Benefit, Harm, and Cost-effectiveness Associated With Magnetic Resonance Imaging Before Biopsy in Age-based and Risk-stratified Screening for Prostate Cancer

IMPORTTANCE: If magnetic resonance imaging (MRI) mitigates overdiagnosis of prostate cancer while improving the detection of clinically significant cases, including MRI in a screening program for prostate cancer could be considered. OBJECTIVE: To evaluate the benefit-harm profiles and cost-effectiveness associated with MRI before biopsy compared with biopsy-first screening for prostate cancer using age-based and risk-stratified screening strategies. DESIGN, SETTING AND PARTICIPANTS: This decision analytical model used a life-table approach and was conducted between December 2019 and July 2020. A hypothetical cohort of 4.48 million men in England aged 55 to 69 years were analyzed and followed-up to 90 years of age. EXPOSURES: No screening, age-based screening, and risk-stratified screening in the hypothetical cohort. Age-based screening consisted of screening every 4 years with prostate-specific antigen between the ages of 55 and 69 years. Risk-stratified screening used age and polygenic risk profiles. MAIN OUTCOMES AND MEASURES: The benefit-harm profile (deaths from prostate cancer, quality-adjusted life-years, overdiagnosis, and biopsies) and cost-effectiveness (net monetary benefit, from a health care system perspective) were analyzed. Both age-based and risk-stratified screening were evaluated using a biopsy-first and an MRI-first diagnostic pathway. Results were derived from probabilistic analyses and were discounted at 3.5% per annum. RESULTS: The hypothetical cohort included 4.48 million men in England, ranging in age from 55 to 69 years (median, 62 years). Compared with biopsy-first age-based screening, MRI-first age-based screening was associated with 0.9% (1368; 95% uncertainty interval [UI], 1370-1409) fewer deaths from prostate cancer, 14.9% (12 370; 95% UI, 11 100-13 670) fewer overdiagnoses, and 33.8% (650 500; 95% UI, 463 200-907 000) fewer biopsies. At 10-year absolute risk thresholds of 2% and 10%, MRI-first risk-stratified screening was associated with between 10.4% (7335; 95% UI, 6630-8098) and 72.6% (51 250; 95% UI, 46 070-56 890) fewer overdiagnosed cancers, respectively, and between 21.7% fewer MRIs (412 100; 95% UI, 411 400-412 900) and 53.5% fewer biopsies (1 016 000; 95% UI, 1 010 000-1 022 000), respectively, compared with MRI-first age-based screening. The most cost-effective strategies at willingness-to-pay thresholds of £20 000 (US $26 000) and £30 000 (US$39 000) per quality-adjusted life-year gained were MRI-first risk-stratified screening at 10-year absolute risk thresholds of 8.5% and 7.5%, respectively. CONCLUSIONS AND RELEVANCE: In this decision analytical model of a hypothetical cohort, an MRI-first diagnostic pathway was associated with an improvement in the benefit-harm profile and cost-effectiveness of screening for prostate cancer compared with biopsy-first screening. These improvements were greater when using risk-stratified screening based on age and polygenic risk profile and may warrant prospective evaluation

Polygenic risk-tailored screening for prostate cancer: A benefit-harm and cost-effectiveness modelling study.

Background The United States Preventive Services Task Force supports individualised decision-making for prostate-specific antigen (PSA)-based screening in men aged 55-69. Knowing how the potential benefits and harms of screening vary by an individual's risk of developing prostate cancer could inform decision-making about screening at both an individual and population level. This modelling study examined the benefit-harm tradeoffs and the cost-effectiveness of a risk-tailored screening programme compared to age-based and no screening.Methods and findings A life-table model, projecting age-specific prostate cancer incidence and mortality, was developed of a hypothetical cohort of 4.48 million men in England aged 55 to 69 years with follow-up to age 90. Risk thresholds were based on age and polygenic profile. We compared no screening, age-based screening (quadrennial PSA testing from 55 to 69), and risk-tailored screening (men aged 55 to 69 years with a 10-year absolute risk greater than a threshold receive quadrennial PSA testing from the age they reach the risk threshold). The analysis was undertaken from the health service perspective, including direct costs borne by the health system for risk assessment, screening, diagnosis, and treatment. We used probabilistic sensitivity analyses to account for parameter uncertainty and discounted future costs and benefits at 3.5% per year. Our analysis should be considered cautiously in light of limitations related to our model's cohort-based structure and the uncertainty of input parameters in mathematical models. Compared to no screening over 35 years follow-up, age-based screening prevented the most deaths from prostate cancer (39,272, 95% uncertainty interval [UI]: 16,792-59,685) at the expense of 94,831 (95% UI: 84,827-105,630) overdiagnosed cancers. Age-based screening was the least cost-effective strategy studied. The greatest number of quality-adjusted life-years (QALYs) was generated by risk-based screening at a 10-year absolute risk threshold of 4%. At this threshold, risk-based screening led to one-third fewer overdiagnosed cancers (64,384, 95% UI: 57,382-72,050) but averted 6.3% fewer (9,695, 95% UI: 2,853-15,851) deaths from prostate cancer by comparison with age-based screening. Relative to no screening, risk-based screening at a 4% 10-year absolute risk threshold was cost-effective in 48.4% and 57.4% of the simulations at willingness-to-pay thresholds of GBP£20,000 (US$26,000) and £30,000 ($39,386) per QALY, respectively. The cost-effectiveness of risk-tailored screening improved as the threshold rose.Conclusions Based on the results of this modelling study, offering screening to men at higher risk could potentially reduce overdiagnosis and improve the benefit-harm tradeoff and the cost-effectiveness of a prostate cancer screening program. The optimal threshold will depend on societal judgements of the appropriate balance of benefits-harms and cost-effectiveness

Have the changes introduced by the 2004 Higher Education Act made higher education admissions in England wider and fairer?

'Widening participation' and 'fair access' have been contested policy areas in English higher education since at least the early 1990s. They were key facets of the 2003 White Paper - The Future of Higher Education - and the subsequent 2004 Higher Education Act, with stated objectives that the reach of higher education should be wider and fairer. In particular, there has been considerable concern about admissions to 'top universities', which have remained socially as well as academically exclusive. The principal policy tools used by the Act were the introduction of variable tuition fees, expanded student grants, discretionary bursaries and the new Office for Fair Access (OFFA). This paper draws on publicly available statistics to assess whether the changes implemented by the 2004 Act have indeed made access to English higher education wider and fairer in relation to young people progressing from state schools and colleges and from lower socio-economic groups. It concludes that, while there is some evidence for modest improvements, these have been concentrated outside the 'top universities', which have seen slippage relative to the rest of the sector. The paper concludes with a discussion of the reasons why financial inducements appear to be a flawed and naive approach to influencing student demand. © 2011 Taylor & Francis

Expression and subcellular localization of cyclin D1 protein in epithelial ovarian tumour cells

The expression of cyclin D1 protein in tumour sections from 81 patients with epithelial ovarian cancer was analysed using immunohistochemistry. The tumours that overexpressed cyclin D1 in more than 10% of neoplastic cells were considered positive. Thus overexpression of cyclin D1 was observed in 72/81 (89%) of the cases examined. Protein was detected in both the nucleus and the cytoplasm in 24/81 (30%) and localized exclusively in the cytoplasm in 48/81 (59%) of the tumours. Cyclin D1 was overexpressed in both borderline and invasive tumours. There was no association between protein overexpression and tumour stage and differentiation. Furthermore, no correlation between cyclin D1 expression and clinical outcome was observed. However, in tumours overexpressing cyclin D1 (n = 72), the proportion displaying exclusively cytoplasmic localization of protein was higher in those with serous compared with non-serous histology (P = 0.004, odds ratio 4.8, 95% confidence interval 1.4–19.1). Western analysis using a monoclonal antibody to cyclin D1 identified a 36 kDa protein in homogenates from seven tumours displaying cytoplasmic only and one tumour demonstrating both nuclear and cytoplasmic immunostaining. Using restriction fragment length polymorphism polymerase chain reaction and PCR-multiplex analysis, amplification of the cyclin D1 gene (CCNDI) was detected in 1/29 of the tumours demonstrating overexpression of cyclin D1 protein. We conclude that deregulation of CCND1 expression leading to both cytoplasmic and nuclear protein localization is a frequent event in ovarian cancer and occurs mainly in the absence of gene amplification. © 1999 Cancer Research Campaig

Cyclin D1 overexpression is an indicator of poor prognosis in resectable non-small cell lung cancer

Cyclin D1 is one of the G1 cyclins that control cell cycle progression by allowing G1 to S transition. Overexpression of cyclin D1 has been postulated to play an important role in the development of human cancers. We have investigated the correlation between cyclin D1 overexpression and known clinicopathological factors and also its prognostic implication on resected non-small-cell lung cancer (NSCLC) patients. Formalin-fixed and paraffin-embedded tumour tissues resected from 69 NSCLC patients between stages I and IIIa were immunohistochemically examined to detect altered cyclin D1 expression. Twenty-four cases (34.8%) revealed positive immunoreactivity for cyclin D1. Cyclin D1 overexpression is significantly higher in patients with lymph node metastasis (50.0% vs 14.4%, P = 0.002) and with advanced pathological stages (I, 10%; II, 53.8%; IIIa, 41.7%, P = 0.048; stage I vs II, IIIa, P = 0.006). Twenty-four patients with cyclin D1-positive immunoreactivity revealed a significantly shorter overall survival than the patients with negativity (24.0 ± 3.9 months vs 50.1 ± 6.4 months, P = 0.0299). Among 33 patients between stages I and II, nine patients with cyclin D1-positive immunoreactivity had a much shorter overall survival (29.7 ± 6.1 months vs 74.6 ± 8.6 months, P = 0.0066). These results suggest that cyclin D1 overexpression is involved in tumorigenesis of NSCLCs from early stage and could be a predictive molecular marker for poor prognosis in resectable NSCLC patients, which may help us to choose proper therapeutic modalities after resection of the tumor. © 1999 Cancer Research Campaig

Frequent and Efficient Use of the Sister Chromatid for DNA Double-Strand Break Repair during Budding Yeast Meiosis

Studies of DNA double-strand break repair during meiosis reveal that a substantial fraction of recombination occurs between sister chromatids

11q13 amplification status and human papillomavirus in relation to p16 expression defines two distinct etiologies of head and neck tumours

Two distinct etiologies of head and neck squamous cell carcinoma (HNSCC) have been proposed, DNA damage owing to tobacco and alcohol exposure and human papillomavirus (HPV) oncogene-mediated transformation. Common genetic alterations in HNSCC include TP53 mutations, 11q13 amplification (amp) and CDKN2A/p16 mutations or promoter methlyation. However, in HPV+ HNSCC it is frequent to observe wild-type TP53 and expression of p16. The relationship of this unusual pattern with 11q13 amp has not been tested. In a retrospective study on 125 HNSCC patients, only 17% (five out of 30) of HPV+ vs 44% (39 out of 89) of HPV − tumours expressed 11q13 amp (adjusted odds ratio (OR)=0.2, 95% confidence interval (CI)=0.1–0.6). A subpopulation of tumours (n=69) were classified according to the three molecular markers, TP53, p16 and 11q13 amp. In addition to wild-type TP53, and p16 expression, HPV+ tumours were more likely not to be amplified at 11q13 (OR=6.5, 95% CI=1.8–23.9). As HPV+ HNSCC lack the genetic alterations which are common in other tumours, we hypothesise that HPV infection may represent an early event in the HNSCC carcinogenic process, thus suggesting a distinct molecular pathway