Periprostatic Adipose Tissue Displays a Chronic Hypoxic State that Limits Its Expandability.

White adipose tissue accumulates at various sites throughout the body, some adipose tissue depots exist near organs whose function they influence in a paracrine manner. Prostate gland is surrounded by a poorly characterized adipose depot called periprostatic adipose tissue (PPAT), which plays emerging roles in prostate-related disorders. Unlike all other adipose depots, PPAT secretes proinflammatory cytokines even in lean individuals and does not increase in volume during obesity. These unique features remain unexplained because of the poor structural and functional characterization of this tissue. This study characterized the structural organization of PPAT in patients compared with abdominopelvic adipose tissue (APAT), an extraperitoneal adipose depot, the accumulation of which is correlated to body mass index. Confocal microscopy followed by three-dimensional reconstructions showed a sparse vascular network in PPAT when compared with that in APAT, suggesting that this tissue is hypoxic. Unbiased comparisons of PPAT and APAT transcriptomes found that most differentially expressed genes were related to the hypoxia response. High levels of the hypoxia-inducible factor 2α confirmed the presence of an adaptive response to hypoxia in PPAT. This chronic hypoxic state was associated with inflammation and fibrosis, which were not further up-regulated by obesity. This fibrosis and inflammation explain the failure of PPAT to expand in obesity and open new mechanistic avenues to explain its role in prostate-related disorders, including cancer.

Biomarker in Active Surveillance for Prostate Cancer: A Systematic Review.

Active surveillance (AS) in prostate cancer (PCa) represents a curative alternative for men with localised low-risk PCa. Continuous improvement of AS patient's selection and surveillance modalities aims at reducing misclassification, simplifying modalities of surveillance and decreasing need for invasive procedures such repeated biopsies. Biomarkers represent interesting tools to evaluate PCa diagnosis and prognosis, of which many are readily available or under evaluation. The aim of this review is to investigate the biomarker performance for AS selection and patient outcome prediction. Blood, urinary and tissue biomarkers were studied and a brief description of use was proposed along with a summary of major findings. Biomarkers represent promising tools which could be part of a more tailored risk AS strategy aiming to offer personalized medicine and to individualize the treatment and monitoring of each patient. The usefulness of biomarkers has mainly been suggested for AS selection, whereas few studies have investigated their role during the monitoring phase. Randomized prospective studies dealing with imaging are needed as well as larger prospective studies with long-term follow-up and strong oncologic endpoints.

The prognostic value of high-grade prostate cancer pattern on MRI-targeted biopsies: predictors for downgrading and importance of concomitant systematic biopsies.

PURPOSE: To assess the proportion and risk factors for downgrading and reclassification to favorable disease in patients having high-grade (HG) prostate cancer (PCa) pattern on magnetic resonance imaging (MRI)-targeted-biopsy (TB). METHODS: From a radical prostatectomy (RP) cohort, we included patients with pre-biopsy positive MRI and HG [defined by Grade Group (GG) ≥ 3] PCa on MRI-TB. All patients also underwent concomitant systematic biopsy (SB). The main endpoints were the rates of downgrading to GG2, overall downgrading, favorable disease (pT2 and GG2) on RP specimens, and biochemical recurrence-free-survival (RFS). We studied the correlations between HG on concomitant SB, final pathological outcomes and biochemical RFS curves. RESULTS: Overall downgrading, downgrading to GG2 disease and favorable disease were noted in 36.2%, 24.1%, and 15.4% respectively. HG on concomitant SB was correlated with pT3-4 disease (p < 0.001), pN1 disease (p < 0.001), positive surgical margins (p = 0.043), PSA recurrence (p = 0.003). In multivariable analysis, the presence of GG4-5 on TB (p = 0.013; OR 0.263) and the presence of HG on concomitant SB (p = 0.010; OR 0.269) were negatively and independently correlated with the risk of downgrading to GG2. The presence of HG on concomitant SB independently predicted RFS with a hazard ratio of 2.173 (p = 0.049; 95% CI 1.005-4.697). CONCLUSIONS: Our data shows that a limited HG restricted to TB can often be associated with a favorable grade in almost a quarter of the cases and downgraded in almost half of the cases. Detailed SB features, mainly the presence of HG on concomitant SB, was associated with a more accurate pathology and oncologic outcomes prediction, pleading for the maintenance of SB in MRI-positive patients.

Immunotherapy in prostate cancer: new horizon of hurdles and hopes.

PURPOSE: Prostate cancer (PCa) is the most common malignancy in men and the cause for the second most common cancer-related death in the western world. Despite ongoing development of novel approaches such as second generation androgen receptor targeted therapies, metastatic disease is still fatal. In PCa, immunotherapy (IT) has not reached a therapeutic breakthrough as compared to several other solid tumors yet. We aimed at highlighting the underlying cellular mechanisms crucial for IT in PCa and giving an update of the most essential past and ongoing clinical trials in the field. METHODS: We searched for relevant publications on molecular and cellular mechanisms involved in the PCa tumor microenvironment and response to IT as well as completed and ongoing IT studies and screened appropriate abstracts of international congresses. RESULTS: Tumor progression and patient outcomes depend on complex cellular and molecular interactions of the tumor with the host immune system, driven rather dormant in case of PCa. Sipuleucel-T and pembrolizumab are the only registered immune-oncology drugs to treat this malignancy. A plethora of studies assess combination of immunotherapy with other agents or treatment modalities like radiation therapy which might increase its antineoplastic activity. No robust and clinically relevant prognostic or predictive biomarkers have been established yet. CONCLUSION: Despite immunosuppressive functional status of PCa microenvironment, current evidence, based on cellular and molecular conditions, encourages further research in this field.

MRI Characteristics Accurately Predict Biochemical Recurrence after Radical Prostatectomy.

BACKGROUND: After radical prostatectomy (RP), biochemical recurrence (BCR) is associated with an increased risk of developing distant metastasis and prostate cancer specific and overall mortality. METHODS: The two-centre study included 521 consecutive patients undergoing RP for positive pre-biopsy magnetic resonance imaging (MRI) and pathologically proven prostate cancer (PCa), after which a combination scheme of fusion-targeted biopsy (TB) and systematic biopsy was performed. We assessed correlations between MRI characteristics, International Society of Urological Pathology (ISUP) grade group in TB, and outcomes after RP. We developed an imaging-based risk classification for improving BCR prediction. RESULTS: Higher Prostate Imaging and Reporting and Data System (PI-RADS) score (p = 0.013), higher ISUP grade group in TB, and extracapsular extension (ECE) on the MRI were significantly associated with more advanced disease (pTstage), higher ISUP grade group (p = 0.001), regional lymph nodes metastasis in RP specimens (p < 0.001), and an increased risk of recurrence after surgery. A positive margin status was significantly associated with ECE-MRI (p < 0.001). Our imaging-based classification included ECE on MRI, ISUP grade group on TB, and PI-RADS accurately predicted BCR (AUC = 0.714, p < 0.001). This classification had more improved area under the curve (AUC) than the standard d'Amico classification in our population. Validation was performed in a two-centre cohort. CONCLUSIONS: In this cohort, PI-RADS score, MRI stage, and ISUP grade group in MRI-TB were significantly predictive for disease features and recurrence after RP. Imaging-based risk classification integrating these three factors competed with d'Amico classification for predicting BCR.

Abiraterone acetate in combination with prednisone in the treatment of prostate cancer: safety and efficacy.

INTRODUCTION: Metastatic prostate cancer is a life-threatening disease and an important public health concern with prevalence rates varying drastically between high- and low-income countries. Androgen-deprivation therapy alone has been the first-line treatment option for decades, temporarily controlling disease until invariable tumor regression. At the castration-resistant stage, metastatic disease becomes lethal. In recent years several new treatments, including second-generation hormone therapies, have proven to be life-prolonging in metastatic castration-resistant prostate cancer, and at an earlier hormone-sensitive stage. Abiraterone acetate in combination with prednisone was the first approved hormone therapy demonstrating survival benefit, and represents, to date, an alternative, or a second-line treatment after taxane-based chemotherapy, in addition to androgen-deprivation therapy, in hormone sensitive, and metastatic castration-resistant prostate cancer. AREA COVERED: We performed a literature review of papers from 2012 to 2020 using PubMed, Web of Science, and Embase searching for the safety and efficacy of abiraterone acetate in prostate cancer management. Search results were limited to phase III-IV trials and post hoc analysis of Phase III trials evaluated Abiraterone acetate in the English language. EXPERT OPINION: This literature review confirms the role of abiraterone acetate in the therapeutic landscape with well-proven safety and efficacy, demonstrated in trials and post-approval studies.

Intercenter reproducibility of software-based fusion biopsies for grade group prediction when targeting suspicious MRI lesions.

PURPOSE: To assess the intercenter reproducibility of software-based fusion targeted biopsy (TB) for grade-group assessment and pretherapeutic evaluation of highly suspicious MRI lesions. PATIENTS AND METHODS: In this study, were included 380 consecutive patients who underwent radical prostatectomy (RP) after prostate cancer diagnosis and a prebiopsy MRI showing Prostate Imaging-Reporting and Data System (PIRADS) score 4 or 5 lesions. All patients underwent systematic biopsies (SB) combined with software-based fusion TB in the 2 centers. Biopsies were only performed by expert urologists or radiologists in a contemporary time frame. The primary endpoint was the center difference of concordance/upgrading rates between biopsy and RP specimens. RESULTS: Pathological features on biopsy and RP specimens were significantly different among centers with more unfavourable disease in center 1. The rate of TB upgrading was 33.6% in center 1 vs. 35.4% (P = 0.860) in center 2. Grading concordance was also comparable among centers (50.0% vs. 47.1%) as well as the SB upgrading rate. Regression analysis did not find any baseline characteristics (Age, prostate-specific antigen, MRI lesions, center) predictive for TB upgrading. These findings were achieved by using fewer TB per lesion in center 1 (2.3 vs. 5.0, P < 0.001), at the expense of more SB cores (14.4 vs. 8.5, P < 0.001). The influence of MRI characteristics (lesion size and number, PIRADS score) on upgrading rates was consistent among centers. CONCLUSIONS: Software-based fusion TB technique leads to comparable outcomes in terms of grade group prediction accuracy in PIRADS 4 to 5 lesions, insignificant between centers, in spite of different non imaging-based aggressiveness features.

Assessment of the Minimal Targeted Biopsy Core Number per MRI Lesion for Improving Prostate Cancer Grading Prediction.

BACKGROUND: To study the impact of MRI characteristics and of targeted biopsy (TB) core number on the final grade group (GG) prediction. MATERIALS AND METHODS: The cohort was 478 consecutive patients who underwent radical prostatectomy (RP) after positive mpMRI (multiparametric magnetic resonance imaging) followed by fusion TB. Endpoints were the upgrading and concordance rates between TB and RP specimens. RESULTS: Upgrading rate after TB was 40.6%. Patients with upgrading had lower PIRADS (Prostate Imaging-Reporting and Data System) scores (p < 0.001), smaller lesion size (p = 0.017), fewer TB cores (p < 0.001), and lower TB density (p = 0.015) compared with cases with grade concordance. There was a significant continuous improvement in upgrading rate when TB core number per lesion increased from 56.3% to 25.6% when <2 or ≥5 TB cores were taken, respectively (p = 0.002). The minimal TB number per lesion to reduce upgrading risk to approximately 30%was 4 in PIRADS 3, and 3 in PIRADS 4-5 cases. CONCLUSIONS: Grade group prediction by TB is significantly improved by higher PIRADS score, larger lesion size, and increased TB per lesion. At least four TB cores should be taken in PIRADS 3 score lesions, whereas three cores seem enough in PIRADS 4-5 cases to improve GG prediction and limit upgrading risk.

Confirmation by Early Oncologic Outcomes After Surgery of the Accuracy of Intermediate-risk Prostate Cancer Classification Based on Magnetic Resonance Imaging Staging and Targeted Biopsy.

Over the past decade, prostate cancer (PCa) diagnosis drastically evolved from systematic biopsies (SBs) to multiparametric magnetic resonance imaging (mpMRI) and targeted biopsy (TB), which have emerged as powerful imaging tools for diagnosis, staging, and preoperative planning. MRI and TB should now be widely adopted for assessing prognosis and be incorporated into predictive models. To date, the standard intermediate risk classification (IRC) defined unfavourable and favourable disease with clinical information and overall biopsy data. Roumiguie et al have proposed a new model based on mpMRI staging and grade group on TB and validated it using radical prostatectomy (RP) pathology (Urol Oncol 2020;38:386-92). The aim of our study was to validate the accuracy of this new IRC with early oncologic outcomes and biochemical recurrence (BCR) after RP. From a prospective database of RP patients with positive prebiopsy mpMRI (Prostate Imaging-Reporting and Data System score ≥3) followed by SB in combination with TB, 454 patients with intermediate-risk PCa were included. Median follow-up was 31.5 mo. The new IRC outperformed the standard IRC in predicting BCR (p = 0.007). The area under the curve was 0.613 for the new MRI- and TB-based IRC versus 0.575 for the standard IRC. This new IRC could optimise the prediction of recurrence risk before treatment decision-making. PATIENT SUMMARY: Outcomes after surgery confirm the accuracy of the new classification of intermediate-risk prostate cancer based on magnetic resonance imaging (MRI) staging and targeted biopsy data. We found that this new classification outperformed the standard classification in predicting biochemical recurrence of cancer for men with positive MRI findings undergoing targeted biopsies.

Decreased accuracy of the prostate cancer EAU risk group classification in the era of imaging-guided diagnostic pathway: proposal for a new classification based on MRI-targeted biopsies and early oncologic outcomes after surgery.

PURPOSE: To assess the performance of EAU risk classification in PCa patients according to the biopsy pathway (standard versus MRI guided) and to develop a new, more accurate, targeted biopsy (TB)-based classification. MATERIALS AND METHODS: We included 1345 patients consecutively operated by radical prostatectomy (RP) since 2014, when MRI and TB were introduced in the diagnostic pathway. Patients underwent systematic biopsy (SB) only (n = 819) or SB and TB (n = 526) prior to RP during the same time period. Pathological and biochemical outcomes were compared between PCa men undergoing SB (SB cohort) and a combination of TB and SB (TB cohort). Kaplan-Meier and Cox regression models were used to assess biochemical recurrence-free survival (RFS). RESULTS: Both cohorts were comparable regarding final pathology and RFS (p = 0.538). The EAU risk classification accurately predicted outcomes in SB cohort, but did not significantly separate low from intermediate risk in TB cohort (p = 0.791). In TB cohort, the new proposed three-group risk classification significantly improved the recurrence risk prediction compared with the EAU risk classification: HR 4 (versus HR 1.2, p = 0.009) for intermediate, and HR 15 (versus HR 6.5, p < 0.001) in high-risk groups, respectively. A fourth group defining very high-risk cases (≥ T2c clinical stage or grade group 5) was also proposed. CONCLUSIONS: The new classification integrating TB findings we propose meaningfully improves the recurrence prediction after surgery in patients undergoing a TB-based diagnostic pathway, compared with standard EAU risk classification which is still relevant for patients undergoing only SB. External validation is needed.

Active surveillance eligibility of MRI-positive patients with grade group 2 prostate cancer: a pathological study.

PURPOSE: To assess the final pathology risk in MRI-positive grade group (GG) 2 prostate cancer (PCa) patients undergoing targeted (TB) and systematic (SB) biopsies, and thereby, the possibility of active surveillance (AS) in this population. PATIENTS AND METHODS: We included 242 consecutive men diagnosed with GG2 PCa by a combination of SB and software-based fusion TB undergoing a radical prostatectomy (RP). The primary endpoints were the pathological findings in RP specimens, including favourable disease which was defined by a pT2 and GG1-2 disease. RESULTS: The rate of upgrading was 33% including 3% of GG 4-5 disease. MRI lesion size (p = 0.038) and tumor length per core (p < 0.001) were significantly lower in case of favourable pathology. Only 34.2% of not organ-confined disease was reported when only SB were positive, compared with 45.7% and 57.1% when GG2 was detected on TB only and on TB plus SB, respectively (p = 0.035). The number of positive cores on SB was significantly higher in not organ-confined disease (4.3 versus 2.9; p = 0.005). The risk of not organ-confined disease was only 20.8% in men who had a PSAD ≤ 0.20 ng/ml/gr, 1-2 positive biopsies and a maximal tumor length ≤ 6 mm per core, compared with 52.3% in men who did not fulfil all these criteria (p = 0.003). CONCLUSIONS: This study identified clinical, imaging, and pathological factors that were significantly associated with the final pathology risk. In case of positive MRI followed by TB showing GG2, AS could be offered in patients having a PSAD ≤ 0.20, a tumor length ≤ 6 mm and 1-2 positive cores.

Sexual Health Problems and Discussion in Colorectal Cancer Patients Two Years After Diagnosis: A National Cross-Sectional Study.

BACKGROUND: Colorectal cancer (CRC) is accompanied by specific treatment-related physical (ostomy, incontinence) and psychosexual (body image, depression) consequences on sexual health. AIM: To assess sexual health of patients with CRC 2 years after diagnosis. METHODS: We selected all patients with CRC from a French nationwide longitudinal study. Data sources included patient questionnaires, medical questionnaires, and medico-administrative databases. MAIN OUTCOME MEASURE: We evaluated sexual health using the Relationship and Sexuality Scale and assessed self-reported rates of discussion about sexuality with health care providers. RESULTS: Across the 487 patients, 258 were men and 229 were women; 77% were diagnosed with colon cancer and 23% with rectal cancer. Overall, 54% of patients reported a decrease in sexual desire, 61% a decrease in frequency of intercourse, and 48% a decrease in the possibility to reach an orgasm. Patients still experiencing fecal incontinence 2 years after diagnosis had decreases in all sexual desire, intercourse, orgasm, and satisfaction Relationship and Sexuality Scale items. Patients with rectal cancer had significantly more frequent troubles with desire and orgasm than did patients with colon cancer (P = .003 and P = .014, respectively). Regarding the discussion about sexuality, only 20% of men, 11% of women, 11% of patients with colon cancer, and 33% of patients with rectal cancer recalled having discussed sexuality with the medical team. Factors independently increasing the chance to have discussed sexuality with the medical team were younger age (odds ratio [OR] = 2.77 [1.31; 5.84]; P = .007), having an ostomy (OR = 2.93 [1.27; 6.73]; P = .011), and radiotherapy (OR = 2.78 [1.23; 6.27]; P = .014). CLINICAL IMPLICATIONS: These results highlight the need for developing interventions to improve information delivery at cancer announcement and for managing sexual troubles during survivorship in patients with CRC, particularly those experiencing fecal incontinence. STRENGTH & LIMITATIONS: Strengths are the sample size and the national representation using the data of a large-scale nation-wide survey, with the possibility of comparing colon and rectal cancers. Limitations are the assessment of sexuality 2 years after diagnosis and using only self-reported measures. CONCLUSION: This study highlights the lack of discussion about sexuality with the oncology team and the need for specific sexual rehabilitation interventions, especially for patients with rectal cancer and fecal incontinence. Developing these aspects may help patients with CRC improve their sexual prognosis. Almont T, Bouhnik A-D, Charif AB, et al. Sexual Health Problems and Discussion in Colorectal Cancer Patients Two Years After Diagnosis: A National Cross-Sectional Study. J Sex Med 2019;16:96-110.