bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations between health-related quality of life and physical activity in bladder cancer survivors: A cross-sectional study.
Authors: Gopalakrishna Ajay , Fantony Joseph J , Longo Thomas Andrew , Inman Brant Allen
Published: February 2017

432

Background: Physical activity has been shown to significantly improve health-related quality of life (HRQOL) and survivorship in a variety of cancer patients. However, little is known about the physical activity patterns of bladder cancer survivors and how these are related to HRQOL in the United States. Our objective was to describe HRQOL and self-reported physical activity patterns and examine the association between these measures in a large cohort of bladder cancer survivors. Methods: Bladder cancer survivors identified through an institutional database were mailed a survey that included the Functional Assessment of Cancer Therapy Bladder Cancer (FACT-Bl) and the International Physical Activity Questionnaire (IPAQ-L). Results: A total of 466 subjects (49% response rate) completed the survey. The mean age was 73 years, 80% were male, and 88% were White. Linear regression indicated a positive correlation between physical activity and physical well being (PWB, P < 0.001), emotional well being (EWB, P < 0.001), and functional well being (FWB, P < 0.001) subscales, as well as the FACT-Bl (P < 0.001), FACT general (P < 0.001), and trial outcome index (TOI, P < 0.001) composite scores. Conversely, total daily sitting time was negatively correlated with all of the aforementioned indices. Adjusting for demographic factors did not alter the findings. Conclusions: Physical activity is positively associated with HRQOL in bladder cancer survivors. Further studies investigating the causal relationship between physical activity and HRQOL in the post-treatment setting in bladder cancer survivors are warranted.
Correlation of myeloid derived suppressor cell (MDSC) populations with clinicopathologic features in urothelial carcinoma (UC).
Authors: Ornstein Moshe Chaim , Diaz-Montero C. Marcela , Rayman Pat A. , Elson Paul , Haywood Samuel , Finke James , Garcia Jorge A. , Rini Brian I. , Stephenson Andrew J. , Campbell Steven C. , Fergany Amr Farouk , Emamekhoo Hamid , Lamenza Marcelo , Stybor Sylvia , Schach Kim , Profusek Pam , Tyler Allison Janine , Ernstoff Marc S. , Grivas Petros
Published: February 2017

434

Background: MDSC are a heterogeneous population of potent immunosuppressive cells with potential predictive/prognostic significance in solid tumors. The association between MDSC and clinicopathologic features in patients (pts) with UC was investigated. Methods: Peripheral blood from 26 non-metastatic UC pts scheduled to undergo cystectomy or nephroureterectomy at Cleveland Clinic was collected. MDSC were enumerated in fresh unfractionated blood (WB) and in peripheral blood mononuclear cells (PBMC). (T)otal MDSC were defined as CD33+/HLADR-; out of T-MDSC, (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+) and (I)mmature (CD15-CD14-) MDSC were identified. CD11b MDSC (Linlo/HLADR-/CD33+/CD11b+) were identified in WB. MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Wilcoxon rank sum test was used to assess associations between MDSC populations and clinicopathologic features. Due to the exploratory nature of the study, p < .10 was considered significant. Results: Of 26 pts, 25 had surgery and 1 is under surveillance. 24 had both WB and PBMC data. 23/26 were men; median age 67. Of 26 pts, all had primarily UC histology; 7 had mixed UC histology, 11 had prior intravesical BCG, 12 neoadjuvant therapy (10 Gem/Cis, 1 Gem/Carbo, 1 unknown). Of 25 pts who had surgery, 5 had pT3/4 stage; 5 had LVI; 9 had CIS. All but 1 had negative LN. Higher levels of specific WB MDSC populations were associated with mixed histology (including squamous), CIS, and higher pT-stage (Table). When compared to a separate cohort of 11 pts with metastatic UC, the % G-MDSC in PBMC was lower in non-metastatic pts (median 0.3 vs. 1.47; p = .05). Conclusions: Although no single MDSC population correlated with all the evaluated clinicopathologic features, higher levels of certain MDSC populations appear to correlate with histology and pT stage. Further validation of blood and tissue is ongoing in a larger cohort. [Table: see text]
External beam radiotherapy and concurrent gemcitabine for muscle-invasive bladder cancer: Toxicities and early outcomes.
Authors: Nack Elana , Rosenberg Jonathan E. , Bochner Bernard H. , Dalbagni Guido , Zelefsky Michael J. , Kollmeier Marisa
Published: February 2017

443

Background: To report toxicities and early outcomes of external beam radiotherapy (EBRT) with concurrent gemcitabine for muscle-invasive bladder cancer (MIBC) Methods: Between 9/04 - 4/15, 85 patients (median age 77) with MIBC (cT2-T4, Nx-3) underwent transurethral resection (TUR) (39 complete, 43 incomplete, 2 unknown) followed by EBRT (median dose 64.8Gy) with concurrent gemcitabine (20-27 mg/m2) twice weekly. 25 patients (29%) received neoadjuvant chemotherapy. Patients were followed q3 months with imaging, cystoscopy and/or cytology. Early ( < 90 days) and late ( > 90 days) toxicities were graded according to the Common Terminology Criteria for Adverse Events (v4.0). Median followup was 19.5 months; 74 (87%) had > 3 month followup. Kaplan-Meier and Cox regression were used for survival and multivariate analyses. Results: Acute grade ≥ 3 hematologic, gastrointestinal or genitourinary toxicity occurred in 18%, 1.5% and 1.3% of patients, respectively. 73/85 (86%) patients received full EBRT course without interruption. 78/85 (92%) received > 50% of the prescribed gemcitabine. The most common reason for a gemcitabine interruption/dose reduction was hematologic (80%). Late grade 3 toxicity included hematuria (n = 5), urinary obstruction (n = 4) and cystitis (n = 1). The 2-year freedom from in-bladder recurrence and bladder-intact survival was 53% and 60%, respectively. The 2-year distant metastasis-free, disease-specific and overall survivals were 66%, 69% and 62%, respectively. A complete TUR was associated with improvements in 2 year bladder-intact (73% vs 51%, p = 0.01), disease-specific (87% vs 54%, p = 0.001), distant metastasis-free (83% vs 52%, p < 0.0001) and overall survival (78% vs 50%, p = 0.003) compared with incomplete TUR. Neoadjuvant chemotherapy and nodal status had no significant impact on survival outcomes. Conclusions: EBRT with concurrent gemcitabine is well-tolerated for MIBC, even in an elderly population. Hematologic (acute) and genitourinary (late) toxicities are most common. Survival outcomes in this unselected population are comparable to prior trials, although longer followup is needed. A complete TUR prior to chemoradiation is strongly recommended.
Incidence, timing, and risk factors for infection after radical cystectomy: Results from the National Surgical Quality Improvement Program.
Authors: Parker William P. , Tollefson Matthew K. , Heins Courtney N. , Habermann Elizabeth B. , Zaid Harras B. , Frank Igor , Thompson Robert Houston , Boorjian Stephen A.
Published: February 2017

445

Background: Radical cystectomy (RC) is the gold standard treatment for muscle-invasive and high-risk non-muscle invasive bladder cancer. However, the procedure has been associated with a high complication rate, including perioperative infection. In addition to resulting in patient morbidity, infections have been suggested as a quality metric. We sought to evaluate the incidence, risk factors, and timing of infection following RC. Methods: The National Surgical Quality Improvement Program (NSQIP) database was queried to identify patients undergoing RC for bladder cancer from 2005-2013 using CPT procedure and ICD-9 diagnosis codes. Infections (urinary tract infection (UTI), surgical site infection (SSI), and sepsis) within 30 days of RC were recorded. Characteristics including age, gender, ethnicity, body-mass index, diabetes, smoking status, renal function, steroid usage, albumin, receipt of perioperative transfusion, and operative time were abstracted, and relative risk of infection was assessed in univariate chi-squared analysis. Results: A total of 3,187 patients were identified, of whom 2604 (81.8%) were male, with a median age of 68.8 years (IQR 62, 77). Postoperative infection was diagnosed in 766 (24%) patients, at a median of 13 days (IQR 8, 19) after RC, with 44.4% occurring prior to hospital discharge. The most common type of infection was SSI (404; 12.7%), followed by sepsis (315; 9.9%), and UTI (309; 9.7%). Factors associated with increased overall infection risk were obesity (RR 1.32; 1.20-1.46; p < 0.001), receipt of a blood transfusion (RR 1.20; 1.10-1.31; p < 0.001), and increased operative time (RR for > 450 min 1.46; 1.26-1.70; p < 0.001). Risk factors for UTI in particular included obesity (RR 1.28; 1.11-1.47; p < 0.001), diabetes (RR 1.38; 1.09-1.75; p = 0.009), and increased operative time (RR for > 450 min 1.45; 1.18-1.78; p < 0.001). Conclusions: Approximately 25% of patients undergoing RC experience an infection within 30 days of surgery, most commonly SSI. Several modifiable risk factors were identified, including blood transfusion and prolonged operative time, that represent potential targets for care improvement.
Programmed death-ligand 1 (PD-L1) characterization of circulating tumor cells (CTCs) and white blood cells (WBCs) in muscle invasive and metastatic bladder cancer patients.
Authors: Anantharaman Archana , Friedlander Terence W. , Lu David , Krupa Rachel , Premasekharan Gayatri , Hough Jeffrey , Edwards Matthew , Graf Ryon , Jendrisak Adam , Louw Jessica , Dugan Lyndsey , Marrinucci Dena C. , Dittamore Ryan Vance , Paris Pamela
Published: February 2017

446

Background: Recent studies indicate that PD-1 and PD-L1 checkpoint inhibitors have activity in chemotherapy refractory patients with muscle invasive (MIBC) and metastatic (mBCa) bladder cancer. PD-L1 expression on tumor cells or lymphocytes may correlate with response to therapy. To identify potential patients who may benefit from PD-1/PD-L1 targeted immunotherapeutics, we utilized a non-invasive blood test to evaluate PD-L1 protein expression in CTCs and WBCs of bladder cancer patients. Methods: Whole blood from 20 patients with MIBC or mBCa were collected and shipped to Epic Sciences. All nucleated cells were plated onto glass slides and subjected to immunofluorescent (IF) staining and CTC identification using scanners and algorithmic analysis. CTCs, defined as traditional (CK+ CD45- w/ intact DAPI+ nuclei and morphologically distinct) or CK- (CK-, CD45-, DAPI+, intact and distinct) were identified. PD-L1 biomarker characterization was assessed by IF staining. UroVysion FISH testing was used to assess genomic abnormalities in a subset of patient samples. Additionally, WBCs (CD45+ cells) were assessed for PD-L1 expression, relative to healthy controls. Results: Eighty percent of patients had mBCa and 20% had MIBC, 70% percent were men, and themedian age was 67 years, (range 43 to 88). Traditional CTCs were detected in 11/20 (55%) patients. Seven out of 20 (35%) patients had PD-L1+ cells, 4 of these patients had exclusively CK-/PD-L1+ CTCs, a subset of which were confirmed as malignant via FISH. CK- CTCs were detected in 14/20 (70%) patients. Five patients had greater than 4-fold PD-L1 positivity in WBCs as compared to healthy donors. Conclusions: Patients with MIBC and mBCa patients have detectable, heterogeneous CTCs with a population of CK-/PD-L1+ CTCs. Utilization of a liquid biopsy to identify patients with PD-L1+ CTCs and PD-L1+ WBCs may enable patient selection or short term therapeutic monitoring for measuring therapeutic efficacy. Further work will investigate association of PD-L1+ CTCs and WBCs with clinical response to PD-1 checkpoint immunotherapy.
uPAR and mTORC2 as coupled targets for therapeutics development in bladder cancer.
Authors: Hau Andrew M. , Gilder Andrew , Hu Jing-jing , Gonias Steven L. , Hansel Donna E.
Published: February 2017

447

Background: Bladder cancer currently ranks as the fifth most common and the single most expensive cancer to manage in the United States. Although it is established that invasive behavior is a major predictor of diminished outcomes for patients with bladder cancer, the molecular mechanisms governing bladder cancer cell invasion are not well understood. The urokinase receptor (uPAR) and mammalian target of rapamycin complex 2 (mTORC2) represent two powerful pro-invasion candidates that have increased expression in high-grade, invasive bladder cancer, though the former has not been characterized in detail in bladder cancer. Therefore, the aims of this study are to characterize the uPAR signaling network and delineate the signaling interplay between mTORC2 and uPAR in bladder cancer. Methods: Using immunoblot and RT-qPCR analyses, we evaluated uPAR expression in a panel of immortalized bladder cancer cell lines: UROtsa, RT4, UMUC3, T24 and J82. uPAR influence on mTORC1 and mTORC2 signaling was determined by immunoblot analysis following targeted gene-silencing of uPAR using siRNA. Additionally, the effects of uPAR knockdown on cell migration and invasion were investigated using modified scratch-wound migration and transwell invasion assays. Lastly, signaling interplay between uPAR and mTORC2 was investigated by evaluating the effects of uPAR and mTORC2 silencing on Rac1 activity. Results: uPAR knockdown in a subset (T24 and J82) of invasive bladder cancer cell lines inhibited mTORC2, but not mTORC1, activity as measured by P-AKT S473 and P-S6 levels. We found that uPAR silencing in T24 and J82 cells resulted in significant reductions in cell migration and invasion through Matrigel. This is likely attributed to inhibition of Rac1 and decreased lamellipodia formation. Conclusions: Collectively, our results identify uPAR and mTORC2 as major regulators of bladder cancer cell invasion and that these two systems are linked through Rac1. Further investigation of uPAR and mTORC2 inhibition using uPAR-targeting antibodies and mTOR inhibitors in an in vivo mouse model of bladder cancer will determine if these signaling pathways are therapeutically beneficial for the treatment of bladder cancer.
miRNA expression profiles in high-grade prostatic intraepithelial neoplasia.
Authors: Eminaga Okyaz , Woetzel Fabian , Fries Jochen , Neiss Susanne , Heitmann Michaela , Engelmann Udo , Heidenreich Axel , Warnecke-Eberz Ute
Published: February 2017

45

Background: High-grade prostatic intraepithelial neoplasia (HGPIN) is widely believed to be a precursor of prostate cancer (PCa). However, little is known about the expression of miRNAs variations in HGPIN compared to normal tissues and PCa. Methods: The expression data of 1054 miRNAs from TCGA were applied to identify relevant miRNAs associated with tumor progression (i.e., miR-98-5p, miR-183-5p, 345-5p, miR-143 miR-210-3p and miR-378-3p). miRNA were isolated by miRNeasy FFPE kit (Qiagen, Hilden, Germany) from paraffin-embedded tissues (FFPE) of prostate specimens with PCa, HGPIN and normal tissues. Early-stage PCa was defined as PCa with pT2 tumor stage, Gleason score <=7a (3+4) and PSA level <10 ng/ml. Quantitative miRNA expression data were acquired and analyzed using a real-time TaqMan-based PCR with the ABI Prism 7900HT (Life Technologies, Darmstadt, Germany). ANOVA analysis were performed to evaluate the expression of miRNAs between HGPIN, Normal and PCa tissues. All statistical analysis was performed using SPSS (IBM, Armonk, USA). P values were adjusted using the false discovery rate for multiple comparisons. The small nuclear U6 RNA was used as an endogenous control. Results: The expression of miR-143-3p, miR-210-3p and miR-345-5p and miR-98-5-p were varied between normal tissue, HGPIN and early-stage PCa. Interestingly, decrease in expression of miR-143.-3p, miR-98-5p and miR-210-3p was associated with tumor development (Normal tissues > HGPIN > early-stage PCa) (FDR<0.001). Furthermore, overexpression of miR-345-5p was observed in normal tissues compared to HGPIN and early-stage PCa, which both showed similar expression level of miR-345-5p. No significant differences in expression of miR-375, miR-183-5p and miR-378-3p were observed between HGPIN and PCa. These miRNAs were interacted with genes related to HIF-1 signaling pathway, p53 signaling pathway, androgen receptor signaling pathway, intrinsic apoptotic signaling pathway, RNA transcription, homologous recombination and non-homologous end-joining. Conclusions: HGPIN shows an altered expression of miRNAs interact with genes related to hypoxia, androgen receptor signaling pathway, cell cycle and epigenetic regulation.
Impact of multidisciplinary bladder cancer care for muscle invasive bladder cancer: A propensity score matched analysis of survival outcomes.
Authors: Kulkarni Girish S. , Hermanns Thomas , Li Kathy , Wei Yanliang , Bhindi Bimal , Kuk Cynthia , Sridhar Srikala S. , van der Kwast Theodorus , Chung Peter W. M. , Bristow Robert G. , Warde Padraig Richard , Milosevic Michael F. , Fleshner Neil Eric , Jewett Michael A.S. , Zlotta Alexandre
Published: February 2017

455

Background: We started in 2008 a Multidisciplinary Bladder Cancer Clinic (MDBCC), where complex bladder cancer patients are assessed concurrently by urologic and radiation oncologists, with support from medical oncologists. Patients have the opportunity to discuss various treatment options including radical cystectomy (RC) or bladder sparing trimodal therapy (TMT; endoscopic resection, radiotherapy and chemotherapy). Although reports have shown comparable outcomes of TMT to cystectomy, no direct comparison to RC has been published and no randomized studies are available. We report our long term outcomes of multidisciplinary care, comparing TMT to surgery using propensity-matched analyses. Methods: Patients seen in our MDBCC receiving TMT for MIBC from 2008 to 2012 were identified and matched, using propensity scores, to patients operated by RC. Matching occurred on age, ECOG status, Charlson comorbidity score, cT stage, cN stage and date of treatment. Overall survival (OS) and disease-specific survival (DSS) were assessed with Cox Proportional hazards modeling and competing risk analysis, respectively. Results: Between 2008 and 2012, 248 patients were assessed in the MDBCC. Of these, 162 (65%) had MIBC. Nearly half (80) opted for radiotherapy +/- concurrent cisplatin chemotherapy and 49 underwent full bladder preservation with TMT as their primary therapy. We matched 48 TMT patients with 48 RC patients with no imbalances. Median age of the cohort was 67.5 years with 29.2% cT3/cT4. With a median follow up time of 3.62 years, there were 19 (39.6%) deaths (7 from bladder cancer) in the RC group and 15 (31.3%) deaths (6 from bladder cancer) in the TMT group. 5 year DSS was 85.2% and 84.7% with TMT and surgery, respectively (p > 0.05). There was no statistically significant difference in DSS between the two groups (HR for TMT 1.31 (0.40-4.23), p = 0.66) or in OS (HR for TMT 0.77 (0.34-1.75), p = 0.53). Conclusions: Bladder cancer patients benefit from a multidisciplinary approach.. In selected patients with MIBC, chemo-radiation yields survival outcomes similar to matched RC patients. BC patients should be offered the possibility to discuss various treatment options.
The impact of histological variants on bladder cancer survival: A population-based analysis.
Authors: Gelpi-Hammerschmidt Francisco , Rodriguez Dayron , Tinay Ilker , Allard Christopher Brian , Blute Michael , Kibel Adam S. , Chang Steven Lee , Trinh Quoc-Dien , Preston Mark A
Published: February 2017

458

Background: We evaluated the clinical and prognostic impact of bladder cancer histologic variants (BCHV) using a large population-based cancer database. Methods: Using the Surveillance, Epidemiology, and End Results database (SEER), we identified bladder cancer patients from 2001-2012, and categorized them according to histological differentiation. 5 year disease-specific survival (DSS) was calculated using the Kaplan-Meier method. Cox proportional hazards regression model was used to predict association with disease-specific mortality (DSM). In addition, we fitted multivariate logistic regression models to predict the impact of histological variants on muscle-invasive status (MI), nodal involvement (NI), and metastatic disease (MD). Results: The cohort included 175,544 urothelial (96.3%) and 6,714 non-urothelial (3.7%) cancers. The latter were divided into: 2,382 squamous cell carcinoma, 1,648 adenocarcinoma, 888 small cell, 912 sarcomatoid, 292 signet-ring cell, 314 neuroendocrine and 278 micropapillary bladder tumors. Urothelial cancers overall had the best 5-year DSS. Of the non-urothelial variants, micropapillary and squamous had the best and worst DSS respectively (p < 0.001). On multivariable analysis predicting DSM, micropapillary and squamous variants had the best and worst prognosis respectively (HR 0.79, p = 0.102 and HR 2.63, p < 0.001), compared to urothelial tumors. On multivariable analysis predicting MI, NI, and MD: squamous (OR 22.76, p < 0.001), micropapillary (OR 3.17, p < 0.001) and adenocarcinoma (OR 4.14, p < 0.001), had higher likelihood respectively, compared to urothelial tumors. Conclusions: Despite accounting for a minority of bladder cancers, BCHV are associated with worst outcomes. It is essential to recognize the potential implications of these variants when deciding treatment. Additional studies are warranted to better characterize the clinical impact of these variants.
Afatinib activity in platinum-refractory metastatic urothelial carcinoma (UC) patients with ErbB alterations: Results of a phase II trial.
Authors: Choudhury Noura , Campanile Alexa , Antic Tatjana , Wade James Lloyd , Stadler Walter Michael , Nakamura Yusuke , O'Donnell Peter H.
Published: February 2017

459

Background: Metastatic UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ErbB3 are frequent in UC and may represent viable therapeutic targets. We studied whether afatinib, an oral, irreversible Erb family blocker, has activity in UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance.The primary endpoint was 3-mo progression-free survival (PFS3) using a Simon two-stage design, with the trial proceeding to stage II if ≥ 30% pts in stage I had PFS3. Pre-specified analysis for EGFR, HER2, ErbB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman) of available archival tumor tissue. Results: The initial enrollment goal of 23 ptswas met: 18 M/5 F, median age 67 (36-82), ECOG 0 in 26%/1 in 74%, Hb < 10 g/dl in 17%, liver metastases in 30%, median time from prior chemotherapy = 3.6 mo. No unexpected toxicities were observed; 2 pts required dose-reduction (grade 3 fatigue, grade 3 rash). 5/23 pts (21.7%) had PFS3 (1 partial response (PR), 4 stable disease). Notably, 5/7 pts (71.4%) with ErbB molecular alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 4.6 (ongoing) and 3.9 (ongoing) mo respectively) while 0/16 without alterations reached PFS3 (p < 0.001, Fisher’s exact). The 2 pts with alterations (both HER2 amplified) who did not reach PFS3 had liver metastases. All 3 pts with ErbB3 somatic mutations were responders. One pt with both HER2 amplification and R103G ErbB3 mutation never progressed on therapy, but discontinued after 10.3 mo due to depressed left ventricular ejection fraction. Average time to progression/discontinuation was 4.9 mo in pts with molecular alterations vs 1.7 mo for pts without alterations (p = 0.03). Conclusions: Afatinib demonstrates significant activity in platinum-refractory UC pts with HER2 and/or ErbB3 alterations. The potential contribution of ErbB3 to afatinib sensitivity is novel. A follow-on phase II study of afatinib in marker-selected refractory UC pts is underway. Clinical trial information: NCT02122172.
The effect of distance to a high-volume center on receipt of treatment for invasive bladder cancer.
Authors: Lomboy Jason , Macey Matthew , Sukhu Troy , Meyer Anne-Marie , Meng Ke , Nielsen Matthew Edward , Pruthi Raj , Wallen Eric , Woods Michael , Smith Angela
Published: February 2017

461

Background: Regionalization of major surgery such as cystectomy has spurred interest in the association of high-volume centers (HVC) & improved postoperative outcomes. However, concerns have been raised regarding access to care, with increasing travel distance playing a role in treatment selection. Our objective was to evaluate the effect of distance to closest HVC on treatment selection for muscle-invasive bladder cancer (MIBC). Methods: Using a linked data resource combining NC Cancer Registry with administrative claims data from Medicare, Medicaid, and private insurance plans, we included adult patients diagnosed with Stage 2 bladder cancer from 2003-2008. We created 2 mutually exclusive treatment groups (standard: cystectomy or chemo-radiation; non-standard: other or no treatment). HVCs were identified as those performing > 15 cystectomies during the study period. Nearest distance was calculated by using straight-line distance between zip code of the patient and closest HVC. Bivariable analyses and multivariable logistic regression were used to evaluate the effect of nearest distance to a HVC on receipt of non-standard treatment for MIBC. Results: 274 patients with confirmed MIBC were identified, with n = 123 undergoing standard and n = 151 non-standard treatment. Mean age of patients in the standard group was 73.1 vs. 77.7 in the non-standard group (p < 0.001). Groups also differed by race and insurance type (minority patients and those with Medicaid or Medicare were more likely to receive non-standard treatment). However, no significant difference was noted for comorbidity, gender, or education. Patients who underwent non-standard therapy had shorter distances to a HVC (73% have a distance of < 30 miles) vs. those who received standard therapy (56%, < 30 miles) (p < 0.004). On multivariable analysis, distance > 30 miles to a HVC was associated with lower likelihood to undergo non-standard therapy (p = 0.005), even when controlling for age, gender, race, comorbidity, insurance and other factors. Conclusions: Distance to HVC is not associated with increased likelihood of receipt of standard therapy for MIBC. Regionalization of care may not significantly impact access to care as previously hypothesized.
Small cell carcinoma of the bladder: Comparison of survival in various treatment modalities at Fox Chase Cancer Center (FCCC) from 1995 to 2015.
Authors: Ghatalia Pooja , Jung Kyungsuk , Litwin Samuel , Bilusic Marijo
Published: February 2017

465

Background: Small cell carcinoma of the bladder (SCBC) is a rare but aggressive neuroendocrine neoplasm. It accounts for only 0.35-0.70% of all bladder tumors. Because of its low incidence, there has been no consensus on the standard treatment of SCBC. We hypothesized that patients (pts) treated over the past 10 years would have better outcomes than those treated earlier, given recent treatment advances in oncology. Methods: We performed retrospective analysis of pts treated at FCCC with confirmed pathologic diagnosis of either SCBC or mixed urothelial and SCBC from 1995 to 2015. Kaplan-Meier estimates were made of the median times and log rank tests were used to compare OS and PFS. Results: We identified 38 pts, 10 women and 28 men who met inclusion criteria. The mean age at diagnosis was 68.2 years, all were Caucasians and 26 pts were smokers. Three pts (8%) had Stage I, 22 (58%) had Stage II, 6 (16%) had Stage III and 7 pts (18%) had Stage IV disease. Radical cystectomy was performed in 26 pts, 3 pts underwent surgery followed by radiation therapy, and 5 pts received primary radiation therapy alone. All but 1 pt received chemotherapy: 32 pts received neoadjuvant chemotherapy, 3 pts received adjuvant chemotherapy and 2 pts received both adjuvant and neoadjuvant chemotherapy. The number of prior lines of therapy, including perioperative chemotherapy as a line, was 1 in 25 pts, 2 in 7, 3 in 2 and 4 in 3 pts. Sixteen pts progressed after the primary treatment with the median time to progression of 7.7 months. The median OS was 397 days (95% CI: (309,633)), and median PFS was 332 days (95% CI: (427,608)). OS estimates are based on all 38 pts; PFS are based on 21 pts. There was no difference in OS (p = 0.752) in 19 pts who were treated before 12/31/2010 vs 19 pts treated after 12/31/2010. No difference was detected in PFS (p = 0.37) based on the earliest 10 (up to February 2010) vs final 11 pts (after February 2010) for whom data was available. Conclusions: No significant improvement in the treatment of SCBC or pt outcomes over the past 10 years was observed. Further data analysis will be aimed at comparing different treatment modalities and pt outcomes.
Evaluation of c-kit (CD 117) expression as a prognostic factor in testicular germ cell tumors: An Izmir Oncology Group (IZOG) study.
Authors: Salman Tarik , Yildiz Elif , Yildiz Ibrahim , Yavuzer Dilek , Unlu Mehtat , Varol Umut , Akyol Murat , Yildiz Yasar , Bayoglu Vedat , Kucukzeybek Yuksel , Alacacioglu Ahmet
Published: February 2017

476

Background: Little progress has been made in the management of testicular germ cell tumors (TGCTs). c-kit (CD 117) is a good target for cancer treatment and possesses an impressive role in the current oncological practice. We aimed to evaluate c-kit expression in early stage TGCTs as a prognostic factor. Methods: Patients with TGCTs who were referred to the Medical Oncology Clinic were included in our study before starting chemotherapy. Immunohistochemistry was performed on formalin-fixed and paraffinembedded three-micrometer thick sections with CD 117 Rabbit Anti c-kit in vitro gene kit. Biochemically, we utilized AFP and β-HCG Immunlite 2000 device with solid phase chemiluminescent immunometric method, and LDH Roche models with the DP-standardized UV method. AFP 0-15 ng/ml, β-HCG < 0.1 mlu/ml and LDH 240-480 mg/dl were considered as normal values. Results: Sixty-five patients were included in our study. Forty-one (63%) patients had nonseminoma tumors (NSGCTs) and 24 (37%) had seminoma. Statistically significant c-kit expression was found in patients with seminoma (p<0.0001). There was no difference between negative or positive c-kit expression in terms of clinicopathological characteristics, including preoperative serum levels of AFP, β-HCG, LDH, lymph node involvement, distant metastasis, and IGCCCG risk classification. No correlation was found between these parameters and 5-year progression free survival (PFS) rate except for tumor stage, presence of lymph node metastasis and IGCCCG score (p=0.001, p=0.04, and p=0.0001, respectively). Five-year PFS rate of patients with positive CD 117 was 72.2% (95% CI, 54.6-89.8), and6.6% (95% CI, 31.2-82.1) for those without CD 117 expression involvement (p=0.12). Conclusions: So far, there has been no significant breakthrough in the treatment of cisplatinrefractory TGCTs in the era of targeted therapies. No prognostic importance of c-kit expression has been found in our study. However, we believe that c-kit expression, in numerical terms, can be considered as a good prognostic factor for patients with TGCTs. The fact that all seminoma cases displayed positive c-kit expression is what we think has driven this result.
High incidence of early metabolic syndrome in germ cell tumor: Report from a tertiary cancer center in India.
Authors: Biswas Bivas , Dabkara Deepak , Ganguly Sandip , Dwary Amit Dutt , Ghosh Indranil , Sen Saugata , Mukhopadhyay Sumit , Mukherjee Satyadip , Gupta Sujoy , Mallick Indranil , Mondal Pradip , De Monish
Published: February 2017

488

Background: Late metabolic syndrome is well known in survivors of testicular germ cell tumor (GCT). Literature about early metabolic syndrome is scarce. Methods: Single institutional review of testicular GCT between June’2011 and December’2014. Patients with minimum post-treatment follow-up of 6 months were screened for signs of metabolic syndrome as per National Cholesterol Education Program (NCEP), if they had recorded blood pressure ≥130/85 mm of Hg and/or ≥10% weight gain from baseline. Partial metabolic syndrome was defined as - at least one abnormal criteria as per NCEP. Results: Sixty-three patients of testicular GCT completed treatment and were eligible for evaluation. Twenty-five patients fulfilled the screening criteria with median follow-up of 15 months (range: 6-40); median age of 35 years (range: 24-65). Treatment protocol was combined platinum based chemotherapy in 68% (n=17/25), single agent carboplatin in 20% (n=5/25), and surveillance only in 12% (n=3/25). Complete metabolic syndrome was found in 36% (n=9/25), partial metabolic syndrome in 44% (n=11/25). Blood pressure ≥130/85 mm of Hg was found in 64% (n=16/25), serum triglyceride ≥1.7 mmol/L in 61% (n=14/23), serum HDL cholesterol <1 mmol/L in 76% (n=16/21), and fasting plasma glucose ≥5.6 mmol/L in 30% (n=6/20). Median weight gain was 5 Kg (range: 2-14). Conclusions: Features of early metabolic syndrome (complete or partial) were detected in 80% of testicular GCT survivors in symptomatic and screened patients, and also in those who were in surveillance or who received single agent carboplatin only. So, all testicular GCT survivors should be screened for early metabolic syndrome and early intervention should be initiated as it may have significant long-term effects on mortality and morbidity.
Significance of serum N-glycan profiling as a diagnostic marker in testicular germ cell tumor.
Authors: Hatakeyama Shingo , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara
Published: February 2017

489

Background: Specific tumor marker for seminoma is still lacking. Moreover, 10% to 15% of the patients with non-seminomatous germ cell tumor (NSGCT) can be expected to have normal marker levels. Glycan-based biomarkers for testicular germ cell tumor (TGCT) have not yet been established. We examined whether the serum N-glycan profiling can be applied to detection in patient with TGCT. Methods: We performed a N-glycan structural analysis of sera from 14 patients with GCT and age-matched 28 healthy volunteers using the glycoblotting methods and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. The intensity of the N-glycans was compared between the TGCT patients and the volunteers to select TGCT associate N-glycans. Optimal cut-off values were determined by receiver operating characteristic (ROC) curves. Selected N-glycans were divided according to cut-off values, and positive numbers of TGCT associated N-glycan was added up to risk classification. Results: Six (43%) had seminoma, and eight (57%) patients had NSGCT in this study. The numbers of patients in stage I, II, III were 5, 2, and 4, respectively. Three patients had extragonadal tumor. The numbers of patients in IGCCC good, intermediate and poor risk were 10, 1, and 3, respectively. There were 3 patients (21%) with negative in any tumor markers. We identified 70 kinds of N-glycans in sera from healthy volunteers and GCT patients. A total 6 of N-glycans; m/z 2336.85, 2378.86, 2890.05, 3195.16, 3341.22, 3560.30 were selected as significantly high intensity in the patient with TGCT than in the healthy volunteers, with the area under the curve (AUC) of 0.81, 0.83, 0.86, 0.84, 0.81, and 0.78, respectively. Tumor associated N-glycans were classified as positive or negative, and scored from 0 to 6 points. Optimal cut-off score for detection was determined by ROC curve, and score > 3 were selected (AUC 0.90, P < 0.001). Based on this classification, 2 of 3 patients with negative tumor markers were categorized as a carrier for TCGT. Conclusions: Although the present study is small and preliminary, serum N-glycan analysis is a potential approaches to discover new biomarkers for TGCT. Further validation study is warranted.
Prognostic value of copy-number alterations of the Cohesin complex in intermediate-risk prostate cancer recurrence.
Authors: So Jonathan , Chua Melvin , Lalonde Emilie , Mahamud Osman , Berlin Alejandro , Dal Pra Alan , Orain Michèle , Hovington Helene , Bergeron Alain , Fradet Yves , Têtu Bernard , Meng Alice , Zhang Junyan , Zafarana Gaetano , Livingstone Julie , Pintilie Melania , van der Kwast Theodorus , Fraser Michael , Boutros Paul , Bristow Robert G.
Published: February 2017

49

Background: The Cohesin complex plays a critical role in mitotic progression and post-replicative DNA damage repair. It serves to bring together sister chromatids both in metaphase and in homologous recombination repair following ionizing radiation. The complex has also been shown to be phosphorylated in the ATM/BRCA1 pathway. The expression of various proteins in the complex are dysregulated in many cancers: breast, prostate, etc. Interestingly, in breast cancer cell lines, Cohesin is required for MYC activation in response to estrogen. Our study sought to correlate copy number alterations in this pivotal complex with biochemical relapse in prostate cancer patients. Methods: Our cohort consists of 284 patients with D’ Amico-classified intermediate-risk prostate cancer, treated with image-guided radiotherapy (IGRT, N = 143) or radical prostatectomy (RadP, N = 141). Pre-treatment biopsies and prostatectomy samples were analyzed using the Affymetrix Oncoscan array. The Phoenix and AUA criteria was used to define biochemical relapse for RadP and IGRT patients respectively. Results: Copy number alterations of RAD21, SMC1B, and STAG1 were observed in 18% (n = 52), 6.3% (n = 18), and 12% (n = 35) of the cohort respectively. They were predominantly losses in SMC1B, but gains in RAD21 and STAG1. All three genes in the Cohesin complex were associated with increased risk of biochemical relapse: RAD21 on chromosome 8 (HR = 1.93, 95% CI 1.23, 3.02, Wald’s p = 0.004), SMC1B on chromosome 22 (HR = 3.37, 95% CI 1.91, 5.94, Wald’s p < 10-4), and STAG1 on chromosome 3 (HR = 1.74, 95% CI 1.04, 2.89, Wald’s p < 0.05). However, when controlled for percent genome alteration and pre-treatment serum PSA levels, only copy number loss of SMC1B was a significant predictor of biochemical relapse (HR = 2.95, 95% CI 1.62, 5.38, Wald’s p < 10-3). Conclusions: We identified a novel association of copy-number alterations in members of the Cohesin complex with biochemical recurrence following radical prostatectomy or image-guided radiotherapy. This points to the central role of Cohesin in cell-cycle and DNA damage pathways promoting prostate cancer progression.
Survival outcomes of patients with metastatic germ cell tumor (mGCT) treated from 1998 to 2012: The Indiana University (IU) experience.
Authors: Adra Nabil , Ku Kimberly Peihsi , Kalra Maitri , Althouse Sandra , Hanna Nasser H. , Einhorn Lawrence H. , Albany Costantine
Published: February 2017

491

Background: Patients with mGCT’s treated between 1975-1990 were classified by the International Germ Cell Cancer Collaborative Group (IGCCCG) into good, intermediate, and poor risk. This study attempts to identify prognostic factors in a contemporary cohort of patients with mGCT treated at IU. Methods: Retrospective analysis of all patients with GCT seen at IU from 1998-2012. 1,341 consecutive patients with mGCT were identified of whom 615 patients received initial chemotherapy at IU and were eligible for analysis. All patients in this cohort were treated with cisplatin-based combination chemotherapy. Kaplan-Meier methods were used for analysis of 5 year progression free survival (PFS) and overall survival (OS). Results: Median age was 29. Median follow up time 5 years. Good, intermediate, and poor risk disease had median AFP of 8, 1822, 291 and median hCG of 8, 5000, 12837 respectively. 89 (14%) patients had seminoma and 526 (86%) had non-seminomatous GCT (NSGCT). Primary site was testis/retroperitoneal in 565 (92%) and mediastinum in 48 (8%). The 5 year PFS and OS for patients with poor risk excluding primary mediastinal NSGCT (PMNSGCT) was 52% and 78% respectively. In contrast, 5 year PFS and OS for patients with PMNSGCT was 49% and 58% respectively. The results comparing outcomes of patients in IGCCCG versus patients at IU are depicted in the table below. Conclusions: In this contemporary retrospective dataset from Indiana University there was improvement in OS for men with poor risk mGCT, possibly due to improved salvage chemotherapy. Only patients with PMNSGCT continue to have poor outcomes and pose a therapeutic challenge due to lack of effective salvage therapy. [Table: see text]
Gene-expression signatures as prognostic for relapse in stage I testicular germ cell tumors (TGCT).
Authors: Lewin Jeremy Howard , Bedard Philippe L. , Hamilton Robert James , Chung Peter W. M. , Moore Malcolm J. , Jewett Michael A.S. , Anson-Cartwright Lynn , Virtanen Carl , Winegarden Neil , Haibe-Kains Benjamin , Warde Padraig Richard , Sweet Joan , Hansen Aaron Richard
Published: February 2017

493

Background: Genomic signatures may compliment pathological features in identifying appropriate patients who may benefit from adjuvant therapy in Stage I (SI) TGCT. This study aimed to identify a gene expression pattern to differentiate between relapsed (R) and non-relapsed (NR) SI TGCT. Methods: Patients with SI non-seminoma (NS) and seminoma (S) were identified from an institutional database from 2000 to 2012. All patients were managed with active surveillance. NR-NS and NR-S patients were defined as having no evidence of relapse after 2 and 3 years of surveillance respectively. Following pathology review, RNA extraction and gene expression analysis was performed on archived paraffin embedded tumor and normal testicular tissue using Illumina Whole Genome DASL Human HT-12 V4 BeadChip. Hierarchical clustering analysis, ANOVA and t-tests were used to evaluate candidate genes and expression patterns that could differentiate NR and R samples. Results: 57 patients (12 R-NS, 15 R-S, 15 NR-NS, 15 NR-S) were identified with median relapse time of 5.6 (2.5-18.1) and 19.3 (4.7-65.3) months in NS and S cohorts respectively. 3 additional normal testis samples were included. Poor prognostic factors were more frequent in R versus NR cases (NS: vascular invasion [5/12 vs 0/15]; S: median size [4cm vs 2.8cm]). Unsupervised hierarchical clustering of 22822 probes randomly separated S from NS, indicating no batch effect. One-way ANOVA revealed 4525 significantly varying probes (p < 0.05) however, no statistically significant gene expression profile differentiated the 4 cohorts. A discriminative gene expression profile between R and NR cases was discovered when combining NS and S samples using 10 (p = 0.03) and 30 (p = 0.03) probe signatures with a 10 fold cross-validation. However, this profile was not observed in the S and NS cohorts individually. Conclusions: A discriminating signature for R and NR was identified for SI testis tumors, but not separately for NS and S. Biological relevance of these signatures is to be determined. Further studies are required to corroborate this profile in NS and S. If validated, these expression patterns could help identify patients beyond standard pathological risk algorithms for optimal management.
Re-irradiation of the pelvis for a genitourinary second malignant neoplasm or a local recurrence after full-dose pelvic radiotherapy for a pelvic cancer: Experience in a high-volume cancer center.
Authors: Kamran Sophia C. , Curreri Stephanie A. , Muralidhar Vinayak , Nguyen Paul L. , Martin Neil E. , Boyajian Richard , Harshman Lauren Christine , Efstathiou Jason A. , Beard Clair
Published: February 2017

494

Background: Re-irradiation (re-RT) with external beam RT following prior pelvic RT has not been reported, given both an absence of guidelines and concerns for toxicity. We sought to characterize bladder and bowel toxicities among patients treated with high-dose palliative re-RT for genitourinary secondary malignant neoplasms (SMN) or local recurrence (LR) following prior RT for pelvic cancer and to assess the response to re-RT with regard to palliation of symptoms. Methods: With IRB approval, the records of 28 consecutive patients with advanced pelvic malignancies given palliative re-RT between 2008-2014 were retrospectively analyzed. Descriptive analyses focused on toxicities and symptom control; responses were evaluated by two independent observers. Results: The cohort contained 27 males and 1 female. Initial cancers included 19 prostate, 4 ureteral, 2 bladder, 2 rectal and 1 penile carcinoma and 1 large cell lymphoma. Median initial RT dose was 63.5 Gy (range, 30-75.6 Gy; 8 unknown). The median time between initial RT and re-RT was 9.5 years (range, 0.2-32 years). At re-RT, there were 16 LRs and 12 SMNs including 14 bladder, 11 prostate, 3 ureteral and 1 penile cancers. Indications for re-RT were most commonly pain and bleeding. Given the severity of symptoms and bulk of disease at the time of re-RT, hypofractionated higher-dose RT was given. Median re-RT dose was 50 Gy (range, 27.5-66 Gy). For patients who received < 60 Gy, the median daily re-RT dose was 250 cGy. Re-RT was well-tolerated; there were no grade 2-4 toxicities. After treatment, 24 patients (92%) had complete resolution of their symptoms. Relief was durable in 67% of patients. Median overall survival was 5.8 months (range, 0.3-38.9 months) and 89% of patients were followed until death. Median follow-up was 5.2 months (range, 0.23-30.2 months). Conclusions: This institutional series suggests that moderate- to high-dose re-RT with median cumulative doses ≥ 100 Gy may achieve successful palliation of pelvic symptoms without undue toxicity in patients previously treated with high-dose RT. These results require validation in a larger prospective cohort.
Discontinuing VEGF-targeted therapy (VEGF-TT) for progression versus toxicity impacts outcomes of second-line therapies in metastatic renal cell carcinoma (mRCC).
Authors: de Velasco Guillermo , Xie Wanling , Donskov Frede , Albiges Laurence , Beuselinck Benoit , Srinivas Sandhya , Agarwal Neeraj , Lee Jae-Lyun , Brugarolas James , Wood Lori , Kollmannsberger Christian K. , Rha Sun Young , North Scott A. , Kanesvaran Ravindran , Rini Brian I. , Broom Reuben James , Yamamoto Haru , Kaymakcalan Marina Dusevic , Heng Daniel Yick Chin , Choueiri Toni K.
Published: February 2017

503

Background: A significant minority of mRCC patients prematurely discontinue first-line (1L) VEGF-TT due to toxicity. Whether clinical outcomes differ in patients receiving second line (2L) TT based on reason for discontinuation of 1L are unknown. Methods: Patients from 15 International mRCC Database Consortium (IMDC) centers who started 2L TT were included and the reason for discontinuation of 1L collected. Treatment outcomes of 2L, including response, time to treatment failure (TTF) and overall survival (OS) were assessed. Results: 1124 patients were identified: 866 patients (77%) discontinued 1L VEGF-TT due to progression, 208 patients (19%) due to toxicity. 50 patients (4%) who discontinue due to other reasons were excluded. The reason for discontinuation of 1L did not differ by IMDC risk group at start of 1L VEGF-TT (p=0.54) or 2L therapy (p=0.52). Median time from 1L VEGF-TT initiation to start of 2L in patients who progressed or stopped prematurely due to toxicity was 9.8 and 7.9 months, respectively. Compared to patients who stopped 1L VEGF-TT due to progression, patients who stopped due to toxicity had longer drug free interval between 1L and 2L (1.4 vs. 0.7 months; p<0.001), greater clinical benefit (CR/PR/SD) in second line (68% vs. 56%; adjusted OR: 1.58 (95%CI:1.07,2.35), p=0.023) and longer OS (17.4 vs. 11.2 months; adjusted HR: 0.69 (0.56,0.84), p=0.0002) adjusted for type of therapy, time to initiation of 2L, IMDC risk group and number of metastases at 2L (Table). Conclusions: mRCC patients with VEGF TT discontinuation 1L due to toxicity have better outcomes with 2L therapy than patients who stop therapy because of progression. These findings should be taken in consideration when designing clinical trials for second-line therapies in mRCC. [Table: see text]