Adrien Bernstein

Partial Gland Treatment of Prostate Cancer Using High-Intensity Focused Ultrasound in the Primary and Salvage Settings: A Systematic Review

Purpose: Advances in prostate imaging, biopsy and ablative technologies have been accompanied by growing enthusiasm for partial gland ablation, particularly using high‐intensity focused ultrasound, to treat prostate cancer. Preserving noncancerous prostate tissue and minimizing damage to the neurovascular bundles and external urethral sphincter may improve functional outcomes. Materials and Methods: A systematic review was performed following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) guidelines using a combination of MeSH® terms, free text search and examination of relevant bibliographies using MEDLINE® and Embase® from the inception of each database through October 10, 2016. We excluded studies describing exclusively whole gland ablation, case reports and series where treatment was followed by immediate resection. Results: A total of 13 studies that enrolled 543 patients were included. Of the studies 11 were performed in the primary setting and 2 in the salvage setting. Median followup ranged from 6 months to 10.6 years. Rates of posttreatment erectile dysfunction and urinary incontinence ranged from 0% to 48% and 0% to 50%, respectively, with definitions varying by study. Overall there were 254 reported complications. Marked heterogeneity between studies limited the ability to pool results regarding functional and oncologic outcomes. A total of 76 patients (14%) subsequently received further oncologic treatment. Conclusions: Early evidence suggests that partial gland ablation is a safe treatment option for men with localized disease. Longer term data are needed to evaluate oncologic efficacy and functional outcomes, and will aid in identifying the optimal candidates for therapy. Standardization of outcomes definitions will allow for better comparison between studies and among treatment modalities.

Complementary histological and genomic analyses reveal marked differences in the developmental trajectories of ovaries in Siberian hamsters raised in long‐ and short‐day lengths

Siberian hamsters (Phodopus sungorus) delay sexual development when raised in short‐day (SD; 10 hr light: 14 hr dark) conditions, which leads to delayed onset of estrous cycles and ovulations as compared to females raised in long‐day (LD; 16 hr light: 8 hr dark) conditions. In addition to the absence of pre‐ovulatory follicles and corpora lutea, the ovaries of SD‐reared Siberian hamsters are characterized by an abundance of hypertrophied granulosa cells (HGCs) that surround atretic oocytes. To determine the age at which the histology of LD and SD ovaries first diverge, including the initial appearance of HGCs in SD conditions, we examined hamster ovaries histologically at 1, 2, 3, 4, 6, 8, 10, and 12 weeks of age. After identifying subtle differences in LD and SD ovarian histology at 4 weeks of age, we searched for differences in ovarian gene expression at 3 and 8 weeks of age, which correspond to the ages when ovarian histology do not differ (3 weeks) versus the earliest age when HGCs were observed (8 weeks). At 3 weeks, only 14 genes were differentially expressed in LD and SD ovaries, whereas 183 genes were differentially expressed at 8 weeks. Overall, our findings demonstrate that ovarian development under SD conditions is not simply arrested at an early stage of LD development, but rather utilizes a developmental path that is distinct from that used in LD ovaries. Mol. Reprod. Dev. 2014.

Contemporary Incidence and Outcomes of Prostate Cancer Lymph Node Metastases

Purpose: The incidence of localized prostate cancer has decreased with shifts in prostate cancer screening. While recent population based studies demonstrated a stable incidence of locoregional prostate cancer, they categorized organ confined, extraprostatic and lymph node positive disease together. However, to our knowledge the contemporary incidence of prostate cancer with pelvic lymph node metastases remains unknown. Materials and Methods: We used SEER (Surveillance, Epidemiology and End Results) data from 2004 to 2014 to identify men diagnosed with prostate cancer. We analyzed trends in the age standardized prostate cancer incidence by stage. The impact of disease extent on mortality was assessed by adjusted Cox proportional hazard analysis. Results: During the study period the annual incidence of nonmetastatic prostate cancer decreased from 5,119.1 to 2,931.9 per million men (IR 0.57, 95% CI 0.56–0.58, p <0.01) while the incidence of pelvic lymph node metastases increased from 54.1 to 79.5 per million men (IR 1.47, 95% CI 1.33–1.62, p <0.01). The incidence of distant metastases in men 75 years old or older reached a nadir in 2011 compared to 2004 (IR 0.81, 95% CI 0.74–0.90, p <0.01) and it increased in 2012 compared to 2011 (IR 1.13, 95% CI 1.02–1.24, p <0.05). The risk of cancer specific mortality significantly increased in men diagnosed with pelvic lymph node metastases (HR 4.5, 95% CI 4.2–4.9, p <0.01) and distant metastases (HR 21.9, 95% CI 21.2–22.7, p <0.01) compared to men with nonmetastatic disease. Conclusions: The incidence of pelvic lymph node metastases is increasing coincident with a decline in the detection of localized disease. Whether this portends an increase in the burden of advanced disease or simply reflects decreased lead time remains unclear. However, this should be monitored closely as the increase in N1 disease reflects an increase in incurable prostate cancer at diagnosis.

Development of a nationally-representative coordinated registry network for prostate ablation technologies

Purpose: The accumulation of data through a prospective, multicenter coordinated registry network is a practical way to gather real world evidence on the performance of novel prostate ablation technologies. Urological oncologists, targeted biopsy experts, industry representatives and representatives of the FDA (Food and Drug Administration) convened to discuss the role, feasibility and important data elements of a coordinated registry network to assess new and existing prostate ablation technologies. Materials and Methods: A multiround Delphi consensus approach was performed which included the opinion of 15 expert urologists, representatives of the FDA and leadership from high intensity focused ultrasound device manufacturers. Stakeholders provided input in 3 consecutive rounds with conference calls following each round to obtain consensus on remaining items. Participants agreed that these elements initially developed for high intensity focused ultrasound are compatible with other prostate ablation technologies. Coordinated registry network elements were reviewed and supplemented with data elements from the FDA common study metrics. Results: The working group reached consensus on capturing specific patient demographics, treatment details, oncologic outcomes, functional outcomes and complications. Validated health related quality of life questionnaires were selected to capture patient reported outcomes, including the IIEF‐5 (International Index of Erectile Function‐5), the I‐PSS (International Prostate Symptom Score), the EPIC‐26 (Expanded Prostate Cancer Index Composite‐26) and the MSHQ‐EjD (Male Sexual Health Questionnaire for Ejaculatory Dysfunction). Group consensus was to obtain followup multiparametric magnetic resonance imaging and prostate biopsy approximately 12 months after ablation with additional imaging or biopsy performed as clinically indicated. Conclusions: A national prostate ablation coordinated registry network brings forth vital practice pattern and outcomes data for this emerging treatment paradigm in the United States. Our multiple stakeholder consensus identifies critical elements to evaluate new and existing energy modalities and devices.

Increased resource use in men with metastatic prostate cancer does not result in improved survival or quality of care at the end of life: Testing in Metastatic Prostate Cancer

Cancer care and end‐of‐life (EOL) care contribute substantially to health care expenditures. Outside of clinical trials, to our knowledge there exists no standardized protocol to monitor disease progression in men with metastatic prostate cancer (mPCa). The objective of the current study was to evaluate the factors and outcomes associated with increased imaging and serum prostate‐specific antigen use in men with mPCa.

Intraductal Carcinoma of the Prostate: A Risk for Rapid Recurrence

Intraductal carcinoma of the prostate (IDC-P), recently defined by the World Health Organization in 2016, is a distinct histologic entity associated with an aggressive clinical course, including increased risk of biochemical recurrence, metastasis, and mortality. Differential diagnosis includes intraductal spread of urothelial carcinoma, prostatic ductal carcinoma, and high-grade prostatic intraepithelial neoplasia. BRCA mutations are associated with an increased risk of IDC-P. The presence of IDC-P on initial biopsy or radical prostatectomy should trigger aggressive treatment and should be considered a contraindication to active surveillance, regardless of tumor volume.

Population-based study of the incidence and survival for intraductal carcinoma of the prostate

PURPOSE The degree to which intraductal carcinoma of the prostate (IDC-P) affects clinical course remains poorly understood owing to small sample sizes from single-center studies. We sought to determine prognostic factors and outcomes associated with IDC-P in radical prostatectomy (RP) specimens. MATERIALS AND METHODS This is a retrospective study of RP during 2004 to 2013 using Surveillance, Epidemiology, and End Results to compare IDC-P with non-IDC-P. The effect of IDC-P on overall and disease-specific survival was assessed using Cox regression with a median follow-up of 4.8 years (interquartile range [IQR]: 2.6-7.0y; P = 0.01). Median prostate-specific antigen at diagnosis in IDC-P vs. non-IDC-P was similar (P = 0.23) at 6.2 (IQR: 4.6-13.0) vs. 6.1ng/ml (IQR: 4.6-9.8). RESULTS We identified 159,777 RP from 2004 to 2013, and 242 (0.002%) had IDC-P pathologic features. IDC-P was associated with a greater likelihood of extraprostatic stage, pT3/T4, 45.9% vs. 21.6% (P<0.001), higher grade, GS≥ 7, 79.3% vs. 62.7% (P<0.001), lymph node metastases, 5.8% vs. 2.4% (P<0.001), and positive surgical margins, 25.6% vs. 19.5% (P = 0.02). IDC-P was associated with a 3-fold increase in prostate cancer-specific mortality relative to non-IDC-P (hazard ratio = 3.0, 95% CI: 1.5-5.7; P<0.01). Limitations include retrospective design and potential underreporting of IDC-P that leads to underestimation of the true effect size. CONCLUSIONS The significance of IDC-P features has been recently recognized by the World Health Organization and it is associated with high-grade, extraprostatic features, and worse prostate cancer-specific mortality. Understanding its prognostic significance better guides adjuvant therapies and clinical trials.

MP69-12 UNDERUTILIZATION OF PALLIATIVE SERVICES IN ADVANCED GENITOURINARY MALIGNANCIES

INTRODUCTION AND OBJECTIVES: Testicular malignancies are the most common solid tumor in men 15-34 years and affect approximately 8400 men in the United States each year. Almost half can be classified as non-seminomatous germ cell tumors (NSGCT). Treatment options for stage I include surveillance, chemotherapy, or retroperitoneal lymph node dissection (RPLND). Our study aimed to examine demographic and socioeconomic trends around treatment patterns. METHODS: Using the National Cancer Database, we retrospectively examined 55,756 patients between January 1, 2004 and December 31, 2013. Data was extracted on 7,657 individuals with ICD histology diagnosis for stage I NSGCT. We obtained data on various demographic and socioeconomic variables including race, education, income, location and health insurance. We used multivariable logistic regression models to estimate odds ratios with 95% confidence intervals. RESULTS: Throughout 2004-2013 fewer patients received RPLND (OR 0.65 [0.55-0.76] p<0.01), and more received chemotherapy (OR 1.26 [1.10-1.43] p<0.01). Compared to other treatments, RPLND was less commonly seen in non-academic centers (OR 0.47 [0.33-0.66] p<0.01), more commonly in the highest volume institutions compared to the lowest volume institutions (OR 4.57 [2.47-8.46] p<0.01), and more commonly seen in those with low income (OR 1.24 [1.06-1.46] p<0.01). Patients living in rural counties compared to metro counties were more likely to receive chemotherapy (OR 1.72 [1.08-2.75] p1⁄40.03). As distance from hospital increased, individuals were more likely to receive any form of treatment versus observation for their disease (OR 1.51 for the greatest vs. the lowest quartile [1.31-1.74] p<0.01). Low income and Medicaid predicted greater chance for any treatment (OR 1.17 [1.04-1.32] p1⁄40.01 and OR 1.45 [1.20-1.74] p<0.01, respectively). No trends were seen for race or education status. CONCLUSIONS: Our study illustrates that fewer patients are undergoing RPLND, which may be due to increased surveillance. RPLND is more commonly practiced at higher volume and academic centers. Education and race do not predict choice of treatment, whereas distance, income and insurance type do predict increased likelihood for receiving treatment overall.

MP16-19 NEOADJUVANT AND ADJUVANT CHEMOTHERAPY FOLLOWING NEPHROURETERECTOMY: CHANGES IN UTILIZATION AND OUTCOMES

INTRODUCTION AND OBJECTIVES: Novel antibodies against immune checkpoint proteins, which led to unleash anti-tumor T cell responses, results in durable long-lasting responses but only in a fraction of patients. RFA of tumors can enhance systemic antitumor immunity through a series of mechanisms. Nevertheless, antitumor immunity induced by RFA is mostly weak and not sufficient enough to eradicate metastatic tumors completely or prevent disease progression durably. We hypothesized that these two different treatment strategies could act synergistically. The purpose of this study is to evaluate whether the combination of RFA and anti-PD-1 antibody could result in both primary tumor control and prevention of lung metastasis in a murine model bearing renal adenocarcinoma. METHODS: Balb/c mice were injected with Renca cells into their left kidney to establish the orthotopical model of renal cancer. One week later, the mice were injected intravenously with Renca cells, which afterwards would spread into various organs particularly into the lung. Then, the mice were treated with IgG alone, anti-PD-1 monoclonal antibodies (mAbs), surgical resection/RFA of the kidney tumor, or surgical resection / RFA + anti-PD-1. anti-PD-1 mAbs were administered by intravenous injection (i.v) every other day for three times. The antitumor effect of the treatment was evaluated by counting the numbers of the tumors in the lung, weighing the lungs and observing the survival time, and the immunological responses were assessed using peripheral blood immune parameters and analyzing the infiltration of CD+4 or CD+8 T cells into the tumors. RESULTS: Treatment of mice bearing kidney tumors with RFA and anti-PD-1 mAbs resulted in significantly greater growth suppression of primary kidney tumors and prolonged survival compared with mice treated with the other modalities. ELISA analysis showed that mice treated with RFA and i.v anti-PD-1 mAbs had higher level of IFN-g, TNF-a in the peripheral blood after treatment compared with the other groups. In the combination therapy group, growth of lung metastases was prevented with fewer numbers of lung metastases and lighter weight of lung. The combined therapy of RFA and anti-PD-1 antibodies significantly increased T-cell infiltration, especially the effector T cells, which upregulated the effector T cells to regulatory T cells ratio. CONCLUSIONS: The combination of RFA and anti-PD-1 mAbs resulted in stronger antitumor immunity and prolonged survival in this preeclinical model of advanced RCC.

PD47-03 FAMILY HISTORY AND INCREASED RISK OF CLINICALLY SIGNIFICANT PROSTATE CANCER IN THE PLCO CANCER SCREENING TRIAL

INTRODUCTION AND OBJECTIVES: A family history (FH) of prostate cancer (CaP) is associated with an increased risk of CaP. However, it remains unclear how this association impacts the need for screening. The aim of this study is to evaluate the impact of FH of the diagnosis of clinically significant CaP in a large national cohort. METHODS: The study included 73,045 men from the control and screening arms of the Prostate Lung Colorectal and Ovarian (PLCO) trial, which had complete information regarding FH and CaP diagnosis. Incidence of clinically significant cancer (CS; intermediate or high risk disease) was compared by FH. The relationship between number of relatives diagnosed and age at CaP diagnosis was evaluated. Multivariable logistic regression was used to estimate odds rato (OR) and 95% confidence intervals (CI). RESULTS: FH was associated with a significantly increased risk of both CaP [OR 1.6, (95% CI 1.5-1.8)] and CS-CaP [OR 1.7 (95% CI 1.5-1.8), respectively]. Furthermore, the impact of FH on CS-CaP increased with the number of family members with CaP; for participants with one relative, the OR was 1.6 (95% CI 1.5-1.8); for those with multiple relatives, the OR increased to 2.2 (95% CI 1.6-3.2). Men with younger relatives with prostate cancer (< 65 vs 65 years) were more likely to be diagnosed with CS-CaP, [OR 1.6, (95%CI 1.3-2.0)]. FH, number of affected relatives and age of relatives remained significant on multivariable analysis controlling for ages, race, smoking history, history of BPH, marital status employment status and study arm. CONCLUSIONS: Detailed FH, including the number of relatives and relatives0 age of at diagnosis significantly affect a man0s risk of CSCaP and should be taken into consideration during individualized counseling about the frequency and intensity of screening.