Background

The antiprostate cancer effects of dietary ω-3 fatty acids (FAs) were previously found to be dependent on host G-protein coupled receptor 120 (GPR120). Using an orthotopic tumor model and an ex-vivo model of bone marrow derived M2-like macrophages, we sought to determine if ω-3 FAs inhibit angiogenesis and activate T-cells, and if these effects are dependent on GPR120.

Methods

Gausia luciferase labeled MycCaP prostate cancer cells (MycCaP-Gluc) were injected into the anterior prostate lobe of FVB mice. After established tumors were confirmed by blood luminescence, mice were fed an ω-3 or ω-6 diet. Five weeks after tumor injection, tumor weight, immune cell infiltration and markers of angiogenesis were determined. An ex-vivo co-culture model of bone marrow derived M2-like macrophages from wild-type or GPR120 knockout mice with MycCap prostate cancer cells was used to determine if docosahexanoic acid (DHA, ω-3 FA) inhibition of angiogenesis and T-cell activation is dependent on macrophage GPR120.

Results

Feeding an ω-3 diet significantly reduced orthotopic MycCaP-Gluc tumor growth relative to an ω-6 diet. Tumors from the ω-3 group had decreased M2-like macrophage infiltration and decreased expression of angiogenesis factors. DHA significantly inhibited M2 macrophage-induced endothelial tube formation and reversed M2 macrophage-induced T-cell suppression, and these DHA effects were mediated, in part, by M2 macrophage GPR120.

Conclusion

Omega-3 FAs delayed orthotopic tumor growth, inhibited M2-like macrophage tumor infiltration, and inhibited M2-like macrophage-induced angiogenesis and T-cell suppression. Given the central role of M2-like macrophages in prostate cancer progression, GPR120-dependent ω-3 FA inhibition of M2-like macrophages may play an important role in prostate cancer therapeutics.

Background

M2-like macrophages are associated with the pathogenesis of castrate-resistant prostate cancer (CRPC). We sought to determine if dietary omega-3 fatty acids (ω-3 FAs) delay the development and progression of CRPC and inhibit tumor-associated M2-like macrophages.

Methods

MycCap cells were grown subcutaneously in immunocompetent FVB mice. Mice were castrated when tumors reached 300 mm². To study effects of dietary ω-3 FAs on development of CRPC, ω-3 or ω-6 diets were started 2 days after castration and mice sacrificed after early regrowth of tumors. To study ω-3 FA effects on progression of CRPC, tumors were allowed to regrow after castration before starting the diets. M2 (CD206+) macrophages were isolated from allografts to examine ω-3 FA effects on macrophage function. Omega-3 fatty acid effects on androgen-deprived RAW264.7 M2 macrophages were studied by RT-qPCR and a migration/ invasion assay.

Results

The ω-3 diet combined with castration lead to greater MycCap tumor regression (tumor volume reduction: 182.2 ± 33.6 mm³) than the ω-6 diet (tumor volume reduction: 148.3 ± 35.2; p = 0.003) and significantly delayed the time to CRPC (p = 0.006). Likewise, the ω-3 diet significantly delayed progression of established castrate-resistant MycCaP tumors (p = 0.003). The ω-3 diet (as compared to the ω-6 diet) significantly reduced tumor-associated M2-like macrophage expression of CSF-1R in the CRPC development model, and matrix metallopeptidase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in the CRPC progression model. Migration of androgen-depleted RAW264.7 M2 macrophages towards MycCaP cells was reversed by addition of docosahexaenoic acid (ω-3).

Conclusions

Dietary omega-3 FAs (as compared to omega-6 FAs) decreased the development and progression of CRPC in an immunocompetent mouse model, and had inhibitory effects on M2-like macrophage function. Clinical trials are warranted evaluating if a fish oil-based diet can delay the time to castration resistance in men on androgen deprivation therapy, whereas further preclinical studies are warranted evaluating fish oil for more advanced CRPC.

INTRODUCTION: Prior studies suggest that white light cystoscopy (WLC) alone can fail to detect cases of non-muscle invasive bladder cancer (NMIBC) vs. blue light cystoscopy (BLC). We describe bladder cancer outcomes and the impact of BLC among NMIBC patients in an equal access setting. MATERIALS AND METHODS: We assessed 378 NMIBC patients within the Veterans Affairs system that had a CPT code for BLC from December 1, 2014 to December 31, 2020. We determined recurrence rates and time to recurrence prior to BLC (ie, after previous WLC if available) and following BLC. We used the Kaplan-Meier method to estimate event-free survival and Cox regression to determine association between BLC and recurrence, progression, and overall survival; and further, whether these outcomes differed by race. RESULTS: Of 378 patients with complete data, 43 (11%) were Black and 300 (79%) White. Median follow-up was 40.7 months from bladder cancer diagnosis. Median time to first recurrence following BLC was longer vs. WLC alone (40 [33-NE] vs. 26 [17-39] months). Recurrence risk was significantly lower following BLC (Hazard Ratio [HR] 0.70; 95% Confidence Interval [CI], 0.54-0.90). There was no significant difference in recurrence (HR 0.69; 95% CI, 0.39-1.20), progression (HR 1.13; 95% CI, 0.32-3.96), and overall survival (HR 0.74; 95% CI, 0.31-1.77) following BLC by Black vs. White race. CONCLUSION: In this study from an equal access setting in the VA, we observed significantly decreased recurrence risk and prolonged time interval to recurrence following BLC vs. WLC alone. There was no difference in bladder cancer outcomes by race.

Objectives

To examine if there is a subset of men with grade group 2 prostate cancer who could be potential candidates for active surveillance.

Methods

We used the Shared Equal Access Regional Cancer Hospital database to identify 776 men undergoing radical prostatectomy from 2006 to 2015 with >8 biopsy cores obtained and complete information. We compared men who fulfilled low-risk disease criteria (clinical stage T1c/T2a; grade group 1; prostate-specific antigen ≤10 ng/mL) with the exception of grade group 2 versus men who met all three low-risk criteria. Logistic regression was used to test the association between grade group and radical prostatectomy pathological features. Biochemical recurrence was examined using Cox models. To examine whether there was a subset of men with low-volume grade group 2 with comparable outcomes to low-risk men, we repeated all analyses limiting the percentage of positive cores in the grade group 2 group to ≤33%, and positive cores to ≤4, ≤3 or ≤2.

Results

Grade group 2 low-risk men had increased risk of pathological grade group 3 or higher (P < 0.001), extraprostatic extension (P < 0.001), seminal vesicle invasion (P < 0.001) and higher risk of biochemical recurrence (hazard ratio = 1.76, P = 0.006). Using increasingly strict definitions of low-volume disease, at ≤2 positive cores there was no difference in adverse pathology between groups (all P > 0.2), except higher pathological grade group (P = 0.006). Biochemical recurrence was similar in men in grade group 1 and grade group 2 (hazard ratio = 1.24; P = 0.529).

Conclusions

Among men with prostate-specific antigen ≤10 ng/mL and clinical stage T1c/T2a, those in grade group 2 with ≤2 total positive cores have similar rates of adverse pathology and biochemical recurrence as men with grade group 1.

We previously reported that a 4- to 6-week low-fat fish oil (LFFO) diet did not affect serum insulin-like growth factor (IGF)-1 levels (primary outcome) but resulted in lower omega-6 to omega-3 fatty acid ratios in prostate tissue and lower prostate cancer proliferation (Ki67) as compared with a Western diet. In this post hoc analysis, the effect of the LFFO intervention on serum pro-inflammatory eicosanoids, leukotriene B4 (LTB4) and 15-S-hydroxyeicosatetraenoic acid [15(S)-HETE], and the cell-cycle progression (CCP) score were investigated. Serum fatty acids and eicosanoids were measured by gas chromatography and ELISA. CCP score was determined by quantitative real-time reverse transcriptase PCR (RT-PCR). Associations between serum eicosanoids, Ki67, and CCP score were evaluated using partial correlation analyses. BLT1 (LTB4 receptor) expression was determined in prostate cancer cell lines and prostatectomy specimens. Serum omega-6 fatty acids and 15(S)-HETE levels were significantly reduced, and serum omega-3 levels were increased in the LFFO group relative to the Western diet group, whereas there was no change in LTB4 levels. The CCP score was significantly lower in the LFFO compared with the Western diet group. The 15(S)-HETE change correlated with tissue Ki67 (R = 0.48; P < 0.01) but not with CCP score. The LTB4 change correlated with the CCP score (r = 0.4; P = 0.02) but not with Ki67. The LTB4 receptor BLT1 was detected in prostate cancer cell lines and human prostate cancer specimens. In conclusion, an LFFO diet resulted in decreased 15(S)-HETE levels and lower CCP score relative to a Western diet. Further studies are warranted to determine whether the LFFO diet antiproliferative effects are mediated through the LTB4/BLT1 and 15(S)-HETE pathways.

Objective

To test the relationship of smoking and aggressive prostate cancer in men undergoing radical prostatectomy.

Methods

A retrospective analysis of 2290 men who underwent radical prostatectomy from the Shared Equal Access Regional Cancer Hospital database from 2000 to 2013 was carried out. There were 1592 (70%) non-smokers and 698 (30%) smokers at radical prostatectomy. Logistic regression was used to examine whether smoking predicted Gleason score (≥4 + 3), margin status, extracapsular extension or seminal vesicle invasion. Linear regression was used to test the relationship between smoking and tumor volume.

Results

Smokers were younger, more likely to be black, had lower body mass index, higher pathological Gleason score, more positive margins and extracapsular extension (all P < 0.05) versus non-smokers. On crude analysis, smoking was associated with positive margins (odds ratio 1.32; P = 0.003) and extracapsular extension (odds ratio 1.26; P = 0.036). After adjusting for multiple clinical factors, smoking remained associated with a 19-35% increased risk of every adverse feature studied, though only the association with extracapsular extension reached significance. On multivariable analysis, a trend for smokers to have larger tumor volumes (geometric mean 5.8 vs 5.3 g; P = 0.062) was found.

Conclusions

In patients undergoing radical prostatectomy, there seems to be a trend for smokers to have worse pathological features compared with non-/former smokers. If confirmed in future studies, smoking should be considered a modifiable risk factor for aggressive prostate cancer.

Background

Black men are disproportionately affected by both cardiovascular disease and prostate cancer. Epidemiologic evidence linking dyslipidemia, an established cardiovascular risk factor, and prostate cancer progression is mixed. As existing studies were conducted in predominantly non-black populations, research on black men is lacking.

Methods

We identified 628 black and 1,020 non-black men who underwent radical prostatectomy and never used statins before surgery in the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Median follow-up was 2.9 years. The impact of preoperative hypercholesterolemia on risk of biochemical recurrence was examined using multivariable, race-stratified proportional hazards. In secondary analysis, we examined associations with low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides, overall and among men with dyslipidemia.

Results

High cholesterol was associated with increased risk of recurrence in black [HR(per10 mg/dL) 1.06; 95% confidence interval (CI), 1.02-1.11] but not non-black men (HR(per10 mg/dL) 0.99; 95% CI, 0.95-1.03; P(interaction) = 0.011). Elevated triglycerides were associated with increased risk in both black and non-black men (HR(per10 mg/dL) 1.02; 95% CI, 1.00-1.03 and 1.02; 95% CI, 1.00-1.02, respectively; P(interaction) = 0.458). There were no significant associations between LDL or HDL and recurrence risk in either race. Associations with cholesterol, LDL, and triglycerides were similar among men with dyslipidemia, but low HDL was associated with increased risk of recurrence in black, but not non-black men with dyslipidemia (P(interaction) = 0.047).

Conclusion

Elevated cholesterol was a risk factor for recurrence in black but not non-black men, whereas high triglycerides were associated with increased risk regardless of race.

Impact

Significantly contrasting associations by race may provide insight into prostate cancer racial disparities.

Background

Preclinical and epidemiologic studies suggest chemopreventive effects of green tea (GT) and black tea (BT) in prostate cancer. In the current study we determined the effect of GT and BT consumption on biomarkers related to prostate cancer development and progression.

Methods

In this exploratory, open label, phase II trial 113 men diagnosed with prostate cancer were randomized to consume six cups daily of brewed GT, BT or water (control) prior to radical prostatectomy (RP). The primary endpoint was prostate tumor markers of cancer development and progression determined by tissue immunostaining of proliferation (Ki67), apoptosis (Bcl-2, Bax, Tunel), inflammation (nuclear and cytoplasmic nuclear factor kappa B [NFκB]) and oxidation (8-hydroxydeoxy-guanosine [8OHdG]). Secondary endpoints of urinary oxidation, tea polyphenol uptake in prostate tissue, and serum prostate specific antigen (PSA) were evaluated by high performance liquid chromatography and ELISA analysis.

Results

Ninety three patients completed the intervention. There was no significant difference in markers of proliferation, apoptosis and oxidation in RP tissue comparing GT and BT to water control. Nuclear staining of NFκB was significantly decreased in RP tissue of men consuming GT (P = 0.013) but not BT (P = 0.931) compared to water control. Tea polyphenols were detected in prostate tissue from 32 of 34 men consuming GT but not in the other groups. Evidence of a systemic antioxidant effect was observed (reduced urinary 8OHdG) only with GT consumption (P = 0.03). GT, but not BT or water, also led to a small but statistically significant decrease in serum prostate-specific antigen (PSA) levels (P = 0.04).

Conclusion

Given the GT-induced changes in NFκB and systemic oxidation, and uptake of GT polyphenols in prostate tissue, future longer-term studies are warranted to further examine the role of GT for prostate cancer prevention and treatment, and possibly for other prostate conditions such as prostatitis.

73 Background: Performance of a pelvic lymph node dissection (PLND) with radical prostatectomy (RP) is critical for staging and treatment of high-risk prostate cancer (PC). Conversely, performance of a PLND in low-risk PC contributes to morbidity with minimal benefit. Robot-assisted laparoscopic RP (RARP) is associated with decreased PLND use. We evaluated PLND use over time, stratified by PC risk group and surgical technique. Methods: We used SEARCH to identify men who had open RP (ORP) or RARP from 2006-2013 with complete data. Univariable logistic regression was used to test the association between age, race, BMI, number of positive cores, AUA risk group, year, center, and surgical technique on PLND use. Multivariable logistic analysis was used to examine surgical technique and PLND performance stratified by AUA risk-group. Spearman correlation was used to examine temporal changes in PLND utilization stratified by risk-group and surgical technique. Results: 1,439 men met inclusion criteria. Of these, 66% had a PLND. On univariable analysis, age, year, number of positive cores, AUA risk group, center, and surgical technique were significantly associated with PLND performance (all p<0.02). On multivariable analysis, when adjusted for age, race, BMI, number of positive cores, year, and center, RARP was associated with a 89% decreased use of PLND in the low-risk group, 85% decreased in intermediate risk, and 86% decreased in high risk men (all p≤0.002). Over time, PLND was increasingly used with RARP in low-risk patients (p=0.022); a trend of increased PLND performance with RARP in high risk men was noted (p=0.077) reaching ~85% in 2012-2013 vs. ~95% in ORP. For ORP, PLND use did not significantly change over time except a trend of fewer PLND in low-risk men which decreased to ~35% (p=0.064) in 2012-2013. Conclusions: Regardless of risk group, PLND is markedly less likely to be performed when a RARP is done. While improved over time, PLND remains over-utilized in low-risk men and under-utilized in high risk men regardless of surgical technique.

Objectives

To examine whether prostate-specific antigen doubling time (PSADT) correlates with metastases, all-cause mortality (ACM), and prostate cancer-specific mortality (PCSM) and to identify PSADT thresholds that can be used clinically for risk stratification in men with M0 castration-resistant prostate cancer (CRPC).

Materials and methods

We collected data on 441 men with M0 CRPC in 2000-2015 at five Veterans Affairs hospitals. Cox models were used to test the association between log-transformed PSADT and the development of metastasis, ACM and PCSM. To identify thresholds, we categorized PSADT into 3-month groups and then combined groups with similar hazard ratios (HRs).

Results

The median (interquartile range) follow-up was 28.3 (14.7-49.1) months. As a continuous variable, PSADT was associated with metastases, ACM and PCSM (HR 1.40-1.68, all P < 0.001). We identified the following PSADT thresholds: <3 months; 3-8.9 months; 9-14. months; and ≥15 months. As a categorical variable, PSADT was associated with metastases, ACM and PCSM (all P < 0.001). Specifically, PSADT <3 months was associated with an approximately ninefold increased risk of metastases (HR 8.63, 95% CI 5.07-14.7) and PCSM (HR 9.29, 95% CI 5.38-16.0), and a 4.7-fold increased risk of ACM (HR 4.71, 95% CI 2.98-7.43) on multivariable analysis compared with PSADT ≥15 months. The median times to metastasis for patients with PSADT <3, 3-8.9, 9-14.9 and ≥15 months were 9, 19, 40 and 50 months, respectively.

Conclusion

Prostate-specific antigen doubling time was a strong predictor of metastases, ACM and PCSM in patients with M0 CRPC. As with patients at earlier disease stages, <3, 3-8.9, 9-14.9 and ≥15 months are reasonable PSADT thresholds for risk stratification in men with M0 CRPC. These thresholds can be used for selecting high-risk men for clinical trials.