Childhood leukemia near nuclear sites in Belgium: An ecological study at small geographical level.

BACKGROUND: A previous investigation of the occurrence of childhood acute leukemia around the Belgian nuclear sites has shown positive associations around one nuclear site (Mol-Dessel). In the following years, the Belgian Cancer Registry has made data available at the smallest administrative unit for which demographic information exists in Belgium, i.e. the statistical sector. This offers the advantage to reduce the potential misclassification due to large geographical scales. METHODS: The current study performed for the period 2006-2016 uses Poisson models to investigate (i) the incidence of childhood acute leukemia within 20 km around the four Belgian nuclear sites, (ii) exposure-response relationships between cancer incidence and surrogate exposures from the nuclear sites (distance, wind direction frequency and exposure by hypothetical radioactive discharges taking into account historical meteorological conditions). All analyses are carried out at statistical sector level. RESULTS: Higher incidence rate ratios were found for children <15 years (7 cases, RR = 3.01, 95% CI: 1.43;6.35) and children <5 years (< 5 cases, RR = 3.62, 95% CI: 1.35;9.74) living less than 5 km from the site of Mol-Dessel. In addition, there was an indication for positive exposure-response relationships with the different types of surrogate exposures. CONCLUSION: Results confirm an increased incidence of acute childhood leukemia around Mol-Dessel, but the number of cases remains very small. Random variation cannot be excluded and the ecological design does not allow concluding on causality. These findings emphasize the need for more in-depth research into the risk factors of childhood leukemia, for a better understanding of the etiology of this disease.

Occurrence and characteristics of faecal immunochemical screen-detected cancers vs non-screen-detected cancers: Results from a Flemish colorectal cancer screening programme.

BACKGROUND: Colorectal cancer (CRC) and its precursor lesions are detected at an early stage by CRC screening programmes, which reduce CRC-related mortality. An important quality indicator for CRC screening is the occurrence of interval CRC (IC) between screening rounds. Currently there is no guideline regarding acceptable levels of ICs in CRC screening programmes, and ICs reported in prior work vary considerably. METHODS: This study describes the occurrence of screen-detected (SD) CRC and non-screen-detected CRC within the population-based CRC screening programme of Flanders, stratified by multiple variables such as sex, age, tumour location and tumour stage between October 2013 and July 2017. In addition, faecal immunochemical test (FIT) IC proportions over the sum of SD-CRCs and FIT-ICs are calculated, together with FIT sensitivity and programme sensitivity to display the effectiveness of detecting CRC by the screening programme. RESULTS: Of 1,212,354 FIT participants, 4094 were diagnosed with SD-CRC, whereas 772 participants were diagnosed with CRC between FIT-screening rounds. Significant associations were shown between people not being SD for CRC and women, older individuals, right-sided tumour location and more advanced tumour stage. Furthermore, a clear distinction was shown between the right-sided and the left-sided colorectum concerning all above-mentioned variables and distributions of tumour stages. CONCLUSION: The Flemish FIT-interval CRC proportion of 15.9% was within the limits of previously published results. In addition, calculations show that the effectiveness of the screening programme is dependent on tumour location, suggesting that future research should report results stratified by location.

Benefits of switching from guaiac-based faecal occult blood to faecal immunochemical testing: experience from the Wallonia-Brussels colorectal cancer screening programme.

BACKGROUND: Faecal immunochemical tests (FITs) have replaced guaiac-based faecal occult blood test (gFOBTs) in several colorectal cancer (CRC) screening programmes. We aimed to evaluate the benefits of this transition based on the Wallonia-Brussels-organised CRC screening programme. METHODS: A total of 1,569,868 individuals aged 50-74 years, who were invited to screening during 2009-2017, were studied by linking their screening records with insurance, pathology and cancer data in the Belgian Cancer Registry. We compared neoplasm detection rates and positive predictive values (PPVs) of gFOBT and FIT at 15 µg haemoglobin per gram cut-off in screen-naive individuals. We furthermore examined the incidence rates of interval cancer in gFOBT- and FIT-based screening programme. RESULTS: Advanced neoplasms were detected less frequently by gFOBT (0.8%) than by FIT (1.3%), with a difference of 0.5% (P < 0.01). PPVs were lower for gFOBT (15.1%) than for FIT (21.7%) for advanced neoplasms (difference 6.6%, P < 0.01). Compared to participants with negative gFOBT, those with negative FIT were 77% less likely to develop interval cancer (incidence rate ratio 0.23, 95% confidence interval 0.16-0.33). CONCLUSION: Our study demonstrated that in an organised CRC screening programme, replacing gFOBT with FIT improved neoplasm detection rate and substantially reduced interval cancer incidence.

Childhood leukaemia near nuclear sites in Belgium, 2002-2008.

This paper describes an ecological study investigating whether there is an excess incidence of acute leukaemia among children aged 0-14 years living in the vicinity of the nuclear sites in Belgium. Poisson regression modelling was carried out for proximity areas of varying sizes. In addition, the hypothesis of a gradient in leukaemia incidence with increasing levels of surrogate exposures was explored by means of focused hypothesis tests and generalized additive models. For the surrogate exposures, three proxies were used, that is, residential proximity to the nuclear site, prevailing winds and simulated radioactive discharges, on the basis of mathematical dispersion modelling. No excess incidence of acute leukaemia was observed around the nuclear power plants of Doel or Tihange nor around the nuclear site of Fleurus, which is a major manufacturer of radioactive isotopes in Europe. Around the site of Mol-Dessel, however, two- to three-fold increased leukaemia incidence rates were found in children aged 0-14 years living in the 0-5, 0-10 and the 0-15 km proximity areas. For this site, there was evidence for a gradient in leukaemia incidence with increased proximity, prevailing winds and simulated radioactive discharges, suggesting a potential link with the site that needs further investigation. An increased incidence of acute leukaemia in children aged 0-14 years was observed around one nuclear site that hosted reprocessing activities in the past and where nuclear research activities and radioactive waste treatment are ongoing.

Trends in net survival from cervical cancer in six European Latin countries: results from the SUDCAN population-based study.

Cancer survival is a key measure of the effectiveness of a healthcare system. As differences in healthcare systems are present among European Latin countries, it is of interest to look specifically at their similarities and differences in terms of cancer survival. Incident cases were extracted from the EUROCARE-V database for France, Italy, Spain, Switzerland, Portugal, and Belgium. One and 5-year net survivals (NS) were calculated for the period 2000-2004 using the Pohar-Perme estimator. Trends in NS over the 1992-2004 period and changes in the pattern of cancer excess mortality rate until 5 years after diagnosis were examined using a multivariate excess mortality rate model. There were moderate differences in age-standardized NS between countries (5-year NS range: 83-88%), but significant differences in the age groups 15-54 and 55-74 years (at 5 years up to +16 and +18% between any two countries). During the study period, excess mortality and NS improved in Italy, Spain, and Portugal. In Italy and Portugal, this improvement was slightly similar at ages 40, 55, and 70 whereas, in Spain, there was a sharp increase in NS at age 55. Because of this improvement, excess mortality and NS were similar in all six countries in 2004. Excess mortality peaked around 1 year after diagnosis in the youngest ages, but decreased gradually in the elderly. Detailed analyses showed differences in excess mortality and NS from cervical cancer between European Latin countries. However, these differences decreased over the study period because of the considerable improvement in Spain, Italy, and Portugal.

Melanoma burden by melanoma stage: Assessment through a disease transition model.

BACKGROUND: The total burden of melanoma has already been studied but little is known about the distribution of this burden amongst localised, node metastatic and distant metastatic stages. METHODS: Disability-adjusted life years (DALY) assesses disease burden, being the sum of years of life with disability (YLD) and years of life lost (YLL). A melanoma disease model was developed in order to predict the evolution of patients from diagnosis until death. The model was applied to a large cohort of 8016 melanoma patients recorded by the Belgian Cancer Registry for incidence years 2009-2011. DALYs were calculated for each American Joint Committee on Cancer stage, considering stage at diagnosis on the one hand and time spent in localised, node metastatic and visceral metastatic stages on the other. Probabilistic sensitivity analyses and scenario analyses were performed to explore uncertainty. FINDINGS: Our analyses resulted in 3.67 DALYs per melanoma, 90.81 per 100,000 inhabitants, or 32.67 per death due to melanoma. The total YLL accounted for 80.4% of the total DALY. Stages I, II, III and IV patients at diagnosis generated, respectively, 27.8%, 32.7%, 26.2% and 13.3% of the total YLL. For the time spent in each stage, localised melanomas, node metastatic melanomas, and distant metastatic accounted, respectively, for 34.8%, 52.6% and 12.6% of the total YLD. Parametric uncertainty was very limited, but the influence of using pre-2010 Global Burden of Disease approaches was substantial. INTERPRETATION: The total DALY for melanoma was consistent with the previous studies. Our results in terms of proportions of DALY/YLL/YLD per stage could be extrapolated to other high-income countries. YLDs generated by localised melanoma which will never metastasize were inferior to YLLs resulting from stage IA melanomas. This result supports the hypothesis that efforts for an earlier diagnosis of melanoma are important. FUNDING: None.

Is melanoma survival influenced by month of diagnosis?

BACKGROUND: Despite being a well-documented phenomenon, seasonal variation in the incidence of cutaneous melanoma is poorly understood, and data on the seasonality of melanoma survival are scarce. We sought to explore the seasonal variation in melanoma incidence and survival in Belgium and to assess the characteristics and outcomes of cases diagnosed during the seasonal peak. METHODS: All cases of invasive cutaneous melanoma-patients over 15 years of age and registered by the Belgian Cancer Registry (BCR) from 2004 to 2009-were included (n=9782). Monthly variations in incidence were estimated by the ratio of the number of cases diagnosed each month to that diagnosed in January (Rmonth/January) using Nam's method. The observed and relative 5-year survival rates were adjusted on patient and tumour characteristics using Cox proportional hazards regression models and generalised linear models with a Poisson error structure, respectively. RESULTS: A peak in melanoma incidence was observed in June (RJune/January=1.64, 95% confidence interval (CI)=1.54-1.73). The 5-year observed survival (OS) and relative survival (RS) rates were significantly higher for patients diagnosed in June compared with other months (OSJune=84%, 95%CI=81-86 versus OSOthermonths=79%, 95%CI=78-80; RSJune=93%, 95%CI=90-95 versus RSothermonths=87%, 95%CI=86-88). After adjustment, the 5-year OS remained significantly higher for patients diagnosed in June (hazard ratioJune=0.78, 95%CI=0.62-0.98); however, the 5-year RS was no longer significantly different for patients diagnosed in June compared with other months (relative excess riskJune=1.16, 95%CI=0.73-1.84). CONCLUSIONS: This study demonstrated a seasonal variation in melanoma incidence in Belgium with a peak in June for the period 2004-2009. When adjusted for patient and tumour characteristics, patients diagnosed in June had higher observed survival rates, but relative survival rates did not differ. Our findings do not support an influence of season of diagnosis on melanoma prognosis.

Thyroid cancer incidence around the Belgian nuclear sites: surrogate exposure modelling.

BACKGROUND: In a recent ecological study among residents living around Belgian nuclear sites (the NUCABEL study), significant increased incidences of thyroid cancer were observed around the two nuclear facilities with industrial and research activities (Mol-Dessel and Fleurus), prompting further research. METHODS: The data from the NUCABEL study were reanalysed to test the hypothesis of a gradient in cancer incidence with increasing levels of exposure from these sites using three measures of surrogate exposure, being (i) residential proximity, (ii) prevailing wind directions and (iii) simulated dispersion of radioactive discharges. Single-site focussed hypothesis tests were complemented with Generalized Additive Models to estimate the exposure-response relationships. RESULTS: For Mol-Dessel, the results of the focussed hypothesis tests were far from significant. For Fleurus, the p-values were much closer to significance with p=0.05 for Bithell's Linear Risk Score using radioactive discharge estimates as surrogate. CONCLUSIONS: The re-analyses refute an association with the nuclear facilities for the site of Mol-Dessel. For the site of Fleurus, one of Europe's major production sites of radio-iodines, the results were less conclusive and further research suggests itself.

Thyroid cancer incidence in the vicinity of nuclear sites in Belgium, 2000-2008.

BACKGROUND: Public health concern about nuclear activities have existed since the 1980s. Most studies on this subject investigated childhood leukemia. Thyroid cancer may be another health outcome of interest, because some nuclear installations are a potential source of radioactive iodine isotopes in the environment and because thyroid cancer is known to occur after exposure to these isotopes. METHODS: This study describes an ecological study investigating whether there is excessive thyroid cancer incidence among residents living in the vicinity of nuclear sites. Single-site analyses using indirect standardization (standardized incidence ratios [SIRs]) and Poisson regression modeling (rate ratios [RRs]) were conducted. The proximity area is typically defined as a circular zone with a radius of 20 km centered on the site. However, the choice of the size of this area is somewhat arbitrary. Therefore, a sensitivity analysis was carried out to investigate whether the results vary with radii of increasing proximity. RESULTS: No increased thyroid cancer incidence was found within the 20 km proximity area around the nuclear power plants of Doel (SIR=0.74 [95% confidence interval (CI)=0.64; 0.84] and RR=0.72 [95% CI=0.63; 0.83]) and Tihange (SIR=0.86 [95% CI=0.70; 1.01] and RR=0.85 [95% CI=0.70; 1.02]). For the sites of Mol-Dessel and Fleurus, where a combination of nuclear research and industrial activities are located, the incidences of thyroid cancer within the 20 km proximity area were higher than expected (Mol-Dessel: SIR=1.19 [95% CI=1.01; 1.36] and RR=1.19 [95% CI=1.02; 1.38]; Fleurus: SIR=1.15 [95% CI=1.02; 1.28] and RR=1.17 [95% CI=1.04; 1.33]). For Chooz, a French nuclear power plant close to the Belgian border, the results were unstable as a result of the small population denominator. For all Belgian nuclear sites, the results were generally insensitive to the choice of the proximity area. CONCLUSIONS: No evidence for excessive thyroid cancer incidence around the Belgian nuclear power plants was found. On the other hand, an increased incidence of thyroid cancer was observed around the sites with other nuclear activities. Further research is recommended to verify whether the observed increases could be related to the site-specific nuclear activities.

Regional variation in thyroid cancer incidence in Belgium is associated with variation in thyroid imaging and thyroid disease management.

CONTEXT: Increased thyroid cancer incidence is at least partially attributed to increased detection and shows considerable regional variation. OBJECTIVE: We investigated whether regional variation in cancer incidence was associated with variations in thyroid disease management. DESIGN: We conducted a retrospective population-based cohort study that involved linking data from the Belgian Health Insurance database and the Belgian Cancer Registry to compare thyroid-related procedures between regions with high and low cancer incidence. MAIN OUTCOME MEASURES: Primary outcome measures were rates of TSH testing, imaging, fine-needle aspiration cytology (FNAC), and thyroid surgery. Secondary study outcomes were proportions of subjects with thyrotoxicosis and nodular disease treated with surgery, of subjects treated with surgery preceded by FNAC or with synchronous lymph node dissection, and of thyroid cancer diagnosis after surgery. RESULTS: The rate of TSH testing was similar, but the rate of imaging was lower in the low incidence region. The rate of FNAC was similar, whereas the rate of surgery was lower in the low incidence region (34 [95% CI 33; 35 ] vs 80 [95% CI 79; 81 ] per 100,000 person years in the high incidence region; P < .05). In the low incidence region compared to the high incidence region, surgery represented a less chosen therapy for euthyroid nodular disease patients (47% [95% CI 46; 48] vs 69% [95% CI 68; 70]; P < .05), proportionally more surgery was preceded by FNAC, more cancer was diagnosed after total thyroidectomy, and thyroid cancer patients had more preoperative FNAC and synchronous lymph node dissection. CONCLUSION: Regional variation in thyroid cancer incidence, most marked for low-risk disease, is associated with different usage of thyroid imaging and surgery, supporting variable detection as a key determinant in geographic variation.

Consistency and inconsistency in testing biomarkers in breast cancer. A GRELL study in cut-off variability in the Romance language countries.

PURPOSE: Biological markers are crucial factors in order to differentiate female breast cancers and to determine the right therapy. This study aims at evaluating whether testing for biomarkers for female breast cancer has similar frequency and characteristics across and within countries. METHODS: Population-based cancer registries of the Association for cancer registration and epidemiology in Romance language countries (GRELL) were asked to complete a questionnaire on biomarkers testing. The data collected referred to invasive female breast cancer cases diagnosed between 2004 and 2009. The investigation focused on 1) the overexpression and amplification of the human epidermal growth factor receptor 2 oncogene (HER2); 2) the expression of oestrogen (ER) and progesterone (PgR) receptors; and 3) the proliferation index (PI). Weighted percentages, the heterogeneity among and within countries, and the correlation between responses and calendar years were evaluated. The study was based on 19,644 breast cancers. RESULTS: Overall, 85.9% of the cases were tested for HER2, 91.8% for both ER and PgR, and 74.1% for proliferative markers. For HER2 and ER-PgR, the frequency of testing increased from 2004 to 2009. Testing varied among countries (HER2 from 82.0% to 95.9%, ER-PgR from 89.3% to 98.9%, PI from 10% to 92%) and also within the same country (e.g. HER2 in Italy from 51% to 99%) as well as within single cancer registries. The most relevant differences were in the scores for positive/negative/not clearly defined HER2 (e.g. HER2 was defined positive if IHC 3+ in 21/33 registries), and in the cut-off of positive cells for ER/PgR (from >0% to >30%) and PI positivity (from >0% to >20%). CONCLUSIONS: Biological markers are widely tested in the Romance language countries; however, the parameters defining their positivity may vary, raising concerns about homogeneity in breast cancer classification and treatment.

Progression-free survival rate as primary end point for phase II cancer clinical trials: application to mesothelioma--The EORTC Lung Cancer Group.

PURPOSE: Phase II cancer clinical trials play a key role in the development of new drugs. These trials should be designed to accurately determine if the drug should be abandoned or if it is sufficiently promising for further investigation in phase III trials. With new cytostatic agents or when the response assessment is difficult, using the progression-free survival rate (PFSR) at a fixed time point, such as 3, 4, 5, or 6 months, instead of the response rate (RR) as the primary end point is an alternative approach. To design future phase II trials, reference values for PFSRs that correspond to drugs with insufficient (P0) and sufficient (P1) clinical activity (CA) are necessary. This article provides these values in mesothelioma. MATERIALS AND METHODS: The European Organisation for Research and Treatment of Cancer database registered ten closed mesothelioma trials (nine phase II trials and one phase III trial) with 523 total patients. Trials were grouped into three categories according to the published RR: significant (n = 259), moderate (n = 142), and insufficient (n = 122) CA. RESULTS: The PFSRs at 3, 4, 5, and 6 months, respectively, were as follows: 72%, 67%, 51%, and 43% in the group with significant CA; 59%, 51%, 42%, and 35% with moderate CA; and 52%, 40%, 34%, and 28% with insufficient CA. CONCLUSION: These values may be used to define relevant P0 and P1 values in future phase II mesothelioma trials that use PFSR as the primary end point.

Evaluation of peritoneal transport properties at onset of peritoneal dialysis and longitudinal follow-up.

BACKGROUND: The clinical determinants of baseline peritoneal membrane (PM) transport characteristics, as evaluated by a hypertonic peritoneal equilibration test (PET), remain ill-defined. Likewise, the longitudinal evolution of PM transport properties in peritoneal dialysis (PD) patients given automated PD (APD) and icodextrin still needs to be determined precisely. The aims of the present study were (1) to determine the clinical and biological factors affecting PM transport characteristics at PD onset and (2) to assess the longitudinal evolution of these markers. METHODS: Seventy-two consecutive patients performed a baseline 3.86% glucose dialysate PET and were enrolled. Subgroups of 35 and 18 patients underwent another PET 1 and 2 year(s) later, respectively, and were included in the longitudinal part. For each patient, clinical and biological data were reviewed and PM transport markers calculated. RESULTS: At onset of PD, angiotensin-converting enzyme (ACE) inhibitor intake (r = 0.31, P = 0.01), presence of a diabetes (r = 0.26, P = 0.03) and body surface area (BSA) (r = 0.26, P = 0.03) independently affected the mass transfer area coefficient (MTAC) of creatinine. Serum albumin (r = -0.46, P<0.001) and net ultrafiltration (r = -0.33, P = 0.009) inversely correlated with MTAC creatinine. Sodium sieving was inversely correlated with BSA (r = -0.33, P = 0.01). Serum albumin also inversely correlated with albumin clearance (r = -0.39, P = 0.02). Finally, the independent covariates that affected alpha2-macroglobulin clearance were age (P = 0.03), diabetes (P = 0.01) and the level of residual renal function (P<0.01). Serum albumin decreased with time on PD (P = 0.02). A rise in small solute transport and a decrease in net ultrafiltration, but no change in protein clearances, were also observed after 2 years of PD. CONCLUSIONS: Transport properties across the PM, as evaluated by MTAC creatinine and sodium sieving determinations, are correlated with anthropometric characteristics (BSA) and by comorbid conditions (witnessed by the presence of diabetes, a low serum albumin concentration and the prescription of an ACE inhibitor). The short-term evolution (2 years) of the PM transport properties of patients on APD and icodextrin is still characterized by a progressive increase in small solute transport and a loss of ultrafiltration capacity, as documented in ancient studies, but not with a modification in protein clearances. This conclusion merits, however, to be further evaluated in a larger cohort of PD patients after a longer follow-up.

Growth in extremely low birth weight infants up to three years.

OBJECTIVE: To evaluate postnatal growth of extremely low birth weight infants (ELBW, <1,000 g) until 36 months of corrected age (CA), and to relate growth outcome to anthropometric parameters at birth, sex, fetal growth status (small or appropriate for gestational age--SGA/AGA), period of admission and major perinatal events. STUDY DESIGN/METHOD: Weight (Wt), height (Ht) and head circumference (HC) were assessed in 159 ELBW infants. Data were standardized with Z-scores following Usher and McLean and Sempe growth curves. Uni- and multivariate statistical analysis were performed. RESULTS: The mean birth weight was 851.2+/-116.5 g. Z-scores decreased from birth to term, at a deeper rate for AGA than for SGA infants (p<0.005 for Ht, Wt, and HC). Between term and 36 months, growth was better in SGA compared with AGA infants (p=0.003 for Ht). Multivariate analysis showed that anthropometric parameters at birth were positive determinants for Wt, Ht and HC at term, and also for Wt and Ht at 36 months CA (Z-scores). Oxygen therapy after 36 weeks of post-conceptional age was a negative determinant influencing growth at 36 months CA (Z-scores). CONCLUSIONS: Significant catch-up growth took place between birth and 36 months, which was greater for SGA than for AGA infants. Anthropometric parameters at birth and oxygen therapy at 36 weeks post-conceptional age are the main predictive factors for growth at 36 months CA.