Biomedical subjects

Huub Straatman

Publications and source records attributed to Huub Straatman.

15 recordsLinked to original sources

PubMed2006

Prediction of recurrence in Ta urothelial cell carcinoma by real-time quantitative PCR analysis: a microarray validation study.

Accurate prediction of tumor recurrence in patients with superficial urothelial cell carcinoma (UCC) might result in a significant reduction of invasive follow-up cystoscopies. A recent study identified a panel of 26 genes from a large cDNA microarray analysis of bladder tumors that discriminated between early- and late-recurring patients with superficial Ta tumors (Dyrskjøt et al., Nat Genet 2003;33:90-6). We aimed to validate this panel of genes in 44 primary Ta UCCs (23 and 21 tumors from patients with short or prolonged recurrence-free periods, respectively), by real-time quantitative PCR. Statistical analysis showed marginal significant different mRNA expression levels between the 2 patient groups. To evaluate a supplementary effect of genes for the identification of patients with short or prolonged recurrence-free intervals, forward logistic regression analysis was applied. This revealed that a combination of the expression profiles of the genes HNRPK, LTB4DH and ANP32B resulted in the best performance, although the combination only marginally increased the predictive value of HNRPK alone. Comparing the receiver-operating-characteristic curves for HNRPK expression among patients with short or prolonged recurrence-free periods, revealed an area under the curve of 0.696 (95% CI, 0.537-0.855). Using the median HNRPK expression level as cut-off, a sensitivity of 69.6% and a specificity of 71.4% were obtained for the identification of patients with short or prolonged recurrence-free periods, respectively. In conclusion, we were not able to confirm the microarray gene expression pattern of the 26 genes shown by Dyrskjøt et al. The discovery of accurate recurrence predictive markers, therefore, remains a challenge.

Gene Expression Profiling↗

PubMed2006

Gene expression analysis for the prediction of recurrence in patients with primary Ta urothelial cell carcinoma.

OBJECTIVES: The individual recurrence-free period after primary surgery of patients with Ta urothelial cell carcinoma (UCC) cannot be predicted accurately. This study aims at discriminating between patients with primary Ta UCC and long or short recurrence-free periods. METHODS: We investigated mRNA expression of 23 genes in 44 primary Ta tumours (23 and 21 tumours were from patients with long [>or=4 yr] or short [<or=2 yr] recurrence-free periods, respectively), using real-time quantitative polymerase chain reaction. The genes were selected from previously published studies and showed a relationship with tumour recurrence in patients with UCC. RESULTS: Differential mRNA expression between the two patient groups indicated statistical significance only for the gene survivin (p=0.0011). Its recurrence predictive value could not be increased by a combination with any of the other genes. Comparison of the receiver operating characteristic curves for survivin expression between patients with long or short recurrence-free intervals revealed an area under the curve of 0.79 (95%CI, 0.65-0.92). Using the median expression (0.84) as cut-off level, survivin identified 71.4% (95%CI, 47.8-88.7) and 69.6% (95%CI, 47.1-86.8) of the patients with long or short recurrence-free periods, respectively. CONCLUSIONS: Our study identifies survivin as the most promising candidate to distinguish between patients with primary Ta UCC and long or short recurrence-free intervals. Therefore, survivin mRNA expression analysis might help the urologist to individualise patient treatment and prevent unnecessary cystoscopies in a subgroup of these patients.

Adult↗

PubMed2006

Accurate prediction of need for invasive treatment in alpha1-blocker treated patients with benign prostatic hyperplasia not possible: bootstrap validation analysis.

OBJECTIVES: Frequently, statistically significant prognostic factors are reported in published studies with suggestions that disease management should be modified. However, the clinical relevance of such factors is rarely quantified. We evaluated the accuracy of predicting the need for invasive treatment among patients with benign prostatic hyperplasia treated conservatively with alpha1-blockers. METHODS: Information on eight prognostic factors was collected from 280 patients treated with alpha1-blockers. Using the proportional hazards regression coefficients, a risk score for retreatment was calculated for each patient. The analyses were repeated on 1000 groups of 280 patients sampled from the original case series. The results from these "bootstrap analyses" were compared with the original results. RESULTS: Three statistically significant predictors of retreatment were identified. The 20% of patients with the greatest risk score had an 18-month risk of retreatment of only 20% (this should ideally approach 100%). Analyses of less than one half of all the bootstrap samples resulted in the same three significant prognostic factors. The 20% of patients with the greatest risk score in each of the 1000 samples experienced a highly variable risk of retreatment of 0% to 42%. CONCLUSIONS: Strongly significant predictors for retreatment suggest the need for a change in disease management, but 4 of the 5 high-risk patients would be overtreated with a modified policy. The subclassification of patients with a relatively low risk and high risk of retreatment appeared far from accurate. Internal validation procedures may warn against the invalid translation of statistical significance into clinical relevance.

Adrenergic alpha-Antagonists↗

PubMed2005

Immune status and eustachian tube function in recurrence of otitis media with effusion.

OBJECTIVE: To study the combined role of immune status and eustachian tube function in the development of recurrent bilateral otitis media with effusion (OME). DESIGN: Prospective cohort study. SETTING: Three academic and general hospitals. PATIENTS: Children aged 2 to 7 years with a first clinical episode of bilateral OME that persisted for at least 3 months; 136 (81%) of 168 eligible children participated. All children received bilateral tympanostomy tubes at study entry. MAIN OUTCOME MEASURE: Recurrence of bilateral OME within 6 months after tube extrusion. RESULTS: Univariate analyses of various immunologic factors (IgA, IgG1, IgG2, IgG3, IgG4, mannose-binding lectin, and the FcgammaRIIa-H/R131 genotype) and eustachian tube function (forced response test) did not show any significant associations with bilateral OME recurrence. Multivariate analyses showed that children with closing pressures higher than the 75th percentile and IgA or IgG2 levels below the 50th percentile of the cohort were more likely to develop recurrent OME than children with closing pressures higher than the 75th percentile and IgA or IgG2 levels above the 50th percentile. The corresponding risk ratios were 6.3 (95% confidence interval [CI], 1.0-40.1) for IgA level and 3.0 (95% CI, 1.1-8.2) for IgG2 level. The multivariate analyses also revealed that increasing serum levels of functional mannose-binding lectin were associated with decreasing probabilities of developing recurrent OME (odds ratio, 0.7; 95% CI, 0.6-1.0). CONCLUSION: Recurrence of bilateral OME after tympanostomy tube placement is more likely in children with a combination of low IgA or low IgG2 levels with poor eustachian tube function and decreased levels of mannose-binding lectin.

Antigens, CD↗

PubMed2005

Identification of androgen-responsive genes that are alternatively regulated in androgen-dependent and androgen-independent rat prostate tumors.

The vast majority of androgen-dependent prostate tumors progress toward incurable, androgen-independent tumors. The identification of androgen-responsive genes, which are still actively transcribed in the tumors of patients who have undergone androgen ablation, may shed light on the molecular mechanisms underlying this phenomenon. To address this question, we chose the Dunning R3327 rat model system, in which the progression from androgen-dependent to -independent tumors is represented by several transplantable prostate-derived tumors. Gene expression profiles were analyzed in normal rat prostates and in the prostates of rats 14 days after castration by use of microarrays containing approximately 5,000 oligonucleotides, together representing more than 4,800 known rat genes. These expression profiles were compared with similarly obtained expression profiles of androgen-dependent and androgen-independent rat prostate tumors. By doing so, a series of known and novel prostate cancer-associated androgen-responsive genes was identified. Within this series, we were able to identify several clusters of genes that are differentially regulated in the various prostate tumors. These genes may serve as (i) novel prognostic identifiers and (ii) novel therapeutic targets.

Androgens↗

PubMed2005

Bayes' theorem: a negative example of a RCT on grommets in children with glue ear.

Bayesian inference presupposes that practitioners' belief in the effectiveness of medical intervention is the product of prior belief and recent evidence from studies. Although increasingly used, up to now the posterior belief calculated according to the theorem has not been compared with an empirically measured posterior belief. We conducted a RCT, which was preceded by elicitation of prior beliefs among ENT-surgeons, and which was followed by elicitation of posterior beliefs among ENT-surgeons, 1 year after completion of the trial. We compared the posterior beliefs of ENT-surgeons about the effect of grommets in children with glue ears, as predicted by Bayes' theorem with actual measured posterior beliefs. The distribution of the measured posterior beliefs was not in line with the calculated posterior, but almost identical to the distribution of the measured prior beliefs. The results showed that our trial had little or no impact on the beliefs of the ENT-surgeons, i.e. they did not adjust their belief to the extent that was expected according to Bayes' theorem.

Bayes Theorem↗

PubMed2005

Multiplex ligation-dependent probe amplification for the detection of chromosomal gains and losses in formalin-fixed tissue.

Molecular analysis on formalin-fixed paraffin-embedded tissue is of increasing importance in diagnostic histopathology and tumor research. Multiplex ligation-dependent probe amplification (MLPA) is a technique that can be used for detection of copy number alterations of up to 45 different DNA sequences in one experiment. It can be performed on partially degraded DNA, which makes this technique very suitable for analysis of formalin-fixed lesions. We tested the reliability of MLPA by analyzing DNA isolated from formalin-fixed melanomas that were previously characterized by comparative genomic hybridization (CGH), and additionally the applicability of MLPA was tested by analyzing 29 routinely processed melanocytic lesions. MLPA appears to be a reliable and efficient method to evaluate DNA copy number changes as 86% of the loci tested revealed concordant CGH results. Discordance mainly involved alterations that were detected by MLPA and not by CGH probably due to a combination of lower resolution of CGH and occasionally false positive MLPA results. For application of MLPA in a diagnostic setting, different probes on a specific region of interest should be used to prevent false positive MLPA results. In a research setting as well as in a diagnostic setting, MLPA is a fast technique to screen large numbers of formalin-fixed lesions for DNA gains and losses.

Aneuploidy↗

PubMed2004

Site-specific familial aggregation of prostate cancer.

Over the last decade, epidemiologic evidence has accumulated in favor of a significant but heterogeneous hereditary component in prostate cancer (PC) susceptibility. In order to map and clone PC susceptibility genes, stratification of PC families into genetically homogeneous groups appears to be a key issue. Subset definition based on age at diagnosis, presumed mode of inheritance, number of affecteds per family and coaggregation of PC with other cancers has already proven successful in some studies. Previously, the finding of the coaggregation of malignancies of the central nervous system within PC families helped to link a prostate-brain cancer susceptibility gene (CAPB) to chromosome 1p36. In this study, we evaluate the risk of PC and malignancies at other sites among first-degree relatives of a large population-based group of Dutch PC patients. A population-based family case-control study was initiated that included Caucasian PC patients newly diagnosed between July 1996 and December 1999. Information on 12,575 first-degree relatives of 704 PC patients and 1,371 controls was collected through postal questionnaires and telephone interviews. All reported PC in first-degree relatives was verified through medical records. In our population, PC has a strong familial component that is reflected by a 2.9-fold increased risk (95% CI = 2.2-3.9) of PC for first-degree relatives of PC patients. This familial risk was somewhat higher among brothers (hazard ratio = 3.9; 95% CI = 2.4-6.4) compared to fathers (hazard ratio = 2.5; 95% CI = 1.7-3.6). Cancers at other sites did not coaggregate with PC. Our data suggest that familial PC, at least in this Western European population, is site-specific, not part of an inherited cancer syndrome.

Aged↗

PubMed2004

Estimating life expectancy and related probabilities in screen-detected breast cancer patients with restricted follow-up information.

Issues such as life expectancy after diagnosis, the number of life years gained by early diagnosis through screening, the probability of dying from breast cancer or of dying from other causes during the lead time period or thereafter can be derived from information on complete survival after diagnosis. A method is presented to estimate complete survival and relevant outcomes after diagnosis of screen-detected cancer when the follow-up period is substantially shorter than the maximum follow-up possible. Survival after diagnosis until death from breast cancer is modelled as the sum of the lead time (LT) and the post-lead time (PLT), where both time periods follow exponential distributions and are assumed to be independent. The survival period after diagnosis until death from causes other than breast cancer (X) is assumed to follow a Gompertz distribution. The survival period after diagnosis until death from any cause (Z) is modelled as the minimum of LT+PLT and X. Maximum likelihood methods were then used to estimate all parameters of Z. This procedure for obtaining maximum likelihood estimates of Z does not need the cause of death (breast cancer or other), which is an advantage over most other methods. Especially in older patients, it may be difficult or even impossible to ascertain the true cause of death. The model was applied to data from the long-term breast cancer screening programme in Nijmegen, the Netherlands. Complete survival was estimated on the basis of survival data on 528 screen-detected breast cancer patients, diagnosed in 1975-1997 and with a mean follow-up of 8.9 years. Estimated life expectancy ranged between 22.3 and 9.0 years for patients diagnosed at the age of 50 and 79 years, respectively, that is, 6.1 and 0.7 life years gained by screening. Through early diagnosis and treatment, screen-detected patients diagnosed at the age of 50 years may have reduced their lifetime risk of dying from breast cancer from 79 per cent to 56 per cent; at the age of 79 the reduction of risk is reduced from 23 per cent to 13 per cent.

Aged↗

PubMed2004

Genetic variants in ZIC1, ZIC2, and ZIC3 are not major risk factors for neural tube defects in humans.

Neural tube defects (NTD) are congenital malformations arising from incomplete neural tube closure during early embryogenesis. Most NTD in humans show complex inheritance patterns, with both genetic and environmental factors involved in the etiology of this malformation. More than 120 mouse models for human NTD exist. NTD have been observed in mice deficient for the Zic family genes, Zic1, Zic2, and Zic3. We performed mutation analysis in the human orthologs of these genes using DNA material from a large panel of NTD patients. In ZIC2 we identified a deletion of one codon that encodes an alanine residue located in the amino terminal alanine stretch of the protein. The deletion was present in one patient, but not in 364 controls. That may suggest a role-albeit small-of this variant in the etiology of NTD in humans. Transmission disequilibrium testing of a frequent polymorphism in the ZIC2 gene (1059C > T, H353H) in parent-spina bifida aperta child triads showed no association with NTD. One silent polymorphism (858G > A, V286V) of unknown significance was identified in ZIC3. Neither mutations nor polymorphisms were found in the coding region or flanking sequences of ZIC1. Our data indicate that ZIC1, ZIC2, and ZIC3 are not major risk factors for NTD in humans.

Child↗

PubMed2004

Periconceptional folate intake by supplement and food reduces the risk of nonsyndromic cleft lip with or without cleft palate.

BACKGROUND: Inadequate maternal vitamin intake during pregnancy has been suggested as a risk factor for cleft lip with or without cleft palate (CLP). The independent role of folate has not been clarified. METHODS: To investigate the association between maternal folate intake by supplement and food and the risk of CLP offspring, a case-control study was conducted in the Netherlands (1998-2000) among 174 mothers of a child with nonsyndromic CLP and 203 mothers of a child without congenital malformations. RESULTS: Daily use of a folic acid supplement by mothers starting from 4 weeks before until 8 weeks after conception gave a 47% CLP risk reduction compared to mothers who did not use these supplements [odds ratio (OR): 0.53, 95% confidence interval (CI): 0.33, 0.85]. Ninety-three percent of the users took a supplement containing folic acid only. Dietary folate intake reduced CLP risk independently in a dose-response manner. The largest risk reductions were found on those mothers who had a diet of more than 200 microg folate per day in combination with a folic acid supplement (OR: 0.26, 95% CI: 0.09, 0.72). CONCLUSIONS: We demonstrated that periconceptional maternal folic acid supplement use was beneficial to reduce the risk for CLP. An additional effect of food folate was shown.

Adult↗

PubMed2004

Policy relevance of Bayesian statistics overestimated?

OBJECTIVES: The observed posterior probability distributions regarding the benefits of surgery for otitis media with effusion (OME) with expected probability distributions, using Bayes' theorem are compared. METHODS: Postal questionnaires were used to assess prior and posterior probability distributions among ear-nose-throat (ENT) surgeons in the Netherlands. RESULTS: In their prior probability estimates, ENT surgeons were quite optimistic with respect to the effectiveness of tube insertion in the treatment of OME. The trial showed no meaningful benefit of tubes on hearing and language development. Posterior probabilities calculated on the basis of prior probability estimates and trial results differed widely from those, elicited empirically 1 year after completion of the trial and dissemination of the results. CONCLUSIONS: ENT surgeons did not adjust their opinion about the benefits of surgical treatment of glue ears to the extent that they should have done according to Bayes' theorem. Users of the results of Bayesian analyses, notably policy-makers, should realize that Bayes' theorem is prescriptive and not necessarily descriptively correct. Health policy decisions should not be based on the untested assumption that health-care professionals use new evidence to adjust their subjective beliefs in a Bayesian manner.

Attitude of Health Personnel↗

PubMed2003

Array-based comparative genomic hybridization for the genomewide detection of submicroscopic chromosomal abnormalities.

Microdeletions and microduplications, not visible by routine chromosome analysis, are a major cause of human malformation and mental retardation. Novel high-resolution, whole-genome technologies can improve the diagnostic detection rate of these small chromosomal abnormalities. Array-based comparative genomic hybridization allows such a high-resolution screening by hybridizing differentially labeled test and reference DNAs to arrays consisting of thousands of genomic clones. In this study, we tested the diagnostic capacity of this technology using approximately 3,500 flourescent in situ hybridization-verified clones selected to cover the genome with an average of 1 clone per megabase (Mb). The sensitivity and specificity of the technology were tested in normal-versus-normal control experiments and through the screening of patients with known microdeletion syndromes. Subsequently, a series of 20 cytogenetically normal patients with mental retardation and dysmorphisms suggestive of a chromosomal abnormality were analyzed. In this series, three microdeletions and two microduplications were identified and validated. Two of these genomic changes were identified also in one of the parents, indicating that these are large-scale genomic polymorphisms. Deletions and duplications as small as 1 Mb could be reliably detected by our approach. The percentage of false-positive results was reduced to a minimum by use of a dye-swap-replicate analysis, all but eliminating the need for laborious validation experiments and facilitating implementation in a routine diagnostic setting. This high-resolution assay will facilitate the identification of novel genes involved in human mental retardation and/or malformation syndromes and will provide insight into the flexibility and plasticity of the human genome.

Chromosome Aberrations↗

PubMed2003

Spouse controls in family case-control studies: a methodological consideration.

In case-control studies on familial aggregation of disease, spouses may be chosen as convenient controls. In this article the pros and cons of this control group are discussed. It is argued that the use of spouse controls can be time- and cost-efficient, because of easy accessibility and their ability to provide proxy data on the patients' relatives if necessary. Furthermore, with spouse controls a higher response rate and less recall bias can be expected compared to population controls. A theoretical drawback is the possibility of assortative mating related to genetic susceptibility of the disease under study. Using a simulation study it is illustrated that even strong assortative mating on a factor, which is strongly correlated with a true risk factor under study, will have a negligible effect on the observed extent of familial aggregation.

Adult↗

PubMed2002

Spitz naevi may express components of the plasminogen activation system.

The plasminogen activation (PA) system is involved in the process of invasion and metastasis. Its major components are urokinase (uPA) and tissue-type plasminogen activator (tPA), plasminogen activation inhibitor type 1 and 2 (PAI-1 and PAI-2) and a receptor for urokinase (uPAR). In this study, the expression of plasminogen activation components in Spitz naevi was compared with that in common and dysplastic naevi on the one hand and primary cutaneous melanomas on the other. Spitz naevi had melanocytic positivity for uPA in 0% (0/36), tPA in 30% (6/20), PAI-1 in 10% (3/35), PAI-2 in 40% (8/21) and uPAR in 60% (13/21) of cases. This far exceeded the expression found in common (n = 25) and dysplastic (n = 15) naevi, which only showed melanocytic positivity for PAI-2 (20% and 15% respectively) and in one dysplastic naevus also for uPAR. This was much (for most components significantly) less than the proportion of primary melanomas with tumour cell positivity, which was 30% (11/38) for uPA, 80% (19/24) for tPA, 75% (28/38) for PAI-1, 80% (19/24) for PAI-2 and 80% (19/24) for uPAR. The main findings of this study are that Spitz naevi, firstly, may express plasminogen activator (tPA), inhibitors and the receptor of the PA system, but in a much smaller proportion than cutaneous melanomas; and secondly, do not express urokinase, whereas some of the melanomas do. uPA positivity may therefore be suggestive of melanoma. However, overlapping staining results imply that the PA system has limited value in the differential diagnosis between Spitz naevus and primary melanoma. As serine protease components are expressed, Spitz naevi may use this proteolytic machinery to accomplish matrix degradation, although in a more restricted, possibly transient manner than melanomas.

Biomarkers, Tumor↗