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1.
Papillomavirus Res ; : 100184, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31505258

RESUMO

Intense research activity in HPV modelling over this decade has necessitated additional guidelines to those for general modelling. A specific framework is required to address different policy questions and unique complexities of HPV modelling. HPV-FRAME is an initiative to develop a consensus statement and quality-based framework for epidemiologic and economic HPV models. Its development involved an established process. Reporting standards have been structured according to seven domains reflecting distinct policy questions in HPV and cancer prevention and categorised by relevance to a population or evaluation. Population-relevant domains are: 1) HPV vaccination in pre-adolescent individuals; 2) HPV vaccination in older individuals; 3) targeted vaccination in men who have sex with men; 4) considerations for individuals living with HIV and 5) considerations for low- and middle-income countries. Additional considerations applicable to specific interventions are: 6) cervical screening or integrated cervical screening and HPV vaccination approaches and 7) alternative vaccine types (e.g. nonavalent) and alternative dosing schedules. HPV-FRAME aims to promote the development of models in accordance with an explicit framework, to better enable target audiences to understand a model's strength and weaknesses in relation to a specific policy question and ultimately improve the model's contribution to informed decision-making.

2.
BMJ Open ; 9(7): e029017, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289088

RESUMO

INTRODUCTION: The clinical course of high-grade cervical intraepithelial neoplasia (CIN2/3) is characterised by a high spontaneous regression rate. Histological assessment is unable to differentiate between CIN2/3 lesions likely to regress and those likely to persist or progress. Most CIN2/3 lesions are treated by surgical excision, leading to overtreatment of a substantial proportion. In this prospective study, we evaluate the value of DNA methylation of host cell genes, which has shown to be particularly sensitive for the detection of advanced CIN2/3 and cervical cancer, in the prediction of regression or non-regression of CIN2/3 lesions. METHODS AND ANALYSIS: This is a multicentre observational longitudinal study with 24-month follow-up. Women referred for colposcopy with an abnormal cervical scrape, who have been diagnosed with CIN2/3 and a small cervical lesion (≤50% of cervix) will be asked to participate. Participants will be monitored by 6-monthly cytological and colposcopic examination. In case of clinical progression, participants will receive treatment and exit the study protocol. At baseline and during follow-up, self-sampled cervicovaginal brushes and cervical scrapes will be collected for high-risk human papillomavirus (HPV) testing and FAM19A4/miR124-2 methylation analysis. A colposcopy-directed biopsy will be taken from all participants at the last follow-up visit. The primary study endpoint is regression or non-regression at the end of the study based on the histological diagnosis. Regression is defined as CIN1 or less. Non-regression is defined as CIN2 or worse. The secondary study endpoint is defined as HPV clearance (double-negative HPV test at two consecutive time-points). The association between methylation status and regression probability will be evaluated by means of χ2 testing. ETHICS AND DISSEMINATION: Ethics approval was obtained in all participating clinics. Results of the main study will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NTR6069; Pre-results.

3.
J Affect Disord ; 256: 509-516, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279250

RESUMO

BACKGROUND: Compelling evidence links elevated levels of C-reactive protein (CRP) and other inflammatory markers to poor treatment outcome of antidepressant medication. Little is known about the contribution of low-grade inflammation to treatment response to electroconvulsive therapy (ECT) in severely depressed patients. METHOD: Associations between serum levels of CRP, interleukin-6, interleukin-10, and tumour necrosis factor-α as well as remission of depression, time to remission, and speed of decline of depressive symptoms were examined in 95 older (mean age: 73.1 years) depressed patients treated with ECT. RESULTS: Moderately elevated levels of CRP at baseline (3 to 10 mg/L), but no other inflammatory markers, were associated with higher remission rates. In patients with moderately elevated CRP levels, the odds ratio for remission was 3.62 (95% confidence interval [CI], 1.09-11.97; p = 0.04). Time to remission was shorter in those with moderately elevated CRP levels (p = 0.05). Speed of decline was higher in patients with moderately elevated CRP levels as compared with those with low CRP levels (decline of 3.2 Montgomery Åsberg Depression Rating Scale points per administration vs. 2.3 points per administration, p = 0.03). LIMITATIONS: Because of the observational design, residual confounding through other lifestyle or demographic factors cannot be ruled out. CONCLUSIONS: Although earlier studies showed that low-grade inflammation contributes to poor treatment response in those treated with antidepressants, our study provides clues that low-grade inflammation does not have such a detrimental effect on the treatment response to ECT. This is underscored by our finding that moderately elevated CRP levels were associated with increased remission rates in depressed patients treated with ECT. Replication studies are warranted.

4.
Gynecol Oncol ; 154(2): 368-373, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31182225

RESUMO

OBJECTIVE: This study evaluates the long-term risk for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) among HPV positive women triaged with FAM19A4/miR124-2 methylation analysis. METHODS: In a post hoc analysis, data on FAM19A4/miR124-2 methylation, cytology, and HPV16/18 genotyping of HPV positive women (n = 1025) from a large population-based screening cohort with 14-year follow-up were evaluated. Cumulative CIN3+ incidences over 3 screening rounds (5-year intervals) of 4 triage strategies were compared: FAM19A4/miR124-2 methylation analysis, cytology, HPV16/18 genotyping with FAM19A4/miR124-2 methylation, and HPV16/18 genotyping with cytology. RESULTS: Kaplan-Meier estimates of 14-year cumulative CIN3+ incidence of HPV positive women with a negative methylation and a negative cytology triage test were comparable (16.3% and 15.6%, respectively). The cumulative CIN3+ incidence of methylation positive and cytology positive women were 39.8% and 46.5%, respectively. HPV16/18 genotyping with methylation and HPV16/18 genotyping with cytology resulted in the lowest 14-year cumulative CIN3+ incidence among triage negative women (10.7% and 10.0%, respectively), but cumulative CIN3+ incidence among triage positive women was lower (33.4% and 35.7%, respectively) compared with triage by methylation alone and cytology alone. CONCLUSIONS: Among HPV positive women of 30 years and older, a negative FAM19A4/miR124-2 methylation triage test provides a similar long-term CIN3+ risk compared with a negative cytology triage test. Because of their high CIN3+ risk, women with a positive methylation triage test could be referred for colposcopy. Therefore, FAM19A4/miR124-2 methylation analysis is a promising alternative to cytology for triage of HPV positive women.

5.
Prev Med ; 125: 5-11, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31054907

RESUMO

Several countries offer HPV self-sampling for screening non-attendees. It is assumed that screening attendees also prefer self-sampling to clinician-based sampling, however, little research has been conducted with respect to this. Women participating in the IMPROVE-study were randomised (1:1) to self- or clinician-collected HPV testing, and HPV-positive women were retested using the other collection method. Three different questionnaires were sent out among a subset of participating women: Q1) HPV-positive women from both study groups were asked about their experiences with self-sampling and clinician-based sampling (n = 497); Q2) HPV-negative women from the self-sampling group were asked about their experiences with self-sampling (n = 2366); and Q3) HPV-negative women in the clinician-collection group were asked about their experiences with clinician-based sampling (n = 2092). Response rates ranged from 71.6 to 79.4%. Women reported significantly lower levels of shame, nervousness, discomfort and pain during self-sampling compared to clinician-based sampling. However, trust in correct sampling was significantly higher during clinician-based sampling. The majority of women in group Q1 preferred self-sampling (76.5%) to clinician-based sampling (11.9%) in future screening, while 11.6% of women reported to have no preference for either method. To conclude, women from a regular screening population have a positive attitude towards self-sampling but express some concerns with respect to accuracy. The majority prefers self-sampling to clinician-based sampling in future screening. Based on these results, a screening approach where women can choose for either self-sampling or clinician-based sampling seems highly justifiable.

6.
Alzheimers Res Ther ; 11(1): 33, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30987684

RESUMO

BACKGROUND: Biomarkers such as cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) have predictive value for progression to dementia in patients with mild cognitive impairment (MCI). The pre-dementia stage takes far longer, and the interpretation of biomarker findings is particular relevant for individuals who present at a memory clinic, but are deemed cognitively normal. The objective of the current study is to construct biomarker-based prognostic models for personalized risk of clinical progression in cognitively normal individuals presenting at a memory clinic. METHODS: We included 481 individuals with subjective cognitive decline (SCD) from the Amsterdam Dementia Cohort. Prognostic models were developed by Cox regression with patient characteristics, MRI, and/or CSF biomarkers to predict clinical progression to MCI or dementia. We estimated 5- and 3-year individualized risks based on patient-specific values. External validation was performed on Alzheimer's Disease Neuroimaging Initiative (ADNI) and an European dataset. RESULTS: Based on demographics only (Harrell's C = 0.70), 5- and 3-year progression risks varied from 6% [3-11] and 4% [2-8] (age 55, MMSE 30) to 38% [29-49] and 28% [21-37] (age 70, MMSE 27). Normal CSF biomarkers strongly decreased progression probabilities (Harrell's C = 0.82). By contrast, abnormal CSF markedly increased risk (5 years, 96% [56-100]; 3 years, 89% [44-99]). The CSF model could reclassify 58% of the individuals with an "intermediate" risk (35-65%) based on the demographic model. MRI measures were not retained in the models. CONCLUSION: The current study takes the first steps in a personalized approach for cognitively normal individuals by providing biomarker-based prognostic models.

7.
Epidemiology ; 30(4): 590-596, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30985528

RESUMO

BACKGROUND: Genotype attribution in high-grade cervical lesions (CIN3+) can be calculated by the hierarchical or proportional method, but these do not account for the genotype distribution in the general population and cannot assess the number of genotype-specific high-grade cervical lesions (CIN3+). METHODS: We present a statistical method for estimating genotype-specific CIN3+ risks and genotype attribution in CIN3+ from cervical screening samples. A key assumption is that genotype-specific infections in women with multiple infections have independent progression risks. We applied the method to 512 human papillomavirus (HPV)-positive women referred for colposcopy and validated it by laser-capture microscopy-polymerase chain reaction. We also compared performance by simulation. RESULTS: For endpoint CIN3+, the summed deviation of attributable fractions between the estimated genotype-specific attributable fractions and laser-capture microscopy polymerase chain reaction-based attributable fractions was similar for the three methods: 0.17 for the new method (95% confidence interval [CI] = 0.091, 0.28), 0.19 (95% CI = 0.11, 0.33) for the hierarchical method and 0.15 (95% CI = 0.085, 0.26) for the proportional method. Simulations indicated that the new method outperformed the other methods for endpoint CIN3+ when the number of HPV-positive women was large. Exclusion of HPV16-positive women had only a small effect on the estimated genotype-specific risks, supporting the independence assumption. CONCLUSIONS: Genotype-specific attribution in CIN3+ can be accurately predicted by a model that assumes independence between genotypes with respect to disease progression. The method can be used to monitor HPV vaccine effectiveness for prevention of genotype-specific CIN3+ and to assess disease risk after vaccination.

8.
BMC Palliat Care ; 18(1): 31, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30922276

RESUMO

BACKGROUND: Opioids are prescribed in over 40% of patients with advanced cancer, but side effects occur frequently. In this study we evaluated the development and treatment of opioid induced constipation (OIC), and OIC resolving effect of methylnaltrexone for different opioid subtypes in daily clinical practice. METHODS: Patients with cancer using opioids were included in a retrospective chart analysis. Baseline characteristics, data on opioid use, laxative use, and OIC were collected. Patients with OIC who were prescribed methylnaltrexone, were included in a prospective observational trial (NCT01955213). RESULTS: Thirty-nine of 327 patients (pts) with cancer who were treated with opioids suffered from OIC (overall prevalence 12%; 95%-CI: 8-15%). The prevalence of OIC was similar in patients treated with oxycodone or fentanyl (12 of 81 pts. vs. 18 of 110 pts., RR 0.9; 95%CI 0.4-2.0). The morphine equivalent daily dose did not significantly differ between opioid subtypes (fentanyl 89 mg (IQR 60-180) vs. oxycodone 40 mg (40-80), P = 0.231). Twenty-two individual patients (7%) were admitted for OIC. Most effective laxatives in admitted patients were enemas, methylnaltrexone, or 4-l polyethylene-glycol solution. In the prospective observational study, the effect of methylnaltrexone could be evaluated in 23 patients. Eleven patients achieved the primary endpoint of ≥2 laxation responses out of the first four doses methylnaltrexone, independent of opioid subtype. CONCLUSIONS: OIC is a burdensome clinical problem independent of opioid subtype. Timely intensification of prophylactic laxative treatment, especially when opioid doses increase, may help to prevent OIC. Clinically overt OIC requires a more intensive laxative regimen with for example methylnaltrexone. TRIAL REGISTRATION: NCT01955213 .

9.
BMC Cancer ; 19(1): 160, 2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782151

RESUMO

BACKGROUND: The Delirium Observation Screening Scale (DOS) was developed to facilitate early recognition of delirium by nurses during routine clinical care. It has shown good validity in a variety of patient populations, but has not yet been validated in hospitalized patients with advanced cancer, although the DOS is commonly used in this setting in daily practice. The aim of this study was to evaluate the accuracy of the DOS in hospitalized patients with advanced cancer using the revised version of the Delirium Rating Scale (DRS-R- 98) as the gold standard. METHODS: Patients with advanced cancer admitted to the medical oncology ward were screened for delirium with the DOS and DRS-R-98. Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) of the DOS were calculated, using a DOS score ≥ 3 as a cut-off for delirium. RESULTS: Ninety-five DOS negative and 98 DOS positive patients were identified. Sensitivity of the DOS, was > 99.9% (95%-CI, 95.8-100.0%), specificity was 99.5% (95%-CI 95.5-99.96%), PPV was 94.6% (95% CI 88.0-97.7), and NPV was > 99.9% (95% CI 96.1-100.0). CONCLUSIONS: The DOS is an accurate screening tool for delirium in patients with advanced cancer. Since it has the benefit of being easily implicated in daily practice, we recommend to educate caregivers to screen patients with advanced cancer by DOS analysis. By early recognition and adequate treatment of this distressing delirium syndrome the quality of life of patients with advanced cancer can be improved. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01539733 (Feb 27, 2012 - retrospectively registered), Netherlands Trial Register NTR2559 (Oct 7, 2010).


Assuntos
Delírio/diagnóstico , Delírio/enfermagem , Neoplasias/complicações , Enfermagem Oncológica , Escalas de Graduação Psiquiátrica , Idoso , Confiabilidade dos Dados , Delírio/etiologia , Diagnóstico Precoce , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Testes Neuropsicológicos , Valor Preditivo dos Testes , Qualidade de Vida
10.
Lancet Oncol ; 20(2): 229-238, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30658933

RESUMO

BACKGROUND: Human papillomavirus (HPV) testing on self-collected samples is a potential alternative to HPV testing on clinician-collected samples, but non-inferiority of its clinical accuracy remains to be assessed in the regular screening population. The IMPROVE study was done to evaluate the clinical accuracy of primary HPV testing on self-collected samples within an organised screening setting. METHODS: In this randomised, non-inferiority trial, women aged 29-61 years were invited to participate in the study as part of their regular screening invitation in the Netherlands. Women who provided informed consent were randomly allocated (1:1, with a block size of ten stratified by age) to one of two groups: a self-sampling group, in which women were requested to collect their own cervicovaginal sample using an Evalyn Brush (Rovers Medical Devices BV, Oss, Netherlands); or a clinician-based sampling group, in which samples were collected by a general practitioner with a Cervex-Brush (Rovers Medical Devices BV). All samples were tested for HPV using the clinically validated GP5+/6+ PCR enzyme immunoassay (Labo Biomedical Products BV, Rijswijk, Netherlands). HPV-positive women in both groups were retested with the other collection method and triaged by cytology and repeat cytology in accordance with current Dutch screening guidelines. Primary endpoints were detection of cervical intraepithelial neoplasia (CIN) of grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+). Non-inferiority of HPV testing on self-collected versus clinician-collected samples was evaluated against a margin of 90% for the relative sensitivity and 98% for the relative specificity. This study is registered at the Dutch Trial register (NTR5078) and has been completed. FINDINGS: Of the 187 473 women invited to participate, 8212 were randomly allocated to the self-sampling group and 8198 to the clinician-based sampling group. After exclusion of women who met the exclusion criteria or who did not return their sample, 7643 women were included in the self-sampling group and 6282 in the clinician-based sampling group. 569 (7·4%) self-collected samples and 451 (7·2%) clinician-collected samples tested positive for HPV (relative risk 1·04 [95% CI 0·92-1·17]). Median follow-up duration for HPV-positive women was 20 months (IQR 17-22). The CIN2+ sensitivity and specificity of HPV testing did not differ between self-sampling and clinician-based sampling (relative sensitivity 0·96 [0·90-1·03]; relative specificity 1·00 [0·99-1·01]). For the CIN3+ endpoint, relative sensitivity was 0·99 (0·91-1·08) and relative specificity was 1·00 (0·99-1·01). INTERPRETATION: HPV testing done with a clinically validated PCR-based assay had similar accuracy on self-collected and clinician-collected samples in terms of the detection of CIN2+ or CIN3+ lesions. These findings suggest that HPV self-sampling could be used as a primary screening method in routine screening. FUNDING: Ministry of Health, Welfare, and Sport (Netherlands), and the European Commission.

11.
Math Biosci ; 309: 92-106, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30659822

RESUMO

Cervical cancer arises differentially from infections with up to 14 high-risk human papillomavirus (HPV) types, making model-based evaluations of cervical cancer screening strategies computationally heavy and structurally complex. Thus, with the high number of HPV types, microsimulation is typically used to investigate cervical cancer screening strategies. We developed a feasible deterministic model that integrates varying natural history of cervical cancer by the different high-risk HPV types with compressed mixture representations of the screened population, allowing for fast computation of screening interventions. To evaluate the method, we built a corresponding microsimulation model. The outcomes of the deterministic model were stable over different levels of compression and agreed with the microsimulation model for all disease states, screening outcomes, and levels of cancer incidence. The compression reduced the computation time more than 1000 fold when compared to microsimulation in a cohort of 1 million women. The compressed mixture representations enable the assessment of uncertainties surrounding the natural history of cervical cancer and screening decisions in a computationally undemanding way.

12.
Curr Opin Otolaryngol Head Neck Surg ; 27(2): 85-90, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30694913

RESUMO

PURPOSE OF REVIEW: To gain the evidence-based knowledge concerning the efficacy of HPV vaccination for oropharyngeal sites and to highlight the trials and strategies for vaccine administration in HPV-dependent head and neck diseases. RECENT FINDINGS: Vaccination can be provided in two injections. There is increasing anecdotal evidence that therapeutic vaccination is effective in treatment of recurrent respiratory papillomatosis. SUMMARY: The availability and broadening spectrum of HPV vaccines make possible the prevention of cervical and other HPV-dependent diseases. Vaccination is now included in the national immunization programs of most industrial countries and will be used, it is hoped, in developing countries within the next few years. In developing countries, few women are screened for cervical precancerous lesions, making immunization even more important. In affluent countries and matured societies, with high coverage of cervical screening, the focus of interest will shift to other HPV-related diseases. The HPV vaccination is effective in preventing oral infection with types targeted by the vaccines.


Assuntos
Neoplasias de Cabeça e Pescoço/prevenção & controle , Neoplasias de Cabeça e Pescoço/virologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/uso terapêutico , Feminino , Humanos , Papiloma/prevenção & controle , Papiloma/virologia , Infecções por Papillomavirus/virologia , Lesões Pré-Cancerosas/prevenção & controle , Lesões Pré-Cancerosas/virologia , Neoplasias do Sistema Respiratório/prevenção & controle , Neoplasias do Sistema Respiratório/virologia
13.
Alzheimers Dement ; 15(3): 465-476, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30555032

RESUMO

INTRODUCTION: In this multicenter study on subjective cognitive decline (SCD) in community-based and memory clinic settings, we assessed the (1) incidence of Alzheimer's disease (AD) and non-AD dementia and (2) determinants of progression to dementia. METHODS: Eleven cohorts provided 2978 participants with SCD and 1391 controls. We estimated dementia incidence and identified risk factors using Cox proportional hazards models. RESULTS: In SCD, incidence of dementia was 17.7 (95% Poisson confidence interval 15.2-20.3)/1000 person-years (AD: 11.5 [9.6-13.7], non-AD: 6.1 [4.7-7.7]), compared with 14.2 (11.3-17.6) in controls (AD: 10.1 [7.7-13.0], non-AD: 4.1 [2.6-6.0]). The risk of dementia was strongly increased in SCD in a memory clinic setting but less so in a community-based setting. In addition, higher age (hazard ratio 1.1 [95% confidence interval 1.1-1.1]), lower Mini-Mental State Examination (0.7 [0.66-0.8]), and apolipoprotein E ε4 (1.8 [1.3-2.5]) increased the risk of dementia. DISCUSSION: SCD can precede both AD and non-AD dementia. Despite their younger age, individuals with SCD in a memory clinic setting have a higher risk of dementia than those in community-based cohorts.

14.
Int J Cancer ; 144(9): 2339-2346, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30565673

RESUMO

We studied whether triage of human papillomavirus (HPV)-positive women participating in an HPV-based screening programme can be improved by including the HPV result at the previous screen in the triage algorithm. We analyzed data of a subgroup of 366 women from the POBASCAM trial, screened by cytology and HPV cotesting. Women were included if they tested HPV-positive in the second HPV-based screening round. We evaluated the clinical performance of 16 strategies, consisting of cytology, HPV genotyping, and/or previous screen HPV result. The clinical endpoint was cervical precancer or cancer (CIN3+). The current Dutch triage testing policy for HPV-positive women is to refer women for colposcopy if they have abnormal cytology at baseline or after 6-18 months. In the second HPV-based screening round, this strategy yielded a negative predictive value (NPV) of 95.8% (95% confidence interval: 91.9-98.2) and colposcopy referral rate of 37.6% (32.3-43.2%). Replacing repeat cytology by the previous screen HPV result yielded a similar NPV (96.9%, 93.3-98.9) and colposcopy referral rate (38.8%, 33.4-44.4). A higher NPV (99.2%, 96.3-100%) at the cost of a higher colposcopy referral rate (49.2%, 43.6-54.8) was achieved when cytology was combined with HPV16/18 genotyping. The other 13 triage strategies yielded a lower NPV, a higher colposcopy referral rate or performed similarly but required additional testing. HPV-positive women in the second HPV-based screening round can be suitably managed by cytology, HPV16/18 genotyping and the HPV result at the previous screen, obviating the need for repeat testing of HPV-positive, cytology negative women.


Assuntos
Neoplasia Intraepitelial Cervical/diagnóstico , Detecção Precoce de Câncer/métodos , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/isolamento & purificação , Infecções por Papillomavirus/diagnóstico , Lesões Pré-Cancerosas/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Adulto , Algoritmos , Neoplasia Intraepitelial Cervical/virologia , Colposcopia , Feminino , Genótipo , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Programas de Rastreamento/métodos , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/virologia
15.
Alzheimers Dement ; 2018 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-30339801

RESUMO

INTRODUCTION: Reimbursement of amyloid-PET is lagging due to the lack of definitive evidence on its clinical utility and cost-effectiveness. The Amyloid Imaging to Prevent Alzheimer's Disease-Diagnostic and Patient Management Study (AMYPAD-DPMS) is designed to fill this gap. METHODS: AMYPAD-DPMS is a phase 4, multicenter, prospective, randomized controlled study. Nine hundred patients with subjective cognitive decline plus, mild cognitive impairment, and dementia possibly due to Alzheimer's disease will be randomized to ARM1, amyloid-PET performed early in the diagnostic workup; ARM2, amyloid-PET performed after 8 months; and ARM3, amyloid-PET performed whenever the physician chooses to do so. ENDPOINTS: The primary endpoint is the difference between ARM1 and ARM2 in the proportion of patients receiving a very-high-confidence etiologic diagnosis after 3 months. Secondary endpoints address diagnosis and diagnostic confidence, diagnostic/therapeutic management, health economics and patient-related outcomes, and methods for image quantitation. EXPECTED IMPACTS: AMYPAD-DPMS will supply physicians and health care payers with real-world data to plan management decisions.

16.
Mod Pathol ; 31(12): 1842-1850, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30135508

RESUMO

In this study, we evaluate the expression of human papillomavirus E4 protein (marker for the onset of a productive infection) and hypermethylation of host-cell CADM1, MAL, and miR124-2 genes (marker for an advanced, transforming infection) in cervical intraepithelial neoplasia (CIN) and cancer. A total of 115 cervical lesions were categorized by 3 pathologists into no dysplasia, CIN1, CIN2, CIN3, or cancer by classical histomorphological grading criteria, and by an immunoscore (cumulative value: 0-6) grading system based on Ki-67 (score: 0-3) and p16ink4a (score: 0-3) expression. Lesions were immunostained for E4 protein and analyzed for hypermethylation of CADM1, MAL, or miR124-2 genes. Expression of E4 and hypermethylation levels were related to CIN grade based on both classical and immunoscore grading. Hypermethylation increased with severity of the lesion as defined by both classical histomorphological grading and immunoscore criteria, and was always present in carcinomas (22/22). Extensive E4 expression decreased with increasing CIN grade and immunoscore, being most frequent in classically graded CIN1 or in lesions with cumulative immunoscore 1-3 and absent in carcinomas. High-grade lesions (CIN2/3 or immunoscore: 4-6) showed less E4 expression, which was inversely related to an increasing hypermethylation. Extensive E4 expression, as observed in a small proportion of high-grade lesions (6/49 and 8/43, respectively), was mostly associated with a negative methylation marker status (5/6 and 7/8, respectively). Our results illustrate the gradual transition of productive CIN (reflected by extensive E4 expression), to advanced transforming CIN (reflected by extensive hypermethylation) and cancer. Expression patterns of E4 and hypermethylation status of host-cell genes, may be used to identify cervical lesions at risk for cervical cancer, providing a better guidance for clinicians on treatment decisions.

17.
Eur J Health Econ ; 2018 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-30051152

RESUMO

BACKGROUND: Vaccine price is one of the most influential parameters in economic evaluations of HPV vaccination programmes. Vaccine tendering is a cost-containment method widely used by national or regional health authorities, but information on tender-based HPV vaccine prices is scarce. METHODS: Procurement notices and awards for the HPV vaccines, published from January 2007 until January 2018, were systematically retrieved from the online platform for public procurement in Europe. Information was collected from national or regional tenders organized for publicly funded preadolescent vaccination programmes against HPV. The influence of variables on the vaccine price was estimated by means of a mixed-effects model. FINDINGS: Prices were collected from 178 procurements announced in 15 European countries. The average price per dose for the first-generation HPV vaccines decreased from €101.8 (95% CI 91.3-114) in 2007 to €28.4 (22.6-33.5) in 2017, whereas the average dose price of the 9-valent vaccine in 2016-2017 was €49.1 (38.0-66.8). Unit prices were, respectively, €7.5 (4.4-10.6) and €34.4 (27.4-41.4) higher for the 4-valent and 9-valent vaccines than for the 2-valent vaccine. Contract volume and duration, level of procurement (region or country), per capita GDP and number of offers received had a significant effect on vaccine price. INTERPRETATION: HPV vaccine procurement is widely used across Europe. The fourfold decrease in the average tender-based prices compared to list prices confirms the potential of tendering as an efficient cost-containment strategy, thereby expanding the indications for cost-effective HPV vaccination to previously ineligible target groups.

18.
J Clin Pathol ; 71(11): 981-988, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30012698

RESUMO

AIMS: To investigate the accuracy and reproducibility of a scoring system for cervical intraepithelial neoplasia (CIN1-3) based on immunohistochemical (IHC) biomarkers Ki-67 and p16ink4a. METHODS: 115 cervical tissue specimens were reviewed by three expert gynaecopathologists and graded according to three strategies: (1) CIN grade based on H&E staining only; (2) immunoscore based on the cumulative score of Ki-67 and p16ink4a only (0-6); and (3) CIN grade based on H&E supported by non-objectified IHC 2 weeks after scoring 1 and 2. The majority consensus diagnosis of the CIN grade based on H&E supported by IHC was used as the Reference Standard. The proportion of test positives (accuracy) and the absolute agreements across pathologists (reproducibility) of the three grading strategies within each Reference Standard category were calculated. RESULTS: We found that immunoscoring with positivity definition 6 yielded the highest proportion of test positives for Reference Standard CIN3 (95.5%), in combination with the lowest proportion of test positives in samples with CIN1 (1.8%). The proportion of test positives for CIN3 was significantly lower for sole H&E staining (81.8%) or combined H&E and IHC grading (84.8%) with positivity definition ≥CIN3. Immunoscore 6 also yielded high absolute agreements for CIN3 and CIN1, but the absolute agreement was low for CIN2. CONCLUSIONS: The higher accuracy and reproducibility of the immunoscore opens the possibility of a more standardised and reproducible definition of CIN grade than conventional pathology practice, allowing a more accurate comparison of CIN-based management strategies and evaluation of new biomarkers to improve the understanding of progression of precancer from human papillomavirus infection to cancer.


Assuntos
Neoplasia Intraepitelial Cervical/química , Inibidor p16 de Quinase Dependente de Ciclina/análise , Imuno-Histoquímica , Antígeno Ki-67/análise , Infecções por Papillomavirus/metabolismo , Neoplasias do Colo do Útero/química , Biópsia , Neoplasia Intraepitelial Cervical/patologia , Neoplasia Intraepitelial Cervical/virologia , Estudos Transversais , Feminino , Humanos , Imuno-Histoquímica/normas , Gradação de Tumores , Variações Dependentes do Observador , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Valor Preditivo dos Testes , Padrões de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia
19.
PLoS One ; 13(7): e0199624, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30005066

RESUMO

BACKGROUND: In the Caribbean region, a notable difference in HPV-prevalence and genotypes distribution between the islands is observed. Recently we found in Curaçao a low incidence of HPV16 and 18 in cervical cancer compared to the standard world population. We aimed to determine HPV-prevalence, HPV-genotype distribution and associated risk-factors in women from Curaçao. METHODS: 5000 women aged 25-65 years were randomly selected from the national Population Register. HPV was detected by means of GP5+/6+PCR EIA and GP 5+/6+amplimers from HPV-positive samples were genotyped with a reverse hybridisation assay. We also collected personal data and data on risk-factors. RESULTS: 1075 women were enrolled in the study. Overall HPV-prevalence was 19.7%. Most frequent genotypes were HPV16 (2.3%), 35 (2.1%) and 52 (1.8%). Twenty-seven women detected with abnormal cytology (i.e.≥ASC-US) were referred for biopsy. In women with normal cytology (n = 1048), HPV-prevalence was 17.9% and the most common high-risk HPV (hrHPV)-types were HPV35 (2.0%), 18 (1.8%), 16 (1.5%) and 52 (1.5%). The highest HPV-prevalence (32.8%) was found in the age-group: 25-34 (n = 247). HPV positive women started sex at a younger age (p = 0.032). CONCLUSIONS: HPV-prevalence in the overall population is high and HPV16 was the most common genotype followed by 35 and 18. In women with normal cytology HPV35 is the most common genotype followed by HPV18, 52 and 16. The high HPV-prevalence (32.8%) in women of 25-34 years argue for introduction of cervical cancer prevention strategies. HPV-type distribution found in Curaçao should be taken into account when considering the choice for prophylactic vaccination.

20.
Int J Cancer ; 143(6): 1541-1548, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29663363

RESUMO

DNA methylation analysis of cervical scrapes using FAM19A4 and mir124-2 genes has shown a good clinical performance in detecting cervical cancer and advanced CIN lesions in need of treatment in HPV-positive women. To date, longitudinal data on the cancer risk of methylation test-negative women are lacking. In our study, we assessed the longitudinal outcome of FAM19A4/mir124-2 methylation analysis in an HPV-positive screening cohort with 14 years of follow-up. Archived HPV-positive cervical scrapes of 1,040 women (age 29-61 years), who were enrolled in the POBASCAM screening trial (ISRCTN20781131) were tested for FAM19A4/mir124-2 methylation. By linkage with the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA), 35 cervical cancers were identified during 14 years of follow-up comprising three screens (baseline, and after 5 and 10 years). The baseline scrape of 36.1% (n = 375) women tested positive for FAM19A4/mir124-2 methylation, including 24 women with cervical cancer in follow-up, and 30.6% (n = 318) had abnormal cytology (threshold borderline dyskaryosis or ASCUS), including 14 women with cervical cancer in follow-up. Within screening round capability of FAM19A4/mir124-2 methylation to detect cervical cancer was 100% (11/11, 95% CI: 71.5-100). Kaplan-Meier estimate of 14-year cumulative cervical cancer incidence was 1.7% (95% CI: 0.66-3.0) among baseline methylation-negative and 2.4% (95% CI: 1.4-3.6) among baseline cytology-negative women (risk difference: 0.71% [95% CI: 0.16-1.4]). In conclusion, a negative FAM19A4/mir124-2 methylation test provides a low cervical cancer risk in HPV-positive women of 30 years and older. FAM19A4/mir124-2 methylation testing merits consideration as an objective triage test in HPV-based cervical screening programs.

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