bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and validation of a bioanalytical assay on LC/MS/MS to quantify enzalutamide and N-desmethylenzalutamide in human plasma.
Authors: Benoist Mette , van der Meulen Eric , Van Oort Inge , Schalken Jack , Gerritsen Winald , Burger David , van Erp Nielka P
Published: February 2017

330

Background: To study the relation between drug exposure and therapeutic effect of enzalutamide and its equipotent metabolite N-desmethylenzalutamide, a bioanalytical assay on liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed and validated to determine plasma concentrations in vivo. Methods: Plasma samples were diluted 10-fold with 20% albumin solution. Protein precipitation with acetonitrile was used to pretreat the diluted plasma. A stable isotope (D6-enzalutamide) was used as the internal standard. During validation five quality controls were used (LLOQ, LQ, MQ, HQ, ULOQ). The method was validated according to EMA guidelines. Results: The LC-MS/MS method was validated over a concentration range from 500-50,000 ng/mL. Within – and between day precisions and accuracies were < 5.1%. The LLOQ of the method was set at 500 ng/ml and the ULOQ was 50,000 ng/mL. Enzalutamide and N-desmethylenzalutamide are stable in plasma for at least 19 days at ambient temperature and at 2-8°C. Stability at -40°C was demonstrated for at least 3 months. Enzalutamide and N-desmethylenzalutamide are stable for at least for 24 hours in whole blood at ambient temperature. Stock solution stability was demonstrated for at least 5 months. Concentration levels of the LQ, MQ and HQ were 1000, 15,015 and 40,040 ng/mL. Conclusions: The bioanalytical method to quantify enzalutamide and N-desmethylenzalutamide is successfully developed and validated. The bioanalytical method is used to support pharmacokinetic study questions and for regular patient care in patients with prostate cancer.
A live cell microfluidics device utilizing phenotypic biomarkers for prostate cancer.
Authors: Albala David , Mouraviev Vladimir , Rieger-Christ Kimberly M. , Sullivan Travis B. , Kella Naveen , Knopf Kevin B. , Rashid Hani H. , Manak Michael S. , Hogan Brad J. , Dixit Gauri , Berger Delaney , Su Wendell R. , Whitfield Matthew J. , Varsanik Jonathan S. , Foroohar Mani , Zappala Stephen M , Chander Ashok C. , Sant Grannum R.
Published: February 2017

338

Background: A novel tissue based biomarker panel is introduced to objectively assess disease aggressiveness and invasive potential of Prostate Cancer (CaP). The biomarker diagnostic platform incorporates both molecular and phenotypic data that may allow an improved understanding of local growth and metastatic potential. The tissue based diagnostic incorporates matrix biology, phenotypic biomarkers, microfluidics, and machine vision. This technology presents the opportunity to culture samples, and both determine and automate biomarker measurements from machine vision algorithm analysis. Data are presented towards clinical validation, the ability to risk stratify, and prediction of local aggressiveness and metastasis. Methods: Conditions were optimized for reliably culturing primary cancer cells in vitro by simulating in vivo conditions on an extracellular matrix formulation. A mcirofluidics device was used to culture live tumor samples ex vivo enabling automated imaging of the label free and label-based biomarkers. Results: The validation study was IRB approved and performed in 200 consecutive CaP radical prostatectomy derived specimens collected between 03/2014 and 09/2015. Data was analyzed with receiver operating characteristics (ROC) generated Area-under-the-Curve (AUC) and specifically included capsular penetration, seminal vesicle invasion, as well as margin-positive disease. AUC Graphs are presented. The study further demonstrated that a normal set of phenotypic biomarkers can produce secondary metrics termed oncogenic potential (OP) and metastatic potential (MP). Concordance analysis supports that OP and MP are integral for distinguishing between benign histology and malignancy, predicting both stage and adverse pathology such as extra-prostatic extension (EPE) and lympho-vascular invasion (LVI). The study results demonstrate AUCs greater than 0.90 in predicting EPE and LVI. Conclusions: Results support the clinical validation of a novel live- cell phenotypic in vitro tumor diagnostic test. This test has the potential to predict adverse pathologies for CaP and may have extended clinical applications to optimize staging and risk stratification.
Metformin (Met): A cost-effective adjunct therapy with enzalutamide (Enza) for metastatic castrate-resistant prostate cancer (mCRPC)?
Authors: Hill Jordan , Paulden Mike , McCabe Christopher , Venner Peter , Danielson Brita Lavender , North Scott A. , Usmani Nawaid
Published: February 2017

340

Background: Several new therapies have changed the landscape of prostate cancer (PCa) treatment, primarily due to their effectiveness in treating patients with mCRPC. Enza has garnered much attention, but is relatively expensive (~$3175/month). Met is less expensive (~$8.00/month) and has been used for decades to treat patients with non-insulin dependent diabetes. Two recent large population-based studies of PCa have demonstrated that diabetics taking Met had improved PCa specific and overall survival compared to those not taking Met. As a result, we hypothesized that Met has the potential to be a cost-effective adjunct therapy to Enza, although it is not currently used as such. Methods: We constructed a Markov-based decision analytic model to compare the cost-effectiveness of Enza alone versus Enza combined with Met. Through expert elicitation, we assumed that adding Met to Enza increases its efficacy by 15%. All other costs, utilities, and transition probabilities were derived from existing literature or expert elicitation. Effectiveness was measured using quality-adjusted life years (QALYs). Costs and QALYs were considered over a lifetime horizon and discounted at 5% per annum. Cost-effectiveness was considered using a willingness to pay threshold of $50 000/QALY. Results: Adding Met to Enza increases expected lifetime costs per patient by $83 651, and improves the expected effectiveness of treatment by 3.74 QALYs, compared to Enza alone. The incremental cost-effectiveness ratio is $22 374/QALY. Accounting for parameter uncertainty, adding Met to Enza has a 72% probability of being cost-effective. Conclusions: Although Met is not currently used as an adjunct therapy to Enza, doing so would likely be cost-effective provided it is as effective as we have assumed in our model. Additionally, our results indicate that the combination of Enza and Met could be among the most cost effective interventions in oncology. However, given the uncertainty around the effectiveness of such an adjunct therapy, our results support the need for further clinical trials to provide more robust evidence of the effectiveness of such a combination therapy in clinical practice.
Once-nightly (QD) dual CYP17-Lyase (L) inhibitor / androgen receptor (AR) antagonist VT-464 in patients with CRPC.
Authors: Shore Neal D. , Nordquist Luke T. , Gupta Shilpa , Fleming Mark T. , Berry William R. , Zhang Jingsong , Kurman Michael R , Eisner Joel Robert , Moore William R.
Published: February 2017

343

Background: VT-464 is an oral, CYP17-L inhibitor and non-clinically an antagonist of the AR and its variants associated with clinical resistance to enzalutamide (ENZ) and abiraterone (AA). The safety, tolerability and initial PD effects (tumor responses, PSA and testosterone (T)-decreases) of QD VT-464 were evaluated in this Phase (Ph) 1/2 study (INO-VT-464-CL-004; NCT02361086). Methods: Chemotherapy-naïve (n = 20) M0 (n = 1) and M1 (n = 19) patients with CRPC prior to (TN, treatment-naïve; n = 9), or after AA (n = 6),ENZ (n = 3) or both (n = 2) were enrolled in sequential dose-cohorts of 600 mg QD with dose titration (DT; 300 mg QD q2w), and 600 and 750 mg QD without DT in 28-day continuous dosing cycles. All doses except the first were given at night with dinner. Patient results through the 750 mg QD cohort are reported (data cut off 17 Aug 2015). Results: Patients received VT-464 without steroids at 600 mg QD+DT (n = 3), 600 mg QD (n = 8) or 750 mg QD (n = 9). Eight patients are on study in cycles 3-12. Most adverse events (AEs) were Grade (Gr) 1 or 2. Fourteen Gr 3 AEs were reported with 7 considered unrelated and 7 ≥ possibly related; 5 of the latter were in the 600 mg QD+DT cohort (bradycardia, hypotension, syncope, hypertension and hyponatremia) with 2 in non-DT cohorts (hypotension, bilateral lower leg weakness). No AEs ≥ Gr 4 were reported. One DLT occurred in the 600 mg QD+DT cohort (syncope). No mineralocorticoid excess syndrome, ACTH response changes, or increased LFTs were observed. Plasma T was below the LOQ (0.03nM) in 67% of patients, with progesterone and cortisol unchanged. Cmax was similar in all cohorts to 450 mg bid (de Bono et al, GU ASCO 2015) but AUC was decreased. All 4 TN patients had PSA declines at 600 mg QD including one 30% and one 50% response; there was one 50% response in the 600 mg QD+DT cohort. Both TN patients treated at 750 mg QD had > 50% response. Of 8 patients with ≥ 1 soft tissue target lesion and ≥ 1 post-baseline scan, 5 had stable disease and 1 had a partial response at Cycle 5. Conclusions: The VT-464 750 mg QD regimen demonstrated potent and selective CYP17 L inhibition and has been selected for all Ph 2 clinical studies based upon improved tolerability, PK and efficacy compared to bid+DT dosing (de Bono et al, GU ASCO 2015). Clinical trial information: NCT02361086.
An RT-PCR assay to monitor circulating free DNA (cfDNA) in castrate resistant prostate cancer (CRPC).
Authors: Diaz Patricia M , Patrsch Katherin , Castellanos Olga O. , Ruderman Daniel , Gross Mitchell E.
Published: February 2017

346

Background: Circulating-free DNA (cfDNA) is elevated in many forms of advanced cancer. We used an RT PCR assay for a highly repetitive DNA element (long-interspersed nuclear element-1; LINE1) to assess cfDNA in patients with CRPC. Methods: Plasma was collected from subjects with metastatic CRPC prior to a change in therapy. DNA was extracted and analyzed with an RT-PCR assay targeting a 297-bp LINE1 amplicon using absolute quantification. Leukocyte DNA and plasma from normal males were used as controls. Serial plasma samples were collected to monitor changes in cfDNA relative to treatment interventions. Results: cfDNA was analyzed at baseline in 54 samples categorized according to treatment context as: chemotherapy-naïve, docetaxel, or post-docetaxel (Table, summarized as means ± SD). While LINE1 was elevated in most patients relative to normal controls, no significant differences were noted across patient groups. No correlation was found between LINE1 and other clinical variables. Longitudinal sampling demonstrated concordant changes in LINE1 and PSA in most subjects, while a discordant pattern was noted in others. Conclusions: The LINE1 RT-PCR assay can be used to monitor cfDNA levels in patients with CRPC and may provide independent information to standard clinical assessments in order to monitor tumor composition and therapeutic response. [Table: see text]
Intermittent abiraterone-acetate administration protocol and prognosis prediction for castrate-resistant prostate cancer.
Authors: Morken Jason David , Cherington Chad , Bryce Alan H. , Kuang Yang
Published: February 2017

353

Background: One mechanism leading to castrate-resistant prostate cancer (CRPC) is upregulation of CYP17. Abiraterone acetate (AA) inhibits CYP17 and continuous AA administration (CAAA) is one the most common and effective CRPC treatments. Mathematical models can be potentially powerful clinical tools for optimizing treatment strategies and eliminating guess work. Here, we introduce a new model which builds on our previous work (Morken JD, Packer A, Everett RA, Nagy JD, Kuang Y. Mechanisms of resistance to intermittent androgen deprivation therapy identified in prostate cancer patients by novel computational method. Cancer Res 2014;74:2673-83.) and may be capable of predicting how patients will respond to CAAA and intermittent AA administration (IAAA). We are currently proposing a personalized IAAA protocol on the basis of these results. Methods: In this ongoing retrospective study, we use PSA data from patients whom underwent CAAA to validate the accuracy of our model of tumor growth and evolution. The PSA output is driven by dynamics of three cell populations—castration-sensitive (CS), castration-resistant abiraterone-sensitive (CSAS), and castration-sensitive abiraterone-resistant (CSAR) cells. We fit the model output to PSA data to find parameter values which minimize normalized mean squared error (NMSE). Once parameters are obtained, we ran simulations employing various IAAA protocols. Results: The model’s PSA dynamics are highly accurate. NMSE is very low across patients ranging from 0.0001-0.0085. Conclusions: Our results suggest that there exists an IAAA protocol for each patient that, at worst, yields the same time to tumor progression as CAAA, yet improves quality of life and reduces cost. In nearly 20% of patients, IAAA appears to delay tumor progression over CAAA. The model is accurate at predicting how patients will respond to CAAA and IAAA for patients whose PSA is regularly monitored. Near-future work aims to personalize IAAA protocol based on patient pre CRPC PSA dynamics and to identify a protocol which delays progression for most patients.
Generating a neoantigen map of advanced urothelial carcinoma by whole exome sequencing.
Authors: Faltas Bishoy , Bhinder Bhavneet , Beltran Himisha , Tagawa Scott T. , Molina Ana M. , Nanus David M. , Elemento Olivier , Rubin Mark A.
Published: February 2017

354

Background: immune-checkpoint blockade is a promising treatment of advanced urothelial carcinoma (UC) that unleashes pre-existing immune responses against recognized tumor antigens. Somatic mutations lead to the formation of neoantigens, which are highly antigenic mutant proteins. Methods: Our objective was to generate a neoantigen map through analysis of whole exome sequencing data of our cohort of patients (pts) with platinum-resistant UC. Whole exome sequencing (WES) data from 73 prospectively collected UC samples from 34 patients were analyzed using our neoantigen prediction pipeline. We defined neoantigens as mutant nonamers with high affinity binding to predicted class I MHC molecules for each patient. HLA haplotypes were inferred from WES of matched germline DNA. Results: A significant correlation between global somatic mutation rates, and neo-epitope burden was observed (R2 = 0.93), a similar correlation was observed between single nucleotide variants (SNV) and neo-epitope burdens (R2 = 0.94). We identified a strong positive correlation between the numbers of pack-years of smoking and neoepitope burden in patients with advanced UC (p = 0.0004). No correlation between global somatic mutational and predicted neoepitope burdens with overall survival was identified. Metastatic samples had a trend of harboring more SNVs (median 49 vs. 22, P = 0.13), and neoepitopes (median 17 vs 12, P = 0.22) compared to primary samples. Interestingly, only 32% of total SNVs and 8 % of neoepitopes (with binding affinities of ≤ 50nM) that were initially identified, reappeared in metastatic samples from the same patients obtained at a later time point. A significant selection against strong binding neo-epitopes was observed in subsequent samples from metastatic tumors (p-value < 0.005). Conclusions: A strong correlation between mutational burden and predicted neoantigenic load was observed in UC. Neoantigenic signatures were shaped by environmental exposures such as smoking. The significant heterogeneity in primary and metastatic neoantigens was possibly due to immunoediting as the tumor evolved. These findings may have important implications for selecting patients for immunotherapeutic approaches.
IMvigor 210, a phase II trial of atezolizumab (MPDL3280A) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC).
Authors: Hoffman-Censits Jean H. , Grivas Petros , Van Der Heijden Michiel Simon , Dreicer Robert , Loriot Yohann , Retz Margitta , Vogelzang Nicholas J. , Perez-Gracia Jose Luis , Rezazadeh Arash , Bracarda Sergio , Yu Evan Y. , Hoimes Christopher J. , Bellmunt Joaquim , Quinn David I. , Petrylak Daniel Peter , Hussain Syed A. , Cui Na , Mariathasan Sanjeev , Abidoye Oyewale O. , Rosenberg Jonathan E.
Published: February 2017

355

Background: The ORR and survival of mUC patients (pts) who progress after platinum-based chemotherapy (pctx) are poor. Atezolizumab (atezo) reinvigorates antitumor immunity by targeting PD-L1 and has shown promising Ph 1 activity in mUC. Methods: IMvigor 210 cohort 2 (NCT02108652) enrolled 316 mUC pts who progressed during or following pctx. Pts received atezo at 1200 mg IV q3w until loss of clinical benefit. The SP142 IHC assay centrally assessed PD-L1 expression. Pts/investigators were blinded to PD-L1 status. Co-primary endpoints were confirmed ORR by RECIST v1.1 per central review (IRF) and modified (m) RECIST per investigator, which were met if null hypothesis (ORR = 10%) was rejected (α = 5%). ORR endpoints were stratified by PD-L1 tumor-infiltrating immune cell (IC) status: IC2/3, IC1/2/3, all comers. Results: Efficacy/safety-evaluable pts (N = 311) had a median age of 66 y, CrCl < 60 mL/min (35%) and ≥ 2 prior regimens for mUC (40%). Many had poor prognostic factors (Table). At 5/5/15 data cutoff (follow up ≥ 24 w), 43/47 responding pts had ongoing responses. Both IRF (Table) and mRECIST ORR correlated with IC status. Durable responses were seen including poor prognostic subgroups (Table). mDOR was not reached in any PD-L1 or prognostic subgroup. mPFS was 2.1 mo in all PD-L1 subgroups. Median treatment duration was 12 w (range 0-46). Treatment-related AEs (most commonly fatigue) occurred in 66% of pts (all Grade); 15% had G3-4 related AE and 4% had G3-4 immune-mediated AE. 27% of AEs led to dose interruption and 3% led to withdrawal. No renal toxicity was seen. Conclusions: IMvigor 210, the first Ph 2 study targeting PD-L1/PD-1 in mUC, demonstrated significantly improved ORR vs historic controls. Responses were durable and associated with higher PD-L1 IC expression; poor prognostic factors did not preclude response. Atezo was well tolerated, and a randomized Ph 3 study vs ctx is ongoing (IMvigor 211; NCT02302807). Clinical trial information: NCT02108652. [Table: see text]
Neutrophiles-to-lymphocytes ratio (NLR): Prognostic value in non-muscle invasive bladder cancer (NMIBC).
Authors: Irani Jacques , Thillou Damien , Bernardeau Simon , Biscans Clément , Sarradin Maxence , Delpech Pierre-Olivier
Published: February 2017

360

Background: The aim of this retrospective study was to evaluate the prognostic value of NLR in NMIBC as it was recently suggested in the literature. Methods: Patients included in the study were diagnosed between 1992 and 2013 with a T1 stage bladder cancer either primarily or following progression. NLR was calculated using the pre-operative (TURB or cystectomy) work-up. Results were expressed as median and interquartile range (IQ) unless indicated otherwise. Results: Seventy-eight patients were analyzed (12 females and 67 males). Mean age: 68.3 years. At diagnosis (1st TURB): median grade according to the WHO 1973 classification: 3 (IQ = 1), median NLR: 3.1 (IQ = 2.4 and range 1.0- 25.7). There was no significant difference between NLR when comparing stage, grade and gender subgroups. During FU (median 6.2 years): median number of TURB: 3.3. Observed NLR was higher in the highest risk groups, however the difference was significant only for grade progression and when comparing pT0 stage vs pTa or higher at the last biopsy/TURB (see table). NLR variation for each patient (NLR at diagnosis – NLR at the last TURB) was not associated with bladder tumor evolution. Conclusions: We found that NLR was higher in NMIBC with a high risk of progression. These data warrant a further evaluation of this potential, readily available prognostic marker in NMIBC. [Table: see text]
Epigenetic silencing and variable expression of SRD5A2 in specific compartments of human prostate.
Authors: Olumi Aria F. , Wang Zongwei , Ge Rongbin , Wu Shulin , Tabetabaei Shahin , Wu Chin-Lee
Published: February 2017

38

Background: The steroid-5α reductase type 2 gene (SRD5A2) and protein play a significant role in the development and growth of prostate tissue. SRD5A2 can be expressed in both the epithelial and stromal compartments of the prostate gland. Previously, we have shown that somatic suppression of SRD5A2 during adulthood is dependent on epigenetic changes associated with methylation of the promoter region of the SRD5A2 gene. Here we determined whether variability of SRD5A2 expression occurs in specific compartments of prostate tissues. Methods: Frozen and formalin-fixed sections of human adult prostate tissue was used. Laser capture microdissection (LCM) was performed to obtain a pure population of epithelial and stromal cells. Approximately 500–600 excised cells were captured, and the methylation pattern of SRD5A2 was determined by DNA methylation pull-down assay kit. The expression of SRD5A2 protein was identified with immunohistochemistry and quantitated by ELISA. Results: In the whole prostate tissue, samples with high SRD5A2 immunoreactivity had much lower levels of SRD5A2 promoter methylation compared to those with low SRD5A2 immunoreactivity. DNA methylation assay for the epithelial compartment closely resembled the findings of the whole prostate tissue. In contrast, the samples from the stromal compartment showed uniform methylation irrespective of the methylation pattern in the epithelial compartment or the whole tissue. The expression of SRD5A2 protein quantitated by ELISA further showed that the variable expression of SRD5A2 is better determined by epithelial compartment expression. Conclusions: Our data suggests that variability of SRD5A2 expression is dependent on the methylation pattern and expression of SRD5A2 in the epithelial compartment and not the stroma. Therefore, if epithelial expression of SRD5A2 is more representative of the whole prostatic tissue expression, then it is logical that SRD5A2 inhibitor’s efficacy is dependent on involution of the epithelial cells. Our findings will have broad implications for the use of 5ARIs in the treatment of BPH and for the chemoprevention of prostate cancer. Grant support: NIH/R01 DK091353
Frequency and clinical implications of pathologic complete response (pCR) at cystectomy for muscle-invasive bladder cancer (MIBC) with or without neoadjuvant chemotherapy (NAC).
Authors: Galsky Matt D. , Stensland Kristian , Sfakianos John , McBride Russell Bailey , Mehrazin Reza , Tsao Che-Kai , Boffetta Paolo , Oh William K.
Published: February 2017

383

Background: Subsets of patients (pts) with MIBC, with or without NAC, have no pathologic evidence of disease at cystectomy. The frequency and implications of pCR in “real world” pts has not been well characterized. Methods: Using the National Cancer Database, pts with cT2-4aN0M0 bladder cancer who underwent cystectomy alone (CYS) or with NAC from 2003-2011 were identified. pCR was defined as pT0N0M0. In the CYS and NAC cohorts, the association between pCR and overall survival was analyzed using Cox proportional hazard methods. Results: 12,245 pts met eligibility (CYS: 10,940; NAC: 1,305). The pCR rate with CYS was 4.8% (95% CI 4.4-5.3%) and with NAC was 21.6% (95% CI 19.4-24.0%). In both cohorts, logistic regression revealed lower cT stage and higher cystectomy volume were associated with increased pCR. pCR was associated with a significant improvement in survival in both cohorts (Table). Conclusions: The frequency of pCR in real world pts was substantially lower than reported in clinical trials; however, pCR was associated with markedly improved survival in both CYS and NAC groups. Molecular predictors of pCR in both groups warrant evaluation. Whether the survival benefit associated with pCR in the CYS cohort simply reflects the “smallest/best” tumors or whether there is a role, and mechanistic rationale, for surgical approaches to increase pCR (i.e., re-TURBT in MIBC) warrants study. Finally, our findings lend further support for use of pCR as an endpoint in NAC clinical trials. [Table: see text]
Safety and efficacy of extended-duration thromboembolic prophylaxis following radical cystectomy.
Authors: Zaid Harras B. , Yang David , Tollefson Matthew K. , Frank Igor , Parker William P. , Thompson Robert Houston , Karnes R. Jeffrey , Boorjian Stephen A.
Published: February 2017

389

Background: Venous thromboembolism (VTE) has been reported in approximately 5-7% of patients undergoing radical cystectomy (RC). While extended-duration pharmacologic prophylaxis (EDPP) has been investigated following surgery for a variety of malignancies, limited data exist in bladder cancer. Herein, we evaluated the efficacy and safety of EDPP after RC. Methods: We instituted a change in our clinical practice beginning in May 2014 such that patients undergoing RC were prescribed 30 days of enoxaparin at discharge. We recorded symptomatic VTE and lymphocele rates within 30 days of RC among patients treated from 5/14-6/15, and compared these outcomes to the cohort of all patients who underwent RC at our institution in the year prior to EDPP implementation. Patients in both groups received subcutaneous unfractionated heparin and mechanical prophylaxis during hospitalization. Patients with a history of VTE prior to surgery (n = 24) were excluded from study. Unadjusted descriptive statistics and univariate analyses were performed using the Pearson or Fisher chi-square test for categorical variables and Wilcoxon rank-sum test for continuous variables. Results: In total, 58 patients who received EDPP and 82 patients who had not received EDPP after RC were included for analysis. Baseline clinicopathologic demographics were similar between the cohorts. We found that only 1 patient (1.9%) discharged with EDPP was diagnosed with a VTE within 30 days of RC, compared to 5 (6.1%) who had not received EDPP. Mean time to VTE was 18.0 days after RC (range 9-28 days). Events consisted of DVT alone (n = 2), DVT and PE (n = 2), and PE alone (n = 2). The odds ratio for VTE in the absence of EDPP was 3.31 (95% CI 0.38, 29.2). Overall, 3 patients developed a symptomatic lymphocele within 30 days of RC: 1 (1.9%) who received EDPP and 2 (2.4%) who had not (p = 0.84). No patient in either cohort was rehospitalized for bleeding complications. Conclusions: Our initial experience suggests that EDPP was associated with a lower rate of VTE following RC, and does not increase the risks of bleeding or symptomatic lymphocele. Future evaluation in a larger-scale prospective clinical trial setting is needed to confirm the benefit of EDPP in RC patients.
Outcome of radical cystectomy series in the management of muscle invasive bladder cancer: Liverpool experience.
Authors: Hussain Syed A. , Khattak Altaf Qadir , Cornford Philip , Weston Robin , Somov Pavlo , Jackson Richard
Published: February 2017

396

Background: Cystectomy has become one of the standard forms of therapy for patients with muscle invasive bladder cancer with long term follow-up data supporting radical surgical management. Methods: Data are collected retrospectively on patients who underwent cystectomy at the Royal Liverpool University Hospital. The aim was to document the overall survival of patients undergoing cystectomy at this centre. Results: Data were collected on 147 patients between September 2007 and June 2013. Median patient age was 66 (IQR: 61, 72) with 33 (23%) females. 107 (73%) patients had muscle invasive TCC, 13 (9%) had recurrent non-muscle invasice disease, 9 (6%) had salvage surgery following radical radiotherapy and 6 (4%) had persistent carcinoma in situ. 28 patients (20%) had hydronephrosis. 34 (23%) patients underwent neo-adjuvant chemotherapy. 2 (1%) patients had Combined synchronous urethrectomy and 5 (3%) had Combined synchronous nephroureterectomy. Post operatively positive lymph nodes were observed in 22 (19%) of surgical specimens and 83 (72%) had persistent muscle invasive disease. Survival rates at 12 and 60 months are 0.92 (0.88, 0.97) and 0.52 (0.39, 0.71) respectively. Multivariate analysis show that post operative T (HR: 3.99 (1.05, 15.18)) and N (HR: 5.40 (2.17, 13.44)) status are both independent predictors of over all survival. Conclusions: Real life data from our centre showed that the patient population and overall survival estimates for patients with muscle invasive bladder cancer treated with radical cystectomy and lymph node dissection are consistent with previous published literature. .
Perioperative outcomes of open and minimally invasive nephroureterectomy and pre-operative predictors of complications: An analysis using the National Surgical Quality Improvement Program database.
Authors: Soodana-Prakash Nachiketh , Pavan Nicola , Balise Raymond R , Nahar Bruno , Rai Samarpit , Ritch Chad , Punnen Sanoj , Satyanarayana Ramgopal , Parekh Dipen , Gonzalgo Mark L.
Published: February 2017

408

Background: Minimally invasive nephroureterectomy (MINU) is an alternative approach to open nephroureterectomy for management of upper tract urothelial carcinoma (UTUC). Oncological outcomes between the two methods has been shown to be similar. We analyzed the NSQIP database to determine if there was a significant difference in perioperative complications between MINU and open nephroureterectomy. Methods: Between 2005 and 2013, a total of 1,027 patients were identified in the National Surgical Quality Improvement Program Database (NSQIP) that underwent nephrouretectomy for UTUC. Pre−operative covariates were analyzed to predict the rates of severe (Clavien−Dindo grade ≥ 3) perioperative complications. Univariate and multivariate logistic regression models (controlling for demographic and comorbid conditions) were built to predict severe complications and exploratory analyses were done to predict 18 common complications. Results: A total of 669 (65%) and 359 (35%) patients underwent MINU and open nephroureterectomy, respectively. Open nephroureterectomy was associated with a higher rate of severe complications (OR 1.87, CI 1.02−3.4, p = 0.04). Post−operative occurrence of pneumonia (OR 4.5, CI 1.7−3.4, p < 0.001) and transfusions (OR 2.5, CI 1.7−3.6, p < 0.0001) were lower for MINU compared to open nephroureterectomy. There were no significant differences between the two surgical methods with respect to incidence of other complications. MINU took longer on average than open nephroureterectomy (median 219 mins vs. 200 mins, p < 0.001). Time to discharge was longer for open nephroureterectomy compared to MINU (median 6.25 days vs. 5 days, p < 0.0001). Conclusions: Post−operative pneumonia and occurrence of severe complications (Clavien−Dindo grade ≥ 3) were higher for the open nephroureterectomy group compared to MINU. These data suggest that MINU is an acceptable surgical approach for management of UTUC that is associated with lower morbidity compared to open nephroureterectomy.
Comorbidity and androgen deprivation therapy use in men undergoing high-dose radiation for unfavorable intermediate- and high-risk prostate cancer.
Authors: Dyer Michael A , Chen Ming-Hui , Braccioforte Michelle H. , Moran Brian Joseph , D'Amico Anthony V.
Published: February 2017

41

Background: Despite evidence of prolonged survival when adding androgen deprivation therapy (ADT) to external beam radiation therapy (EBRT) in men with unfavorable intermediate- and high-risk prostate cancer (PC), some of these men are not receiving ADT. We explored whether comorbidity can explain this discrepancy given the observation that survival may be shortened in men with moderate to severe comorbidity who receive ADT. Methods: Between 10/1997 and 5/2013, 3,348 men with unfavorable intermediate- (2,380 patients; 70.7%) or high-risk (986 patients; 29.3%) PC were treated at the Prostate Cancer Foundation of Chicago using brachytherapy with or without neoadjuvant EBRT and/or ADT, and formed the study cohort. A multivariable logistic regression analysis was used to evaluate whether comorbidity (history of congestive heart failure [CHF] and/or myocardial infarction [MI]) was associated with decreased odds of ADT use in men with unfavorable intermediate- or high-risk PC, adjusting for age, PC prognostic factors, year of brachytherapy, and EBRT use. Results: Among patients with unfavorable-intermediate-risk PC, 31.2% received ADT, and in the high-risk cohort, 38.3%, 12.3%, and 4.8% received up to 6, >6-18, or >18 months of ADT respectively. In men with high-risk PC, a history of CHF/MI was not significantly associated with decreased odds of ADT use of any duration (all p values >0.71), but the odds of ADT use decreased over time (adjusted odds ratio (AOR) 0.87, 95% confidence interval (CI) [0.83,0.91], p<0.0001; AOR 0.93, 95% CI [0.87,0.99], p=0.023; AOR 0.92, 95% CI [0.83,1.01], p=0.089, for up to 6, >6-18, and >18 months respectively, with no ADT as the reference). Similarly, in men with unfavorable intermediate-risk PC, a history of CHF/MI was not significantly associated with decreased odds of ADT use (p=0.49), whereas the odds of ADT use decreased significantly over time (AOR 0.96, 95% CI [0.94,0.98], p=0.0009). Conclusions: While ADT use has decreased over time in men with unfavorable intermediate- and high-risk PC undergoing brachytherapy with or without supplemental EBRT, this decrease does not appear to be occurring in men with a history of CHF or MI.
Long-term oncological and functional outcomes of prostate sparing cystectomy: Single tertiary care institution experience.
Authors: Perez-Reggeti Jose Ignacio , Sanchez-Salas Rafael , Linares Espinos Estefania , Ingels Alexandre , Sivaraman Arjun , Saad Mohamed , Rozet Francois , Barret Eric , Galiano Marc , Cathala Nathalia , Mombet Annick , Prapotnich Dominique , Cathelineau Xavier
Published: February 2017

413

Background: To analyze the oncological and functional outcome of Prostate Sparing Cystectomy (PSC) in the treatment of Bladder Cancer (BC) in a single tertiary care referral institution. Methods: At our institution, we treated 147 patients (1992 – 2014) with PSC for muscle invasive BC and recurrent high grade non-muscle invasive BC. Out of these, 64 patients received a standardized PSC technique featuring a Millin adenomectomy between 2001 – 2014 and composed the population of the study. Inclusion criteria were: Normal prostate examination and prostate specific antigen (PSA) +/- negative transrectal ultrasound guided biopsies; Frozen section negative for cancer in prostatic urethra prostate base, distal ureters and trigone. Oncological outcome was evaluated with Overall survival (OS); Cancer-specific survival (CSS); Recurrence-free survival (RFS). Functional outcomes: Continence - being pad-free or leak-free requiring ≤ 1 pad per day/night. Sexual function was assessed by self- reported erectile function sufficient for intercourse with or without medical treatment. Results: Median age was 62 years (IQR 55-67,5) with a median follow-up of 70 months (IQR 46-103). Thirty one (48,4%) patients ≤ pT1, 19 (29,7%) pT2, 14 (21,9%) ≥ pT3 at pathological diagnosis. Lymphadenectomy was performed in 95,3% of the cases. Positive lymph nodes were found in 4.9% patients and 3.1% patients showed positive surgical margins. Ten patients (15,7%) had Clavien grade 3–5 complications.The 5 and 10-y survival rates were OS: 84,7% and 68,3%; CSS: 84,7% and 77,5%; RFS: 76% and 65,5% respectively. No case of recurrence at the remnant prostatic urothelium was observed. Pad-free and leak-free continence, were achieved in 85.9% and 93.8% for daytime continence respectively, with 50% and 85,9% for night continence, respectively. Erectile function was maintained in 56,3%. Prostate cancer was diagnosed in 3 (4,7%) patients, 2 at the pathology report of the adenomectomy followed with active surveillance, and 1 was diagnosed during the follow up being treated with brachytherapy. Conclusions: PSC appears to be an oncologically safe procedure with adequate functional outcomes in treating selected patients with BC.
Incidence and characterization of pure non-urothelial bladder and upper tract cancers: A 10-year review.
Authors: Gupta Kanika , El Bahesh Ehab , Finianos Antoine Nafez , Clark Brandon , Simmens Samuel , Aragon-Ching Jeanny B.
Published: February 2017

414

Background: Bladder cancer is the sixth most common malignancy in the United States. Urothelial carcinoma makes up 90% of bladder cancer histology, which may be pure or mixed. It includes adenocarcinoma (Ad), squamous (SqC), glandular, sarcomatoid (St), micropapillary, small cell (SC) and plasmacytoid variants. Pure non-urothelial cancers have worse overall survival compared to urothelial cancer with mixed histologic features. However, little research has been done to characterize pure non-urothelial histologies, and there are no randomized clinical trials evaluating treatment modalities for non-urothelial cancers. This retrospective study characterizes pure non-urothelial cancers and their treatments. Methods: A retrospective chart review of the last 10 years was performed using data from the George Washington University Cancer Center Tumor Registry Data. Statistical analysis was done using the Fisher’s test and Kaplan-Meier survival curves. Results: Out of 449 consecutive patients with bladder cancers, 19 patients had pure non-urothelial carcinoma (4.2%): 7 SqC, 6 Ad, 3 SC, 2 lymphoma (Ly), and 1 St. SqC and Ad were more likely than SC to be diagnosed at an advanced stage (p = 0.04), with median age of diagnosis at 53.5 years for Ad, 68 years for SC and 69 years for Sq. None of the SC metastasized. Primary treatment for 94% of patients was a surgical intervention (9 TURBT, 2 partial cystectomy, 2 radical cystectomy, and 2 nephroureterectomy); 1 received neoadjuvant therapy. 11 patients received adjuvant chemotherapy – 7 with gemcitabine-based regimens and 10 with platinum-based regimens. While not statistically significant, median overall survival varied – 404 days for Ad, 213 days for SqC, and 1567 days for SC. Conclusions: SC was a more favorable histology when compared to SqC or Ad, presenting at an earlier stage with lower incidence of metastasis that perhaps reflected the improved overall survival. Identifying patients with more aggressive disease earlier allows for the potential role for more aggressive therapies that may result in improved outcomes. While the sample size is small, it identifies characteristics and potential differences between bladder cancer with rare histologies.
Examining the effect that prior bladder manipulation and BCG treatment have on false positive rates of blue-light cystoscopy biopsies.
Authors: Mount Andrew , Williams Stephen Bentley , Dinney Colin P. N. , Grossman H. Barton , Pettaway Curtis Alvin , Chapin Brian Francis , Navai Neema , Matin Surena F. , Graber William F. , Kamat Ashish M.
Published: February 2017

416

Background: One of the criticisms of blue-light cystoscopy (BL) is the relatively high rate of false positive biopsies when used in the real world setting. There is no consensus on which patient factors, if any, might be contributing to this high false positive rate. The purpose of this study is to determine whether having a cystoscopy, TURBT or BCG treatment recently resulted in higher rates of false positive blue-light (BL) biopsies. Methods: We performed an IRB-approved retrospective study looking at a total of 116 consecutive patients who underwent simultaneous BL and WL between January 2013 to December 2014. Pathology and operative reports were reviewed to determine the grade and stage of the tumors. Clinical notes were utilized to determine how recently they had a cystoscopy, TURBT, and BCG treatment. The false positive rates of both BL and WL were calculated, and Fisher’s exact test was utilized to determine if the time from the patients’ most recent bladder manipulation or BCG treatment had a significant effect on the false positive BL rate. Results: Of the 46 (28.6%) BL positive biopsies, 29 (63.0%) were false positives. When stratified by potential causes of false positive for BL we found the following: one (3.4%) had bladder manipulation within 14 days, 8 (27.6%) within 30 days, 19 (65.5%) within 60 days, and 10 (34.5%) had bladder manipulation beyond 60 days prior to the biopsy. When looking at intravesical BCG as a cause for false positive, we found prior BCG use in 18 (62%) patients of those with false positive BL compared to 12 (70.6%) patients of those with true positive BL biopsies (p = 1.0). Of the 18 patients with false positive BL biopsies who had BCG previously: 1 (5.6%) had BCG within 6 weeks, 5 (27.8%) had BCG within 12 weeks, and 13 (72.2%) had BCG greater than 12 weeks prior to biopsy. None of these associations were found to be statistically significant. Despite the high percentage of false positive lesions, it is important to note that in patients who had tumors visualized only with BL, 11 (26.8%) were high-grade, including one patient with T1 tumor and 8 with CIS. Conclusions: There was no relationship between recent bladder manipulation or BCG treatment and false positive BL biopsies.
The utility of neutrophil-to-lymphocyte ratio in determining survival outcomes in patients treated with neoadjuvant chemotherapy and radical cystectomy for high-risk bladder cancer.
Authors: Mmeje Chinedu O. , Slade Austen , Slack Rebecca , Navai Neema , Gao Jianjun , Siefker-Radtke Arlene O. , Kamat Ashish M. , Dinney Colin P. N. , Shah Jay Bakul
Published: February 2017

419

Background: Pre-operative neutrophil-to-lymphocyte ratio (NLR) has been found to be associated with adverse pathological results and poor long-term outcomes in patients treated with radical cystectomy (RC) for urothelial carcinoma (UC). We aimed to evaluate the predictive utility of NLR in patients treated with neoadjuvant chemotherapy (NAC) and RC for high-risk UC. Methods: We reviewed the records of 585 patients treated with NAC and RC at our institution from 2000-2013. We calculated NLR before initiation of NAC (pre-chemo NLR) and during the recovery window between NAC and RC (post-chemo NLR).. We excluded patients with concomitant infection, blood disorder, or second malignancy. We used univariate and multivariate CART models to determine the optimal NLR cut-off for survival outcomes. We estimated disease-specific (DSS) and overall survival (OS) using the Kaplan-Meier method. We used Cox proportional hazards regression to explore the association of NLR with DSS and OS. Results: 584 patients had NLR information in our cohort. The median follow-up among survivors was 4.9 years (IQR 2.4 – 8.8 years). We identified optimal NLR cut-points of 7.1 for pre-chemo, 4.9 for post-chemo, and 1.9 for change in NLR [(post-chemo) – (pre-chemo)]. Post-chemo NLR showed the strongest association with OS and DSS. Patients with a post-chemo NLR ≥ 4.9 (n = 103) had a 5-yr DSS and OS of 42% and 33% respectively, compared to 69% and 58% for patients with an NLR < 4.9 (n = 481). In the multivariable analysis, post-chemo NLR ≥ 4.9 was an independent predictor of DSS (HR = 2.5 [95% CI:1.8, 3.6] p < 0.001 ), and OS (HR = 2.1 [95% CI:1.6, 2.8] p < 0.001). Conclusions: A post-chemo NLR ≥ 4.9 is associated with poor DSS and OS in patients treated with NAC and RC. These findings may help guide treatment planning for adjuvant therapy following RC in patients with high-risk clinically localized bladder cancer.
Human antigen R as a predictive marker for response to gemcitabine-based chemotherapy in advanced cisplatin-resistant urothelial cancer.
Authors: Miyata Yasuyoshi , Mitsunari Kensuke , Asai Akihiro , Matsuo Tomohiro , Ohba Kojiro , Sakai Hideki
Published: February 2017

421

Background: In patients with advanced urothelial cancer (UC), a combined therapy of cisplatin (CDDP) and gemcitabine (GEM) is the most commonly used first (1st)-line systematic chemotherapy. Although no regimen for CDDP-resistant UC has been established, GEM-based regimens are often used in these patients. In other cancers, HuR status in cancer cells is closely associated with response to GEM. The aim of this study was to establish the predictive value of HuR expression for disease progression and survival in UC patients treated with GEM-based regimens as 1st or second (2nd)-line chemotherapy. Methods: Fifty patients with advanced UC were included in the study. As 1st-line chemotherapy, MVEC (methotrexate, vinblastine, epirubicin, and CDDP) and GC therapy were performed in 34 (68.0%) and 16 patients (32.0%), respectively. After progression, 45 patients (90.0%) were treated with combined GEM and paclitaxel (PTX) therapy, and 5 patients (10.0%) were treated with GEM monotherapy. Cytoplasmic and nuclear Human antigen R (HuR) expression was evaluated using immunohistochemical techniques. The relationships between HuR expression and local response and outcome were analyzed. Results: In 1st-line chemotherapy, no anti-cancer effects were associated with nuclear or cytoplasmic HuR expression. In 2nd-line chemotherapy, although nuclear HuR expression also had no significant relationship to anti-cancer effects, local tumor response was significantly better if there was positive cytoplasmic HuR expression (P = 0.002). Multivariate analyses revealed that cytoplasmic HuR expression was a significant predictive marker for longer overall survival (hazard ratio, 0.22; 95% confidential interval, 0.09–0.56; P = 0.001). There is no significant relationship between nuclear HuR expression and parameters of anti-cancer effects. Conclusions: Cytoplasmic HuR expression is a significant predictive marker of response to GEM-based chemotherapy in CDDP-resistant UC. Despite limitations of a small retrospective study, our results might have important information to discuss the treatment strategies and warrant further basic and clinical research.
MRI-transrectal ultrasound cognitive fusion-targeted transperineal template-guided saturation prostate biopsies in a consecutive cohort of men.
Authors: Matzkin Haim , Dekalo Snir , Mabjeesh Nicola J
Published: February 2017

43

Background: MRI of the prostate may improve diagnostic accuracy of prostate cancer. Different fusion approaches with transrectal ultrasound images are employed. Objective: To determine the detection rate of prostate cancer in men undergoing transperineal template-guided saturation biopsy (TTSB) with MRI-based cognitive fusion. Methods: Between the years 2010-2015, 164 consecutive men underwent a multiple-core prostate TTSB. Univariable and multivariable logistic regression analyses were used to address the relationship between clinical TTSB parameters and prostate cancer detection rate. Covariates consisted of age, prostate-specific antigen (PSA), prostate volume, PSA density, digital rectal examination findings, existence of suspicious prostate lesions on MRI, number of previous negative biopsy sets, and number of cores taken during TTSB. Results: Mean age was 65 years and mean PSA was 14 ng/ml, mean prostate volume was 63 ml. Seventy percent of patients had at least two previous negative transrectal biopsy series and another 19% had at least one negative biopsy. One-hundred and fourteen patients (70%) underwent prostate MRI prior to the biopsy. The detection rate of prostate cancer among these patients was 46% of which 69% had Gleason score ≥ 7. Men with a suspicious lesion on MRI (n=80) had a detection rate of 50%, compared to 33% in patients with negative MRI study. On multivariate analysis, the most significant independent predictive factor was PSA density (p= 0.001). Other nearly significant parameters were suspicious MRI lesion, prostate volume and suspicious digital examination. Of note, the prostate cancer detection rate among patients with no MRI study prior to TTSB was 26%. Conclusions: Utilizing MRI cognitive fusion approach increases the detection rate of clinically significant prostate cancer (Gleason score ≥ 7). In patients with existing suspicion for prostate cancer after multiple negative standard TRUS-guided biopsies, performing TTSB after taking into consideration the findings on MRI and PSA density will increase dramatically the detection rate of significant disease.