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OBJECTIVE: To estimate the cost-effectiveness of the levonorgestrel intrauterine system (LNG-IUS) as an endometrial cancer prevention strategy in women with obesity. METHODS: A Markov decision-analytic model was used to compare 5 strategies in women with a body mass index of 30 or greater: 1) Usual care 2) LNG-IUS for 5 years 3) LNG-IUS for 7 years 4) LNG-IUS for 5 years, replaced once for a total of 10 years 5) LNG-IUS for 7 years, replaced once for a total of 14 years. Obesity was presumed to be associated with a 3-fold relative risk of endometrial cancer incidence and a 2.65-fold disease-specific mortality. The LNG-IUS was assumed to confer a 50% reduction in cancer incidence over the period of the LNG-IUS insertion. Outcomes were incremental cost-effectiveness ratios, calculated in 2019 Canadian dollars (CAD) per year of life saved. One-way and two-way sensitivity analyses were performed. RESULTS: The LNG-IUS strategy was considered cost-effective if the cost of the intervention is less than $66,400 CAD ($50,000 US dollars) per year of life saved. The strategy becomes cost-effective if the LNG-IUS is inserted at age 57 (strategy #2), at age 52 for strategy #3, at age 51 for strategy #4 and at age 45 for strategy #5, when compared to usual care. The results are stable to variations in cost but sensitive to the estimated risk reduction of the LNG-IUS and the impact of obesity on endometrial cancer incidence and disease-specific mortality. CONCLUSION: The LNG-IUS is a cost-effective method of endometrial cancer prevention in women with obesity.
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Agentes Anticonceptivos Hormonales/economía , Análisis Costo-Beneficio , Neoplasias Endometriales/economía , Neoplasias Endometriales/prevención & control , Dispositivos Intrauterinos Medicados/economía , Levonorgestrel/economía , Obesidad/complicaciones , Factores de Edad , Anciano , Anciano de 80 o más Años , Canadá , Agentes Anticonceptivos Hormonales/uso terapéutico , Neoplasias Endometriales/etiología , Femenino , Costos de la Atención en Salud/estadística & datos numéricos , Humanos , Levonorgestrel/uso terapéutico , Cadenas de Markov , Persona de Mediana Edad , Modelos Económicos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
OBJECTIVES: There is uncertainty surrounding the prognostic value and clinical utility of peritoneal cytology in endometrial cancer. Our primary objective was to determine if positive cytology is associated with disease-free and overall survival in women treated surgically for endometrial cancer, specifically those with low or intermediate risk disease. METHODS: This was a retrospective population-based cohort study of British Columbia Cancer Registry patients who underwent surgery with peritoneal washings for endometrioid-type endometrial cancer from 2003 to 2009. Low risk was defined as Stage IA grade 1 or 2, and intermediate risk defined as Stage IA grade 3, or Stage IB grade 1 or 2 tumours. Five-year overall and disease free-survival were assessed using Kaplan-Meier estimation. Potential covariates including peritoneal cytology, grade, depth of myometrial invasion, LVSI, age, and adjuvant therapy were evaluated in a multivariable Cox proportional hazards model. RESULTS: There were 849 patients, of whom 370 (43.6%) and 298 (35.1%) had low- and intermediate-risk disease, respectively. Overall, forty-nine (5.8%) patients had positive cytology, including 6 and 9 with low- and intermediate-risk respectively (2.2% within low and intermediate risk combined). Positive peritoneal cytology was not significantly associated with disease-free (HR 3.17, 95% CI 0.91-11.03) or overall survival (HR 1.33, 95% CI 0.47-3.76) in low and intermediate risk patients. Only age and extensive LVSI were associated with lower overall survival (HR 1.10, 95% CI 1.08-1.13, and HR 2.39, 95% CI 1.02-5.61, respectively). CONCLUSIONS: Positive peritoneal cytology was not associated with disease-free and overall survival in women with low and intermediate risk endometrial cancer.
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Carcinoma Endometrioide/patología , Neoplasias Endometriales/patología , Cavidad Peritoneal/patología , Colombia Británica/epidemiología , Carcinoma Endometrioide/epidemiología , Carcinoma Endometrioide/mortalidad , Estudios de Cohortes , Neoplasias Endometriales/epidemiología , Neoplasias Endometriales/mortalidad , Femenino , Humanos , Estimación de Kaplan-Meier , Miometrio/patología , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic, relapsing mental illness. Selective serotonin reuptake inhibitors block serotonin transporters (SERTs) and are the mainstay of treatment for OCD. SERT abnormalities are reported in drug-free patients with OCD, but it is not known what happens to SERT levels during treatment. This is important as alterations in SERT levels in patients under treatment could underlie poor response, or relapse during or after treatment. The aim of the present study was first to validate a novel approach to measuring SERT levels in people taking treatment and then to investigate SERT binding potential (BP) using [11C]DASB PET in patients with OCD currently treated with escitalopram in comparison with healthy controls. METHOD: Twelve patients and age- and sex-matched healthy controls were enrolled. The patients and healthy controls underwent serial PET scans after administration of escitalopram and blood samples for drug concentrations were collected simultaneously with the scans. Drug-free BPs were obtained by using an inhibitory E max model we developed previously. RESULTS: The inhibitory E max model was able to accurately predict drug-free SERT BP in people taking drug treatment. The drug-free BP in patients with OCD currently treated with escitalopram was significantly different from those in healthy volunteers [Cohen's d = 0.03 (caudate), 1.16 (putamen), 1.46 (thalamus), -5.67 (dorsal raphe nucleus)]. CONCLUSIONS: This result extends previous findings showing SERT abnormalities in drug-free patients with OCD by indicating that altered SERT availability is seen in OCD despite treatment. This could account for poor response and the high risk of relapse in OCD.
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Bencilaminas , Encéfalo/diagnóstico por imagen , Radioisótopos de Carbono , Trastorno Obsesivo Compulsivo/diagnóstico por imagen , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Adulto , Encéfalo/metabolismo , Estudios de Casos y Controles , Núcleo Caudado/diagnóstico por imagen , Núcleo Caudado/metabolismo , Citalopram/uso terapéutico , Femenino , Humanos , Masculino , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Trastorno Obsesivo Compulsivo/metabolismo , Tomografía de Emisión de Positrones , Putamen/diagnóstico por imagen , Putamen/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Tálamo/diagnóstico por imagen , Tálamo/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Obsessive-compulsive disorder (OCD) has been associated with abnormal cognitive and emotional functions and these dysfunctions may be dependent on the disruption of dynamic interactions within neuronal circuits associated with emotion regulation. Although several studies have shown the aberrant cognitive-affective processing in OCD patients, little is known about how to characterize effective connectivity of the disrupted neural interactions. In the present study, we applied effective connectivity analysis using dynamic causal modeling to explore the disturbed neural interactions in OCD patients. METHOD: A total of 20 patients and 21 matched healthy controls performed a delayed-response working memory task under emotional or non-emotional distraction while undergoing functional magnetic resonance imaging. RESULTS: During the delay interval under negative emotional distraction, both groups showed similar patterns of activations in the amygdala. However, under negative emotional distraction, the dorsolateral prefrontal cortex (DLPFC) and the orbitofrontal cortex (OFC) exhibited significant differences between groups. Bayesian model averaging indicated that the connection from the DLPFC to the OFC was negatively modulated by negative emotional distraction in patients, when compared with healthy controls (p < 0.05, Bonferroni-corrected). CONCLUSIONS: Exaggerated recruitment of the DLPFC may induce the reduction of top-down prefrontal control input over the OFC, leading to abnormal cortico-cortical interaction. This disrupted cortico-cortical interaction under negative emotional distraction may be responsible for dysfunctions of cognitive and emotional processing in OCD patients and may be a component of the pathophysiology associated with OCD.
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Emociones , Trastorno Obsesivo Compulsivo/diagnóstico por imagen , Corteza Prefrontal/fisiopatología , Adolescente , Adulto , Teorema de Bayes , Mapeo Encefálico/métodos , Estudios de Casos y Controles , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , República de Corea , Adulto JovenRESUMEN
BACKGROUND: Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the molecular categories identified in The Cancer Genome Atlas is proposed. METHODS: Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared. RESULTS: Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry as a surrogate for 'copy-number' status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined 'high-risk' group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves. CONCLUSIONS: Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffin-embedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials.
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Neoplasias Endometriales/clasificación , Neoplasias Endometriales/genética , Anciano , ADN Polimerasa II/genética , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/patología , Femenino , Genes p53 , Humanos , Persona de Mediana Edad , Mutación , Fosfohidrolasa PTEN/genética , Proteínas de Unión a Poli-ADP-Ribosa , Estudios RetrospectivosRESUMEN
Foam cell formation from macrophage is a major cause of atherosclerosis. An efficient macrophage-specific promoter is required for the targeting to macrophages. In this study, we develop a macrophage-specific synthetic promoter for the therapeutic application of adiponectin (APN), an antiatherogenic gene. Synthetic promoter-146 (SP146), registered on the NCBI website (http://www.ncbi.nlm.nih.gov/nuccore/DQ107383), was tested for promoter activities in two non-macrophage cell lines (293 T, HeLa) and a macrophage cell line (RAW264.7, bone marrow-derived macrophages). To enforce macrophage specificity, partial elements of p47(phox) including the PU.1 site with various lengths (-C1, -C2 and -C3) were inserted next to the synthetic promoters. SP146-C1 showed the highest specificity and efficacy in RAW264.7 cells and was selected for development of an APN-carrying macrophage-specific promoter. Green fluorescent protein (GFP)- or APN-expressing lentivirus under SP146-C1 (Lenti-SP-GFP or Lenti-SP-APN, respectively) showed the highest expression efficacy in RAW264.7 cells compared with the non-macrophage cell lines. APN overexpression in RAW264.7 cells successfully inhibited intracellular lipid accumulation, and atherosclerotic lesions and lipid accumulation were significantly reduced by Lenti-SP-APN in ApoE-/- atherosclerosis mice. In conclusion, the synthetic promoter SP146-C1, combined with a p47(phox) promoter element, was successfully developed to target macrophage, and macrophage-specific introduction of APN under SP146-C1 was shown to ameliorate the atherosclerotic pathology.
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Adiponectina/genética , Aterosclerosis/genética , Terapia Genética , Regiones Promotoras Genéticas , Adiponectina/uso terapéutico , Animales , Aterosclerosis/patología , Aterosclerosis/terapia , Células Espumosas/metabolismo , Células Espumosas/patología , Células HeLa , Humanos , Lentivirus/genética , Macrófagos/metabolismo , Ratones , Datos de Secuencia MolecularRESUMEN
BACKGROUND: Substantial empirical evidence has indicated impairment in the cognitive functioning of patients with obsessive-compulsive disorder (OCD) despite inconsistencies. Although several confounding factors have been investigated to explain the conflicting results, the findings remain mixed. This study aimed to investigate cognitive dysfunction in patients with OCD using a meta-analytic approach. METHOD: The PubMed database was searched between 1980 and October 2012, and reference lists of review papers were examined. A total of 221 studies were identified, of which 88 studies met inclusion criteria. Neuropsychological performance and demographic and clinical variables were extracted from each study. RESULTS: Patients with OCD were significantly impaired in tasks that measured visuospatial memory, executive function, verbal memory and verbal fluency, whereas auditory attention was preserved in these individuals. The largest effect size was found in the ability to recall complex visual stimuli. Overall effect estimates were in the small to medium ranges for executive function, verbal memory and verbal fluency. The effects of potentially confounding factors including educational level, symptom severity, medication status and co-morbid disorders were not significant. CONCLUSIONS: Patients with OCD appear to have wide-ranging cognitive deficits, although their impairment is not so large in general. The different test forms and methods of testing may have influenced the performance of patients with OCD, indicating the need to select carefully the test forms and methods of testing used in future research. The effects of various confounding variables on cognitive functioning need to be investigated further and to be controlled before a definite conclusion can be made.
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Trastornos del Conocimiento/fisiopatología , Trastorno Obsesivo Compulsivo/fisiopatología , Trastornos del Conocimiento/etiología , Humanos , Trastorno Obsesivo Compulsivo/complicacionesRESUMEN
The objective of this study was to evaluate the effect of 0.1% pilocarpine mouthwash in xerostomic patients. Sixty volunteers were randomly allocated to two groups. The experimental group used 0.1% pilocarpine solution, and the control group used 0.9% saline. The short- and long-term effects of pilocarpine were investigated by measuring the severity of oral dryness, minor salivary flow rates and unstimulated whole salivary flow rate at predetermined times. The severity of oral dryness was decreased in both groups at 0, 30 and 60 min after mouthwashing, with no significant difference between the groups. Buccal and labial secretions were increased in both groups, but only the experimental group exhibited increased palatal secretion. Labial and palatal secretions, but not buccal secretion, differed between the groups. The unstimulated whole salivary flow rate was increased in the experimental group and differed from that in the control group. After 4 weeks, the severity of oral dryness was decreased in both groups and did not differ between them. The oral dryness at night or on awakening significantly decreased in both groups, with no significant difference between them, but the oral dryness at other times of the day and the difficulty in swallowing foods were not significantly changed in both groups. Minor salivary and unstimulated whole salivary flow rates did not increase in both groups. Until 1 h after mouthwashing, 0.1% pilocarpine mouthwash increased minor salivary and unstimulated whole salivary secretions, but was not superior compared with 0.9% saline at relieving subjective oral dryness.
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Antisépticos Bucales/uso terapéutico , Agonistas Muscarínicos/uso terapéutico , Pilocarpina/uso terapéutico , Salivación/efectos de los fármacos , Xerostomía/tratamiento farmacológico , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Saliva/metabolismo , Resultado del TratamientoRESUMEN
OBJECTIVE: To compare the effects of sodium lauryl sulfate (SLS)-free and SLS-containing dentifrice in patient with recurrent aphthous stomatitis (RAS). MATERIALS AND METHODS: The design of this study was a double-blind crossover trial. The 90 subjects were divided into three groups: group I used SLS-free (a commercially available SLS-free dentifrice) and SLS-A (SLS-free + 1.5% SLS), group II used SLS-A and SLS-B (a commercially available 1.5% SLS-containing dentifrice), and group III used SLS-free and SLS-B. The subjects used one of the two assigned dentifrices for 8 weeks and then the other for the following 8 weeks. The order of the dentifrices used was selected at random, and there was a 2-week washout period between the two phases. The clinical parameters (number of ulcers, number of episodes, duration of ulcers, mean pain score) were compared between the two phases for each group. RESULTS: The number of ulcers and episodes did not differ significantly between SLS-A, SLS-B, and SLS-free. Only duration of ulcers and mean pain score was significantly decreased during the period using SLS-free. CONCLUSION: Although SLS-free did not reduce the number of ulcers and episodes, it affected the ulcer-healing process and reduces pain in daily lives in patients with RAS.
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Dentífricos/uso terapéutico , Dodecil Sulfato de Sodio/efectos adversos , Estomatitis Aftosa/tratamiento farmacológico , Tensoactivos/efectos adversos , Adulto , Estudios Cruzados , Dentífricos/química , Método Doble Ciego , Dolor Facial/inducido químicamente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadísticas no Paramétricas , Cepillado DentalRESUMEN
OBJECTIVE: Obsessive-compulsive disorder (OCD) is characterized by the dysfunction of control and reward mechanisms. However, only few neuroimaging studies of OCD have examined the reward processing. We examined the neural responses during incentive processing in OCD. METHOD: Twenty unmedicated patients with OCD and 20 age-, sex-, and IQ-matched healthy controls underwent functional magnetic resonance imaging while performing a modified monetary incentive delay task. RESULTS: Compared with controls, patients with OCD showed increased ventral striatal activation in the no-loss minus loss outcome contrast and a significant positive correlation between the ventral striatal activation and compulsion symptom severity. In addition, patients with OCD showed increased activations in the frontostriatal regions in the gain minus no-gain outcomes contrast. During loss anticipation, patients with OCD showed less activations in the lateral prefrontal and inferior parietal cortices. However, during gain anticipation, patients with OCD and healthy controls did not differ in the ventral striatal activation. CONCLUSION: These findings provide neural evidence for altered incentive processing in unmedicated patients with OCD, suggesting an elevated sensitivity to negatively affect stimuli as well as dysfunction of the ventral striatum.
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Ganglios Basales , Imagen por Resonancia Magnética , Trastorno Obsesivo Compulsivo , Corteza Prefrontal , Adulto , Anticipación Psicológica , Atención , Ganglios Basales/patología , Ganglios Basales/fisiopatología , Mapeo Encefálico , Emociones , Femenino , Humanos , Masculino , Motivación , Trastorno Obsesivo Compulsivo/patología , Trastorno Obsesivo Compulsivo/fisiopatología , Corteza Prefrontal/patología , Corteza Prefrontal/fisiopatología , RecompensaRESUMEN
The frequent economic losses incurred with H9N2 low pathogenic avian influenza viruses (LPAI) infection have raised serious concerns for the poultry industry. A 1-dose regimen with inactivated H9N2 LPAI vaccine could not prevent vaccinated poultry from becoming infected and from shedding wild viruses. A study was conducted to determine whether a 2-dose regimen of inactivated H9N2 LPAI vaccine could enhance the immunologic response in chickens. Such gel-primed and mineral oil-boosted regimen has produced encouraging results associated with improved immune responses to an H9N2 LPAI. This strategy could be cost effective and helpful for preventing avian influenza virus in the poultry industry.
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Pollos , Subtipo H9N2 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Gripe Aviar/prevención & control , Adyuvantes Inmunológicos , Animales , Anticuerpos Antivirales/sangre , Geles , Esquemas de Inmunización , Inmunización Secundaria , Aceite Mineral , Organismos Libres de Patógenos Específicos , Vacunas de Productos InactivadosRESUMEN
Nucleic acids can be complexed with cationic polymer to form DNA nanoparticles (polyplex) which are then immobilized on the surface coated extracellular matrix protein (ECM), the process termed as reverse transfection. ECM-containing proteins provide a surface for cell attachment and sustain the release of polyplexes from their surface, thereby inducing transgene expression for prolonged period of time. Consequently, long-term expression of the desired protein can be achieved with the smaller amount of required DNA, as compared to bolus delivery. First of all, we investigated the different ECM components as a coating material and the range of optimal coating density in different ECM was examined for enhanced transfection to neighboring cells. Reporter genes such as luciferase (luc) and enhanced green fluorescent protein (eGFP) were initially used to quantitate transfection efficiencies from polyplex from the coated ECMs of Collagen type I (Col I), fetal bovine serum protein (FBS), bovine serum albumin (BSA). DNA was complexed with positively charged polyethyleneimine (PEI) at N/P ratio 9. Our initial work exhibited that, in the case of both NIH/3T3 cell line and bone marrow stromal (D1) cell line, Col I facilitated the greatest cell adhesion compared to the other coating proteins and 0.5 microg/cm2 of Col I coating density resulted in highest transfection efficiency. On the other hand, comparison of reverse delivery system with atelocollagen-I have shown that reverse delivery system to yield ten times higher transfection efficiency than atelocollagen-PEI/DNA delivery system and one hundred times higher than atelocollagen-naked plasmid delivery system. Moreover, the amount of DNA used for reverse delivery system was much lower than the other systems. This methodology would be applied to induce cellular differentiation in 3-dimensional scaffold after coating scaffolds with genes inducing the differentiation in the nanoparticle formulation. Our final goal is to search for the optimal conditions for the differentiation of stem cells to specific cell types.
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ADN/genética , Genes Reporteros/genética , Células Madre Mesenquimatosas/fisiología , Nanocápsulas/química , Transfección/métodos , Animales , Línea Celular , Composición de Medicamentos/métodos , Ensayo de Materiales , Ratones , Células 3T3 NIH , Nanocápsulas/ultraestructuraRESUMEN
The survival rate of Korean H5N1 highly pathogenic avian influenza (HPAI) viruses was investigated at different temperatures under the laboratory conditions. The estimated survival days for a starting viral concentration of 10(6.5) 50% egg infectious dose/0.1 mL were 930, 1,042, and 3,213 d at 4 degrees C; 226, 232, and 293 d at 20 degrees C; and 51, 55, and 58 d at 30 degrees C for A/chicken/Korea/ES/03, A/chicken/Korea/IS/06, and A/chicken/Korea/Gimje/08 (Gimje/08) viruses, respectively. The stability of the Gimje/08 virus was statistically significant compared with the other 2 viruses except for the data between Gimje/08 and A/chicken/Korea/IS/06 virus at 30 degrees C. This result indicated that the survival rate of 3 Korean HPAI viruses is different at various temperatures, which might have partially influenced the large scale of HPAI outbreak in Korea in 2008.
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Subtipo H5N1 del Virus de la Influenza A/fisiología , Subtipo H5N1 del Virus de la Influenza A/patogenicidad , Gripe Aviar/epidemiología , Alantoides/virología , Animales , Pollos/virología , Subtipo H5N1 del Virus de la Influenza A/crecimiento & desarrollo , Gripe Aviar/virología , Análisis de Regresión , Organismos Libres de Patógenos Específicos , TemperaturaRESUMEN
Background: Data showing the value of neoadjuvant chemotherapy (nact) followed by interval debulking surgery (ids) in the management of advanced-stage serous endometrial carcinoma (eca) are limited; the aim of the present study was to expand the knowledge about that treatment strategy in patients with advanced eca, including endometrioid eca. Methods: Data were collected retrospectively from all patients with advanced-stage eca treated with nact between 2005 and 2014 at 3 oncology referral centres. Primary outcomes were the radiologic response to nact and achievement of optimal or complete ids. Secondary outcomes were recurrence rate and progression-free and overall survival. Results: Of 102 eca cases included, a complete radiologic response was achieved in only 4 cases, with a partial response being achieved in 72% (64% of endometrioid cases, 80% of serous cases). Complete ids was achieved in 62% of the endometrioid cases and in 56% of the serous eca cases, with optimal ids achieved in 31% and 28% of those cases respectively. Survival rates were calculated for all patients with complete and optimal ids; recurrence was observed in 56% and 67% of the cases respectively, and progression-free survival was 18 months and 13 months respectively. Median survival duration was 24 months for endometrioid eca and 28 months for serous eca. Conclusions: For patients with advanced eca who are not suitable for primary debulking, nact followed by ids can be considered regardless of histologic subtype. The treatment options for this group of patients are limited and have to be explored.
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Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/cirugía , Adulto , Anciano , Quimioterapia Adyuvante , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/patología , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Análisis de SupervivenciaRESUMEN
OBJECTIVE: Dopamine dysregulation has been implicated in the pathophysiology of schizophrenia. The present study was performed to examine whether unaffected relatives at high genetic risk of schizophrenia have dopamine dysregulation in comparison with healthy controls. METHOD: Eleven unaffected relatives from families with two or more first- or second-degree relatives with schizophrenia (n = 9) or with a monozygotic schizophrenic twin (n = 2) and 11 age- and sex-matched controls were examined using positron emission tomography (PET) with [(11)C] raclopride. Subjects also underwent extensive neuropsychological testing. RESULTS: Subjects with high genetic risk showed a loss of asymmetry of D(2) receptors in the putamen in comparison with healthy controls. In addition, they showed significantly poorer performance on neuropsychological tests than controls. CONCLUSION: Our results suggest that dopamine dysregulation and neuropsychological dysfunction may be present in subjects at high genetic risk of schizophrenia. However, further studies are required to confirm these findings.
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Familia/psicología , Lateralidad Funcional/genética , Predisposición Genética a la Enfermedad/psicología , Putamen/fisiopatología , Receptores de Dopamina D2/genética , Esquizofrenia/genética , Adolescente , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/psicología , Femenino , Marcadores Genéticos/genética , Humanos , Imagenología Tridimensional , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas/estadística & datos numéricos , Tomografía de Emisión de Positrones/métodos , Adulto JovenRESUMEN
It is unclear if BRCA mutation carriers diagnosed with advanced endometrial cancer have a better prognosis compared to sporadic cases. From a population database of BRCA1 and 2 mutation carriers in Southwestern Ontario, Canada, we identified three women with advanced-stage endometrial cancer. They were 57, 59, and 64 years of age, and of English/Scottish, Ashkenazi Jewish, and English heritage, respectively. They had different mutations in BRCA1 (Q1240X:C3837T; 68_69delAG; 1961delA). One had a sarcomatoid carcinoma and two had uterine papillary serous carcinoma. All had stage IVB disease, with surgery followed by adjuvant chemotherapy and/or radiotherapy. Follow-up has ranged from 3.3 to 14.6 years. They are still alive and well with no evidence of recurrent disease. This observation raises the question as to whether BRCA mutations may be associated with a better prognosis in patients with advanced endometrial cancer.
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Carcinoma Endometrioide/genética , Carcinoma Endometrioide/mortalidad , Neoplasias Endometriales/genética , Neoplasias Endometriales/mortalidad , Mutación de Línea Germinal , Recurrencia Local de Neoplasia/mortalidad , Carcinoma Endometrioide/patología , Carcinoma Endometrioide/terapia , Terapia Combinada , Supervivencia sin Enfermedad , Neoplasias Endometriales/patología , Neoplasias Endometriales/terapia , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Genes BRCA1 , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Medición de Riesgo , Muestreo , Tasa de Supervivencia , Factores de TiempoRESUMEN
Adjuvant therapy of early-stage uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CCC) is controversial. We conducted a prospective cohort study to evaluate outcomes of patients with early-stage UPSC or CCC who were followed without adjuvant therapy after complete surgical staging. From 2000 to 2006, we evaluated all consecutive patients with stage IA/IB UPSC or CCC who had surgical staging by a gynecological oncologist at the London Health Sciences Centre, Canada. Follow-up consisted of history and physical examination every 3 months for 2 years, then every 6 months for the next 3 years. Primary outcome measure was 2-year disease-free survival. There were 22 evaluable patients. Mean patient age was 63.4 years. Median number of pelvic and para-aortic lymph nodes resected was 15 (range 2-39) and 4 (range 0-12), respectively. Thirteen had UPSC, seven had CCC, and two had both UPSC and CCC. Nine had stage IA and 13 had stage IB disease. Median follow-up was 25 months (range 6-72). Only one patient has recurred (stage IB UPSC, isolated vault recurrence 10 months after surgery), but she is well 9 months after receiving pelvic radiotherapy and vault brachytherapy. Two-year disease-free survival was 95%. These results suggest that adjuvant therapy may not be necessary for stage IA and IB UPSC and CCC after surgical staging. Further prospective evaluation of different adjuvant therapy practices is required for early-stage UPSC and CCC, which may be useful in the design of future clinical trials.
Asunto(s)
Adenocarcinoma de Células Claras/radioterapia , Cistadenocarcinoma Papilar/radioterapia , Cistadenocarcinoma Seroso/radioterapia , Estadificación de Neoplasias/métodos , Radioterapia Adyuvante/métodos , Neoplasias Uterinas/radioterapia , Adenocarcinoma de Células Claras/mortalidad , Adenocarcinoma de Células Claras/patología , Adenocarcinoma de Células Claras/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Cistadenocarcinoma Papilar/mortalidad , Cistadenocarcinoma Papilar/patología , Cistadenocarcinoma Papilar/cirugía , Cistadenocarcinoma Seroso/mortalidad , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/cirugía , Femenino , Estudios de Seguimiento , Humanos , Escisión del Ganglio Linfático , Metástasis Linfática , Persona de Mediana Edad , Recurrencia , Análisis de Supervivencia , Neoplasias Uterinas/mortalidad , Neoplasias Uterinas/patología , Neoplasias Uterinas/cirugíaRESUMEN
Fewer than 20% of women with endometrial cancer have positive nodes, and an accurate noninvasive imaging modality to assess lymph node status would be helpful in selecting those who need lymphadenectomy. The objective of this pilot study was to evaluate positron emission tomography with computed tomography (pet-ct) in predicting nodal status before surgery for endometrial cancer. Twelve patients were enrolled at a single tertiary care centre. The sensitivity and specificity of preoperative pet-ct in predicting nodal status were 53.3% and 99.6% respectively. Using pet-ct, all metastatic nodes may not necessarily be detected, especially nodes with microscopic disease. The sensitivity of this imaging modality has to be improved before it can routinely be used in the preoperative evaluation of endometrial cancer.
RESUMEN
OBJECTIVES: Severe fever with thrombocytopenia syndrome (SFTS) virus has a variety of central nervous system (CNS) manifestations. However, there are limited data regarding SFTS-associated encephalopathy/encephalitis (SFTSAE) and its mechanism. METHODS: All patients with confirmed SFTS who underwent cerebrospinal fluid (CSF) examination due to suspected acute encephalopathy were enrolled in three referral hospitals between January 2013 and October 2016. Real-time RT-PCR for SFTS virus and chemokine/cytokines levels from blood and CSF were analysed. RESULTS: Of 41 patients with confirmed SFTS by RT-PCR for SFTS virus using blood samples, 14 (34%) underwent CSF examination due to suspected SFTSAE. All 14 patients with SFTSE revealed normal protein and glucose levels in CSF, and CSF pleocytosis was uncommon (29%, 4/14). Of the eight patients whose CSF was available for further analysis, six (75%) yielded positive results for SFTS virus. Monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) level in CSF were significantly higher than those in serum (geometric mean 1889 pg/mL in CSF versus 264 pg/mL in serum for MCP-1, p = 0.01, and geometric mean 340 pg/mL in CSF versus 71 pg/mL in serum for IL-8, p = 0.004). CONCLUSIONS: The CNS manifestation of SFTS as acute encephalopathy/encephalitis is a common complication of SFTS. Although meningeal inflammation was infrequent in patients with SFTSAE, SFTS virus was frequently detected in CSF with elevated MCP-1 and IL-8. These findings indicate that possible direct invasion of the CNS by SFTS virus with the associated elevated cytokine levels in CSF may play an important role in the pathogenesis of SFTSAE.
Asunto(s)
Encefalopatías/etiología , Encefalopatías/patología , Líquido Cefalorraquídeo/virología , Encefalitis/etiología , Encefalitis/patología , Fiebre por Flebótomos/complicaciones , Phlebovirus/aislamiento & purificación , Anciano , Anciano de 80 o más Años , Citocinas/sangre , Citocinas/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios RetrospectivosRESUMEN
YKP1358 is a novel serotonin (5-HT(2A)) and dopamine (D(2)) antagonist that, in preclinical studies, fits the general profile of an atypical antipsychotic. We conducted a D(2) receptor occupancy study with YKP1358 in healthy volunteers using positron emission tomography (PET) to measure the D(2) receptor occupancy of YKP1358 and to characterize its relationship to plasma drug concentrations. A single oral dose, parallel group, dose-escalation (100, 200, and 250 mg) study was performed in 10 healthy male volunteers with the PET radiotracer [(11)C]raclopride. The D(2) receptor occupancy of striatum was measured pre-dose, and at 2, 5, and 10 h after YKP1358 administration. Serial blood samples were taken for measurement of plasma YKP1358 concentrations. D(2) receptor occupancy by YKP1358 increased to 53-83% at 2 h, and then decreased afterwards, ranging from 40-64% at 5 h to 20-51% at 10 h. The YKP1358 dose-plasma concentration relationship exhibited extensive variability, but there was a good relationship between plasma concentrations and D(2) receptor occupancy that was well predicted by a sigmoid E(max) model using nonlinear mixed effects modeling. To our knowledge, this is the first study in which the relationship between plasma concentration and the biomarker of D(2) receptor occupancy was modeled using nonlinear mixed effects modeling. It is anticipated that these results will be useful in estimating for subsequent studies the initial doses of YKP1358 required to achieve a therapeutically effective range of D(2) receptor occupancy.