Sphingosine Kinase-1 Is Central to Androgen-Regulated Prostate Cancer Growth and Survival

BACKGROUND: Sphingosine kinase-1 (SphK1) is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival. METHODOLOGY/PRINCIPAL FINDINGS: Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT) to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE)-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway--by negatively impacting SphK1 activity--could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity. CONCLUSIONS/SIGNIFICANCE: We report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a compensatory mechanism allowing prostate cancer cells to survive in androgen-depleted environment, giving support to its inhibition as a potential therapeutic strategy to delay/prevent the transition to androgen-independent prostate cancer

Résultats carcinologiques du traitement du cancer de la prostate de stade pT3 après prostatectomie totale (étude rétrospective de 246 cas)

Objectifs : Déterminer survie et facteurs pronostiques du cancer de la prostate pT3M0 (TNM 2002) après prostatectomie totale (PT). Méthode : Etude rétrospective de 246 pT3. traitements complémentaires : 53 radiothérapies adjuvantes (RTa), 71 radiothérapies de rattrapage, 54 hormonothérapies. Définition de la récidive biologique (RB): 2 valeurs du PSA>0,2 ng/ml. Résultats : Age médian : 65 ans, suivi moyen : 84 mois, PSA préopératoire (PSAi) : 12,8 ng/ml. Effectif : 170 pT3a, 76 pT3b. Taux de survie sans RB, sans métastase, spécifique et globale à 10 ans : 54%, 86%, 92% et 75%. Taux de contrôle local : 95%. Facteurs prédictifs de RB : score de Gleason, PSAi, pT3b et absence de RTa. Facteurs prédictifs de survie globale : PSAi et score de Gleason. Conclusion : Les taux de survie et de contrôle local justifient la prise en charge du stade pT3 par une association thérapeutique comprenant une PT. Les facteurs pronostiques les plus prédictifs de survie sont le PSAi et le score de Gleason.PARIS-BIUM (751062103) / SudocSudocFranceF

[Nitric oxide pathway and female lower urinary tract. Physiological and pathophysiological role].

International audienceGOAL: The aim was to review the literature on nitric oxide and female lower urinary tract. MATERIAL: A literature review through the PubMed library until December, 31 2012 was carried out using the following keywords: lower urinary tract, bladder, urethra, nervous central system, innervation, female, women, nitric oxide, phosphodiesterase, bladder outlet obstruction, urinary incontinence, overactive bladder, urinary tract infection. RESULTS: Two nitric oxide synthase isoforms, the neuronal (nNOS) and the endothelial (eNOS), are constitutively expressed in the lower urinary tract. Nevertheless, nNOS is mainly expressed in the bladder neck and the urethra. In the bladder, NO modulates the afferent neurons activity. In pathological condition, inducible NOS expression induces an increase in detrusor contractility and bladder wall thickness and eNOS facilitates Escherichia coli bladder wall invasion inducing recurrent urinary tract infections. In the urethra, NO play a major role in smooth muscle cells relaxation. CONCLUSION: The NO pathway plays a major role in the female lower urinary tract physiology and physiopathology. While it acts mainly on bladder outlet, in pathological condition, it is involved in bladder dysfunction occurrence

Complications for radical cystectomy: Impact of the American Society of Anesthesiologists Score

Objectives: To report the perioperative events after radical cystectomy and urinary diversion in bladder cancer in terms of major and minor complications and to seek statistical relationships with patient's characteristics and surgical procedures. Methods: One hundred and sixty-one radical cystectomies performed in the modern era in two academic hospitals were reviewed. Preoperative patients characteristics (age, sex, hemoglobin, total protein, weight and height) and perioperative data (operative time, type of urinary diversion, associated procedures, blood transfusion, seniority of the surgeon) were recorded. Perioperative morbidity was defined by any adverse event during hospital stay or within 30 days after surgery, those requesting an additional stay of more that 3 days in the intensive care unit or a reoperation being classified as major complications. Significant relationships were sought for classes by Student's t test for comparison of quantitative variables and Yate's corrected χ2 test for categorical variables. Spearman's rank correlation test was used for comparison of quantitative variables. Results: Major complications were observed in 41 patients (25.5%) and resulted in 14 reoperations (8.7% reoperation rate). Most of them were diversion-related and were statistically related to the ASA score ≥3 (p < 0.01, 5.7 odds ratio). Compared to sophisticated means of diversion, cutaneous diversion resulted in minimal operative time and hospital stay. No relationships between age, body mass index, biological parameters, type of diversion, associated procedure, surgeon's experience and postoperative complications could be evidenced. Uneventful recovery resulted in a 16.6 days mean hospital stay, minor complications induced a significant 3.8 days additional stay and major complications resulted in major lengthening of hospital stay (21.2 days mean additional stay). Conclusion: ASA scores equal to or greater than 3 were associated with major complications and most specially those related to the type of urinary diversion. Therefore, we recommend special care in the selection of the type of urinary diversion and further preoperative evaluation inclusive of nutritional assessment. Copyright © 2001 S. Karger AG, Basel.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Subinguinal microsurgical varicocelectomy vs. percutaneous embolization in infertile men: Prospective comparison of reproductive and functional outcomes

Résumé Contexte La varicocèle est une affection caractérisée par une dilatation et tortuosité des veines du plexus veineux pampiniforme du sac scrotal. La présence de varicocèle est associée à un risque accru d'altération des paramètres du sperme. Cette étude vise à comparer la norme actuelle des procédures de traitement par varicocèle: la ligature microscopique sous-inguinale à l'embolisation percutanée en termes d'amélioration des paramètres spermatiques, de fertilité et de morbidité dans l'hôpital universitaire de Toulouse(France). Soixante-seize patients atteints de varicocèle clinique, d'altération des paramètres spermatiques et d'infertilité ont subi une intervention (microchirurgie dans 49 cas réalisées par un seul urologue et embolisation dans 27 cas) et ont fait l'objet d'une analyse prospective. Les données étudiées sont les suivantes: paramètres du sperme, grossesses spontanées, douleur, effets secondaires, temps de récupération et satisfaction globale. Tous les patients ont été contactés en janvier 2015 afin de déterminer les grossesses spontanées. Résultats En préopératoire, il n’existait aucune différence sur les items cliniques et biologiques entre les deux groupes. Sur la population globale, on observe une amélioration significative de la concentration spermatique à 3, 6, 9 et 12 mois (p = <0,001, <0,001, 0,012, 0,018) et de la motilité à 6 mois (p = 0,002). La concentration de spermatozoïdes était plus élevée à 6 mois dans le groupe d'embolisation percutané (13,42 vs 8,09; p = 0,043). Avec un suivi médian de 4 ans, 27 grossesses sont survenues (taux de grossesse spontanée de 35.5%). Il n'y avait pas de différence significative entre les procédures sur la qualité du sperme, le taux de grossesse et la satisfaction globale. Les patients traités par embolisation percutanée ont rapporté un temps de récupération plus rapide (p = 0,002) et moins de douleur postopératoire (p = 0,007). Conclusion Notre étude montre que l'embolisation percutanée semble être une alternative équivalente à la ligature microscopique sous-inguinale en terme d'amélioration de la qualité du sperme, du taux de grossesse et de la satisfaction globale avec un léger avantage sur la morbidité post-opératoire

Cellular Senescence in Renal and Urinary Tract Disorders

International audienceCellular senescence is a state of cell cycle arrest induced by repetitive cell mitoses or different stresses, which is implicated in various physiological or pathological processes. The beneficial or adverse effects of senescent cells depend on their transitory or persistent state. Transient senescence has major beneficial roles promoting successful post-injury repair and inhibiting malignant transformation. On the other hand, persistent accumulation of senescent cells has been associated with chronic diseases and age-related illnesses like renal/urinary tract disorders. The deleterious effects of persistent senescent cells have been related, in part, to their senescence-associated secretory phenotype (SASP) characterized by the release of a variety of factors responsible for chronic inflammation, extracellular matrix adverse remodeling, and fibrosis. Recently, an increase in senescent cell burden has been reported in renal, prostate, and bladder disorders. In this review, we will summarize the molecular mechanisms of senescence and their implication in renal and urinary tract diseases. We will also discuss the differential impacts of transient versus persistent status of cellular senescence, as well as the therapeutic potential of senescent cell targeting in these diseases

Focal Treatment for Unilateral Prostate Cancer Using High-Intensity Focal Ultrasound: A Comprehensive Study of Pooled Data

Background: Focal therapy for prostate cancer (PCa) remains experimental. Aim of the current study is to review available evidence and perform a pooled analysis exploring oncologic and functional results of high intensity focus ultrasound (HIFU) focal therapy for the treatment of unilateral PCa. Methods: The National Library of Medicine Database was searched for relevant articles. A wide search was performed, including the combination of following words: "HIFU," "prostate," "cancer," and "focal." Overall, 167 articles were reviewed. Of these, seven articles were identified and eligible for the pooled analysis. Data on HIFU hemiablation or focal prostate ablation, oncologic and functional results were pooled from these seven studies that included 366 men with unilateral PCa. Results: In the 366 analyzed cases, mean age was 67 years (95% confidence interval 66-69), and mean preoperative prostate-specific antigen was 6.4 ng/cc (5.5-7.4). Three studies included PCa up to Gleason 7 (3 + 4), three studies did include also Gleason 7 (4 + 3), whereas one study had no limitation in terms of Gleason score. Regarding early complications, low-grade Clavien-Dindo I-II were reported in 26% (16-37), whereas high-grade Clavien-Dindo ≥III were found in 3.8% (0-8.6). Analyzing oncologic outcomes mean follow-up was 26 months (23-31): at one year after HIFU, negative biopsy rate for clinically significant PCa was 87% (79-96), whereas salvage treatment-free survival rate was 92% (85-98). Regarding functional outcomes, reported potency rates were 74% (64-84), and continence 96% (91-100), although definitions of potency and continence were not homogenous across studies. Conclusions: This pooled analysis of the results of focal HIFU treatment of PCa shows promising oncologic and functional outcomes. Well-selected patients may be candidates for such a conservative partial treatment of the gland. Well-designed trials are awaited to compare HIFU focal treatment with current standard of care.SCOPUS: ar.jinfo:eu-repo/semantics/publishe