Rotterdam Cohort Research Articles

Acceleration of skeletal maturation in Central Europe over the last two decades: insights from two cohorts of healthy children

BackgroundDeviations between the determination of bone age (BA) according to Greulich and Pyle (G&P) and chronological age (CA) are common in Caucasians. Assessing these discrepancies in a population over time requires analysis of large samples and low intra-observer variability in BA estimation, both can be achieved with artificial intelligence-based software. The latest software-based reference curve contrasting the BA determined by G&P to the CA of Central European children dates back over two decades.ObjectiveTo examine whether the reference curve from a historical cohort from the Netherlands (Rotterdam cohort) between BA determined by G&P and CA still applies to a current Central European cohort and derive a current reference curve.Materials and methodsThis retrospective single-center study included 1,653 children and adolescents (aged 3–17 years) who had received a radiograph of the hand following trauma. The G&P BA estimated using artificial intelligence-based software was contrasted with the CA, and the deviations were compared with the Rotterdam cohort.ResultsAmong the participants, the mean absolute error between BA and CA was 0.92 years for girls and 0.97 years for boys. For the ages of 8 years (boys) and 11 years (girls) and upward, the mean deviation was significantly greater in the current cohort than in the Rotterdam cohort. The reference curves of both cohorts also differed significantly from each other (P < 0.001 for both boys and girls).ConclusionThe BA of the current Central European population and that of the curve from the Rotterdam cohort from over two decades ago differ. Whether this effect can be attributed to accelerated bone maturation needs further evaluation.

Identification of hospitalized mortality of patients with COVID-19 by machine learning models based on blood inflammatory cytokines.

Coronavirus disease 2019 (COVID-19) spread worldwide and presented a significant threat to people's health. Inappropriate disease assessment and treatment strategies bring a heavy burden on healthcare systems. Our study aimed to construct predictive models to assess patients with COVID-19 who may have poor prognoses early and accurately. This research performed a retrospective analysis on two cohorts of patients with COVID-19. Data from the Barcelona cohort were used as the training set, and data from the Rotterdam cohort were used as the validation set. Cox regression, logistic regression, and different machine learning methods including random forest (RF), support vector machine (SVM), and decision tree (DT) were performed to construct COVID-19 death prognostic models. Based on multiple clinical characteristics and blood inflammatory cytokines during the first day of hospitalization for the 138 patients with COVID-19, we constructed various models to predict the in-hospital mortality of patients with COVID-19. All the models showed outstanding performance in identifying high-risk patients with COVID-19. The accuracy of the logistic regression, RF, and DT models is 86.96, 80.43, and 85.51%, respectively. Advanced age and the abnormal expression of some inflammatory cytokines including IFN-α, IL-8, and IL-6 have been proven to be closely associated with the prognosis of patients with COVID-19. The models we developed can assist doctors in developing appropriate COVID-19 treatment strategies, including allocating limited medical resources more rationally and early intervention in high-risk groups.

MiRNAs Correlate with HLA Expression in Uveal Melanoma: Both Up- and Downregulation Are Related to Monosomy 3.

Simple SummaryUveal melanoma (UM) is a rare ocular malignancy that often gives rise to metastases. Tumours with an inflammatory phenotype have an especially bad prognosis. As an increased HLA expression and the presence of tumour-infiltrating lymphocytes and macrophages may be regulated by miRNAs, we set out to investigate whether any miRNAs are associated with inflammatory parameters in this malignancy. Some miRNAs were increased in UM with a high HLA expression and high T cell numbers, while others were decreased, showing two opposing patterns; however, both patterns were related to the tumour’s chromosome 3/BAP1 status. We conclude that specific miRNAs are related to the inflammatory phenotype and that these are differentially expressed between disomy 3/BAP1-positive versus monosomy 3/BAP1-negative UM.MicroRNAs are known to play a role in the regulation of inflammation. As a high HLA Class I expression is associated with a bad prognosis in UM, we set out to determine whether any miRNAs were related to a high HLA Class I expression and inflammation. We also determined whether such miRNAs were related to the UM’s genetic status. The expression of 125 miRNAs was determined in 64 primary UM from Leiden. Similarly, the mRNA expression of HLA-A, HLA-B, TAP1, BAP1, and immune cell markers was obtained. Expression levels of 24 of the 125 miRNAs correlated with expression of at least three out of four HLA Class I probes. Four miRNAs showed a positive correlation with HLA expression and infiltration with leukocytes, 20 a negative pattern. In the first group, high miRNA levels correlated with chromosome 3 loss/reduced BAP1 mRNA expression, in the second group low miRNA levels. The positive associations between miRNA-22 and miRNA-155 with HLA Class I were confirmed in the TCGA study and Rotterdam cohort, and with TAP1 in the Rotterdam data set; the negative associations between miRNA-125b2 and miRNA-211 and HLA-A, TAP1, and CD4 were confirmed in the Rotterdam set. We demonstrate two patterns: miRNAs can either be related to a high or a low HLA Class I/TAP1 expression and the presence of infiltrating lymphocytes and macrophages. However, both patterns were associated with chromosome 3/BAP1 status, which suggests a role for BAP1 loss in the regulation of HLA expression and inflammation in UM through miRNAs.

Targeted social care for highly vulnerable pregnant women: design of the Mothers of Rotterdam cohort study

Introduction: Evidence shows that low socioeconomic status SES is related to decreased mental health of the individual. Exposure to determinants such as low income, unemployment, being a single parent, and living in a deprived neighbourhood increases levels of chronic stress. This results in diminishing overall resources to cope with stressful situations, making them more vulnerable for unhealthy and unfavourable behaviour, and a decreased health status of the individual. These negative effects do not only create a vulnerability in the individual for poor health, but effect the next generation already during pregnancy. Therefore, policies targeting highly vulnerable pregnant women potentially have far-reaching effects. Within the Netherlands, Rotterdam has the highest percentage of children growing up in poverty 25%, in a family living on welfare 19%, with a low parental level of education 20%, and with one or both parents being unemployed 10%. Furthermore, 57% of the children in Rotterdam grow up in a deprived neighbourhood. Description of policy context, objective and targeted population: In the Netherlands, social care is usually carried out by a community social care team: a multidisciplinary team of professionals located in the neighbourhood of their clients. Based on the needs of the client, care is either focused on adult issues such as financial problems or problems regarding children and adolescents such as underperformance at school. This strict separation of the social care in adult- and child-care is suboptimal in the care of highly vulnerable pregnant women, since impact of risk and adversity is not limited to one generation and can simultaneously affect both parents and children. Within Rotterdam, the Erasmus Medical Centre, the municipality, and a non-profit organization are combining their expertise to improve the psycho-social situation of highly vulnerable pregnant women. Ultimately, this will result in a healthy development of the unborn child. This targeted social care integrates medical and social care in a long-term and intensive support program. This support focusses on all issues a women and her child can encounter during pregnancy and after giving birth: health, housing, employment, social functioning, mother-child interaction and child development. In the “Mothers of Rotterdam” study, we aim to prospectively evaluate the effectiveness of the holistic approach compared to regular care provided by the community social care teams. Highlights and transferability: This program promotes societal valorisation of knowledge through valuable collaboration between academics, government and a non-profit organization by supporting the healthy development of future generations. Due to the pragmatic character of the study, randomization of participants is not possible, but is determined by a natural experiment. Therefore, this ecologically valid study design allows for results directly generalizable to the actual population, although it increases the risk of true effects being masked by unmeasured confounders. Conclusion: This study will provide unique insights into a notoriously difficult to reach population of highly vulnerable pregnant women, their problems and potential care pathways for these problems.

Targeted social care for highly vulnerable pregnant women: protocol of the Mothers of Rotterdam cohort study

IntroductionSocial vulnerability is known to be related to ill health. When a pregnant woman is socially vulnerable, the ill health does not only affect herself, but also the health and...

Vertebral Fracture: Diagnostic Difficulties of a Major Medical Problem.

Vertebral Fracture: Diagnostic Difficulties of a Major Medical Problem.

Determinants and Predictors of Grief Severity and Persistence: The Rotterdam Study

Objective: We aimed to explore correlates and predictors of bereavement severity and persistence (triggered by “loss of a loved one”; referent group partner loss) in the Rotterdam cohort. Method: We used linear regression to examine factors associated with grief severity using a cross-sectional analysis and logistic regression to determine prospective associations. Results: Cross-sectionaly, females, child-lost, higher depressive symptoms, lower education, and difficulties in daily activities were independently associated with a higher bereavement severity. Prospectively (6 years; response rate 71%), the baseline value of the grief severity was the single predictor significantly associated with grief persistence. Discussion: Our results suggest that only grief severity is independently associated with grief persistence. Further studies are needed to confirm our findings.

Loss of SRY-box2 (SOX2) expression and its impact on survival of patients with oesophageal adenocarcinoma.

BackgroundOesophageal adenocarcinoma (OAC) is a highly aggressive malignancy with poor survival, which is highly variable amongst patients with comparable conventional prognosticators. Therefore molecular biomarkers are urgently needed to improve the prediction of survival in these patients. SRY (sex determining region Y)‐box 2, also known as SOX2, is a transcription factor involved in embryonal development of the gastrointestinal tract as well as in carcinogenesis. The purpose of this study was to see whether SOX2 expression is associated with survival in patients with OAC.Methods SOX2 was studied by immunohistochemistry in patients who had undergone potentially curative oesophagectomy for adenocarcinoma. Protein expression of SOX2 was evaluated using tissue microarrays from resection specimens, and results were analysed in relation to the clinical data by Cox regression analysis. SOX2 was evaluated in two independent OAC cohorts (Rotterdam cohort and a multicentre UK cohort).ResultsLoss of SOX2 expression was independently predictive of adverse overall survival in the multivariable analysis, adjusted for known factors influencing survival, in both cohorts (Rotterdam cohort: hazard ratio (HR) 1·42, 95 per cent c.i. 1·07 to 1·89, P = 0·016; UK cohort: HR 1·54, 1·08 to 2·19, P = 0·017). When combined with clinicopathological staging, loss of SOX2 showed an increased effect in patients with pT1–2 tumours (P = 0·010) and node‐negative OAC (P = 0·038), with an incrementally adverse effect on overall survival for stage I OAC with SOX2 loss (HR 3·18, 1·18 to 8·56; P = 0·022).Conclusion SOX2 is an independent prognostic factor for long‐term survival in OAC, especially in patients with stage I OAC.

IJU this issue

Treatment of advanced renal cell carcinoma has progressed significantly in the past decade. Pal et al. (Duarte, CA, USA) reported a large retrospective review of advanced renal cell carcinoma in the USA. They reviewed the medical charts of 1173 patients from 318 physicians, and indicated that sunitinib and everolimus remain the most commonly used first and second targeted therapies, respectively. This article shed light on real-world practice in the USA. Cancer-related death is rare for men with biopsy-confirmed prostate cancer and a Gleason score of ≤6. This seems to be partly explained by undergrading of biopsies. Alberts et al. (Rotterdam, the Netherlands) retrospectively reviewed the biopsy specimens of 98 men with a Gleason score of ≤6 or 3 + 4 = 7. This review included 15 men who died, and had a clinical T 1/2 Gleason score of ≤6 at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam cohort. They also confirmed that the International Society of Urological Pathology 2014 grading system was more accurate for prognostic assessment than the classic Gleason score. This issue includes two interesting Original Articles focusing on prostate biopsy. Shoji et al. (Tokyo, Japan) reported the accuracy of a new technique, real-time magnetic resonance imaging-transrectal ultrasound fusion transperineal target biopsy for biopsy-naïve men. They concluded that targeted biopsy is superior to conventional systemic biopsy. However, a systemic biopsy is still important, because although targeted biopsy alone diagnosed 79% of significant cancers, combined targeted + systematic biopsies diagnosed 95% of significant cancers. Kamei et al. (Tokyo, Japan) reported the prevalence and characteristics of fecal antimicrobial-resistant Escherichia coli in Japanese men undergoing transrectal prostate biopsy. Transrectal biopsy is a common procedure for the diagnosis of prostate cancer, but it has a risk of life-threatening infectious complications. Current guidelines recommend prophylactic use of fluoroquinolone. However, the results of the study revealed fecal carriage rates of fluoroquinolone-resistant E. coli and extended-spectrum b-lactamase-producing E. coli at 9.8% and 5.9%, respectively. An important article in functional urology, Ferreira et al. (Le Mans, France) reported the midterm outcomes of laparoscopic implantation of artificial urinary sphincters in women with intrinsic sphincter deficiency. They reported that 76% of patients experienced resolution, and 16% reported improvement of incontinence. The report was one of the largest series with the longest follow up for this patient population. This issue included two interesting Case Reports. The first report by Fahmy et al. (Selangor, Malaysia) described a unique ureteral substitution technique using buccal mucosa for a 64-year-old woman with a long proximal ureteral stricture after multiple bowel surgeries. Postoperative renal function was improved. The second report by Sugino et al. (Nagoya, Japan) presented a case of the successful treatment of an impacted ureteral stone in a 2-year-old girl with a single session of combined percutaneous nephrostomy and ureteroscopy using a holmium laser.

Commentary on “Development and External Validation of a Model Predicting Death After Surgery in Patients With a Ruptured Abdominal Aortic Aneurysm”

The Dutch Aneurysm Score (DAS) for predicting mortality risk after surgical intervention for ruptured abdominal aortic aneurysm (rAAA)1von Meijenfeldt G.C.I. van Beek S.C. Bastos Gonclaves F. Verhagen H.J.M. Zeebregts C.J. Vahl A.C. et al.Development and external validation of a model predicting death after surgery in patients with a ruptured abdominal aortic aneurysm.Eur J Vasc Endovasc Surg. 2017; 53: 168-174Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar has three supportive and promising features. First, it can be quickly calculated from four easily obtained pre-procedure variables: age, lowest in-hospital systolic blood pressure, cardiopulmonary resuscitation, and hemoglobin level. A computer/tablet/phone app would be helpful. Second, its development included both open AAA repair and EVAR. Older rAAA mortality scores were developed using only open repair. However, the multivariable logistic regression model used to develop DAS with an Amsterdam cohort did not identify intervention method to be a significant predictor of mortality. Perhaps this was in part because of the Amsterdam cohort having only 15% of patients treated with EVAR. In contrast, the two Danish cohorts used to externally validate DAS, and the Glasgow Aneurysm Score (GAS), had higher EVAR rates (Rotterdam cohort 37% and Groningen cohort 35%). Third, both DAS and GAS performed and calibrated well on external validations, with DAS having slightly better discrimination. It remains to be determined how the DAS and GAS perform and compare when externally validated against rAAA mortality data from other regions or countries. In a recent report Krenzien et al.2Krenzien F. Wiltberger G. Hau H.M. Matia I. Benzig C. Atanasov G. et al.Risk stratification of ruptured abdominal aortic aneurysms in patients treated by open surgical repair.Eur J Vasc Endovasc Surg. 2016; 51: 30-36Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar found that including intraperitoneal hemorrhage as an independent variable improved the accuracy of a rAAA mortality risk model for open repair. Intraperitoneal hemorrhage was not a pre-procedure variable, having been determined by the operating surgeon. The standard diagnostic test for rAAA is CT scanning, which can also detect significant intraperitoneal hemorrhage. DAS did not include this variable in the mix undergoing multivariable logistic regression risk analysis. When designing new or modifying current rAAA mortality risk scores, consideration should be given for using a cohort that has similar numbers of patients with open and EVAR as well as the presence or absence of intraperitoneal hemorrhage on CT scan. The authors stated premise for developing DAS was that the decision whether or not to proceed with intervention in a patient with rAAA is very difficult in daily practice. Some may not agree that this is difficult. Patients presenting with rAAA who have pre-existing moribund conditions such as terminal cancer or severe major stroke are not candidates for surgical intervention independent of rAAA mortality prediction score. Given the essentially 100% mortality of patients with rAAA not undergoing operation, it seems reasonable to consider AAA repair for patients who are expected to have a reasonable life expectancy and quality of life if they survive the procedure. On external validation DAS predicted a death rate greater than 80% for six patients, of whom one survived. The 95% CI for 1 of 6 surviving is 3% to 56%, not a convincing statistic. I would have difficulty advising patients and families not to undergo repair of a rAAA if DAS or GAS predicts a high morbidity. While mortality risk scores are a valuable aid for patients and families making the urgent decision regarding intervention, the only realistic chance of survival is with surgery. Even if the odds are low it is worth the effort. Healthcare agencies, systems, and bureaucrats should not use rAAA predicted mortality scores to control cost by limiting care. Development and External Validation of a Model Predicting Death After Surgery in Patients With a Ruptured Abdominal Aortic Aneurysm: The Dutch Aneurysm ScoreEuropean Journal of Vascular and Endovascular SurgeryVol. 53Issue 2PreviewThe decision whether or not to proceed with surgical intervention of a patient with a ruptured abdominal aortic aneurysm (rAAA) is very difficult in daily practice. The primary objective of the present study was to develop and to externally validate a new prediction model: the Dutch Aneurysm Score (DAS). Full-Text PDF Open Archive

Long-term invasive follow-up of the everolimus-eluting bioresorbable vascular scaffold: five-year results of multiple invasive imaging modalities.

Invasive imaging modalities have shown restoration of vasomotion, prevention of restenosis and, most importantly, increase in lumen area between six months and two years after first-generation everolimus-eluting bioresorbable vascular scaffold (Absorb BVS) implantation. Our aim was to assess whether these positive findings were sustained in the long term. Patients included in the ABSORB cohort A from the Thoraxcenter Rotterdam cohort underwent coronary catheterisation including angiography, intravascular ultrasound (IVUS), virtual histology, optical coherence tomography (OCT) and vasomotion testing at five years. Eight out of 16 patients underwent catheterisation and scaffold assessment with multiple imaging modalities. A trend towards an increase in minimum luminal diameter was observed between two and five years by angiography (1.95±0.37 mm vs. 2.14±0.38 mm; p=0.09). IVUS data showed an increase in mean lumen area at five years (6.96±1.13 mm2) compared to six months (6.17±0.74 mm2; p=0.06) and two years (6.56±1.16 mm2; p=0.12), primarily due to a persistent reduction in plaque area size between six months and five years (9.17±1.86 mm2 vs. 7.57±1.63 mm2; p=0.03). The necrotic core area was reduced at five years compared to post-procedural results. In OCT, an increase in mean and minimal luminal area was observed. Moreover, no scaffold struts could be identified and a smooth endoluminal lining was observed. The scaffolded coronary segment did not show signs of endothelial dysfunction with acetylcholine testing. At five years, the Absorb BVS is no longer discernible by any invasive imaging method and endothelial function is restored. Late luminal enlargement persists up to five years of follow-up without adaptive vessel remodelling.

OCT Assessment of the Long-Term Vascular Healing Response 5 Years After Everolimus-Eluting Bioresorbable Vascular Scaffold

Although recent observations suggest a favorable initial healing process of the everolimus-eluting bioresorbable vascular scaffold (BVS), little is known regarding long-term healing response. This study assessed the in vivo vascular healing response using optical coherence tomography (OCT) 5 years after elective first-in-man BVS implantation. Of the 14 living patients enrolled in the Thoraxcenter Rotterdam cohort of the ABSORB A study, 8 patients underwent invasive follow-up, including OCT, 5 years after implantation. Advanced OCT image analysis included luminal morphometry, assessment of the adluminal signal-rich layer separating the lumen from other plaque components, visual and quantitative tissue characterization, and assessment of side-branch ostia "jailed" at baseline. In all patients, BVS struts were integrated in the vessel and were not discernible. Both minimum and mean luminal area increased from 2 to 5 years, whereas lumen eccentricity decreased over time. In most patients, plaques were covered by a signal-rich, low-attenuating layer. Minimum cap thickness over necrotic core was 155 ± 90 μm. One patient showed plaque progression and discontinuity of this layer. Side-branch ostia were preserved with tissue bridge thinning that had developed in the place of side-branch struts, creating a neo-carina. At long-term BVS follow-up, we observed a favorable tissue response, with late luminal enlargement, side-branch patency, and development of a signal-rich, low-attenuating tissue layer that covered thrombogenic plaque components. The small size of the study and the observation of a different tissue response in 1 patient warrant judicious interpretation of our results and confirmation in larger studies.

External validation of the OHTS-EGPS model for predicting the 5-year risk of open-angle glaucoma in ocular hypertensives

AimsTo independently evaluate and compare the performance of the Ocular Hypertension Treatment Study-European Glaucoma Prevention Study (OHTS-EGPS) prediction equation for estimating the 5-year risk of open-angle glaucoma (OAG) in four...

Long-term invasive follow-up of the everolimus-eluting bioresorbable vascular scaffold: five-year results of multiple invasive imaging modalities

Background: Invasive imaging modalities have shown restoration of vasomotion, prevention of restenosis and most importantly increase in lumen area between 6-months and 2-years after first-generation everolimus-eluting bioresorbable vascular scaffold (Absorb BVS) implantation. Our aim was to assess whether these positive findings were sustained in the long-term. Methods: Patients included in the ABSORB Cohort A from the Thoraxcenter Rotterdam cohort underwent coronary catheterization including angiography, intravascular-ultrasound (IVUS), virtual histology, optical coherence tomography (OCT) and vasomotion testing at 5-years. Results: Eight out of 16 patients underwent catheterization and scaffold assessment with multiple imaging modalities. A trend towards an increase in minimum luminal diameter was observed between 2- and 5-years by angiography (1.95±0.37 mm versus 2.14±0.38; p=0.09). IVUS data showed an increase in mean lumen area at 5-years (6.96±1.13 mm2) compared to 6-months (6.17±0.74 mm2; p=0.06) and 2-years (6.56±1.16 mm2; p=0.12), primarily due to a persistent reduction in plaque area size between 6-months and 5-years (9.17±1.86 mm2 versus 7.57±1.63 mm2; p=0.03). The necrotic core area was reduced at 5-years compared to post-procedural results. In OCT, an increase in mean and minimal luminal area was observed. Moreover, no scaffold struts could be identified and a smooth endoluminal lining was observed. The scaffolded coronary segment did not show signs of endothelial dysfunction with acetylcholine testing. ![Figure][1] Figure 1. OCT-IVUS Conclusions: At 5-years, the Absorb BVS is no longer discernible by any invasive imaging method and endothelial function is restored. Late luminal enlargement persists up to 5-years of follow-up without adaptive vessel remodelling. [1]: pending:yes

Optimisation of an automated drusen-quantifying software for the analysis of drusen distribution in patients with age-related macular degeneration

The purpose of this study is to optimise the settings of the Retinal Image Analysis Laboratory (RIALAB), a semi-automatic drusen quantification software, in planning for high-throughput quantification of drusen in clinical studies of age-related macular degeneration (AMD). A comparison of five different settings in RIALAB was made on 67 images from the Rotterdam eye study (population-based study) and 56 images from the fellow eye of patients with active neovascular AMD in King's College Hospital, London (hospital-based study). The 'Few Outer' setting was the best setting, with it being most appropriate for 52 (77.6%) of the Rotterdam cohort and 47 (83.9%) for the London cohort. Pearson's χ(2)-test revealed both results to be statistically significant (P<0.0001). RIALAB is a viable algorithm and software package that can detect, quantify, and analyse drusen efficiently in both population-based and hospital-based studies. We have shown that the 'Few Outer' drusen setting can be employed as the default setting, with fine-tuning only needed in a minority of cases, thus helping to speed up workflow.

Development of radiological knee osteoarthritis in patients with knee complaints

ObjectivesIt is currently impossible to identify which patients with knee complaints presenting to the general practitioner will develop knee osteoarthritis (OA) pathology at a later stage. This study examines the...

Abstract P3-10-22: Prognostic Significance of Aurora Kinase A Expression in Three Cohorts of Node-Negative Breast Cancer Patients

Abstract Background: Aurora kinase A (AURKA) is important for cell cycle progression. Inhibitors that target AURKA are currently in clinical development. We examined the prognostic impact of AURKA in three cohorts of node-negative breast cancer patients without adjuvant systemic therapy (n=766). Methods: AURKA (probe set ID 204092_s_at) was analysed utilizing microarray based gene-expression data of three independent and previously published cohorts of node-negative breast cancer patients (Mainz, Rotterdam, TRANSBIG). In addition to AURKA, we examined the prognostic impact of age, histological grade, tumor size, estrogen receptor (ER) and HER2. Metastasis-free survival (MFS) was analyzed with univariate and multivariate Cox regression. Results: AURKA displayed a strong positive correlation with grade (P&amp;lt;0.001), tumor size (P&amp;lt;0.001), HER2 (P&amp;lt;0.001), and a negative correlation with ER (P&amp;lt;0.001), respectively. Patients with higher expression of IGKC showed shorter MFS in the Mainz cohort (HR 1.629, 95% CI 1.243-2.134, P&amp;lt;0.001), Rotterdam cohort (HR 1.567, 95% CI 1.271-1.933, P&amp;lt;0.001), and TRANSBIG cohort (HR 1.331, 95% CI 1.081-1.640, p=0.007), respectively. Accordingly, AURKA was significant in univariate analysis in the whole cohort of patients (HR 1.523, 95% CI 1.343-1.726, P&amp;lt;0.001). Using multivariate Cox regression, only tumor size retained its independent prognostic significance (HR 1.818, 95% CI 1.196-2.765, p=0.005). AURKA (HR 1.221, 95% CI 0.987-1.511, p=0.065) and histological grade (HR 1.551, 95% CI 0.955-2.520, p=0.076) showed only borderline significance for MFS. Conclusion: AURKA has prognostic relevance in three independent cohorts of node-negative breast cancer patients making it a suitable target for therapy with Aurora kinase inhibitors. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-22.

What is the role of digital rectal examination in men undergoing serial screening of serum PSA levels?

This Practice Point commentary discusses the study by Gosselaar et al. that reports the performance characteristics of digital rectal examination (DRE) in men from the Rotterdam cohort of the European Randomized Study of Screening for Prostate Cancer. The authors reported that the positive predictive value of DRE for detecting the presence of prostate cancer was 48.6% in the first round of screening, decreasing to 29.9% and 21.2% in the second and third rounds, respectively. Nevertheless, an abnormal DRE was associated with a significantly increased risk of very high-grade disease during all screening rounds, indicating that it provides useful additional prognostic information. This study adds to a considerable body of evidence supporting a role for DRE in early detection of prostate cancer.

Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study

Hyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout. Genome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (p<5.0 x 10(-8)) or the Rotterdam cohort (p<1.0 x 10(-7)) were evaluated with gout. The results obtained in white participants were combined using meta-analysis. Three loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7.0 x 10(-168) and 2.9 x 10(-18) for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2.5 x 10(-60) and 9.8 x 10(-4)), and rs1165205 in SLC17A3 (p=3.3 x 10(-26) and 0.33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0.59 per T allele, 95% CI 0.52-0.68, p=7.0 x 10(-14)), rs2231142 (1.74, 1.51-1.99, p=3.3 x 10(-15)), and rs1165205 (0.85, 0.77-0.94, p=0.002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1.71, 1.06-2.77, p=0.028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272-351 mumol/L in the Framingham cohort, 269-386 mumol/L in the Rotterdam cohort, and 303-426 mumol/L in white participants of the ARIC study) and gout (frequency 2-13% in the Framingham cohort, 2-8% in the Rotterdam cohort, and 1-18% in white participants in the ARIC study). We identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk for gout.

A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity

Anti-Müllerian hormone (AMH) inhibits primordial follicle recruitment in the mouse ovary. We hypothesize that in women AMH signaling also regulates the usage of the primordial follicle pool and hence influences the onset of menopause. Since age at menopause has a strong genetic component, we investigated the role of AMH signaling using a candidate gene approach. In two large population-based cohorts of Dutch post-menopausal women (n = 2381 and n = 248), we examined the association between two polymorphisms, one in the AMH gene and one in the AMH type II receptor (AMHR2) gene, and natural age at menopause. The AMH Ile(49)Ser polymorphism (rs10407022) was not associated with age at menopause in either cohort. In the Rotterdam cohort, the AMHR2 -482 A > G polymorphism (rs2002555) was associated with age at menopause in interaction with the number of offspring (P = 0.001). Nulliparous women homozygous for the G-allele entered menopause 2.6 years earlier compared with nulliparous women homozygous for the A-allele (P = 0.005). In the LASA cohort, women with the G/G genotype tended to enter menopause 2.8 years earlier compared with the A/A genotype (P = 0.063). The observed association of the AMHR2 -482 A > G polymorphism with natural age at menopause suggests a role for AMH signaling in the usage of the primordial follicle pool in women.