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A comparison of prostate cancer survival in England, Norway and Sweden: a population-based study.

PURPOSE: The objective of the study was to compare patterns of survival 2001-2004 in prostate cancer patients from England, Norway and Sweden in relation to age and period of follow-up. SUBJECTS AND METHODS: Excess mortality in men with prostate cancer was estimated using nation-wide cancer register data using a period approach for relative survival. 179,112 men in England, 23,192 in Norway and 59,697 in Sweden were included. RESULTS: In all age groups, England had the lowest survival, particularly so among men aged 80+. Overall age-standardised five-year survival was 76.4%, 80.3% and 83.0% for England, Norway and Sweden, respectively. The majority of the excess deaths in England were confined to the first year of follow-up. CONCLUSION: The results indicate that a small but important group of older patients present at a late stage and succumb early to their cancers, possibly in combination with severe comorbidity, and this situation is more common in England than in Norway or Sweden.

Targeting chemotherapy to advanced bladder cancer patients most likely to benefit.

Evaluation of: Vickers AJ, Cronin AM, Kattan MW et al.; The International Bladder Cancer Nomogram Consortium: Clinical benefits of a multivariate prediction model for bladder cancer: a decision analytic approach. Cancer 115(23), 5460-5469 (2009). The prognosis from muscle-invasive bladder cancer is poor. Improvements in survival can be made with the use of chemotherapy. The best results are obtained using multiagent regimens, which increase cure rates by approximately 5%. Thus, few patients benefit when compared with treatment morbidity. This low complete response rate makes powering of clinical trials difficult and may prevent them determining which patients benefit most from chemotherapy. Here, we discuss work by Vickers et al. reporting a decision-based analysis using a nomogram to determine the benefit for individual patients from chemotherapy. This decision aid can reduce the number of patients treated by 0.006, without compromising recurrence. The authors conclude that a nomogram-derived 25% risk threshold produced better targeting of chemotherapy than the current standard criteria (mostly using pathological stage).

BMP-6 over-expression in prostate cancer is associated with increased Id-1 protein and a more invasive phenotype.

Bone morphogenetic protein-6 (BMP-6) has been strongly implicated in prostate cancer development and bone metastasis. Our previous data showed that BMP-6 mRNA was absent in patients with benign prostatic hyperplasia, but evident in primary tumours with established secondary skeletal metastases. To examine the role of BMP-6 in prostate cancer progression, we have developed a BMP-6-regulatable, doxycycline-inducible gene expression system. BMP-6 induction by doxycycline addition led to increased levels of BMP-6 RNA and protein, associated with nuclear translocation of SMADs and activation of the downstream target gene Id-1. BMP-6 protein did not enhance the proliferation rate of PC3M cells but did significantly increase the rate of migration and invasion in both PC3M and DU145 cells. Increased metalloproteinase (MMP-1 and MMP-9) mRNA levels were also observed following BMP-6 induction. Luciferase reporter assays confirmed BMP-6-mediated activation of MMP-1 and MMP-9 promoters, indicating direct transcriptional activation of MMPs by BMP-6. BMP-6 stimulation also led to an increase in phosphorylation levels of MAPK proteins. We next examined the effects of BMP-6 on the downstream gene Id-1 in a cohort of prostate cancer patients. A tissue microarray (TMA) was constructed and samples stained for BMP-6 and Id-1 expression. We observed a significant increase in the intensity of staining of epithelial BMP-6 in the cancer cases compared to the benign cases (Mann-Whitney U test, p < 0.0005) and in the intensity of staining of epithelial Id-1 in the cancer cases compared to the benign cases (Mann-Whitney U test, p = 0.015). We further observed a significant positive correlation between epithelial staining for Id-1 and BMP-6 (p = 0.001) across all samples for both benign and cancer cases. These data demonstrate that BMP-6 promotes migration and invasion of prostate cancer cells, potentially through activation of Id-1 and MMP activation.

What are the practitioner-level determinants for inappropriate PSA testing?

Neuro-fuzzy modeling: an accurate and interpretable method for predicting bladder cancer progression.

PURPOSE: New methods are required to improve the prediction of cancer progression as traditional statistical tests have limited accuracy. Accurate predictions would allow physicians to offer specific treatment according to individual patient risk. While predictive improvements are obtained using ANN, the hidden nature of these networks prevents insight and has hindered their widespread implementation. NFM is an alternate form of artificial intelligence using fuzzy logic (which is a multivalued logic which provides reasoning under uncertainty). By defuzzification the NFM rule base becomes transparent to overcome the black box nature of ANN. MATERIALS AND METHODS: Combinations of clinicopathological (tumor stage and grade, patient age, gender, and smoking status) and molecular (immunohistochemical expression of p53 and methylation status of 11 loci) data from 117 patients were used to develop and compare predictive models of tumor progression using NFM, ANN and LR. RESULTS: NFM (88% to 100% sensitivity, 97% to 100% specificity and 94% to 100% accuracy) predicted the presence and timing of cancer progression more accurately than ANN (81% to 87%, 95% to 100% and 89% to 90%, p = 0.002) and LR 3%, 61% to 72% and 47% to 53%, p = 0.00005). NFM was able to interrogate the clinicopathological and molecular data, and select the most important parameters (age, grade, stage, smoking, methylation) for progression prediction. CONCLUSIONS: Intelligent systems and molecular biomarkers improved the accuracy of cancer progression predictions. NFM appeared superior to ANN in terms of accuracy, sensitivity, specificity and transparency. The use of NFM in routine clinical practice warrants further validation.

Staging in prostate cancer.

This article reviews the conventional current techniques that are used for staging prostate cancer. The advantages and limitations of each modality are described. Attention is focused on the areas in which progress is rapidly being made and is likely to be developed in the future.

Very low PSA concentrations and deletions of the KLK3 gene.

BACKGROUND: Prostate-specific antigen (PSA), a widely used biomarker for prostate cancer (PCa), is encoded by a kallikrein gene (KLK3, kallikrein-related peptidase 3). Serum PSA concentrations vary in the population, with PCa patients generally showing higher PSA concentrations than control individuals, although a small proportion of individuals in the population display very low PSA concentrations. We hypothesized that very low PSA concentrations might reflect gene-inactivating mutations in KLK3 that lead to abnormally reduced gene expression. METHODS: We have sequenced all KLK3 exons and the promoter and searched for gross deletions or duplications in KLK3 in the 30 individuals with the lowest observed PSA concentrations in a sample of approximately 85 000 men from the Prostate Testing for Cancer and Treatment (ProtecT) study. The ProtecT study examines a community-based population of men from across the UK with little prior PSA testing. RESULTS: We observed no stop codons or frameshift mutations, but we did find 30 single-base genetic variants, including 3 variants not described previously. These variants included missense variants that could be functionally inactivating and splicing variants. At this stage, however, we cannot confidently conclude whether these variants markedly lower PSA concentration or activity. More importantly, we identified 3 individuals with different large heterozygous deletions that encompass all KLK3 exons. The absence of a functional copy of KLK3 in these individuals is consistent with their reduced serum PSA concentrations. CONCLUSIONS: The clinical interpretation of the PSA test for individuals with KLK3 gene inactivation could lead to false-negative PSA findings used for screening, diagnosis, or monitoring of PCa.

DNA damage response in peritumoral regions of oesophageal cancer microenvironment.

Oesophageal cancer is a highly aggressive disease, ranking among the 10 most common cancers in the world. Oesophageal cancer patients often suffer from multi-origin tumours, and therefore, it is important to improve our understanding of the complex biology, which underpins microenvironmental interactions in this disease. Extensive evidence indicates that the interaction of tumours with their microenvironment may play a crucial role in tumour initiation and progression. In this study, we analysed DNA damage response (DDR), immune cell invasion and cancer progression in 47 patients with oesophageal cancer from three different regions (tumour tissue, tumour-proximal non-malignant tissue and distant non-malignant tissue). Accumulated DDR (positive staining for γH2AX and phospho-ATM) was evident within tumour tissue and significantly increased in non-malignant tissue surrounding the tumour cells although activation of p53 by phosphorylation at serine 15 was observed only in tumour tissue. The level of DDR detected in cancer microenvironment depended largely on the distance from the tumour, as stronger DDR was observed in tumour-proximal areas compared with that in tumour-distant tissue. Induction of DDR in non-malignant tissues correlated with increased invasion of lymphocytes and macrophages and with precancerous progression. Our results support that DDR is induced in oesophageal cancer surrounding non-malignant epithelial cells, via activation of an inflammatory process, which in turn contributes to the progression of precancerous lesions. These findings provide novel pathological evidence for inflammation and DDR in influencing non-metastatic progression of cancer in its microenvironment.

Development of a complex intervention improved randomization and informed consent in a randomized controlled trial.

OBJECTIVE: Multicenter randomized trials are required for pragmatic evaluations of health care interventions, but recruitment is difficult. Systematic reviews failed to identify robust strategies to improve recruitment. We developed and evaluated a complex intervention to increase levels of randomization and informed consent. STUDY DESIGN AND SETTING: The ProtecT (Prostate testing for cancer and Treatment) trial compares radical surgery, radical conformal radiotherapy, and active monitoring for men aged 50-69 years with localized prostate cancer. The intervention was developed using qualitative research methods (content, thematic and conversation analysis). Rates of randomization and immediate acceptance of allocation were measured every 6 months to evaluate the impact of the intervention. RESULTS: The complex intervention comprised reviews of centers falling below study targets, training programmes, documents and individually tailored feedback. Over 65% of eligible participants consented to randomization. Trial participants became increasingly well informed as immediate acceptance of allocation rose from 65% to 81% between 2001 and 2005. CONCLUSION: This complex intervention resulted in high levels of randomization and informed consent in a difficult trial. The generic aspects of the intervention could be applied to other trials to maximize randomization and informed consent, and allow the mounting of trials previously considered too difficult.

Factors distinguishing general practitioners who more readily participated in a large randomized trial were identified.

OBJECTIVE: To investigate factors associated with the successful recruitment of general practices to a randomized controlled trial. STUDY DESIGN AND SETTING: Analysis of accrual of primary care centers to a randomized controlled trial in the UK. RESULTS: Those practices promptly agreeing to take part had better target achievement and a higher proportion of white British residents locally. Participating practices had a mean Quality and Outcomes Framework attainment of 92% of the points available, whereas nonparticipating practices achieved 88% (P=0.009). Participating practices were located in areas with a higher proportion of white British residents (mean 89%), in comparison to nonparticipating practices (mean 84%, P=0.004). Reasons given by practices to explain nonparticipation were primarily related to internal factors, with 38% of practices approached saying that they could not participate for such reasons. CONCLUSION: There are some small differences between participating practices and nonparticipants in achievement of government targets and in the local ethnic mix. The primary reason given by practices for nonparticipation was workload or time pressures, with over a third of practices reporting being prevented by issues relating to practice organization. It may be that practices with workload or organizational difficulties require additional support to participate in research.

Identification of new genetic risk factors for prostate cancer.

There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.

Low risk research using routinely collected identifiable health information without informed consent: encounters with the Patient Information Advisory Group.

Current UK legislation is impacting upon the feasibility and cost-effectiveness of medical record-based research aimed at benefiting the NHS and the public heath. Whereas previous commentators have focused on the Data Protection Act 1998, the Health and Social Care Act 2001 is the key legislation for public health researchers wishing to access medical records without written consent. The Act requires researchers to apply to the Patient Information Advisory Group (PIAG) for permission to access medical records without written permission. We present a case study of the work required to obtain the necessary permissions from PIAG in order to conduct a large scale public health research project. In our experience it took eight months to receive permission to access basic identifying information on individuals registered at general practices, and a decision on whether we could access clinical information in medical records without consent took 18 months. Such delays pose near insurmountable difficulties to grant funded research, and in our case 560,000pound of public and charitable money was spent on research staff while a large part of their work was prohibited until the third year of a three year grant. We conclude by arguing that many of the current problems could be avoided by returning PIAG's responsibilities to research ethics committees, and by allowing "opt-out" consent for many public health research projects.

Lack of noggin expression by cancer cells is a determinant of the osteoblast response in bone metastases.

Prostate and mammary cancer bone metastases can be osteoblastic or osteolytic, but the mechanisms determining these features are unclear. Bone morphogenetic and Wnt proteins are osteoinductive molecules. Their activity is modulated by antagonists such as noggin and dickkopf-1. Differential expression analysis of bone morphogenetic and Wnt protein antagonists in human prostate and mammary cancer cell lines showed that osteolytic cell lines constitutively express in vitro noggin and dickkopf-1 and at least one of the osteolytic cytokines parathyroid hormone-related protein, colony-stimulating factor-1, and interleukin-8. In contrast, osteoinductive cell lines express neither noggin nor dickkopf-1 nor osteolytic cytokines in vitro. The noggin differential expression profile observed in vitro was confirmed in vivo in prostate cancer cell lines xenografted into bone and in clinical samples of bone metastasis. Forced noggin expression in an osteoinductive prostate cancer cell line abolished the osteoblast response induced in vivo by its intraosseous xenografts. Basal bone resorption and tumor growth kinetics were marginally affected. Lack of noggin and possibly dickkopf-1 expression by cancer cells may be a relevant mechanism contributing to the osteoblast response in bone metastases. Concomitant lack of osteolytic cytokines may be permissive of this effect. Noggin is a candidate drug for the adjuvant therapy of bone metastasis.

The prostate cancer prevention trial and its messages.

Do height-related variations in insulin-like growth factors underlie the associations of stature with adult chronic disease?

Tall people, particularly those with long legs, have an increased risk of developing cancer but a reduced risk of cardiovascular disease and type II diabetes. We examined associations of stature and body mass index with IGF-I, IGF-II, and IGF binding protein (IGFBP)-2 and IGFBP-3 in 274 men aged 50-70 yr to investigate whether variations in growth factor levels underlie associations of anthropometry with a number of adult diseases. Height and leg and trunk length were not strongly associated with circulating levels of IGF-I, IGF-II, or IGFBP-3. The molar ratio of IGF-I/IGFBP-3 increased with increases in the leg/trunk length ratio (P = 0.06). IGFBP-2 was positively associated with leg length and inversely associated with trunk length. Mean levels of IGFBP-2 (in nanograms per milliliter) across quartiles of increasing leg length were 504.4 493.6, 528.7, and 578.8 (P(trend) = 0.06), and for trunk length were 615.2, 507.2, 498.6, 488.5 (P(trend) < 0.01), suggesting that variations in IGFBP-2, or a factor influencing its levels in the circulation, may contribute to biological mechanisms underlying height-disease associations. We conclude that whereas growth-influencing exposures during childhood, which may operate through effects on IGF-I levels, have long-term influences on disease risk, they do not necessarily program IGF-I levels throughout life. The associations of anthropometry with IGFBP-2 merit additional investigation.

Genetic instability and transitional cell carcinoma of the bladder.

The development of cancer occurs in a stepwise fashion, with each step representing the mutation in one of several key genes. However, the mutation rate of somatic cells is too low to account for the number of mutations required for a cell to undergo carcinogenesis. Thus, the development of genetic instability is a vital early step towards carcinogenesis. We review the evidence for genetic instability, with particular reference to transitional cell carcinoma of the bladder. Both microsatellite instability and chromosomal instability are present in this tumour, and we discuss their incidence and clinical implications.

Serum insulin-like growth factor-I is positively associated with serum prostate-specific antigen in middle-aged men without evidence of prostate cancer.

We have examined the relationship between serum insulin-like growth factor-I (IGF-I) and prostate-specific antigen in 367 healthy men without evidence of prostate cancer and found a positive association (P = 0.05). In men without prostate cancer, serum prostate-specific antigen is closely related to prostate size, and our findings, therefore, suggest that IGF-I may induce prostatic epithelial proliferation. Higher circulating levels of IGF-I have been associated with increased risk of both prostate cancer and possibly benign prostatic hyperplasia. Greater rates of cell proliferation induced by IGF-I may be a key biological pathway underlying these disorders.

Screening for prostate cancer remains controversial.

Ethics of clinical trials from bayesian perspective: randomisation to clinical trials may solve dilemma of treatment choice in prostate cancer.

Distinct patterns of microsatellite instability are seen in tumours of the urinary tract.

To date, two forms of microsatellite instability (MSI) have been described in human cancer. MSI typical of hereditary nonpolyposis colon cancer (HNPCC), is due to deficient DNA mismatch repair (MMR) and is defined with mono- and dinucleotide repeat microsatellites. A second variety of instability is best seen at selective tetranucleotide repeats (EMAST; elevated microsatellite alterations at select tetranucleotides). While MSI occurs infrequently in bladder cancers, EMAST is common. Sporadic tumours with the largest proportion showing MSI are those found most frequently in HNPCC kindreds. While bladder cancer is not frequently seen in HNPCC, upper urinary tract tumours (UTTs) are. Having previously found a low frequency of MSI in bladder cancer, we sought to determine the relative levels of MSI and EMAST in transitional cell carcinoma (TCC) of the upper and lower urinary tracts. Microsatellite analysis was performed at 10 mono- and dinucleotide and eight tetranucleotide loci, in 89 bladder and 71 UTT TCC. Contrasting patterns of instability were seen in urinary tumours. In bladder cancer, MSI was rare and EMAST was common. The presence of EMAST was not related to tumour grade, stage, subsequent outcome or immunohistochemical expression of the MMR proteins. In UTT, while MSI occurred frequently, EMAST was seen less frequently than in bladder cancer. When TCC of the upper and lower urinary tracts are compared, MSI-H is more frequent in UTT and EMAST more frequent in bladder cancer. Our findings show that, as for colorectal cancer, the pattern of MSI varies with location in the urinary tract. In addition, we have confirmed that MSI and EMAST are discrete forms of MSI, and that the presence of EMAST does not affect tumour phenotype.