Impact of an Expanded Definition of Family History on Outcomes of Active Surveillance for Prostate Cancer.

PURPOSE: Despite family history being an established risk factor for prostate cancer, the role of a broader definition of family history inclusive of not just prostate cancer but other genetically related malignancies has not been investigated in the active surveillance population. Here, we evaluate the impact of an expanded definition of family history on active surveillance outcomes. MATERIALS AND METHODS: Patients undergoing active surveillance for prostate cancer at Massachusetts General Hospital from 1997-2019 with detailed data available on family cancer history were identified. Primary outcome was biopsy progression-free survival, and secondary outcomes were treatment-free survival, adverse pathological features at prostatectomy, and biochemical recurrence after treatment. Statistical analyses were conducted using the Kaplan-Meier method and Cox regression. RESULTS: Among 855 evaluable patients, 300 (35.1%) patients had any family history of prostate cancer, and 95 (11.1%) had a family history of related malignancies suggestive of a hereditary cancer syndrome. Family history of prostate cancer alone was not associated with biopsy progression, whereas family history suggestive of a hereditary cancer syndrome was associated with a significantly increased risk of biopsy progression (HR 1.43, 95%CI 1.01-2.02), independent of other known clinicopathological risk factors in multivariable analysis. Similarly, family history suggestive of a hereditary cancer syndrome was associated with significantly lower treatment-free survival (HR 1.58, 95%CI 1.14-2.18) in multivariable analysis. No significant association was found between family history and adverse features on surgical pathology or biochemical recurrence. CONCLUSIONS: An expanded family history suggestive of a hereditary cancer syndrome is an independent predictor of biopsy progression during active surveillance. Men with such a family history may still be offered active surveillance but should be counseled regarding the higher risk of disease progression.

Outcomes of Active Surveillance for Men With Intermediate Risk Prostate Cancer: A Population-Based Analysis.

OBJECTIVE: To assesses if active surveillance (AS) is an appropriate treatment modality for patients with intermediate risk (IR) prostate cancer (PCa) utilizing population-level data to compare the survival outcomes of men with low risk (LR) and IR PCa initially treated with AS, watchful waiting (WW) or active treatment (AT). METHODS: In total, 166,244 patients were initially identified in the surveillance, epidemiology, and end results database using biopsy Gleason grade group (GG) alone-GG1 and GG2. In total, 94,891 patients with GG1 and GG2 disease were further stratified by National Comprehensive Cancer Network risk categories-LR, favorable IR (fIR), and unfavorable IR (uIR). Predictors of cancer-specific (CSS) and overall survival (OS) were analyzed, stratified by risk classification and initial treatment-AT (first-line curative surgery or radiotherapy), AS or WW, utilizing the new "Watchful waiting recode (2010+)" variable. RESULTS: We found GG2 patients on AS had worse CSS and OS than GG2 patients who received AT and GG1 patients treated with AS or AT; these trends persist within the National Comprehensive Cancer Network fIR and uIR cohorts. WW patients (GG1, GG2, LR, fIR, and uIR) had the worst survival outcomes of any cohort (log-rank tests P < .05). CONCLUSIONS: We demonstrate a significantly worse 5-year CSS and OS for men with GG2, fIR, and uIR PCa treated with AS compared to AT. Our analysis suggests that AS should not be the preferred treatment modality for IR PCa.

Pretest Genetic Education Video Versus Genetic Counseling for Men Considering Prostate Cancer Germline Testing: A Patient-Choice Study to Address Urgent Practice Needs.

PURPOSE: Germline testing (GT) for prostate cancer (PCA) is now central to treatment and hereditary cancer assessment. With rising demand for and shortage of genetic counseling (GC), tools to deliver pretest informed consent across practice settings are needed to improve access to GT and precision care. Here, we report on Evaluation and Management for Prostate Oncology, Wellness, and Risk (EMPOWER), a patient-choice study for pretest video-based genetic education (VBGE) versus GC to inform urgent practice needs. PATIENTS AND METHODS: Men with PCA or at risk for PCA (family history of PCA) were eligible and could choose pretest VBGE or GC. Outcomes included decisional conflict for GT, change in genetics knowledge, satisfaction, and intention to share results with family and/or providers. Descriptive statistics summarized results with counts and percentages for categorical variables and mean ± standard deviation for continuous variables. Data were compared with Fisher's exact, chi-squared, or Wilcoxon two-sample tests. Mean change in genetics knowledge was compared with t tests. The significance level was set a priori at .05. RESULTS: Data on the first 127 participants were analyzed. Characteristics were White (85.8%), bachelor's degree (66.9%), and PCA diagnosis (90.6%). The majority chose VBGE (71%) versus GC (29%; P < .001). No differences were observed in decisional conflict for GT or satisfaction. Cancer genetics knowledge improved in both groups without significant difference (+0.9 VBGE, +1.8 GC, P = .056). Men who chose VBGE had higher intention to share GT results (96.4% VBGE v 86.4% GC, P = .02). Both groups had high rates of GT uptake (VBGE 94.4%, GC 92%). CONCLUSION: A substantial proportion of men opted for pretest VBGE, with comparable patient-reported outcomes and uptake of GT. The results support the use of pretest video to address the critical GC shortage in the precision era.

Methods for extracellular vesicle isolation from cancer cells.

Cells are known to release different types of vesicles such as small extracellular vesicles (sEVs) and large extracellular vesicles (LEVs). sEVs and LEVs play important roles in intercellular communication, pre-metastatic niche formation, and disease progression; both can be detected cell culture media and biological fluids. sEVs and LEVs contain a variety of protein and RNA cargo, and they are believed to impact many biological functions of the recipient cells upon their internalization or binding to cell surface proteins. It has recently been established that standard isolation techniques, such as differential ultracentrifugation, yield a mixed population of EVs. However, density gradient ultracentrifugation has been reported to allow the isolation of sEVs without cellular debris. Here, we describe the most common methods used to isolate sEVs from cell culture medium, mouse and human plasma, and a new technique for isolating sEVs from tissues as well. This article also provides detailed procedures to isolate LEVs.

Prostate cancer sheds the αvß3 integrin in vivo through exosomes.

The αvß3 integrin has been shown to promote aggressive phenotypes in many types of cancers, including prostate cancer. We show that GFP-labeled αvß3 derived from cancer cells circulates in the blood and is detected in distant lesions in NOD scid gamma (NSG) mice. We, therefore, hypothesized that αvß3 travels through exosomes and tested its levels in pools of vesicles, which we designate extracellular vesicles highly enriched in exosomes (ExVs), and in exosomes isolated from the plasma of prostate cancer patients. Here, we show that the αvß3 integrin is found in patient blood exosomes purified by sucrose or iodixanol density gradients. In addition, we provide evidence that the αvß3 integrin is transferred through ExVs isolated from prostate cancer patient plasma to ß3-negative recipient cells. We also demonstrate the intracellular localization of ß3-GFP transferred via cancer cell-derived ExVs. We show that the ExVs present in plasma from prostate cancer patients contain higher levels of αvß3 and CD9 as compared to plasma ExVs from age-matched subjects who are not affected by cancer. Furthermore, using PSMA antibody-bead mediated immunocapture, we show that the αvß3 integrin is expressed in a subset of exosomes characterized by PSMA, CD9, CD63, and an epithelial-specific marker, Trop-2. Finally, we present evidence that the levels of αvß3, CD63, and CD9 remain unaltered in ExVs isolated from the blood of prostate cancer patients treated with enzalutamide. Our results suggest that detecting exosomal αvß3 integrin in prostate cancer patients could be a clinically useful and non-invasive biomarker to follow prostate cancer progression. Moreover, the ability of αvß3 integrin to be transferred from ExVs to recipient cells provides a strong rationale for further investigating the role of αvß3 integrin in the pathogenesis of prostate cancer and as a potential therapeutic target.

The association between imported factors and prisoners' mental health: Implications for adaptation and intervention.

In the United Kingdom (UK) the prison population has increased by around one third since the turn of the millennium amid growing concern over the correctional mission of prisons, the number of prisoners exhibiting mental health difficulties and high levels of recidivism. This study aims to explore the relationship between 'imported' (pre-prison) factors and prisoner mental health status. Prisoners (N = 756) from two UK prisons completed an established measure of mental health (General Health Questionnaire: GHQ-12) and a bespoke survey on pre-prison characteristics and experiences (for example, dispositions, childhood abuse, substance misuse, learning difficulties and employment). Prevalence of mental health difficulties was high, with 40.3% reaching the 'caseness' threshold. Binary logistic regression and odds ratio analyses were used to explore the ability of imported factors to predict mental health 'caseness' and the direction of influence. Collectively, the imported factors correctly predicted the caseness category of 76.5% of participants (p < .001). Pre-prison dispositions proved to be strong predictors of caseness as did childhood sexual abuse and learning difficulties at school. We found the direction of influence of three imported factors differed from all others: unemployment, prior experience of prison and a history of substance misuse. These three factors are associated with a lower rate of mental health caseness. It is of concern that, on release, these same factors are likely to militate against re-integration into society. Imported factors can serve as powerful predictors of 'within-prison' mental health status, but practitioners need to be cognisant of the relative importance and direction of influence of factors, as evidenced by these findings.

Exosomal αvß6 integrin is required for monocyte M2 polarization in prostate cancer.

Therapeutic approaches aimed at curing prostate cancer are only partially successful given the occurrence of highly metastatic resistant phenotypes that frequently develop in response to therapies. Recently, we have described αvß6, a surface receptor of the integrin family as a novel therapeutic target for prostate cancer; this epithelial-specific molecule is an ideal target since, unlike other integrins, it is found in different types of cancer but not in normal tissues. We describe a novel αvß6-mediated signaling pathway that has profound effects on the microenvironment. We show that αvß6 is transferred from cancer cells to monocytes, including ß6-null monocytes, by exosomes and that monocytes from prostate cancer patients, but not from healthy volunteers, express αvß6. Cancer cell exosomes, purified via density gradients, promote M2 polarization, whereas αvß6 down-regulation in exosomes inhibits M2 polarization in recipient monocytes. Also, as evaluated by our proteomic analysis, αvß6 down-regulation causes a significant increase in donor cancer cells, and their exosomes, of two molecules that have a tumor suppressive role, STAT1 and MX1/2. Finally, using the Ptenpc-/- prostate cancer mouse model, which carries a prostate epithelial-specific Pten deletion, we demonstrate that αvß6 inhibition in vivo causes up-regulation of STAT1 in cancer cells. Our results provide evidence of a novel mechanism that regulates M2 polarization and prostate cancer progression through transfer of αvß6 from cancer cells to monocytes through exosomes.