Interpreting Overdiagnosis Estimates in Population-based Mammography Screening

Estimates of overdiagnosis in mammography screening range from 1% to 54%. This review explains such variations using gradual implementation of mammography screening in the Netherlands as an example. Breast cancer incidence without screening was predicted with a micro-simulation model. Observed breast cancer incidence (including ductal carcinoma in situ and invasive breast cancer) was modeled and compared with predicted incidence without screening during various phases of screening program implementation. Overdiagnosis was calculated as the difference between the modeled number of breast cancers with and the predicted number of breast cancers without screening. Estimating overdiagnosis annually between 1990 and 2006 illustrated the importance of the time at which overdiagnosis is measured. Overdiagnosis was also calculated using several estimators identified from the literature. The estimated overdiagnosis rate peaked during the implementation phase of screening, at 11.4% of all predicted cancers in women aged 0–100 years in the absence of screening. At steady-state screening, in 2006, this estimate had decreased to 2.8%. When different estimators were used, the overdiagnosis rate in 2006 ranged from 3.6% (screening age or older) to 9.7% (screening age only). The authors concluded that the estimated overdiagnosis rate in 2006 could vary by a factor of 3.5 when different denominators were used. Calculations based on earlier screening program phases may overestimate overdiagnosis by a factor 4. Sufficient follow-up and agreement regarding the chosen estimator are needed to obtain reliable estimates

Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer

The main cause of prostate cancer-related mortality is the development of hormone-refractory disease. Circulating serum levels of IL-6 are raised in hormone-refractory prostate cancer patients and evidence from cell line studies suggests that the IL-6R/JAK/STAT3 pathway may be involved in development of this disease. In the current study we investigate if expression levels of these family members are implicated in the development of hormone-refractory prostate cancer. Immunohistochemistry using IL-6R, JAK1, STAT3, pSTAT3Tyr705 and pSTAT3Ser727 antibodies was performed on 50 matched hormone-sensitive and hormone-refractory tumours pairs. An increase in expression of cytoplasmic IL-6 receptor, with the development of hormone-refractory prostate cancer was associated with reduced time to relapse (P=0.0074) while an increase in expression of cytoplasmic pSTAT3Tyr705 was associated with reduced patient survival (P=0.0003). In addition, those patients with high expression of cytoplasmic pSTAT3Tyr705 in their hormone-refractory tumours had significantly shorter time to death from biochemical relapse and overall survival in comparison to those patients with low expression of cytoplasmic pSTAT3Tyr705 (P=0.002 and P=0.0027, respectively). Activation of STAT3, via phosphorylation is associated with reduced patient survival, suggesting that activation of the IL-6R/JAK/STAT3 pathway is involved with development of hormone-refractory prostate cancer

Novel contrast-enhanced ultrasound imaging in prostate cancer

The purposes of this paper were to present the current status of contrast-enhanced transrectal ultrasound imaging and to discuss the latest achievements and techniques now under preclinical testing. Although grayscale transrectal ultrasound is the standard method for prostate imaging, it lacks accuracy in the detection and localization of prostate cancer. With the introduction of contrast-enhanced ultrasound (CEUS), perfusion imaging of the microvascularization became available. By this, cancer-induced neovascularisation can be visualized with the potential to improve ultrasound imaging for prostate cancer detection and localization significantly. For example, several studies have shown that CEUS-guided biopsies have the same or higher PCa detection rate compared with systematic biopsies with less biopsies needed. This paper describes the current status of CEUS and discusses novel quantification techniques that can improve the accuracy even further. Furthermore, quantification might decrease the user-dependency, opening the door to use in the routine clinical environment. A new generation of targeted microbubbles is now under pre-clinical testing and showed avidly binding to VEGFR-2, a receptor up-regulated in prostate cancer due to angiogenesis. The first publications regarding a targeted microbubble ready for human use will be discussed. Ultrasound-assisted drug delivery gives rise to a whole new set of therapeutic options, also for prostate cancer. A major breakthrough in the future can be expected from the clinical use of targeted microbubbles for drug delivery for prostate cancer diagnosis as well as treatmen

Upregulation of MAPK pathway is associated with survival in castrate-resistant prostate cancer

BACKGROUND: Recent evidence has implicated the MAP kinase (MAPK) pathway with the development of castrate-resistant prostate cancer (CRPC). We have previously reported gene amplification of critical members of this pathway with the development of castrate-resistant disease. In addition, we have shown that rising Raf-1 expression, with the development of CRPC, influences time to biochemical relapse. We therefore sought to further analyse the role of both Raf-1 and its downstream target MAPK in the molecular pathogenesis of CRPC. METHODS: Protein expression of Raf-1 and MAPK, including their activation status, was analysed using immunohistochemistry in a database of 65 paired tumour specimens obtained before and after the development of CRPC and correlated with other members of the pathway. RESULTS: Patients whose nuclear expression of MAPK rose with the development of CRPC had a significantly shorter median time to death following biochemical relapse (1.40 vs 3.00 years, P=0.0255) as well as reduced disease-specific survival when compared with those whose expression fell or remained unchanged (1.16 vs 2.62 years, P=0.0005). Significant correlations were observed between protein expression of Raf-1 and MAPK with the type 1 receptor tyrosine kinases, Her2 and epidermal growth factor receptor, as well as the transcription factor AP-1 in CRPC tumours. CONCLUSION: We conclude that the Her2/Raf-1/MAPK/AP-1 axis may promote the development of CRPC, leading to early relapse, and reduced disease-specific survival. In addition, members of the pathway may act as novel therapeutic and/or diagnostic targets for prostate cancer. British Journal of Cancer (2011) 104, 1920-1928. doi:10.1038/bjc.2011.163 www.bjcancer.com Published online 10 May 2011 (C) 2011 Cancer Research U

Biological versus chronological ovarian age:implications for assisted reproductive technology

<p>Abstract</p> <p>Background</p> <p>Women have been able to delay childbearing since effective contraception became available in the 1960s. However, fertility decreases with increasing maternal age. A slow but steady decrease in fertility is observed in women aged between 30 and 35 years, which is followed by an accelerated decline among women aged over 35 years. A combination of delayed childbearing and reduced fecundity with increasing age has resulted in an increased number and proportion of women of greater than or equal to 35 years of age seeking assisted reproductive technology (ART) treatment.</p> <p>Methods</p> <p>Literature searches supplemented with the authors' knowledge.</p> <p>Results</p> <p>Despite major advances in medical technology, there is currently no ART treatment strategy that can fully compensate for the natural decline in fertility with increasing female age. Although chronological age is the most important predictor of ovarian response to follicle-stimulating hormone, the rate of reproductive ageing and ovarian sensitivity to gonadotrophins varies considerably among individuals. Both environmental and genetic factors contribute to depletion of the ovarian oocyte pool and reduction in oocyte quality. Thus, biological and chronological ovarian age are not always equivalent. Furthermore, biological age is more important than chronological age in predicting the outcome of ART. As older patients present increasingly for ART treatment, it will become more important to critically assess prognosis, counsel appropriately and optimize treatment strategies. Several genetic markers and biomarkers (such as anti-Müllerian hormone and the antral follicle count) are emerging that can identify women with accelerated biological ovarian ageing. Potential strategies for improving ovarian response include the use of luteinizing hormone (LH) and growth hormone (GH). When endogenous LH levels are heavily suppressed by gonadotrophin-releasing hormone analogues, LH supplementation may help to optimize treatment outcomes for women with biologically older ovaries. Exogenous GH may improve oocyte development and counteract the age-related decline of oocyte quality. The effects of GH may be mediated by insulin-like growth factor-I, which works synergistically with follicle-stimulating hormone on granulosa and theca cells.</p> <p>Conclusion</p> <p>Patients with biologically older ovaries may benefit from a tailored approach based on individual patient characteristics. Among the most promising adjuvant therapies for improving ART outcomes in women of advanced reproductive age are the administration of exogenous LH or GH.</p

Neural pattern similarity predicts long-term fear memory

Although certain changes in the brain may reflect fear learning, there are no known markers that indicate whether an aversive experience will develop into fear memory. We examined the moment-to-moment dynamics of human fear learning by applying multi-voxel pattern analysis to single-trial blood oxygen level-dependent magnetic resonance imaging data. We found that the long-term behavioral expression of fear memory could be predicted from neural patterns at the time of learning

Quantifying learning‐dependent changes in the brain: Single trial multivoxel pattern analysis requires slow event related fMRI

Single-trial analysis is particularly useful for assessing cognitive processes that are intrinsically dynamic, such as learning. Studying these processes with fMRI is problematic, as the low signal-to-noise ratio of fMRI requires the averaging over multiple trials, obscuring trial-by-trial changes in neural activation. The superior sensitivity of multivoxel pattern analysis over univariate analyses has opened up new possibilities for single-trial analysis, but this may require different fMRI designs. Here, we measured fMRI and pupil dilation responses during discriminant aversive conditioning, to assess associative learning in a trial-by-trial manner. The impact of design choices was examined by varying trial spacing and trial order in a series of five experiments (total n = 66), while keeping stimulus duration constant (4.5 s). Our outcome measure was the change in similarity between neural response patterns related to two consecutive presentations of the same stimulus (within-stimulus) and between patterns related to pairs of different stimuli (between-stimulus) that shared a specific outcome (electric stimulation vs. no consequence). This trial-by-trial similarity analysis revealed clear single-trial learning curves in conditions with intermediate (8.1–12.6 s) and long (16.5–18.4 s) intervals, with effects being strongest in designs with long intervals and counterbalanced stimulus presentation. No learning curves were observed in designs with shorter intervals (1.6–6.1 s), indicating that rapid event-related designs—at present, the most common designs in fMRI research—are not suited for single-trial pattern analysis. These findings emphasize the importance of deciding on the type of analysis prior to data collection