Obesity favours the occurrence of locally disseminated prostate cancer in the periprostatic adipose tissue (PPAT) surrounding the prostate gland. Here we show that adipocytes from PPAT support the ...directed migration of prostate cancer cells and that this event is strongly promoted by obesity. This process is dependent on the secretion of the chemokine CCL7 by adipocytes, which diffuses from PPAT to the peripheral zone of the prostate, stimulating the migration of CCR3 expressing tumour cells. In obesity, higher secretion of CCL7 by adipocytes facilitates extraprostatic extension. The observed increase in migration associated with obesity is totally abrogated when the CCR3/CCL7 axis is inhibited. In human prostate cancer tumours, expression of the CCR3 receptor is associated with the occurrence of aggressive disease with extended local dissemination and a higher risk of biochemical recurrence, highlighting the potential benefit of CCR3 antagonists in the treatment of prostate cancer.
Purpose To measure the precision in placement of a biopsy needle in a magnetic resonance (MR) imaging-detected target with transrectal ultrasonography (US), to document the clinical relevance of ...precision, and to report on the precision of cognitive and software-based registrations. Materials and Methods This prospective study was approved by the institutional review board and performed between June 2013 and September 2013. Patients provided informed verbal consent. Two cores each were obtained with cognitive and fusion techniques in 88 patients with a Prostate Imaging Reporting and Data System version 1 score of at least 3. Precision was measured with Euclidian geometry by using the Digital Imaging and Communications in Medicine archives of the biopsy as the distance from the core to the center (dCC) and the distance from the core to the surface of the target modeled as a sphere. To address clustering of data from multiple cores in the same patients, analyses of precision focused on the best shot for a patient or a technique. The Welch unequal variance t test and Yates corrected χ
test were used as appropriate. Results Mean precision was 2.5 mm (95% confidence interval: 1.8 mm, 3.3 mm). Positive cores were closer to the center than were negative cores (dCC: 1.7 mm vs 3.1 mm, respectively; P = .025). More cancers were detected with on-target than off-target cores (33 of 71 cores 46.5% vs three of 17 cores 17.6%; P = .03). Cores obtained with the fusion technique achieved a higher precision than did cores obtained with the cognitive technique (dCC: 2.8 mm vs 7.1 mm, respectively; P < .0001). Targeted cores demonstrated cancer in 44 patients. Fewer cancers were detected with the cognitive technique than with the fusion technique (31 of 44 patients 70.5% vs 40 of 44 patients 90.9%; P = .03). Conclusion A deformable MR imaging/transrectal US image registration system achieved a higher precision and depicted cancer in more patients than did the cognitive freehand technique.
RSNA, 2018.
Focal therapy (FT) and partial gland ablation (PGA) are quickly adopted by urologists and radiologists as an option for the management of localized prostate cancer.
To find consensus on a ...standardized nomenclature and to define a follow-up guideline after FT and PGA for localized prostate cancer in clinical practice.
A review of the literature identified controversial topics in the field of FT. Online questionnaires were distributed to experts during three rounds, with the goal to achieve consensus on debated topics. The consensus project was concluded with a face-to-face meeting in which final conclusions were formulated.
Controlled feedback of responses of previous rounds were summarized and returned to the participants allowing them to re-evaluate their decisions. The level of agreement to achieve consensus on a topic was set at 80%.
Sixty-five experts participated in this interdisciplinary consensus study (72% urologists; 28% radiologists). The experts propose the use of the herein standardized nomenclature for ablative procedures. After FT/PGA, the following tests should be performed to assess treatment outcomes: prostate-specific antigen (PSA), imaging, biopsies, and functional outcome assessment. Although not a reliable marker for treatment failure, PSA should be measured every 3 mo in the 1st year and every 6 mo thereafter. Magnetic resonance imaging is the preferred image modality and should be performed at 6 and 18 mo after treatment. A systematic 12-core transrectal ultrasound-guided biopsy combined with a targeted biopsy of the treated area should be performed 6–12 mo after treatment. Functional outcomes should be obtained 3–6 mo after treatment for the first time and until stability is attained.
The panel recommends the use of the proposed nomenclature and follow-up protocols to generate reliable data supporting a broader implementation of FT as a standard of care for select patients with localized prostate cancer.
In this report, we present expert opinion on the use of a standardized nomenclature, and surveillance methodologies after focal therapy and partial gland ablation for localized prostate cancer.
In this report, we present expert opinion on the use of a standardized nomenclature and surveillance methodologies after focal therapy and partial gland ablation for localized prostate cancer. The panel recommends the use of the proposed nomenclature and follow-up protocols to generate reliable data supporting a broader implementation of focal therapy as a standard of care for select patients with localized prostate cancer.
Pelvic exenteration combines multiple organ resections and functional reconstruction. Many techniques have been described for urinary reconstruction, although only a few are routinely used. The aim ...of this review is to focus beyond the technical aspects and the advantages and disadvantages of each technique, and to include a critical analysis of continent techniques in the gynecologic and urologic literature. Selecting a technique for urinary reconstruction must take into account the constraints entailed by the natural history of the disease, patient characteristics, healthcare institution, and surgeon experience. In gynecologic oncology, the Bricker ileal conduit is the most commonly employed diversion, followed by the self-catheterizable pouch and orthotopic bladder replacement. Continent and non-continent diversions present similar immediate and long-term complication rates, including lower tract urinary infections and pyelonephritis (5-50%), ureteral stricture (3-27%), urolithiasis (5-25%), urinary fistula (5%), and more rarely, vitamin B
deficiency and metabolic acidosis. Urinary incontinence for the ileal orthotopic neobladder (50%), stoma-related complications for the Bricker ileal conduit (24%), difficulty with self-catheterization (18%) for the continent pouch, and induction of secondary malignancy for the ureterosigmoidostomy (3%) are the most relevant technique-related complications following urinary diversion. The self-catheterizable pouch and orthotopic bladder require a longer learning curve from the surgical team and demand adaptation from the patient compared with the ileal conduit. Quality of life between different techniques remains controversial, although it would seem that young patients may benefit from continent diversions. We consider that centralization of pelvic exenteration in referral centers is crucial to optimize the oncologic and functional outcomes of complex ablative reconstructive surgery.
The purpose of the review is to summarize the recent data on circulating tumor cells (CTC) use in clinical practice. We performed a systematic literature search using two databases (Medline and ...Scopus) over the past five years and the following terms: (CTC OR “circulating tumor cells” OR “liquid biopsy”) AND prostate. The primary outcome was CTC predictive value for prostate cancer (PC) progression and survival. The secondary outcomes were the CTC predictive value for therapy response and the results of CTC detection depending on the assessment method. In metastatic PC, the CTC count showed itself to be a prognostic marker in terms of clinically important features, namely survival rates and response to treatment. CTC concentration was significantly associated with the overall survival and progression-free survival rates. A strong association between the overall survival or progression-free survival rate and CTC concentration could be observed. Variant-7 androgen receptors-positive (AR-V7-positive) patients showed a poor response to androgen receptor signaling (ARS) inhibitors, but this did not compromise their response to taxanes. In localized PC, only positive Cluster of Differentiantion 82 protein (CD82+) correlated with a higher survival rate. CTC count and AR-V7 expression showed itself to be a valuable biomarker for survival in metastatic PC and response to ARS-inhibitors. CTC diagnostic performance for localized PC or for screening and early detection is not high enough to show additional value over the other biomarkers.
The reduction in the normal level of tissue oxygen tension or hypoxia is a characteristic of solid tumors that triggers the activation of signaling pathways promoting neovascularization, metastasis, ...increased tumor growth, and resistance to treatments. The activation of the transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha) has been identified as the master mechanism of adaptation to hypoxia. In a recent study, we identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway, which elicits various cellular processes including cell proliferation, cell survival, or angiogenesis, as a new modulator of HIF-1alpha activity under hypoxic conditions. Here, we consider how the SphK1/S1P signaling pathway could represent a very important target for therapeutic intervention in cancer.
This is the first report of sphingosine 1-phosphate lyase (SPL) protein expression and enzymatic activity in human neoplasm. This enzyme drives irreversible degradation of sphingosine 1-phosphate ...(S1P), a bioactive lipid associated with resistance to therapeutics in various cancers, including prostate adenocarcinoma. In fresh human prostatectomy specimens, a remarkable decrease in SPL enzymatic activity was found in tumor samples, as compared with normal adjacent tissues. A significant relationship between loss of SPL expression and higher Gleason score was confirmed in tissue microarray (TMA) analysis. Moreover, SPL protein expression and activity were inversely correlated with those of sphingosine kinase-1 (SphK1), the enzyme producing S1P. SPL and SphK1 expressions were independently predictive of aggressive cancer on TMA, supporting the relevance of S1P in prostate cancer. In human C4-2B and PC-3 cell lines, silencing SPL enhanced survival after irradiation or chemotherapy by decreasing expression of proteins involved in sensing and repairing DNA damage or apoptosis, respectively. In contrast, enforced expression of SPL sensitized cancer cells to irradiation or docetaxel by tilting the ceramide/S1P balance toward cell death. Interestingly, the S1P degradation products failed to sensitize to chemo- and radiotherapy, supporting the crucial role of ceramide/S1P balance in cancer. Of note, the combination of SPL enforced expression with a SphK1 silencing strategy by further decreasing S1P content made prostate cancer cells even more sensitive to anticancer therapies, suggesting that a dual strategy aimed at stimulating SPL, and inhibiting SphK1 could represent a future approach to sensitize cancer cells to cancer treatments.
Purpose
The current COVID-19 pandemic is transforming our urologic practice and most urologic societies recommend to defer any surgical treatment for prostate cancer (PCa) patients. It is unclear ...whether a delay between diagnosis and surgical management (i.e., surgical delay) may have a detrimental effect on oncologic outcomes of PCa patients. The aim of the study was to assess the impact of surgical delay on oncologic outcomes.
Methods
Data of 926 men undergoing radical prostatectomy across Europe for intermediate and high-risk PCa according to EAU classification were identified. Multivariable analysis using binary logistic regression and Cox proportional hazard model tested association between surgical delay and upgrading on final pathology, lymph-node invasion (LNI), pathological locally advanced disease (pT3–4 and/or pN1), need for adjuvant therapy, and biochemical recurrence. Kaplan–Meier analysis was used to estimate BCR-free survival after surgery as a function of surgical delay using a 3 month cut-off.
Results
Median follow-up and surgical delay were 26 months (IQR 10–40) and 3 months (IQR 2–5), respectively. We did not find any significant association between surgical delay and oncologic outcomes when adjusted to pre- and post-operative variables. The lack of such association was observed across EAU risk categories.
Conclusion
Delay of several months did not appear to adversely impact oncologic results for intermediate and high-risk PCa, and support an attitude of deferring surgery in line with the current recommendation of urologic societies.
Bone metastasis remains the most frequent and the deadliest complication of prostate cancer (PCa). Mechanisms leading to the homing of tumor cells to bone remain poorly characterized. Role of ...chemokines in providing navigational cues to migrating cancer cells bearing specific receptors is well established. Bone is an adipocyte-rich organ since 50 to 70% of the adult bone marrow (BM) volume comprise bone marrow adipocytes (BM-Ads), which are likely to produce chemokines within the bone microenvironment. Using in vitro migration assays, we demonstrated that soluble factors released by
primary BM-Ads are able to support the directed migration of PCa cells in a CCR3-dependent manner. In addition, we showed that CCL7, a chemokine previously involved in the CCR3-dependent migration of PCa cells outside of the prostate gland, is released by
BM-Ads. These effects are amplified by obesity and ageing, two clinical conditions known to promote aggressive and metastatic PCa. In
tumors, we found an enrichment of CCR3 in bone metastasis vs. primary tumors at mRNA levels using Oncomine microarray database. In addition, immunohistochemistry experiments demonstrated overexpression of CCR3 in bone versus visceral metastases. These results underline the potential importance of BM-Ads in the bone metastatic process and imply a CCR3/CCL7 axis whose pharmacological interest needs to be evaluated.
Radiotherapy is widely used as a radical treatment for prostate cancer, but curative treatments are elusive for poorly differentiated tumors where survival is just 15% at 15 years. Dose escalation ...improves local response rates but is limited by tolerance in normal tissues. A sphingosine analogue, FTY720 (fingolimod), a drug currently in phase III studies for treatment of multiple sclerosis, has been found to be a potent apoptosis inducer in prostate cancer cells. Using in vitro and in vivo approaches, we analyzed the impact of FTY720 on sphingolipid metabolism in hormone-refractory metastatic prostate cancer cells and evaluated its potential as a radiosensitizer on cell lines and prostate tumor xenografts. In prostate cancer cell lines, FTY720 acted as a sphingosine kinase 1 (SphK1) inhibitor that induced prostate cancer cell apoptosis in a manner independent of sphingosine-1-phosphate receptors. In contrast, γ irradiation did not affect SphK1 activity in prostate cancer cells yet synergized with FTY720 to inhibit SphK1. In mice bearing orthotopic or s.c. prostate cancer tumors, we show that FTY720 dramatically increased radiotherapeutic sensitivity, reducing tumor growth and metastasis without toxic side effects. Our findings suggest that low, well-tolerated doses of FTY720 could offer significant improvement to the clinical treatment of prostate cancer.
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