Dieuwertje E. Kok

Blood lipid levels and prostate cancer risk; a cohort study.

It has been hypothesized that blood lipid levels might be associated with prostate cancer risk. The aim of the present study was to evaluate the association between serum total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and prostate cancer risk in a cohort study among 2842 Dutch men. By the end of follow-up, 64 incident cases of prostate cancer were identified. Serum total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides were evaluated as potential risk factors for prostate cancer using multivariable Cox proportional hazards regression models. These analyses were restricted to men who never used cholesterol-lowering drugs (2118 men, 43 cases). Higher total and higher LDL cholesterol were significantly associated with an increased risk of prostate cancer (hazards ratios (HR) and 95% confidence interval (CI) per mmol l−1 were 1.39 (95% CI 1.03–1.88) and 1.42 (95% CI 1.00–2.02), respectively). Similar results were observed for aggressive prostate cancer, whereas for non-aggressive prostate cancer a significant association with HDL cholesterol was found (HR 4.28, 95% CI 1.17–15.67). The results of this study suggest that blood lipid levels may influence risk of prostate cancer. However, the exact roles of different cholesterol fractions on prostate cancer aggressiveness should be further evaluated.

Comparison of methods to assess body fat in non-obese six to seven-year-old children

BACKGROUND & AIM Different non-invasive methods exist to evaluate total body fat in children. Most methods have shown to be able to confirm a high fat percentage in children with overweight and obesity. No data are available on the estimation of total body fat in non-obese children. The aim of this study is to compare total body fat, assessed by different methods in non-obese children. METHODS We compared total body fat, assessed by isotope dilution, dual energy X-ray, skinfold thickness, bioelectrical impedance analysis, combination of these methods as well as BMI in 30 six to seven-year-old children. RESULTS The children had a mean BMI of 16.01kg/m(2) (range 13.51-20.32) and five children were overweight according to international criteria. Different methods showed rather different absolute values for total body fat. Bland-Altman analysis showed that the difference between the DEXA method and isotope dilution was dependent on the fat percentage. Children with the same BMI show a marked variation in total body fat ranging from 8% to 22% as estimated from the isotope dilution method. CONCLUSION Non-invasive methods are presently not suited to assess the absolute amount of total body fat in 6-7 years old children.

Body mass index as a prognostic marker for biochemical recurrence in Dutch men treated with radical prostatectomy

To investigate whether body mass index (BMI) is a prognostic factor for biochemical recurrence (BCR) in Dutch men after radical prostatectomy (RP), as although epidemiological studies of obesity in relation to prostate cancer have provided conflicting results, recent studies from the USA suggest that a higher BMI is a risk factor for progression of prostate cancer.

The prognostic role of the pathological T2 subclassification for prostate cancer in the 2002 Tumour-Nodes-Metastasis staging system.

To evaluate the prognostic role of the 2002 Tumour‐Nodes‐Metastasis (TNM) pT2 subclassification for biochemical recurrence (BCR) after radical prostatectomy (RP) for prostate cancer.

A single institution experience with biochemical recurrence after radical prostatectomy for tumors that on pathology are of small volume or “insignificant”

OBJECTIVE Small volume prostate cancers (<0.5 cc, svPC), and insignificant prostate cancers (<0.5 cc and Gleason scores <7, InsigPC) are considered clinically insignificant by some investigators. The aim of this study is to determine the biochemical recurrence rate (BCR) of svPC and InsigPC in prostatectomy specimens. METHODS In total, 502 patients with prostate cancer, treated with radical prostatectomy (RP) between 1992 and 2005 and with detailed pathological classification, were included in the present study. Patients were postoperatively followed for a median period of 39.5 months (0.6-150). A total of 82 specimens (16.3%) with svPC including 64 (12.8%) with InsigPC were identified. BCR was defined as 2 consecutive PSA levels >0.10 ng/ml. RESULTS In the total group, the median age at the time of surgery was 62.7 years (42.4-73.4) and the median preoperative PSA level was 8.0 ng/ml. Patients with InsigPC had Gleason scores of 4 in 7%, 5 in 37%, and 6 in 56%. Positive surgical margins were identified in 13 (15.9%) svPC and in 8 (12.7%) InsigPC specimens. The 5-year risk of BCR for the svPC group and the insigPC group was 10% (95% CI 2-18%, 7 and 5 patients, respectively) vs. 35% (95% CI 29-41%) in the rest of the cohort (log rank P = 0.001). CONCLUSION Patients with svPC and patients with InsigPC have a significantly lower risk of BCR. However, even in this seemingly very favorable patient group, 1 in 10 patients will develop a BCR after RP. Therefore, new studies are needed to examine what the prognostic relevance is of small-volume tumors.

Persistent organic pollutants alter DNA methylation during human adipocyte differentiation

Ubiquitous persistent organic pollutants (POPs) can accumulate in humans where they might influence differentiation of adipocytes. The aim of this study was to investigate whether DNA methylation is one of the underlying mechanisms by which POPs affect adipocyte differentiation, and to what extent DNA methylation can be related to gene transcription. Adipocyte differentiation was induced in two human cell models with continuous exposure to different POPs throughout differentiation. From the seven tested POPs, perfluorooctanesulfonic acid (PFOS) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) decreased lipid accumulation, while tributyltin (TBT) increased lipid accumulation. In human mesenchymal stem cells (hMSCs), TCDD and TBT induced opposite gene expression profiles, whereas after PFOS exposure gene expression remained relatively stable. Genome-wide DNA methylation analysis showed that all three POPs affected DNA methylation patterns in adipogenic and other genes, possibly related to the phenotypic outcome, but without concomitant gene expression changes. Differential methylation was predominantly detected in intergenic regions, where the biological relevance of alterations in DNA methylation is unclear. This study demonstrates that POPs, at environmentally relevant levels, are able to induce differential DNA methylation in human differentiating adipocytes.

Comprehensive DNA Methylation and Gene Expression Profiling in Differentiating Human Adipocytes

Insight into the processes controlling adipogenesis is important in the battle against the obesity epidemic and its related disorders. The transcriptional regulatory cascade involved in adipocyte differentiation has been extensively studied, however, the mechanisms driving the transcription activation are still poorly understood. In this study, we explored the involvement of DNA methylation in transcriptional regulation during adipocyte differentiation of primary human mesenchymal stem cells (hMSCs). Genome‐wide changes in DNA methylation were measured using the Illumina 450K BeadChip. In addition, expression of 84 adipogenic genes was determined, of which 43 genes showed significant expression changes during the differentiation process. Among these 43 differentially expressed genes, differentially methylated regions (DMRs) were detected in only three genes. By comparing genome‐wide DNA methylation profiles in undifferentiated and differentiated adipocytes 793 significant DMRs were detected. Pathway analysis revealed the adipogenesis pathway as the most statistically significant, although only a small number of genes were differentially methylated. Genome‐wide DNA methylation changes for single probes were most often located in intergenic regions, and underrepresented close to the transcription start site. In conclusion, DNA methylation remained relatively stable during adipocyte differentiation, implying that changes in DNA methylation are not the underlying mechanism regulating gene expression during adipocyte differentiation. J. Cell. Biochem. 117: 2707–2718, 2016.

A short-term intervention with selenium affects expression of genes implicated in the epithelial-to-mesenchymal transition in the prostate

In parallel with the inconsistency in observational studies and chemoprevention trials, the mechanisms by which selenium affects prostate cancer risk have not been elucidated. We conducted a randomized, placebo-controlled trial to examine the effects of a short-term intervention with selenium on gene expression in non-malignant prostate tissue. Twenty-three men received 300 μg selenium per day in the form of selenized yeast (n=12) or a placebo (n=11) during 5 weeks. Prostate biopsies collected from the transition zone before and after intervention were analysed for 15 participants (n=8 selenium, n=7 placebo). Pathway analyses revealed that the intervention with selenium was associated with down-regulated expression of genes involved in cellular migration, invasion, remodeling and immune responses. Specifically, expression of well-established epithelial markers, such as E-cadherin and epithelial cell adhesion molecule EPCAM, was up-regulated, while the mesenchymal markers vimentin and fibronectin were down-regulated after intervention with selenium. This implies an inhibitory effect of selenium on the epithelial-to-mesenchymal transition (EMT). Moreover, selenium was associated with down-regulated expression of genes involved in wound healing and inflammation; processes which are both related to EMT. In conclusion, our explorative data showed that selenium affected expression of genes implicated in EMT in the transition zone of the prostate.

Risk of prostate cancer among cancer survivors in the Netherlands

BACKGROUND In parallel with increasing numbers of cancer patients and improving cancer survival, the occurrence of second primary cancers becomes a relevant issue. The aim of our study was to evaluate risk of prostate cancer as second primary cancer in a population-based setting. METHODS Data from the Netherlands Cancer Registry were used to estimate standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for prostate cancer as second primary cancer. The effect of time since first cancer diagnosis, specific first cancer sites, age, and pelvic radiotherapy was taken into account. RESULTS Out of 551,553 male patients diagnosed with a first primary cancer between 1989 and 2008, 9243 patients were subsequently diagnosed with prostate cancer. Overall, cancer survivors showed an increased risk (SIR 1.3, 95% CI 1.2-1.3) of prostate cancer. The increased prostate cancer risk was limited to the first year of follow-up for the majority of the specific first cancer sites. More than 10 years after the first cancer diagnosis, only melanoma patients were at increased risk (SIR 1.5, 95% CI 1.2-1.9), while patients with head or neck cancers were at decreased risk (SIR 0.7, 95% CI 0.5-0.9) of being diagnosed with prostate cancer. Patients who underwent primary pelvic radiotherapy for their first cancer had a decreased risk of prostate cancer in the long term (SIR 0.5, 95% CI 0.4-0.6). CONCLUSIONS Our data showed that cancer survivors have an increased prostate cancer risk in the first year following a first cancer diagnosis, which is most likely the result of active screening or incidental detection.

Dietary Intake of Magnesium or Calcium and Chemotherapy-Induced Peripheral Neuropathy in Colorectal Cancer Patients

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and severe side-effect in colorectal cancer (CRC) patients. This study assessed the association between habitual dietary intake of magnesium or calcium and prevalence and severity of chronic CIPN in CRC patients receiving adjuvant chemotherapy. For this prospective cohort study, 196 CRC patients were considered. Magnesium and calcium intake was determined using a food frequency questionnaire at diagnosis, during and after chemotherapy. Chronic CIPN was assessed 12 months after diagnosis using the quality of life questionnaire CIPN20. Prevalence ratios were calculated to assess the association between magnesium or calcium intake and the prevalence of CIPN. Multivariable linear regression analysis was used to assess the association between magnesium or calcium intake and severity of CIPN. CIPN was reported by 160 (82%) patients. Magnesium intake during chemotherapy was statistically significantly associated with lower prevalence of CIPN (prevalence ratio (PR) 0.53, 95% confidence interval (CI) 0.32, 0.92). Furthermore, higher dietary intake of magnesium during (β −1.08, 95% CI −1.95, −0.22) and after chemotherapy (β −0.93, 95% CI −1.81, −0.06) was associated with less severe CIPN. No associations were found for calcium intake and the prevalence and severity of CIPN. To conclude, we observed an association between higher dietary magnesium intake and lower prevalence and severity of CIPN in CRC patients.