BACKGROUND AND OBJECTIVE:The quality and reporting of prostate magnetic resonance imaging (MRI) are operator dependent, leading to variations in estimates such as positive predictive value across sites. This impacts patient counseling, risk modeling, and risk calculators. This study assessed variation in Prostate Imaging Reporting and Data System (PI-RADS) score classification and subsequent probability of grade group (GG) ≥2 + prostate cancer. METHODS:Data from the Prostate Biopsy Collaborative Group, including multiple sites in North America, Europe, and Asia Pacific, were analyzed. Patients underwent multiparametric MRI (mpMRI) of the prostate followed by prostate biopsy during the years 2010-2023. Only those with MRI-targeted biopsy and PI-RADS score ≥3 were included. The risk of being assigned PI-RADS 4 or 5 and risk of GG ≥2 disease for these scores were estimated using logistic regression. KEY FINDINGS AND LIMITATIONS:The cohort included 7325 biopsies from 7320 unique patients from 13 sites. A two-fold variation in the probability of PI-RADS 4 or 5 assignment across sites persisted even after adjustment for patient risk (heterogeneity p < 0.001 for both). There were significant differences in the absolute risk of GG ≥2 disease for PI-RADS 4 and 5 (heterogeneity p < 0.001 for both), varying between 23% and 68% and between 49% and 87%, respectively. The use of prostate biopsy as a reference standard has limitations but reflects typical usage of mpMRI in clinical practice. CONCLUSIONS AND CLINICAL IMPLICATIONS:The probability of being assigned PI-RADS 4 or 5 and subsequent detection of GG ≥2 disease varies widely between institutions. This impacts counseling, risk stratification, and clinical practice, necessitating better standardization in the performance and interpretation of mpMRI.

BACKGROUND:Frailty is emerging as an important determinant for quality of life (QoL) and emotional health in older patients with cancer, and specifically in long-term prostate cancer survivors, but quantitative studies are lacking. The current study assesses the prevalence of frailty and its association with QoL and emotional health in long-term prostate cancer survivors after radical prostatectomy. PATIENTS AND METHODS:A total of 2,979 prostate cancer survivors from the multicenter German Familial Prostate Cancer cohort completed questionnaires on frailty (Groningen Frailty Indicator [GFI]), QoL (EORTC QoL Questionnaire-Core 30), and emotional health (anxiety/depression symptoms via the Patient Health Questionnaire-4). Modified Poisson regression analysis was used to assess factors associated with frailty. RESULTS:Average patient age was 79.4 years [SD, 6.4 years] and average time since radical prostatectomy was 17.4 years [SD, 3.8 years]. Among the cohort, 33.1% (n=985) of patients were classified as frail (GFI ≥4). Frail patients reported worse emotional health than nonfrail patients (depression symptoms: 24.0% vs 4.0%; anxiety symptoms: 20.6% vs 2.0%; both P<.001) and lower QoL (mean [SD], 53.4 [19.2] vs 72.7 [16.0]); P<.001). Higher age (relative risk [RR], 1.02; 95% CI, 1.01-1.03) and worse depressive (RR, 1.18; 95% CI, 1.12-1.24) and anxiety symptoms (RR, 1.17; 95% CI, 1.11-1.23) were associated with frailty. Living in a partnership (RR, 0.76; 95% CI, 0.67-0.86) and a higher QoL (RR, 0.86 for a 10-point increase; 95% CI, 0.84-0.89) were associated with nonfrailty. CONCLUSIONS:In a large German cohort, every third long-term prostate cancer survivor after radical prostatectomy was frail. The association of frailty with lower QoL and poorer mental health indicates the need for an integrated care approach including further geriatric assessment and possible interventions to improve health outcomes targeted to frail patients.

Background. For patients with complicated type 1 diabetes having, for example, hypoglycemia unawareness and end-stage renal disease because of diabetic nephropathy, combined pancreas and kidney transplantation (PKT) is the therapy of choice. However, the shortage of available grafts and complex impact of risk factors call for individualized, impartial predictions of PKT and pancreas transplantation (PT) outcomes to support physicians in graft acceptance decisions. Methods. Based on a large European cohort with 3060 PKT and PT performed between 2006 and 2021, the 3 primary patient outcomes time to patient mortality, pancreas graft loss, and kidney graft loss were visualized using Kaplan-Meier survival curves. Multivariable Cox proportional hazards models were developed for 5- and 10-y prediction of outcomes based on 26 risk factors. Results. Risk factors associated with increased mortality included previous kidney transplants, rescue allocations, longer waiting times, and simultaneous transplants of other organs. Increased pancreas graft loss was positively associated with higher recipient body mass index and donor age and negatively associated with simultaneous transplants of kidneys and other organs. Donor age was also associated with increased kidney graft losses. The multivariable Cox models reported median C-index values were 63% for patient mortality, 62% for pancreas loss, and 55% for kidney loss. Conclusions. This study provides an online risk tool at https://riskcalc.org/ptop for individual 5- and 10-y post-PKT and PT patient outcomes based on parameters available at the time of graft offer to support critical organ acceptance decisions and encourage external validation in independent populations.

BackgroundErectile dysfunction (ED), premature ejaculation (PE), and low libido (LL) are reported as the most common male sexual dysfunctions.ObjectiveTo evaluate the prevalence of ED, PE, and LL and associations with lifestyle risk factors and comorbidities in middle-aged men.Materials and methodsThis study included a population-based random sample of 2500 50-year-old men who completed validated questionnaires, including the International Index of Erectile Function, the Erection Hardness Score, the Sexual Complaints Screener, and further questionnaires. Multiple logistic regression of outcomes ED, PE, and LL was used to model the association with explanatory factors.ResultsThe prevalence of at least one sexual dysfunction was 30%. 21%, 5.2%, and 7.2% of men had ED, PE, and LL, respectively. The risk of ED increased with PE (odds ratio [OR]: 1.94, 95% confidence interval [95%CI]: 1.22-3.08), LL (OR: 2.04, 95%CI: 1.26-3.29), higher waist circumference (OR: 2.23, 95%CI: 1.67-2.96), and lower urinary tract symptoms (LUTS) (OR: 1.88, 95%CI: 1.39-2.55), partnership was associated with a lower risk (OR: 0.57, 95%CI: 0.39-0.85). The risk of PE increased with ED (OR: 1.94, 95%CI: 1.23-3.07), partnership (OR:5.42, 95%CI: 1.30-22.60), depression (OR: 2.37, 95%CI: 1.09-5.14), and LUTS (OR: 2.42, 95%CI: 1.52-3.87), and decreased with physical activity (OR: 0.44, 95%CI: 0.21-0.93). The risk of LL increased with ED (OR: 2.09, 95%CI: 1.31-3.34) and poorer self-rated health (OR: 2.97, 95%CI: 1.54-5.71).Discussion and conclusionsRoughly one in three 50-year-old men experience some form of sexual dysfunction and risk factors identified in this study underline the multifactorial nature of ED, PE, and LL. Many risk factors are modifiable which underlines the role of patient education. Modifiable risk factors should be addressed in patient education and men should take active measures to remove the risk posed by these factors.

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You have accessJournal of UrologyCME1 Apr 2023MP67-13 RELATIONSHIP BETWEEN FRAILTY AND MENTAL HEALTH AND QUALITY OF LIFE IN LONG-TERM PROSTATE CANCER SURVIVORS AFTER RADICAL PROSTATECTOMY Kathleen Herkommer, Valentin Meissner, Lukas Lunger, Kolja Imhof, Matthias Jahnen, Donna Ankerst, Andreas Dinkel, Stefan Schiele, and Juergen Gschwend Kathleen HerkommerKathleen Herkommer More articles by this author , Valentin MeissnerValentin Meissner More articles by this author , Lukas LungerLukas Lunger More articles by this author , Kolja ImhofKolja Imhof More articles by this author , Matthias JahnenMatthias Jahnen More articles by this author , Donna AnkerstDonna Ankerst More articles by this author , Andreas DinkelAndreas Dinkel More articles by this author , Stefan SchieleStefan Schiele More articles by this author , and Juergen GschwendJuergen Gschwend More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003330.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Aging-related deficits that eventually manifest as frailty are emerging as an important determinant for mental health and quality of life in older patients with cancer. The objective of the current study was (I) to assess the prevalence of frailty and (II) to elucidate the relationship between frailty and mental health as well as quality of life in long-term prostate cancer survivors after radical prostatectomy. METHODS: 2979 prostate cancer survivors from the multicenter German Familial Prostate Cancer Database were included. Patients completed standardized patient-reported outcome measures on the outcomes of interest frailty (Groningen Frailty indicator), quality of life (EORTC QLQ-C30), and anxiety/depressive symptoms (PHQ-4). Additionally, sociodemographic and clinicopathological factors as well as cancer-related self-perception were assessed. Chi square tests were used to detect differences of selected variables in frail and non-frail patients. RESULTS: The patients’ mean age was 79 years (SD=6.4) and mean time since radical prostatectomy was 18 years (SD=3.7). 33% (985/2979) of the patients were classified as frail. Regarding mental health and quality of life, frail patients reported more often depressive (24% vs. 4.0%; p<0.01) and anxiety (21% vs. 2.0%; p<0.01) symptoms and lower quality of life (mean quality of life score of 50 out of 100 vs. 70 out of 100; p<0.01) compared to non-frail patients. Frail patients were older (81 vs. 79 years; p<0.01), less often partnered (80% vs. 90%; p<0.01), and less often satisfied with their economic situation 96% vs. 99%; p<0.01) compared to non-frail patients. Frail patients had more often a secondary cancer (16% vs 12%; p<0.01), biochemical recurrence since radical prostatectomy (41% vs. 34%; p<0.01), and were more often under current prostate cancer therapy (15% vs. 8.0%; p<0.01). Cancer-related self-perception showed significant differences between frail and non-frail patients (p<0.01). For instance, frail patients perceived themselves more often as “victim” (3.0% vs. 1.4%), whereas non-frail patients favored the term “cancer conqueror” (10% vs. 7.4%). CONCLUSIONS: Prevalence of frailty is high in elderly long-term prostate cancer survivors. The association with poorer mental health and lower quality of life indicates the need for an integrated care approach including further geriatric assessment and possible interventions to improve health outcomes of these patients. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e948 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kathleen Herkommer More articles by this author Valentin Meissner More articles by this author Lukas Lunger More articles by this author Kolja Imhof More articles by this author Matthias Jahnen More articles by this author Donna Ankerst More articles by this author Andreas Dinkel More articles by this author Stefan Schiele More articles by this author Juergen Gschwend More articles by this author Expand All Advertisement PDF downloadLoading ...

Supplemental Table 1: Comparison of epidemiological risk factors in Barrett patients (n= 587) and population controls (n= 587) matched by gender and age

Purpose:We sought to determine whether clinical risk factors and morphometric features on preoperative imaging can be utilized to identify those patients with cT1 tumors who are at higher risk of upstaging (pT3a).Materials and Methods:We performed a retrospective international case-control study of consecutive patients treated surgically with radical or partial nephrectomy for nonmetastatic renal cell carcinoma (cT1 N0) conducted between January 2010 and December 2018. Multivariable logistic regression models were used to study associations of preoperative risk factors on pT3a pathological upstaging among all patients, as well as subsets with those with preoperative tumors <= 4 cm, renal nephrometry scores, tumors <= 4 cm with nephrometry scores, and clear cell histology. We also examined association with pT3a subsets (renal vein, sinus fat, perinephric fat).Results:Among the 4,092 partial nephrectomy and 2,056 radical nephrectomy patients, pathological upstaging occurred in 4.9% and 23.3%, respectively. Among each group independent factors associated with pT3a upstaging were increasing preoperative tumor size, increasing age, and the presence of diabetes. Specifically, among partial nephrectomy subjects diabetes (OR=1.65; 95% CI 1.17, 2.29), male sex (OR=1.62; 95% CI 1.14, 2.33), and increasing BMI (OR=1.03; 95% CI 1.00, 1.05 per 1 unit BMI) were statistically associated with upstaging. Subset analyses identified hilar tumors as more likely to be upstaged (partial nephrectomy OR=1.91; 95% CI 1.12, 3.16; radical nephrectomy OR=2.16; 95% CI 1.44, 3.25).Conclusions:Diabetes and higher BMI were associated with pathological upstaging, as were preoperative tumor size, increased age, and male sex. Similarly, hilar tumors were frequently upstaged.

Objectives To investigate prevalence, course, and predictors of longitudinal decision regret in long‐term prostate cancer (PCa) survivors treated by radical prostatectomy (RP). Patients and Methods A total of 1003 PCa survivors from the multicentre German Familial PCa Database completed questionnaires on average 7 years after RP in 2007 and at follow‐up 13 years later in 2020. Patients completed standardised patient‐reported outcome measures on decision regret, decision‐making, health‐related quality of life, and psychosocial factors. Hierarchical multivariable logistic regression was used to assess predictors of longitudinal decision regret. Results Decision regret increased significantly over time (9.0% after 6.9 years in 2007 and 12% after 19 years in 2020; P = 0.009). Favourable localised PCa (odds ratio [OR] 1.97, 95% confidence interval [CI] 1.05–3.68), decision regret in 2007 (OR 6.38, 95% CI 3.55–11.47), and a higher depression score (OR 1.37, 95% CI 1.03–1.83) were associated with decision regret in 2020. Shared decision‐making (OR 0.55, 95% CI 0.33–0.93) was associated with less decision regret. Conclusion The findings of the present study underline the perseverance of decision regret in long‐term PCa survivors and the definitive need for involving patients in the decision‐making process to mitigate regret over the long term.

Abstract Background Patients with localized prostate cancer (PC) are faced with a wide spectrum of therapeutic options at initial diagnosis. Following radical prostatectomy (RP), PC patients may experience regret regarding their initial choice of treatment, especially when oncological and functional outcomes are poor. Impacts of psychosocial factors on decision regret, especially after long-term follow-up, are not well understood. This study aimed to investigate the prevalence and determinants of decision regret in long-term PC survivors following RP. Methods 3408 PC survivors (mean age 78.8 years, SD = 6.5) from the multicenter German Familial PC Database returned questionnaires after an average of 16.5 (SD = 3.8) years following RP. The outcome of decision regret concerning the initial choice of RP was assessed with one item from the Decision Regret Scale. Health-related quality of life (HRQoL), PC-anxiety, PSA-anxiety, as well as anxiety and depressive symptoms were considered for independent association with decision regret via multivariable logistic regression. Results 10.9% (373/3408) of PC survivors reported decision regret. Organ-confined disease at RP (OR 1.39, 95%CI 1.02–1.91), biochemical recurrence (OR 1.34, 1.00-1.80), low HRQoL (OR 1.69,1.28–2.24), depressive symptoms (OR 2.32, 1.52–3.53), and prevalent PSA anxiety (OR 1.88,1.17–3.01) were significantly associated with increased risk of decision regret. Shared decision-making reduced the odds of decision regret by 40% (OR 0.59, 0.41–0.86). Conclusions PC survivors may experience decision regret even after 16 years following RP. Promoting shared decision-making in light of both established and novel, potentially less invasive treatments at initial diagnosis may help mitigate long-term regret. Awareness regarding patients showing depressive symptoms or PSA anxiety should be encouraged to identify patients at risk of decision regret in need of additional psychological support.

Projections of warmer global temperatures in fast-approaching time horizons warrant planning strategies for reducing impacts on human morbidity and mortality. This study sought to determine whether increases in temperature and other changes in weather indices had an impact on rates of fatal accidents occurring in the popular mountainous regions of Austria, with the purpose of improving prevention and accident-mitigation strategies in the mountains. The study was based on the merging of 3285 fatal outdoor accidents reported by the Austrian Alpine Safety Board for the period 2006 to 2018 with daily meteorological data from 43 nearby climate stations during the same period. Multivariable logistic regression was used to model the odds of one or more fatal accidents per station and day with weather indices as predictors, controlling for weekend effects bringing more visitors to the mountains. Separate prediction models were performed for summer and winter activities, as well as for specific disciplines. Even after adjustment for concomitant effects impacting mountain fatal accidents, the daily weather indices of temperature, relative humidity, global radiation, cloudiness, snow cover and precipitation were statistically significantly associated with fatal-accident risk. In particular, a 1 degrees increase in temperature was associated with a 13% increase in odds of a mountain-biking accident in the summer and an 8% increase in odds of a mountain suicide in the winter. An increase in global radiation by 1 kW h M-2 was associated with an 11% and 28% increase in fatal-accident odds for mountaineering in the summer and touring in the winter, respectively.

BACKGROUND:European kidney donation shortages mandate efficient organ allocation by optimizing the prediction of success for individual recipients. OBJECTIVE:To develop the first European online risk tool for kidney transplant outcomes on the basis of recipient-only and recipient plus donor characteristics. DESIGN, SETTING, AND PARTICIPANTS:We used individual recipient and donor risk factors and three outcomes (death, death with functioning graft [DWFG], and graft loss) for 32 958 transplants within the Eurotransplant kidney allocation system and the Eurotransplant senior program between January 2006 and May 2018 in eight European countries to develop and validate a risk tool. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Cox proportional-hazards models were used to analyze the association of risk factors with overall patient mortality, and proportional subdistribution hazard regression models for their association with graft loss and DWFG. Prediction models were developed with recipient-only and recipient-donor risk factors. Sensitivity analyses based on time-specific area under the receiver operating characteristic curve (AUC) with leave-one-country-out validation were performed and calibration plots were generated. RESULTS AND LIMITATIONS:The 10-yr cumulative incidence rate was 37% for mortality, 12% for DWFG, and 41% for graft loss. In recipient-donor models the leading risk factors for mortality were recipient diabetes (hazard ratio [HR] 10.73), retransplantation (HR 3.08 per transplant), and recipient age (HR 1.08). Effects were similar for DWFG. For graft loss, diabetes (subdistributional HR [SHR] 1.32), increased donor age (SHR 1.02), and prolonged cold ischemia time (SHR 1.02) had increased SHRs. All p values were <0.001. CONCLUSIONS:Previously identified risk factors for outcomes following kidney transplants allow for outcome prediction with 10-yr AUC values of up to 0.81. PATIENT SUMMARY:Using European data, we estimated individual risks to predict the success of kidney transplants and support physicians in decision-making. An online tool is now available (https://riskcalc.org/ktop/) for predicting kidney transplant outcomes both before and after a donor has been identified.

Background We compared six commonly used logistic regression methods for accommodating missing risk factor data from multiple heterogeneous cohorts, in which some cohorts do not collect some risk factors at all, and developed an online risk prediction tool that accommodates missing risk factors from the end-user. Methods Ten North American and European cohorts from the Prostate Biopsy Collaborative Group (PBCG) were used for fitting a risk prediction tool for clinically significant prostate cancer, defined as Gleason grade group ≥ 2 on standard TRUS prostate biopsy. One large European PBCG cohort was withheld for external validation, where calibration-in-the-large (CIL), calibration curves, and area-underneath-the-receiver-operating characteristic curve (AUC) were evaluated. Ten-fold leave-one-cohort-internal validation further validated the optimal missing data approach. Results Among 12,703 biopsies from 10 training cohorts, 3,597 (28%) had clinically significant prostate cancer, compared to 1,757 of 5,540 (32%) in the external validation cohort. In external validation, the available cases method that pooled individual patient data containing all risk factors input by an end-user had best CIL, under-predicting risks as percentages by 2.9% on average, and obtained an AUC of 75.7%. Imputation had the worst CIL (-13.3%). The available cases method was further validated as optimal in internal cross-validation and thus used for development of an online risk tool. For end-users of the risk tool, two risk factors were mandatory: serum prostate-specific antigen (PSA) and age, and ten were optional: digital rectal exam, prostate volume, prior negative biopsy, 5-alpha-reductase-inhibitor use, prior PSA screen, African ancestry, Hispanic ethnicity, first-degree prostate-, breast-, and second-degree prostate-cancer family history. Conclusion Developers of clinical risk prediction tools should optimize use of available data and sources even in the presence of high amounts of missing data and offer options for users with missing risk factors.

Clinical risk prediction models are commonly developed in a post-hoc and passive fashion, capitalizing on convenient data from completed clinical trials or retrospective cohorts. Impacts of the models often end at their publication rather than with the patients. The field of clinical risk prediction is rapidly improving in a progressively more transparent data science era. Based on collective experience over the past decade by the Prostate Biopsy Collaborative Group (PBCG), this paper proposes the following four data science-driven strategies for improving clinical risk prediction to the benefit of clinical practice and research. The first proposed strategy is to actively design prospective data collection, monitoring, analysis and validation of risk tools following the same standards as for clinical trials in order to elevate the quality of training data. The second suggestion is to make risk tools and model formulas available online. User-friendly risk tools will bring quantitative information to patients and their clinicians for improved knowledge-based decision-making. As past experience testifies, online tools expedite independent validation, providing helpful information as to whether the tools are generalizable to new populations. The third proposal is to dynamically update and localize risk tools to adapt to changing demographic and clinical landscapes. The fourth strategy is to accommodate systematic missing data patterns across cohorts in order to maximize the statistical power in model training, as well as to accommodate missing information on the end-user side too, in order to maximize utility for the public.

Abstract Background: Missing risk factors, whether random or not measured at all, across different hospitals and patients provide challenges, both for the developers of online clinical risk tools and the patients trying to use such tools. This paper provides a development and end-user solution to the commonly encountered limitations of clinical risk tool based decision making due to missing information.Methods: Six state-of-the-art logistic regression approaches accommodating missing data were compared using prostate cancer data from ten North American and European cohorts from the Prostate Biopsy Collaborative Group (PBCG). An additional large European PBCG cohort was withheld for external validation, where calibration-in-the-large (CIL), calibration curves, and area-underneath-the-receiver-operating characteristic curve (AUC) were evaluated. Ten-fold leave-one-cohort-internal validation further validated the optimal missing data approach.Results: Among 12,703 biopsies from 10 training cohorts, 3,597 (28%) had clinically significant prostate cancer, compared to 1,757 of 5,540 (32%) in the external validation cohort. In external validation, the available cases method that pooled individual patient data containing all risk factors input by an end-user had best CIL, under-predicting risks as percentages by 2.9% on average, and obtained an AUC of 75.7%. Imputation had the worst CIL (-13.3%). The available cases method was further validated as optimal in internal cross-validation and thus used for development of an online risk tool. For end-users of the risk tool, two risk factors were mandatory: serum prostate-specific antigen (PSA) and age, and ten were optional: digital rectal exam, prostate volume, prior negative biopsy, 5-alpha-reductase-inhibitor use, prior PSA screen, African ancestry, Hispanic ethnicity, first-degree prostate-, breast-, and second-degree prostate-cancer family history.Conclusion: Developers of clinical risk prediction tools should optimize use of available data and sources even in the presence of high amounts of missing data and offer options for users with missing risk factors.

Background:External validation of risk calculators (RCs) is necessary to determine their clinical applicability beyond the setting in which these were developed. Objective:To assess the performance of the Rotterdam Prostate Cancer RC (RPCRC) and the Prostate Biopsy Collaborative Group RC (PBCG-RC). Design setting and participants:We used data from the prospective, population-based STHLM3 screening study, performed in 2012-2015. Participants with prostate-specific antigen ≥3 ng/ml who underwent systematic prostate biopsies were included. Outcome measurements and statistical analysis:Probabilities for clinically significant prostate cancer (csPCa), defined as International Society of Urological Pathology grade ≥2, were calculated for each participant. External validity was assessed by calibration, discrimination, and clinical usefulness for both original and recalibrated models. Results and limitations:Out of 5841 men, 1054 (18%) had csPCa. Distribution of risk predictions differed between RCs; median risks for csPCa using the RPCRC and PBCG-RC were 3.3% (interquartile range [IQR] 2.1-7.1%) and 20% (IQR 15-28%), respectively. The correlation between RC risk estimates on individual level was moderate (Spearman's r = 0.55). Using the RPCRC's recommended risk threshold of ≥4% for finding csPCa, 36% of participants would get concordant biopsy recommendations. At 10% risk cut-off, RCs agreed in 23% of cases. Both RCs showed good discrimination, with areas under the curves for the RPCRC of 0.74 (95% confidence interval [CI] 0.72-0.76) and the PBCG-RC of 0.70 (95% CI 0.68-0.72). Calibration was adequate using the PBCG-RC (calibration slope: 1.13 [95% CI 1.03-1.23]), but the RPCRC underestimated the risk of csPCa (calibration slope: 0.73 [0.68-0.79]). The PBCG-RC showed a net benefit in a decision curve analysis, whereas the RPCRC showed no net benefit at clinically relevant risk threshold levels. Recalibration improved clinical benefit, and differences between RCs decreased. Conclusions:Assessment of calibration is essential to ensure the clinical value of risk prediction tools. The PBCG-RC provided clinical benefit in its current version online. On the contrary, the RPCRC cannot be recommended in this setting. Patient summary:Predicting the probability of finding prostate cancer on biopsy differed between two assessed risk calculators. After recalibration, the agreement of the models improved, and both were shown to be clinically useful.

Background A model was built that characterized effects of individual factors on five-year prostate cancer (PCa) risk in the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial (PLCO) and the Selenium and Vitamin E Cancer Prevention Trial (SELECT). This model was validated in a third San Antonio Biomarkers of Risk (SABOR) screening cohort. Methods A prediction model for 1- to 5-year risk of developing PCa and Gleason > 7 PCa (HG PCa) was built on PLCO and SELECT using the Cox proportional hazards model adjusting for patient baseline characteristics. Random forests and neural networks were compared to Cox proportional hazard survival models, using the trial datasets for model building and the SABOR cohort for model evaluation. The most accurate prediction model is included in an online calculator. Results The respective rates of PCa were 8.9%, 7.2%, and 11.1% in PLCO (n = 31,495), SELECT (n = 35,507), and SABOR (n = 1790) over median follow-up of 11.7, 8.1 and 9.0 years. The Cox model showed higher prostate-specific antigen (PSA), BMI and age, and African American race to be associated with PCa and HGPCa. Five-year risk predictions from the combined SELECT and PLCO model effectively discriminated risk in the SABOR cohort with C-index 0.76 (95% CI [0.72, 0.79]) for PCa, and 0.74 (95% CI [0.65,0.83]) for HGPCa. Conclusions A 1- to 5-year PCa risk prediction model developed from PLCO and SELECT was validated with SABOR and implemented online. This model can individualize and inform shared screening decisions.

Risk factors for natural tree mortality in managed forests, excluding wind and snow induced breakage, fires and thinning, can be difficult to identify due to correlated confounders of long- and short-term weather patterns with tree age. This study quantified the association of annual and long-term 30-year average temperature and precipitation effects on individual tree death across Europe from 2011 to 2020 for European beech, sessile and pedunculate oak, silver birch, black pine, Austrian oak, Scots pine, European hornbeam, and Norway spruce. For each species, logistic regression approaches for predicting annual mortality evaluated the influence of age, exposition and weather effects on individual tree death, while accounting for multi-collinearity of risk factors. For all species except sessile oak, higher 30-year-temperature averages were associated with higher odds of tree mortality. Effect size of other risk factors varied among species, with similar weather associations between Austrian and sessile oak on the one hand, and Scots pine, Norway spruce and pedunculate oak on the other hand. In particular, warmer winters reduced mortality for silver birch, sessile and Austrian oaks, while having the opposite association for the other species. Sessile oak was most robust against drought effects and could serve as an important tree species under climate change scenarios.

Invasive nonfunctioning (NF) pituitary neuroendocrine tumors (PitNETs) are non-resectable neoplasms associated with frequent relapses and significant comorbidities. As the current therapies of NF-PitNETs often fail, new therapeutic targets are needed. The observation that circulating angiopoietin-2 (ANGPT2) is elevated in patients with NF-PitNET and correlates with tumor aggressiveness prompted us to investigate the ANGPT2/TIE2 axis in NF-PitNETs in the GH3 PitNET cell line, primary human NF-PitNET cells, xenografts in zebrafish and mice, and in MENX rats, the only autochthonous NF-PitNET model. We show that PitNET cells express a functional TIE2 receptor and secrete bioactive ANGPT2, which promotes, besides angiogenesis, tumor cell growth in an autocrine and paracrine fashion. ANGPT2 stimulation of TIE2 in tumor cells activates downstream cell proliferation signals, as previously demonstrated in endothelial cells (ECs). Tie2 gene deletion blunts PitNETs growth in xenograft models, and pharmacological inhibition of Angpt2/Tie2 signaling antagonizes PitNETs in primary cell cultures, tumor xenografts in mice, and in MENX rats. Thus, the ANGPT2/TIE2 axis provides an exploitable therapeutic target in NF-PitNETs and possibly in other tumors expressing ANGPT2/TIE2. The ability of tumor cells to coopt angiogenic signals classically viewed as EC-specific expands our view on the microenvironmental cues that are essential for tumor progression.