RESUMO
BACKGROUND: Stereotactic radiosurgery (SRS) is a frequently chosen treatment for patients with brain metastases and the number of long-term survivors is increasing. Brain necrosis (e.g. radionecrosis) is the most important long-term side effect of the treatment. Retrospective studies show a lower risk of radionecrosis and local tumor recurrence after fractionated stereotactic radiosurgery (fSRS, e.g. five fractions) compared with stereotactic radiosurgery in one or three fractions. This is especially true for patients with large brain metastases. As such, the 2022 ASTRO guideline of radiotherapy for brain metastases recommends more research to fSRS to reduce the risk of radionecrosis. This multicenter prospective randomized study aims to determine whether the incidence of adverse local events (either local failure or radionecrosis) can be reduced using fSRS versus SRS in one or three fractions in patients with brain metastases. METHODS: Patients are eligible with one or more brain metastases from a solid primary tumor, age of 18 years or older, and a Karnofsky Performance Status ≥ 70. Exclusion criteria include patients with small cell lung cancer, germinoma or lymphoma, leptomeningeal metastases, a contraindication for MRI, prior inclusion in this study, prior surgery for brain metastases, prior radiotherapy for the same brain metastases (in-field re-irradiation). Participants will be randomized between SRS with a dose of 15-24 Gy in 1 or 3 fractions (standard arm) or fSRS 35 Gy in five fractions (experimental arm). The primary endpoint is the incidence of a local adverse event (local tumor failure or radionecrosis identified on MRI scans) at two years after treatment. Secondary endpoints are salvage treatment and the use of corticosteroids, bevacizumab, or antiepileptic drugs, survival, distant brain recurrences, toxicity, and quality of life. DISCUSSION: Currently, limiting the risk of adverse events such as radionecrosis is a major challenge in the treatment of brain metastases. fSRS potentially reduces this risk of radionecrosis and local tumor failure. TRIAL REGISTRATION: ClincalTrials.gov, trial registration number: NCT05346367 , trial registration date: 26 April 2022.
Assuntos
Neoplasias Encefálicas , Lesões por Radiação , Radiocirurgia , Humanos , Adolescente , Radiocirurgia/efeitos adversos , Qualidade de Vida , Estudos Retrospectivos , Estudos Prospectivos , Resultado do Tratamento , Neoplasias Encefálicas/patologia , Lesões por Radiação/epidemiologia , Lesões por Radiação/etiologia , Lesões por Radiação/cirurgiaRESUMO
OBJECTIVE: Pre-eclampsia is a vascular complication of pregnancy, associated with a long-term risk of cerebrovascular and mental disorders. We explored whether formerly pre-eclamptic women exhibit differences in functional brain organization, especially in regions that may explain the commonly reported emotional symptoms and cognitive complaints even years after the pregnancy. METHODS: Formerly pre-eclamptic women and control women with a history of normotensive pregnancy underwent structural and functional 7-Tesla magnetic resonance imaging scans. Using graph theoretical analysis, the efficiency and clustering coefficient of the functional brain network were investigated. The study included local analysis focusing on particular brain structures, such as the limbic system and the prefrontal cortex, and global analysis of the whole cerebrum. Univariable and multivariable linear regression was used to investigate the relationship between brain network-related graph measures and the group (formerly pre-eclamptic or control). RESULTS: A total of 17 control parous women and 55 women with a history of pre-eclampsia were recruited. The time intervals between the index pregnancy and recruitment were 8.0 and 5.6 years for the two groups, respectively. Compared with control women, formerly pre-eclamptic women had higher local efficiency in the prefrontal cortex (P = 0.048) and anterior cingulate cortex (P = 0.03) but lower local efficiency and local clustering coefficient in the amygdala (P = 0.004 and P = 0.02, respectively) and parahippocampal cortex (P = 0.007 and P = 0.008, respectively). No differences were found in the global functional brain organization. CONCLUSIONS: Compared to controls with a history of normotensive pregnancy, formerly pre-eclamptic women displayed a different local functional brain organization. These differences in functional connectivity, especially in the limbic regions and the prefrontal cortex, are in line with the psychological and cognitive complaints reported commonly by women with a history of pre-eclampsia. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Assuntos
Pré-Eclâmpsia , Pressão Sanguínea , Feminino , Humanos , Sistema Límbico/diagnóstico por imagem , Sistema Límbico/patologia , Imageamento por Ressonância Magnética , Córtex Pré-Frontal/diagnóstico por imagem , GravidezRESUMO
OBJECTIVE: Pre-eclampsia is a hypertensive complication of pregnancy that is associated with an increased risk of long-term cardiovascular and cerebrovascular disorders. Although the underlying mechanism of persistent susceptibility to cerebral complications after pre-eclampsia remains largely unclear, impaired blood-brain barrier (BBB) integrity has been suggested to precede several cerebrovascular diseases. In this study, we aimed to investigate the integrity of the BBB years after pre-eclampsia. METHODS: This was an observational study of premenopausal formerly pre-eclamptic women and controls with a history of normotensive pregnancy who underwent cerebral magnetic resonance imaging (MRI) at ultra-high field (7 Tesla) to assess the integrity of the BBB. Permeability of the BBB was determined by assessing leakage rate and fractional leakage volume of the contrast agent gadobutrol using dynamic contrast-enhanced MRI. BBB leakage measures were determined for the whole brain and lobar white and gray matter. Multivariable analyses were performed, and odds ratios were calculated to compare women with and those without a history of pre-eclampsia, adjusting for potential confounding effects of age, hypertension status at MRI and Fazekas score. RESULTS: Twenty-two formerly pre-eclamptic women (mean age, 37.8 ± 5.4 years) and 13 control women with a history of normotensive pregnancy (mean age, 40.8 ± 5.5 years) were included in the study. The time since the index pregnancy was 6.6 ± 3.2 years in the pre-eclamptic group and 9.0 ± 3.7 years in controls. The leakage rate and fractional leakage volume were significantly higher in formerly pre-eclamptic women than in controls in the global white (P = 0.001) and gray (P = 0.02) matter. Regionally, the frontal (P = 0.04) and parietal (P = 0.009) cortical gray matter, and the frontal (P = 0.001), temporal (P < 0.05) and occipital (P = 0.007) white matter showed higher leakage rates in formerly pre-eclamptic women. The odds of a high leakage rate after pre-eclampsia were generally higher in white-matter regions than in gray-matter regions. CONCLUSION: This observational study demonstrates global impairment of the BBB years after a pre-eclamptic pregnancy, which could be an early marker of long-term cerebrovascular disorders. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Assuntos
Hipertensão , Pré-Eclâmpsia , Adulto , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/patologia , Meios de Contraste , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , GravidezRESUMO
Current antileishmanial treatment is hampered by limitations, such as drug toxicity and the risk of treatment failure, which may be related to parasitic drug resistance. Given the urgent need for novel drugs, the Drugs for Neglected Diseases initiative (DNDi) has undertaken a drug discovery program, which has resulted in the identification of aminopyrazoles, a highly promising antileishmanial chemical series. Multiple experiments have been performed to anticipate the propensity for resistance development. Resistance selection was performed by successive exposure of Leishmania infantum promastigotes (in vitro) and intracellular amastigotes (both in vitro and in golden Syrian hamsters). The stability of the resistant phenotypes was assessed after passage in mice and Lutzomyia longipalpis sandflies. Whole-genome sequencing (WGS) was performed to identify mutated genes, copy number variations (CNVs), and somy changes. The potential role of efflux pumps (the MDR and MRP efflux pumps) in the development of resistance was assessed by coincubation of aminopyrazoles with specific efflux pump inhibitors (verapamil, cyclosporine, and probenecid). Repeated drug exposure of amastigotes did not result in the emergence of drug resistance either in vitro or in vivo Selection at the promastigote stage, however, was able to select for parasites with reduced susceptibility (resistance index, 5.8 to 24.5). This phenotype proved to be unstable after in vivo passage in mice and sandflies, suggesting that nonfixed alterations are responsible for the elevated resistance. In line with this, single nucleotide polymorphisms and indels identified by whole-genome sequencing could not be directly linked to the decreased drug susceptibility. Copy number variations were absent, whereas somy changes were detected, which may have accounted for the transient acquisition of resistance. Finally, aminopyrazole activity was not influenced by the MDR and MRP efflux pump inhibitors tested. The selection performed does not suggest the rapid development of resistance against aminopyrazoles in the field. Karyotype changes may confer elevated levels of resistance, but these do not seem to be stable in the vertebrate and invertebrate hosts. MDR/MRP efflux pumps are not likely to significantly impact the activity of the aminopyrazole leads.
Assuntos
Antiprotozoários , Resistência a Medicamentos , Leishmania infantum , Pirazóis/farmacologia , Animais , Antiprotozoários/farmacologia , Cricetinae , Variações do Número de Cópias de DNA , Resistência a Medicamentos/genética , Leishmania infantum/efeitos dos fármacos , Leishmania infantum/genética , CamundongosRESUMO
BACKGROUND: When glioma patients experience long-term seizure freedom the question arises whether antiepileptic drugs (AEDs) should be continued. As no prospective studies exist on seizure recurrence in glioma patients after AED withdrawal, we evaluated the decision-making process to withdraw AEDs in glioma patients, and seizure outcome after withdrawal. METHODS: Patients with a histologically confirmed low grade or anaplastic glioma were included. Eligible patients were seizure free ≥ 1 year from the date of last antitumor treatment, or ≥ 2 years since the last seizure when seizures occurred after the end of the last antitumor treatment. Patients and neuro-oncologists made a shared decision on the preferred AED treatment (i.e. AED withdrawal or continuation). Primary outcomes were: (1) outcome of the shared decision-making process and (2) rate of seizure recurrence. RESULTS: Eighty-three patients fulfilled all eligibility criteria. However, in 12/83 (14%) patients, the neuro-oncologist had serious objections to AED withdrawal. Therefore, 71/83 (86%) patients were analyzed; In 46/71 (65%) patients it was decided to withdraw AED treatment. In the withdrawal group, 26% (12/46) had seizure recurrence during follow-up. Seven of these 12 patients (58%) had tumor progression, of which three within 3 months after seizure recurrence. In the AED continuation group, 8% (2/25) of patients had seizure recurrence of which one had tumor progression. CONCLUSION: In 65% of patients a shared decision was made to withdraw AEDs, of which 26% had seizure recurrence. AED withdrawal should only be considered in carefully selected patients with a presumed low risk of tumor progression.
Assuntos
Anticonvulsivantes/administração & dosagem , Glioma/complicações , Convulsões/tratamento farmacológico , Suspensão de Tratamento/estatística & dados numéricos , Adulto , Idoso , Feminino , Seguimentos , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Prospectivos , Recidiva , Projetos de Pesquisa , Convulsões/etiologia , Fatores de TempoRESUMO
This committee opinion reviews the laser-based vaginal devices for treatment of genitourinary syndrome of menopause, vaginal laxity, and stress urinary incontinence. The United States Food and Drug Administration has issued a warning for unsubstantiated advertising and use of energy-based devices. Well-designed case-control studies are required to further investigate the potential benefits, harm, and efficacy of laser therapy in the treatment of genitourinary syndrome of menopause, vaginal laxity, and stress urinary incontinence. The therapeutic advantages of nonsurgical laser-based devices in urogynecology can only be recommended after robust clinical trials have demonstrated their long-term complication profile, safety, and efficacy.
Assuntos
Lasers de Estado Sólido/uso terapêutico , Terapia com Luz de Baixa Intensidade , Incontinência Urinária por Estresse/terapia , Vagina/patologia , Doenças Vaginais/terapia , Vulva/patologia , Atrofia/radioterapia , Atrofia/cirurgia , Feminino , Humanos , Lasers de Estado Sólido/efeitos adversos , Terapia com Luz de Baixa Intensidade/efeitos adversos , Menopausa , SíndromeRESUMO
OBJECTIVE: It is difficult to predict the presence of histological risk factors for lymph node metastasis (LNM) before endoscopic treatment of T1 colorectal cancer (CRC). Therefore, endoscopic therapy is propagated to obtain adequate histological staging. We examined whether secondary surgery following endoscopic resection of high-risk T1 CRC does not have a negative effect on patients' outcomes compared with primary surgery. DESIGN: Patients with T1 CRC with one or more histological risk factors for LNM (high risk) and treated with primary or secondary surgery between 2000 and 2014 in 13 hospitals were identified in the Netherlands Cancer Registry. Additional data were collected from hospital records, endoscopy, radiology and pathology reports. A propensity score analysis was performed using inverse probability weighting (IPW) to correct for confounding by indication. RESULTS: 602 patients were eligible for analysis (263 primary; 339 secondary surgery). Overall, 34 recurrences were observed (5.6%). After adjusting with IPW, no differences were observed between primary and secondary surgery for the presence of LNM (OR 0.97; 95% CI 0.49 to 1.93; p=0.940) and recurrence during follow-up (HR 0.97; 95% CI 0.41 to 2.34; p=0.954). Further adjusting for lymphovascular invasion, depth of invasion and number of retrieved lymph nodes did not alter this outcome. CONCLUSIONS: Our data do not support an increased risk of LNM or recurrence after secondary surgery compared with primary surgery. Therefore, an attempt for an en-bloc resection of a possible T1 CRC without evident signs of deep invasion seems justified in order to prevent surgery of low-risk T1 CRC in a significant proportion of patients.
Assuntos
Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Excisão de Linfonodo , Recidiva Local de Neoplasia , Reoperação , Idoso , Colonoscopia/efeitos adversos , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Complicações Pós-Operatórias/etiologia , Reoperação/efeitos adversos , Fatores de Risco , Fatores de TempoRESUMO
To assess the applicability of perfusion-weighted (PWI) magnetic resonance (MR) imaging in clinical practice, as well as to evaluate the changes in PWI in brain metastases before and after stereotactic radiotherapy (SRT), and to correlate these changes to tumor status on conventional MR imaging. Serial MR images at baseline and at least 3 and 6 months after SRT were retrospectively evaluated. Size of metastases and the relative cerebral blood volume (rCBV), assessed with subjective visual inspection in the contrast enhanced area, were evaluated at each time point. Tumor behavior of metastases was categorized into four groups based on predefined changes on MRI during follow-up, or on histologically confirmed diagnosis; progressive disease (PD), pseudoprogression (PsPD), non-progressive disease (non-PD) and progression unspecified (PU). Twenty-six patients with 42 metastases were included. Fifteen percent (26/168) of all PW images could not be evaluated due to localization near large vessels or the scalp, presence of hemorrhage artefacts, and in 31% (52/168) due to unmeasurable residual metastases. The most common pattern (52%, 13/25 metastases) showed a high rCBV at baseline and low rCBV during follow-up, occurring in metastases with non-PD (23%, 3/13), PsPD (38%, 5/13) and PU (38%, 5/13). Including only metastases with a definite outcome generally showed low rCBV in PsPD or non-PD, and high rCBV in PD. Although non-PD and PsPD may be distinguished from PD after SRT using the PW images, the large proportion of images that could not be assessed due to artefacts and size severely hampers value of PWI in predicting tumor response after SRT.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/secundário , Angiografia por Ressonância Magnética/métodos , Radiocirurgia/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estatísticas não ParamétricasRESUMO
Primary mouse macrophages are frequently used to provide an in vitro intracellular model to evaluate antileishmanial drug efficacy. The present study compared the phenotypic characteristics of Swiss, BALB/c, and C57BL/6 mouse bone marrow-derived macrophages and peritoneal exudate cells using different stimulation and adherence protocols upon infection with a Leishmania infantum laboratory strain and two clinical isolates. Evaluation parameters were susceptibility to infection, permissiveness to amastigote multiplication, and impact on drug efficacy. Observed variations in infection of peritoneal exudate cells can mostly be linked to changes in the inflammatory cytokine profiles (IL-6, TNF-α, KC/GRO) rather than to differences in initial production of nitric oxide and reactive oxygen species. Optimization of the cell stimulation and adherence conditions resulted in comparable infection indices among peritoneal exudate cells and the various types of bone marrow-derived macrophages. BALB/c-derived bone marrow-derived macrophages were slightly more permissive to intracellular amastigote replication. Evaluation of antileishmanial drug potency in the various cell systems revealed minimal variation for antimonials and paromomycin, and no differences for miltefosine and amphotericin B. The study results allow to conclude that drug evaluation can be performed in all tested primary macrophages as only marginal differences are observed in terms of susceptibility to infection and impact of drug exposure. Combined with some practical considerations, the use of 24-h starch-stimulated, 48-h adhered, Swiss-derived peritoneal exudate cells can be advocated as an efficient, reliable, relatively quick, and cost-effective tool for routine drug susceptibility testing in vitro whenever the use of primary cells is feasible.
Assuntos
Antiprotozoários/uso terapêutico , Leishmania infantum/efeitos dos fármacos , Leishmania infantum/imunologia , Leishmaniose/tratamento farmacológico , Leishmaniose/imunologia , Macrófagos/imunologia , Anfotericina B/uso terapêutico , Animais , Antimônio/uso terapêutico , Células Cultivadas , Resistência a Medicamentos/genética , Feminino , Interleucina-6/sangue , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Testes de Sensibilidade Parasitária , Paromomicina/uso terapêutico , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/sangueRESUMO
OBJECTIVES: The decision to perform secondary surgery after endoscopic resection of T1 colorectal cancer (CRC) depends on the risk of lymph node metastasis and the risk of incomplete resection. We aimed to examine the incidence and risk factors for incomplete endoscopic resection of T1 CRC after a macroscopic radical endoscopic resection. METHODS: Data from patients treated between 2000 and 2014 with macroscopic complete endoscopic resection of T1 CRC were collected from 13 hospitals. Incomplete resection was defined as local recurrence at the polypectomy site during follow-up or malignant tissue in the surgically resected specimen in case secondary surgery was performed. Multivariate regression analysis was performed to analyze factors associated with incomplete resection. RESULTS: In total, 877 patients with a median follow-up time of 36.5 months (interquartile range 16.0-68.3) were included, in whom secondary surgery was performed in 358 patients (40.8%). Incomplete resection was observed in 30 patients (3.4%; 95% confidence interval (CI) 2.3-4.6%). Incomplete resection rate was 0.7% (95% CI 0-2.1%) in low-risk T1 CRC vs. 4.4% (95% CI 2.7-6.5%) in high-risk T1 CRC (P=0.04). Overall adverse outcome rate (incomplete resection or metastasis) was 2.1% (95% CI 0-5.0%) in low-risk T1 CRC vs. 11.7% (95% CI 8.8-14.6%) in high-risk T1 CRC (P=0.001). Piecemeal resection (adjusted odds ratio 2.60; 95% CI 1.20-5.61, P=0.02) and non-pedunculated morphology (adjusted odds ratio 2.18; 95% CI 1.01-4.70, P=0.05) were independent risk factors for incomplete resection. Among patients in whom no additional surgery was performed, who developed recurrent cancer, 41.7% (95% CI 20.8-62.5%) died as a result of recurrent cancer. CONCLUSIONS: In the absence of histological high-risk factors, a 'wait-and-see' policy with limited follow-up is justified. Piecemeal resection and non-pedunculated morphology are independent risk factors for incomplete endoscopic resection of T1 CRC.
Assuntos
Adenocarcinoma/cirurgia , Neoplasias Colorretais/cirurgia , Recidiva Local de Neoplasia/etiologia , Recidiva Local de Neoplasia/patologia , Adenocarcinoma/secundário , Idoso , Colectomia , Colonoscopia , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Neoplasia Residual , Reoperação , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Conduta ExpectanteRESUMO
OBJECTIVES: Despite a continued search for novel antileishmanial drugs, treatment options remain restricted to a few standard drugs, e.g. antimonials, miltefosine, amphotericin B and paromomycin. Although these drugs have now been used for several decades, their mechanism of action still remains partly hypothetical and their dynamics of cidal action and time-to-kill are still poorly documented. METHODS: An in vitro time-to-kill assay on intracellular amastigotes of the laboratory reference strains Leishmania donovani (MHOM/ET/67/L82) and Leishmania infantum [MHOM/MA(BE)/67/ITMAP263] evaluated the cidal action dynamics of the listed reference drugs at three different concentrations: at IC50, 2â×âIC50 and the near cytotoxic dose level (CC90: determined on MRC-5 cells). This assay focused on identifying the minimal exposure time needed to completely eliminate viable intracellular amastigotes, using the standard microscopic Giemsa assay and the promastigote back-transformation assay. RESULTS: While 100% reduction was microscopically apparent for most drugs, the promastigote back-transformation assay clearly demonstrated a concentration- and time-dependent cidal mechanism. The time-to-kill at 2â×âIC50 was ≥240 h for pentavalent antimony (77 µg eq./mL), 96 h for trivalent antimony (44 µg eq./mL), 168 to >240 h for miltefosine (10 µM), 168 h for paromomycin (100 µM) and >240 h for amphotericin B (2 µM). No differences were noted between both Leishmania species. CONCLUSIONS: Evaluation of the concentration- and time-dependent cidal activity using the promastigote back-transformation assay revealed striking differences in efficacy of the different antileishmanial reference drugs. This assay should allow in-depth pharmacodynamic evaluation of novel drug leads in comparison with the existing antileishmanial drug repertoire.
Assuntos
Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/fisiologia , Leishmania infantum/efeitos dos fármacos , Leishmania infantum/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Concentração Inibidora 50 , Testes de Sensibilidade Parasitária , Fatores de TempoRESUMO
BACKGROUND: Genomewide association studies (GWASs) of asthma have identified single-nucleotide polymorphisms (SNPs) that modestly increase the risk for asthma. This could be due to phenotypic heterogeneity of asthma. Bronchial hyperresponsiveness (BHR) is a phenotypic hallmark of asthma. We aim to identify susceptibility genes for asthma combined with BHR and analyse the presence of cis-eQTLs among replicated SNPs. Secondly, we compare the genetic association of SNPs previously associated with (doctor's diagnosed) asthma to our GWAS of asthma with BHR. METHODS: A GWAS was performed in 920 asthmatics with BHR and 980 controls. Top SNPs of our GWAS were analysed in four replication cohorts, and lung cis-eQTL analysis was performed on replicated SNPs. We investigated association of SNPs previously associated with asthma in our data. RESULTS: A total of 368 SNPs were followed up for replication. Six SNPs in genes encoding ABI3BP, NAF1, MICA and the 17q21 locus replicated in one or more cohorts, with one locus (17q21) achieving genomewide significance after meta-analysis. Five of 6 replicated SNPs regulated 35 gene transcripts in whole lung. Eight of 20 asthma-associated SNPs from previous GWAS were significantly associated with asthma and BHR. Three SNPs, in IL-33 and GSDMB, showed larger effect sizes in our data compared to published literature. CONCLUSIONS: Combining GWAS with subsequent lung eQTL analysis revealed disease-associated SNPs regulating lung mRNA expression levels of potential new asthma genes. Adding BHR to the asthma definition does not lead to an overall larger genetic effect size than analysing (doctor's diagnosed) asthma.
Assuntos
Asma/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Pulmão/metabolismo , Locos de Características Quantitativas , Alelos , Asma/epidemiologia , Estudos de Casos e Controles , Mapeamento Cromossômico , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Pulmão/imunologia , Masculino , Metanálise como Assunto , Países Baixos/epidemiologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Vigilância da PopulaçãoRESUMO
BACKGROUND AND PURPOSE: Conventional magnetic resonance imaging (MRI) has limited value for differentiation of true tumor progression and pseudoprogression in treated glioblastoma multiforme (GBM). Perfusion weighted imaging (PWI) may be helpful in the differentiation of these two phenomena. Here interobserver variability in routine radiological evaluation of GBM patients is assessed using MRI, including PWI. METHODS: Three experienced neuroradiologists evaluated MR scans of 28 GBM patients during temozolomide chemoradiotherapy at three time points: preoperative (MR1) and postoperative (MR2) MR scan and the follow-up MR scan after three cycles of adjuvant temozolomide (MR3). Tumor size was measured both on T1 post-contrast and T2 weighted images according to the Response Assessment in Neuro-Oncology criteria. PW images of MR3 were evaluated by visual inspection of relative cerebral blood volume (rCBV) color maps and by quantitative rCBV measurements of enhancing areas with highest rCBV. Image interpretability of PW images was also scored. Finally, the neuroradiologists gave a conclusion on tumor status, based on the interpretation of both T1 and T2 weighted images (MR1, MR2 and MR3) in combination with PWI (MR3). RESULTS: Interobserver agreement on visual interpretation of rCBV maps was good (κ = 0.63) but poor on quantitative rCBV measurements and on interpretability of perfusion images (intraclass correlation coefficient 0.37 and κ = 0.23, respectively). Interobserver agreement on the overall conclusion of tumor status was moderate (κ = 0.48). CONCLUSIONS: Interobserver agreement on the visual interpretation of PWI color maps was good. However, overall interpretation of MR scans (using both conventional and PW images) showed considerable interobserver variability. Therefore, caution should be applied when interpreting MRI results during chemoradiation therapy.
Assuntos
Glioblastoma/diagnóstico por imagem , Imageamento por Ressonância Magnética/normas , Humanos , Angiografia por Ressonância Magnética/normas , Pessoa de Meia-Idade , Variações Dependentes do Observador , Estudos RetrospectivosRESUMO
BACKGROUND: Endoscopic mucosal resection (EMR) is currently the most used technique for resection of large distal colorectal polyps. However, in large lesions EMR can often only be performed in a piecemeal fashion resulting in relatively low radical (R0)-resection rates and high recurrence rates. Endoscopic submucosal dissection (ESD) is a newer procedure that is more difficult resulting in a longer procedural time, but is promising due to the high en-bloc resection rates and the very low recurrence rates. We aim to evaluate the (cost-)effectiveness of ESD against EMR on both short (i.e. 6 months) and long-term (i.e. 36 months). We hypothesize that in the short-run ESD is more time consuming resulting in higher healthcare costs, but is (cost-) effective on the long-term due to lower patients burden, a higher number of R0-resections and lower recurrence rates with less need for repeated procedures. METHODS: This is a multicenter randomized clinical trial in patients with a non-pedunculated polyp larger than 20 mm in the rectum, sigmoid, or descending colon suspected to be an adenoma by means of endoscopic assessment. Primary endpoint is recurrence rate at follow-up colonoscopy at 6 months. Secondary endpoints are R0-resection rate, perceived burden and quality of life, healthcare resources utilization and costs, surgical referral rate, complication rate and recurrence rate at 36 months. Quality-adjusted-life-year (QALY) will be estimated taking an area under the curve approach and using EQ-5D-indexes. Healthcare costs will be calculated by multiplying used healthcare services with unit prices. The cost-effectiveness of ESD against EMR will be expressed as incremental cost-effectiveness ratios (ICER) showing additional costs per recurrence free patient and as ICER showing additional costs per QALY. DISCUSSION: If this trial confirms ESD to be favorable on the long-term, the burden of extra colonoscopies and repeated procedures can be prevented for future patients. TRIAL REGISTRATION: NCT02657044 (Clinicaltrials.gov), registered January 8, 2016.
Assuntos
Adenoma/cirurgia , Neoplasias Colorretais/cirurgia , Ressecção Endoscópica de Mucosa/economia , Ressecção Endoscópica de Mucosa/métodos , Adenoma/patologia , Colonoscopia , Neoplasias Colorretais/patologia , Efeitos Psicossociais da Doença , Análise Custo-Benefício , Ressecção Endoscópica de Mucosa/efeitos adversos , Custos de Cuidados de Saúde , Humanos , Recidiva Local de Neoplasia , Qualidade de VidaRESUMO
BACKGROUND: Asthma, rhinitis and eczema often co-occur in children, but their interrelationships at the population level have been poorly addressed. We assessed co-occurrence of childhood asthma, rhinitis and eczema using unsupervised statistical techniques. METHODS: We included 17 209 children at 4 years and 14 585 at 8 years from seven European population-based birth cohorts (MeDALL project). At each age period, children were grouped, using partitioning cluster analysis, according to the distribution of 23 variables covering symptoms 'ever' and 'in the last 12 months', doctor diagnosis, age of onset and treatments of asthma, rhinitis and eczema; immunoglobulin E sensitization; weight; and height. We tested the sensitivity of our estimates to subject and variable selections, and to different statistical approaches, including latent class analysis and self-organizing maps. RESULTS: Two groups were identified as the optimal way to cluster the data at both age periods and in all sensitivity analyses. The first (reference) group at 4 and 8 years (including 70% and 79% of children, respectively) was characterized by a low prevalence of symptoms and sensitization, whereas the second (symptomatic) group exhibited more frequent symptoms and sensitization. Ninety-nine percentage of children with comorbidities (co-occurrence of asthma, rhinitis and/or eczema) were included in the symptomatic group at both ages. The children's characteristics in both groups were consistent in all sensitivity analyses. CONCLUSION: At 4 and 8 years, at the population level, asthma, rhinitis and eczema can be classified together as an allergic comorbidity cluster. Future research including time-repeated assessments and biological data will help understanding the interrelationships between these diseases.
Assuntos
Asma/epidemiologia , Asma/imunologia , Eczema/epidemiologia , Eczema/imunologia , Rinite Alérgica/epidemiologia , Rinite Alérgica/imunologia , Distribuição por Idade , Asma/genética , Criança , Pré-Escolar , Análise por Conglomerados , Estudos de Coortes , Comorbidade , Estudos Transversais , Eczema/genética , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Internacionalidade , Masculino , Fenótipo , Prevalência , Rinite Alérgica/genética , Índice de Gravidade de Doença , Distribuição por SexoRESUMO
BACKGROUND: There is evidence for a relation of TV viewing with adiposity and increased cardiometabolic risk factors in children and adolescents. It is unclear to what extent this relation is mediated by snacking and lack of physical activity. We determined whether associations of screen time with adiposity and cardiometabolic markers were mediated by these behaviours. METHODS: Children from a population-representative Dutch birth cohort (n=1447) reported screen time and other lifestyle factors by a questionnaire around the age of 11 years (range 10-14) and had anthropometry and cardiometabolic markers measured around the age of 12 years (range 12-14). Adjusted associations of screen time with snacking, physical activity, adiposity and cardiometabolic markers (total-to-high-density lipoprotein cholesterol (TC/HDLC) ratio, blood pressure, glycated haemoglobin) were assessed by using formal mediation analysis. We tested the hypothesized paths by structural equation modeling, which allows quantification of the indirect effects associated with potential mediators. RESULTS: Children with ⩾20 h screen time per week consumed more snacks (1.9 vs 1.3 portions per day) and were less physically active (4.3 vs 4.8 days per week) than children with maximum 6 h screen time. Screen time was directly associated with higher adiposity (standardized ß=0.10-0.12 depending on the outcome, P<0.001), and indirectly through less physical activity. The association of screen time with TC/HDLC ratio was almost completely mediated by adiposity (ß=0.39, P<0.0001), and to a minor extent by physical activity (ß=-0.06, P=0.02). There was no direct association of screen time with TC/HDLC ratio. CONCLUSIONS: The adverse association of screen time with adiposity was partly mediated by physical activity, but not by snacking. The association of screen time with TC/HDLC ratio was almost completely mediated by adiposity. Our results may suggest that future efforts in society and public health should be directed to replace screen time with physical activity for reducing children's adiposity and cardiometabolic risk.
Assuntos
Adiposidade , Doenças Cardiovasculares/prevenção & controle , Computadores , Comportamento Alimentar , Doenças Metabólicas/prevenção & controle , Comportamento Sedentário , Lanches , Televisão , Biomarcadores , Índice de Massa Corporal , Doenças Cardiovasculares/epidemiologia , Criança , Escolaridade , Comportamento Alimentar/psicologia , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Estudos Longitudinais , Masculino , Doenças Metabólicas/epidemiologia , Países Baixos/epidemiologia , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: A novel data-driven approach was used to identify wheezing phenotypes in pre-schoolchildren aged 0-8 years, in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort. Five phenotypes were identified: never/infrequent wheeze, transient early wheeze, intermediate onset wheeze, persistent wheeze and late onset wheeze. It is unknown which perinatal risk factors drive development of these phenotypes. OBJECTIVE: The objective of the study was to assess associations of perinatal factors with wheezing phenotypes and to identify possible targets for prevention. METHODS: In the PIAMA study (n = 3963), perinatal factors were collected at 3 months, and wheezing was assessed annually until the age of 8 years. Associations between perinatal risk factors and the five wheezing phenotypes were assessed using weighted multinomial logistic regression models. Odds ratios were adjusted for confounding variables and calculated with 'never/infrequent wheeze' as reference category. RESULTS: Complete data were available for 2728 children. Risk factors for transient early wheeze (n = 455) were male gender, maternal and paternal allergy, low maternal age, high maternal body mass index, short pregnancy duration, smoking during pregnancy, presence of older siblings and day-care attendance. Risk factors for persistent wheeze (n = 83) were male gender, maternal and paternal allergy, and not receiving breastfeeding for at least 12 weeks. Intermediate onset wheeze (n = 98) was associated with a lower birth weight and late onset wheeze (n = 45) with maternal allergy. CONCLUSION AND CLINICAL RELEVANCE: We identified different risk factors for specific childhood wheezing phenotypes. Some of these are modifiable, such as maternal age and body mass index, smoking, day-care attendance and breastfeeding, and may be important targets for prevention programmes.
Assuntos
Sons Respiratórios/etiologia , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Exposição Materna , Razão de Chances , Exposição Paterna , Assistência Perinatal , Fenótipo , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Fatores de RiscoRESUMO
BACKGROUND: Diagnostic and accidental food allergic reactions may be modified by the matrix containing the allergenic food. Previous studies of double-blind, placebo-controlled food challenges (DBPCFCs) with peanut found an effect of the fat content of the challenge matrix on the severity of the challenge reactions. OBJECTIVE: The aim of this study was to examine whether the fat content of the food matrix is related to eliciting dose and reaction severity in DBPCFCs with heated hen's egg. METHODS: Sensitized egg allergic children (n = 59) undergoing DBPCFCs with egg as a routine diagnostic procedure in our tertiary care centre were evaluated retrospectively. Three different recipes were used for the food matrix: vanilla pudding, pancake and minced meat, containing 22.8%, 31.9% and 52.7% fat (weighted average), respectively. The eliciting dose (i.e. the highest cumulative dose to which the child reacted) was analyzed by Kaplan-Meier log-rank statistic and by Cox regression. Reaction severity was quantified by using an index (range 1-12) and was analysed by multiple linear regression analysis. RESULTS: The overall influence of type of recipe on eliciting dose was not significant (P = 0.12). The rate of response to minced meat (with the highest fat content) was not significantly different from pudding [HR = 0.61 (0.26-1.45, P = 0.26) or pancake (HR = 1.41 (0.50-3.99), P = 0.52] after adjustment for confounders. The type of recipe did not influence the severity of the challenge reaction. The severity of the challenge reaction for minced meat compared to pudding and pancake was 1.06 (0.52-2.16), P = 0.87 and 0.81 (0.32-2.01), P = 0.64, respectively, after correction for confounders. CONCLUSION AND CLINICAL RELEVANCE: In contrast to similar research with peanut, no significant influence of the fat content of the matrix was found on the eliciting dose or severity of the reaction in 59 DBPCFCs with hen's egg. Matrix fat content differences comparable to those reported here may not be an important co-determinant of reaction severity for all allergenic foods.
Assuntos
Alérgenos/imunologia , Gorduras na Dieta/efeitos adversos , Hipersensibilidade Alimentar/diagnóstico , Alimentos , Pré-Escolar , Relação Dose-Resposta Imunológica , Ovos/efeitos adversos , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Vascular endothelial growth factor (VEGF) is implicated in airway remodelling and asthma development. We studied VEGFA gene variants and plasma levels and the development of lung function, bronchial hyperresponsiveness and asthma in childhood. METHODS: We analysed 13 SNPs in the VEGFA gene in 411 children from the COPSAC2000 high-risk birth cohort. Asthma was diagnosed prospectively, and lung function measurements were obtained at birth and 6 years of age. Plasma VEGF levels were measured at 18 months of age. We used a Bonferroni adjusted significance level. Findings were replicated in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort at age 8. RESULTS: At age six, three SNPs from the same linkage block were associated with FEV1 (rs699947, P = 1.31E-05), independent of asthma, and there were suggestive associations between FEV1/FVC ratio and rs833052 and maximal mid-expiratory flow and rs6900017. Replication in the PIAMA cohort showed borderline association between FEV1 and rs699947 and significant meta-analysis result. SNPs upstream and nearby rs699947 were nominally associated with VEGF plasma levels. VEGF levels were not associated with asthmatic symptoms or lung function measures. CONCLUSIONS AND CLINICAL RELEVANCE: VEGF gene variants are associated with lung function at school age, but not at birth, suggesting a role of VEGF in post-natal lung function development.
Assuntos
Asma/genética , Asma/fisiopatologia , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/fisiopatologia , Variação Genética , Fator A de Crescimento do Endotélio Vascular/genética , Fatores Etários , Pré-Escolar , Feminino , Humanos , Recém-Nascido , Desequilíbrio de Ligação , Masculino , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Testes de Função Respiratória , Fatores de RiscoRESUMO
BACKGROUND: There are conflicting study results regarding the association of exposure to visible mould and fungal components in house dust with respiratory and allergic diseases in children. It has been suggested that functional polymorphisms of the GSTP1 gene may influence the risk for allergic disorders through an impaired defence against oxidant injury. METHODS: We examined in six birth cohorts of over 14 000 children whether the association between early exposure to reported mould at home in relation to respiratory and allergic diseases is modified by a single nucleotide polymorphism of the GSTP1 gene. RESULTS: We observed a positive association of mould exposure with nasal symptoms (2-10 year) aOR: 1.19 (1.02-11.38). Further, there was a borderline significant increased risk of rhinoconjunctivitis (6-8 year) in children homozygous for the minor allele Val/Val, aOR: 1.25 (0.98-1.60). In stratified analyses, subjects homozygous for the minor allele and exposed to mould at home were at increased risk for early wheezing aOR: 1.34 (1.03-1.75), whereas the major allele may confer susceptibility for later nasal outcomes, (6-8 year) aOR: 1.20 (1.00-1.45) and (2-10 year) aOR: 1.30 (1.04-1.61), respectively. For none of the health outcomes studied, we found gene by environment interactions. CONCLUSION: A genetic influence of the GSTP1 gene cannot be ruled out, but the magnitude of the effect is a matter of further research. In conclusion, the interplay between gene and environments is complex and remains subject of further study.