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BACKGROUND: Oncologists tend to under-report subjective symptoms during cancer treatment. This study describes the under-reporting rate of selected symptoms and explores its association with overall survival (OS). A secondary aim is to test the association of patient-reported symptoms with OS. PATIENTS AND METHODS: This is a post hoc analysis on data pooled from 12 randomized trials, promoted by the National Cancer Institute of Naples (Italy), enrolling patients between 2002 and 2019, with published primary analyses. Occurrence and grade of six side-effects (anorexia, nausea, vomiting, constipation, diarrhea and fatigue) reported by physicians were compared with corresponding symptoms reported by patients in quality-of-life (QoL) questionnaires. Under-reporting was defined as the rate of cases reported grade 0 by the physician while grade ≥1 by the patient. Prognostic value was tested in a multivariable model stratified by trial, including age, sex and performance status as confounders. A landmark threshold was defined for OS analyses. RESULTS: 3792 patients with advanced lung, ovarian, pancreatic, breast or colorectal cancer were pooled; 2603 (68.6%) were eligible having at least one toxicity assessment and one QoL questionnaire, before the first planned disease restaging. Concordance between physicians' and patients' reporting was low with Cohen's k coefficients ranging from 0.03 (fatigue) to 0.33 (vomiting). Under-reporting ranged from 52.7% (nausea) to 80.5% (anorexia), and was not associated with OS. Patient-reported anorexia, vomiting and fatigue ('a little' or more) were significantly associated with shorter OS. CONCLUSIONS: Under-reporting of treatment side-effects is frequent, but it does not affect OS. Patients' reported symptoms should be used for prognostic evaluation.
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Neoplasias , Qualidade de Vida , Humanos , Anorexia/complicações , Fadiga/etiologia , Náusea/etiologia , Neoplasias/terapia , Neoplasias/complicações , Prognóstico , Vômito , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
AIM: Acromegaly is a rare chronic disease, caused by the over-secretion of growth hormone (GH), that creates a pro-inflammatory state, but the exact mechanisms by which GH or insulin-like growth factor 1 (IGF-1) act on inflammatory cells are not fully understood. Aim of the study was to evaluate Interleukin-33 (IL33) and the skin perfusion of hands in patients with acromegaly (AP) and healthy controls (HC). METHODS: IL33 have been assessed in 40 AP and 40 HC. IL 33 was determined and skin perfusion of hands was assessed by laser speckle contrast analysis (LASCA) in both populations. RESULTS: IL33 was significantly higher in AP compared to HC [45.72 pg/ml (IQR 28.74-60.86) vs 14 pg/ml (IQR 6.5535); p < 0.05]. At LASCA, peripheral blood perfusion (PBP) was significantly lower in AP compared to HC [53.39 pU (IQR 40.94-65.44) vs 87 pU (IQR 80-98) p < 0.001]. The median values of ROI1, ROI2 and ROI3 were significantly lower in AP compared to HC [97.32 pU (IQR 50.89-121.69) vs 131 pU (IQR 108-135); p < 0.001], [58.68 pU (IQR 37.72-84.92) vs 83 pU (IQR 70-89), p < 0.05] and HC [52.16 (34.47-73.78) vs 85 (78-98), p < 0.001], respectively. The proximal-distal gradient (PDG) was observed in 18 of 40 (45%) AP. CONCLUSION: Serum IL33 is higher in AP compared to HC; conversely a reduction of PBP of hands was present in AP compared to HC, probably due to endothelial dysfunction, strictly dependent on acromegaly and are not influenced by the choice of treatment.
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Acromegalia , Inflamação , Interleucina-33 , Humanos , Acromegalia/metabolismo , Acromegalia/sangue , Acromegalia/complicações , Acromegalia/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Interleucina-33/sangue , Interleucina-33/metabolismo , Inflamação/metabolismo , Adulto , Estudos de Casos e Controles , Microvasos/patologia , Microvasos/metabolismo , Pele/irrigação sanguínea , Pele/patologia , Pele/metabolismo , Biomarcadores/sangue , Doença Crônica , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/metabolismo , Imagem de Contraste de Manchas a Laser/métodos , Estudos de Coortes , Mãos , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/análiseRESUMO
PURPOSE: Sexual dysfunctions are often experienced by male patients with acromegaly, due to a combination of hypogonadism and other comorbidities, but are a scarcely investigated complication. Erectile dysfunction is also closely related to cardiovascular diseases through endothelial dysfunction. Therefore, this project aimed to assess the prevalence of erectile dysfunction in a population of acromegalic men and evaluate its association with cardio-metabolic disorders, also exploring associations with androgen and estrogen receptor gene polymorphisms. METHODS: Sexually active men aged 18-65 with previous diagnosis of acromegaly were recruited. Clinical and laboratory data were retrospectively collected. Each patient also provided a blood sample for AR and ERß gene polymorphisms analyses and filled out the IIEF-15 questionnaire. RESULTS: Twenty men with previous diagnosis of acromegaly (mean age 48.4 ± 10.0 years) were recruited. 13/20 subjects (65%) had erectile dysfunction, but only four had a concurrent biochemical hypogonadism, with no significant correlation with IIEF-15 scores. Total testosterone negatively correlated with sexual intercourse satisfaction domain (ρ = - 0.595; p = 0.019) and general satisfaction domain (ρ = - 0.651; p = 0.009). IGF-1 levels negatively correlated with biochemical hypogonadism (ρ = - 0.585; p = 0.028). The number of CAG and CA repeats in AR and ERß receptors genes was not significantly associated with IIEF-15 scores or with GH/IGF-1 levels, but a negative correlation between CA repeats and the presence of cardiomyopathy (ρ = - 0.846; p = 0.002) was present. CONCLUSIONS: Men with acromegaly have a high prevalence of erectile dysfunction, but it does not appear to be correlated with treatments, testosterone levels and AR/ER-beta signaling. Nonetheless, a shorter CA polymorphic trait (ERbeta) is associated with the presence of cardiomyopathy. If confirmed, these data may suggest an association between an incorrect hormonal balance and increased cardiovascular risk in acromegaly subjects.
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Acromegalia , Cardiomiopatias , Disfunção Erétil , Hipogonadismo , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Androgênios , Disfunção Erétil/epidemiologia , Disfunção Erétil/genética , Acromegalia/complicações , Acromegalia/genética , Fator de Crescimento Insulin-Like I/genética , Estudos Retrospectivos , Receptor beta de Estrogênio/genética , Testosterona , Hipogonadismo/complicações , Hipogonadismo/epidemiologia , Hipogonadismo/genética , Polimorfismo Genético , EstrogêniosRESUMO
Major depressive disorder (MDD) is a complex illness that is arising as a growing public health concern. Although several brain areas are related to this type of disorders, at the cellular level, the parvalbumin-positive cells of the hippocampus interplay a very relevant role. They control pyramidal cell bursts, neuronal networks, basic microcircuit functions, and other complex neuronal tasks involved in mood disorders. In resistant depressions, the efficacy of current antidepressant treatments drops dramatically, so the new rapid-acting antidepressants (RAADs) are being postulated as novel treatments. Ketamine at subanesthetic doses and its derivative metabolites have been proposed as RAADs due to their rapid and sustained action by blocking N-methyl-d-aspartate (NMDA) receptors, which in turn lead to the release of brain-derived neurotrophic factor (BDNF). This mechanism produces a rapid plasticity activation mediated by neurotransmitter homeostasis, synapse recovery, and increased dendritic spines and therefore, it is a promising therapeutic approach to improve cognitive symptoms in MDD.
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Transtorno Depressivo Maior , Ketamina , Humanos , Ketamina/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Parvalbuminas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/metabolismo , Antidepressivos/uso terapêutico , Interneurônios/metabolismo , Hipocampo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismoRESUMO
INTRODUCTION: Stroke is highly prevalent in Latin America and one of the leading causes of morbidity and mortality in the world. Educating children about stroke has been established as an effective method to detect symptoms early, reduce hospital visits, and raise awareness among adults. OBJECTIVE: To analyze the effectiveness of a mobile application to improve knowledge and understanding of stroke among children. METHOD: We conducted a focus group session including 12 children in order to analyze the behavior of 6 questions previously validated by expert neurologists. Subsequently, 105 primary school students between the ages of 7 and 12 completed a questionnaire on stroke symptoms and how to contact the emergency services before and after using an application on stroke symptoms. Qualitative analyses and the Student t test were used to verify the existence of differences between pre- and post-intervention test results. RESULTS: After a single 40-min working session with the application, between 50% and 67% of the children were able to identify the signs of stroke, and 96.2% knew the national emergency services telephone number. Statistical analysis revealed statistically significant differences before and after the intervention with the digital application (t=19.54; p<0.001) and intragroup differences in the post-intervention test results (t=40.71; p<0.001). CONCLUSION: Primary school children who used our digital application increased their knowledge, understanding, and learning of stroke symptoms.
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Serviços Médicos de Emergência , Acidente Vascular Cerebral , Adulto , Criança , Humanos , Acidente Vascular Cerebral/diagnóstico , Aprendizagem , Inquéritos e QuestionáriosRESUMO
Objective.To decipher brain network dynamic remodeling from electroencephalography (EEG) during a complex postural control (PC) task combining virtual reality and a moving platform.Approach.EEG (64 electrodes) data from 158 healthy subjects were acquired. The experiment is divided into several phases, and visual and motor stimulation is applied progressively. We combined advanced source-space EEG networks with clustering algorithms to decipher the brain networks states (BNSs) that occurred during the task.Main results.The results show that BNS distribution describes the different phases of the experiment with specific transitions between visual, motor, salience, and default mode networks coherently. We also showed that age is a key factor that affects the dynamic transition of BNSs in a healthy cohort.Significance.This study validates an innovative approach, based on a robust methodology and a consequent cohort, to quantify the brain networks dynamics in the BioVRSea paradigm. This work is an important step toward a quantitative evaluation of brain activities during PC and could lay the foundation for developing brain-based biomarkers of PC-related disorders.
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Encéfalo , Fenômenos Fisiológicos do Sistema Nervoso , Humanos , Encéfalo/fisiologia , Eletroencefalografia/métodos , Mapeamento Encefálico , Equilíbrio Postural , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Maintaining angiogenesis inhibition and switching the chemotherapy backbone represent the current second-line therapy in patients with RAS-mutant metastatic colorectal cancer (mCRC). Regorafenib, an oral multikinase inhibitor, prolonged overall survival (OS) in the chemorefractory setting. MATERIALS AND METHODS: STREAM was an academic, multicenter, single-arm phase II trial, evaluating the activity of regorafenib in RAS-mutant mCRC, in terms of the rate of patients who were progression-free after 6 months from study entry (6mo-PF). Patients were pretreated with fluoropyrimidine, oxaliplatin, and bevacizumab. According to Simon's two-stage design, ≥18 patients 6mo-PF were needed in the overall population (N = 46). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS), and OS. Early metabolic response by [18F]2-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography ([18F]-FDG PET/CT) scan was an exploratory endpoint. EudraCT Number: 2015-001105-13. RESULTS: The number of patients 6mo-PF was 8/22 at the first stage and 14/46 in the overall population. The ORR was 10.9%, disease control rate was 54.6%, median (m)PFS was 3.6 months [95% confidence interval (CI) 1.9-6.7 months], mOS was 18.9 months (95% CI 10.3-35.3 months), and mPFS2 (from study entry to subsequent-line progression) was 13.3 months (95% CI 8.4-19.7 months). Long benefiter patients (>6mo-PF) significantly more often had a single metastatic site and lung-limited disease. No unexpected toxicity was reported. Grade ≥3 events occurred in 39.1% of patients, with hand-foot syndrome (13%), fatigue, and hyperbilirubinemia (6.5%) occurring mostly. Baseline metabolic assessment was associated with OS in the multivariate analysis, while early metabolic response was not associated with clinical outcomes. CONCLUSIONS: The study did not meet its primary endpoint. However, regorafenib was well tolerated and did not preclude subsequent treatments. Patients with good prognostic features (single metastatic site and lung-limited disease) reported clinical benefit with regorafenib. The exploratory metabolic analysis suggests that baseline [18F]-FDG PET/CT might be useful to select patients with a favorable outcome. A chemotherapy-free interval with regorafenib was associated with durable disease control in a selected group of patients with favorable clinical characteristics.
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Neoplasias do Colo , Neoplasias Colorretais , Humanos , Fluordesoxiglucose F18/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Piridinas/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológicoRESUMO
Objective.To define a new neurophysiological signature from electroencephalography (EEG) during a complex postural control task using the BioVRSea paradigm, consisting of virtual reality (VR) and a moving platform, mimicking the behavior of a boat on the sea.Approach.EEG (64 electrodes) data from 190 healthy subjects were acquired. The experiment is composed of 6 segments (Baseline, PRE, 25%, 50%, 75%, POST). The baseline lasts 60 s while standing on the motionless platform with a mountain view in the VR goggles. PRE and POST last 40 s while standing on the motionless platform with a sea simulation. The 3 other tasks last 40 s each, with the platform moving to adapt to the waves, and the subject holding a bar to maintain its balance. The power spectral density (PSD) difference for each task minus baseline has been computed for every electrode, for five frequency bands (delta, theta, alpha, beta, and low-gamma). Statistical significance has been computed.Main results.All the bands were significant for the whole cohort, for each task regarding baseline. Delta band shows a prefrontal PSD increase, theta a fronto-parietal decrease, alpha a global scalp power decrease, beta an increase in the occipital and temporal scalps and a decrease in other areas, and low-gamma a significant but slight increase in the parietal, occipital and temporal scalp areas.Significance.This study develops a neurophysiological reference during a complex postural control task. In particular, we found a strong localized activity associated with certain frequency bands during certain phases of the experiment. This is the first step towards a neurophysiological signature that can be used to identify pathological conditions lacking quantitative diagnostics assessment.
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Eletroencefalografia , Equilíbrio Postural , Humanos , Eletroencefalografia/métodos , Equilíbrio Postural/fisiologiaRESUMO
BACKGROUND: Subgroup analyses of randomized controlled trials are very common in oncology; nevertheless, the methodological approach has not been systematically evaluated. The present analysis was conducted with the aim of describing the prevalence and methodological characteristics of the subgroup analyses in randomized controlled trials in patients with advanced cancer. METHODS: A systematic literature search using PubMed was carried out to identify all phase III randomized controlled trials conducted in adult patients affected by locally advanced or metastatic solid tumours, published between 2017 and 2020. RESULTS: Overall, 253 publications were identified. Subgroup analyses were reported in 217 (86%) publications. A statistically significant association of presence of subgroup analysis with study sponsor was observed: subgroup analyses were reported in 157 (94%) for-profit trials compared with 60 (70%) non-profit trials (P < 0.001). Description of the methodology of subgroup analysis was completely lacking in 82 trials (38%), only cited without methodological details in 100 trials (46%) and fully described in 35 trials (16%). Forest plot of subgroup analyses for the primary endpoint was available in 195 publications (77%). Among publications with reported forest plots, the median number of subgroups for primary endpoint was 19 (range 6-78). Out of the 217 publications with subgroup analyses, authors discuss the heterogeneity of treatment effect among different subgroups in 173 publications (80%), although a formal test for interaction for subgroup analysis of primary endpoint was reported for at least one variable only in 60 publications (28%). Correction for multiplicity was explicitly carried out only in nine trials (4%). CONCLUSIONS: The very high prevalence of subgroup analyses in published papers, together with their methodological weaknesses, makes advisable an adequate education about their correct presentation and correct reading. More attention about proper planning and conduction of subgroup analysis should be paid not only by readers, but also by authors, journal editors and reviewers.
Assuntos
Neoplasias , Adulto , Humanos , Neoplasias/epidemiologia , Neoplasias/terapia , Oncologia , Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Bone is an extraordinary biological material that continuously adapts its hierarchical microstructure to respond to static and dynamic loads for offering optimal mechanical features, in terms of stiffness and toughness, across different scales, from the sub-microscopic constituents within osteons-where the cyclic activity of osteoblasts, osteoclasts, and osteocytes redesigns shape and percentage of mineral crystals and collagen fibers-up to the macroscopic level, with growth and remodeling processes that modify the architecture of both compact and porous bone districts. Despite the intrinsic complexity of the bone mechanobiology, involving coupling phenomena of micro-damage, nutrients supply driven by fluid flowing throughout hierarchical networks, and cells turnover, successful models and numerical algorithms have been presented in the literature to predict, at the macroscale, how bone remodels under mechanical stimuli, a fundamental issue in many medical applications such as optimization of femur prostheses and diagnosis of the risk fracture. Within this framework, one of the most classical strategies employed in the studies is the so-called Stanford's law, which allows uploading the effect of the time-dependent load-induced stress stimulus into a biomechanical model to guess the bone structure evolution. In the present work, we generalize this approach by introducing the bone poroelasticity, thus incorporating in the model the role of the fluid content that, by driving nutrients and contributing to the removal of wastes of bone tissue cells, synergistically interacts with the classical stress fields to change homeostasis states, local saturation conditions, and reorients the bone density rate, in this way affecting growth and remodeling. Through two paradigmatic example applications, i.e. a cylindrical slice with internal prescribed displacements idealizing a tract of femoral diaphysis pushed out by the pressure exerted by a femur prosthesis and a bone element in a form of a bent beam, it is highlighted that the present model is capable to catch more realistically both the transition between spongy and cortical regions and the expected non-symmetrical evolution of bone tissue density in the medium-long term, unpredictable with the standard approach. A real study case of a femur is also considered at the end in order to show the effectiveness of the proposed remodeling algorithm.
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Remodelação Óssea , Modelos Biológicos , Fenômenos Biomecânicos , Densidade Óssea , Fêmur , Nutrientes , Estresse MecânicoRESUMO
OBJECTIVE: Maintaining upright posture is a complex task governed by the integration of afferent sensorimotor and visual information with compensatory neuromuscular reactions. The objective of the present work was to characterize the visual dependency and functional dynamics of cortical activation during postural control. APPROACH: Proprioceptic vibratory stimulation of calf muscles at 85 Hz was performed to evoke postural perturbation in open-eye (OE) and closed-eye (CE) experimental trials, with pseudorandom binary stimulation phases divided into four segments of 16 stimuli. 64-channel EEG was recorded at 512 Hz, with perturbation epochs defined using bipolar electrodes placed proximal to each vibrator. Power spectra variation and linearity analysis was performed via fast Fourier transformation into six frequency bands (Δ, 0.5-3.5 Hz; θ, 3.5-7.5 Hz; α, 7.5-12.5 Hz; ß, 12.5-30 Hz; [Formula: see text], 30-50 Hz; and [Formula: see text], 50-80 Hz). Finally, functional connectivity assessment was explored via network segregation and integration analyses. MAIN RESULTS: Spectra variation showed waveform and vision-dependent activation within cortical regions specific to both postural adaptation and habituation. Generalized spectral variation yielded significant shifts from low to high frequencies in CE adaptation trials, with overall activity suppressed in habituation; OE trials showed the opposite phenomenon, with both adaptation and habituation yielding increases in spectral power. Finally, our analysis of functional dynamics reveals novel cortical networks implicated in postural control using EEG source-space brain networks. In particular, our reported significant increase in local θ connectivity may signify the planning of corrective steps and/or the analysis of falling consequences, while α band network integration results reflect an inhibition of error detection within the cingulate cortex, likely due to habituation. SIGNIFICANCE: Our findings principally suggest that specific cortical waveforms are dependent upon the availability of visual feedback, and we furthermore present the first evidence that local and global brain networks undergo characteristic modification during postural control.
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Córtex Cerebral/fisiologia , Habituação Psicofisiológica/fisiologia , Rede Nervosa/fisiologia , Equilíbrio Postural/fisiologia , Propriocepção/fisiologia , Vibração , Adaptação Fisiológica/fisiologia , Adulto , Eletroencefalografia/métodos , Feminino , Humanos , Masculino , Adulto JovemRESUMO
Total Hip Arthroplasty requires pre-surgical evaluation between un-cemented and cemented prostheses. A Patient with intra-operative periprosthetic fracture and another with a successful outcome were recruited, and their finite element models were constructed by processing CT data, assuming elastic-plastic behavior of the bone as function of the local density. To resemble the insertion of the prosthesis into the femur, a fictitious thermal dilatation is applied to the broach volume. Strain-based fracture risk factor is estimated, depicting results in terms of the total mechanical strain expressed using a simple "traffic lights" color code to provide immediate, concise, and intelligible pre-operative information to surgeons.
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Fraturas do Fêmur/cirurgia , Artroplastia de Quadril , Feminino , Fêmur/diagnóstico por imagem , Fêmur/cirurgia , Humanos , Masculino , Fatores de Risco , Estresse MecânicoRESUMO
AIMS: Glucagon-like peptide-1 (GLP-1) agonists improve glycaemic control in type 2 diabetes mellitus (DM). Outcome trials investigating macro and microvascular effects of GLP-1 agonists reported conflicting results. The aim of this study was to assess, in a meta-analysis, the effects of GLP-1 agonists on mortality, major nonfatal cardiovascular (CV) events, renal and retinal events. DATA SYNTHESIS: MEDLINE, Cochrane, ISI Web of Science, SCOPUS and ClinicalTrial.gov databases were searched for articles published until June 2017. Randomized trials enrolling more than 200 patients, comparing GLP-1 versus placebo or active treatments in patients with DM, and assessing outcomes among all-cause death, CV death, MI, stroke, HF, diabetic retinopathy and nephropathy were included. 77 randomized trials enrolling 60,434 patients were included. Compared to control, treatment with GLP-1 significantly reduced the risk of all-cause death (RR: 0.888; CI: 0.804-0.979; p = 0.018) and the risk of CV death (RR: 0.858; CI: 0.757-0.973; p = 0.017). GLP-1 agonists did not affect the risk of MI (RR: 0.917; CI: 0.830-1.014; p = 0.092) as well as the risk of stroke (RR: 0.882; CI: 0.759-1.023; p = 0.097), HF (RR: 0.967; CI: 0.803-1.165; p = 0.725), retinopathy (RR: 1.000; CI: 0.807-1.238; p = 0.997) and nephropathy (RR: 0.866; CI: 0.625-1.199; p = 0.385). CONCLUSIONS: Treatment with GLP-1 agonists in DM patients is associated with a significant reduction of all cause and CV mortality.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Peptídeo 1 Semelhante ao Glucagon/agonistas , Hipoglicemiantes/uso terapêutico , Incretinas/uso terapêutico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/mortalidade , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Incretinas/efeitos adversos , Medição de Risco , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Resultado do TratamentoRESUMO
AIM: The aim of this review was to summarize evidence on the role of Vitamin D deficiency in heart failure (HF), from pathophysiological mechanisms to clinical effects of Vitamin D supplementation. DATA SYNTHESIS: Chronic HF secondary to left ventricular (LV) systolic dysfunction is a growing health problem, still associated with poor clinical outcome. In recent years, experimental and epidemiological evidence focused on the role of Vitamin D in HF. Cross sectional studies demonstrated that prevalence of HF is increased in patients with Vitamin D deficiency or parathyroid hormone (PTH) plasma level increase, whereas longitudinal studies showed enhanced risk of developing new HF in patients with Vitamin D deficiency. In addition, in patients with established HF, low plasma levels of Vitamin D are associated with worsening clinical outcome. Yet, clinical studies did not definitively demonstrate a benefit of Vitamin D supplementation for preventing HF or ameliorating clinical outcome in patients with established HF. CONCLUSIONS: Despite convincing experimental and epidemiological data, treatment with Vitamin D supplementation did not show clear evidence of benefit for preventing HF or influencing its clinical course. Ongoing clinical studies will hopefully shed lights on the effects of Vitamin D supplementation on clinical endpoints along the spectrum of HF.
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Insuficiência Cardíaca/epidemiologia , Deficiência de Vitamina D/epidemiologia , Vitamina D/sangue , Animais , Biomarcadores/sangue , Doença Crônica , Suplementos Nutricionais , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Humanos , Hormônio Paratireóideo/sangue , Prevalência , Fatores de Risco , Resultado do Tratamento , Função Ventricular Esquerda , Remodelação Ventricular , Vitamina D/uso terapêutico , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/mortalidadeRESUMO
Purpose To establish a recommended phase II dose (RP2D) for the oral smoothened inhibitor sonidegib in combination with paclitaxel; secondary objectives include evaluation of safety, tolerability, markers of Hedgehog (Hh) signaling and preliminary antitumor activity. Methods Patients with advanced solid tumors were enrolled in cohorts of escalating sonidegib dose levels (400mg, 600mg and 800mg orally, once daily on days 1-28) in combination with paclitaxel 80 mg/m2 on days 1, 8 and 15 in 4-weekly cycles. Dose-limiting toxicities (DLTs) were assessed using CTCAE v4. Once the RP2D was defined, patients with advanced ovarian carcinoma were treated at this dose level in an expansion phase. Biomarkers of Hh signaling were assessed by immunohistochemistry in archival tissue and antitumor activity evaluated using RECIST 1.1. Results 18 patients were treated: 3 at 400 mg, 3 at 600 mg and 12 at 800 mg sonidegib. Only one patient treated at 800 mg presented a DLT (prolonged neutropenia resulting in failure to receive 75% of the planned sonidegib dose). However, 4 of 12 patients treated at 800 mg had their sonidegib dose reduced for toxicity after cycle 1. Hh biomarker (SHH, Patched, SMO and GLI1) staining did not correlate with clinical activity. Best response was partial response in 3 patients (2 ovarian, 1 breast cancer) and stable disease >4 cycles in 3 patients (2 ovarian, 1 anal cancer). Conclusions The combination of sonidegib and paclitaxel is tolerable and evidence of antitumor activity was identified. The RP2D of sonidegib was 800 mg in combination with paclitaxel 80mg/m2.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Receptor Smoothened/antagonistas & inibidores , Administração Oral , Idoso , Biomarcadores Tumorais , Compostos de Bifenilo/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Paclitaxel/administração & dosagem , Prognóstico , Piridinas/administração & dosagemRESUMO
OBJECTIVE: Hypersensitivity reactions (HSR) are frequently reported in patients rechallenged with carboplatin for recurrent ovarian cancer (ROC) and represent a critical issue, since discontinuation of the platinum-based therapy could affect prognosis. Several strategies to allow platinum rechallenge have been described, with controversial outcomes. The aim of this study is to illustrate a 10-year experience with cisplatin in patients with a previous HSR to carboplatin or at risk for allergy. METHODS: A retrospective review of all patients with platinum sensitive ROC retreated with carboplatin was performed between January 2007 and May 2016 at the Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples. RESULTS: Among 183 patients, 49 (26.8%) presented HSR to carboplatin, mainly during second line therapy. Mean number of cycles before HSR was 8 (range 3-17). G2, G3 and G4 reaction were detected in 83%, 15% and 2% of patients, respectively. In a multivariate analysis including age, hystotype, BRCA status, previous known HSR, and combination drug administered, only the type of carboplatin-based doublet used as 2nd line therapy was found to significantly affect HSR development, with a protective effect of PLD (pegylated liposomal doxorubicin) (p = 0.014, OR = 0.027). Thirty seven patients (77%) with a previous HSR to carboplatin were rechallenged with cisplatin. Treatment was generally well tolerated. 5 patients (13.1%) experienced mild HSR to cisplatin, successfully managed in all cases. 14 patients were treated with cisplatin even without a carboplatin-related HSR due to other allergies. Among these, only one developed HSR (7.1%). CONCLUSIONS: Cisplatin rechallenge is a feasible approach in patients experiencing HSR to carboplatin to maintain the beneficial effect of platinum while reducing hypersensitivity-related risks.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/efeitos adversos , Cisplatino/administração & dosagem , Hipersensibilidade a Drogas/etiologia , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/imunologia , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Polietilenoglicóis/administração & dosagem , Estudos Retrospectivos , GencitabinaRESUMO
Computed tomography (CT) provides both anatomical and density information about tissues. Bone is segmented by raw images and Finite Element Method (FEM) voxel-based meshing technique is achieved by matching each CT voxel to a single finite element (FE). As a consequence of the automated model reconstruction, unstable elements - i.e. elements insufficiently anchored to the whole model and thus potentially involved in partial rigid body motion - can be generated, a crucial problem in obtaining consistent FE models, hindering mechanical analyses. Through the classification of instabilities on topological connections between elements, a numerical procedure is proposed in order to avoid unconstrained models.
Assuntos
Osso e Ossos/ultraestrutura , Análise de Elementos Finitos , Biologia Computacional , Humanos , Processamento de Imagem Assistida por Computador , Modelos Biológicos , Tomografia Computadorizada por Raios XRESUMO
Muscle degeneration has been consistently identified as an independent risk factor for high mortality in both aging populations and individuals suffering from neuromuscular pathology or injury. While there is much extant literature on its quantification and correlation to comorbidities, a quantitative gold standard for analyses in this regard remains undefined. Herein, we hypothesize that rigorously quantifying entire radiodensitometric distributions elicits more muscle quality information than average values reported in extant methods. This study reports the development and utility of a nonlinear trimodal regression analysis method utilized on radiodensitometric distributions of upper leg muscles from CT scans of a healthy young adult, a healthy elderly subject, and a spinal cord injury patient. The method was then employed with a THA cohort to assess pre- and postsurgical differences in their healthy and operative legs. Results from the initial representative models elicited high degrees of correlation to HU distributions, and regression parameters highlighted physiologically evident differences between subjects. Furthermore, results from the THA cohort echoed physiological justification and indicated significant improvements in muscle quality in both legs following surgery. Altogether, these results highlight the utility of novel parameters from entire HU distributions that could provide insight into the optimal quantification of muscle degeneration.