bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular profiling of non-urothelial bladder cancer: Adenocarcinoma and squamous cell carcinoma.
Authors: Geynisman Daniel M. , Arguello David , Reddy Sandeep K. , Gatalica Zoran
Published: February 2017

423

Background: Adenocarcinoma (ADA) and squamous cell carcinoma (SCC) are rare and often aggressive histologic subtypes of bladder cancer. For advanced disease, no clear standard therapies exist and NCCN guidelines suggest only fluorouracil, cisplatin, paclitaxel and ifosfamide as possible options. Thus, novel therapies based on underlying tumor biology are needed. The purpose of this study was to identify potential therapeutic options for these histologic subtypes, utilizing multiplatform tumor profiling. Methods: 49 ADA and 24 SCC specimenswere tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (Sanger or next generation sequencing [NGS]), gene amplification (CISH or FISH), and protein expression (immunohistochemistry [IHC]). 52% of cases were from metastatic sites. Results: Both ADA and SCC exhibited high rates of TP53 aberrations (82.4% and 72.7%, respectively). Sequencing revealed mutations in BRCA2 (14.3%), SMAD4 (12.5%), PTEN (11.8%), KRAS (8.7%), NRAS (5.6%), and KIT (5.3%) in ADA. In addition, PIK3CA (21.4%), HRAS (18.2%), BRCA1 (16.7%), BRCA2 (16.7%), and FBXW7 (9.1%) mutations were detected in SCC. Amplification in EGFR (27.3%) and ERBB2/HER2 (16.7%) were found in ACA. Meanwhile, only one ERBB2 (6.3%) amplification was found in SCC using ISH. MET was not amplified in either ACA or SCC. For both ACA and SCC, EGFR had the highest level of protein expression (100% and 85.7%, respectively). Of note, PD-1 (44.4% in both) and PD-L1 (11.1% and 22.2% in ACA and SCC, respectively) were expressed in both subtypes. Although differential rates of somatic alterations, amplification, and protein expression were found between ADA and SCC, only TLE3 was significant (19.2% versus 60.0%, respectively, p = 0.0154). Conclusions: Differential results in gene alteration, amplification, and protein expression imply the potential utility of tumor profiling in guiding therapeutic decision-making in ADA and SCC of the bladder. PIK3CA/AKT/mTOR pathway aberrations are similar to what has been reported in urothelial bladder cancer. Targeting the PD-1/PD-L1 axis may be a therapeutic option. Further studies are warranted in both diseases.
First multicenter experience with thermotherapy and mitomycin of high risk NMIBC with a new recirculation system (COMBAT).
Authors: Voegeli Thomas Alexander , Volkmer Bjoern
Published: February 2017

425

Background: At a temperature of 43° (109°F) cytotoxicity of mitomycin increases 10 fold to tumor cells if used for instillation therapy of superficial bladder cancer (NMIBC).In the last years high organ preservation rates were reported for high risk NMIBC after radiofrequency induced hyperthermia and mitomycin (Synergo System).Unfortunately side effects were frequent and discontinuitation of 40% were reported with this method thus thermotherapy combined with instillation this therapy has not been very common.We here report about the first experience with a newly developed device using a recirculation heating system (COMBAT). Methods: After diagnosis by complete TUR/ReTUR patients received 40 mg mitomycin (mito-extra,medac) via transurethral catheter for 1 h heated up to constant 43° by a circulation pump system (COMBAT). Side effects were recorded pprospectively before and after each teratment and during follow up and success was validated by TUR/biopsy if possible. Results: A total of 20 patients were treated from 11/14-9/15 in 5 institutions. Follow up until now is 1-10 month (mean 8 m). All patients had high risk NMIBC including BCG failures. Therapy must be abondened in 1 patient after the 5th treatment, 50% had dysuria during treatment but symptoms decreased after the last treatment in all patients. 2 patients experienced mild allergic reaction also seen under conventional instillation therapy with mitomycin and were treated by corticosteroids. ReTUR was performed in 17/20 patients and revealed a persistent/recurrent tumor pTa GIII in 1 out of 20 patients. Conclusions: Compared to the microwave driven heating system the new device with recirculation of heated mitomycin seems to have less side effects without major complications. Treatment discontinuitation was recorded in 1/20 patients. Given the assumption that this system has the same high rate of organ preservation as the Synergo System at even much lower costs, it may alter the therapy algorythm in high risk NMIBC. Despite our first promising oncological results further research with longer follow up is necessary.Two prospective randomized studies are now underway in England and Spain and first results are awaited in 2 years.
First intravesical α-radioimmunotherapy of human urothelial carcinoma in men as a new therapy for carcinoma in situ after BCG failure.
Authors: Autenrieth Michael E , Kurz Florian , Horn Thomas , Seidl Christof , Morgenstern Alfred , Scheidhauer Klemens , Bruchertseifer Frank , Gschwend Juergen E. , Senekowitsch-Schmidtke Reintraud
Published: February 2017

427

Background: Failure to respond to BCG in patients with carcinoma in situ (CIS) of the urinary bladder is problematic, since those tumours often have the potential to progress to muscle invasion. radical cystectomy remains the mainstay after BCG failure.Because treatment of mice bearing intravesical human bladder cancer xenografts with Bi-213-anti-EGFR-MAb turned out highly efficient (Pfost B et al. 2009, J of Nucl Med 50:1700-1708), the aim of this pilot study was to evaluate tolerability and safety of the α-emitter radioimmunoconjugate in patients after BCG failure. Methods: The alpha-emitter Bi-213 was eluted from a generator system provided by the Institute for Transuranium Elements (European Commission, JRC, Karlsruhe, Germany) and coupled to the anti-EGFR-mAb (Cetuximab, Merck, Germany) via the chelating agent CHX-A”-DTPA. 7 patients suffering from carcinoma in situ of the bladder who had histologically proven residual tumor after BCG induction therapy were included. After emptying the bladder an activity between 9,9 mCi and 22,2 mCi in 40 ml NaCl of Bi-213-anti-EGFR-mAb via a transurethral catheter was instilled. Distribution of Bi-213-anti-EGFR-mAb was monitored by SPECT/CT. Treatment was terminated by emptying of the radioimmunoconjugate from the bladder 120 min after injection. Efficacy was evaluated via endoscopy and histology six weeks after instillation. Results: All patients showed excellent toleration of the treatment without any side effects. SPECT/CT monitoring clearly revealed location of the Bi-213-anti-EGFR-MAb immunoconjugate only in the bladder without extravasation. Treatment resulted in complete eradication of tumor cells in 3 patients and persistent tumor detection in the other 4 patients. Conclusions: Intravesical instillation of Bi-213-anti-EGFR-mAb is a promising therapeutic option for treatment of in situ bladder cancerafterBCG failure for patients who wish to preserve the bladder.
Multicenter prospective phase II trial of neoadjuvant (neo) dose dense gemcitabine and cisplatin (DD-GC) in patients (pts) with muscle-invasive bladder cancer (MIBC).
Authors: Balar Arjun Vasant , Iyer Gopa , Milowsky Matthew I. , Huang William C. , Woods Michael , Donat S. Machele , Herr Harry W. , Dalbagni Guido , Bochner Bernard H. , Ostrovnaya Irina , Al-Ahmadie Hikmat , Rose Tracy Lynn , Riches Jamie Cathleen , Kania Brooke Elizabeth , Regazzi Ashley Marie , McCoy Asia S. , Delbeau Daniela , Rosenberg Jonathan E. , Bajorin Dean F.
Published: February 2017

436

Background: Cisplatin-based chemotherapy before radical cystectomy (RC) improves survival in pts with MIBC. DD-GC therapy is active in the metastatic setting [6 cycles (cy), 18 months median survival; Bamias et al, 2012)] and as neo therapy (3 cy, 44% ≤ pT1 rate; Plimack et al, 2014), but the optimal dose and number of cy of neo therapy has not been defined. We prospectively evaluated the activity and safety of 6 cy of neo DD-GC over 12 weeks in MIBC. Methods: Pts with T2-4aN0 disease received six 14-day cy of DD-GC as follows: G 2500 mg/m2 day 1, C 35 mg/m2 days 1 and 2, pegfilgrastim day 3. RC with bilateral pelvic lymph node dissection was planned within 8 weeks of DD-GC completion, regardless of clinical response. The primary endpoint was pathologic response ( ≤ pT1) rate ≥ 55% (exact Binomial one-sided test). Pts not undergoing RC were deemed non-responders regardless of clinical stage after DD-GC. Pts receiving < 3 cy were inevaluable and replaced. All pts were evaluable for toxicity. Results: 49 pts (40 male) were enrolled. Median age was 64 (range: 37-78). Clinical stage was T2N0 (32 pts), T3N0 (12 pts), and T4aN0 (5 pts). Toxicities resulting in cy delay and/or dose modifications included thrombocytopenia (9 pts), renal insufficiency (5 pts), vascular access complication (2 pts), ototoxicity (1 pt), significant urinary symptoms (1 pt), and transient ischemic attack (1 pt). Three pts are inevaluable for the primary endpoint ( < 3 cy). As of 9/7/15, 2 pts are pending RC. Of the 44 pts evaluable for response to date, 31 completed 6 cy of DD-GC, 6 pts completed 5, 3 pts completed 4, and 4 pts completed 3 (median: 6 cy). The median time to RC was 46 days. Four of 44 pts did not undergo RC (consent withdrawal, pt refusal, disease progression prior to RC, death from other causes). Trial accrual has closed with completion of clinical and pathologic data expected by 11/1/15. Of 40 pts with RC pathology available to date, 24 (60%) were ≤ pT1 and 7 (18%) were pT0. Conclusions: Six cy of DD-GC is an active well-tolerated neo chemotherapy regimen in pts with MIBC. The pathologic response rate is encouraging. Thrombocytopenia was the most common toxicity resulting in cy delays/dose modifications. Clinical trial information: NCT01589094.
Racial disparities in quality metrics of muscle invasive bladder cancer (MIBC).
Authors: Mullane Stephanie A. , Meyer Christian , Choueiri Toni K. , Preston Mark A , Nguyen Paul L. , Bellmunt Joaquim , Trihn Quoc-Dien
Published: February 2017

442

Background: There is conflicting evidence regarding MIBC treatment and outcomes. Our aim was to assess the variation in four quality metrics (neoadjuvant chemotherapy, time to treatment ≤ 3 months, ≥ 10 lymph nodes removed, use of continent urinary diversion) according to race. Methods: Using the National Cancer Database (NCDB), we identified 17,944 MIBC patients undergoing radical cystectomy. Race was stratified into non-Hispanic White (nHW), African-American (AA), Asian (A) and Hispanic/Latino (H). Uni- and multivariable analyzes examined the association between race and receipt of quality metrics, accounting for baseline characteristics. Cox regression model was used to calculate differences in overall survival(OS). Results: Baseline characteristics (insurance status, income, education, age, sex, facility type, Charlston Comorbidity Index) were significantly different between races. We did not observe any difference in the number of quality metrics received ( ≤ 1 vs ≥ 2) according to race (p = 0.161). However, there were significant differences for time to treatment and diversion type (p = 0.002, 0.012). Blacks had a significantly worse OS after adjustment for significant confounders (OR: 1.224, CI: 1.113-1.347). Conclusions: Even after accounting for treatment disparities, AA have a worse OS, warranting further investigation into potential biologic and epidemiologic factors affecting race and MIBC.
Predictive models for improved prognostication and selection of neoadjuvant and adjuvant systemic chemotherapy in upper tract urothelial cell carcinoma.
Authors: Vernez Simone Lucia , Lotan Yair , Shariat Shahrokh F. , Sagalowsky Arthur I. , Morgan Jacob B , Raman Jay D. , Wood Christopher G. , Weizer Alon Z. , Roscigno Marco , Montorsi Francesco , Bolenz Christian , Kassouf Wassim , Margulis Vitaly , Youseff Ramy F
Published: February 2017

456

Background: Chemotherapy is still underutilized in management of upper tract urothelial carcinoma (UTUC). We created pre and post-operative predictive tools combining independent prognostics to guide selection of patients for neoadjuvant and adjuvant chemotherapy. Methods: From the UTUC collaboration database (1,453 patients who underwent radical nephroureterectomy [RNU] at 13 academic institutions); a preoperative predictive model was created using 659 patients in whom all preoperative prognostic variables were available and a post-operative model was created using 586 patients with non-metastatic/ high-grade UTU. After multivariable survival analyses, a backward step-down selection process was applied to create a preoperative nomogram. Internal validation was performed using 200 bootstrap resamples. For the postoperative model, TALL score was created based on the sum of the independent prognostic variables. Results: Preoperative model: Grade, architecture and location of the tumor were independently associated with nonorgan confined disease. A nomogram including these 3 variables achieved 76.6% accuracy in predicting nonorgan confined upper tract urothelial cancer. Postoperative model: TALL score (1-7) was the sum of T ( ≤ T1 = 1, T2 = 2, T3 = 3 and T4 = 4), A (papillary = 0 and sessile = 1), LVI (absent = 0 and present = 1) and L (lymphadenectomy = 0 and no lymphadenectomy = 1). Five-year disease-free survival (DFS) and cancer-specific survival (CSS) were stratified into four risk categories according to the TALL score: low (TALL 0-2; 86 % DFS and 90 % CSS), intermediate (TALL = 3; 71 % DFS and 75 % CSS), high (TALL = 4; 57 % DFS and 58 % CSS) and very high risk (TALL ≥ 5; 34 % DFS and 38 % CSS) using Kaplan-Meier survival analyses. TALL score was externally validated in a single-center cohort of 85 UTUC patients. Conclusions: We developed validated multivariable prognostic tools for prediction of locally advanced UTUC and oncological outcomes after RNU for UTUC. These prediction models can be used for patient counseling, selection for neoadjuvant/adjuvant systemic therapies and design of clinical trials.
A non-invasive urine exosome gene expression assay (ExoIntelliScore Prostate) to predict pathologic stage and grade in the prostatectomy specimen.
Authors: Donovan Michael , Eastham James Andrew , Patel Vipul , McKiernan James M , Noerholm Mikkel , Belzer Susan , Bentink Stefan , O'Neill Vince
Published: February 2017

46

Background: Non-invasive screening tools that add predictive value for identifying high-grade, Gleason score (GS) ≥7 should impact on the current diagnostic and subsequent treatment decision process. We have developed standardized processes to isolate exosomal-RNA from first-catch, non-DRE, urine specimens and have validated a three gene signature (ExoIntelliScore Prostate) that reliably differentiates GS7+ from GS6 and benign at the time of an initial biopsy. In addition to the biopsy outcomes, we sought to understand the performance of the assay in predicting objective pathology in the prostatectomy specimen. Methods: Pre-radical prostatectomy first-catch non-DRE urine specimens were collected from 5 urology practices (academic/community practices) without preservative, stored at 2-8C (up to 2 weeks) and shipped on ice to a central laboratory (Exosome Diagnostics, St. Paul, MN). Exosomes were isolated and RNA extraction performed. RT-qPCR RNA copy numbers of ERG and PCA3 were normalized to SPDEF. Spearman and Pearson correlation along with AUC was used to evaluate performance. Results: Pre-RP urine samples from 430 patients were collected: 16% GS6, 45% GS7 (3+4), 39% (>/=GS4+3) and 85% PSA <10 ng/mL. 359 patients had complete clinical and ExoIntelliScore Prostate assay results with comparable demographics. Importantly, the Exo106 significantly correlated with prostatectomy GS (p=0.025; Spearman’s rank-order). In addition, Exo106 significantly correlated with both tumor volume and pathologic stage (p=0.002, Pearson). Conclusions: A previously validated non-invasive urine exosome gene signature (ExoIntelliScore Prostate) accurately reflects what is present within the prostatectomy specimen with respect to grade, stage and tumor volume. Such information could be incorporated into the treatment decision process, including active surveillance.
Differential expression of FOXF1 in bladder cancer metastases and association with established bladder cancer subtypes.
Authors: Sundi Debasish , Choi Woonyoung , Jayaratna Isuru Sampath , McConkey David James , Dinney Colin P. N.
Published: February 2017

464

Background: FOXF1 is a transcription factor that may act as a tumor suppressor by interaction with p53. We identified FOXF1 to be highly differentially expressed in a discovery set of primary bladder cancers and matched nodal metastases. Here we study FOXF1 in preclinical models and define the association of FOXF1 with clinical bladder cancer phenotypes in several independent cohorts. Methods: Whole genome mRNA gene expression profiling (GEP) using Illumina HT12v3-4 chips was performed on paired primary tumors and nodal metastases from a cystectomy cohort. Among the top differentially expressed genes, FOXF1 was identified as a candidate regulator of cancer cell invasion. Murine orthotopic xenografts were established from human bladder cancer cell lines (UC-3, UC-14), and mRNA expression was assessed by real-time PCR. Four independent clinical cohorts with GEP data were subtyped as luminal, p53-like, or basal according to a validated gene expression signature (Choi et al., Cancer Cell2014). Associations between FOXF1 expression with survival after cystectomy (adjusted Cox models) and bladder cancer subtype (ANOVA) were assessed. High gene expression was defined as expression > median. Results: In the initial discovery set, FOXF1 expression was 3.6-fold lower in nodal metastases than paired primary tumors (n = 33, p < 0.001). Among xenografts with nodal metastases, FOXF1 expression was 1.4-fold lower in the metastases (n = 9, p = 0.0886). In two clinical cohorts (MDA Discovery n = 73 and GSE13507 n = 55), high FOXF1 expression was associated with improved cancer specific survival (HR = 0.35, p = 0.046) and overall survival (HR = 0.45, p = 0.006), respectively. In two other cohorts (MDA Validation n = 57 and GSE32894 n = 93), FOXF1 was not associated with survival after treatment. In all four cohorts, FOXF1 was most highly expressed in tumors subtyped as p53-like (p ≤ 0.0024 for all cohorts). Conclusions: FOXF1 is differentially expressed between primary and metastatic bladder cancer lesions. Across multiple independent cohorts, FOXF1 is more highly expressed among p53-like tumors known to be resistant to neoadjuvant chemotherapy, suggesting that this may be a novel predictive biomarker.
A multiplex immunoassay for the non-invasive detection of bladder cancer.
Authors: Rosser Charles Joel , Shimizu Yoshiko , Furuya Hideki , Bryant-Greenwood Peter , Chan Owen , Dai Yunfeng , Thornquist Mark , Goodison Steve
Published: February 2017

471

Background: Urine based assays that can non-invasively detect bladder cancer (BCa) have the potential to reduce unnecessary and invasive procedures. The purpose of this study was to develop a multiplex immunoassay that can accurately and simultaneously monitor 10 diagnostic urinary protein biomarkers for application as a non-invasive test for BCa detection Methods: A custom electrochemiluminescent (ECL) multiplex assay was constructed (Meso Scale Diagnostics, LLC, Rockville, MD) to detect the following urinary proteins; IL8, MMP9, MMP10, ANG, APOE, SDC1, A1AT, PAI1, CA9 and VEGFA. Voided urine samples from two cohorts (cohort #1 n = 62 and cohort #2 n = 200) were collected prior to cystoscopy and samples were analyzed blinded to the clinical status of the participants. Means (±SD) and receiver operating characteristic (ROC) curve analysis were used to compare assay performance and to assess the diagnostic accuracy of the diagnostic signature. Results: Comparative diagnostic performance analyses revealed an AUROC value of 0.9258 for the multiplex assay and 0.9467 for the combination of the single-target ELISA assays (p = 0.625), so there was no loss of diagnostic utility for the MSD multiplex assay. Analysis of the independent 200-sample cohort using the multiplex assay achieved an overall diagnostic sensitivity of 0.85, specificity of 0.81, positive predictive value 0.82 and negative predictive value 0.84. Conclusions: It is technically feasible to simultaneously monitor complex urinary diagnostic signatures in a single assay without loss of performance. The described protein-based assay has the potential to be developed for the non-invasive detection of BCa.
Comprehensive genomic profiling (CGP) of advanced nonseminomatous testicular germ cell tumors (NSGCT) to reveal clinically relevant genomic alterations (CRGA) to guide targeted therapy.
Authors: Elvin Julia Andrea , Patterson Christina , Chalmers Zachary Rockow , Ali Siraj Mahamed , Brennan Timothy , Chmielecki Juliann , Stephens Phil , Boyle L. Eamonn , Ross Jeffrey S. , Miller Vincent A.
Published: February 2017

477

Background: NSGCT, the most common solid malignancy in U.S. men ages 18-35, has a > 95% 5-year survival due to exquisite chemosensitivity; however, chemoresistant recurrences still contribute to 400 NSGCT deaths/year. We queried CGP results of the largest collection to date of recurrent NSGCT (n = 28) to identify targeted therapy options for this subset of high risk patients. Methods: DNA was extracted from 28 FFPE NSGCT clinical specimens. Hybridization captured libraries of 236 (FoundationOne, n = 20) or 305 (FoundationOne, n = 8) genes, plus select introns frequently rearranged in cancer were sequenced to high ( > 605x), uniform coverage. All classes of genomic alterations (GA; base subs, in/dels, rearrangements, and copy number alterations) were evaluated. CRGA were defined as GA associated with on-label targeted therapies and targeted therapies in mechanism-driven clinical trials. CGP coverage data was used to assess for chromosome 12p arm amplifications. Results: 28 samples (29% primary, 71% metastasis) from patients (avg 33.7 y) with recurrent NSGCT of predominant pattern of yolk sac tumor (43%), embryonal carcinoma (18%), choriocarcinoma (18%), or unspecified/mixed (21%) were profiled. 57% of NSGCT had chromosome 12p amplification ( > 6 copies). 89% had at least one GA not localized to chromosome 12p, including CRGA of CRKL (11%), MCL1 (11%), MDM2 (11%), GNAS (11%), KRAS (SV 7%), AURKA (7%), KIT (7%). CRGA in each of: AKT1, AKT2, BRAF, ERBB2, NF1, PIK3R2, PDGFRA, STK11 were identified in a single case. To date, we are aware of one patient in whom treatment with everolimus was initiated on the basis of the CGP results (inactivating point mutations in STK11 and PIK3R2) and who experienced marker stabilization lasting 5 months suggesting a biologic effect of this therapy. Conclusions: GA not accounted for by 12p amplification are present at a higher frequency than previously reported in recurrent or treatment-resistant NSGCT. The prevalence of CRGA and clinical response to targeted therapy in one such patient support the utility of CGP to identify additional therapeutic options for high risk NSGCT and warrants additional study.
Racial differences in treatment decision-making patterns and decisional regret in patients with localized prostate cancer.
Authors: Kim Daniel J. , Hurwitz Lauren , Cullen Jennifer , Hudak Jane , Colston Maryellen , Travis Judith , Elsamanoudi Sally , Rosner Inger L.
Published: February 2017

48

Background: Racial disparities in prostate cancer (PCa) incidence, health-related quality of life (HRQoL), treatment outcomes, and decisional regret have been reported. This study evaluated decision-making in African American (AA) and Caucasian (CA) patients with localized PCa to better understand HRQoL domains associated with post-treatment regret. Methods: This is a prospective cohort study evaluating patients with low- and intermediate-risk PCa in a racially diverse, equal access health-care setting who enrolled in a multidisciplinary clinic at Walter Reed National Military Medical Center. Demographic, clinical, and treatment outcomes data were collected. Validated questionnaires were administered, including the Control Preferences scale, Decision Regret scale (DRS), Expanded Prostate Cancer Index Composite (EPIC), and Medical Outcomes Study Short Form (SF36). Questionnaires were given at fixed intervals post-treatment. Results: A total of 297 (37.8%) AA and 489 (62.2%) CA patients were included in this study. AA patients were more likely to elect radiation therapy (RT) and less likely to elect radical prostatectomy (RP) or active surveillance. AA patients preferred more physician involvement in decision-making. Significantly higher regret was observed for AA patients after RP at 6 and 24 months, compared to CA patients. Only 6-month urinary bother was associated with regret in AA patients while, among CA patients, regret was associated with mental health and sexual bother. Among XRT patients, multiple HRQoL domains were associated with regret in AA patients, while only 36-month mental health was associated with regret in CA patients. Conclusions: Several key differences were noted across race in terms of HRQoL domains that were associated with patient regret. This cohort is now being followed for patient satisfaction with medical care. Such data may further help physicians tailor conversations with patients during treatment decision making to optimize HRQoL and minimize regret.
Comparison of survival outcomes for African American and Caucasian men with advanced penile cancer in Florida.
Authors: Ritch Chad , Pavan Nicola , Rai Samarpit , Soodana-Prakash Nachiketh , Balise Raymond R , Parekh Dipen , Gonzalgo Mark L.
Published: February 2017

490

Background: Studies suggest that there may be disparity in clinical outcomes for African−American men (AAM) compared to Caucasian men (CM) with penile squamous cell carcinoma (SCC). We sought to determine whether there was a survival difference for African American versus Caucasian men, particularly in locally advanced and metastatic cases of penile SCC where disease mortality is highest. Methods: Using the Florida Cancer Data System, we identified men diagnosed with penile SCC, from 2004 to 2014. We excluded men who were diagnosed on autopsy or at the time of death and with < 6 months of follow up. Demographic variables including: age, follow−up, stage, race and treatment type were compared between AAM and CM. Treatment type was categorized as surgery alone or surgery plus additional therapy (chemotherapy and/or radiation). For locally advanced and metastatic disease, we compared treatment type and overall survival (OS) between AAM and CM. A multivariable model was developed to determine significant predictors of OS. Results: Of the 653 men with penile SCC, 198 [38 (19%) AAM and 160 (81%) CM] had locally advanced and/or metastatic disease. Median follow up for the entire cohort was 12.5 mos. For all stages, AAM demonstrated a significantly decreased median OS compared to CM (26 vs. 37 mos, p=0.03). For locally advanced and metastatic disease, there was a persistent, but non−significant, trend toward disparity in median OS between AAM and CM (17 vs. 23 mos, p=0.06). Fewer AAM compared to CM received surgery plus additional therapy for locally advanced and/or metastatic disease [8 (21%) vs. 42 (26%)], but this difference was not statistically significant. After adjusting for age, stage, and treatment type, AAM had increased likelihood of death from penile SCC (HR 1.63, p=0.015). Conclusions: Mortality rates from penile SCC remain high in contemporary series. For AAM in Florida, advanced stage at presentation, along with treatment disparity, may partially explain decreased survival rates. Further studies are needed to determine the additional socioeconomic, as well as potential biologic, factors that may predict the relatively poor outcome observed in AA men with penile SCC.
Incidence and severity of prostate cancer in 360 hypogonadal men treated with testosterone undecanoate injections (TU) for up to 8 years and 296 untreated hypogonadal controls.
Authors: Haider Ahmad , Haider Karim Sultan
Published: February 2017

50

Background: Testosterone therapy (TTh) in middle-aged and elderly men is still associated with concerns regarding prostate cancer (PCa). In this registry study, we investigated the incidence of PCa in hypogonadal patients on long-term treatment with TU in comparison to an untreated hypogonadal control group (CTRL). Methods: In a cumulative registry study, 360 men (mean age: 57.37±7.29 years, range: 33-70) with testosterone (T) ≤12.1 nmol/L received TU 1000 mg every 12 weeks following an initial interval of 6 weeks for up to 8 years. 296 hypogonadal men (mean age: 64.79±4.28 years, range: 57-74) decided against TTh, mainly due to financial reasons. Prostate volume (PV) and PSA were measured and digital rectal examination (DRE)/ transrectal ultrasound (TRUS) performed before treatment initiation and then regularly every 3-6 months. Biopsies were performed when indicated according to EAU guidelines. Results: From baseline to 8 years, PV increased from 29.24±10.38 to 31.13±11.45 ml in the T group and remained stable from 34.45±5.89 to 33.51±12 in CTRL. PSA increased slightly from 1.74 ± 0.93 to 1.83±0.93 ng/ml in the T group and remained stable from 2.25±1.34 to 2.19±1.17 in CTRL. In T-treated patients, 7 men (1.9%) were diagnosed with PCa. In the control group, 12 (4.1%) were diagnosed with PCa. The incidence per 10,000 years was 30.05 in the T group and 63.54 in CTRL. The mean age of PCa patients was 64 years in the T group and 65 years in CTRL. All patients underwent radical prostatectomy. The predominant Gleason score was 3 in all patients in the T group, lymph nodes and surgical margins were negative. In CTRL, three men had a predominant Gleason score of 3, 8 had 4, and 1 had 5. 7 patients had positive lymph nodes and no patient had a positive surgical margin. Conclusions: Long-term treatment with TU in hypogonadal men undergoing regular monitoring according to EAU guidelines does not increase the incidence of PCa in comparison to an untreated hypogonadal CTRL group. PCa was more severe in the CTRL group.
T-cell receptor (TCR) repertoire in metastatic renal cell carcinoma (RCC) patients treated with first-line vascular endothelial growth factor receptor blockade.
Authors: Ho Thai Huu , Gagnon Robert Charles , Liu Yuan , Hodi F. Stephen , Signoretti Sabina , Choueiri Toni K.
Published: February 2017

501

Background: Reports have demonstrated an inverse relationship between suppression of immune surveillance mechanisms and activation of the vascular endothelial growth factor receptor (VEGFR) pathway suggesting that T cell repertoires may impact response to VEGFR blockade. We evaluated the association between clinical outcomes and T cell repertoire in metastatic RCC patients receiving a front-line anti-VEGFR, pazopanib. Methods: Pre-treatment RCC tumors were analyzed from VEG105192, a phase III study of mRCC patients randomized (2:1) to pazopanib (paz) 800 mg daily vs placebo (pbo) for TCR gamma (TCRG) and TCR beta (TCRB) CDR3 regions. Using the Adaptive Biotechnologies immunoSEQ Assay, we assessed TCR clonality, a measure of total repertoire represented by expanded clones, and entropy, a measure of evenness and diversity. PD-L1 was evaluated by immunohistochemistry (IHC) H-Scores. The goal of the study was to determine if the repertoire of T cell clones was associated with progression-free survival as a clinical endpoint. Results: In the cohort with available tissue, the median PFS was 10.8 and 5.5 months (mos) for paz and pbo, respectively. TCRB (n = 114) and TCRG (n = 43 pbo, 109 paz) clonality ranged from 0-0.31 and 0-0.98, and entropy from 1-12.1 and 0-10.37, respectively. TCRB and TCRG entropy were highly correlated (Spearman’s R = 0.92, n = 114). Samples from the pbo-treated group with higher TCRG entropy, defined as the top 25th percentile, were associated with an improved median PFS (12.8 months) when compared to the lower 75th percentile (3.1 months, P = 0.023); similar trends were seen for TCRB entropy. Neither entropy nor clonality was associated with maximal reduction in tumor volume in the paz-treated group. PD-L1 H-scores were not associated with entropy or clonality (P > 0.05). Conclusions: Our data suggests that RCC samples with higher entropy are associated with a favorable prognosis. Identification of tumors with restricted TCRB/G chain usage and less diverse repertoire, as represented by lower entropy and higher clonality, may impact responses to VEGFR blockade and requires further study. Clinical trial information: NCT00334282.
Combined DNA-methylation intensity and clinical risk score to stratify patients for high-grade disease.
Authors: Van Neste Leander , Stewart Grant , Gaston Sandra Marlene , Grizzle William E. , Adams George W. , Kearney Gary P , Epstein Jonathan I , Harrison David James , Partin Alan W. , Van Criekinge Wim
Published: February 2017

51

Background: Prostate cancer (PCa) diagnostics remains challenging due to fear of over-diagnosis and overtreatment. Due to low accuracy of PSA too many men are biopsied that do not have a subsequent PCa diagnosis or that have indolent disease. Furthermore, persistent risk factors and fear of missed PCa leads to many unnecessary repeat biopsies. Most prostate tumors have epigenetic DNA-methylation aberrations, which display a field effect that can be observed in normal-appearing surrounding tissue, and that could help alleviate biopsy-sampling errors. Methods: A training cohort of methylation-positive men with a negative index biopsy followed by either a Gleason score (GS) ≥ 7 (n=43) or cancer-negative (n=226) repeat biopsy was evaluated. Using the initial negative biopsy, men were stratified for the likelihood of harboring high-grade PCa focusing on a methylation intensity algorithm involving GSTP1, RASSF1 and APC. This algorithm was validated in a cohort of 102 men, with either a PCa-free (n=20), GS6 (n=46), or GS≥7 (n=36) biopsies. Results: The methylation intensity-based algorithm was developed on PCa-negative index biopsies and optimized to predict the presence of GS≥7 cancer in a repeat biopsy. The methylation intensity was significantly higher in GS≥7 compared to PCa-free repeat biopsies (p<0.001). Men with GS6 PCa detected upon repeat biopsy exhibited intermediate intensities. When combined into one model with clinical risk factors (age, pathology, DRE, PSA), an area under the curve (AUC) of 0.762 was obtained, which was significantly higher than the AUC of PSA (0.574; p=0.004) or the AUC of the clinical risk as calculated by the PCPT risk calculator (0.618; p=0.029). In the validation set, an AUC of 0.818 was obtained, with higher intensities for men with GS≥7 disease compared to men with GS6 PCa (p=0.002). Conclusions: The risk score can identify clinically significant cancer in PCa-negative biopsies and is strongly correlated with the GS of PCa-positive biopsies. The risk score could better stratify men for the need for repeat biopsy and the risk of harboring occult clinically significant PCa. The same algorithm could be used to segregate likely under-graded men from active surveillance candidates.
Single-institutional analysis of patients with clear-cell papillary renal cell carcinoma.
Authors: Casuscelli Jozefina , Winer Andrew G. , Reznik Eduard , Xu Jianing , Manley Brandon , Chouhan Jyoti , Reuter Victor E. , Tickoo Satish , Russo Paul , Coleman Jonathan A. , Hsieh James , Hakimi A. Ari
Published: February 2017

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Background: Recently clear cell papillary renal cell carcinoma (cpRCC) has been recognized as new histologic subtype with immunohistochemical profiles that differentiate it from clear cell (ccRCC) and papillary (pRCC) RCC. Several previous studies highlighted the indolent behaviour of this entity in the reported cases. Our primary objective is to further elucidate the genomic and clinical characteristics of cpRCC. Methods: 44 patients with cpRCC were selected from the MSKCC database with surgery performed between 2007 and 2014. Only tumors with appropriate histological configuration and immunohistochemically confirmed CAIX and CK7 positivity and CD10 negativity were included. Whole exome sequencing (WES) was performed on 5 cpRCC tumor samples and one sample was analyzed by next-generation sequencing (MSK-IMPACT). A further comparison was made to 825 ccRCC and 219 pRCC tumors with initial pT1 diagnosis from our institutional database. Differences in the variables across groups were analyzed with the Chi-Square and the Kruskal–Wallis tests. To visualize and test the survival distribution differences, we used Kaplan–Meier plots and Log-rank tests. Results: Sequencing did not reveal VHL mutations or other known driver mutations commonly seen in ccRCC or pRCC and no recurrent mutations were identified. The median follow up period for cpRCC was 27 months, for ccRCC 59 months and for pRCC 63 months. cpRCC frequently co-occured with ccRCC or other RCC subtypes (17/44 cases). Female patients developed cpRCC significantly more frequently than ccRCC or pRCC (47.7% P<0.001) and Kruskal-Wallis test revealed differences in tumor size between the 3 groups (cpRCC median size 2.5 cm, P<0.001). Recurrence, metastatic development and death from kidney cancer was observed in ccRCC (3.7%, 2.3% and 0.8%) and in pRCC (4.5%, 1.8% and 2%), but not in the cpRCC cohort. Conclusions: cpRCC is genomically distinct from ccRCC and pRCC and lacks driver mutations commonly associated with aggressive disease. The tumors tend to present smaller than other RCC subtypes, commonly co-occur with other RCCs and disproportionately affect women. Extended follow-up of larger cohorts is necessary to confirm the true indolent nature of cpRCC.
Early tumor shrinkage under first-line tyrosine kinase inhibitor as a surrogate endpoint of overall survival in patients with metastatic renal cell carcinoma.
Authors: Miyake Hideaki , Harada Ken-ichi , Fujisawa Masato
Published: February 2017

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Background: The objective of this study was to assess the prognostic impact of early tumor shrinkage induced by first-line tyrosine kinase inhibitors (TKIs) on overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC). Methods: This study included a total of 185 consecutive Japanese patients with mRCC, consisting of 120 and 65 who were treated with sunitinib and sorafenib, respectively, for at least 3 months as first-line therapy. Prognostic outcomes in these 185 patients were retrospectively assessed focusing on the significance of tumor shrinkage at 12 weeks after the introduction of TKIs as a predictive factor of OS. Results: As the best responses to TKIs, 3, 40, 105 and 37 were judged to show a complete response, partial response, stable disease and progressive disease, respectively. The median progression-free survival (PFS) and OS in the 185 patients was 7.3 and 33.6 months, respectively. At 12 weeks after the introduction of TKIs, 9 patients reached a tumor shrinkage from -100 to -50%, 42 patients from -49 to -25%, 59 patients from -24 to 0%, and the remaining 70 patients had a gain of tumor size or new metastatic lesions. The median OS stratified according to tumor shrinkage at 12 weeks after the introduction of TKIs as shown above was 59.2, 39.1, 27.8 and 19.1 months, respectively. Univariate analysis identified the Memorial Sloan-Kettering Cancer Center (MSKCC) classification, Heng risk classification, C-reactive protein (CRP) level, lymph node metastasis, bone metastasis, liver metastasis, number of metastatic organs, histological subtype, sarcomatoid feature, PS and tumor shrinkage as significant predictors of OS. Of these significant factors, only the MSKCC classification, CRP level, liver metastasis and tumor shrinkage were shown to be independently associated with OS by multivariate analysis. Conclusions: These findings suggest that tumor shrinkage at 12 weeks after the introduction of TKIs was shown to have a significant impact on the OS in mRCC patients; therefore, early tumor shrinkage could be used as a reliable surrogate endpoint of OS in patients with mRCC receiving TKI as first-line agent.
Impact of metformin on outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC): Results from a pooled clinical trials database.
Authors: Hamieh Lana , McKay Rana R. , Mickey Suzanne S , Lin Xun , Simantov Ronit , Choueiri Toni K.
Published: February 2017

531

Background: Metformin has been shown to confer anti-neoplastic properties in several tumor types. Its effect on outcomes in mRCC patients has not been completely characterized. In this study, we evaluated the role of metformin on survival outcomes in pts with mRCC. Methods: We conducted a retrospective study of pts with mRCC treated on several phase II and III clinical trials from 2003-2013. We analyzed overall survival (OS) in the metformin users versus non-users using the Cox regression model and the Kaplan-Meier method. Results: We identified 4,736 pts with mRCC including 486 diabetic pts of whom 218 (4.6%) were metformin users. The majority were <65 years of age (69%), male (71%), with clear-cell histology (89%) and prior nephrectomy (70%). With regard to IMDC risk groups, 14%, 42%, and 24% had favorable, intermediate, and poor-risk disease, respectively. Pts received treatment with sunitinib (n=1,059), sorafenib (n=772), axitinib (n=896), temsirolimus (TEM) (n=457), TEM + interferon (IFN)-α (n=208), bevacizumab (BEV) + TEM (n=393), BEV + IFN-α (n=391), or IFN-α (n=560); overall 3,044 (64%) received first-line therapy. In the total cohort, metformin use did not impact OS when compared to users of other anti-diabetic agents (p=0.17) or non-diabetics (p=0.69). In diabetic pts, metformin use did not confer a survival advantage when stratified by type of therapy and IMDC risk group. However, in the cohort of diabetic pts receiving sunitinib (n=128), metformin use was associated with an improvement in OS when compared to users of non-metformin anti-diabetic agents (29.3 versus 20.9 months, respectively, p=0.0008, HR 0.051, 95% CI 0.009, 0.292). Conclusions: This is the largest study to date investigating the role of metformin on outcomes in mRCC pts. In this analysis, we demonstrate that concomitant use of metformin may improve survival in diabetic pts with mRCC treated with sunitinib. Based on preclinical data, we hypothesize that the mechanism underlying this survival benefit may be related to synergistic inhibition of the MAPK pathway. However, the study is limited by the small number of diabetic patients. Larger prospective studies are warranted to validate these results.
Who could be appropriate candidates for partial nephrectomy in localized renal cell carcinoma? Selection by preoperative factors.
Authors: Nagao Kazuhiro , Sakano Shigeru , Fujii Nakanori , Kobayashi Keita , Inoue Ryo , Yamamoto Yoshiaki , Matsumoto Hiroaki , Matsuyama Hideyasu ,   Yamaguchi Uro-Oncology Group
Published: February 2017

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Background: Chronic kidney disease (CKD) is a risk factor for the cardiovascular disease, which affect to the patients’ survival, while an EORTC randomized control trial did not show superiority of partial nephrectomy (PN) against localized renal cell carcinoma (RCC) in overall survival compared to radical nephrectomy (RN). We aimed to evaluate the role of operative methods affecting the survival and tried to estimate a predictive model for high risk CKD after surgery. Methods: We reviewed the data of 357 cases with clinical T1 RCC treated by RN (292 cases, RN group) or PN (65 cases, PN group) at Yamaguchi University Hospital or its related hospitals. We supposed the cases with CKD stage 3b or higher after surgery as high risk CKD. And we set the primary endpoints as the ratio of the cases with high risk CKD and overall survival after surgery. Results: Median follow-up period after surgery was 70 months (3-161). Statistically significant difference in performance status and clinical T stage were observed between the groups, but not in other patients’ characteristics. Mean values of preoperative eGFR were 69.2 and 65.5 ml/min/1.73m2 in RN and PN group, which decreased to 46.0 and 57.9 at 5 years after surgery, respectively. There was a significant difference in the incidence of high risk CKD between RN (39.3%) and PN group (2.2%) at 5 years after surgery. During follow up period, 17 cases (4.4%) were inducted to dialysis, there was no difference in the incidence between the RN and PN group. Multivariate analysis showed that eGFR ( < 72 ml/min/1.73m2; Odds ratio 15.3), proteinuria (Odds ratio 3.84), smoking (Odds ratio 2.76), BMI ( > 23; Odds ratio 2.66) and age ( > 67 years old; Odds ratio 2.47) could be significant predictive factors for high risk CKD at 5years after surgery. Our predicting model for high risk CKD showed 86.8% of sensitivity and 74.8% of specificity. But there was no significant difference in overall survival between the RN and PN group. Conclusions: Although there was a significant difference in the incidence of high risk CKD between RN and PN group, operative methods did not affect to the survival. Postoperative high risk CKD could be predictable by preoperative clinical factors.
Archexin, a novel AKT-1–specific inhibitor for the treatment of metastatic renal cancer: Preliminary phase I data.
Authors: Tagawa Scott T. , Chatta Gurkamal S. , Mazhari Reza , Benaim Ely
Published: February 2017

550

Background: Archexin (RX-0201) is a 20-mer oligonucleotide that is complementary to AKT-1 messenger ribonucleic acid (mRNA). The specificity of Archexin's effect on AKT-1 mRNA levels was examined in human renal cell carcinoma (von Hippel-Lindau protein-deficient renal cell carcinoma cell line) UMRC2 cells and resulted in decreased AKT-1 mRNA levels. Methods: The current study is a proof of concept phase Ib/2, multicenter, open label 2-stage study for subjects who progressed on at least 1 VEGF-targeted therapy. Stage 1 is an open-label, dose-escalation phase Ib study of Archexin administered in combination with everolimus. Archexin is administered by a 24 hour continuous intravenous infusion for 14 days followed by 7 days of rest. It is hypothesized that 250 mg/m2/day or a lower dose of Archexin will be identified as safe and well-tolerated when administered in combination with 10 mg of everolimus. The dose of Archexin identified in Stage 1 will be studied further in Stage 2 which is the randomized, open-label, 2-arm study of Archexin in combination with 10 mg of everolimus versus 10 mg of everolimus alone. Plasma concentrations were measured using a validated LC-MS/MS assay, and noncompartmental pharmacokinetic parameters were calculated using WinNonlin, Version 6.4. Results: Five subjects with metastatic clear cell renal carcinoma received 125 mg/m2/day (n = 3) or 200 mg/m2/day (n = 2) of Archexin with 10 mg of everolimus administered daily. Two subjects have had stable disease for 160 and 257 days. The most frequently reported treatment related adverse events for the combination were thrombocytopenia, vomiting and fatigue; no dose limiting toxicities have been reported currently. At all dose levels post-infusion, Archexin plasma concentrations increased rapidly and quickly reached a virtual plateau. Upon cessation of infusion on Day 14, plasma concentrations declined rapidly. Conclusions: At the dose levels tested, Archexin, in combination with everolimus, appears to be well tolerated in patients with metastatic renal cancer. Dose escalation/modification is ongoing to determine the recommended phase II dose of Archexin to be studied further in Stage 2 (randomized) when combined with everolimus. Clinical trial information: NCT02089334.