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Sökning: WFRF:(Aly Markus)

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1.
  • Aly, Markus (författare)
  • Prostate cancer diagnostics - complications and ways to reduce unnecessary biopsies
  • 2014
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Introduction: Prostate cancer is the most common form of cancer among men in Sweden. There has been a rapid increase in the incidence rate of prostate cancer following the introduction of PSA testing and, today, more than 1800 men are diagnosed with the disease annually in Stockholm, Sweden. This increased testing has, however, not led to any significant reduction in the mortality of prostate cancer. There is no official screening programme for prostate cancer in Sweden, however, more than 60% of men above the age of 60 have undergone a PSA test in the last 5 years. What is less known is what proportion of men undergo a prostate biopsy after a PSA test and within what time frame. The majority of men undergoing a prostate biopsy are not diagnosed with a prostate cancer. In a setting where the PSA test had a better specificity these men would not have to undergo a prostate biopsy. To perform a prostate biopsy is not without risks. Serious infectious complications following prostate biopsies have been reported to be increasing in other parts of the world. The serious infectious complication rate in Stockholm, following a prostate biopsy, is not known. Aims: To investigate if genetic markers, SNPs, can be used as a complement to PSA to predict which men with a PSA <10 ng/mL need to undergo prostate biopsies. To explore the prostate biopsy rates and results in Stockholm and to investigate when PSA testing leads to prostate biopsies and to what extent these prostate biopsies cause side effects in terms of severe infections. Material and Methods: In Study I, 8088 men were identified who underwent at least one prostate biopsy in Stockholm between 2005 and 2007. Those alive and younger than 80 years of age, were invited to donate blood and fill out a questionnaire. 2542 men were included in the analysis when restricted to age less than 80, alive at time of invitation, valid PIN, and a PSA <10 ng/mL. In Study II, 860 men aged 50 to 69 years with a PSA of 1-3 ng/mL without a history of prostate cancer or previous prostate biopsies were invited to undergo a prostate biopsy. 172 men were stratified into low-, intermediate- and high-risk groups according to their genetic score and then underwent a prostate biopsy. In Studies I and II, a genetic score, based on the known SNPs associated with a risk of prostate cancer at the time of the study in combination with PSA and other predictive factors, was created and used in a prediction model to enhance specificity in men with a PSA<10 ng/mL and sensitivity in men with a PSA of 1-3 ng/mL. In Study III, men who had undergone at least one prostate biopsy in Stockholm from 2003 to 2012 were included. Biopsies done in 2003 were acknowledged but not included in the analysis. Migration data was used for population analysis. Data from 38 800 biopsies was analysed. Main outcome in the study was time from PSA test to prostate biopsy. In Study IV, prostate biopsies (n=44 047) done from 2003 to 2012 were included and linked by the use of PIN to microbiological data resources to identify blood cultures taken and available biograms. The main variable studied for outcome was year of biopsy. Logistic regression and time to event were used to address associations. The net reclassification index was used to evaluate the predictive performance of the genetic risk score. In all the studies men were linked to several health registers, such as the Swedish Cancer Register, the National Prostate Cancer Register, the Swedish Cause of Death Register, the National Patient Register, and the Total Population Register. Results: In Study I, up to 23% of the prostate biopsies could have been avoided by using a genetic risk score in combination with age, family history, PSA and f/t PSA. The proportion of missed cancers would be between 5.8 and 12% depending on the risk cut-off used. The proportion of aggressive cancers missed would be between 3.3 and 8.3%. In Study II, the proportion of cancers diagnosed in the low-, intermediate- and high-risk groups was 18, 28 and 37 %, respectively (p<0.05). A borderline significant trend was seen between a higher genetic risk score and the risk of an aggressive prostate cancer. In Study III, 58 and 45% of men in aged 50-59 and 60-69 years of age, respectively, with a PSA between 4 and 10 ng/mL underwent a prostate biopsy within one year of the PSA test. For men with a PSA >10 ng/mL the proportion was 67 and 58% respectively. One out of eight men with an advanced prostate cancer had a first known PSA of >4 ng/mL more than 6 months prior to their diagnosis. In Study IV, the proportion of men with a positive blood culture within 30 days of the prostate biopsy in 2003 was 0.38 and 1.14% in 2012. Year of biopsy was highly significant as a risk factor for undergoing a blood culture and was robust both in the simple - and the adjusted analysis. Young age and low PSA values were associated with a risk of undergoing a blood culture. Men with a high Charlson Comorbidity Index had an increased risk of undergoing a blood culture. Bacteria resistant to common prophylactic antibiotics were more frequently found in blood cultures in the later years of the study than in the early years. Conclusion: A genetic risk score can be used to enhance the sensitivity and specificity of PSA in men undergoing an investigation for prostate cancer. By reducing the number of unnecessary biopsies the number of men suffering from severe infectious complications will be reduced as well as the number diagnosed with a low-risk prostate cancer. The proportion of relatively young men not undergoing a prostate biopsy within one year of the PSA test, although their result was pathological, was surprisingly high. One way to solve this problem would be to introduce a structured follow-up after PSA testing.
2.
  • Dadaev, Tokhir, et al. (författare)
  • Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.
  • 2018
  • Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.
3.
  • Gusev, Alexander, et al. (författare)
  • Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation
  • 2016
  • Ingår i: Nature communications. - 2041-1723. ; 7, s. 10979
  • Tidskriftsartikel (refereegranskat)abstract
    • Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
4.
  • Jäderling, Fredrik, et al. (författare)
  • Preoperative staging using magnetic resonance imaging and risk of positive surgical margins after prostate-cancer surgery
  • 2019
  • Ingår i: Prostate Cancer and Prostatic Diseases. - Nature Publishing Group. - 1365-7852. ; 22:3, s. 391-398
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: It is unclear whether preoperative staging using Magnetic Resonance Imaging (MRI) reduces the risk of positive margins in prostate cancer. We aimed to assess the effect on surgical margins and degree of nerve sparing of a pelvic MRI presented at a preoperative MRI conference. Methods: Single institution, observational cohort study including 1037 men that underwent robot assisted radical prostatectomy between October 2013 and June 2015. Of these, 557 underwent a preoperative MRI combined with a preoperative MRI conference and 410 did not. With whole-mount prostate specimen histopathology as gold standard we assessed the ability of MRI in finding the index tumor and the sensitivity and specificity for extra prostatic extension. We calculated relative risks for positive surgical margins and non-nerve sparing procedure, adjusting for preoperative risk factors using stabilized inverse-probability weighting. Results: MRI detected the index tumor in 80% of the cases. Non-organ confined disease (pT3) at histology was present in the MRI and the non-MRI group in 42% and 24%, respectively. Rate of positive surgical margins comparing the MRI and non-MRI groups was 26.7% and 33.7%, respectively, relative risk 0.79 [95% CI 0.65-0.96], weighted relative risk (wRR) 0.69 [95% CI 0.55-0.86]. The wRR of extensive positive surgical margins was 0.45 [95% CI 0.31-0.67]. Undergoing MRI was also associated with an increased risk of being operated with a non-nerve sparing technique (wRR, 1.84 [95% CI 1.11-3.03]). Conclusions: Our study suggests that preoperative prostate MRI in combination with a preoperative MRI conference affects the degree of nerve-sparing surgery and reduces positive surgical margins.
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5.
  • Lophatananon, Artitaya, et al. (författare)
  • Height, selected genetic markers and prostate cancer risk : results from the PRACTICAL consortium.
  • 2017
  • Ingår i: British Journal of Cancer. - 0007-0920 .- 1532-1827. ; 117:5, s. 734-743
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a possible role for its association with the risk of aggressive prostate cancer.METHODS: We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases and 6016 controls and a subset of high grade cases (2480 cases). We explored height, polymorphisms in genes related to growth processes as main effects and their possible interactions.RESULTS: The results suggest that height is associated with high-grade prostate cancer risk. Men with height &gt;180 cm are at a 22% increased risk as compared to men with height &lt;173 cm (OR 1.22, 95% CI 1.01-1.48). Genetic variants in the growth pathway gene showed an association with prostate cancer risk. The aggregate scores of the selected variants identified a significantly increased risk of overall prostate cancer and high-grade prostate cancer by 13% and 15%, respectively, in the highest score group as compared to lowest score group.CONCLUSIONS: There was no evidence of gene-environment interaction between height and the selected candidate SNPs.Our findings suggest a role of height in high-grade prostate cancer. The effect of genetic variants in the genes related to growth is seen in all cases and high-grade prostate cancer. There is no interaction between these two exposures.
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8.
  • Porserud, Andrea, et al. (författare)
  • Objectively measured mobilisation is enhanced by a new behaviour support tool in patients undergoing abdominal cancer surgery
  • 2019
  • Ingår i: European Journal of Surgical Oncology. - 0748-7983. ; 45:10, s. 1847-1853
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: Mobilisation reduces the risk of complications after abdominal surgery. Despite that, patients spend most of their time immobilised during hospital stay. Hence, the aim of this study was to evaluate a tool called the Activity board, which includes behaviour change techniques, regarding effects on mobilisation and postoperative recovery after abdominal cancer surgery.MATERIAL AND METHODS: Patients who were planned for abdominal surgery due to colorectal, ovarian or urinary bladder cancer, and at least three postoperative days at Karolinska University Hospital were included in this non-randomised controlled trial, from January 2017 to May 2018. The patients were allocated to Activity board or standard treatment when they were admitted to hospital. Mobilisation was evaluated objectively with activity monitor the first three postoperative days, and postoperative recovery was assessed continuously during hospital stay.RESULTS: In total, 133 patients, mean (sd) age 68.1 (12.3) years were included. The patients with the Activity board had postoperatively higher levels of mobilisation, compared to standard treatment, as mean value over the first three days, steps, median (min-max) 1057 (3-10433) and 360 (0-6546), respectively (p = 0.001), and for each day separately. Further, the group with the Activity board had a shorter length of stay, 6 (3-13), compared to standard treatment 7 (3-14) (p = 0.027).CONCLUSION: The Activity board is an effective tool to enhance mobilisation after abdominal surgery due to cancer, in hospital settings. Using the Activity board could lead to improved postoperative recovery.
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9.
  • Schumacher, Fredrick R., et al. (författare)
  • Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci
  • 2018
  • Ingår i: Nature Genetics. - NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 50:7, s. 928-936
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P &lt; 5.0 x 10(-8)) with PrCa and one locus significantly associated with early-onset PrCa (&lt;= 55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 x 10(-9); G&gt;C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 x 10(-9); T&gt;G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.
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10.
  • Szulkin, Robert, et al. (författare)
  • Prediction of individual genetic risk to prostate cancer using a polygenic score.
  • 2015
  • Ingår i: The Prostate. - 0270-4137 .- 1097-0045. ; 75:13, s. 1467-74
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction.METHODS: We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls.RESULTS: The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk.CONCLUSIONS: Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.
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