly in time and space. Second, we performed a common garden experiment that revealed genetic variation among populations in herbivore resistance and a chemical defence, but no genetic variation in a biotic defence. Third, we sampled 20 populations on a much larger geographical scale and showed great variation in attack rates by the two herbivores and a chemical defence. Finally, we showed that herbivory is not correlated with a chemical defence in the 20 field populations. Our study shows that to understand the evolution of ecological interactions it is crucial to investigate how the outcome of the interaction and the important species traits vary geographically and seasonally.
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Crotalaria/fisiologia , Herbivoria , Mariposas/fisiologia , Animais , Evolução Biológica , Crotalaria/genética , Feminino , Variação Genética , Masculino , Estações do AnoRESUMO
New onset of diabetes is associated with the use of statins. We have recently demonstrated that pravastatin-treated hypercholesterolemic LDL receptor knockout (LDLr-/- ) mice exhibit reductions in insulin secretion and increased islet cell death and oxidative stress. Here, we hypothesized that these diabetogenic effects of pravastatin could be counteracted by treatment with the antioxidant coenzyme Q 10 (CoQ 10 ), an intermediate generated in the cholesterol synthesis pathway. LDLr -/- mice were treated with pravastatin and/or CoQ 10 for 2 months. Pravastatin treatment resulted in a 75% decrease of liver CoQ 10 content. Dietary CoQ 10 supplementation of pravastatin-treated mice reversed fasting hyperglycemia, improved glucose tolerance (20%) and insulin sensitivity (>2-fold), and fully restored islet glucose-stimulated insulin secretion impaired by pravastatin (40%). Pravastatin had no effect on insulin secretion of wild-type mice. In vitro, insulin-secreting INS1E cells cotreated with CoQ 10 were protected from cell death and oxidative stress induced by pravastatin. Simvastatin and atorvastatin were more potent in inducing dose-dependent INS1E cell death (10-15-fold), which were also attenuated by CoQ 10 cotreatment. Together, these results demonstrate that statins impair ß-cell redox balance, function and viability. However, CoQ 10 supplementation can protect the statins detrimental effects on the endocrine pancreas.
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Hipercolesterolemia/tratamento farmacológico , Células Secretoras de Insulina/efeitos dos fármacos , Pravastatina/efeitos adversos , Receptores de LDL/metabolismo , Ubiquinona/análogos & derivados , Animais , Linhagem Celular , Sobrevivência Celular , Diabetes Mellitus/induzido quimicamente , Suplementos Nutricionais , Feminino , Teste de Tolerância a Glucose , Peróxido de Hidrogênio , Insulina , Fígado/metabolismo , Camundongos , Camundongos Knockout , Pravastatina/uso terapêutico , Receptores de LDL/genética , Ubiquinona/farmacologiaRESUMO
Se efectuó un estudio descriptivo y transversal de 46 pacientes con más de 18 años de edad, pertenecientes al consultorio 34 del área de salud del municipio de Majagua, provincia Ciego de Ávila, desde septiembre de 2015 hasta febrero de 2016. A todos los integrantes de la serie se les indicaron exámenes complementarios, tales como microalbuminuria, filtrado glomerular, creatinina, conteo de Addis y urea. No se realizaron estudios imagenológicos debido a la lejanía, las dificultades con el transporte y el equipo de ultrasonografía. La alteración de los marcadores renales estuvo presente en la mitad de los afectados con factores de riesgo, lo cual permitió detectar la enfermedad renal crónica de manera precoz en ese grupo poblacional
A descriptive and cross-sectional study of 46 patients older than 18 years, belonging to the doctor's office 34 of the health area in Majagua, Ciego de Ávila, was carried out from September, 2015 to February, 2016. The complementary tests were indicated to all the members of the series, such as microalbuminuria, glomerular filtration rate, creatinine, Addis and urea counts . The imagenologic studies were not carried out due to the long distance, difficulties with the transportation and the ultrasonography equipment. The disorder of renal markers was present in half of those affected patients with risk factors, which allowed to detect earlier the chronic renal disease in that population group
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Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Fatores de Risco , Insuficiência Renal Crônica/epidemiologia , Rim/fisiopatologia , Atenção Primária à Saúde , Epidemiologia Descritiva , Estudos TransversaisRESUMO
The exploration of new niches for microorganisms capable of degrading recalcitrant molecules is still required. We hypothesized the gut microbiota associated with insect-resistant lines carry pesticide degrading bacteria, and predicted they carry bacteria selected to degrade pesticides they were resistant to. We isolated and accessed the pesticide-degrading capacity of gut bacteria from the gut of fifth instars of Spodoptera frugiperda strains resistant to lambda-cyhalothrin, deltamethrin, chlorpyrifos ethyl, spinosad and lufenuron, using insecticide-selective media. Sixteen isolates belonging to 10 phylotypes were obtained, from which four were also associated with the susceptible strain. However, growth of gut bacteria associated with larvae from the susceptible strain was not obtained in any of the insecticide-based selective media tested. Growth of isolates was affected by the concentration of insecticides in the media, and all grew well up to 40 µg/ml. The insecticide-degrading capacity of selected isolates was assessed by GC or LC-MS/MS analyses. In conclusion, resistant strains of S. frugiperda are an excellent reservoir of insecticide-degrading bacteria with bioremediation potential. Moreover, gut-associated bacteria are subjected to the selection pressure imposed by insecticides on their hosts and may influence the metabolization of pesticides in insects.
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Microbioma Gastrointestinal/fisiologia , Inseticidas/farmacologia , Animais , Bactérias/efeitos dos fármacos , Benzamidas/farmacologia , Biotecnologia , Combinação de Medicamentos , Cromatografia Gasosa-Espectrometria de Massas , Macrolídeos/farmacologia , Nitrilas/farmacologia , Piretrinas/farmacologia , Spodoptera/microbiologia , Espectrometria de Massas em TandemRESUMO
Danaus butterflies sequester pyrrolizidine alkaloids (PAs) from nectar and leaves of various plant species for defense and reproduction. We tested the hypothesis that the southern monarch butterfly Danaus erippus shows innate preferences for certain flower colors and has the capacity to develop learned preferences for artificial flowers presenting advantageous floral rewards such as PAs. We predicted that orange and yellow flowers would be innately preferred by southern monarchs. Another prediction is that flowers with both sucrose and PAs would be preferred over those having sucrose only, regardless of flower color. In nature, males of Danaus generally visit PA sources more often than females, so we expected that males of D. erippus would exhibit a stronger learned preference for PA sources than the females. In the innate preference tests, adults were offered artificial non-rewarding yellow, orange, blue, red, green, and violet flowers. Orange and yellow artificial flowers were most visited by southern monarchs, followed by blue and red ones. No individual visited either green or violet flowers. For assessing learned preferences for PA flowers over flowers with no PAs, southern monarchs were trained to associate orange flowers with sucrose plus the PA monocrotaline vs. yellow flowers with sucrose only; the opposite combination was used to train another set of butterflies. In the tests, empty flowers were offered to trained butterflies. Neither males nor females showed learned preferences for flower colors associated with PAs in the training set. Thus, southern monarchs resemble the sister species Danaus plexippus in their innate preferences for orange and yellow flowers. Southern monarchs, similarly to temperate monarchs, might not be as PA-demanding as are other danaine species.
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Borboletas/fisiologia , Flores/metabolismo , Néctar de Plantas/metabolismo , Alcaloides de Pirrolizidina/metabolismo , Animais , Comportamento Animal , Cor , Feminino , Preferências Alimentares , Aprendizagem , Masculino , Monocrotalina/metabolismo , Sacarose/metabolismoRESUMO
Larvae of tortoise beetles are postulated to have fecal shields as the main defensive strategy against predators. Such a device protects beetles both physically and chemically. In order to examine how larvae Chelymorpha reimoseri are protected against predatory ants, which frequently visit extrafloral nectaries in their host plant, the morning glory Ipomoea carnea, we conducted anti-predation bioassays with live 5th instars. In the field, larvae in contact with ants had survival between 40 and 73 %, independently of shield presence. In the laboratory, when exposed to Camponotus crassus, larvae with shields had significantly higher survival (85 %) than those without shields (64 %). In both scenarios, larval survival was significantly higher when compared with palatable Spodoptera frugiperda larvae, as the latter were all consumed. We also observed that when C. reimoseri larvae showed no movement, the ants walked on them without attacking. We hypothesized that if the larval integument has a pattern of cuticular compounds (CCs) similar to that of its host plant, larvae would be rendered chemically camouflaged. In the field and laboratory, the freeze-dried palatable larvae of S. frugiperda treated with CCs of 5th instar C. reimoseri and left on I. carnea leaves were significantly less removed by ants than controls without these compounds. We also found a similarity of approximately 50 % between the CCs in C. reimoseri larvae and I. carnea host leaves. Both findings provide evidence in support of the hypothesis that chemical camouflage plays an important role in larval defense, which is reported for the first time in an ectophagous leaf beetle larva.
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Formigas/fisiologia , Besouros/fisiologia , Cadeia Alimentar , Comportamento Predatório , Animais , Brasil , Galinhas/fisiologia , Besouros/química , Besouros/crescimento & desenvolvimento , Fezes/química , Cromatografia Gasosa-Espectrometria de Massas , Tegumento Comum/fisiologia , Ipomoea/química , Larva/química , Larva/fisiologia , Folhas de Planta/química , Spodoptera/fisiologiaRESUMO
Se realizó un estudio descriptivo, longitudinal y prospectivo de 2 401 pacientes con hipertensión arterial, pertenecientes al área de salud del Policlínico Universitario "Ramón López Peña" de Santiago de Cuba, desde enero de 2010 hasta igual mes de 2012, a fin de caracterizarles según variables clínicas y epidemiológicas de interés. En la serie se encontró una elevada incidencia de esta afección en los adolescentes y una alta prevalencia en la cuarta y quinta décadas de la vida, sobre todo en quienes tenían antecedentes patológicos familiares de ese proceso morboso y factores de riesgo asociados. Las complicaciones aparecieron después de 10 años de evolución clínica en aquellos con descontrol de su padecimiento, atribuible fundamentalmente al abandono del tratamiento y/o mal uso de los fármacos, en su mayoría consistentes en diuréticos tiazídicos e inhibidores de la enzima de conversión de la angiotensina, además del escaso empleo de medicamentos no farmacológicos. Se impone continuar insistiendo en la educación sanitaria relacionada con esta enfermedad crónica no trasmisible en la atención primaria de salud.
A descriptive, longitudinal and prospective study was conducted in 2 401 patients with hypertension, belonging to the health area of "Ramón López Peña" University Polyclinic of Santiago de Cuba, from January 2010 to the same month of 2012, in order to characterize them according to clinical and epidemiological variates of interest. In the series a high incidence of this condition in adolescents and a high prevalence in the fourth and fifth decades of life were found, especially in those who had family medical history of the disease and associated risk factors. Complications appeared after 10 years of clinical course in those with uncontrolled condition, attributable mainly to the discontinuation of treatment and/or misuse of drugs, mostly consisting in thiazide diuretics and inhibitors of the angiotensin converting enzyme in addition to the limited use of non-pharmacological drugs. It is imposed to continue insisting on health education related to this chronic non-communicable disease in primary health care.
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Fatores de Risco , Hipertensão , Atenção Primária à Saúde , Doença Crônica , Incidência , PrevalênciaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: In Brazilian traditional medicine, Arctium lappa (Asteraceae), has been reported to relieve gastrointestinal symptoms. AIM OF THE STUDY: In the present study, we investigated the effects of the lactone sesquiterpene onopordopicrin enriched fraction (ONP fraction) from Arctium lappa in an experimental colitis model induced by 2,4,6 trinitrobenzene sulfonic acid and performed experiments to elucidate the underlying action mechanisms involved in that effect. MATERIALS AND METHODS: ONP fraction (25 and 50 mg/kg/day) was orally administered 48, 24 and 1 h prior to the induction of colitis and 24 h after. The inflammatory response was assessed by gross appearance, myeloperoxidase (MPO) activity, tumor necrosis factor alpha (TNF-α) levels and a histological study of the lesions. We determined cyclooxygenase (COX)-1 and -2 protein expressions by western blotting and immunohistochemistry assays. RESULTS: TNBS group was characterized by increased colonic wall thickness, edema, diffuse inflammatory cell infiltration, increased MPO activity and TNF-α levels. On the contrary, ONP fraction (25 and 50 mg/kg) treatment significantly reduced the macroscopic inflammation scores (p<0.05 and p<0.01, respectively) and morphological alterations associated with an increase in the mucus secretion. Similarly, the degree of neutrophil infiltration and the cytokine levels were significantly ameliorated. Moreover, COX-2 expression was up regulated in TNBS-treated rats. In contrast, ONP fraction (50 mg/kg) administration reduced COX-2 overexpression. CONCLUSIONS: We have shown that the ONP fraction obtained from Arctium lappa exert marked protective effects in acute experimental colitis, confirming and justifying, at least in part, the popular use of this plant to treat gastrointestinal diseases.
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Anti-Inflamatórios/uso terapêutico , Arctium , Colite/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Animais , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Masculino , Peroxidase/metabolismo , Fitoterapia , Folhas de Planta , Ratos , Ratos Wistar , Ácido Trinitrobenzenossulfônico , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: This study analyzes the morbidity and the contribution of different causes of death to the outcome of patients with locally advanced head and- neck cancer after weekly cisplatin plus concomitant boost accelerated radiation treated in our center. MATERIALS AND METHODS: Ninety-four patients with locally advanced head and neck carcinoma were included in this phase II trial consisting of concomitant boost radiation plus concurrent weekly cisplatin. The 43 patients treated in our centered with long-term follow-up were analyzed. Patients received radiotherapy with a concomitant boost scheme (1.8 Gy on days 1-40 and 1.5 Gy boost on days 25-40 with a total dose of 72 Gy) and concurrent cisplatin, 40 mg/m(2) weekly, for the first 4 weeks. RESULTS: Most patients (93 %) received both radiation and complete chemotherapy according to protocol. Severe late toxicity presented were subcutaneous (5 %), larynx (2 %) and esophagous (5 %). Grade I-II late toxicity included mainly xerostomy (30 %), skin (16 %) and mucosal (16 %) toxicity. With a median follow-up of 95 months (9-135), the median overall survival and progression-free survival were 26 and 19 months, respectively (95 % CI 1-52; and 95 % CI 0-45); 60 % of the patients died because of head and neck cancer and 12 % of a second neoplasm, while 27 % of non-cancer patients died. CONCLUSIONS: Patients with locoregionally advanced head and neck cancer treated with concomitant boost accelerated radiation plus chemotherapy show significant risks of mortality from causes other than disease progression.
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Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Cisplatino/administração & dosagem , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/terapia , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma de Células Escamosas/patologia , Causas de Morte , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Cisplatino/efeitos adversos , Progressão da Doença , Esquema de Medicação , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Radioterapia Adjuvante/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
For drugs such as anticancer agents every effort should be made to minimize inter-patient variability in drug exposure in order to maximize the benefit while maintaining an acceptable risk level of serious adverse effects. Anticancer drugs generally have a preferential route of elimination, either in urine or in bile and feces. In consequence, dose individualization to renal and liver function permits excessive toxicity to be avoided and expected therapeutic benefit to be achieved. However, less is known about the most appropriate starting doses of antineoplastic agents in these individuals. In this review, we discuss trials that have specifically assessed new targeted agents dosing strategies (mainly monoclonal antibodies and tyrosine kinase inhibitors) in the setting of overt biochemical renal and liver dysfunction and we proportionate recommendations and practical guidelines for dose individualization.
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Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Terapia de Alvo Molecular , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Proteínas Tirosina Quinases/antagonistas & inibidoresRESUMO
The adverse effects associated to traditional chemotherapy are well known and broadly studied. In the recent years several tyrosine kinase inhibitors have been approved for cancer treatment and numerous are under investigation. These drugs target specific mutated/overexpressed tyrosin kinase receptors and frecuently their pharmacokinetic/pharmacodinamic behavior is not fully elucidated. These new drugs may interact with non-antineoplastic drugs leading to undesirable adverse effects. In this article, we will discuss different types of drug interactions and briefly review the pharmacokinetics and mechanisms of action of tyrosine kinase inhibitors in clinical use, with a particular emphasis on the risk of the occurrence of such interactions based on currently available scientific evidence.
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Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Interações Medicamentosas , HumanosRESUMO
Arctium lappa L. has been used in folk medicine as a diuretic, depurative, and digestive stimulant and in dermatological conditions. The mechanisms involved in the anti-ulcerogenic activity of the sesquiterpene onopordopicrin (ONP)-enriched fraction (termed the ONP fraction), obtained from A. lappa leaves, were studied. The gastroprotective mechanism of the ONP fraction was evaluated in experimental in vivo models in rodents, mimicking this disease in humans. ONP fraction (50 mg/kg, p.o.) significantly inhibited the mucosal injury induced by ethanol/HCl solution (75%), indomethacin/bethanecol (68.9%), and stress (58.3%). When the ONP fraction was investigated in pylorus ligature, it did not induce alteration in the gastric volume but did modify the pH and total acid concentration of gastric juice. ONP fraction significantly increased serum somatostatin levels (82.1±4.1 vs. control group 12.7±4 pmol/L) and decreased serum gastrin levels (62.6±6.04 vs. control group 361.5±8.2 µU/mL). Mucus production was not significantly altered by the ONP fraction. Gastroprotection by the ONP fraction was completely inhibited by N-ethylmaleimide treatment and did not modify the effect in the animals pretreated with l-N(G)-nitroarginine methyl ester. These results suggest an antisecretory mechanism involved with the antiulcerogenic effect of the ONP fraction. However, only endogenous sulfhydryls play an important role in gastroprotection of the ONP fraction.
Assuntos
Arctium/química , Gastrinas/metabolismo , Lactonas/farmacologia , Óxido Nítrico/metabolismo , Sesquiterpenos/farmacologia , Somatostatina/metabolismo , Compostos de Sulfidrila/metabolismo , Animais , Antiulcerosos/farmacologia , Betanecol/metabolismo , Etanol/efeitos adversos , Etilmaleimida , Cromatografia Gasosa-Espectrometria de Massas , Suco Gástrico/efeitos dos fármacos , Mucosa Gástrica/efeitos dos fármacos , Indometacina/efeitos adversos , Indometacina/metabolismo , Masculino , Medicina Tradicional , Extratos Vegetais/farmacologia , Folhas de Planta/química , Ratos , Ratos WistarRESUMO
AIM: Oncologists should carefully weigh up the risks and benefits of palliative chemotherapy in patients with advanced solid tumours (AST) and poor general status from the standpoint both of medical and ethical issues and of healthcare resources required. This study is intended to assess the impact on overall survival of palliative chemotherapy in patients with AST and admitted to hospital as a result of their poor ECOG status. MATERIALS AND METHODS: We performed a retrospective analysis of 92 hospitalised patients with AST, ECOG 3-4, who were treated with palliative chemotherapy. Uni- and multivariate statistical analyses were conducted to determine the impact of clinical and disease variables (number of previous chemotherapy lines, presence of comorbidities, presentation of anorexia-cachexia syndrome, delirium, dyspnoea, ascitis, brain metastases, T-cell count, albumin, haemoglobin and LDH) on survival in this patient population. RESULTS: Mean age was 54 years (range 15-80). No chemotherapy had been given for advanced disease in 74%, 13% had received one line, 6% 2 lines and 7% ≥3 lines. Median survival, i.e., after initiation of chemotherapy to death, in these patients was 33 days (range 1-1390). The median of chemotherapy cycles was 1. In the multivariate analysis, no previous chemotherapy, and absence of anorexia-cachexia syndrome and of comorbidities was associated with significantly improved survival in patients. Forty-nine percent of patients died within 30 days of therapy, 28% died between days 30 and 90, and only 23% of patients lived longer than 90 days. Grade 3-4 toxicities mainly entailed blood disorders, namely anaemia 8%, neutropenia 13% and thrombocytopenia 8%. Six patients (5%) developed sepsis after therapy; of these, 3 died from this toxicity, 1 patient suffered cardiac toxicity, one patient leukoencephalopathy and 1 patient acute pulmonary thromboembolism. CONCLUSION: Palliative chemotherapy given to patients with AST and ECOG 3-4 with short life expectancy provided no benefit for survival. As a result, we may be over-treating these patients and contributing to poor-quality care.