Samuel Haywood

Myeloid derived suppressor cell subset accumulation in renal cell carcinoma parenchyma is associated with intratumoral expression of IL-1β, IL-8, CXCL5 and Mip-1α

Purpose: Little is known about the association between myeloid-derived suppressor cell (MDSC) subsets and various chemokines in patients with renal cell carcinoma (RCC) or the factors that draw MDSC into tumor parenchyma. Experimental Design: We analyzed polymorphonuclear MDSC (PMN-MDSC), monocytic MDSC (M-MDSC), and immature MDSC (I-MDSC) from the parenchyma and peripheral blood of 48 patients with RCC, isolated at nephrectomy. We analyzed levels of IL1β, IL8, CXCL5, Mip-1α, MCP-1, and Rantes. Furthermore, we performed experiments in a Renca murine model to assess therapeutic synergy between CXCR2 and anti-PD1 and to elucidate the impact of IL1β blockade on MDSC. Results: Parenchymal PMN-MDSC have a positive correlation with IL1β, IL8, CXCL5, and Mip-1α, and I-MDSC correlate with IL8 and CXCL5. Furthermore, peripheral PMN-MDSC correlate with tumor grade. Given that PMN-MDSC express CXCR2 and parenchymal PMN-MDSC correlated with IL8 and CXCL5, we assessed the response of CXCR2 blockade with or without anti-PD1. Combination therapy reduced tumor weight and enhanced CD4+ and CD8+ T-cell infiltration. In addition, anti-IL1β decreased PMN-MDSC and M-MDSC in the periphery, PMN-MDSC in the tumor, and peripheral CXCL5 and KC. Anti-IL1β also delayed tumor growth. Conclusions: Parenchymal PMN-MDSC have a positive correlation with IL1β, IL8, CXCL5, and Mip-1α, suggesting they may attract PMN-MDSC into the tumor. Peripheral PMN-MDSC correlate with tumor grade, suggesting prognostic significance. Anti-CXCR2 and anti-PD1 synergized to reduce tumor weight and enhanced CD4+ and CD8+ T-cell infiltration in a Renca murine model, suggesting that CXCR2+ PMN-MDSC are important in reducing activity of anti-PD1 antibody. Finally, anti-IL1β decreases MDSC and delayed tumor growth, suggesting a potential target for MDSC inhibition. Clin Cancer Res; 23(9); 2346–55. ©2016 AACR.

Intermediate-Term Outcomes for Men with Very Low/Low and Intermediate/High Risk Prostate Cancer Managed by Active Surveillance

Purpose: We compare intermediate term clinical outcomes among men with favorable risk and intermediate/high risk prostate cancer managed by active surveillance. Materials and Methods: A total of 635 men with localized prostate cancer have been on active surveillance since 2002 at a high volume academic hospital in the United States. Median followup is 50.5 months (IQR 31.1–80.3). Time to event analysis was performed for our clinical end points. Results: Of the cohort 117 men (18.4%) had intermediate/high risk disease. Overall 5 and 10‐year all cause survival was 98% and 94%, respectively. Cumulative metastasis‐free survival at 5 and 10 years was 99% and 98%, respectively. To date no cancer specific deaths had been observed. Overall freedom from intervention was 61% and 49% at 5 and 10 years, respectively. Overall cumulative freedom from failure of active surveillance, defined as metastasis or biochemical failure after local therapy with curative intent, was 97% and 91% at 5 and 10 years, respectively. Of the men 21 (9.9%) experienced biochemical failure after deferred treatment and the 5‐year progression‐free probability was 92%. Compared to men with favorable risk disease those with intermediate/high risk cancer experienced no difference in metastases, surveillance failure or curative intervention. However, patients at higher risk were at significantly increased risk for all cause mortality, likely reflecting patient selection factors. These conclusions may be limited by the small number of events and the duration of our study. Conclusions: Patients with localized prostate cancer who are on active surveillance demonstrated a low rate of active surveillance failure, prostate cancer specific mortality and metastases regardless of baseline risk.

Response to the U.S. Preventative Services Task Force decision on prostate cancer screening

The population-level data demonstrate that the inception of prostate-specific antigen (PSA) screening has lowered mortality for prostate cancer over the past 2 decades. However, more recent evidence from randomized trials has presented conflicting results regarding the benefit of PSA screening for prostate cancer mortality. Using available data, the U.S. Preventative Services Task Force recently recommended against PSA screening for prostate cancer. However, prostate cancer continues to kill over 30,000 men annually, and as such, completely abandoning screening for this disease is a disservice to many patients. Rather, the emphasis should be on utilizing evidence-based medicine to reduce overdiagnosis and overtreatment through less frequent screening for low-risk individuals or those unlikely to benefit from screening, halting further screening when appropriate, and utilizing observational strategies in patients unlikely to suffer clinically significant effects of prostate cancer over their anticipated life expectancy.

Myeloid-derived suppressors cells (MDSC) correlate with clinicopathologic factors and pathologic complete response (pCR) in patients with urothelial carcinoma (UC) undergoing cystectomy

BACKGROUND Myeloid derived suppressor cells (MDSC) are heterogeneous immunosuppressive cells with potential predictive and prognostic roles in cancer. The association between MDSC, clinicopathologic factors, and pathologic response in patients with bladder urothelial carcinoma (UC) was explored. METHODS Peripheral blood or tissue were collected from patients with UC undergoing definitive surgery. MDSCs levels were measured in peripheral blood mononuclear cells and fresh tumor tissue. MDSCs were identified by flow cytometry and defined as total MDSC (T-MDSC) CD33+/HLADR-. From this population, 3 subsets were identified: polymorphonuclear-MDSC (PMN-MDSC) defined as CD33+/HLADR-/CD15+/CD14-, monocytic-MDSC (M-MDSC) defined as CD33+/HLADR-/CD15-/CD14+, and immature-MDSC (I-MDSC) defined as CD33+/HLADR-/CD15-/CD14-. MDSC populations were presented as % of live nucleated blood cells. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations, clinicopathologic factors, and pathologic complete response (pCR). RESULTS 85 patients scheduled to undergo cystectomy from February 2015 through Dec 2016 were included. All patients had blood drawn for analysis and 23 patients had residual tumor tissue collected for analysis at the time of surgery. Of these 85, 74 (87%) were men with a median age at diagnosis of 68 (range: 44-87). Pure UC was the most common histology (75%); 28 (35%) patients had prior treatment with intravesical therapy and 36 (42%) were treated with neoadjuvant chemotherapy, primarily gemcitabine plus cisplatin (n = 24). On surgical pathology, 18 (21%) of the patients had pCR, 11 (13%) had positive lymph nodes, and 20 patients (24%) had lymphovascular invasion. Statistically significant associations were found between circulating MDSC levels and pCR rates (P<0.01), absolute neutrophil-lymphocyte ratio (P = 0.008), and histology (P = 0.01). Tumor % M-MDSCs were negatively associated with lymphovascular invasion (P = 0.04). There were no significant correlations between peripheral blood mononuclear cells and tumor MDSC subtypes. CONCLUSIONS Blood and tissue MDSC levels correlate with several clinicopathologic factors and may predict for pCR. Future studies are needed to highlight the role of MDSC in predicting long-term outcomes and to determine the clinical implications of these findings.

Prognostic Significance of a Negative Confirmatory Biopsy on Reclassification Among Men on Active Surveillance

OBJECTIVE To examine the association between absence of disease on confirmatory biopsy and risk of pathologic reclassification in men on active surveillance (AS). MATERIALS AND METHODS Men with grade groups 1 and 2 disease on AS between 2002 and 2015 were identified who received a confirmatory biopsy within 1 year of diagnosis and ≥3 biopsies overall. The primary outcomes were pathologic reclassification by grade (any increase in primary Gleason pattern or Gleason score) or volume (>33% of sampled cores involved or increase in the number of cores with >50% involvement). The effect of a negative confirmatory biopsy survival was evaluated using Kaplan-Meier analysis and a Cox proportional hazards modeling. RESULTS Out of 635 men, 224 met inclusion criteria (median follow-up: 55.8 months). A total of 111 men (49.6%) had a negative confirmatory biopsy. Decreased grade reclassification (69.7% vs 83.9%; P = .01) and volume reclassification (66.3% vs 87.4%; P = .004) was seen at 5 years for men with a negative confirmatory biopsy compared with those with a positive biopsy. On adjusted analysis, a negative confirmatory biopsy was associated with a decreased risk of grade reclassification (hazard ratio, 0.51; 95% confidence interval, 0.28-0.94; P = .03) and volume reclassification (hazard ratio, 0.32; 95% confidence interval, 0.17-0.61; P = .0006) at a median of 4.7 years. CONCLUSION Absence of cancer on the confirmatory biopsy is associated with a significant decrease in rate of grade and volume reclassification among men on AS. This information may be used to better counsel men on AS.

Impact of 5α-Reductase Inhibitors on Disease Reclassification among Men on Active Surveillance for Localized Prostate Cancer with Favorable Features

Purpose: We determined the effect of 5&agr;‐reductase inhibitors on disease reclassification in men with prostate cancer optimally selected for active surveillance. Materials and Methods: In this retrospective review we identified 635 patients on active surveillance between 2002 and 2015. Patients with favorable cancer features on repeat biopsy, defined as absent Gleason upgrading, were included in the cohort. Patients were stratified by those who did or did not receive finasteride or dutasteride within 1 year of diagnosis. The primary end point was grade reclassification, defined as any increase in Gleason score or predominant Gleason pattern on subsequent biopsy. This was assessed by multivariable Cox proportional hazards regression analysis. Results: At diagnosis 371 patients met study inclusion criteria, of whom 70 (19%) were started on 5&agr;‐reductase inhibitors within 12 months. Median time on active surveillance was 53 vs 35 months in men on vs not on 5&agr;‐reductase inhibitors (p <0.01). Men on 5&agr;‐reductase inhibitors received them for a median of 23 months (IQR 6–37). On actuarial analysis there was no significant difference in grade reclassification for 5&agr;‐reductase inhibitor use in patients overall or in the very low/low risk subset. The overall percent of patients who experienced grade reclassification was similar at 13% vs 14% (p = 0.75). After adjusting for baseline clinicopathological features 5&agr;‐reductase inhibitors were not significantly associated with grade reclassification (HR 0.80, 95% CI 0.31–1.80, p = 0.62). Furthermore, no difference in adverse features on radical prostatectomy specimens was observed in treated patients (p = 0.36). Conclusions: Among our cohort of men on active surveillance 5&agr;‐reductase inhibitor use was not associated with a significant difference in grade reclassification with time.

Gene Expression Testing as a Predictor of Adverse Pathology after Radical Prostatectomy: Implications for Choosing Patients for Active Surveillance

TMA = tissue microarray Prostate cancer is the most common noncutaneous malignancy affecting American men. Prostate specific antigen testing has directed a stage migration toward earlier diagnosis but has also likely resulted in over diagnosis and overtreatment of prostate cancer. Active surveillance has gained traction as a management strategy for prostate cancer but uncertainty regarding the risk of a particular cancer limits its acceptance. Specifically misclassification and difficulty predicting adverse pathology make risk stratification complex. The use of gene expression testing has shown recent promise in predicting adverse pathology at prostatectomy. Several biopsy based commercial tests are available, and their evidence and use are reviewed. The ability of these tests to predict pathological outcomes may identify patients who could be ideal candidates for active surveillance. This review highlights the importance of identifying patients with adverse pathology at diagnosis and incorporating these tests into the landscape of diagnosis and management. Despite significant improvements in the diagnosis and management of prostate cancer, this entity remains the most common noncutaneous malignancy affecting American men. Approximately 1 in 6 men will be diagnosed with prostate cancer during their lifetime. Use of prostate specific antigen screening programs has been successful in directing a stage migration of prostate cancer toward diagnosis at earlier disease stage. However, because of over diagnosis and overtreatment, this strategy remains controversial, highlighting a continued need for improvement in determination of clinically significant disease. The use of biopsy based gene expression profiling in prostate cancer has demonstrated recent promise, with several commercial tests available to predict the presence of adverse pathological features that identify patients who may not be ideal candidates for active surveillance. This review highlights the importance of identifying those patients with adverse pathology at diagnosis and incorporation of these tests into the landscape of diagnosis and treatment.

PD55-12 OLDER AGE AT DIAGNOSIS AND DISEASE VOLUME PREDICT UPGRADING ON CONFIRMATORY BIOPSY IN PROSTATE CANCER PATIENTS BEING CONSIDERED FOR ACTIVE SURVEILLANCE

RESULTS: 3669 patients underwent RP between 1/1/04 and 12/31/15. Of these, 1454, 251 and 1361 patients fulfilled criteria for very low/low, favorable intermediate, and unfavorable intermediate-risk groups, respectively. Median follow-up was 37 months. Patients in the favorable intermediate group had significantly higher rates of Gleason score upgrading (16% vs 6%; p<0.001) and non organ-confined disease (16% vs 11%; p1⁄40.035) than those in low risk group. Time to biochemical recurrence for the favorable intermediate group did not differ significantly from the low risk group (p1⁄40.057), but was significantly longer than unfavorable intermediates (p1⁄40.003) (Figure 1). CONCLUSIONS: Compared to very low/low risk prostate cancer patients, men with favorable intermediate-risk disease had significantly higher rates of more aggressive, non-organ confined disease at RP, and trended toward worse biochemical progression free survival. However, when compared to unfavorable intermediate risk patients, it appears the magnitude of these differences would not preclude AS as a reasonable option for appropriately selected patients with favorable intermediate risk prostate cancer.

PD55-11 IS FAVORABLE INTERMEDIATE RISK PROSTATE CANCER REALLY FAVORABLE? IMPLICATIONS FOR ACTIVE SURVEILLANCE STRATEGIES

RESULTS: 3669 patients underwent RP between 1/1/04 and 12/31/15. Of these, 1454, 251 and 1361 patients fulfilled criteria for very low/low, favorable intermediate, and unfavorable intermediate-risk groups, respectively. Median follow-up was 37 months. Patients in the favorable intermediate group had significantly higher rates of Gleason score upgrading (16% vs 6%; p<0.001) and non organ-confined disease (16% vs 11%; p1⁄40.035) than those in low risk group. Time to biochemical recurrence for the favorable intermediate group did not differ significantly from the low risk group (p1⁄40.057), but was significantly longer than unfavorable intermediates (p1⁄40.003) (Figure 1). CONCLUSIONS: Compared to very low/low risk prostate cancer patients, men with favorable intermediate-risk disease had significantly higher rates of more aggressive, non-organ confined disease at RP, and trended toward worse biochemical progression free survival. However, when compared to unfavorable intermediate risk patients, it appears the magnitude of these differences would not preclude AS as a reasonable option for appropriately selected patients with favorable intermediate risk prostate cancer.

Phytotherapy in Chronic Pelvic Pain

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common condition with significant impact on quality of life. Multiple etiologies are implicated including inflammation, infection, neuropathy, and pelvic muscle spasm. Ideal therapy is typically multimodal with treatments focused on the patient’s clinical phenotype. Traditional pharmacologic treatments have often failed in clinical trials. Interest has thus increased in the use of alternative treatments such as phytotherapies. However, it is imperative that these treatments receive the same rigorous evaluation as do the more traditional pharmaceuticals to help provide evidence-based medicine for patients with CP/CPPS. The increased attention to phytotherapies in the literature has provided practitioners with clinical trials of these agents to guide therapy. Commonly used treatments within this area are pollen extracts, quercetin, saw palmetto, and traditional Chinese herbal medicine. This chapter will serve to review each of these phytotherapies and further investigate the scientific data for each.