L. Regis

Simultaneous Treatment with Statins and Aspirin Reduces the Risk of Prostate Cancer Detection and Tumorigenic Properties in Prostate Cancer Cell Lines

Nowadays prostate cancer is the most common solid tumor in men from industrialized countries and the second leading cause of death. At the ages when PCa is usually diagnosed, mortality related to cardiovascular morbidity is high; therefore, men at risk for PCa frequently receive chronic lipid-lowering and antiplatelet treatment. The aim of this study was to analyze how chronic treatment with statins, aspirin, and their combination influenced the risk of PCa detection. The tumorigenic properties of these treatments were evaluated by proliferation, colony formation, invasion, and migration assays using different PCa cell lines, in order to assess how these treatments act at molecular level. The results showed that a combination of statins and aspirin enhances the effect of individual treatments and seems to reduce the risk of PCa detection (OR: 0.616 (95% CI: 0.467–0.812), P < 0.001). However, if treatments are maintained, aspirin (OR: 1.835 (95% CI: 1.068–3.155), P = 0.028) or the combination of both drugs (OR: 3.059 (95% CI: 1.894–4.939), P < 0.001) represents an increased risk of HGPCa. As observed at clinical level, these beneficial effects in vitro are enhanced when both treatments are administered simultaneously, suggesting that chronic, concomitant treatment with statins and aspirin has a protective effect on PCa incidence.

Behavior of chemiluminescent assays to measure serum testosterone during androgen deprivation therapy.

DOI: 10.1111/iju.13180 PCa guidelines recommend ST measurement during ADT in order to evaluate its efficacy and to diagnose the CR status. Regulatory agencies and PCa guidelines consider 50 ng/dL as the castration level of ST, although some studies suggest that lower levels are associated with better outcomes of the disease. During the 1980s, the FDA established the castration level of ST at 50 ng/dL, based on studies carried out in patients who had undergone surgical castration. This level corresponded to the LLOQ from the RIAs that had been used so far. In 2000, using a recently introduced CLIA, Oefelein et al. redefined the castration level of ST at 20 ng/dL in a group of 35 patients who had undergone surgical castration. The median level of ST was 15 ng/dL and the range 2–30 ng/dL. Surprisingly the level selected by the author corresponded to the 75th percentile of the distribution. In 2007, Morote et al. also using a CLIA declared 32 ng/dL to be “the castrate level of ST with clinical impact” because it represented the lowest level of ST capable of significantly discriminating the progression-free survival of CR in a group of 73 non-metastatic PCa patients subjected to LHRH agonist. Nowadays, CLIAs, which are usually integrated in automated platforms, are widely used in clinical practice to measure ST given that they are sensitive, fast and inexpensive. However CLIAs have a disturbing lack of accuracy and reproducibility, especially at low levels. That is why since 2007 the American Endocrine Society recommends only LC/GC MSMS to measure ST. These methods extract the testosterone in an initial step, avoiding its overdetection caused by contamination mainly with other steroids, and MSMS ensures an accurate and reproducible measurement in a second step. However, direct CLIAs continue to be the most widely used method to determine ST in clinical practice. Because of a recent change of the platforms used in our reference laboratory and the lack of information about the behavior of CLIAs to measure ST in PCa patients undergoing ADT, we carried out a prospective study in order to evaluate two commercial CLIAs. Between July and December 2015, ST measurement was requested in 249 patients with histologically confirmed PCa undergoing continuous LHRH agonist treatment as part of their routine control. Blood collection was carried out between 08.00 and 10.00 hours, and two aliquots of serum were processed in the automated Cobas 8000 (Roche Diagnostics Inc., Indianapolis, IN, USA) (PC8000) and the Advia-Centaur XPi (Siemens, Munich, Germany) (PA-CXPi) platforms, both using CLIA to measure ST directly. The LLOQ were 2.5 and 10 ng/dL, respectively. According to the manufacturers’ information, the intra-assay coefficients of variation ranged between 1.7% and 4.6% in the PC8000, and between 2.3% and 6.2% in PA-CXPi. The mean age of the study group was 74 years (range 48–89 years). ADT was indicated as the primary treatment in 89 patients (35.7%) with metastatic PCa, 118 (47.4%) patients who were treated with radiation therapy and 42 (16.9%) patients having a high risk of dissemination failure after primary treatment of PCa. The average period of LHRH agonist treatment was 19.6 months (range 4–57 months). The study was carried out in accordance with the ethical standards of the Helsinki Declaration II, and written informed consent was obtained. The levels of ST measured in the PC8000 were significantly lower than those measured in the PA-CXPi, P < 0.001, and the correlation between both measurements was only moderate, r = 0.55. The median levels and ranges were 7.8 ng/dL (range <2.5–54.6 ng/dL) and 33.4 ng/dL (range <10–91.6 ng/dL), respectively. The 95th percentiles corresponded to 34.6 and 75.9 ng/dL, respectively. These levels were below 20 ng/dL, between 20 and 50 ng/dL, and above 50 ng/dL in 193 (77.5%), 54 (21.7%) and two (0.8%) cases in the PC8000, and 62 (24.9%), 134 (53.8%) and 53 (21.3%) cases in the PA-CXPi (Fig. 1). The present study highlights the different behavior of direct CLIAs to measure ST in PCa patients undergoing ADT. This fact could compromise the ADT efficacy evaluation as well as the diagnosis of CR. As the automated CLIAs continue to be widely used to determine ST, because LC/GC MSMS technology is not available in most clinical laboratories, a careful selection of the CLIA used to measure ST in PCa patients under ADT is recommended.

Free Testosterone During Androgen Deprivation Therapy Predicts Castration‐Resistant Progression Better Than Total Testosterone

The optimal degree of testosterone suppression in patients with prostate cancer undergoing androgen deprivation therapy remains in question. Furthermore, serum free testosterone, which is the active form of testosterone, seems to correlate with intraprostatic testosterone. Here we compared free and total serum testosterone as predictors of survival free of castration resistance.

Hormonal response recovery after long-term androgen deprivation therapy in patients with prostate cancer.

Abstract Objective: The aim of this study was to evaluate hormonal recovery after cessation of androgen deprivation therapy (ADT) in a group of elderly prostate cancer patients. Materials and methods: Forty patients with locally advanced or metastatic prostate cancer, with a mean age of 71.5 years [95% confidence interval (CI) 69.1–73.9], were treated with ADT for a mean duration of 74.6 months (95% CI 59.7–89.5 months). Mean follow-up time after ADT cessation was 36.5 months (95% CI 30.6–42.3 months). Serum testosterone and luteinizing hormone (LH) were determined at 6 month intervals after ADT cessation. Results: After 18 months of follow-up, all patients had recovered normal LH levels, while 38% of patients still presented castration levels of testosterone (< 50 ng/dl). A multivariate analysis was performed to find factors related to testosterone recovery (testosterone >50 ng/dl). Neither age at start of ADT nor clinical stage reached statistical significance. Only time under ADT was correlated with testosterone recovery (p = .031). Kaplan–Meier curves were obtained. Mean time for testosterone recovery was 14.5 months (95% CI 6.5–22.6 months) in patients treated with ADT for less than 60 months compared to 29.3 months (95% CI 19.6–39.1 months) in patients treated with ADT for more than 60 months (log-rank p = .029). Conclusions: Age did not correlate with testosterone recovery in a group of elderly prostate cancer patients in whom ADT was stopped. Testosterone recovery after ADT cessation was significantly correlated with time under ADT treatment. Significant implications related to economic aspects of the dosage schedule may be considered.

Determinación de la testosterona sérica durante la supresión androgénica en pacientes con cáncer de próstata: una revisión sistemática

INTRODUCTION Clinical practice guidelines recommend measuring serum testosterone (ST) during androgenic suppression (AS) to assess its efficacy and define castration resistance (CR). The objectives of this systematic review were to assess the level of scientific evidence that justify checking ST levels during AS, when to perform it and for what purpose. MATERIAL AND METHODS We performed a search in PubMed with the following mesh terms: androgen suppression, testosterone, and prostate cancer. The search was narrowed to original articles published in English. RESULTS We found 8 publications that analysed the clinical impact of ST concentrations during AS. In all of the series, ST was measured using chemiluminescent assays. However, only indirect methods based on liquid or gas chromatography for its extraction and subsequent quantification using mass spectrometry are recommended, especially for measuring low levels. The endpoints were specific survival and CR-free survival. Six studies were retrospective. The series were not uniform in terms of clinical stage, types of AS and ST assessment methods. In general, low ST levels (<20ng/dL or <32ng/dL) were related to longer CR-free survival. The measurements were performed every 3 or 6 months. Four studies confirmed the beneficial effect of adding bicalutamide when detecting microelevations above 50ng/dL. CONCLUSIONS The level of scientific evidence justifying the measurement of ST during AS is low, and the methods employed for quantifying ST levels are inadequate. However, we consider it useful to check ST levels during AS, and there appears to be an association between low ST levels and better disease outcomes. In the event of microelevations above 50ng/dL, we recommend the administration of bicalutamide.

Bladder Cancer in an Inguinoscrotal Vesical Hernia

We present the case of a 79-year-old male who, due to hematuria, underwent cystoscopy that showed a lesion in the bladder dome. Transurethral resection was attempted, but access to the tumor by this route was impossible. Given the findings, a body CT scan was performed showing an inguinoscrotal hernia with vesical carcinoma contained. Open surgical treatment of the vesical carcinoma contained within the inguinoscrotal hernia was performed in conjunction with the hernia repair. The anatomical pathology report confirmed a high-grade urothelial carcinoma (stage pT2b) with a free resection margin of <1 mm. Adjuvant radiotherapy was selected for subsequent treatment. The presence of bladder tumor in an inguinoscrotal hernia is an uncommon finding and a diagnostic delay can be assumed. The initial therapeutic plan may need to be changed from the usual approaches due to the atypical presentation.

Serum Testosterone Levels in Prostate Cancer Patients Undergoing Luteinizing Hormone-Releasing Hormone Agonist Therapy

Background Serum testosterone measurement is recommended to assess the efficacy of androgen deprivation therapy (ADT) and to diagnose castration resistance in patients with prostate cancer (PCa). Currently, the accepted castrate level of serum testosterone is 50 ng/dL. Liquid chromatography and tandem mass spectrometry (LC MSMS) is the appropriate method to measure testosterone, especially at low levels. However, worldwide, chemiluminescent assays (CLIAs) are used in clinical laboratories, despite their lack of accuracy and reproducibility, because they are automatable, fast, sensitive, and inexpensive. Materials and Methods We compared serum testosterone levels measured using LC MSMS and CLIAs in 126 patients with PCa undergoing luteinizing hormone‐releasing hormone (LHRH) agonist therapy. Results The median serum testosterone level was 14.0 ng/dL (range, 2.0‐67.0 ng/dL) with LC MSMS and 31.9 ng/dL (range, 10.0‐91.6 ng/dL) with CLIA (P < .001). The serum testosterone levels, measured using LC MSMS, were < 20 ng/dL in 83 patients (65.9%), 20 to 50 ng/dL in 40 (31.7%), and > 50 ng/dL in 3 patients (2.4%). These ranges were found in 34 (27%), 72 (57.1%), and 20 (15.9%) patients when testosterone was measured using CLIA (P < .001). The castrate level of serum testosterone using LC MSMS and CLIA was 39.8 ng/dL (95% confidence interval [CI], 37.1‐43.4 ng/dL) and 66.5 ng/dL (95% CI, 62.3‐71.2 ng/dL), respectively. Conclusion We found that CLIA overestimated the testosterone levels in PCa patients undergoing LHRH agonist therapy. Thus, the castration level was incorrectly considered inadequate with CLIA in almost 15% of patients. The true castration level of serum testosterone using an appropriate method is < 50 ng/dL. Micro‐Abstract Prostate cancer guidelines have recommended serum testosterone measurement during androgen deprivation therapy to assess its efficacy and diagnose castration resistance. The present study compared the testosterone levels from a widely used chemiluminescent assay (CLIA) and liquid chromatography tandem mass spectrometry method, which is the recommended method, in prostate cancer patients undergoing luteinizing hormone‐releasing hormone agonist therapy. The CLIA overestimated the testosterone levels and suggested, incorrectly, the presence of inadequate castration in ≤ 15% of patients.

Cambios hormonales después del tratamiento de cáncer de próstata localizado. Comparación entre radioterapia de haz externo y prostatectomía radical

OBJECTIVE To determine the influence of radical prostatectomy (RP) and external beam radiation therapy (EBRT) on the hypothalamic pituitary axis of 120 men with clinically localized prostate cancer treated with RP or EBRT exclusively. MATERIALS AND METHODS 120 patients with localized prostate cancer were enrolled. Ninety two patients underwent RP and 28 patients EBRT exclusively. We measured serum levels of luteinizing hormone, follicle stimulating hormone (FSH), total testosterone (T), free testosterone, and estradiol at baseline and at 3 and 12 months after treatment completion. RESULTS Patients undergoing RP were younger and presented a higher prostate volume (64.3 vs. 71.1 years, p<0.0001 and 55.1 vs. 36.5 g, p<0.0001; respectively). No differences regarding serum hormonal levels were found at baseline. Luteinizing hormone and FSH levels were significantly higher in those patients treated with EBRT at three months (luteinizing hormone 8,54 vs. 4,76 U/l, FSH 22,96 vs. 8,18 U/l, p<0,0001) while T and free testosterone levels were significantly lower (T 360,3 vs. 414,83ng/dl, p 0,039; free testosterone 5,94 vs. 7,5pg/ml, p 0,018). At 12 months FSH levels remained significantly higher in patients treated with EBRT compared to patients treated with RP (21,01 vs. 8,51 U/l, p<0,001) while T levels remained significantly lower (339,89 vs. 402,39ng/dl, p 0,03). CONCLUSIONS Prostate cancer treatment influences the hypothalamic pituitary axis. This influence seems to be more important when patients with prostate cancer are treated with EBRT rather than RP. More studies are needed to elucidate the role that prostate may play as an endocrine organ.

Revisión sistemática de los factores pronósticos del carcinoma renal

CONTEXT AND OBJECTIVES The natural history of renal cell carcinoma is heterogeneous. Some scenarios can be found in terms of clinical presentation, clinical evolution or type of recurrence (local/metastatic). The aim of this publication is to analyze the most important prognostic factors published in the literature. EVIDENCE ACQUISITION A literature review ob published papers was performed using the Pubmed, from first Motzers classification published in 1999 to 2015, according to PRISMA declaration. Search was done using the following keywords: kidney neoplasm, kidney cancer, renal cell carcinoma, prognostic factors, mortality, survival and disease progression. Papers were classified according to level of evidence, the number of patients included and the type of study performed. EVIDENCE SYNTHESIS The evolution in the knowledge of molecular pathways related to renal oncogenesis and the new targeted therapies has left to remain obsolete the old prognostic models. Its necessary to perform a continuous review to actualize nomograms and to adapt them to the new scenarios. CONCLUSIONS Is necessary to perform a proper external validation of existing prognostic factors using prospective and multicentric studies to add them into the daily urologist clinical practice.

MP85-16 STUDY OF ALTERED RATIOS OF PROTEIN KINASE CK2 CATALYTIC SUBUNITS AND REGULATORY SUBUNIT (CK2BETA) IN RENAL CELL CARCINOMA. RELATION WITH EPITELIAL-TO-MESENCHYMAL TRANSITION MARKERS (IL-6/STAT3)

INTRODUCTION AND OBJECTIVES: Epitelial-to-mesenchymal transition (EMT) is a well characterised process linked to tumour progression and metastasis in a number of carcinomas. EMT enables carcinoma cells to lose cell to cell contacts and endows them with stem cell-like properties to invade and initiate metastasis. Recent reports have identified EMT as potentially playing a significant role in RCC disease recurrence, invasion and metastasis. Several signalling pathways like HIF/2 and IL-6/STAT, are well known inducers of the EMT phenotype. Protein kinase CK2 is a constitutively active serine/threonine kinase consisting of two catalytic subunits (CK2alpha/alpha’) and two regulatory subunits (CK2Beta) and is present in the nucleus and cytoplasm of all eukaryotic cells. The imbalance of CK2 catalytic and regularory subunits, due to underexpression of CK2Beta subunit, has been correlated with the expression of EMT markers. In clear cell renal cell carcinoma (ccRCC), the alterations in the ratios between CK2 subunits during the neoplasic process seems to participate at different stages of tumour progression METHODS: We analyzed the expression and distribution of CK2 subunits in samples of clear cell renal carcinomas (ccRCC) and renal healthy tissue from the same patients by immunohistochemistry on TMAs and Western-blot in a total of 98 patients. Tumour registry data and patient outcome were retrospectivelly collected and correlates with clinicopathological data (F€ urhman grade, pT stage and Risk group) and with IL-6/STAT inmunoexpression RESULTS: We observed an increase of CK2 in tumors. Regarding the subcellular distribution in normal tissue CK2alpha is predominantly cytoplasmic whereas tumors markedly increased in the core, with only a slight decrease in the cytoplasm, indicating nuclear overexpression CK2alpha tumors. CK2Beta changes are more discreet and its nuclear accumulation in tumors could be due to translocation from the cytoplasm, which is a marked decrease. Using 786-O cells, derived ccRCC pVHL deficient, and 786-O cells stably transfected with an expression vector pVHL, we have observed that the presence of VHL not decrease but it increases CK2alpha levels by altering the ratio between CK2alpha/CK2Beta. It was observed higher survival in the subset patients with underexpression of CK2sBeta although log-rank was not significant (0,301). The combination of overexpression of STAT3 and underexpression ok CK2Beta seems to provide a higher survival hazard ratio of 4,252 (95% IC, 1,182-18.413) CONCLUSIONS: The results indicate CK2alpha overexpression in clear cell renal cell carcinoma by a mechanism that does not appear due to inactivation of VHL. In patients with underexpression of IL-6/STAT3, CK2Beta was no able to discriminate any behaviour, but the patients defined as poor prognostic when STAT3 was overexpressed has similar survival than those that had underexpression of STAT3. The combination of overexpression of STAT3 and underexpression of CK2Beta provided a higher survival rate