Environmental and genetic aspects are reflected in the development of prostate cancer. In this context, there is growing evidence that chronic inflammation is involved in the regulation of cellular ...events in prostate carcinogenesis, including disruption of the immune response and regulation of the tumour microenvironment.
One of the best surrogates of chronic inflammation in prostate cancer is interleukin 6 (IL‐6). Serum IL‐6 levels are elevated in patients with untreated metastatic or castration‐resistant prostate cancer (CRPC) and correlate negatively with tumour survival and response to chemotherapy. Via multiple signal pathways including the Janus tyrosine family kinase (JAK)‐signal transducer and activator of transcription (STAT) pathway, the extracellular signal‐regulated kinase 1 and 2 (ERK1/2)‐mitogen activated protein kinase (MAPK) pathway, and the phosphoinositide 3‐kinase (PI3‐K) pathway, IL‐6 is able to promote prostate cancer cell proliferation and inhibit apoptosis in vitro and in vivo.
IL‐6 is associated with aggressive prostate cancer phenotype and may be involved in the metastatic process through regulation of epithelial–mesenchymal transition (EMT) and homing of cancer cells to the bone.
A substantial body of evidence suggests that IL‐6 plays a major role in the transition from hormone‐dependent to CRPC, most notably through accessory activation of the androgen receptor.
Collectively, these data have stimulated the development of agents targeting IL‐6 signalling pathways. A chimeric anti‐IL‐6 monoclonal antibody has been tested in clinical trials, with mixed results.
Biocompatible gold nanoparticles designed to absorb light at wave-lengths of high tissue transparency have been of particular interest for biomedical applications. The ability of such nanoparticles ...to convert absorbed near-infrared light to heat and induce highly localized hyperthermia has been shown to be highly effective for photothermal cancer therapy, resulting in cell death and tumor remission in a multitude of preclinical animal models. Here we report the initial results of a clinical trial in which laser-excited gold-silica nanoshells (GSNs) were used in combination with magnetic resonance–ultrasound fusion imaging to focally ablate low-intermediate-grade tumors within the prostate. The overall goal is to provide highly localized regional control of prostate cancer that also results in greatly reduced patient morbidity and improved functional outcomes. This pilot device study reports feasibility and safety data from 16 cases of patients diagnosed with low- or intermediate-risk localized prostate cancer. After GSN infusion and high-precision laser ablation, patients underwent multiparametric MRI of the prostate at 48 to 72 h, followed by postprocedure mpMRI/ultrasound targeted fusion biopsies at 3 and 12 mo, as well as a standard 12-core systematic biopsy at 12 mo. GSN-mediated focal laser ablation was successfully achieved in 94% (15/16) of patients, with no significant difference in International Prostate Symptom Score or Sexual Health Inventory for Men observed after treatment. This treatment protocol appears to be feasible and safe in men with low- or intermediate-risk localized prostate cancer without serious complications or deleterious changes in genitourinary function.
Abstract Background Although the initial robot-assisted radical prostatectomy (RARP) series showed 12-mo potency rates ranging from 70% to 80%, the few available comparative studies did not permit ...any definitive conclusion about the superiority of this technique when compared with retropubic radical prostatectomy (RRP) and laparoscopic radical prostatectomy (LRP). Objectives The aims of this systematic review were (1) to evaluate the current prevalence and the potential risk factors of erectile dysfunction after RARP, (2) to identify surgical techniques able to improve the rate of potency recovery after RARP, and (3) to perform a cumulative analysis of all available studies comparing RARP versus RRP or LRP. Evidence acquisition A literature search was performed in August 2011 using the Medline, Embase, and Web of Science databases. Only comparative studies or clinical series including >100 cases reporting potency recovery outcomes were included in this review. Cumulative analysis was conducted using Review Manager v.4.2 software designed for composing Cochrane Reviews (Cochrane Collaboration, Oxford, UK). Evidence synthesis We analyzed 15 case series, 6 studies comparing different techniques in the context of RARP, 6 studies comparing RARP with RRP, and 4 studies comparing RARP with LRP. The 12- and 24-mo potency rates ranged from 54% to 90% and from 63% to 94%, respectively. Age, baseline potency status, comorbidities index, and extension of the nerve-sparing procedure represent the most relevant preoperative and intraoperative predictors of potency recovery after RARP. Available data seem to support the use of cautery-free dissection or the use of pinpointed low-energy cauterization. Cumulative analyses showed better 12-mo potency rates after RARP in comparison with RRP (odds ratio OR: 2.84; 95% confidence interval CI: 1.46–5.43; p = 0.002). Only a nonstatistically significant trend in favor of RARP was reported after comparison with LRP (OR: 1.89; p = 0.21). Conclusions The incidence of potency recovery after RARP is influenced by numerous factors. Data coming from the present systematic review support the use of a cautery-free technique. This update of previous systematic reviews of the literature showed, for the first time, a significant advantage in favor of RARP in comparison with RRP in terms of 12-mo potency rates.
Extracellular vesicles (EVs) offer many opportunities in early-stage disease diagnosis, treatment monitoring, and precision therapy owing to their high abundance in bodily fluids, accessibility from ...liquid biopsy, and presence of nucleic acid and protein cargo from their cell of origin. Despite their growing promise, isolation of EVs for analysis remains a labor-intensive and time-consuming challenge given their nanoscale dimensions (30-200 nm) and low buoyant density. Here, we report a simple, size-based EV separation technology that integrates 1024 nanoscale deterministic lateral displacement (nanoDLD) arrays on a single chip capable of parallel processing sample fluids at rates of up to 900 μL h-1. Benchmarking the nanoDLD chip against commonly used EV isolation technologies, including ultracentrifugation (UC), UC plus density gradient, qEV size-exclusion chromatography (Izon Science), and the exoEasy Maxi Kit (QIAGEN), we demonstrate a superior yield of ∼50% for both serum and urine samples, representing the ability to use smaller input volumes to achieve the same number of isolated EVs, and a concentration factor enhancement of up to ∼3× for both sample types, adjustable to ∼60× for urine through judicious design. Further, RNA sequencing was carried out on nanoDLD- and UC-isolated EVs from prostate cancer (PCa) patient serum samples, resulting in a higher gene expression correlation between replicates for nanoDLD-isolated EVs with enriched miRNA, decreased rRNA, and the ability to detect previously reported RNA indicators of aggressive PCa. Taken together, these results suggest nanoDLD as a promising alternative technology for fast, reproducible, and automatable EV-isolation.
Abstract Context Pelvic lymph node dissection (PLND) in prostate cancer is the most effective method for detecting lymph node metastases. However, a decline in the rate of PLND during radical ...prostatectomy (RP) has been noted. This is likely the result of prostate cancer stage migration in the prostate-specific antigen-screening era, and the introduction of minimally invasive approaches such as robot-assisted radical prostatectomy (RARP). Objective To assess the efficacy, limitations, and complications of PLND during RARP. Evidence acquisition A review of the literature was performed using the Medline, Scopus, and Web of Science databases with no restriction of language from January 1990 to December 2012. The literature search used the following terms: prostate cancer, radical prostatectomy, robot-assisted , and lymph node dissection. Evidence synthesis The median value of nodal yield at PLND during RARP ranged from 3 to 24 nodes. As seen in open and laparoscopic RP series, the lymph node positivity rate increased with the extent of dissection during RARP. Overall, PLND-only related complications are rare. The most frequent complication after PLND is symptomatic pelvic lymphocele, with occurrence ranging from 0% to 8% of cases. The rate of PLND-associated grade 3–4 complications ranged from 0% to 5%. PLND is associated with increased operative time. Available data suggest equivalence of PLND between RARP and other surgical approaches in terms of nodal yield, node positivity, and intraoperative and postoperative complications. Conclusions PLND during RARP can be performed effectively and safely. The overall number of nodes removed, the likelihood of node positivity, and the types and rates of complications of PLND are similar to pure laparoscopic and open retropubic procedures.
Over the years, several techniques for performing robot-assisted prostatectomy have been implemented in an effort to achieve optimal oncological and functional outcomes.
To provide an evidence-based ...description and video-based illustration of currently available dissection techniques for robotic prostatectomy.
A literature search was performed to retrieve articles describing different surgical approaches and techniques for robot-assisted radical prostatectomy (RARP) and to analyze data supporting their use. Video material was provided by experts in the field to illustrate these approaches and techniques.
Multiple surgical approaches are available: extraperitoneal, transvesical, transperitoneal posterior, transperitoneal anterior, Retzius sparing, and transperineal. Surgical techniques for prostatic dissection sensu strictu are the following: omission of the endopelvic fascia dissection, bladder neck preservation, incremental nerve sparing by means of an antegrade or retrograde approach, and preservation of the puboprostatic ligaments and dorsal venous complex. Recently, techniques for total or partial prostatectomy have been described.
Different surgical approaches and techniques for robotic prostatectomy have been analyzed.
Two randomized controlled trials evaluating the extraperitoneal versus the transperitoneal approach have demonstrated similar results. Level I evidence on the Retzius-sparing approach demonstrated earlier return to continence than the traditional anterior approach. The question whether Retzius-sparing RARP is associated with a higher rate of positive surgical margins is still open due to the intrinsic bias in terms of surgical expertise in the available comparative studies. This technique also offers an advantage in patients who have received kidney transplantation. Retrospective evidence suggests that the more the anatomical dissection (eg., more periprostatic tissue is preserved), the better the functional outcome in terms of continence. Yet, two randomized controlled trials evaluating the different techniques of dissection have so far been produced. Partial prostatectomies should not be offered outside clinical trials.
Several techniques and approaches are available for prostate dissection during RARP. While the Retzius-sparing approach seems to provide earlier return to continence than the traditional anterior transperitoneal approach, no technique has been proved to be superior to other(s) in terms of long-term outcomes in randomized studies.
We have summarized available approaches for the surgical treatment of prostate cancer. Specifically, we described the different techniques that can be adopted for the surgical removal of the prostate using robotic technology.
Abstract Context Despite the large diffusion of robot-assisted radical prostatectomy (RARP), literature and data on the oncologic outcome of RARP are limited. Objective Evaluate lymph node yield, ...positive surgical margins (PSMs), use of adjuvant therapy, and biochemical recurrence (BCR)–free survival following RARP and perform a cumulative analysis of all studies comparing the oncologic outcomes of RARP and retropubic radical prostatectomy (RRP) or laparoscopic radical prostatectomy (LRP). Evidence acquisition A systematic review of the literature was performed in August 2011, searching Medline, Embase, and Web of Science databases. A free-text protocol using the term radical prostatectomy was applied. The following limits were used: humans; gender (male); and publications dating from January 1, 2008. A cumulative analysis was conducted using Review Manager software v.4.2 (Cochrane Collaboration, Oxford, UK) and Stata 11.0 SE software (StataCorp, College Station, TX, USA). Evidence synthesis We retrieved 79 papers evaluating oncologic outcomes following RARP. The mean PSM rate was 15% in all comers and 9% in pathologically localized cancers, with some tumor characteristics being the most relevant predictors of PSMs. Several surgeon-related characteristics or procedure-related issues may play a major role in PSM rates. With regard to BCR, the very few papers with a follow-up duration >5 yr demonstrated 7-yr BCR-free survival estimates of approximately 80%. Finally, all the cumulative analyses comparing RARP with RRP and comparing RARP with LRP demonstrated similar overall PSM rates (RARP vs RRP: odds ratio OR: 1.21; p = 0.19; RARP vs LRP: OR: 1.12; p = 0.47), pT2 PSM rates (RARP vs RRP: OR: 1.25; p = 0.31; RARP vs LRP: OR: 0.99; p = 0.97), and BCR-free survival estimates (RARP vs RRP: hazard ratio HR: 0.9; p = 0.526; RARP vs LRP: HR: 0.5; p = 0.141), regardless of the surgical approach. Conclusions PSM rates are similar following RARP, RRP, and LRP. The few data available on BCR from high-volume centers are promising, but definitive comparisons with RRP or LRP are not currently possible. Finally, significant data on cancer-specific mortality are not currently available.
Impairment of double-stranded DNA break (DSB) repair is essential to many cancers. However, although mutations in DSB repair proteins are common in hereditary cancers, mechanisms of impaired DSB ...repair in sporadic cancers remain incompletely understood. Here, we describe the first role for a long noncoding RNA (lncRNA) in DSB repair in prostate cancer. We identify PCAT-1, a prostate cancer outlier lncRNA, which regulates cell response to genotoxic stress. PCAT-1 expression produces a functional deficiency in homologous recombination through its repression of the BRCA2 tumor suppressor, which, in turn, imparts a high sensitivity to small-molecule inhibitors of PARP1. These effects reflected a posttranscriptional repression of the BRCA2 3'UTR by PCAT-1. Our observations thus offer a novel mechanism of "BRCAness" in sporadic cancers.
Intratumor heterogeneity in prostate cancer Yadav, Shalini S.; Stockert, Jennifer A.; Hackert, Victoria ...
Urologic oncology,
August 2018, 2018-08-00, 20180801, Letnik:
36, Številka:
8
Journal Article
Recenzirano
Prostate cancer (PCa) has long been thought of as a disease with a heterogeneous phenotype. It can manifest in men as benign growths that can be safely watched or as more aggressive malignancies that ...can prove fatal. Recent investigations at the genomic, histopathological and molecular levels have identified tumor heterogeneity, the phenomenon of individual tumor cells presenting distinct genomic and phenotypic characteristics, as one of the most confounding and complex factors underlying PCa diagnosis, prognosis, and treatment. Despite tremendous progress made over the course of the last decade we still have an incomplete understanding of the extent and effect of intra- and inter-tumoral heterogeneity in the course of PCa progression. For example, a primary tumor can be classified into one of several molecular subgroups depending on whether the cancer has a particular gene fusion or a mutation which in turn might yield some patient-specific therapeutic regimen, but this same type of heterogeneous growth can be spatially or temporally restricted proving it difficult to detect during biopsy. We therefore present here a comprehensive review of the various studies addressing intra-tumor heterogeneity in PCa and in the context of that seen in other solid tumors. We discuss the impact of heterogeneity on clinical decision-making in treating both primary and metastatic lesions and how our understanding of this heterogeneity might help in developing better diagnostic tools and biomarkers and in guiding the selection of better therapeutic strategies.
•Intra-tumor heterogeneity (ITH) in prostate cancer is a major confounding factor influencing disease progression.•Cancer stem cell, clonal (liner, braided river, or neutral), and punctuated-evolution models have been proposed to understand ITH.•Multifocal tumors in the prostate are common, and further challenge accurate prognosis.•Monoclonal origin and field effect hypotheses have been proposed to explain multifocality in prostate cancer.•ITH also plays a role in metastasis, and circulating tumor cell (CTC) and disseminated tumor cell (DTC) spread and survival.
Extracellular vesicles (EVs) have brought great momentum to the non-invasive liquid biopsy procedure for the detection, characterization, and monitoring of cancer. Despite the common use of PSA ...(prostate-specific antigen) as a biomarker for prostate cancer, there is an unmet need for a more specific diagnostic tool to detect tumor progression and recurrence. Exosomes, which are EVs that are released from all cells, play a large role in physiology and pathology, including cancer. They are involved in intercellular communication, immune function, and they are present in every bodily fluid studied-making them an excellent window into how cells are operating. With liquid biopsy, EVs can be isolated and analyzed, enabling an insight into a potential therapeutic value, serving as a vehicle for drugs or nucleic acids that have anti-neoplastic effects. The current application of advanced technology also points to higher-sensitivity detection methods that are minimally invasive. In this review, we discuss the current understanding of the significance of exosomes in prostate cancer and the potential diagnostic value of these EVs in disease progression.
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