Flemish breast cancer screening programme: 15 years of key performance indicators (2002-2016).

BACKGROUND: We examined 15 years of key performance indicators (KPIs) of the population-based mammography screening programme (PMSP) in Flanders, Belgium. METHODS: Individual screening data were linked to the national cancer registry to obtain oncological follow-up. We benchmarked crude KPI results against KPI-targets set by the European guidelines and KPI results of other national screening programmes. Temporal trends were examined by plotting age-standardised KPIs against the year of screening and estimating the Average Annual Percentage Change (AAPC). RESULTS: PMSP coverage increased significantly over the period of 15 years (+ 7.5% AAPC), but the increase fell to + 1.6% after invitation coverage was maximised. In 2016, PMSP coverage was at 50.0% and opportunistic coverage was at 14.1%, resulting in a total coverage by screening of 64.2%. The response to the invitations was 49.8% in 2016, without a trend. Recall rate decreased significantly (AAPC -1.5% & -5.0% in initial and subsequent regular screenings respectively) while cancer detection remained stable (AAPC 0.0%). The result was an increased positive predictive value (AAPC + 3.8%). Overall programme sensitivity was stable and was at 65.1% in 2014. In initial screens of 2015, the proportion of DCIS, tumours stage II+, and node negative invasive cancers was 18.2, 31.2, and 61.6% respectively. In subsequent regular screens of 2015, those proportions were 14.0, 24.8, and 65.4% respectively. Trends were not significant. CONCLUSION: Besides a suboptimal attendance rate, most KPIs in the Flemish PMSP meet EU benchmark targets. Nonetheless, there are several priorities for further investigation such as a critical evaluation of strategies to increase screening participation, organising a biennial radiological review of interval cancers, analysing the effect that preceding opportunistic screening has on the KPI for initial screenings, and efforts to estimate the impact on breast cancer mortality.

Does the Flemish colorectal cancer screening programme reach equity in FIT uptake?

BACKGROUND: To investigate colorectal cancer (CRC) screening rates by the faecal immunochemical test (FIT) according to sociodemographic characteristics and nationality. METHODS: Men and women, aged 56-74, invited to participate in the Flemish CRC screening programme in 2013 and 2014 were included in this study. We analysed the association between CRC screening uptake and sex, age, (first and current) nationality and several proxies for socio-economic status (SES). The statistical analysis was based on descriptive analyses and logistic regression models. RESULTS: A total of 1 184 426 persons were included in our analysis. The overall screening uptake was 52.3%, uptake varied by sex, age, nationality and SES. Lower participation rates were associated with the youngest and oldest age categories (56-60 and 70-74) and being male. All nationalities other than Belgian or Dutch were significantly less screened. Lower uptake of screening was also associated with several proxy's for low SES, such as having an allowance for being disabled, not being able to work, being an extended minor and having a social allowance/minimum wage. The descriptive analysis showed a 27% difference in CRC screening uptake between the (early) retired and the people entitled to a minimum wage. CONCLUSIONS: There is a significant difference between screening uptake and demographic and socio-economic variables in the first 2 years of the population-based screening programme in Flanders. Based on the study results, implementing strategies to improve participation in those subgroups is needed.

Structure-based drug design, synthesis and biological assays of P. falciparum Atg3-Atg8 protein-protein interaction inhibitors.

The proteins involved in the autophagy (Atg) pathway have recently been considered promising targets for the development of new antimalarial drugs. In particular, inhibitors of the protein-protein interaction (PPI) between Atg3 and Atg8 of Plasmodium falciparum retarded the blood- and liver-stages of parasite growth. In this paper, we used computational techniques to design a new class of peptidomimetics mimicking the Atg3 interaction motif, which were then synthesized by click-chemistry. Surface plasmon resonance has been employed to measure the ability of these compounds to inhibit the Atg3-Atg8 reciprocal protein-protein interaction. Moreover, P. falciparum growth inhibition in red blood cell cultures was evaluated as well as the cyto-toxicity of the compounds.

Incidence of symptomatic hemorrhage in patients with lobar microbleeds.

BACKGROUND AND PURPOSE: Lobar microbleeds suggestive of cerebral amyloid angiopathy (CAA) are often identified on MRI in the absence of lobar intracerebral hemorrhage (ICH). We compared the baseline characteristics and risk of subsequent ICH among such patients to those presenting with CAA-related lobar ICH. METHODS: Clinical data (demographics, risk factors), apolipoprotein E genotype, neuroimaging markers of CAA severity (microbleed counts, leukoaraiosis volume), and clinical outcomes (incidence rates of ICH and death during a mean follow-up of 5.3±3.8 years) were compared between 63 patients enrolled because of incidentally found microbleeds and 316 with CAA-related ICH, in our prospectively enrolled cohort. Predictors of incident ICH were explored in the microbleed-only patients using multivariable Cox regression models. RESULTS: Microbleed-only patients shared similar demographic, apolipoprotein E, and vascular risk profiles with lobar ICH patients, but had more lobar microbleeds (median, 10 versus 2; P<0.001) and higher leukoaraiosis volumes (median, 31 versus 23 mL; P=0.02). Microbleed-only patients had a nontrivial incidence rate of ICH, not different from patients presenting with ICH (5 versus 8.9 per 100 person-years; adjusted hazard ratio, 0.58; 95% confidence interval, 0.31-1.06; P=0.08). Microbleed-only patients had a higher mortality rate (hazard ratio, 1.67; 95% confidence interval, 1.1-2.6) compared with ICH survivors. Warfarin use and increasing age were independent predictors of future ICH among microbleed-only patients after correction for other covariates. CONCLUSIONS: Patients presenting with isolated lobar microbleeds on MRI have a genetic, neuroimaging, and hemorrhagic risk profile suggestive of severe CAA pathology. They have a substantial risk of incident ICH, potentially affecting decisions regarding anticoagulation in clinical situations.

Quantifying independent risk factors for failing to rescreen in a breast cancer screening program in Flanders, Belgium.

BACKGROUND: Mammographic screening may reduce breast cancer mortality by about 20%, provided participation is high and women screen regularly. We quantified independent risk factors for failing to rescreen and built a model to predict how rescreening rates change if these risk factors would be modified. METHODS: Multivariate analysis was used to analyze data from a prospective study which included a self-administered questionnaire and rescreening status 30months after a t0 mammogram, using a random sample of women 50-67years (Belgium 2010-2013). RESULTS: A false positive result at the most recent past mammogram (Odds Ratio=5.0, 95% Confidence Interval 3.6-6.8), an interval until new invitation greater than 25months (Odds Ratio=4.8 for >29months, 95% Confidence Interval 2.9-8.1), waiting times in the mammography unit >1h (Odds Ratio=2.1, 95% Confidence Interval 1.2-3.7) and difficulties in reaching the unit (Odds Ratio=2.5, 95% Confidence Interval 1.4-4.4) were the strongest independent predictors for failing to rescreen. The area under the curve of the receiver operating characteristic analysis was 0.705 for the model development stage and 0.717 for the validation stage and goodness-of-fit was good. CONCLUSIONS: Maintaining an invitation cycle of maximum 25months, limiting waiting time in the mammography unit and lowering the number of false positives could increase breast cancer screening compliance.

Breast cancer phenotype, nodal status and palpability may be useful in the detection of overdiagnosed screening-detected breast cancers.

BACKGROUND: Breast cancer remains the leading cause of female cancer death despite improvements in treatment and screening. Screening is often criticized for leading to overdiagnosis and overtreatment. However, few have attempted to identify overdiagnosed cases. PATIENTS AND METHODS: A large, consecutive series of patients treated for primary operable, screening-detected, breast cancer (n = 1610). Details from pathology and clinical reports, treatment and follow-up were available from our prospectively managed database. Univariate and multivariate Cox proportional models were used to study the prognostic variables in screening-detected breast cancers for distant metastatic and breast cancer-specific survival. RESULTS: We included 1610 patients. The mean/median follow-up was 6.0/6.0 years. Univariate analysis: tumor size, palpability, breast cancer phenotype and nodal status were predictors of distant metastasis and breast cancer-specific death. Multivariate analysis: palpability, breast cancer phenotype and nodal status remained independent prognostic variables. Palpability differed by breast cancer phenotype. CONCLUSION: Screening-detected breast cancer is associated with excellent outcome. Palpability, nodal status and breast cancer phenotype are independent prognostic variables that may select patients at increased risk for distant metastatic relapse and breast cancer-specific death. Overdiagnosed cases reside most likely in the nonpalpable node negative subgroup with a Luminal A phenotype.

Cerebral microbleeds and macrobleeds: should they influence our recommendations for antithrombotic therapies?

Intracerebral hemorrhage (ICH, or macrobleeds) and cerebral microbleeds-smaller foci of hemosiderin deposits commonly detected by magnetic resonance imaging of older adults with or without ICH-are both associated with an increased risk of future ICH. These hemorrhagic pathologies also share risk factors with ischemic thromboembolic conditions that may require antithrombotic therapy, requiring specialists in cardiology, internal medicine, and neurology to weigh the benefits vs hemorrhagic risks of antithrombotics in individual patients. This paper will review recent advances in our understanding of hemorrhage prone cerebrovascular pathologies with a particular emphasis on use of these markers in decision making for antithrombotic use.

Bringing clerkship grading back to the bedside.

BACKGROUND: The hallmark of medical education is learning from patients through interactions at the bedside. However, many medical schools incorporate clinical clerkship grading systems that incentivize time away from patient care activities to focus on examinations of medical knowledge. The purpose of this innovation was to develop a grading system that encouraged development of competencies beyond medical knowledge, including patient care, communication, and professionalism skills. METHODS: In 2016, the authors convened a diverse workgroup to reform the clerkship grading approach at their institution. The group reviewed relevant literature and discussed approaches used by other institutions. They developed a competency-based criterion system. For each of four competency domains (patient care, medical knowledge (examination score), professionalism, and communication/teamwork), students received a designation of inadequate, competent, or exemplary. The highest grade ("honors") was awarded to students who met the criteria for exemplary performance in at least two domains. It was a primarily compensatory model, although to achieve competency (pass) scoring was non-compensatory (acceptable performance in all categories). RESULTS: A total of 231 medical students received 1499 clerkship grades during the 2018-2019 year. Compared to previous years, more students (40% vs. 15%) received honors. A substantial proportion (43%) received honors without achieving an exemplary designation in the medical knowledge domain (i.e., standardized examination). FINDINGS AND DISCUSSION: The revised grading system provided several avenues for students to excel and receive honors in their clerkships allowing for recognition of students who excelled in patient care-related areas other than standardized examinations.

Identification of ganglion cell neurites in human subretinal and epiretinal membranes.

AIM: To determine whether neural elements are present in subretinal and epiretinal proliferative vitreoretinopathy (PVR) membranes as well as in diabetic, fibrovascular membranes removed from patients during vitrectomy surgery. METHODS: Human subretinal and epiretinal membranes of varying durations were immunolabelled with different combinations of antibodies to glial fibrillary acidic protein, vimentin, neurofilament protein and laminin. RESULTS: Anti-neurofilament-labelled neurites from presumptive ganglion cells were frequently found in epiretinal membranes and occasionally found in subretinal membranes. In addition, the neurites were only observed in regions that also contained glial processes. CONCLUSIONS: These data demonstrate that neuronal processes are commonly found in human peri-retinal cellular membranes similar to that demonstrated in animal models. These data also suggest that glial cells growing out of the neural retina form a permissive substrate for neurite growth and thus may hold clues to factors that support this growth.

First results of the Flemish colorectal cancer screening program : start-up- period late 2013.

BACKGROUND AND AIMS: Investigation of the first participation rate and follow-up results of the Flemish colorectal cancer screening program. PATIENTS AND METHODS: In 2013 five age cohorts with an even age between 66 and 74 year old (n=243 335) were invited by mail to return a completed iFOBT. Participants who tested positive (≥75ng/ml) were referred to a follow-up colonoscopy. RESULTS: Participation rate was 48.4% (n=117 774). Overall positivity rate was 10.1%, and 78.1% of those tested positive underwent a colonoscopy. The positive predictive value of colonoscopy for CRC was 8.2%, for advanced adenoma 16.9% and for non-advanced adenoma 36.5%. CONCLUSIONS: Based on the EU-guidelines 35% was expected as participation for a first screening round, thus a participation rate of 48.4% is more than acceptable for a first screening year. The high positivity rate can partly be explained by including only the older ages in the start-up-period and by the first year of mass screening in Flanders. (Acta gastroenterol. belg., 2016, 79, 421-428).

Intracranial atherosclerosis and cerebral small vessel disease in intracerebral hemorrhage patients.

BACKGROUND: The association between cerebral small vessel diseases (cSVD) and intracranial atherosclerosis is debated and conflicting results have been reported. We sought to investigate this association in patients with intracerebral hemorrhage (ICH), due to severe cSVD. METHODS: Consecutive ICH patients were divided into those meeting criteria for cerebral amyloid angiopathy (CAA) and those with deep hypertensive ICH consistent with hypertensive cSVD (HTN-SVD). White matter hyperintensity volumes (WMH) and microbleed counts (MB) were measured on MRI. CTA was rated for severity of intracranial carotid calcifications and for presence of >50% intracranial stenosis (ICS). Associations of intracranial atherosclerosis severity with type of SVD (CAA vs HTN-cSVD) and with imaging and clinical markers of cSVD burden were analyzed. RESULTS: The cohort included 253 CAA and 90 HTN-SVD patients. In multivariable models, the type of cSVD (CAA vs. HTN-cSVD) was not associated with calcification severity (OR=1.04, 95% CI [0.62-3.5], p=0.37) or presence of ICS (OR=0.84, 95% CI [0.21-2.74], p=0.78). We found no association between intracranial atherosclerosis (calcifications and stenoses) and parenchymal markers of cSVD severity (WMH and MB, adjusted p≥0.2 for all comparisons) and no association with presence of dementia before ICH (adjusted p≥0.2 for both comparisons). CONCLUSIONS: We found no association between intracranial atherosclerosis and parenchymal or clinical consequences of cSVD, suggesting that cSVDs while sharing some risk factors are not influenced by upstream larger vessel pathologies.

Association of Key Magnetic Resonance Imaging Markers of Cerebral Small Vessel Disease With Hematoma Volume and Expansion in Patients With Lobar and Deep Intracerebral Hemorrhage.

IMPORTANCE: Hematoma expansion is an important determinant of outcome in spontaneous intracerebral hemorrhage (ICH) due to small vessel disease (SVD), but the association between the severity of the underlying SVD and the extent of bleeding at the acute phase is unknown to date. OBJECTIVE: To investigate the association between key magnetic resonance imaging (MRI) markers of SVD (as per the Standards for Reporting Vascular Changes on Neuroimaging [STRIVE] guidelines) and hematoma volume and expansion in patients with lobar or deep ICH. DESIGN, SETTING, AND PARTICIPANTS: Analysis of data collected from 418 consecutive patients admitted with primary lobar or deep ICH to a single tertiary care medical center between January 1, 2000, and October 1, 2012. Data were analyzed on March 4, 2016. Participants were consecutive patients with computed tomographic images allowing ICH volume calculation and MRI allowing imaging markers of SVD assessment. MAIN OUTCOMES AND MEASURES: The ICH volumes at baseline and within 48 hours after symptom onset were measured in 418 patients with spontaneous ICH without anticoagulant therapy, and hematoma expansion was calculated. Cerebral microbleeds, cortical superficial siderosis, and white matter hyperintensity volume were assessed on MRI. The associations between these SVD markers and ICH volume, as well as hematoma expansion, were investigated using multivariable models. RESULTS: This study analyzed 254 patients with lobar ICH (mean [SD] age, 75 [11] years and 140 [55.1%] female) and 164 patients with deep ICH (mean [SD] age 67 [14] years and 71 [43.3%] female). The presence of cortical superficial siderosis was an independent variable associated with larger ICH volume in the lobar ICH group (odds ratio per quintile increase in final ICH volume, 1.49; 95% CI, 1.14-1.94; P = .004). In multivariable models, the absence of cerebral microbleeds was associated with larger ICH volume for both the lobar and deep ICH groups (odds ratios per quintile increase in final ICH volume, 1.41; 95% CI, 1.11-1.81; P = .006 and 1.43; 95% CI, 1.04-1.99; P = .03; respectively) and with hematoma expansion in the lobar ICH group (odds ratio, 1.70; 95% CI, 1.07-2.92; P = .04). The white matter hyperintensity volumes were not associated with either hematoma volume or expansion. CONCLUSIONS AND RELEVANCE: In patients admitted with primary lobar or deep ICH to a single tertiary care medical center, the presence of cortical superficial siderosis was an independent variable associated with larger lobar ICH volume, and the absence of cerebral microbleeds was associated with larger lobar and deep ICHs. The absence of cerebral microbleeds was independently associated with more frequent hematoma expansion in patients with lobar ICH. We provide an analytical framework for future studies aimed at limiting hematoma expansion.

[The investigation of gene-environment interaction using case-control comparisons]. / Het bestuderen van gen-omgevingsinteracties met behulp van patiënt-controlevergelijkingen.

Many chronic diseases are caused by the interaction of genes and environmental factors. Genetic epidemiologic research seeks to elucidate the role of genetic factors and their interaction with environmental factors in the occurrence of disease. Gene-environment interaction can be assessed using different types of case-control comparisons. The classic case-control design is suitable to investigate the association between multiple genes and environmental factors. Results can be presented in a two-by-four table. In a case-parents design, the genotype of each case is compared with the genotype of a fictitious control formed by the non-transmitted alleles from each parent. In a case-only design, the relationship between a genotype and an environmental factor is examined in a population of affected cases only. Both the case-parents and the case-only designs assume independence between genotype and environmental factors in the control group.

Epidemiology of chronic pain and its treatment in The Netherlands.

BACKGROUND: Chronic pain is common; however, good epidemiological data are scarce. Such information can help all the involved stakeholders to make responsible decisions about health budgets and prioritisation. This study aims to provide best-evidence epidemiological information about chronic pain in the Netherlands. METHODS: We performed a systematic search which yielded 16,619 references, 119 Dutch studies were relevant. We selected at least three studies per question that provided the most recent, representative and valid data. RESULTS: The prevalence of moderate to severe general chronic pain among Dutch adults was estimated at 18%. This prevalence was 27% and 55% for any cancer pain. Up to 74% of patients with general or non-cancer chronic pain get treated; this percentage is little higher for patients with cancer pain. A substantial proportion of the patients receive drug treatment for their pain, mainly NSAIDs, but also non-pharmacological interventions for pain are being used. Up to 43% of the chronic non-cancer pain patients report not receiving treatment and up to 79% of the patients believe their pain is inadequately treated. All studies reported a detrimental effect of chronic pain on quality of life, activities of daily living and mental health. Chronic pain is also associated with direct and indirect medical costs, and patients may have decreased income and additional out-of pocket expenses. CONCLUSION: Chronic pain occur s frequently, has a negative impact on the patient and society and treatment may not always be adequate. Chronic pain should be seen as an important public health problem deserving more attention of Dutch healthcare workers and policy makers.

Validation of the IMMIDIET food frequency questionnaire in an adult Belgian population: a report from the Belgian case-control study on bladder cancer risk.

We evaluated the performance of the IMMIDIET food frequency questionnaire (FFQ) used to collect dietary data for the Belgian case-control study on bladder cancer. Thirty-seven men and women aged 50 years and older were recruited from the University Hospital in Leuven, Belgium. Participants completed the IMMIDIET FFQ, a 7-day diet diary and a 24-hour diet recall. Median intakes and inter-quartile ranges were calculated for 27 foods and nutrients from each dietary assessment method. All dietary factors were log-transformed and adjusted for energy using the nutrient density method. Pearson correlation coefficients were used to compare the different dietary assessment methods. Bland-Altman plots were also used to assess levels of agreement between the dietary methods. Energy, fruit and vegetable intake estimates were higher from the IMMIDIET FFQ compared with the two reference methods.The highest deattenuated correlations between the FFQ and 7-day diary were meat (0.58), bread (0.44), fruit (0.38) and fish (0.38). The highest deattenuated correlations between the FFQ and 24-hour recall were for fruit (0.72), fat (0.48), alcohol (0.44), cholesterol (0.42), monounsaturated fatty acid (0.42) and polyunsaturated fatty acid (0.41). Generally, correlation was lower for the micro-nutrients except for phosphorus (0.42), vitamin C (0.41) and calcium (0.40). The IMMIDIET FFQ is an appropriate instrument to measure usual dietary intake for the Belgian case-control study on bladder cancer risk. Further investigation of nutritional assessment methods is necessary.

The investigation of a geographical cluster of bladder cancer.

Previous analyses of the Limburg Cancer registry (LIKAR) indicated the existence of a geographical cluster of bladder cancer incidence, particularly transitional cell carcinomas, amongst males in the surrounding area of the Belgian cities Hasselt and Alken. In subsequent ecologic analyses no risk factors were identified which could explain the existence of this cluster. Therefore, an epidemiological case-control study has been performed in the province of Limburg to explore the possible determinants of the cluster. The following cluster determinants were investigated: socio-demographic characteristics, life style factors, occupational and environmental exposures, and genetic predisposition. A weight was assigned to all the study subjects. Secondly, we used unconditional logistic regression to calculate crude odd ratios (ORs) and 95% confidence intervals (CIs) for each source of exposure and bladder cancer. Thirdly, we used a multivariate logistic regression analysis which included all the parameters found to be significant at the 0.1 significance level in the univariate analysis. Although some of the specific odds ratios decreased compared with the crude results, the overall excess did not change specifically. In conclusion, we were not able to identify a clear-cut explanation for the existence of the geographical cluster. We therefore recommend an increased surveillance of bladder cancer incidence for 3 to 5 years. If the "excess" of cancer cases has occurred due to random variation, the rate will return to the "expected" range in the next years. If the rate remains elevated, further studies may need to be performed using investigative tools that are not available currently.

Interval cancers in the beginning years of the breast cancer screening programme in the Belgian province of Limburg.

OBJECTIVE: To assess the occurrence of interval breast cancers among those women who attended the mammography screening programme in the Belgian province of Limburg. Interval cancers are tumours that are being diagnosed before the next scheduled screening round and are related to the sensitivity and the screening interval. METHODS: Biennial screening is provided to all women aged 50-69. The records of the screening programme were linked to those of the cancer registry. The interval cancer rate, expressed as a proportion of the underlying (expected) breast cancer incidence rate was calculated. The observed interval cancer incidence is the number of interval cancers per 10,000 'negative' screening tests. RESULTS: The interval cancer rate in the first year was 25.37% for all cancers (ductal carcinoma in situ included) and 21.7% when the analysis was restricted to invasive tumours. Proportional incidence of interval cancer in the second year after screening was 12.02% for all cancers. CONCLUSION: In conclusion, the interval cancer rates in the Belgian province of Limburg were compatible with the European guidelines. However, increasing the recall rate in our programme and systematically reviewing the interval cancers may improve the quality of the programme even further.