Predicting prostate cancer : on the use of biomarkers in prostate cancer diagnostics

Aims The aims of this thesis work were to answer the following questions. Paper I: How prevalent is testing and retesting with prostate-specific antigen (PSA)?; Paper II: Is a genetic score based on single-nucleotide polymorphisms (SNPs) informative regarding the risk of prostate cancer (PCa) in men with low PSA?; Paper III: Are the commercially available tests Prostate Health Index (PHI) and the four-kallikrein panel comparable in aiding biopsy decisions?; Paper IV: Do commonly used medications affect PSA and the risk of PCa? Methods In Paper I and Paper IV, the population-based PSA cohort STHLM0 was used together with registry-based data. Paper I described limited-duration point prevalence of testing and survival analysis describing retesting with PSA. Paper IV determined differences in PCa risk and PSA level among men using aspirin, statin, metformin or no medication. Paper II included 172 men with PSA at 1‒3ng/ml. Participants were invited according to their genetic score and underwent prostate biopsy. Risk of prostate cancer was assessed using logistic regression. Paper III included 531 men who had undergone a first prostate biopsy. Predictive models were compared using receiver-operating characteristics (ROC/AUC) and calculation of biopsies that could be avoided. Results Paper I: During a 9-year study period, 46%, 68%, and 77% of men without previous PCa and aged 50–59 years, 60–69 years, and 70–79 years, respectively, had a PSA test. The probability of retesting with PSA was PSA- and age-dependent, with a 26-month cumulative incidence of 0.34 if the first PSA value was < 1 ng/ml. Paper II: PCa was diagnosed in 47 of 172 men with PSA levels of 1‒3ng/ml (27%), with Gleason sum of ≥ 7 in 10 of them (5.8%). There was an increase in the odds ratio of 1.60 with increasing genetic risk score. The absolute difference in risk of positive biopsy was 19 percentage points, comparing the high and low genetic risk groups (37% vs. 18%). Paper III: The four-kallikrein panel showed AUCs of 69.0 when predicting PCa of any grade and 71.8 when predicting high-grade cancer (Gleason score ≥ 7). Similar values were found for PHI (70.4 and 71.1, respectively). Both models had higher AUCs than a base model with PSA value and age. Using a 10% predicted risk of high-grade PCa by the four-kallikrein panel or PHI = 39 as cutoff for biopsy saved 29% of the biopsies performed, at a cost of delayed diagnosis for 10% of the men with highgrade cancer. Paper IV: There were no significant associations between aspirin or any antidiabetic medication and the risk of PCa. Men using any statin had an increased risk of both high-grade PCa and PCa overall (OR = 1.25; OR = 1.16). Compared to men without the medication, the level of the first PSA was lower in men using aspirin, statin, metformin, or insulin. Conclusions Although screening for PCa is not recommended in Sweden, PSA testing in Stockholm County was high in men aged over 50 years. A risk score based on SNPs predicts biopsy outcome in previously unbiopsied men with PSA levels of 1–3 ng/ml. Furthermore, we found that two blood tests, the PHI and the four-kallikrein panel, performed similarly in predicting prostate biopsy outcome. Introduction of such risk stratification tools could increase the proportion of men being classified in line with their true risk of PCa. We found no protective effect of aspirin, statins, or antidiabetics in terms of overall risk of prostate cancer or high-grade cancer

Структура и стабильность бессвинцового сплава Zn-10 мас. % Sn, полученного сверхбыстрым затвердеванием

Материалы XIII Междунар. науч.-техн. конф. (науч. чтения, посвящ. 125-летию со дня рождения П. О. Сухого), Гомель, 22 окт. 2020 г

Prostate Age Gap: An MRI Surrogate Marker of Aging for Prostate Cancer Detection

Background Aging is the most important risk factor for prostate cancer (PC). Imaging techniques can be useful to measure age-related changes associated with the transition to diverse pathological states. However, biomarkers of aging from prostate magnetic resonance imaging (MRI) remain to be explored. Purpose To develop an aging biomarker from prostate MRI and to examine its relationship with clinically significant PC (csPC, Gleason score ≥7) risk occurrence. Study Type Retrospective. Population Four hundred and sixty-eight (65.97 ± 6.91 years) biopsied males, contributing 7243 prostate MRI slices. A deep learning (DL) model was trained on 3223 MRI slices from 81 low-grade PC (Gleason score ≤6) and 131 negative patients, defined as non-csPC. The model was tested on 90 negative, 52 low-grade (142 non-csPC), and 114 csPC patients. Field Strength/Sequence 3-T, axial T2-weighted spin sequence. Assessment Chronological age was defined as the age of the participant at the time of the visit. Prostate-specific antigen (PSA), prostate volume, Gleason, and Prostate Imaging-Reporting and Data System (PI-RADS) scores were also obtained. Manually annotated prostate masks were used to crop the MRI slices, and a DL model was trained with those from non-csPC patients to estimate the age of the patients. Following, we obtained the prostate age gap (PAG) on previously unseen csPC and non-csPC cropped MRI exams. PAG was defined as the estimated model age minus the patient's age. Finally, the relationship between PAG and csPC risk occurrence was assessed through an adjusted multivariate logistic regression by PSA levels, age, prostate volume, and PI-RADS ≥ 3 score. Statistical Tests T-test, Mann–Whitney U test, permutation test, receiver operating characteristics (ROC), area under the curve (AUC), and odds ratio (OR). A P value <0.05 was considered statistically significant. Results After adjusting, there was a significant difference in the odds of csPC (OR = 3.78, 95% confidence interval [CI]: 2.32–6.16). Further, PAG showed a significantly larger bootstrapped AUC to discriminate between csPC and non-csPC than that of adjusted PI-RADS ≥ 3 (AUC = 0.981, 95% CI: 0.975–0.987).publishedVersio

Leveraging multi-view data without annotations for prostate MRI segmentation: A contrastive approach

An accurate prostate delineation and volume characterization can support the clinical assessment of prostate cancer. A large amount of automatic prostate segmentation tools consider exclusively the axial MRI direction in spite of the availability as per acquisition protocols of multi-view data. Further, when multi-view data is exploited, manual annotations and availability at test time for all the views is commonly assumed. In this work, we explore a contrastive approach at training time to leverage multi-view data without annotations and provide flexibility at deployment time in the event of missing views. We propose a triplet encoder and single decoder network based on U-Net, tU-Net (triplet U-Net). Our proposed architecture is able to exploit non-annotated sagittal and coronal views via contrastive learning to improve the segmentation from a volumetric perspective. For that purpose, we introduce the concept of inter-view similarity in the latent space. To guide the training, we combine a dice score loss calculated with respect to the axial view and its manual annotations together with a multi-view contrastive loss. tU-Net shows statistical improvement in dice score coefficient (DSC) with respect to only axial view (91.25+-0.52% compared to 86.40+-1.50%,P<.001). Sensitivity analysis reveals the volumetric positive impact of the contrastive loss when paired with tU-Net (2.85+-1.34% compared to 3.81+-1.88%,P<.001). Further, our approach shows good external volumetric generalization in an in-house dataset when tested with multi-view data (2.76+-1.89% compared to 3.92+-3.31%,P=.002), showing the feasibility of exploiting non-annotated multi-view data through contrastive learning whilst providing flexibility at deployment in the event of missing views.Comment: Under revie

SPRIT: Identifying horizontal gene transfer in rooted phylogenetic trees

<p>Abstract</p> <p>Background</p> <p>Phylogenetic trees based on sequences from a set of taxa can be incongruent due to horizontal gene transfer (HGT). By identifying the HGT events, we can reconcile the gene trees and derive a taxon tree that adequately represents the species' evolutionary history. One HGT can be represented by a rooted Subtree Prune and Regraft (<smcaps>R</smcaps>SPR) operation and the number of <smcaps>R</smcaps>SPRs separating two trees corresponds to the minimum number of HGT events. Identifying the minimum number of <smcaps>R</smcaps>SPRs separating two trees is NP-hard, but the problem can be reduced to fixed parameter tractable. A number of heuristic and two exact approaches to identifying the minimum number of <smcaps>R</smcaps>SPRs have been proposed. This is the first implementation delivering an exact solution as well as the intermediate trees connecting the input trees.</p> <p>Results</p> <p>We present the SPR Identification Tool (SPRIT), a novel algorithm that solves the fixed parameter tractable minimum <smcaps>R</smcaps>SPR problem and its GPL licensed Java implementation. The algorithm can be used in two ways, exhaustive search that guarantees the minimum <smcaps>R</smcaps>SPR distance and a heuristic approach that guarantees finding a solution, but not necessarily the minimum one. We benchmarked SPRIT against other software in two different settings, small to medium sized trees i.e. five to one hundred taxa and large trees i.e. thousands of taxa. In the small to medium tree size setting with random artificial incongruence, SPRIT's heuristic mode outperforms the other software by always delivering a solution with a low overestimation of the <smcaps>R</smcaps>SPR distance. In the large tree setting SPRIT compares well to the alternatives when benchmarked on finding a minimum solution within a reasonable time. SPRIT presents both the minimum <smcaps>R</smcaps>SPR distance and the intermediate trees.</p> <p>Conclusions</p> <p>When used in exhaustive search mode, SPRIT identifies the minimum number of <smcaps>R</smcaps>SPRs needed to reconcile two incongruent rooted trees. SPRIT also performs quick approximations of the minimum <smcaps>R</smcaps>SPR distance, which are comparable to, and often better than, purely heuristic solutions. Put together, SPRIT is an excellent tool for identification of HGT events and pinpointing which taxa have been involved in HGT.</p

Serum neurofilament light levels are correlated to long-term neurocognitive outcome measures after cardiac arrest

OBJECTIVE: To explore associations between four methods assessing long-term neurocognitive outcome after out-of-hospital cardiac arrest and early hypoxic-ischemic neuronal brain injury assessed by the biomarker serum neurofilament light (NFL), and to compare the agreement for the outcome methods. METHODS: An explorative post-hoc study was conducted on survivor data from the international Target Temperature Management after Out-of-hospital Cardiac Arrest trial, investigating serum NFL sampled 48/72-hours post-arrest and neurocognitive outcome 6 months post-arrest. RESULTS: Among the long-term surviving participants (N = 457), serum NFL (n = 384) was associated to all outcome instruments, also when controlling for demographic and cardiovascular risk factors. Associations between NFL and the patient-reported Two Simple Questions (TSQ) were however attenuated when adjusting for vitality and mental health. NFL predicted results on the outcome instruments to varying degrees, with an excellent area under the curve for the clinician-report Cerebral Performance Category (CPC 1-2: 0.90). Most participants were classified as CPC 1 (79%). Outcome instrument correlations ranged from small (Mini-Mental State Examination [MMSE]-TSQ) to strong (CPC-MMSE). CONCLUSIONS: The clinician-reported CPC was mostly related to hypoxic-ischemic brain injury, but with a ceiling effect. These results may be useful when selecting methods and instruments for clinical follow-up models

Biochemical Recurrence and Risk of Mortality Following Radiotherapy or Radical Prostatectomy

Importance: Stratifying patients with biochemical recurrence (BCR) after primary treatment for prostate cancer based on the risk of prostate cancer-specific mortality (PCSM) is essential for determining the need for further testing and treatments. Objective: To evaluate the association of BCR after radical prostatectomy or radiotherapy and its current risk stratification with PCSM. Design, Setting, and Participants: This population-based cohort study included a total of 16 311 male patients with 10 364 (64%) undergoing radical prostatectomy and 5947 (36%) undergoing radiotherapy with curative intent (cT1-3, cM0) and PSA follow-up in Stockholm, Sweden, between 2003 and 2019. Follow-up for all patients was until death, emigration, or end of the study (ie, December 31, 2018). Data were analyzed between September 2022 and March 2023. Main Outcomes and Measures: Primary outcomes of the study were the cumulative incidence of BCR and PCSM. Patients with BCR were stratified in low- and high-risk according to European Association of Urology (EAU) criteria. Exposures: Radical prostatectomy or radiotherapy. Results: A total of 16 311 patients were included. Median (IQR) age was 64 (59-68) years in the radical prostatectomy cohort (10 364 patients) and 69 (64-73) years in the radiotherapy cohort (5947 patients). Median (IQR) follow-up for survivors was 88 (55-138) months and 89 (53-134) months, respectively. Following radical prostatectomy, the 15-year cumulative incidences of BCR were 16% (95% CI, 15%-18%) for the 4024 patients in the low D'Amico risk group, 30% (95% CI, 27%-32%) for the 5239 patients in the intermediate D'Amico risk group, and 46% (95% CI, 42%-51%) for 1101 patients in the high D'Amico risk group. Following radiotherapy, the 15-year cumulative incidences of BCR were 18% (95% CI, 15%-21%) for the 1230 patients in the low-risk group, 24% (95% CI, 21%-26%) for the 2355 patients in the intermediate-risk group, and 36% (95% CI, 33%-39%) for the 2362 patients in the high-risk group. The 10-year cumulative incidences of PCSM after radical prostatectomy were 4% (95% CI, 2%-6%) for the 1101 patients who developed low-risk EAU-BCR and 9% (95% CI, 5%-13%) for 649 patients who developed high-risk EAU-BCR. After radiotherapy, the 10-year PCSM cumulative incidences were 24% (95% CI, 19%-29%) for the 591 patients in the low-risk EAU-BCR category and 46% (95% CI, 40%-51%) for the 600 patients in the high-risk EAU-BCR category. Conclusions and Relevance: These findings suggest the validity of EAU-BCR stratification system. However, while the risk of dying from prostate cancer in low-risk EAU-BCR after radical prostatectomy was very low, patients who developed low-risk EAU-BCR after radiotherapy had a nonnegligible risk of prostate cancer mortality. Improving risk stratification of patients with BCR is pivotal to guide salvage treatment decisions, reduce overtreatment, and limit the number of staging tests in the event of PSA elevations after primary treatment.</p

Neuropsychological outcome after cardiac arrest: a prospective case control sub-study of the Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest trial (TTM2)

Background: This study is designed to provide detailed knowledge on cognitive impairment after out-of-hospital cardiac arrest (OHCA) and its relation to associated factors, and to validate the neurocognitive screening of the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest trial (TTM2-trial), assessing effectiveness of targeted temperature management after OHCA. Methods: This longitudinal multi-center clinical study is a sub-study of the TTM2-trial, in which a comprehensive neuropsychological examination is performed in addition to the main TTM2-trial neurocognitive screening. Approximately 7 and 24 months after OHCA, survivors at selected study sites are invited to a standardized assessment, including performance-based tests of cognition and questionnaires of emotional problems, fatigue, executive function and insomnia. At 1:1 ratio, a matched control group from a cohort of acute myocardial infarction (MI) patients is recruited to perform the same assessment. We aim to include 100 patients per group. Potential differences between the OHCA patients and the MI controls at 7 and 24 months will be analyzed with a linear regression, using composite z-scores per cognitive domain (verbal, visual/constructive, working memory, episodic memory, processing speed, executive functions) as primary outcome measures. Results from OHCA survivors on the main TTM2-trial neurocognitive screening battery will be compared with neuropsychological test results at 7 months, using sensitivity and specificity analyses. Discussion: In this study we collect detailed information on cognitive impairment after OHCA and compare this to a control group of patients with acute MI. The validation of the TTM2 neurocognitive screening battery could justify its inclusion in routine follow-up. Our results may have a potential to impact on the design of future follow-up strategies and interventions after OHCA

ZEN-definisjonen – En veileder for ZEN-pilotområder. Versjon 3.0. norsk

Denne tredje utgaven av ZEN-definisjonsveilederen bygger på versjon 1.0 og 2.0 av ZEN-definisjonsveilederne og ZEN-definisjonsrapporter. Denne rapporten presenterer ZEN KPI-verktøyet i mer detalj og gir mer informasjon om ZEN KPI-referanse-, grense-, og målverdier. En stor endring inkluderer å løfte prosess-nøkkelindikatorer ut av stedskvaliteterkategorien og å tilpasse dem til en prosessveileder for design og planlegging av ZEN-områder. Detaljer har blitt supplert for hver nøkkelindikator for å forklare i hvilken grad de bidrar til målsetningen av ZEN samt gir eksempler på beste praksis. Noen nye nøkkelindikatorer har blitt lagt til. Navnet på kategorien stedskvaliteter har blitt endret til byform og arealbruk.This third version of the ZEN definition guideline report builds upon version 1.0 and 2.0 of the ZEN definition guideline reports and series of ZEN definition reports. This report gives further details on the ZEN KPI tool and on ZEN KPI reference, limit, and target values. A major change involves lifting the process KPIs out of spatial qualities and incorporating them into a process guideline for designing ZENs. Details have been added to each KPI to explain to what degree it contributes to the main goal of ZEN, and examples of best practice are given. Additional power KPIs have been added. The spatial qualities category has been renamed to urban form and land use.publishedVersio

Hip and spine bone mineral density are greater in master sprinters, but not endurance runners compared with non-athletic controls

Summary: We examined bone density in older athletes and controls. Sprinters had greater hip and spine bone density than endurance athletes and controls, whereas values were similar in the latter two groups. These results could not be explained by differences in impact, muscle size or power between sprint and endurance athletes. Purpose: We examined the relationship between prolonged participation in regular sprint or endurance running and skeletal health at key clinical sites in older age, and the factors responsible for any associations which we observed. Methods: We recruited 38 master sprint runners (28 males, 10 females, mean age 71 ± 7 years), 149 master endurance runners (111 males, 38 females, mean age 70 ± 6 years) and 59 non-athletic controls (29 males, 30 females, mean age 74 ± 5 years). Dual X-ray absorptiometry was used to assess hip and spine bone mineral density (BMD), body composition (lean and fat mass), whilst jump power was assessed with jumping mechanography. In athletes, vertical impacts were recorded over 7 days from a waist-worn accelerometer, and details of starting age, age-graded performance and training hours were recorded. Results: In ANOVA models adjusted for sex, age, height, body composition, and jump power, sprinter hip BMD was 10 and 14% greater than that of endurance runners and controls respectively. Sprinter spine BMD was also greater than that of both endurance runners and controls. There were no differences in hip or spine BMD between endurance runners and controls. Stepwise regression showed only discipline (sprint/endurance), sex, and age as predictors of athlete spine BMD, whilst these variables and starting age were predictive of hip BMD. Conclusions: Regular running is associated with greater BMD at the fracture-prone hip and spine sites in master sprinters but not endurance runners. These benefits cannot be explained by indicators of mechanical loading measured in this study including vertical impacts, body composition or muscular output