Risk of cardiovascular disease following gonadotropin-releasing hormone agonists vs antagonists in prostate cancer: Real-world evidence from five databases.

Observational studies in prostate cancer (PCa) have shown an increased risk of cardiovascular disease (CVD) following gonadotropin-releasing hormone (GnRH) agonists, whereas randomised-controlled trials have shown no associations. Compared to GnRH agonists, GnRH antagonists have shown less atherosclerotic effects in preclinical models. We used real-world data from five countries to investigate CVD risk following GnRH agonists and antagonists in PCa men. Data sources included cancer registries, primary and secondary healthcare databases. CVD event was defined as an incident or fatal CVD. Multivariable Cox proportional hazard models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), which were pooled using random-effects meta-analysis. Stratified analyses were conducted by history of CVD and age (75 years). A total of 48 757 men were on GnRH agonists and 2144 on GnRH antagonists. There was no difference in risk of any CVD for men on GnRH antagonists and agonists (HR: 1.25; 95% CI: 0.96-1.61; I2 : 64%). Men on GnRH antagonists showed increased risk of acute myocardial infarction (HR: 1.62; 95% CI: 1.11-2.35; I2 : 0%) and arrhythmia (HR: 1.55; 95% CI: 1.11-2.15, I2 : 17%) compared to GnRH agonists. Having a history of CVD was found to be an effect modifier for the associations with some CVD subtypes. Overall, we did not observe a difference in risk of overall CVD when comparing GnRH antagonists with agonists-though for some subtypes of CVD we noted an increased risk with antagonists. Further studies are required to address potential confounding caused by unadjusted variables such as severity of CVD history and PCa stage.

Development and external validation of a nomogram to predict lymph node invasion after robot assisted radical prostatectomy.

BACKGROUND: Prediction of lymph node invasion (LNI) after radical prostatectomy has been rarely assessed in robotically assisted laparoscopic radical prostatectomy (RALP) series. We aimed to develop and externally validate a pretreatment nomogram for the prediction of LNI following RALP in patients with high- and intermediate-risk prostate cancer. METHODS: 1654 RALP patients were prospectively collected between 2009 and 2016 from academic and community hospitals. We included patients with intermediate- and high-risk prostate cancer who underwent pelvic lymph node dissection (e-PLND). Logistic regression analysis was applied to construct a nomogram to predict LNI. Centers were randomly assigned to the training cohort (80%) and validation cohort (20%). The discriminative accuracies were evaluated by the areas under the curve and by the calibration plot. The net benefit of the nomogram to predict LNI was assessed by decision curve analysis and a cut-off was proposed. RESULTS: In total, 14% of the patients in our cohort had pN1 disease. Applying logistic regression analysis, the following covariates were chosen to develop the nomogram: initial PSA, clinical T stage, biopsy Gleason sum, and proportion of positive biopsy cores. The nomogram showed a median discriminative accuracy of 73% and excellent calibration. The net benefit of the model ranged between 7% and 51% predicted risk of LNI. A cut-off to perform e-PLND was set at 7%. This would permit a 29% of avoidable e-PLND, missing 9.4% of patients with LNI. CONCLUSIONS: We developed and externally validated a nomogram to predict LNI in patients treated with RALP from a prospective, multi-institutional, nationwide series. A risk of LNI > 7% is proposed as cut-off above which e-PLND is recommended.

Current Management of pT3b Prostate Cancer After Robot-assisted Laparoscopic Prostatectomy.

BACKGROUND: Robot-assisted radical prostatectomy (RALP) in high-risk and locally advanced prostate cancer (PCa) is gaining increasing traction. The optimal use of additional treatments for PCa with seminal vesicle invasion (pT3b) after RALP remains ill explored. OBJECTIVE: To evaluate the management of pT3b PCa after RALP in current clinical practice. DESIGN, SETTING, AND PARTICIPANTS: As part of the prospective Belgian RALP Consortium project (October 2009-March 2016), 796 patients with pT3b disease were evaluated. INTERVENTION: Robot-assisted radical prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Population and perioperative characteristics were described to assess surgical outcome. Multivariable regression analyses were used to identify independent predictors of lymph node invasion (pN1), positive surgical margins (R+), postoperative morbidity, and additional treatments. RESULTS AND LIMITATIONS: In this prospective population-based registry, 85% of patients with clinical high-risk locally advanced PCa received pelvic lymph node dissection (PLND). Early postoperative complications (0-30 d) were observed in 68 patients (8.5%). During oncologic follow-up (median 12 mo), 63% of pN1 patients and 56% of R+ patients received additional therapy. Performing PLND (necessary for assessing pN1 status) was a specific predictor for androgen deprivation therapy only, whereas R+ and younger age were independent predictors for radiotherapy only. Limitations include the nonstandardized policy on additional treatments among hospitals. CONCLUSIONS: In current practice, RALP is performed with acceptable morbidity for PCa with seminal vesicle invasion and the use of postoperative additional treatments is influenced by different patient, tumor, and surgical variables. Despite the recommendations, 15-21% of patients do not receive adequate pelvic lymph node staging and adjuvant therapy is given in 38% of patients. Full and correct staging of the real disease extent remains important in the management of these patients. PATIENT SUMMARY: This study on prostate cancer with seminal vesicle invasion after robot-assisted prostatectomy evaluates the use of additional treatments in current clinical practice. Additional treatments for advanced prostate cancer should be patient-adjusted according to the disease extent.

Development and External Validation of Nomograms To Predict Adverse Pathological Characteristics After Robotic Prostatectomy: Results of a Prospective, Multi-institutional, Nationwide series.

BACKGROUND: The possibility of predicting pathologic features before surgery can support clinicians in selecting the best treatment strategy for their patients. We sought to develop and externally validate pretreatment nomograms for the prediction of pathological features from a prospective multicentre series of robotic-assisted laparoscopic prostatectomy (RALP) procedures. DESIGN, SETTING, AND PARTICIPANTS: Between 2009 and 2016, data from 6823 patients undergoing RALP in 25 academic and community hospitals were prospectively collected by the Belgian Cancer Registry. Logistic regression models were applied to predict extraprostatic extension (EPE; pT3a,b-4), seminal vesicle invasion (SVI; pT3b), and high-grade locally advanced disease (HGLA; pT3b-4 and Gleason score [GS] 8-10) using the following preoperative covariates: prostate-specific antigen, clinical T stage, biopsy GS, and percentage of positive biopsy cores. Internal and external validation was performed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The stability of the model was assessed via tenfold cross-validation using 80% of the cohort. The nomograms were independently externally validated using the test cohort. The discriminative accuracy of the nomograms was quantified as the area under the receiver operating characteristic curve and graphically represented using calibration plots. RESULTS AND LIMITATION: The nomograms predicting EPE, SVI, HGLA showed discriminative accuracy of 77%, 82%, and 88%, respectively. Following external validation, the accuracy remained stable. The prediction models showed excellent calibration properties. CONCLUSIONS: We developed and externally validated multi-institutional nomograms to predict pathologic features after RALP. These nomograms can be implemented in the clinical setting or patient selection in clinical trials. PATIENT SUMMARY: We developed novel nomograms using nationwide data to predict postoperative pathologic features and lethal prostate cancer.

Current trends in patient enrollment for robotic-assisted laparoscopic prostatectomy in Belgium.

BACKGROUND: During the last decade, an inverse stage migration has been observed in radical prostatectomy series at tertiary centers. However, it remains unclear whether similar trends can also be observed in solely robotic practices, including nonreferral centers. The aim of this study was to investigate the clinical and pathological trends in robotic-assisted laparoscopic prostatectomy (RALP) enrollment in Belgium over a period of 6 years through an analysis of a prospective registry. METHODS: A prospective, multicenter database was constructed: consecutive patients undergoing RALP in Belgium from 2010 to 2015 were enrolled, and 7366 men were analyzed. Variations in clinical and pathological variables were explored as a function of the enrollment year with proportional odds for categorical variables and with linear regressions for continuous variables. RESULTS: Net increases were observed in the prostate-specific antigen levels, cT stage, and biopsy Gleason scores across the study years (P < .001). The rate of low-risk prostate cancer (PCa) decreased from 36% in 2010 to 21% in 2015, whereas the rate of intermediate-risk PCa rose from 47% to 58%, and the rate of high-risk PCa rose from 17% to 21%. In parallel, the pT2 stage rate decreased from 76% to 64%, and the rate of Gleason 6 (3 + 3) cases was reduced from 45% to 23% (P < .001). Conversely, the pT3a stage rate rose from 16% to 24%, the pT3b stage rate rose from 7% to 11%, and the rate of Gleason 7 (4 + 3) cases rose from 7% to 21% (P < .0001). Finally, more patients underwent node dissection, and positive lymph nodes were increasingly diagnosed (from 3% in 2010 to 7% in 2015). CONCLUSIONS: During the last 6 years of RALP implementation in Belgium, there was a significant increase in the enrollment of intermediate- and high-risk PCa patients. This yielded a significant increase in adverse pathological characteristics. These results suggest a paradigm shift in PCa treatment, with radical robotic surgery increasing for intermediate- and high-risk patients. Cancer 2017;123:4139-4146. © 2017 American Cancer Society.

Atlantic forest bird communities provide different but not fewer functions after habitat loss.

Habitat loss often reduces the number of species as well as functional diversity. Dramatic effects to species composition have also been shown, but changes to functional composition have so far been poorly documented, partly owing to a lack of appropriate indices. We here develop three new community indices (i.e. functional integrity, community integrity of ecological groups and community specialization) to investigate how habitat loss affects the diversity and composition of functional traits and species. We used data from more than 5000 individuals of 137 bird species captured in 57 sites in the Brazilian Atlantic Forest, a highly endangered biodiversity hotspot.Results indicate that habitat loss leads to a decrease in functional integrity while measures of functional diversity remain unchanged or are even positively affected. Changes to functional integrity were caused by (i) a decrease in the provisioning of some functions, and an increase in others; (ii) strong within-guild species turnover; and (iii) a replacement of specialists by generalists. Hence, communities from more deforested sites seem to provide different but not fewer functions. We show the importance of investigating changes to both diversity and composition of functional traits and species, as the effects of habitat loss on ecosystem functioning may be more complex than previously thought. Crucially, when only functional diversity is assessed, important changes to ecological functions may remain undetected and negative effects of habitat loss underestimated, thereby imperiling the application of effective conservation actions.

Fluctuating asymmetry and environmental stress: understanding the role of trait history.

While fluctuating asymmetry (FA; small, random deviations from perfect symmetry in bilaterally symmetrical traits) is widely regarded as a proxy for environmental and genetic stress effects, empirical associations between FA and stress are often weak or heterogeneous among traits. A conceptually important source of heterogeneity in relationships with FA is variation in the selection history of the trait(s) under study, i.e. traits that experienced a (recent) history of directional change are predicted to be developmentally less stable, potentially through the loss of canalizing modifiers. Here we applied X-ray photography on museum specimens and live captures to test to what extent the magnitude of FA and FA-stress relationships covary with directional shifts in traits related to the flight apparatus of four East-African rainforest birds that underwent recent shifts in habitat quality and landscape connectivity. Both the magnitude and direction of phenotypic change varied among species, with some traits increasing in size while others decreased or maintained their original size. In three of the four species, traits that underwent larger directional changes were less strongly buffered against random perturbations during their development, and traits that increased in size over time developed more asymmetrically than those that decreased. As we believe that spurious relationships due to biased comparisons of historic (museum specimens) and current (field captures) samples can be ruled out, these results support the largely untested hypothesis that directional shifts may increase the sensitivity of developing traits to random perturbations of environmental or genetic origin.

Intraclutch variation in avian eggshell pigmentation: the anaemia hypothesis.

Many passerine species lay eggs that are speckled with dark protoporphyrin pigmentation. Because protoporphyrin is mainly derived from the blood, we here formulate and test a new hypothesis that links an increase in anaemia along the laying sequence to within-clutch variation in egg pigmentation. More intense pigmentation is expected if pigments accumulate during enhanced red blood cell production in response to anaemia. Reduced pigmentation is expected if pigments are derived from the degradation of red blood cells that circulate in smaller numbers due to blood loss. To test this hypothesis, we manipulated anaemia in great tit (Parus major) females by infesting the nests with hen fleas (Ceratophyllus gallinae) prior to egg laying. Polychromatophil (i.e., immature red blood cells) percentage, as a measure of blood cell production, was positively correlated with parasite load confirming that female great tits experienced stronger anaemia when infested with haematophagous parasites during egg laying. We found a positive relationship between spot darkness and laying order that weakened under high parasite load. This result suggests that anaemia in females due to blood-sucking parasites led to diminished protoporphyrin from disintegrated red blood cells and hence a decreased deposition of protoporphyrin. However, the overall increase in pigment darkness along the laying sequence suggests that pigments also accumulate by enhanced red blood cell production caused by anaemia due to egg production itself.

Effects of early developmental conditions on innate immunity are only evident under favourable adult conditions in zebra finches.

Long-term effects of unfavourable conditions during development can be expected to depend on the quality of the environment experienced by the same individuals during adulthood. Yet, in the majority of studies, long-term effects of early developmental conditions have been assessed under favourable adult conditions only. The immune system might be particularly vulnerable to early environmental conditions as its development, maintenance and use are thought to be energetically costly. Here, we studied the interactive effects of favourable and unfavourable conditions during nestling and adult stages on innate immunity (lysis and agglutination scores) of captive male and female zebra finches (Taeniopygia guttata). Nestling environmental conditions were manipulated by a brood size experiment, while a foraging cost treatment was imposed on the same individuals during adulthood. This combined treatment showed that innate immunity of adult zebra finches is affected by their early developmental conditions and varies between both sexes. Lysis scores, but not agglutination scores, were higher in individuals raised in small broods and in males. However, these effects were only present in birds that experienced low foraging costs. This study shows that the quality of the adult environment may shape the long-term consequences of early developmental conditions on innate immunity, as long-term effects of nestling environment were only evident under favourable adult conditions.

Variation in innate immunity in relation to ectoparasite load, age and season: a field experiment in great tits (Parus major).

It remains largely unknown which factors affect the innate immune responses of free-living birds. Nevertheless, the degree of innate immunity may play a crucial role in an individual's survival as it procures the first defence against pathogens. We manipulated the ectoparasite load of great tit (Parus major) nests by infesting them with hen fleas (Ceratophyllus gallinae) before egg laying. We subsequently quantified natural antibody (NAb) concentration and complement activation in nestlings and adult females during breeding and post-breeding periods. NAb concentrations increased in nestlings and adult females breeding in flea-infested nest boxes during the nestling provisioning period, but not in breeding females during incubation. In contrast, parasite abundance did not affect levels of complement activity in females. NAb levels of nestlings were already fully developed at the end of the nestling stage, but complement activation was only observed post-fledging. Concentrations of NAbs and complement activation of adult females were significantly lower during the breeding season compared with post-breeding levels, but did not differ between incubation and chick rearing. Further experimental studies in species that vary in life-history strategies will allow us to unravel the mechanisms underlying the observed variation in innate immune defences.