bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of predictive clinical markers of outcome in patients with metastatic clear-cell renal cell carcinoma (mRCC) treated with tyrosine-kinases inhibitors (TKI) in first line: A C Camargo Cancer Center experience.
Authors: Ferreira Camila Nassif Martins , Rinck José Augusto , Albuquerque Christiane Silveira Marinho , Costa Tatiana Vieira , Urvanegia Ana Claudia Machado , Corassa Marcelo , Formiga Maria Nirvana Cruz , Lourenço Abbade Dettino Aldo , Tariki Milena Shizue , Pinto Flavio Augusto Ismael , Oliveira Thiago Bueno , Salvadori Marcela Marinelli
Published: March 2017

525

Background: TKI have improved the prognosis of patients with mRCC, but rarely lead to durable response. Predictive clinical biomarkers have been studied in the last few years, but most are still controversial. Objective: Identify the role of the clinical and laboratorial biomarkers of prognosis and outcome in mRCC. Methods: A retrospective study with mRCC treated with VEGFR-TKi in first line at A C Camargo Cancer Center (Jan-07 to Apr-16). Studied biomarkers: induced hypertension (HTN), acquiried hypothyroidism, proteinuria, and neutrophil to lymphocyte ratio (NLR). Data were analized in relation to progression free survival (PFS), overall survival (OS), and objetive response rate (ORR) stratified by each marker. Results: We included 94 patients (76.6% sunitinib, 21.3% pazopanib, 2.1% sorafenib). Overall, ORR to VEGFR-TKI was 41.1%; clinical benefit rate was 82.1% (43% Stable disease). Median PFS was 11.4 months (mo)(CI 95% 8.7-14.1) and median OS was 32.1 mo(CI 95% 23.4-40.8). HTN was numerically associated with longer PFS (20.1 vs. 8.2 mo) and OS (37.2 vs. 28.2 mo), but not statistically significant. Only high level TSH (>10) was associated with significant longer PFS and OS, p=0.001 and p<0.001, respectively. There was no association between proteinuria and better outcome. Finally, NLR≥3 pre-treatment was independent prognostic factor, and NLR≥3 post treatment (12aweek) predicted poor OS (9.6 vs 33.9 mo). A “NLR conversion” (before ≥3, turn to <3) was associated with longer OS (28.2 vs. 11.6 mo, p=0.0012). Conclusions: TSH elevation is a good biomarker of better outcome in patients in treatment with TKI. NLR is an important inflamatory marker associated with shorter survival and NLR conversion can be an early biomarker of better outcome to mRCC patients in first line.
A phase 1 study of alpha-1,3-galactosyltransferase-expressing allogeneic renal cell carcinoma immunotherapy in patients with metastatic renal cell cancer.
Authors: Hammers Hans J. , Drake Charles G. , Zakharia Yousef , Kennedy Eugene Paul , Vahanian Nicholas N. , Link Charles J. , Agarwal Neeraj
Published: March 2017

528

Background: HyperAcute Renal (HAR) immunotherapy consists of two allogeneic renal cancer cell lines that have been genetically modified to express the carbohydrate α(1,3)Gal, to which humans have an inherent pre-existing immunity. HAR is designed to leverage this mechanism to educate the immune system towards antigens expressed by the patient’s own tumor cells. Methods: This study is a Phase 1 dose escalation trial of HAR for patients with Renal cell carcinoma (RCC). Eligible patients had recurrent or metastatic RCC with a clear cell component. Trial was a standard 3+3 design with patients receiving weekly intradermal injection of HAR (150 x106 cells/300 x106 cells intradermally) for 4 weeks followed by biweekly injections for 10 weeks. After the initial determination of dose-limiting toxicity, an expansion cohort up to 14 patients was enrolled. The primary endpoint was safety and determination of a maximum tolerated dose (MTD). Secondary endpoints are efficacy and immunological correlates. Results: A total of 18 patients (4 low dose, 14 high dose) were enrolled. The MTD was set at 300 x106 cells intradermally with no dose limiting toxicity (DLT). The most frequently reported adverse events (regardless of attribution), occurring in ≥ 20% of subjects, were abdominal pain, fatigue, pain, and injection site reactions. The most frequently reported laboratory abnormality (regardless of attribution) was anemia in 20% of subjects. There have been 5 reported serious adverse events, none deemed related to HAR. Conclusions: RCC is considered an immunogenic tumor based on its response rate to immune checkpoint blockade and IL-2, occasional spontaneous regression, and the high level of tumor T cell infiltration. HAR was well tolerated in this patient population. Therefore, RCC is an appropriate tumor type to target with combination immunotherapy including HAR. Updated results will be presented. Clinical trial information: NCT02035358.
Contemporary incidence and epidemiologic trends of brain metastases at renal cell carcinoma diagnosis.
Authors: Sun Maxine , de Velasco Guillermo , Brastianos Priscilla Kaliopi , Moreira Raphael Brandao , Nguyen Paul L. , Trinh Quoc-Dien , Choueiri Toni K.
Published: March 2017

529

Background: The incidence of brain metastases (BM) in patients with renal cell carcinoma (RCC) is hypothesized to have increased in the last two decades.Our objective was to provide an overview of recent incidence trends in patients with primary renal cell carcinoma (RCC) and BM at diagnosis using a nationally representative cancer cohort originating from the US. Secondary objectives include developing a tool for prediction of BM at diagnosis and to assess their oncological outcomes, and externally validating it in second database. Methods: All patients with a primary diagnostic confirmation of RCC within the Surveillance, Epidemiology, and End Results (SEER, 2010–2013) database and the National Cancer Database (NCDB, 2010–2012) were abstracted. The incidence proportions (% IP) and 95% confidence intervals (CI) of BM were calculated. A 1000-bootstrap corrected multivariable logistic regression models was developed for prediction of BM at diagnosis using the SEER cohort. Backward variable selection was conducted to identify the most parsimonious model. Model performance was evaluated via measures of predictive accuracy in the NCDB cohort. Results: The overall % IP of BM at RCC diagnosis was 1.51% (95% CI: 1.39–1.64) in the SEER and 1.37% (95% CI: 1.29–1.45%) in the NCDB. The odds of harbouring BM at RCC diagnosis varied significantly according to sociodemographic and clinical characteristics. Following backward variable selection within the SEER database, only histology, tumor size, and cN stages were retained in the final model. Predictive accuracy was adequate in the external validation cohort (C-statistic: 0.778). Median time to any death was 6.37 months in patients with BM. After adjusting for confounders, patients with BM were more likely to succumb to any death than those without BM at diagnosis (hazard ratio: 1.87, 95% CI: 1.71–2.05, p<0.001). Conclusions: The incidence of BM in patients with RCC is increasing. The oncological outcomes of such patients remain poor and their treatment management variable. A clinical risk model can predict the presence of BM at diagnosis and may justify baseline imaging in asymptomatic but high-risk patients.
Active surveillance: Do low-income patients adhere to the protocol?
Authors: Kraus Ryan , Ji Lingyun , Jennelle Richard , Groshen Susan , Ballas Leslie K
Published: March 2017

53

Background: Use of active surveillance (AS) in low-risk prostate cancer (PC) is up from 10% in 2006 to 40% in 2013 according to the CaPSURE registry. The data that provides evidence for the use of AS were among patients adhering to follow-up schedules. There are no data illustrating if patients not on a study follow through with their AS. Based on our experience at a large safety-net hospital with a multi-ethnic, low-income population and a nearby university-based hospital, we hypothesize that AS patients at a safety-net hospital fail to follow-up more frequently than those at a university-based hospital. Methods: We performed a retrospective chart review of patients with non-metastatic prostate cancer who initiated AS at Los Angeles County Hospital (LAC) and Norris Cancer Center (NCC) between 1/1/2008-1/1/2015. Competing-risks regression analyses were used to examine the difference in the rates of AS patients being lost to follow-up (LTFU) between the two institutions, as well as the association between LTFU and patient characteristics, with patients who ended AS due to any reasons treated as competing risks. Results: We found 116 patients at LAC and 90 patients at NCC who met the AS criteria of this study. Patients at both hospitals had similar tumor characteristics. Patients at LAC and NCC differed, however, in median income, race, primary language spoken, median miles residing from hospital, and mean percent that graduated from high school in their zip code. There was a statistically significant difference between the rates of AS patients being LTFU at the two institutions. After two years, 48% of patients at LAC were LTFU vs. 16% of AS patients at NCC. Patients stay on AS for a median of 7.4 months at LAC vs. 22.8 months at NCC. On multivariable analysis (MVA), patients at NCC were more likely to be LTFU if they had a lower household income. At LAC, the MVA found that patients that lived further from LAC were significantly more likely to adhere to AS. Conclusions: Patients undergoing AS at LAC were LTFU at a high rate. AS can only be an effective strategy if patients actually undergo surveillance. We need further investigation to evaluate whether we should recommend AS at safety-net hospitals.
A phase II study of alternative sunitinib scheduling in patients with metastatic renal cell carcinoma.
Authors: Jonasch Eric , Slack Rebecca , Geynisman Daniel M. , Milowsky Matthew I. , Rathmell Kimryn , Stovall Summer , Juarez Donna , Plimack Elizabeth R. , Tannir Nizar M. , Rini Brian I.
Published: March 2017

533

Background: Sunitinib is an oral antiangiogenic agent indicated for the treatment of metastatic renal cell carcinoma (mRCC). Sunitinib is given in a 4 week on, 2 week off (4/2) schedule. Significant toxicities are observed in patients in the 3rd and 4thweeks of therapy. We hypothesized that a 2 week on, 1 week off (2/1) schedule would provide improved toxicity without compromising efficacy. Methods: A multicenter, single arm study was performed, with all patients initiating sunitinib 50mg on a 2/1 schedule. Schedule and dose alterations were performed if grade > 3 toxicities were observed. The primary objective was to determine the percentage of patients who experienced grade > 3 fatigue, diarrhea, or HFS. The sample size of 60 patients was selected to ensure that the upper bound of a 95% confidence would fall below the standard schedule rate of 25%-30% if the sample rate was 10%-15%, respectively. Secondary outcomes included response rate (RR), progression free survival (PFS), and dose reductions. Results: Between August 2014 and April 2016, a total of 60 patients were enrolled, and 59 were treated. Patients had a median age of 65.5 years (ranging from 45-92). 24% of patients (14/59) had grade 3 or higher fatigue, diarrhea, or HFS (95% CI: 13.6%, 36.6%). This is similar to the average of the 4 week on, 2 week off schedule of 25%-30%, and the lower bound of the confidence interval is in the center of our target rate of 10%-15%. Among events that are at least possibly related to study drug, patients were most likely to experience the expected events of diarrhea (75% with 5 grade 3 events), fatigue (71% with 6 grade 3 events), and HFS (54% with 3 grade 3 events). 22 (37%) patients responded (25.0%, 50.9%). Among patients with secondary endpoint data available, median PFS was 19.3 months (95% CI: 8.2, NR) and 33/56 (59%) of patients underwent dose reduction. Conclusions: Sunitinib administered in a 2/1 schedule in this study did not result in a lower rate of grade 3 or higher fatigue, diarrhea, or HFS when compared to historical data from trials employing a 4/2 schedule. Efficacy data were comparable to studies employing a 4/2 schedule. Clinical trial information: NCT02060370.
Pathological determinants of oncologic outcomes in stage II renal cell carcinoma: An international multicenter analysis.
Authors: Hamilton Zachary , Han Daniel , Beksac Alp Tuna , Berquist Sean , Hassan Abd−elrahma , Field Charles , Bloch Aaron , Proudfoot James , Patterson Anthony , Ozen Haluk , Lane Brian R. , Derweesh Ithaar
Published: March 2017

535

Background: Clinical Stage II Renal Cell Carcinoma (RCC) is a heterogeneous disease characterized by disparate oncological outcomes. The risk of progression and recurrence can vary widely. We analyzed risk factors associated with oncological outcomes in a contemporary cohort. Methods: Retrospective multicenter analysis of patients who underwent surgical excision of clinical stage 2 (T2) renal mass between 1998-2015. Patients with tumors amenable to nephron−sparing surgery, baseline chronic kidney disease, or bilateral renal masses were provided an option for partial nephrectomy (PN), otherwise radical nephrectomy (RN) was performed. Lymphadenectomy (LND) was performed at the discretion of the surgeon due to concern for lymphadenopathy on preoperative imaging or at time of surgery. Patients with pN+ disease and pathological pT upstaging/downstaging were excluded. Primary endpoint was Recurrence Free Survival (RFS). Univariable linear regression, Kaplan−Meier Analysis (KMA) log−rank test, and multivariable analysis (MVA) for factors related to RFS and overall survival (OS) were performed. Results: 695 patients were analyzed (mean age 59.3 years, median follow up 49.6 months, 61.4% male/38.6% female, 545 RN/150 PN, 193 LND/502 no LND). MVA for factors associated with worsened RFS revealed lymphovascular invasion (LVI, HR 2.27, p=0.002), positive margins (HR 2.67, p=0.008), and tumor grade 3/4 (HR 2.04, p<0.008). MVA for decreased OS revealed LVI (HR 2.58, p=0.003), positive margins (HR 2.34, p=0.044), and tumor grade 3/4 (HR 2.08, p=0.023) as risk factors. KMA revealed 5 year RFS of 76.1% for LVI negative and 46% for LVI positive patients (p<0.001), and 5 year RFS of 78.1% for Tumor Grade I/II and 53.7% for Tumor Grade III/IV (p<0.001). KMA revealed 5 year OS of 79.2% for LVI negative and 60.6% for LVI positive patients (p<0.001). Conclusions: For Stage II RCC, LVI, positive margin, and tumor grade III/IV are independently associated with worsened RFS and OS. Further investigation is requisite and may add weight to consider these specific stage II RCC patients as a higher risk subgroup with implications for staging revision and clinical trial design.
Treatment patterns after the use of the 17-gene Genomic Prostate Score assay in Veterans newly diagnosed with clinically low-risk prostate cancer.
Authors: Lynch Julie Ann , Rothney Megan , Salup Raoul , Ercole Cesar Emilio , Mathur Sharad , Duchene David , Basler Joseph W. , Hernandez Javier , Liss Michael Andre , Porter Michael P , Wright Jonathan L. , Risk Michael Christopher , Efimova Olga , Denes Bela Stephen , Febbo Phillip G. , Dash Atreya
Published: March 2017

54

Background: Active surveillance (AS) is a recommended management approach for low risk prostate cancer (PCa). Studies have shown high rates of AS in the Veterans Administration (VA), but concerns about missing aggressive disease lead to variation between centers. The 17-gene Genomic Prostate Score (GPS) has been validated to predict likelihood of favorable pathology (LFP) in men with clinically low risk PCa. This study compared treatment patterns before and after introduction of the GPS to determine if the assay influenced treatment patterns. Methods: Men newly diagnosed with PCa who met NCCN criteria for very low (VL), low (L), or intermediate (INT) risk PCa were eligible. Chart review of men across 6 VA medical centers (VAMCs) established treatment in untested patients in 2013-2014. In 2015, Veterans at the same VAMCs were offered the assay in a prospective study measuring treatment recommendations before and after the assay and treatment implemented based on chart review. Results: There were 200 men in the untested cohort. Characteristics: age (median = 66, range:43-83), Gleason Score (GS) (3+3:64%, 3+4:37%), PSA (mean = 6.6, range:0.7-20), NCCN risk (VL:18%, L:37%, INT:46%). There were 190 men in the prospective study with complete data. NCCN risk group: age (median = 66, range:50-85), GS (3+3:74%, 3+4:26%), PSA (mean = 6.4, range:0.4-18.1), VL:22%, L:43%, INT:35%. GPS ranged from 0-61 and LFP ranged from 38%-91%. GPS identified 24 patients who had more favorable pathology and 13 patients who had less favorable pathology than would be expected using NCCN alone. 62% of untested Veterans pursued AS compared to 74% of tested Veterans. AS increases between untested and tested cohorts were 1% in VL, 16% in L, and 3% in INT. Conclusions: Both untested and tested patients had clinical characteristics representative of low risk PCa in the VA. Use of AS increased in tested Veterans compared to untested, with the largest increases observed in NCCN low risk patients. The 17-gene assay used biological information to provide refined risk estimates in tested Veterans, assisting physicians in appropriately identifying candidates for AS or immediate treatment.
Conditional biochemical recurrence-free survival and cancer-specific mortality after radical prostatectomy at long term follow-up.
Authors: Barreras Silvia Garcia , Sanchez-Salas Rafael , Nunes-Silva Igor , Secin Fernando P. , Srougi Victor , Baghdadi Mohammed , Barret Eric , Rozet François , Galiano Marc , Cathelineau Xavier
Published: March 2017

55

Background: To estimate the conditional biochemical recurrence-free survival (BCR) rates and cancer-specific mortality (CSM) for men with clinically localized prostate cancer (PCa) treated with radical prostatectomy (RP) at our institution. Methods: A total of 3576 patients underwent laparoscopic radical prostatectomy (LARP) and 2619 men were treated with robotic radical prostatectomy (RARP) in the last 15 years. BCR of primary treatment was defined as PSA > 0.2 ng/dl. PCa death was defined as patients who died with metastasis in an androgen independent setting. Kaplan-Meier and Cox regression methods were used to estimate the conditional survival probabilities and CSM. Results: The median follow-up was 8.49 years (IQR 4.01-12.97). A total of 92 (1.48%) patients (80 LARP and 12 RARP) died of disease. Positive surgical margins (PSM) were identified in 1202 patients (19.4%); of these, 664 (55.24%) had organ confined disease and 523 (43.51%) had extraprostatic extension (EPE). BCR-free survival rate was found significantly higher with RARP (83% vs 77% for LARP at 10 years; p < 0.001). For patients with PSA < 10 ng/dl BCR-free survival at 10 years was 80% vs 64% for PSA 10-20 ng/dl, and 59% for PSA > 20ng/dl; p > 0.001. Conditional probability of BCR after surgery 1st year was 6.7%. Those who reach the 2nd year of surgery without recurrence had a relapse probability of 4%, (cumulative probability 9.8%) That probability falls to 3.5% after the 3rd year (cumulative probability 13%), 2% after the 4th year (cumulative probability 15%) and is 2.1% after the 5th year (cumulative probability 17%). After 10 years of follow-up without recurrence, the possibility of relapse was 0.8%, (cumulative probability 21%). Men without BCR had a clinical trend of higher CSM at 10 years (7% vs 2% no BCR; p 0.06). Within the patients who develop BCR, those with BCR in the first three years of follow-up had higher CSM (9% vs 4% for BCR after 3 years; p 0.04). Conclusions: BRC free survival outcomes are affected by risk factors associated with type of surgery and prognosis in PCa. The period elapsed from RP is associated with BCR-free survival and the risk of recurrence decrease with increasing survival.
Comparison of Gleason upgrading rates in transrectal ultrasound systematic random biopsies versus US-MRI fusion biopsies for prostate cancer.
Authors: Carneiro Arie , Kayano Paulo Priante , Castilho Tiago MendonÃÂ§a Lopez , Sivaraman Arjun , Claros Oliver Rojas , Serpa Neto Ary , Filippi Renee Zon , Baroni Ronaldo Hueb , Lemos Gustavo Caserta
Published: March 2017

57

Background: US-MRI fusion biopsy (FB) showed that it improves the detection of clinically significant prostate cancer (PCa). A more accurate diagnostic method is desirable to avoid misclassification, which in turn is particularly important in appropriate decision making on treatment for PCa (active surveillance or focal therapy or radical treatment). We aimed to compare the Gleason upgrading (GU) rates and the concordance of the Gleason scores in the biopsy versus final pathology after the surgery in patients who underwent only TRUS systematic random biopsies versus US-MRI FB for PCa. Methods: A retrospective analysis of patients’ prospective collected data that underwent prostate biopsy and subsequent radical prostatectomy were included from January 2011 to June 2016 at our institution. The study cohort was divided into: US-MRI FB (Group A) and only TRUS systematic random biopsy (Group B). US-MRI FB was performed in patients who had a previous MRI with a focal lesion classified by Likert score ≥ 3, otherwise a TRUS systematic random biopsy was performed. All biopsies and surgical specimens were analyzed by the same uropathologist and MRIs were analyzed by two expert urological radiologists. Results: 73 men underwent US-MRI FB and 89 TRUS systematic random biopsy. The GU rate was higher in group B (31.5% vs 16.4%; p = 0.027). GU according to Gleason grade pattern was higher in Group B against Group A (40.4% vs 23.3%; p = 0.02). Analyses from separate Gleason grade pattern showed that Gleason score 3+4 presented less GU in group A (24.1% vs 52.6%; p = 0.043). The Bland-Altman plot analysis showed a higher bias in Group B compared to group A (-0.27 [-1.40 to 0.86] vs -0.01 [-1.42 to 1.39]). In the multivariable logistic regression the only independent predictor of GU was the use of TRUS systematic random biopsy (2.64 [1.11 – 6.28]; p = 0.024). Conclusions: The US-MRI FB appears to be related to a decrease in GU rate and an increase in the concordance between biopsy and final pathology in comparison to TRUS random biopsy, that leads to greater accuracy on diagnosis and better treatment decision.
Validation of GEMCaP as a DNA based biomarker to predict disease recurrence in patients undergoing prostatectomy for prostate cancer.
Authors: Nguyen Hao Gia , Welty Christopher , Lindquist Karla , Ngo Vy , Gilbert Elizabeth , Bengtsson Henrik , Magi-Galluzzi Cristina , Jean-Gilles Jerome , Yao Jorge , Cooperberg Matthew R. , Messing Edward M. , Klein Eric A. , Carroll Peter , Paris Pamela
Published: March 2017

58

Background: There are currently no validated DNA based biomarkers available for routine clinical use to predict prostate cancer recurrence after prostatectomy. The Genomic Evaluators of Metastatic Cancer of the Prostate (GEMCaP) assay is a tumor genotype using copy number for a set of genomic loci. We aim to validate the GEMCaP assay using an external cohort of intermediate and high risk patients. Methods: We randomly identified 203 patients who had undergone radical prostatectomy at the Cleveland Clinic (CC) and University of Rochester (UR) from 2000-2005. DNA from macrodissected cancer tissues were subjected to high resolution array comparative genomic hybridization (aCGH) using Agilent’s oligonucleotide microarray platform. A high GEMCaP score was defined as > 20% of the genomic loci exhibiting copy number gain or loss in a given tumor. Cox regression was used to evaluate associations between the GEMCaP score and risk of biochemical recurrence in univariate and multivariate analyses adjusted for the CAPRA-S score. The outcome was biochemical failure defined as PSA > 0.2. Results: We report the results from 140 patients, with sufficient DNA and acceptable aCGH, 54 from the CC cohort and 86 from the UR cohort. Median time to recurrence was 45.3 months and median follow-up among those who did not recur was 120.2 months. Based on the CAPRA-S score, 39.3% were low-risk, 42.2% were intermediate-risk and 18.5% were high-risk. 30.7% of the cohort had a high GEMCAP score ( ≥ 20%). A high GEMCaP score was associated with higher risk of biochemical recurrence (HR 2.69, 95%CI 1.51-4.77) and remained associated with biochemical recurrence after adjusting for the CAPRA-S score (HR 1.91, 95% CI 1.05-3.48). The C-index for GEMCaP alone was 0.64, and improved when combined with CAPRA-S (C-index = 0.76). Conclusions: In this validation study, a high GEMCaP score was associated with biochemical recurrence in two external cohorts. This remained true after adjusting for clinical and pathologic factors as accounted for by the CAPRA-S score. The GEMCaP biomarker could be an efficient and effective clinical risk assessment tool to identify prostate cancer patients for early adjuvant therapy.
Incidence of periprostatic white adipose tissue inflammation in men with prostate cancer.
Authors: Gucalp Ayca , Iyengar Neil M. , Zhou Xi K. , Giri Dilip D. , Falcone Domenick J. , Wang Hanhan , Williams Samantha , Krasne Margaret D. , Yaghnam Ibrahim , Kunzel Brian , Morris Patrick G. , Jones Lee , Pollak Michael N. , Laudone Vincent Paul , Scher Howard I. , Hudis Clifford A. , Scardino Peter T. , Eastham James Andrew , Dannenberg Andrew J.
Published: March 2017

63

Background: Obesity, a common cause of chronic inflammation, is associated with an increased risk of high grade, lethal prostate cancer (PC) and poor outcomes. The existence or clinical importance of periprostatic white adipose tissue inflammation (WATi) in patients (pts) with PC has not been previously described. We examined the relationships among periprostatic WATi and 1) tumor clinicopathologic features, and 2) host factors including age, body mass index (BMI), and circulating metabolic factors. Methods: Periprostatic WAT was collected prospectively from men with PC undergoing radical prostatectomy. WATi was defined by the presence of dead/dying adipocytes surrounded by macrophages forming crown-like structures (CLS). Tumor characteristics and host factors were measured. Wilcoxon rank-sum, Chi-square, or Fisher’s exact tests were used to examine the relationship between WATi and tumor and host characteristics. Results: From 11/2011-8/2015, periprostatic WAT was obtained from 169 pts (median age 62 years, range: 39 -77). Fasting blood samples were collected from 154 pts. CLS were present in 84 (49.7%) of pts. Presence of CLS was associated with higher median BMI (P = 0.02); 40/65 (61.5%) obese pts, 36/83 (43.4 %) overweight pts, and 8/21 (38.1 %) normal weight pts had CLS. Pts with CLS were more likely to have high grade prostate cancer (Gleason grade group IV/V, P = 0.02), larger adipocytes (P = 0.004), and positive surgical margins at the time of surgery (P = 0.04). WATi correlated with higher circulating levels of insulin, triglycerides, and leptin/adiponectin ratio, and lower high density lipoprotein cholesterol, compared to pts without WATi (P’s < 0.05). Conclusions: Periprostatic WATi is common in men with PC. It is associated with high grade PC and alterations in systemic factors that contribute to PC development and progression. Periprostatic WATi may represent a therapeutic target for improving PC risk and outcomes.
A systematic review and meta-analysis to evaluate the influence of surgical method on specimen margins and biochemical recurrence after radical prostatectomy for high-risk prostate cancer.
Authors: Srougi Victor , Bessa Jose , Baghdadi Mohammed , Nunes-Silva Igor , Barreras Silvia Garcia , Barret Eric , Rozet Francois , Galiano Marc , Sanchez-Salas Rafael , Cathelineau Xavier
Published: March 2017

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Background: To date there is no robust evidence comparing the outcomes of robotic and open radical prostatectomies in patients with high-risk prostate cancer. The purpose of this study is to perform a meta-analysis comparing the rates of positive surgical margins (PSM) and biochemical recurrence (BCR) between open radical prostatectomy (ORP) and robot-assisted radical prostatectomy (RARP) in patients with high-risk prostate cancer. Methods: A systematic review was performed on Pubmed, Embase and Scopus databases in August 2016, according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. References retrieved were evaluated using the Newcastle-Ottawa scale and the Black and Down’s tool for quality assessment. Nine retrospective cohorts comparing ORP and RARP were selected and included in the meta-analysis. Results: Nine studies reported the PSMs. Patients treated with RARP presented less risk of PSMs (risk difference -0.04, p 0.02) than those treated with ORP. Five articles reported hazard ratios for BCR-free survival. Patients treated with RARP had less risk of BCR (HR 0.72, 95% CI 0.58-0.89) than those treated with ORP. Reports for PSM assessment were considered of adequate quality, while the studies retrieved for BCR assessment were considered limited because of the heterogeneity of their results. Conclusions: Patients with high-risk prostate cancer treated with RARP have less risk of having PSM and BCR when compared to those treated with ORP. A strong conclusion is precluded due to the observational nature of the studies retrieved for our analysis.
Radiotherapy versus radical prostatectomy for Gleason score 9-10 prostate adenocarcinoma: A multi-institutional comparative analysis of 1001 patients treated in the modern era.
Authors: Kishan Amar Upadhyaya , Ciezki Jay P. , Shaikh Talha , Stock Richard , Merrick Gregory Stephen , Jeffrey Demanes D. , Wang Jason , Said Jonathan W. , Fiano Ryan , Raghavan Govind , Sandler Kiri Ann , Reddy Chandana A. , Nickols Nicholas George , Aronson William J. , Sadeghi Ahmad , Kamrava Mitchell , Steinberg Michael L. , Horwitz Eric M. , Kupelian Patrick , King Christopher R.
Published: March 2017

7

Background: To compare the outcomes of a modern cohort of patients with Gleason Score (GS) 9-10 prostate adenocarcinoma (CaP) following treatment with external beam radiotherapy (EBRT), extremely dose-escalated radiotherapy (as exemplified by EBRT with a brachytherapy boost [EBRT+BT]), and radical prostatectomy (RP). Methods: One-thousand-and-one patients with biopsy GS 9-10 CaP who received definitive treatment between 2000 and 2013 were included (347 treated with EBRT, 330 with EBRT+BT, and 324 with RP). Kaplan-Meier analysis and multivariate Cox regression compared 5- and 10-year rates of distant metastasis-free survival (DMFS), cancer-specific survival (CSS), and overall survival (OS). Prostate cancer-mortality (PCSM) rates were compared with a competing risk analysis. Results: The median followup periods were 4.8, 6.4, and 5.1 years among patients receiving EBRT, EBRT + BT, and RP. The median doses among EBRT and EBRT+BT patients were equivalent to 78 Gy and 90 Gy in 2 Gy fractions. Over 90% of patients treated with EBRT or EBRT+BT received ADT (median durations of 18 months and 12 months, respectively). Nearly 40% of RP patients received postoperative RT, primarily in the salvage setting. Five- and 10-year DMFS rates were significantly higher with EBRT+BT (91.6% and 81.3%) than with EBRT (79.6% and 65.8%; p < 0.0001) or RP (77.9% and 60.1%; p < 0.0001). Five- and 10-year PCSM rates were significantly lower with EBRT+BT (3.8% and 14.1%) than with EBRT (10.3% and 25.2%; 5- and 10-year hazard ratios of 0.38 and 0.47; p = 0.003) or RP (8.9% and 20.3%; 5- and 10-year hazard ratios of 0.39 and 0.55; p = 0.02). Overall 5- and 10-year OS rates were 85.7% and 64.7% and were similar between cohorts (p > 0.1). Conclusions: Extremely dose-escalated radiotherapy offered improved systemic control and reduced PCSM when compared with either EBRT or RP. Notably, this was achieved despite a significantly shorter median duration of ADT than in the EBRT arm. This is hypothesis generating as it suggests that improved local control via dose-escalation may have systemic control and survival implications even for patients with very high risk disease.
Effect of dose to penile bulb (PB) on patient and clinician-reported erectile function (EF) in standard (SF) and hypofractionated (HF) prostate IGRT.
Authors: Murray Julia , Dean Jamie , Mossop Helen , Griffin Clare , Hall Emma , Dearnaley David P. , Gulliford Sarah
Published: March 2017

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Background: PB dose has been hypothesised as predictor of EF post RT, however, PB dose volume effects are not well established. We determined PB dose response characteristics & dose volume constraints using data from randomised trial of prostate IGRT with patient (PRO) & clinician reported (CRO) outcomes. Methods: 293 men were treated within CHHiP IGRT substudy (CRUK/06/16) & randomised to receive 2Gy (SF) or 3Gy (HF) per fraction, without or with daily online IGRT with standard (SM) or reduced (RM) CTV-PTV margins. EF was assessed with RMH CRO & at one time-point (>3 years after RT) with IIEF-5. Men were excluded if impotent at baseline. Planning CT & dose distributions were imported into analysis software (VODCA) & PB contoured. All dose distributions were converted into EQD2 (α/β ratio 3Gy), a separate analysis was done using physical dose (PD) for HF cohort. PB dose volume parameters were analysed & atlases of complication incidence (ACI) evaluated using PRO & CRO. Dose volume constraints using PD & EQD2 were derived using ROC analysis (Youden index) & assessed against the no information rate. Results: Complete dosimetric with CRO & PRO data were available for 175 & 100 men respectively. Of these, men treated with SM vs RM had a higher rate of impotence at 2 & 4 years (49% vs 40% & 47% vs 39%). This was also seen in men recording severe ED (46% vs 37%). ACI indicated a dose volume response. Statistically significant PB dose constraints were derived using EQD2 (SF & HF) & PD for HF cohort (Table). Results using PRO were more pronounced than with CRO. Conclusions: There is a dose volume effect between PB & EF characterised using PRO & CRO. Results suggest that reduction of mean PB dose to <20Gy may lead to an increase of potency preservation rates after prostate RT for both 2Gy & 3Gy schedules. Clinical trial information: ISRCTN97182923. [Table: see text]
The diverse genomic landscape of low-risk prostate cancer.
Authors: Cooperberg Matthew R. , Erho Nicholas , Chan June M. , Feng Felix Yi-Chung , Cowan Janet E. , Ong Kaye , Alshalalfa Mohammed , Kolisnik Tyler , Margrave Jennifer , Aranes Maria , du Plessis Marguerite , Buerki Christine , Zhao Shuang , Tenggara Imelda , Davicioni Elai , Carroll Peter
Published: March 2017

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Background: Active surveillance (AS) is becoming standard of care for men with low-risk prostate cancer; however a need exists for better tools to assess which men are optimal candidates for AS. In this study we compare genomic expression profiles of AS candidates against higher-risk radical prostatectomy (RP) patients to characterize the genomics of clinically low-risk prostate cancer. Methods: Biopsies from 473 UCSF patients potentially suitable for AS (stage ≤ cT2N0M0, PSA ≤ 10 ng/ml, Gleason 3+3 or low-volume 3+4 ) were profiled using the Affymetrix HuEx microarray to generate RNA expression data. These cases were compared to 2043 RP cases previously profiled on the same microarray platform. Scores for 21 published prognostic signatures were calculated and pathway associated genes were summarized to provide levels of patient risk and pathway activity. Results: Of the 473 AS biopsies profiled, 408 (86%) passed quality control and were used for analysis. Based on the quartiles of average scores for 21 prognostic signature risk models, 49%, 36%, 11%, and 4%, respectively, were classified into the 1st, 2nd, 3rd, or 4th score quartiles. Considering only the clinically low-risk patients at diagnosis, 356 (87%) were low, 45 (11%) were intermediate and 7 (2%) were high risk. Genomic risk was positively associated with cell cycle related pathways (p < 0.001) and negatively associated with apical junction (p < 0.001), epithelial−mesenchymal transition (p < 0.001), and androgen receptor (p < 0.05) pathways. Clustering of patients based on the expression of 36 pathways revealed two biologic groups corresponding to putative basal and luminal subtypes. Compared to higher risk RP patients, the low risk prostate cancer tumors at diagnosis were enriched for basal-like tumors (20% vs 33%, p < 0.001). Conclusions: Although only 2% of low risk AS candidates have high risk genomic characteristics, very substantial genomic heterogeneity exists in this population, and pathway activation overlaps significantly with higher-risk RP patients. These results suggest that even in potential AS candidates, genomic profiling could eventually be used to better guide management.
A clinical trial for the safety and immunogenicity of a DNA-based immunotherapy in men with biochemically (PSA) relapsed prostate cancer.
Authors: Shore Neal D. , Heath Elisabeth I. , Nordquist Luke T. , Cheng Heather H. , Bhatt Kamalnayan , Carroll Nicholas , Kraynyak Kimberly , Lee Jessica , Van Tornout Jan , Sacchetta Brian , Tagawa Scott T. , Parikh Rahul Atul , Tutrone Ronald F. , Garcia Jorge A. , Whang Young E. , Lin Jianqing , Kelly William Kevin , Csiki Ildiko , Bagarazzi Mark L.
Published: March 2017

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Background: Introducing amino acid sequence changes in highly expressed self-antigens for androgen sensitive prostate cancer pts might be sufficient to break tolerance, thus a DNA vaccine was developed using SynCon PSA and PSMA (INO-5150) that share 96.8 and 91.6% sequence identities to these native antigens, respectively. Administration of these antigens to prostate cancer pts along with plasmid encoded adjuvant IL-12 (INO-9012) via electroporation (EP) using the CELLECTRA5P device is postulated to break tolerance, resulting in an antigen-specific immune response which could lead to stabilization of disease progression. Methods: This Phase I, open-label, multicenter study included prostate cancer pts post-definitive therapy with a rising PSA ≥ 1.0 ng/ml after surgery, or ≥ 2.0 ng/ml above nadir after RT and PSA doubling time > 3 months, testosterone > 150 ng/dL and no evidence of metastasis within 12 months. INO-5150 with or without INO-9012 was administered IM followed by EP in 4 arms: low (2 mg) or high dose (8.5 mg) INO-5150 alone or with 1 mg INO-9012 on Day 0 and at week 3, 12, and 24 in 60 planned pts (15 pts/arm). DLT assessments were performed after dosing of the first 3 pts of each arm at Week 4. Results: Enrollment is complete in all 4 arms and at data cut-off (10Oct16), 62 enrolled pts received at least one, 60 pts received 3 and about half, 28 pts (10 in arm A, 8 in B, 7 in C, and 3 in D) received all 4 vaccinations. Safety: there were no DLTs noted. Four pts had five Grade 3 SAEs noted as pre-syncope, cardiac disorder, hospitalization for fall, ALT and AST elevation. No Grade 4-5 AEs were noted. Grade 1-3 treatment-emergent AEs occurred in 50 (81%) pts: 12 (75%) in arm A, 13 (87%) B, 13 (87%) C, and 12 (75%) in D. The most common AEs were injection site pain (24/39%), erythema (13/21%), swelling (12/19%), bruising (10/16%), hyperglycemia (8/13%) and fatigue (6/10%), all Grade 1-2. Assessments of immunological response, PSA kinetics and correlation with clinical outcome are ongoing and will be presented. Conclusions: INO-5150 (+) or (-) INO-9012 is generally safe and well-tolerable at all 4 dose levels in a biochemically relapsed prostate cancer patient population. Clinical trial information: NCT02514213.
Gender disparity: Overlooking hereditary prostate cancer.
Authors: Bowling Lauren , Espenschied Carin , Jackson Michelle , Mak Bryan , LaDuca Holly
Published: March 2017

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Background: Prostate cancer (PC) has been associated with germline mutations in several genes, most often BRCA2. Recently, 11.8% of men with metastatic PC were found to have germline mutations in BRCA and other DNA-repair genes. These mutations are equally inherited by men and women, both have elevated cancer risks, and National Comprehensive Cancer Network (NCCN) testing and management guidelines exist for male and female carriers. Despite this, over 95% of patients who have hereditary cancer multi-gene panel testing (MGPT) are women. We sought to describe detection rate and mutation spectrum of MGPT in men with PC compared to women with breast cancer (BC). Methods: Test results were reviewed for PC patients and female BC patients who had MGPT (Jun 2013 – May 2016) for up to 49 genes. Clinical history was obtained from test request forms. Results: Of 654 PC probands, 100 germline mutations were identified in 93 men (14.2%), significantly more than women with BC (8.6%; 6,215/71,728; p = 2.5e-5). Most mutations in PC patients were in BRCA (40.9%), followed by ATM (20.4%), CHEK2 (15.0%) and Lynch syndrome-associated genes (9.7%). Of the 100 total mutations, 94% were in genes that would impact management recommendations for them and/or their relatives. The median time from PC diagnosis to MGPT was 6 years, compared to 1 year for female BC. Nearly 57% (53/93) of mutation-positive men had multiple primary cancers, 79.2% of which had PC first. Of BRCA positives with multiple primaries (n = 21), over 90% developed PC followed by subsequent cancers, yet testing was not initiated until another cancer developed. Conclusions: In this cohort of men with PC, MGPT identified germline mutations at significantly higher rates than females with BC. Furthermore, 59.1% (55/93) of mutation positive PC probands had BRCA and/or ATM, making them possibly eligible for a PARP-inhibitor clinical trial. Unfortunately, time from PC diagnosis to MGPT was several years longer than women, allowing many to develop subsequent cancers that may have been prevented or detected earlier with knowledge of the germline mutation. Increased awareness among clinicians is needed to identify more male mutation carriers to enable appropriate cancer risk management for themselves and their relatives.
Utilization of pelvic lymph node dissection for low-risk prostate cancer.
Authors: Modi Parth K. , Bock Megan , Kim Sinae , Singer Eric A. , Parikh Rahul
Published: March 2017

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Background: National guidelines suggest against pelvic lymph node dissection (PLND) for patients with low-risk prostate cancer (PCa). However, the actuarial rate of PLND in this population is unknown. This study aimed to characterize the use of PLND in contemporary cohort of men with low-risk PCa undergoing robotic assisted radical prostatectomy (RARP). Methods: The National Cancer Database was queried for PCa patients who underwent RARP from 2010 to 2013. Patients who underwent PLND were identified and patient clinicodemographic and hospital characteristics were abstracted. The primary outcome measure was receipt of PLND. Secondary outcome measures included number of lymph nodes evaluated and number of lymph nodes positive for cancer. Unadjusted and multivariate regression analyses were conducted to identify predictors of receipt of PLND. Analysis of clustered data was employed to account for hospital-level correlation in utilization. Results: Of 51,971 patients with low-risk PCa who underwent RARP, 19,059 (36.7%) received PLND. Lymph node positivity was identified in 0.4% of low-risk patients and 4.6% of intermediate/high risk patients. Predictors of PLND in low-risk patients included rural residence (OR 1.157), treatment at academic institutions (OR 1.492) or high-volume (OR 1.327) facilities. Mean number of lymph nodes obtained in low-risk patients was lower than in intermediate- or high-risk patients (4.74 vs 5.86, P < 0.0001). In multivariate analysis, black race was associated with significantly fewer lymph nodes retrieved. Intermediate or high risk PCa; rural residence; and treatment at an academic, high-volume, or West region facility were independently associated with a higher yield of retrieved lymph nodes. Conclusions: PLND is performed for greater than one-third of low-risk PCa patients undergoing RARP in this large hospital-based data set. Our study demonstrated a low likelihood (0.4%) of detecting nodal metastasis in this population, thus validating the national recommendations against PLND. Rural residence and treatment at high-volume and academic centers are associated with receipt of PLND. Reasons for the variation in practice patterns should be investigated to improve the quality of PCa care.
Prospectively collected baseline erectile function (EF) in 1,173 consecutive newly diagnosed prostate cancer patients referred for radiotherapy.
Authors: Nicholson Jill , Kelly Paul J.
Published: March 2017

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Background: Preservation of EF is a goal of care for many men with newly diagnosed prostate cancer. In order to accurately counsel patients regarding their likely treatment outcome, an assessment of baseline EF, and screening for known risk factors, should form part of the assessment of all prostate cancer patients. Methods: We performed a retrospective review of prospectively-collected data regarding baseline EF in men with prostate cancer referred for a radiotherapy opinion. 1173 consecutive patients referred over a 5.5 year period from 2011-16 were included. All patients were offered the opportunity to complete the International Index of Erectile Function (IIEF-5) questionnaire in privacy. Information on known risk factors such as age, vascular comorbidity, smoking and alcohol history, and cardiovascular risk factors was recorded. Results: Of the 1173 patients, 233 were excluded due to metastatic disease at referral. Of the remaining 940 with localised disease, 812 (86%) completed the questionnaire. 561 (69%) successfully filled the questionnaire yielding a score. A further 251 (31%) commented on the questionnaire without completing the score (see table). Median age was 66years (IQR 62-71). 574(61%) had known risk factors for erectile dysfunction such as hypertension or diabetes. 173 (18.5%) had a history of peripheral, cardiovascular, or cerebrovascular disease. Smoking and alcohol history was available for 645 patients, 353(60%) had a smoking history, and 450(70%) had a history of alcohol use. Conclusions: In this population, there is a high prevalence of baseline erectile dysfunction (IIEF-5 ≤16), 242/561 (43%). Additionally, significant numbers of patients were sexually inactive or unconcerned regarding ED. Known risk factors for erectile dysfunction were common in this population, many of which are modifiable. [Table: see text]