Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

Background Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes. Methods We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants. Results Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects. Conclusions Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application

Salvage radiotherapy for patients with PSA relapse after radical prostatectomy: a single institution experience

<p>Abstract</p> <p>Background</p> <p>To assess the efficacy of salvage radiotherapy (RT) for persistent or rising PSA after radical prostatectomy and to determine prognostic factors identifying patients who may benefit from salvage RT.</p> <p>Methods</p> <p>Between 1990 and 2003, 59 patients underwent RT for PSA recurrence after radical prostatectomy. Patients received a median of 66 Gy to the prostate bed with 3D or 2D RT. The main end point was biochemical failure after salvage RT, defined as an increase of the serum PSA value >0.2 ng/ml confirmed by a second elevation.</p> <p>Results</p> <p>Median follow-up was 38 months. The 3-year and 5-year bDFS rates were 56.1% and 41.2% respectively. According to multivariate analysis, only preRT PSA ≥1 ng/ml was associated with biochemical relapse.</p> <p>Conclusion</p> <p>When delivered early, RT is an effective treatment after radical prostatectomy. Only preRT PSA ≥1 ng/ml predicted relapse.</p

Hippocampal Neurogenesis and Dendritic Plasticity Support Running-Improved Spatial Learning and Depression-Like Behaviour in Stressed Rats

Exercise promotes hippocampal neurogenesis and dendritic plasticity while stress shows the opposite effects, suggesting a possible mechanism for exercise to counteract stress. Changes in hippocampal neurogenesis and dendritic modification occur simultaneously in rats with stress or exercise; however, it is unclear whether neurogenesis or dendritic remodeling has a greater impact on mediating the effect of exercise on stress since they have been separately examined. Here we examined hippocampal cell proliferation in runners treated with different doses (low: 30 mg/kg; moderate: 40 mg/kg; high: 50 mg/kg) of corticosterone (CORT) for 14 days. Water maze task and forced swim tests were applied to assess hippocampal-dependent learning and depression-like behaviour respectively the day after the treatment. Repeated CORT treatment resulted in a graded increase in depression-like behaviour and impaired spatial learning that is associated with decreased hippocampal cell proliferation and BDNF levels. Running reversed these effects in rats treated with low or moderate, but not high doses of CORT. Using 40 mg/kg CORT-treated rats, we further studied the role of neurogenesis and dendritic remodeling in mediating the effects of exercise on stress. Co-labelling with BrdU (thymidine analog) /doublecortin (immature neuronal marker) showed that running increased neuronal differentiation in vehicle- and CORT-treated rats. Running also increased dendritic length and spine density in CA3 pyramidal neurons in 40 mg/kg CORT-treated rats. Ablation of neurogenesis with Ara-c infusion diminished the effect of running on restoring spatial learning and decreasing depression-like behaviour in 40 mg/kg CORT-treated animals in spite of dendritic and spine enhancement. but not normal runners with enhanced dendritic length. The results indicate that both restored hippocampal neurogenesis and dendritic remodelling within the hippocampus are essential for running to counteract stress

Adherence to Treatment Guidelines and Associated Survival in Older Patients with Prostate Cancer: A Prospective Multicentre Cohort Study

International audienceThe guidelines on prostate cancer treatment in older men recommend evaluating the patient’s underlying health status before treatment selection. We aimed to evaluate the frequency of a guideline–discordant treatment (GDT), identify factors associated with GDT, and assess the relationship between GDT and overall survival. We studied patients with prostate cancer aged 70 or older included in the ELCAPA cohort between 2010 and 2019. Multivariable logistic regression assessed GDT-associated factors. The restricted mean survival time (RMST) assessed the 24- and 36-month OS using stabilized inverse probability of treatment weighting of propensity scores. We included 356 patients (median age: 81 years), and 164 (46%) received a GDT (95% confidence interval (CI) = (41–51%)). Patients with metastases were less likely to receive a GDT (adjusted odds ratio (95% CI) = 0.34 (0.17–0.69); p = 0.003). After weighting, the RMST at 24 months was shorter in the GDT group (13.9 months, vs. 17 months for compliant treatments; difference (95% CI): −3.1 months (−5.3, −1.0); p = 0.004). RMST at 36 months was 18.5 months, vs. 21.8 months (difference: −3.3 months (−6.7, 0.0); p = 0.053). GDT is common in older patients with prostate cancer and especially those with non-metastatic disease. GDT was associated with worse survival, independently of health status and tumour characteristics

Résultats de l’enquête de pratique des urologues français pour l’activité de cancérologie au cours de la pandémie COVID-19

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Impact de la pandémie de COVID-19 sur l’activité chirurgicale au sein des services d’urologie de l’Assistance Publique – Hôpitaux de Paris

International audienceIntroduction: As a result of the COVID-19 pandemic in France, all non-emergency surgical activity has been cancelled since March 12, 2020. In order to anticipate the reinstatement of delayed interventions, surgical activity reduction analysis is essential. The objective of this study was to evaluate the reduction of urological surgery in adult during the COVID-19 pandemic compared to 2019.Material: The data regarding urological procedures realized in the 8 academic urological departments of Parisians centres (AP-HP) were compared over two similar periods (14-29 March 2019 and 12-27 March 2020) using the centralized surgical planning software shared by these centres. Procedure title, type of surgery and outpatient ratio were collected. The interventions were sorted into 16 major families of urological interventions.Results: Overall, a 55% decrease was observed concerning urological procedures over the same period between 2019 and 2020 (995 and 444 procedures respectively). Oncology activity and emergencies decreased by 31% and 44%. The number of kidney transplantations decreased from 39 to 3 (-92%). Functional, andrological and genital surgical procedures were the most impacted among the non-oncological procedures (-85%, -81% and -71%, respectively). Approximatively, 1033 hours of surgery have been delayed during this 16-day period.Conclusion: Lockdown and postponement of non-urgent scheduled urological procedures decisions has led to a drastic decrease in surgical activity in AP-HP. Isolated kidney transplantation has been stopped (national statement). Urologists must anticipate for lockdown exit in order to catch-up delayed surgeries.Level of evidence: 3.IntroductionEn conséquence de la pandémie de COVID-19 en France, toute activité chirurgicale non urgente a dû être annulée à partir du 12 mars 2020. Afin d’anticiper la reprise des interventions décalées, une quantification de la réduction d’activité est nécessaire. L’objectif de l’étude était d’évaluer comparativement à 2019 la réduction d’activité chirurgicale urologique adulte pendant la pandémie de COVID-19.Matériel et méthodesNous avons comparé le nombre d’interventions urologiques pratiquées dans les 8 services universitaires d’urologie de l’Assistance Publique – Hôpitaux de Paris (AP–HP) sur deux périodes comparables (14–29 mars 2019 et 12–27 mars 2020) à l’aide du logiciel de planification opératoire et du PMSI partagé par ces centres. L’intitulé d’intervention et le type de chirurgie ont été collectés et regroupées en 16 catégories.RésultatsUne baisse de l’activité globale à l’AP–HP en urologie de 55 % entre 2019 et 2020 (995 et 444 interventions respectivement) a été constatée sur les 8 services. L’activité oncologique et les urgences ont diminué de 31 % et 44 %. L’activité de transplantation rénale, la chirurgie fonctionnelle et andrologique ont subi les plus fortes baisses d’activité par les interventions non oncologiques (−92 %, −85 % et −81 %, respectivement). Environ 1033 heures d’intervention devront être reprogrammées pour rattraper le programme opératoire annulé.ConclusionLe confinement et le report des interventions chirurgicales « non urgentes » ont entraîné une diminution drastique de l’activité chirurgicale au sein de l’AP–HP. Pendant cette période, les urologues ont été sollicités pour d’autres tâches mais doivent désormais s’atteler à organiser la période de reprise d’activité pour éviter une crise organisationnelle en urologique.Niveau de preuve3

The level of evidence for the use of biomarkers in the early detection of prostate cancer

International audienceTo systematically review the evidence for the use of PSA and other biomarkers in the early detection of prostate cancer, we searched PubMed for clinical trials and studies assessing PSA and other biomarkers in the early detection of prostate cancer, published between 2000 and May 2013 that included >200 subjects. The level of evidence (LOE) for clinical utility was evaluated using the tumor marker utility grading system. A total of 84 publications, corresponding to 70 trials and studies were selected for inclusion in this review. We attributed a level of evidence (LoE) of IA to PSA for early PCa detection, but we do not recommend its use in mass screening. Emerging biomarkers were assessed in prospective case-control and cohort studies: PCA3 (n=3); kallikreins (n=3); [-2]proPSA (n=5); fusion oncogenes (n=2). These studies used biopsy results for prostate cancer to determine specificity and sensitivity, but they did not assess the effect on PCa mortality. The LoE attributed was III-C. PSA can be used for early prostate cancer detection but mass screening is not recommended. Studies on other biomarkers suggest that they could be used, individually or in combination, to improve the selection of patients with elevated PSA levels for biopsy, but RCTs assessing their impact on prostate cancer management and mortality are needed. A better use of available tests is possible for men at risk in order to maximize the risk-benefit ratio