K.K.H. Aben

Expert review remains important in the histopathological diagnosis of cutaneous melanocytic lesions

Aims:u2002 To assess the type of problems encountered in diagnosing melanocytic lesions and to evaluate the contribution of expert review.

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 mmolu2009l−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.

Recurrent urinary tract infection and risk of bladder cancer in the Nijmegen bladder cancer study

Background:Controversy exists on whether urinary tract infection (UTI) is a risk factor for urinary bladder cancer (UBC). Here, the association is investigated using data from one of the largest bladder cancer case–control studies worldwide.Methods:Information on (i) history and age at onset of regular cystitis (‘regular low-UTI’) and (ii) number and age at onset of UTI treated with antibiotics (‘UTI-ab’) from 1809 UBC patients and 4370 controls was analysed. Odds ratios (ORs) and 95% confidence intervals (CI) adjusted for age, education, smoking, and use of aspirin/ibuprofen were generated, for men and women separately.Results:Regular low-UTI was associated with an increased UBC risk (men: OR (95% CI) 6.6 (4.2–11); women: 2.7 (2.0–3.5)), with stronger effects in muscle-invasive UBC. Statistically significant decreased risks (ORs ∼0.65) were observed for up to five UTI-ab, specifically in those who (had) smoked and experienced UTI-ab at a younger age. In women, UTI experienced after menopause was associated with a higher UBC risk, irrespective of the number of episodes.Conclusions:Regular cystitis is positively associated with UBC risk. In contrast, a limited number of episodes of UTI treated with antibiotics is associated with decreased UBC risk, but not in never-smokers and postmenopausal women.

Better survival in patients with metastasised kidney cancer after nephrectomy: a population-based study in the Netherlands.

AIMnCytoreductive nephrectomy is considered beneficial in patients with metastasised kidney cancer but only a minority of these patients undergo cytoreductive surgery. Factors associated with nephrectomy and the independent effect of nephrectomy on survival were evaluated in this study.nnnMETHODSnPatients were selected from the population-based cancer registry and detailed data were retrieved from clinical files. Factors associated with nephrectomy were evaluated by logistic regression analyses. Cox proportional hazard regression analysis was performed to evaluate factors associated with survival; a propensity score reflecting the probability of being treated surgically was included in order to adjust for confounding by indication.nnnRESULTSn37.5% of 328 patients diagnosed with metastatic kidney cancer between 1999 and 2005 underwent nephrectomy. Patients with a low performance score, high age, ≥2 comorbid conditions, ≥2 metastases, low or high BMI, weight loss, elevated lactate dehydrogenase, elevated alkaline phosphatase, female gender and liver or bone metastases were less likely to be treated surgically. Three year survival was 25% and 4% for patients with and without nephrectomy, respectively (p<0.001). After adjustment for other prognostic factors including the propensity score, nephrectomy remained significantly associated with better survival (Hazard ratio: 0.52, 95% Confidence interval: 0.37-0.73).nnnCONCLUSIONSnEven after accounting for prognostic profile, patients still benefit from a nephrectomy; an approximately 50% reduction in mortality was observed. It is, therefore, recommended that patients with metastasised disease receive cytoreductive surgery when there is no contraindication. Trial results on cytoreductive surgery combined with targeted molecular therapeutics are awaited for.

No improvement in renal cell carcinoma survival: a population-based study in the Netherlands.

BACKGROUNDnThe increased finding of kidney incidentalomas and more frequent surgery in patients with renal cell cancer (RCC) metastases may have improved survival from the disease. However, recent data on survival of unselected population-based series of patients with RCC are sparse.nnnMETHODSnWe collected the follow-up data for all the patients registered with RCC in the population-based cancer registry held by the Comprehensive Cancer Centre East, the Netherlands.nnnRESULTSnPatients (1504) diagnosed with RCC between 1989 and 2002 were included. Eighty-three percent of all tumours were histologically confirmed; 17% of all diagnoses were based on clinical examination only. The latter group was older, had a worse stage distribution, often did not receive any kind of therapy and showed a 5-year relative survival of 8%. Five-year relative survival for patients with a histologically confirmed RCC was 60% and did not improve over the last 15 years. A low resection rate in patients with metastasis was observed, most pronounced in elderly, without a tendency of increase in more recent years.nnnCONCLUSIONnThe relative survival of RCC did not improve over the years. The resection rate in patients with metastasised disease did not increase over time, despite current knowledge concerning its benefit on tumour complications, time to progression and response to immunotherapy.

The effect of the ATG16L1 Thr300Ala polymorphism on susceptibility and outcome of patients with epithelial cell-derived thyroid carcinoma

Epithelial cell-derived thyroid carcinoma (TC) is the most common endocrine malignancy. Increasing evidence suggests that autophagy, a complex process of autodigestion in conditions of cellular stress, plays an important role in the pathophysiology of the TC malignant process. One of the main mammalian autophagy proteins is autophagy related 16-like 1 (ATG16L1), which is essential for autophagosome formation, induction of autophagy, and modulation of inflammation (Saitoh et al. 2008). Subsequently, defective autophagy in ATG16L1 knockout mice results in an increased production of the proinflammatory cytokine interleukin 1b (IL1b; Saitoh et al. 2008) that is also known to affect the growth and differentiation of different malignant cell types (Apte & Voronov 2002). Considering the potential role of both autophagy and IL1b in the pathology of TC, we hypothesized that genetic variation in ATG16L1 influences the susceptibility for and the outcome of TC. One single nucleotide polymorphism of the ATG16L1 gene (c.898AOG, Thr300Ala, rs2241880) has been shown to affect the autophagy process (Cooney et al. 2010) and also to modulate production of IL1b in human cells (Plantinga et al. 2011). We investigated whether this ATG16L1 polymorphism is associated with the susceptibility or clinical outcome of TC. One hundred and thirty nine patients (75% women, mean age 39G13 (S.D.) years) with histologically confirmed TC (papillary (70%), follicular TC (24%), or both (6%)), who visited the outpatient clinic at the Department of Endocrinology of our centre, were included. Primary treatment consisted of (near-) total thyroidectomy in all patients and modified radical neck dissections in patients with confirmed nodal metastases, followed by ablation with radioactive iodine (I, RAI) of residual thyroid tissue. Initial cure is

DNA adducts in skin biopsies and 1-hydroxypyrene in urine of psoriasis patients and healthy volunteers following treatment with coal tar.

Coal tar ointments (CTO) are frequently used in the treatment of psoriasis and eczema, but CTO contain carcinogenic polycyclic aromatic hydrocarbons (PAH). PAH are absorbed and metabolized in the skin. In psoriasis, the skin barrier is altered and therefore, absorption and metabolism of PAH may differ from healthy skin. In this study, levels of urinary 1-hydroxypyrene and PAH-DNA adducts in the skin were studied in psoriatic patients and healthy volunteers. Three punch biopsies were taken from the lower back of 10 male volunteers and from a psoriatic plaque in 10 male patients. A surface of 6.25 cm(2) was treated with CTO. After 96 h CTO was removed and another three skin biopsies were collected from the treated area. DNA was isolated from skin biopsies and urine was collected during and after the exposure period. After 24h, a twofold lower 1-hydroxypyrene urinary excretion was observed in patients compared to healthy volunteers and after 48 h, this difference reached statistical significance (p<0.05). Over 96 h the median level of the sum of PAH-DNA adducts, analyzed by (32)P-post-labeling, increased from 3.5 before CTO administration to 21.1 adducts per 10(8) nucleotides in volunteers, and from 1.0 to 3.6 adducts per 10(8) nucleotides in patients. At 96 h, PAH-DNA levels were higher in healthy volunteers than in patients (p<0.05). Biomarkers for uptake, bioavailability and bioactivation of PAH were lower in patients compared to volunteers. These data suggest a lower risk of carcinogenic effects of CTO in psoriatic skin compared to healthy skin.

A germline homozygote deletion of the glutathione-s-transferase Mu1 gene predisposes to bladder cancer

Introduction and Objectives: Numerous studies have shown smoking and specific occupational exposures to be risk factors for bladder cancer. The risk of bladder cancer may be modified by the activity of carcinogen metabolizing enzymes. The glutathione-S-transferase Mu1 enzyme (GSTM1) detoxifies arylepoxides which are formed after exposure to certain polycyclic aromatic hydrocarbons and possibly aromatic amines. Approximately 40% of Caucasians lack GSTM1 activity due to a homozygous deletion of the GSTM1 locus on chromosome 1p13 (GSTM1 0/0 genotype). The aim of this study was to evaluate the combined effect of smoking and GSTM1 genotype on the risk of bladder cancer. Materials and Methods: Sixty-one patients with transitional cell carcinoma of the bladder and 69 controls matched for age and sex were enrolled from the outpatient clinic. Lifestyle information was collected with a standardized questionnaire. DNA was extracted from white blood cells. The GSTM1 genotype was determined by a PCR-based method. Results: 92% of the 61 patients had a history of smoking compared with 81% of the controls. There was a significant dose-response relationship for pack-years of smoking (trend test: p = 0.003). The proportion of GSTM1 0/0 genotype among patients was 62% compared with 43% among controls (odds ratio = 2.1; 95% CI 1.1–4.3). The expected interaction between smoking and GSTM1 genotype was not observed. Conclusions: This study confirms the findings that a germline homozygous deletion of the GSTM1 gene predisposes to bladder cancer. An interaction with smoking was not found.

Lower incidence of urothelial cell carcinoma due to the concept of a clonal origin.

Synchronous and metachronous tumours are frequently observed in the urinary tract and may be explained by the concept of field cancerisation, i.e. exposure to carcinogens leads to independent transformation of many urothelial cells resulting in genetically unrelated tumours. However, increasing evidence supports the concept of clonality, i.e. the progeny of a single transformed cell spreads through the urinary system resulting in genetically related tumours. The aim of this study was to review the molecular biological evidence for both concepts and to assess the consequences of a clonality assumption on the incidence of urothelial cell carcinoma (UCC). In total 1198 non-invasive and 1113 invasive (> or = T1) UCCs of the bladder were registered as incident tumours in 1996-1997 by three Dutch cancer registries following the current registration rules of the International Association of Cancer Registries (IACR). Assuming clonality, the number of non-invasive and invasive bladder UCCs decreased by 10.9% and 11.5% respectively. A decline of 8.5% and 9.5% was found for UCCs of the ureter and renal pelvis, respectively. Current registration rules have substantial impact on the incidence estimates of UCC. New insights into the molecular biology of UCC should be translated into registration rules.

Reproducibility of self-reported melanoma risk factors in melanoma patients.

As melanoma researchers continue to investigate environmental and lifestyle-related risk factors, questionnaire data remain important. The reproducibility of a questionnaire on melanoma risk factors was investigated using a test–retest approach in 389 Dutch melanoma patients. In 2011, 389 melanoma patients filled out a questionnaire on melanoma risk factors twice. Test–retest reproducibility was assessed by calculating kappas (&kgr;), weighted kappas (&kgr;w), and intraclass correlation coefficients (ICCs) for categorical, ordinal, and continuous variables, respectively. Stratified analyses were carried out by sex, age group, education level, and time since diagnosis. The median time between the questionnaires was 31 days. The reproducibility was substantial for questions on phenotypic characteristics (&kgr;/&kgr;w/ICC=0.62–0.77), fair-to-substantial for sun exposure and sun protection behavior (&kgr;/&kgr;w/ICC=0.38–0.79), and moderate for sunburn history (&kgr;/&kgr;w=0.42–0.51). No clear differences were observed between men and women. Younger patients showed a better reproducibility in nine of the 29 questions compared with older patients and higher educated patients showed a better reproducibility in four of the 29 questions. Patients with a diagnosis shorter than 1.5 years ago had a better reproducibility in four out of 29 items compared with patients with a diagnosis 1.5–3.0 years ago. Our study showed that self-reported information on melanoma risk factors is fairly well reproducible. Although this does not guarantee validity, this type of questionnaire seems to be useful in research settings. The reproducibility is slightly better in young patients and patients with a higher education level, which can be taken into account when interpreting results from epidemiological studies.