Vincent Fradet

Nuclear Factor-κB Nuclear Localization Is Predictive of Biochemical Recurrence in Patients with Positive Margin Prostate Cancer

Purpose: Radical prostatectomy (RP) patients with positive surgical margins are at increased risk for recurrence, emphasizing the need for prognostic markers to stratify probable outcome for optimal patient management decisions. We tested the hypothesis that nuclear localization of nuclear factor (NF)-κB, a transcription factor involved in the regulation of cell growth, angiogenesis, invasion, and apoptosis, is associated with an increased risk of biochemical recurrence after RP. Experimental Design: Analyses addressed data from 42 patients (age range, 52–72 years; mean age, 63.7 years) who exhibited positive surgical margins after RP. Immunohistochemical analysis of NF-κB (p65) was performed on the positive margin tissue. A nuclear staining cutoff of >5% was considered positive. The relation between nuclear NF-κB expression and biochemical recurrence (prostate-specific antigen >0.3 ng/mL and rising) after RP was tested in univariate and multivariate Cox regression models. Results: Biochemical recurrence was recorded in 23 patients (54.8%; median follow-up, 3.2 years). Univariate Cox regression demonstrated a 4.9-fold (95% confidence interval, 1.5–16.7; P = 0.01) higher rate of recurrence in men with NF-κB > 5%. In the multivariate model, after controlling for primary (P = 0.004) and secondary (P = 0.7) Gleason patterns, lymph node (P = 0.06) and seminal vesicle invasion (P = 0.2), and preoperative prostate-specific antigen (P = 0.009), NF-κB > 5% was associated with a 6.2-fold higher risk of biochemical recurrence (95% confidence interval, 1.7–23.5; P = 0.007). Conclusions: In univariate and multivariate analysis, NF-κB nuclear expression was strongly predictive of biochemical recurrence in patients with positive surgical margins after RP. We propose that nuclear NF-κB may serve as a useful independent molecular marker for stratifying patients at risk for recurrence.

The Impact of Solitary and Multiple Positive Surgical Margins on Hard Clinical End Points in 1712 Adjuvant Treatment–Naive pT2–4 N0 Radical Prostatectomy Patients

BACKGROUNDnPositive surgical margins (PSMs) increase the risk of biochemical recurrence (BCR) after radical prostatectomy (RP), but their impact on hard clinical end points is a topic of ongoing discussion.nnnOBJECTIVEnTo evaluate the influence of solitary PSMs (sPSMs) and multiple PSMs (mPSMs) on important clinical end points.nnnDESIGN, SETTING, AND PARTICIPANTSnData from 1712 patients from the Centre Hospitalier Universitaire de Québec with pT2-4 N0 prostate cancer (PCa) and undetectable prostate-specific antigen after RP were analyzed.nnnINTERVENTIONnRP without neoadjuvant or adjuvant treatment.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnKaplan-Meier analysis estimated survival functions, and Cox proportional hazards models addressed predictors of clinical end points.nnnRESULTS AND LIMITATIONSnMedian follow-up was 74.9 mo. A total of 1121 patients (65.5%) were margin-negative, 281 patients (16.4%) had sPSMs, and 310 patients (18.1%) had mPSMs. A total of 280 patients (16.4%) experienced BCR, and 197 patients (11.5%) were treated with salvage radiotherapy (SRT). Sixty-eight patients (4.0%) received definitive androgen deprivation therapy, 19 patients (1.1%) developed metastatic disease, and 15 patients (0.9%) had castration-resistant PCa (CRPC). Thirteen patients (0.8%) died from PCa, and 194 patients (11.3%) died from other causes. Ten-year Kaplan-Meier estimates for BCR-free survival were 82% for margin-negative patients, 72% for patients with sPSMs, and 59% for patients with mPSMs (p<0.0001). Time to metastatic disease, CRPC, PCa-specific mortality (PCSM), or all-cause mortality did not differ significantly among the three groups (p=0.991, p=0.988, p=0.889, and p=0.218, respectively). On multivariable analysis, sPSMs and mPSMs were associated with BCR (hazard ratio [HR]: 1.711; p=0.001 and HR: 2.075; p<0.0001), but sPSMs and mPSMs could not predict metastatic disease (p=0.705 and p=0.242), CRPC (p=0.705 and p=0.224), PCSM (p=0.972 and p=0.260), or all-cause death (p=0.102 and p=0.067). The major limitation was the retrospective design.nnnCONCLUSIONSnIn a cohort of patients who received early SRT in 70% of cases upon BCR, sPSMs and mPSMs predicted BCR but not long-term clinical end points. Adjuvant radiotherapy for margin-positive patients might not be justified, as only a minority of patients progressed to end points other than BCR. PCSM was exceeded 15-fold by competing risk mortality.

ω–3 Fatty Acids, Genetic Variants in COX-2 and Prostate Cancer

Dietary intake of fish and ω–3 polyunsaturated fatty acids (ω–3 PUFAs) may decrease the risk of prostate cancer development and progression to advanced stage disease. This could reflect the anti-inflammatory effects of PUFAs, possibly through mediation of cyclooxygenase (COX), a key enzyme in fatty acid metabolism and inflammation. Despite promising experimental evidence, epidemiological studies have reported somewhat conflicting results regarding the effects of fish/PUFAs on prostate cancer development and progression. The literature suggests that fish, and particularly long-chain ω–3 PUFAs, may have a more pronounced protective effect on biologically aggressive tumors or on their progression, and less on early steps of carcinogenesis. Moreover, the impact of LC ω–3 PUFAs may be modified by variation of the COX-2 gene. Overall, results to date support the hypothesis that long-chain ω–3 PUFAs may impact prostate inflammation and carcinogenesis via the COX-2 enzymatic pathway.

Risk factors for bladder cancer recurrence after nephroureterectomy for upper tract urothelial tumors: Results from the Canadian Upper Tract Collaboration

OBJECTIVEnTo evaluate risk factors for bladder cancer recurrence in a cohort of patients treated with radical nephroureterectomy (RNU).nnnPATIENTS AND METHODSnAt 10 Canadian University Centers, we retrospectively evaluated data, between 1990 and 2010, from 743 patients who were free from bladder cancer and were previously treated with RNU for upper tract urothelial cancer.nnnRESULTSnOf 743 patients, 167 (22.5%) developed bladder tumors after a median time of 17.2 months after RNU. Multivariable analysis detected age (hazard ratio [HR] = 1.028; 95% CI: 1.010-1.046; P = 0.0018), tumor location in both the renal pelvis and the ureter (HR = 2.205; 95% CI: 1.355-3.589; P = 0.0015), the use of adjuvant systemic chemotherapy (HR = 2.309; 95% CI: 1.439-3.705; P = 0.0005), and laparoscopic surgery (HR = 1.876; 95% CI: 1.226-2.87; P = 0.0037) as risk factors for bladder cancer recurrence. Open excision of a bladder cuff (HR = 0.661; 95% CI: 0.453-0.965; P = 0.0319) and transurethral resection of the intramural ureter (HR = 0.548; 95% CI: 0.306-0.981; P = 0.0429) on comparison with extravesical resection decreased the risk of bladder cancer recurrence significantly. Major limitations were the retrospective design and partially missing data, although the significance of variables did not change in the imputation analysis.nnnCONCLUSIONnOlder patients, those with tumor location in both the renal pelvis and the ureter, and those treated with adjuvant systemic chemotherapy were found at higher risk for intravesical recurrence, as were those having undergone extravesical ureterectomy or laparoscopic RNU.

Prostatic and Dietary Omega-3 Fatty Acids and Prostate Cancer Progression during Active Surveillance

The association between omega-3 (ω-3) fatty acids and prostate cancer has been widely studied. However, little is known about the impact of prostate tissue fatty acid content on prostate cancer progression. We hypothesized that compared with the estimated dietary ω-3 fatty acids intake and the ω-3 fatty acids levels measured in red blood cells (RBC), the prostate tissue ω-3 fatty acid content is more strongly related to prostate cancer progression. We present the initial observations from baseline data of a phase II clinical trial conducted in a cohort of 48 untreated men affected with low-risk prostate cancer, managed under active surveillance. These men underwent a first repeat biopsy session within 6 months after the initial diagnosis of low-risk prostate cancer, at which time 29% of the men had progressed from a Gleason score of 6 to a Gleason score of 7. At the first repeat biopsy session, fatty acid levels were assessed with a food-frequency questionnaire, and determined in the RBC and in the prostate tissue biopsy. We found that eicosapentaenoic acid (EPA) was associated with a reduced risk of prostate cancer progression when measured directly in the prostate tissue. Thus, this initial interim study analysis suggests that prostate tissue ω-3 fatty acids, especially EPA, may be protective against prostate cancer progression in men with low-risk prostate cancer. Cancer Prev Res; 7(7); 766–76. ©2014 AACR.

FDG-PET/CT for pre-operative staging and prognostic stratification of patients with high-grade prostate cancer at biopsy

BackgroundThe role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in prostate cancer (PCa) has not been well defined yet. Because high-grade PCa tends to exhibit increased glycolytic rate, FDG-PET/CT could be useful in this setting. The aim of this study was to assess the value of FDG-PET/CT for pre-operative staging and prognostic stratification of patients with high-grade PCa at biopsy.MethodsFifty-four patients with a Gleason sum ≥8 PCa at biopsy underwent FDG-PET/CT as part of the staging workup. Thirty-nine patients underwent radical prostatectomy (RP) and pelvic lymph node (LN) dissection, 2 underwent LN dissection only, and 13 underwent non-surgical treatments. FDG-PET/CT findings from clinical reports, blinded reading and quantitative analysis were correlated with clinico-pathological characteristics at RP.ResultsSuspicious foci of increased FDG uptake were found in the prostate, LNs and bones in 44, 13 and 6% of patients, respectively. Higher clinical stage, post-RP Gleason sum and pattern, and percentage of cancer involvement within the prostate were significantly associated with the presence of intraprostatic FDG uptake (IPFU) (Pu2009<u20090.05 in all cases). Patients without IPFU who underwent RP were downgraded to Gleason ≤7 in 84.6% of cases, as compared to 30.8% when IPFU was reported (Pu2009=u20090.003). Qualitative and quantitative IPFU were significantly positively correlated with post-RP Gleason pattern and sum, and pathological T stage. Absence and presence of IPFU were associated with a median 5-year cancer-free survival probability of 70.2 and 26.9% (Pu2009=u20090.0097), respectively, using the CAPRA-S prognostic tool.ConclusionThese results suggest that, among patients with a high-grade PCa at biopsy, FDG-PET/CT could improve pre-treatment prognostic stratification by predicting primary PCa pathological grade and survival probability following RP.

High level of mature tumor-infiltrating dendritic cells predicts progression to muscle invasion in bladder cancer

A prognostic value for tumor-associated macrophages (TAMs) and tumor-infiltrating dendritic cells (TIDCs) has been reported in many human cancers. The objective of this study is to determine the prognostic value of CD83(+) mature TIDCs and CD68(+) TAMs in non-muscle-invasive bladder cancer at first diagnosis. Immunohistochemistry staining was performed with anti-CD68 and anti-CD83 monoclonal antibodies on tissue sections from 93 formalin-fixed, paraffin-embedded tissue blocks from pTa and pT1 bladder tumors. A scoring index based on the average density of observed positive cells in the papillary axis, the stroma, lymphoid aggregates, and into tumor foci was calculated for each patient. Comparison of baseline characteristics with marker levels was done using Pearson χ(2) or Fisher exact test. Kaplan-Meier analyses and Cox regression models were fitted to evaluate the prognostic value of TIDCs and TAMs. The absence of both CD68(+) TAMs and CD83(+) TIDCs was associated with tumor recurrence. The presence of TIDCs was associated with a significant risk of progression to muscle-invasive cancer (hazard ratio, 8.253; P = .0179). Patients were risk stratified using age and TIDC score. Patients 70 years or older with a high score of TIDCs had a 56% progression-free survival after 6 years compared with 94% for patients younger than 70 years with a low score of TIDCs. None of 20 patients with a low score of TAMs progressed. These data indicate that the presence of mature TIDCs and possibly TAMs may help risk-stratify patients at the time of first diagnosis of non-muscle-invasive bladder cancer and may be useful in tailoring follow-up and treatment strategies.

IL-8 secretion in primary cultures of prostate cells is associated with prostate cancer aggressiveness

Background Chronic inflammation is believed to be a major factor in prostate cancer initiation and promotion and has been studied using prostate cancer cells and immortalized cell lines. However, little is known about the contribution of normal cells to the prostatic microenvironment and inflammation. We aim to study the contribution of normal prostate epithelial cells to prostate inflammation and to link the inflammatory status of normal cells to prostate cancer aggressiveness. Materials and methods Short-term primary cell cultures of normal epithelial prostate cells were derived from prostate biopsies from 25 men undergoing radical prostatectomy, cystoprostatectomy, or organ donation. Cells were treated with polyinosinic:polycytidylic acid, a mimic of double-stranded viral RNA and a potent inducer of the inflammatory response. Secretion of interleukin (IL)-8 in the cell culture medium by untreated and treated cells was measured and we determined the association between IL-8 levels in these primary cell cultures and prostate cancer characteristics. The Fligner–Policello test was used to compare the groups. Results Baseline and induced IL-8 secretion were highly variable between cultured cells from different patients. This variation was not related to drug use, past medical history, age, or preoperative prostate-specific antigen value. Nonetheless, an elevated secretion of IL-8 from normal cultured epithelial cells was associated with prostate cancer aggressiveness (P=0.0005). Conclusion The baseline secretion of IL-8 from normal prostate epithelial cells in culture is strongly correlated with cancer aggressiveness and may drive prostate cancer carcinogenesis. A better characterization of individual prostate microenvironment may provide a basis for personalized treatment and for monitoring the effects of strategies aimed at preventing aggressive prostate cancer.

Diagnostic performance of ultrasound for macroscopic hematuria in the era of multidetector computed tomography urography.

Purpose The objective of this study was to evaluate the diagnostic performance of ultrasound for detecting urinary tract neoplasm in the setting of macroscopic hematuria by using multidetector computed tomography urography (MDCTU) and cystoscopy as the reference standard. Methods This retrospective study was approved by our institutional review board. Patients with macroscopic hematuria who were investigated with an abdominal or renal ultrasound, an MDCTU, and a cystoscopy between January 2007 and December 2009, were eligible (95 patients). Exclusion criteria were time interval >12 months between index and reference tests or the absence of histopathologic proof of malignancy. Ultrasound results of the remaining 86 patients were collected and compared with the reference standard test, which was the combination of MDCTU for the assessment of upper urinary tract and cystoscopy for assessment of the lower urinary tract. The final diagnosis of neoplasm was based on pathologic findings. Results Urinary tract neoplasm was diagnosed in 20% of the patients (17/86). Sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios of ultrasound for detecting urinary tract neoplasms were 35.3% (6/17), 89.9% (62/69), 46.2% (6/13), 84.9% (62/73), 3.48 (95% confidence interval, 1.34-9.02), and 0.72 (95% confidence interval, 0.5-1.3), respectively. Conclusion Sensitivity of ultrasound for the evaluation of macroscopic hematuria in the era of MDCTU is lower than expected. Results of our study suggest that patients with macroscopic hematuria should undergo MDCTU as first-line imaging modality, with little added benefit from ultrasound.

The European Nutrigenomics Organisation

Joint Research Activities are divided between Focus Teams, the Nutrigenomics Information Portal and other key activities, e.g. nutrigenomics research guidelines and workshops. Focus Teams are striving for integration within the same research theme across the partnership. The Nutrigenomics Information Portal (www.nugo.org) is part of the NuGO website and NuGO is working with centres worldwide to generate pages off ering access to essential information for all nutrition researchers.