Selection of microsatellite markers for bladder cancer diagnosis without the need for corresponding blood

Microsatellite markers are used for loss-of-heterozygosity, allelic imbalance and clonality analyses in cancers. Usually, tumor DNA is compared to corresponding normal DNA. However, normal DNA is not always available and can display aberrant allele ratios due to copy number variations in the genome. Moreover, stutter peaks may complicate the analysis. To use microsatellite markers for diagnosis of recurrent bladder cancer, we aimed to select markers without stutter peaks and a constant ratio between alleles, thereby avoiding the need for a control DNA sample. We investigated 49 microsatellite markers with tri- and tetranucleotide repeats in regions commonly lost in bladder cancer. Based on analysis of 50 blood DNAs the 12 best performing markers were selected with few stutter peaks and a constant ratio between peaks heights. Per marker upper and lower cut off values for allele ratios were determined. LOH of the markers was observed in 59/104 tumor DNAs. We then determined the sensitivity of the marker panel for detection of recurrent bladder cancer by assaying 102 urine samples of these patients. Sensitivity was 63% when patients were stratified for LOH in their primary tumors. We demonstrate that up-front selection of microsatellite markers obliterates the need for a corresponding blood sample. For diagnosis of bladder cancer recurrences in urine this significantly reduces costs. Moreover, this approach facilitates retrospective analysis of archival tumor samples for allelic imbalance

MRI-targeted or standard biopsy for prostate-cancer diagnosis

Background Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography-guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited. Methods In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography-guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12-core, transrectal ultrasonography-guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer. Results A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, -13 percentage points; 95% CI, -19 to -7; P<0.001). Conclusions The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography-guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027 .)

Equivocal pi-rads three lesions on prostate magnetic resonance imaging: Risk stratification strategies to avoid mri-targeted biopsies

We aimed to investigate the relation between largest lesion diameter, prostate-specific antigen density (PSA-D), age, and the detection of clinically significant prostate cancer (csPCa) using first-time targeted biopsy (TBx) in men with Prostate Imaging—Reporting and Data System (PI-RADS) 3 index lesions. A total of 292 men (2013–2019) from two referral centers were included. A multivariable logistic regression analysis was performed. The discrimination and clinical utility of the built model was assessed by the area under the receiver operation curve (AUC) and decision curve analysis, respectively. A higher PSA-D and higher age were significantly related to a higher risk of detecting csPCa, while the largest index lesion diameter was not. The discrimination of the model was 0.80 (95% CI 0.73–0.87). When compared to a biopsy-all strategy, decision curve analysis showed a higher net benefit at threshold probabilities of ≥2%. Accepting a missing ≤5% of csPCa diagnoses, a risk-based approach would result in 34% of TBx sessions and 23% of low-risk PCa diagnoses being avoided. In men with PI-RADS 3 index lesions scheduled for first-time TBx, the balance between the number of TBx sessions, the detection of low-risk PCa, and the detection of csPCa does not warrant a biopsy-all strategy. To minimize the risk of missing the diagnosis of csPCa but acknowledging the need of avoiding unnecessary TBx sessions and overdiagnosis, a risk-based approach is advisable

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Hyper-radiosensitivity affects low-dose acute myeloid leukemia incidence in a mathematical model.

In vitro experiments show that the cells possibly responsible for radiation-induced acute myeloid leukemia (rAML) exhibit low-dose hyper-radiosensitivity (HRS). In these cells, HRS is responsible for excess cell killing at low doses. Besides the endpoint of cell killing, HRS has also been shown to stimulate the low-dose formation of chromosomal aberrations such as deletions. Although HRS has been investigated extensively, little is known about the possible effect of HRS on low-dose cancer risk. In CBA mice, rAML can largely be explained in terms of a radiation-induced Sfpi1 deletion and a point mutation in the remaining Sfpi1 gene copy. The aim of this paper is to present and quantify possible mechanisms through which HRS may influence low-dose rAML incidence in CBA mice. To accomplish this, a mechanistic rAML CBA mouse model was developed to study HRS-dependent AML onset after low-dose photon irradiation. The rAML incidence was computed under the assumptions that target cells: (1) do not exhibit HRS; (2) HRS only stimulates cell killing; or (3) HRS stimulates cell killing and the formation of the Sfpi1 deletion. In absence of HRS (control), the rAML dose-response curve can be approximated with a linear-quadratic function of the absorbed dose. Compared to the control, the assumption that HRS stimulates cell killing lowered the rAML incidence, whereas increased incidence was observed at low doses if HRS additionally stimulates the induction of the Sfpi1 deletion. In conclusion, cellular HRS affects the number of surviving pre-leukemic cells with an Sfpi1 deletion which, depending on the HRS assumption, directly translates to a lower/higher probability of developing rAML. Low-dose HRS may affect cancer risk in general by altering the probability that certain mutations occur/persist

The assessment of the April 2020 chernobyl wildfires and their impact on Cs-137 levels in Belgium and The Netherlands.

In April 2020, several wildfires took place in and around the Chernobyl exclusion zone. These fires reintroduced radioactive particles deposited during the 1986 Chernobyl disaster into the atmosphere, causing concern about a possible radiation hazard. Several countries and several stations of the International Monitoring System measured increased Cs-137 levels. This study presents the analyses made by RIVM and SCK CEN/RMI during the April 2020 wildfires. Furthermore, more in-depth research was performed after the wildfires. A statistical analysis of Cs-137 detections is presented, comparing the April 2020 detections with historical detections. Inverse atmospheric transport modelling is applied to infer the total released Cs-137 during the wildfires. Finally, it is assessed whether the Cs-137 detections in Belgium and the Netherlands can be attributed to the wildfires

Prediction of High-grade Prostate Cancer Following Multiparametric Magnetic Resonance Imaging: Improving the Rotterdam European Randomized Study of Screening for Prostate Cancer Risk Calculators

Background: The Rotterdam European Randomized Study of Screening for Prostate Cancer risk calculators (ERSPC-RCs) help to avoid unnecessary transrectal ultrasound-guided systematic biopsies (TRUS-Bx). Multivariable risk stratification could also avoid unnecessary biopsies following multiparametric magnetic resonance imaging (mpMRI). Objective: To construct MRI-ERSPC-RCs for the prediction of any- and high-grade (Gleason score ≥3 + 4) prostate cancer (PCa) in 12-core TRUS-Bx ± MRI-targeted biopsy (MRI-TBx) by adding Prostate Imaging Reporting and Data System (PI-RADS) and age as parameters to the ERSPC-RC3 (biopsy-naïve men) and ERSPC-RC4 (previously biopsied men). Design, setting, and participants: A total of 961 men received mpMRI and 12-core TRUS-Bx ± MRI-TBx (in case of PI-RADS ≥3) in five institutions. Data of 504 biopsy-naïve and 457 previously biopsied men were used to adjust the ERSPC-RC3 and ERSPC-RC4. Outcome measurements and statistical analysis: Logistic regression models were constructed. The areas under the curve (AUCs) of the original ERSPC-RCs and MRI-ERSPC-RCs (including PI-RADS and age) for any- and high-grade PCa were compared. Decision curve analysis was performed to assess the clinical utility of the MRI-ERSPC-RCs. Results and limitations: MRI-ERSPC-RC3 had a significantly higher AUC for high-grade PCa compared with the ERSPC-RC3: 0.84 (95% confidence interval [CI] 0.81–0.88) versus 0.76 (95% CI 0.71–0.80, p < 0.01). Similarly, MRI-ERSPC-RC4 had a higher AUC for high-grade PCa compared with the ERSPC-RC4: 0.85 (95% CI 0.81–0.89) versus 0.74 (95% CI 0.69–0.79, p < 0.01). Unlike for the MRI-ERSPC-RC3, decision curve analysis showed clear net benefit of the MRI-ERSPC-RC4 at a high-grade PCa risk threshold of ≥5%. Using a ≥10% high-grade PCa risk threshold to biopsy for the MRI-ERSPC-RC4, 36% biopsies are saved, missing low- and high-grade PCa, respectively, in 15% and 4% of men who are not biopsied. Conclusions: We adjusted the ERSPC-RCs for the prediction of any- and high-grade PCa in 12-core TRUS-Bx ± MRI-TBx. Although the ability of the MRI-ERSPC-RC3 for biopsy-naïve men to avoid biopsies remains questionable, application of the MRI-ERSPC-RC4 in previously biopsied men in our cohort would have avoided 36% of biopsies, missing high-grade PCa in 4% of men who would not have received a biopsy. Patient summary: We have constructed magnetic resonance imaging-based Rotterdam European Randomized study of Screening for Prostate Cancer (MRI-ERSPC) risk calculators for prostate cancer prediction in transrectal ultrasound-guided biopsy and MRI-targeted biopsy by incorporating age and Prostate Imaging Reporting and Data System score into the original ERSPC risk calculators. The MRI-ERSPC risk calculator for previously biopsied men could be used to avoid one-third of biopsies following MRI. The magnetic resonance imaging-based Rotterdam European Randomized Study of Screening for Prostate Cancer (MRI-ERSPC) risk calculators include age and Prostate Imaging Reporting and Data System as parameters, and predict (Gleason ≥3 + 4) prostate cancer in transrectal ultrasound-guided systematic biopsy and MRI-targeted biopsy. The MRI-ERSPC risk calculator could help avoid one-third of biopsies following MRI in previously biopsied men

Results of the microsatellite analysis of pre-TUR urine samples.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0043345#s3" target="_blank">Results</a> of the microsatellite analysis of pre-TUR urine samples.</p