What is the effect of MRI with targeted biopsies on the rate of patients discontinuing active surveillance? A reflection of the use of MRI in the PRIAS study

Background The reduction of overtreatment by active surveillance (AS) is limited in patients with low-risk prostate cancer (PCa) due to high rates of patients switching to radical treatment. MRI improves biopsy accuracy and could therewith affect inclusion in or continuation of AS. We aim to assess the effect of MRI with target biopsies on the total rate of patients discontinuing AS, and in particular discontinuation due to Grade Group (GG) reclassification. Methods Three subpopulations included in the prospective PRIAS study with GG 1 were studied. Group A consists of patients diagnosed before 2009 without MRI before or during AS. Group B consists of patients diagnosed without MRI, but all patients underwent MRI within 6 months after diagnosis. Group C consists of patients who underwent MRI before diagnosis and during follow-up. We used cumulative incidence curves to estimate the rates of discontinuation. Results In Group A (n = 500), the cumulative probability of discontinuing AS at 2 years is 27.5%; GG reclassification solely accounted for 6.9% of the discontinuation. In Group B (n = 351) these numbers are 30.9 and 22.8%, and for Group C (n = 435) 24.2 and 13.4%. The three groups were not randomized, however, baseline characteristics are highly comparable. Conclusions Performing an MRI before starting AS reduces the cumulative probability of discontinuing AS at 2 years. Performing an MRI after already being on AS increases the cumulative probability of discontinuing AS in comparison to not performing an MRI, especially because of an increase in GG reclassification. These results suggest that the use of MRI could lead to more patients being considered unsuitable for AS. Considering the excellent long-term cancer-specific survival of AS before the MRI era, the increased diagnostic accuracy of MRI could potentially lead to more overtreatment if definitions and treatment options of significant PCa are not adapted.Peer reviewe

The measurement of membranous urethral length using transperineal ultrasound prior to radical prostatectomy

Objective: To compare preoperative membranous urethral length (MUL) measurements using magnetic resonance imaging (MRI) with two-dimensional transperineal ultrasound imaging (TPUS) in two supine positions on two separate days in men prior to radical prostatectomy. Materials and methods: MUL was prospectively measured in 18 male volunteers using MRI and on two separate occasions in two different patient positions using TPUS; the patient supine with the knees extended (Supine) and supine with the knees flexed to 70 degrees (Supine KF). Agreement between TPUS and MRI measurements of MUL was assessed using Bland-Altman method comparison techniques and a two-way mixed-effects single measures intraclass correlation (ICC). Test-retest reliability was assessed using a two-way random effects single measures ICC. Results: The mean difference in MUL measurements between MRI and i) TPUS Supine was -0.8 mm (95% limits of agreement (LOA): -3.2, 1.7) and ii) TPUS Supine KF was -0.8mm (95% LOA: -3.5, 1.9). ICC indicated a point estimate of excellent agreement between MRI and TPUS Supine ICC 0.93 (95% CI: 0.76, 0.98) and TPUS Supine KF ICC 0.91 (95 0 /0CI 0.79, 0.97). There was excellent agreement between TPUS Supine and TPUS Supine KF (ICC 0.98, 95% CI: 0.96, 0.99) with a mean difference of 0.3mm (95% LOA: -1.2 to 1.3mm). Conclusions: Preoperative MUL can be reliably measured using TPUS and demonstrates excellent agreement with MRI measurements of MUL. TPUS provides clinicians with an accessible non-invasive alternative to MRI for the measurement of MUL that can be used in outpatient urological settings and for patients where MRI is contraindicated

The effect of TGFβRI inhibition on fibroblast heterogeneity in hypertrophic scar 2D in vitro models.

In burn patients, wound healing is often accompanied by hypertrophic scarring (HTS), resulting in both functional and aesthetic problems. HTSs are characterized by abundant presence of myofibroblasts (MFs) residing in the dermis. HTS development and MF persistence is primarily regulated by TGF-β signalling. A promising method to target the transforming growth factor receptor I (TGFβRI; also known as activin-like kinase 5 (ALK5)) is by making use of exon skipping through antisense oligonucleotides. In HTS the distinguishing border between the papillary dermis and the reticular dermis is completely abrogated, thus exhibiting a one layered dermis containing a heterogenous fibroblast population, consisting of papillary fibroblasts (PFs), reticular fibroblasts (RFs) and MFs. It has been proposed that PFs, as opposed to RFs, exhibit anti-fibrotic properties. Currently, it is still unclear which fibroblast subtype is most affected by exon skipping treatment. Therefore, the aim of this study was to investigate the effect of TGFβRI inhibition by exon skipping in PF, RF and HTS fibroblast monocultures. Morphological analyses revealed the presence of a PF-like population after exon skipping in the different fibroblast cultures. This observation was further confirmed by the expression of genes specific for PFs, demonstrated by qPCR analyses. Further investigations on mRNA and protein level revealed that indeed MFs and to a lesser extent RFs are targeted by exon skipping. Furthermore, collagen gel contraction analysis showed that ALK5 exon skipping reduced TGF-β- induced contraction together with decreased alpha-smooth muscle actin expression levels. In conclusion, we show for the first time that exon skipping primarily targets pro-fibrotic fibroblasts. This could be a promising step towards reduced HTS development of burn tissue

A Multivariable Approach Using Magnetic Resonance Imaging to Avoid a Protocol-based Prostate Biopsy in Men on Active Surveillance for Prostate Cancer-Data from the International Multicenter Prospective PRIAS Study

Publisher Copyright: Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.BACKGROUND: There is ongoing discussion whether a multivariable approach including magnetic resonance imaging (MRI) can safely prevent unnecessary protocol-advised repeat biopsy during active surveillance (AS). OBJECTIVE: To determine predictors for grade group (GG) reclassification in patients undergoing an MRI-informed prostate biopsy (MRI-Bx) during AS and to evaluate whether a confirmatory biopsy can be omitted in patients diagnosed with upfront MRI. DESIGN, SETTING, AND PARTICIPANTS: The Prostate cancer Research International: Active Surveillance (PRIAS) study is a multicenter prospective study of patients on AS (www.prias-project.org). We selected all patients undergoing MRI-Bx (targeted ± systematic biopsy) during AS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A time-dependent Cox regression analysis was used to determine the predictors of GG progression/reclassification in patients undergoing MRI-Bx. A sensitivity analysis and a multivariable logistic regression analysis were also performed. RESULTS AND LIMITATIONS: A total of 1185 patients underwent 1488 MRI-Bx sessions. The time-dependent Cox regression analysis showed that age (per 10 yr, hazard ratio [HR] 0.84 [95% confidence interval {CI} 0.71-0.99]), MRI outcome (Prostate Imaging Reporting and Data System [PIRADS] 3 vs negative HR 2.46 [95% CI 1.56-3.88], PIRADS 4 vs negative HR 3.39 [95% CI 2.28-5.05], and PIRADS 5 vs negative HR 4.95 [95% CI 3.25-7.56]), prostate-specific antigen (PSA) density (per 0.1 ng/ml cm3, HR 1.20 [95% CI 1.12-1.30]), and percentage positive cores on the last systematic biopsy (per 10%, HR 1.16 [95% CI 1.10-1.23]) were significant predictors of GG reclassification. Of the patients with negative MRI and a PSA density of <0.15 ng/ml cm3 (n = 315), 3% were reclassified to GG ≥2 and 0.6% to GG ≥3. At the confirmatory biopsy, reclassification to GG ≥2 and ≥3 was observed in 23% and 7% of the patients diagnosed without upfront MRI and in 19% and 6% of the patients diagnosed with upfront MRI, respectively. The multivariable analysis showed no significant difference in upgrading at the confirmatory biopsy between patients diagnosed with or without upfront MRI. CONCLUSIONS: Age, MRI outcome, PSA density, and percentage positive cores are significant predictors of reclassification at an MRI-informed biopsy. Patients with negative MRI and a PSA density of <0.15 ng/ml cm3 can safely omit a protocol-based prostate biopsy, whereas in other patients, a multivariable approach is advised. Being diagnosed with upfront MRI appears not to significantly affect reclassification risk; hence, a confirmatory MRI-Bx cannot totally be omitted yet. PATIENT SUMMARY: A protocol-based prostate biopsy while on active surveillance can be omitted in patients with negative magnetic resonance imaging (MRI) and prostate-specific antigen density <0.15 ng/ml cm3. A confirmatory biopsy cannot simply be omitted in all patients diagnosed with upfront MRI.Peer reviewe

Deep-Sequencing Analysis Reveals that the miR-199a2/214 Cluster within DNM3os Represents the Vast Majority of Aberrantly Expressed MicroRNAs in Sézary Syndrome

Dermatology-oncolog

Feeding Behaviour, Swimming Activity and Boldness Explain Variation in Feed Intake and Growth of Sole (Solea solea) Reared in Captivity

The major economic constraint for culturing sole (Solea solea) is its slow and variable growth. The objective was to study the relationship between feed intake/efficiency, growth, and (non-) feeding behaviour of sole. Sixteen juveniles with an average (SD) growth of 2.7 (1.9) g/kg0.8/d were selected on their growth during a 4-week period in which they were housed communally with 84 other fish. Selected fish were housed individually during a second 4-week period to measure individual feed intake, growth, and behaviour. Fish were hand-fed three times a day during the dark phase of the day until apparent satiation. During six different days, behaviour was recorded twice daily during 3 minutes by direct observations. Total swimming activity, frequency of burying and of escapes were recorded. At the beginning and end of the growth period, two sequential behavioural tests were performed: “Novel Environment” and “Light Avoidance”. Fish housed individually still exhibited pronounced variation in feed intake (CV = 23%), growth (CV = 25%) and behavior (CV = 100%). Differences in feed intake account for 79% of the observed individual differences in growth of sole. Fish with higher variation in feed intake between days and between meals within days had significantly a lower total feed intake (r = −0.65 and r = −0.77) and growth. Active fish showed significantly higher feed intake (r = 0.66) and growth (r = 0.58). Boldness during both challenge tests was related to fast growth: (1) fish which reacted with a lower latency time to swim in a novel environment had significantly higher feed intake (r = −0.55) and growth (r = −0.66); (2) fish escaping during the light avoidance test tended to show higher feed intake (P<0.1) and had higher growth (P<0.05). In conclusion, feeding consistency, swimming activity in the tank, and boldness during behavioral tests are related to feed intake and growth of sole in captivity

Effectiveness of Cardiovascular Evaluations and Interventions on Fall Risk: A Scoping Review

Objective: cardiovascular abnormalities are consistently associated with fall risk in older people. However, little research has been done to assess the effect of cardiovascular interventions on fall risk. The aim of this scoping review is to explore the current literature on the effectiveness of cardiovascular evaluations and interventions in reducing fall risk in older people. Design: scoping review. Data sources: Medline, Cochrane Library, and WHO ICTRP Search Portal were systematically searched. Selection criteria: randomized controlled trials (RCTs) and intervention studies of community-dwelling adults aged ≥50 years or with a mean age of >60 years that assessed the effect of a cardiovascular assessment and interventions in reducing fall risk. Key search concepts were “falls” and “aged”, and terms for different cardiovascular evaluations and interventions were included. The Cochrane Checklist for risk of bias and the ROBINS-I tool were used to assess the quality of the studies. Results: seven studies were included. The majority showed a reduction in falls after cardiovascular evaluation and intervention. Two out of four studies that focused on carotid sinus hypersensitivity (CSH) as a modifiable cardiovascular risk factor for falls, showed a significant reduction in falls after pacemaker implantation. Two studies that looked at sinus node dysfunction (SND) both showed a significant reduction in falls after pacemaker implantation. One study showed that 33% of the patients experienced a fall after cardiovascular evaluation and intervention, whereas all patients fell before assessment. Conclusions: the majority of the included studies showed a reduction in falls after the intervention. However, the number of published papers regarding the effect of cardiovascular assessment and interventions on falls is small. A standardized assessment of cardiovascular risk factors may be essential in preventing falls in older adults and could consequently reduce injuries, loss of quality of life, deaths, and fall-related expenditures