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Although active surveillance (AS) is an increasingly adopted treatment paradigm for management of very low risk prostate cancer, many men and their partners face a variety of AS-related psychosocial stressors. Stressors may include anxiety and fear of progression, which may negatively affect short- and long-term psychosocial adjustment and influence early withdrawal from AS in order to seek definitive therapies such as surgery or radiation. Here we describe the protocol for an NCI-funded trial, which seeks to examine the efficacy of mindfulness training compared with a time/attention-matched health promotion control condition in a geographically generalizable sample of men on AS and their spouses.Using a randomized, controlled, partially double-blinded study design, this study involves the delivery of 8 weeks of standardized mindfulness training (MBSR; mindfulness-based stress reduction) and patient reported outcomes over a 12-month period (proposed enrollment of 80 men on AS and spouses), compared with a health promotion control (proposed enrollment of 80 men on AS and spouses) that has been matched for time and attention. Baseline (T1) measures (e.g., anxiety, fear of progression, quality of life) are administered just prior to randomization to the two study arms, followed by repeated assessments at 2 months (T2), 6 months (T3) and 12 months (T4).This study has the potential to offer men and their partners on AS with important educational and self-regulatory skills to better cope and adjust with known stressors related to being placed on this protocol.

Funder: Victorian Cancer Agency, Funder: NIHR Manchester Biomedical Research Centre, Funder: Cancer Research UK, Funder: Cancer Council Tasmania, Funder: Instituto de Salud Carlos III, Funder: Cancer Australia, Funder: NIHR Oxford Biomedical Research Centre, Funder: Fundación Científica de la Asociación Española Contra el Cáncer, Funder: Cancer Council South Australia, Funder: Swedish Cancer Society, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Institut Català de la Salut, Funder: Cancer Council Victoria, Funder: Prostate Cancer Foundation of Australia, Funder: National Institutes of Health, BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

In a pilot randomized controlled trial, examine the feasibility and preliminary efficacy of an 8-week, mindfulness training program (Mindfulness Based Stress Reduction) in a sample of men on active surveillance on important psychological outcomes including prostate cancer anxiety, uncertainty intolerance and posttraumatic growth.Men were randomized to either mindfulness (n = 24) or an attention control arm (n = 19) and completed self-reported measures of prostate cancer anxiety, uncertainty intolerance, global quality of life, mindfulness and posttraumatic growth at baseline, 8 weeks, 6 months and 12 months.Participants in the mindfulness arm demonstrated significant decreases in prostate cancer anxiety and uncertainty intolerance, and significant increases in mindfulness, global mental health and posttraumatic growth. Participants in the control condition also demonstrated significant increases in mindfulness over time. Longitudinal increases in posttraumatic growth were significantly larger in the mindfulness arm than they were in the control arm.While mindfulness training was found to be generally feasible and acceptable among participants who enrolled in the 8-week intervention as determined by completion rates and open-ended survey responses, the response rate between initial enrollment and the total number of men approached was lower than desired (47%). While larger sample sizes are necessary to examine the efficacy of mindfulness training on important psychological outcomes, in this pilot study posttraumatic growth was shown to significantly increase over time for men in the treatment group. Mindfulness training has the potential to help men cope more effectively with some of the stressors and uncertainties associated with active surveillance. Copyright © 2016 John WileySons, Ltd.

To investigate the association between magnetic resonance (MR) spectroscopically measured fatty acid composition of periprostatic adipose tissue and pathological markers of prostate cancer aggressiveness.Periprostatic adipose (PPA) and subcutaneous adipose (SQA) tissue from prostate cancer patients undergoing radical prostatectomy were examined ex vivo by proton MR spectroscopy at 14.1T (n = 31). Fractions of monounsaturated, polyunsaturated, total unsaturated, and saturated fatty acids, as well as T2 relaxation times were measured from the spectra. Univariate and multivariate analyses based on receiver operating characteristic (ROC) and support vector machines (SVM) were used to evaluate the association between differential measures of fatty acid levels in the PPA and SQA tissues and Gleason score and extracapsular extension (ECE), which are pathological measures of prostate cancer aggressiveness.Both pathological markers for aggressive prostate cancer have separable patterns in the MRS features space. The association between ECE and PPA tissue fatty acid composition is linear (area under receiver operating characteristic curve (AROC) and 95% confidence intervals [CIs]: 1.00, [1.00, 1.00]), along the Δ(fM /fS ) measure, and is marked by elevated monounsaturated and reduced saturated fatty acids in the PPA tissue relative to SQA. In contrast, the association between Gleason score and PPA tissue fatty acid composition is nonlinear (classifier AROC and 95% CIs: 0.86, [0.71, 1.00]).Fatty acid composition is altered in the PPA tissue of patients with aggressive prostate cancer. Ex vivo MR spectroscopy may be a useful tool in studying the altered fatty acid metabolism in prostate cancer.

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: It has been suggested that a very short positive margin does not confer additional risk of BCR after radical prostatectomy. This study shows that even very short PSM is associated with increased risk of BCR.To re-evaluate, in a larger cohort with longer follow-up, our previously reported finding that a positive surgical margin (PSM) ≤ 1 mm may not confer an additional risk for biochemical recurrence (BCR) compared with a negative surgical margin (NSM).Margin status and length were evaluated in 2866 men treated with radical prostatectomy (RP) for clinically localized prostate cancer at our institution from 1994 to 2009. We compared the BCR-free survival probability of men with NSMs, a PSM ≤ 1 mm, and a PSM1 mm using the Kaplan-Meier method and a Cox regression model adjusted for preoperative prostate-specific antigen (PSA) level, age, pathological stage and pathological Gleason score (GS).Compared with a NSM, a PSM ≤ 1 mm was associated with 17% lower 3-year BCR-free survival for men with pT3 and GS ≥ 7 tumours and a 6% lower 3-year BCR-free survival for men with pT2 and GS ≤ 6 tumours (log-rank P0.001 for all). In the multivariate model, a PSM ≤ 1 mm was associated with a probability of BCR twice as high as that for a NSM (hazard ratio [HR] 2.2), as were a higher PSA level (HR 1.04), higher pathological stage (HR 2.7) and higher pathological GS (HR 3.7 [all P0.001]).In men with non-organ-confined or high grade prostate cancer, a PSM ≤ 1 mm has a significant adverse impact on BCR rates.

Actions of many herbal medicine products for cancer treatment are linked to an altered production of TGF-β in the target cells. An altered TGF-β production in the target cells will have profound effects on the patients. Therefore, it is important that we review the pros and cons of these products on cancer development and progression in terms of TGF-β signaling. It has been well established that TGF-β is growth inhibitory to benign cells or early stages of cancer cells but it is tumor promoting and metastatic for advanced malignancies. Further, many dietary components can alter gene-specific DNA methylation levels in systemic and in target tissues. Since TGF-β signaling in cancer is closely linked to the DNA methylation profiles, we also review the effect of dietary components on DNA methylation. In light of this knowledge, it is important to note that many natural products that can induce TGF-β production in the target cells may be beneficial in preventing cancer development but may be harmful for cancer patients, especially when they harbor advanced stage cancer. A discussion of the effect of herbal natural products on cancer can be divided into three categories. The first category of herbal medicine products will be those related to the induction of cancer as far as TGF-β is concerned. Since TGF-β is growth inhibitory and pro-apoptosis to benign cells, any herbal medication that can induce the production of TGF-β in the target cells will be beneficial to the patients. However, such herbal medicine may not necessarily be beneficial for patients with established and advanced cancer. The second category of herbal products will inhibit TGF-β signaling and will reduce TGF-β mediated growth promotion and metastasis in advanced cancers. For patients with established and advanced cancer, agents that can inhibit the production of TGF-β may also inhibit cancer growth and metastasis. Finally, the third category of herbal products has no impact on TGF-β signaling, such as lycopene.

Our goal was to evaluate the role of radioimmunoscintigraphy (RIS) directed against prostate-specific membrane antigen (PSMA) in influencing postprostatectomy radiotherapy (RT) toxicity and biochemical control.The records of 107 postprostatectomy RT patients were reviewed. The group for whom no RIS scan was obtained (group A, n = 54) was identified as was the group for whom a RIS scan was obtained (group B, n = 53). Group B was further subdivided into those who had a RIS and CT-scan correlation to aid in treatment planning (subgroup B1, n = 40) versus those who did not (subgroup B2, n = 13). Gastrointestinal (GI) and genitourinary (GU) toxicities were reviewed for each of these groups and subgroups and compared. Biochemical failures (defined as 2 successive PSA rises after a nadir ofor=0.2 ng/mL) were identified to generate biochemical failure-free survival (BFFS) curves for each of the groups and subgroups.No significant differences in late toxicity were observed between any group or subgroup. However, acute GI toxicity was higher in group B versus group A (P = 0.026), and acute GU toxicity was higher in subgroup B2 versus subgroup B1 (P = 0.050). Overall, most toxicity was grade 1 or 2; only one case of grade 3 toxicity and no cases of grade 4 or 5 toxicity were observed. Three-year BFFS was higher for group B versus group A (80.7% vs. 75.5%) and for subgroup B1 versus subgroup B2 (84.5% vs. 71.6%). On multivariate analysis of pretreatment (age, race), surgical/staging (stage, grade, margin status, extracapsular extension, lymph node status, seminal vesicle invasion, post-radical retropubic prostatectomy [RRP] prostate-specific antigen [PSA] nadir, maximum post-RRP PSA, and RRP-to-RT interval), and treatment (hormone therapy, RT dose, RT technique, RIS scan, and RIS/CT correlation) factors on BFFS, the only covariate reaching significance was RIS/CT correlation (P = 0.042).A small BFFS advantage was observed in patients for whom RIS was used to guide RT decision making and treatment planning; however, this advantage only reached significance in this study for those for whom the RIS/CT correlation was used to guide target definition. The improved PSA control using RIS was achieved with a small increase in acute toxicity but with no observed change in late toxicity. These findings can serve as the basis for prospective studies in this area of investigation.

The aim of this study was to evaluate the role of radioimmunoscintigraphy (RIS) directed against prostate-specific membrane antigen (PSMA) in influencing postradical retropubic prostatectomy (RRP) radiotherapy (RT) decision making.The records of consecutive patients who underwent RRP, who were referred for consideration of RT, and for whom an RIS scan was obtained were reviewed. The RT decisions, with regard to (a) the decision to offer RT and (b) the general volume to be treated [prostate fossa (PF) only versus PF + pelvis (P)] before knowledge of the RIS findings were charted. The RIS findings, with regard to uptake in the PF, uptake in the P, or extrapelvic (EP) uptake were tabulated. Then, the RT treatment decisions based on the RIS knowledge were evaluated and compared with the pre-RIS RT treatment decisions.Of the 54 patients originally referred for post-RRP RT, the initial decision was to recommend RT to the PF only in 52 cases and to PF+P in 2 cases. The RIS findings were as follows: PF only, 43 patients; PF+P, 8 patients; PF+EP, 2 patients; PF+P+EP, 1 patient. After knowledge of these RIS results, the decision to offer RT was withdrawn in 4 of 54 patients (7.4%; P = 0.046). Furthermore, RIS changed the general treatment volume (PF only to PF+P) in 6 of 54 patients (11.1%; P = 0.015). In total, RIS altered the RT decision in 10 of 54 patients (18.5%; P = 0.0067). Three-year biochemical failure-free survival (with failure defined as 2 consecutive prostate-specific antigen [PSA] rises above 0.2 ng/mL after PSA nadir) was 78%; no patient, disease, or treatment factor reached statistical significance on univariate or multivariate analysis.RIS was found to influence post-RRP RT decision making for the identification of patients not likely to benefit from RT and for guiding general target volume definition.

The goal of this study was to evaluate the role of radioimmunoscintigraphy (RIS) directed against prostate-specific membrane antigen in modifying postprostatectomy prostate fossa clinical target volume (CTV) definition.The records of 25 postprostatectomy patients who received external-beam radiotherapy after prostatectomy and who underwent vessel-based RIS/planning CT registration were reviewed. For each patient, the CTV that would have been treated (CTV(pre)) before this registration was compared with that defined after the registration (CTV(post)). In addition, using a standard dose of 66 Gy in 2-Gy fractions, the corresponding bladder and rectum dose volume histograms were compared using 2 endpoints: volume receivingor =60 Gy (V60) and area under the curve (AUC).The mean CTV(pre) vs. CTV(post) volumes were 24.4 vs. 35.0 cm(3), respectively (P = 0.032). The V60 results for CTV(pre) and CTV(post) were 32.7 vs. 41.0 cm(3), respectively, for the rectum (P = 0.168) and 33.9 vs. 46.6 cm(3), respectively, for the bladder (P = 0.015). The AUC results for CTV(pre) and CTV(post) were 4,027 vs. 4,516 Gy x cm(3), respectively, for the rectum (P = 0.396) and 4,782 vs. 5,561, respectively, for the bladder (P = 0.119). No Radiation Therapy Oncology Group grade 3, 4, or 5 (acute or late, gastrointestinal, or genitourinary) toxicity was observed. Two-year biochemical failure-free survival (with failure defined as 2 consecutive prostate-specific antigen rises above 0.2ng/mL) was 87% for the cohort.Incorporating RIS uptake resulted in significant modifications in CTV definition. The consequences of these modifications on the rectum V60 or AUC or on the bladder AUC were not significant, although the bladder V60 did increase. However, observed toxicity was low, with acceptable short-term biochemical control, suggesting that treatment to the modified CTV was tolerable.

16 Background: We retrospectively assessed the clinical application of Prostate Specific Antigen Velocity (PSA V) in the IMPACT study (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in men at higher genetic risk and controls). This is a case-control prostate cancer (PrCa) screening study for men with a known genetic predisposition to PrCa; participants with a single PSA reading above 3ng/ml are offered diagnostic TRUS prostate biopsies (PB). Methods: We calculated PSA velocity (PSA V) using all three validated methods, including the arithmetic mean, the linear regression and the first and last readings equations. Pearson chi-square test was used to compare PSA V between four genetic groups: BRCA1 carriers and BRCA1 negative controls and BRCA2 carriers and BRCA2 negative controls. Results: PSA V data were evaluated in 191 men who underwent a PB with a total of 57 PrCas diagnosed. PSA V using both a threshold of 0ng/ml/year and 0.75ng/ml/year in any of the three methods was not predictive of PrCa diagnosis in BRCA1/2 controls and BRCA1 carriers. Conversely, BRCA2 carriers with a PSA V over 0.75ng/ml/year (by linear regression) were 5 times more likely to be diagnosed with PrCa [95%CI=1.5-14; p=0.003]. Interestingly PSA V using linear regression was predictive of clinically significant tumours as defined by Gleason Score (GS) >= 7. Regardless of their genetic status, men with a PSA V over 0.75/ng/ml/year were 3 times more likely to have a clinically significant PrCa [95% CI: 1.006-11.107; p=0.045] whereas men with a BRCA2 mutation were 12 times more likely [95%CI: 1.1-98; p=0.039]. Conclusions: PSA V is an important tool for identifying which men with a BRCA2 mutation would benefit from a prostatic biopsy and could be incorporated into a predictive model, along with the total PSA value. PSA V also predicts for tumour aggressiveness regardless of genetic predisposition, but more so for those with a known high risk gene mutation. Clinical trial information: NCT00261456.

Hematuria is an extremely common condition, and almost always requires a complete urologic evaluation. The urologist must have a thorough knowledge of the urologic causes of hematuria as well as the nonurologic causes. In this chapter we provide an overview of hematuria and discuss important aspects of the history and physical examination. We then discuss the evaluation and differential diagnosis of hematuria, including unusual urologic causes and the more common nonurologic causes of hematuria.