Correlation between the presence of the nuclear AR-V7 androgen receptor and clinical evolution of prostate cancer: in vitro analysis of a combination of compounds targeting PI3K

Introduzione: PCa è una malattia multiforme e biologicamente molto eterogenea. Diversi meccanismi chiave nella progressione della malattia da androgeno-dipendente ad androgeno-indipendente (CRCP) possono essere attribuiti ad alterazione nella via di segnalazione di AR. Scopo: Il disegno del nostro progetto è di valutare in vitro gli effetti di diversi composti che hanno come target mutazioni diverse coinvolte nello sviluppo e nella progressione del tumore della prostata e confrontare questi risultati con l’esperienza clinica di risposta alla terapia di pazienti con PCa con diversa progressione ed espressione di AR-V7 nel nucleo. Materiali e Metodi: Docetaxel, appartiene al gruppo dei taxani. L’abiraterone, inibitore del CYP17A1, ha come bersaglio l’attività sia della 17α-idrossilasi che della 17,20-liasi. L’enzalutamide, inibitore non steroideo di seconda generazione che legandosi al AR con maggiore affinità, riduce l'efficienza della traslocazione nucleare di AR e compromette sia il legame del DNA agli elementi di risposta degli androgeni che il reclutamento di coattivatori. La linea cellulare LnCaP deriva da un linfonodo di un paziente con cancro della prostata metastatico, mantiene la sensibilità agli androgeni. Esprime PSA (prostate specific antigen) e PSMA (Prostate specific membrane antigen), mantiene p53 wt e presenta PTEN (phosphatase and tensin homolog) mutato che porta all’attivazione costitutiva della via di AKT. VCaP sono cellule che derivano da metastasi vertebrali isolate da una vertebra lombare di un paziente refrattario alla terapia ormonale. Queste cellule esprimono PSA e PAP (prostatic acid phosphatase). VCaP esprimono AR wt ma presentano un’amplificazione di AR risultando in livelli più elevati di AR-FL, inoltre presentano la variazione di splicing 7, AR-V7. Esprimono PTEN ed il gene di fusione TMPRSS2-ERGPTEN. Risultati: Su queste cellule stiamo valutando gli inibitori di PI3K/AKT/ mTOR, Wortmannin e RAD001 in combinazione con farmaci che interferiscono con la via di AR. Inoltre abbiamo valutato l’inibizione sulla survivina nelle cellule trattate con una combinazione di YM155 e Abiraterone, Enzalutamide, o Docetaxel. La Wortmannin, inibisce PI3K; RAD001, inibitore di mTOR; YM155, inibisce la survivina. Abbiamo scelto diverse concentrazioni e i trattamenti sono stati effettuati per 24, 48 e 72 ore. La sopravvivenza è stata valutata con MTT, e la morte delle cellule con la colorazione del tripan blue. Infine per valutare la capacità delle cellule trattate di rientrare nel ciclo cellulare abbiamo allestito un test di clonogenicità dopo trattamenti di 24 ore. Le cellule trattate a 24 ore sono state processate per l’estrazione dell’RNA, dobbiamo valutare in RT-PCR l’espressione di alcuni geni per vedere l’azione dei composti sul ciclo cellulare (ciclina D, p27) e l’apoptosi (Bcl-2, Bvl-xl e Bax e survivina). Abbiamo studiato i primer ( ciclina D1, p27, Bcl-2, Bvl-xl e Bax e survivina ) e messo a punto le condizioni di RT-PCR, usando il SYBR Green, più adeguate per vedere l’assetto di questi geni comparati al gene GADPH. Conclusioni: Dai primi risultati è emerso che il docetaxel ha una maggiore capacità di inibire la crescita cellulare di entrambe le linee cellulari: dopo trattamento con 5nM solo il 14% e il 30% rispettivamente LnCaP e delle VCap continuano a proliferare. Il trattamento con Abiraterone riduce del solo 40% la crescita delle LnCap e del 20% quella delle VCaP, mentre l’Enzalutamide riduce del 55% le LnCaP (sopravvivono 45%) e del 30% (sopravvivono 70%) le VCap. Il trattamento di queste cellule con inibitori di PI3K/AKT/mTor effettivamente riduce la sopravvivenza delle cellule esaminare. Da questi primi risultati sulle LnCap emerge inibendo PI3K/mTor aumenta anche l’efficacia del trattamento di sostanze che agiscono su momenti diversi della sensibilità agli androgeni. Sulle VCaP abbiamo un quadro meno completo, queste cellule crescono molto lentamente

Beyond the immune suppression: the immunotherapy in prostate cancer

Prostate cancer (PCa) is the second most common cancer in men.Aswell in many other human cancers, inflammation and immune suppression have an important role in their development.We briefly describe the host components that interact with the tumor to generate an immune suppressive environment involved in PCa promotion and progression.Different tools provide to overcome the mechanisms of immunosuppression including vaccines and immune checkpoint blockades. With regard to this, we report results of most recent clinical trials investigating immunotherapy in metastatic PCa (Sipuleucel-T, ipilimumab, tasquinimod, Prostvac-VF, and GVAX) and provide possible future perspectives combining the immunotherapy to the traditional therapie

Laparoscopic versus open radical prostatectomy in high prostate volume cases: impact on oncological and functional results

To prospectively compare the laparoscopic versus open approach to RP in cases with high prostate volume and to evaluate a possible diferente impact of prostate volume

A meta-analysis and systematic review of randomized controlled trials with degarelix versus gonadotropin-releasing hormone agonists for advanced prostate cancer

Our aim was to systematically evaluate the benefits of degarelix as antagonist versus agonists of gonadotropin-releasing hormones (GnRH) for the treatment of advanced prostate cancer (PC). This comparison was performed either in terms of biochemical or oncological or safety profiles. To this end we, carried out a systematic review and meta-analysis of the literature.We selected only studies directly and prospectively analyzing the two treatments in the same population (randomized phase III studies). We followed the Preferred Reporting Items for Systematic Reviews and meta-analyses process for reporting studies.After we eliminated studies according to the exclusion criteria, 9 publications were considered relevant to this review. These articles described 5 clinical trials that were eligible for inclusion. The follow-up duration in all trials did not exceed 364 days. This meta-analysis and review comprised a total of 1719 men, 1061 randomized to degarelix versus 658 to GnRH agonists treatment for advanced PC. Oncological results were evaluated only in 1 trial (CS21:408 cases) and they were not the primary endpoints of the study. Treatment emerging adverse events were reported in 61.4% and 58.8% of patients in the degarelix and GnRH agonists group, respectively (odds ratio, OR = 1.17; 95% confidence interval, 95% CI: 0.78-1.77, P > 0.1). Treatment related severe cardiovascular side effects were reported (trial CS21-30-35) in 1.6% and 3.6% of patients in the degarelix and GnRH agonists group, respectively (OR = 0.55, 95% CI: 0.26-1.14, P > 0.1).Our analysis evidences relevant limitations in particular for the comparative evaluation of the efficacy and the oncological results related to degarelix

Influence of statin use on clinicopathological characteristics of localized prostate cancer and outcomes obtained after radical prostatectomy: a single center study

To assess the impact of statin use on biochemical recurrence (BCR) of prostate cancer after radical prostatectomy (RP)

Using next generation matrices to estimate the proportion of infections that are not detected in an outbreak

Contact tracing, where exposed individuals are followed up to break ongoing transmission chains, is a key pillar of outbreak response for infectious disease outbreaks. Unfortunately, these systems are not fully effective, and infections can still go undetected as people may not remember all their contacts or contacts may not be traced successfully. A large proportion of undetected infections suggests poor contact tracing and surveillance systems, which could be a potential area of improvement for a disease response. In this paper, we present a method for estimating the proportion of infections that are not detected during an outbreak. Our method uses next generation matrices that are parameterized by linked contact tracing data and case line-lists. We validate the method using simulated data from an individual-based model and then investigate two case studies: the proportion of undetected infections in the SARS-CoV-2 outbreak in New Zealand during 2020 and the Ebola epidemic in Guinea during 2014. We estimate that only 5.26% of SARS-CoV-2 infections were not detected in New Zealand during 2020 (95% credible interval: 0.243 – 16.0%) if 80% of contacts were under active surveillance but depending on assumptions about the ratio of contacts not under active surveillance versus contacts under active surveillance 39.0% or 37.7% of Ebola infections were not detected in Guinea (95% credible intervals: 1.69 – 87.0% or 1.70 – 80.9%)

Value of magnetic resonance spectroscopy imaging and dynamic contrast-enhanced imaging for detecting prostate cancer foci in men with prior negative biopsy

Purpose: This study aimed to prospectively analyze the role of magnetic resonance spectroscopy imaging (MRSI) and dynamic-contrast enhancement magnetic resonance (DCEMR) in the detection of prostate tumor foci in patients with persistently elevated prostate-specific antigen levels (in the range of >= 4 ng/mL to <10 ng/mL) and prior negative random trans-rectal ultrasound (TRUS)-guided biopsy. Experimental Design: This was a prospective randomized single-center study. One hundred and eighty eligible cases were included in the study. Patients in group A were submitted to a second random prostate biopsy, whereas patients in group B were submitted to a (1)H-MRSI-DCEMR examination and samples targeted on suspicious areas were associated to the random biopsy. Results: At the second biopsy, a prostate adenocarcinoma histologic diagnosis was found in 22 of 90 cases (24.4%) in group A and in 41 of 90 cases (45.5%) in group B (P = 0.01). On a patient-by-patient basis, MRSI had 92.3% sensitivity, 88.2% specificity, 85.7% positive predictive value (PPV), 93.7% negative predictive value (NPV), and 90% accuracy; DCEMR had 84.6% sensitivity, 82.3% specificity, 78.5% PPV, 87.5% NPV, and 83.3% accuracy; and the association MRSI plus DCEMR had 92.6% sensitivity, 88.8% specificity, 88.7% PPV, 92.7% NPV, and 90.7% accuracy, for predicting prostate cancer detection. Conclusions: The combination of MRSI and DCEMR showed the potential to guide biopsy to cancer foci in patients with previously negative TRUS biopsy. To avoid a potential bias, represented from having taken more samples in group B (mean of cores, 12.17) than in group A (10 cores), in the future a MRSI/DCEMR directed biopsy could be prospectively compared with a saturation biopsy procedure. Clin Cancer Res; 16(6); 1875-83. (C) 2010 AACR

Modern role of magnetic resonance and spectroscopy in the imaging of prostate cancer

Recently, a large number of studies have shown that the addition of proton 1H-spectroscopic imaging (1H-MRSI) and dynamic contrast enhanced imaging (DCEMR) to magnetic resonance (MR) could represent a powerful tool for the management of prostate cancer (CaP) in most of its aspects. This combination of MR techniques can substantially sustain the clinical management of patients with CaP at different levels: in particular, (1) in the initial assessment, reducing the need for more extensive biopsies and directing targeted biopsies; (2) in the definition of a biochemical progression after primary therapies, distinguishing between fibrotic reaction and local recurrence from CaP. (C) 2011 Elsevier Inc. All rights reserved

Integrated models, frameworks and decision support tools to guide management and planning in Northern Australia. Final report

[Extract] There is a lot of interest in developing northern Australia while also caring for the unique Australian landscape (Commonwealth of Australia 2015). However, trying to decide how to develop and protect at the same time can be a challenge. There are many modelling tools available to inform these decisions, including integrated models, frameworks, and decision support tools, but there are so many different kinds that it’s difficult to determine which might be best suited to inform different decisions. To support planning and development decisions across northern Australia, this project aimed to create resources to help end-users (practitioners) to assess: 1. the availability and suitability of particular modelling tools; and 2. the feasibility of using, developing, and maintaining different types of modelling tools

Which factors can influence post-operative renal function preservation after nephron-sparing surgery for kidney cancer: a critical review

Introduction: The aim of this article was to compare different surgical approaches to perform nephron-sparing surgery (NSS) in terms of preservation of renal function. Material and methods: We critically reviewed the literature from January 2000 to December 2020 including studies comparing different surgical techniques. Results: A total of 51 studies met the inclusion criteria. Functional outcomes were evalutated in terms of percentual change of estimated glomerular filtration rate (eGFR) and impaired renal function (IRF) on scintigraphy. In cases with a mean age <60 years, the mean decrease in eGFR after NSS was 11.7% and that of IRF 10.0%, whereas higher changes were found in cases with a mean age ≥60 years. For open NSS, the mean eGFR and IRF changes were 15.3% and 21.1%, respectively; using the laparoscopic approach, the mean percentual eGFR and IRF changes were 13.9% and 11.1%, respectively; in robotic cases, the mean eGFR and IRF changes were 10.8% and 13.1%, respectively. In cases performed with global ischemia, the mean eGFR and IRF changes were 12.7% and 15.1%, respectively. Similar results were found distinguishing ischemia time ≤20 and >20 minutes, whereas using the off-clamp technique the mean decreases in eGFR and IRF were only 4.2% and 6%, respectively. Conclusions: Patients' age, tumor size, off-clamp technique, and robot-assisted approach were significant independent predictive factors able to influence renal function changes after NSS. A lower reduction of eGFR and IRF after NSS was reported in patients aged <60 years, submitted to a robot-assisted procedure, and using selective and cold ischemia <20 minutes or an off-clamp technique